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Abstract The objective of this study is to ascertain whether subvalvular papillary muscle repair in conjunction with restrictive mitral valve annuloplasty represents the most efficacious treatment for patients presenting with secondary ischemic mitral regurgitation, as compared to restrictive mitral valve annuloplasty alone and to mitral valve replacement. A network meta-analysis was conducted to investigate outcomes of randomized controlled trials, propensity-matched studies, and observational studies, comparing various treatments for secondary ischemic mitral regurgitation. The average follow-up duration for late mortality was 4.4 years. Coronary artery bypass grafting (CABG) without mitral valve surgery had a late mortality incidence of 3.7%. Restrictive mitral annuloplasty demonstrated a rate of 6.5%, while restrictive mitral annuloplasty + CABG resulted in a rate of 4.1%. Subvalvular papillary muscle repair plus restrictive mitral annuloplasty ± CABG and mitral valve replacement + CABG had rates of 4.4% and 5.1%. SUCRA analysis showed that CABG was the most effective treatment for reducing late mortality (70.0%). This was followed by subvalvular papillary muscle repair plus restrictive mitral annuloplasty with or without CABG (62.4%). The top strategy for decreasing early death, reoperation, and readmission to the hospital for heart failure is subvalvular papillary muscle repair plus restrictive mitral annuloplasty with or without CABG, based on SUCRA probabilities (84.6%, 85.54%, and 86.3%, respectively). Subvalvular papillary muscle repair plus restrictive mitral annuloplasty ± CABG has potential to reduce the risks associated with early mortality, reoperation, and re-hospitalization for heart failure. However, further research is required to substantiate these findings.

Abstract Objectives To validate the correlation between histopathological findings and quantitative magnetic resonance imaging (qMRI) fat fraction (FF) and water T2 mapping in patients with idiopathic inflammatory myopathy (IIM). Methods The study included 13 patients with histopathologically confirmed IIM who underwent dedicated thigh qMRI scanning within 1 month before open muscle biopsy. For the biopsied muscles, FF derived from the iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantitation (IDEAL-IQ) and T2 time from T2 mapping with chemical shift selective fat saturation were measured using a machine learning software. Individual histochemical and immunohistochemical slides were evaluated using a 5-point Likert score. Inter-reader agreement and the correlation between qMRI markers and histopathological scores were analyzed. Results Readers showed good to perfect agreement in qMRI measurements and most histopathological scores. FF of the biopsied muscles was positively correlated with the amount of fat in histopathological slides (p = 0.031). Prolonged T2 time was associated with the degree of variation in myofiber size, inflammatory cell infiltration, and amount of connective tissues (p ≤ 0.008 for all). Conclusions Using the machine learning-based muscle segmentation method, a positive correlation was confirmed between qMRI biomarkers and histopathological findings of patients with IIM. This finding provides a basis for using qMRI as a non-invasive tool in the diagnostic workflow of IIM. Relevance statement By using ML-based muscle segmentation, a correlation between qMRI biomarkers and histopathology was found in patients with IIM: qMRI is a potential non-invasive tool in this clinical setting. Key points • Quantitative magnetic resonance imaging measurements using machine learning-based muscle segmentation have good consistency and reproductivity. • Fat fraction of idiopathic inflammatory myopathy (IIM) correlated with the amount of fat at histopathology. • Prolonged T2 time was associated with muscle inflammation in IIM. Graphical Abstract

The high incidence of atrial fibrillation (AFib) following cardiac surgery (postoperative atrial fibrillation, POAF) relies on specific surgical features. However, in the setting of POAF, the role of the microbiome in the modulation of cardiac fibrosis is still not clear. This study aimed to analyze the effect of the microbiome and its main metabolic product (trimethylamine-N-oxide, TMAO) in the fibrosis of myocardial tissue, to investigate its role in POAF. Patients undergoing elective cardiac surgery with cardiopulmonary bypass, central atrio-caval cannulation and no history of AFib, were included. A fragment of the right atrium was analyzed for qualitative and mRNA-quantitative evaluation. A preoperative blood sample was analyzed with enzyme-linked immunosorbent assay (ELISA). A total of 100 patients have been included, with POAF occurring in 38%. Histologically, a higher degree of fibrosis, angiogenesis and inflammation has been observed in POAF. Quantitative evaluation showed increased mRNA expression of collagen-1, collagen-3, fibronectin, and transforming growth factor beta (TGFb) in the POAF group. ELISA analysis showed higher levels of TMAO, lipopolysaccharide and TGFb in POAF, with similar levels of sP-selectin and zonulin. TMAO ≥ 61.8 ng/mL (odds ratio, OR 2.88 [1.35–6.16], p = 0.006), preoperative hemoglobin < 13.1 g/dL (OR 2.37 [1.07–5.24], p = 0.033) and impaired right ventricular function (OR 2.38 [1.17–4.83], p = 0.017) were independent predictors of POAF. Also, TMAO was significantly associated with POAF by means of increased fibrosis. Gut microbiome product TMAO is crucial for myocardial fibrosis, which is a key factor for POAF. Patients in preoperative sinus rhythm who will develop POAF have increased genetic expression of pro-fibrotic genes and enhanced fibrosis in histological staining. Elevated TMAO level (≥61.8 ng/mL) is an independent risk factor for POAF.

Abstract Acute caffeine intake has been found to increase working memory (WM)-related brain activity in healthy adults without improving behavioral performances. The impact of daily caffeine intake—a ritual shared by 80% of the population worldwide—and of its discontinuation on working memory and its neural correlates remained unknown. In this double-blind, randomized, crossover study, we examined working memory functions in 20 young healthy non-smokers (age: 26.4 ± 4.0 years; body mass index: 22.7 ± 1.4 kg/m2; and habitual caffeine intake: 474.1 ± 107.5 mg/day) in a 10-day caffeine (150 mg × 3 times/day), a 10-day placebo (3 times/day), and a withdrawal condition (9-day caffeine followed by 1-day placebo). Throughout the 10th day of each condition, participants performed four times a working memory task (N-Back, comprising 3- and 0-back), and task-related blood-oxygen-level-dependent (BOLD) activity was measured in the last session with functional magnetic resonance imaging. Compared to placebo, participants showed a higher error rate and a longer reaction time in 3- against 0-back trials in the caffeine condition; also, in the withdrawal condition we observed a higher error rate compared to placebo. However, task-related BOLD activity, i.e., an increased attention network and decreased default mode network activity in 3- versus 0-back, did not show significant differences among three conditions. Interestingly, irrespective of 3- or 0-back, BOLD activity was reduced in the right hippocampus in the caffeine condition compared to placebo. Adding to the earlier evidence showing increasing cerebral metabolic demands for WM function after acute caffeine intake, our data suggest that such demands might be impeded over daily intake and therefore result in a worse performance. Finally, the reduced hippocampal activity may reflect caffeine-associated hippocampal grey matter plasticity reported in the previous analysis. The findings of this study reveal an adapted neurocognitive response to daily caffeine exposure and highlight the importance of classifying impacts of caffeine on clinical and healthy populations.

Abstract Quantitative muscle MRI (water-T2 and fat mapping) is being increasingly used to assess disease involvement in muscle disorders, while imaging techniques for assessment of the dynamic and elastic muscle properties have not yet been translated into clinics. In this exploratory study, we quantitatively characterized muscle deformation (strain) in patients affected by facioscapulohumeral muscular dystrophy (FSHD), a prevalent muscular dystrophy, by applying dynamic MRI synchronized with neuromuscular electrical stimulation (NMES). We evaluated the quadriceps muscles in 34 ambulatory patients and 13 healthy controls, at 6-to 12-month time intervals. While a subgroup of patients behaved similarly to controls, for another subgroup the median strain decreased over time (approximately 57% over 1.5 years). Dynamic MRI parameters did not correlate with quantitative MRI. Our results suggest that the evaluation of muscle contraction by NMES-MRI is feasible and could potentially be used to explore the elastic properties and monitor muscle involvement in FSHD and other neuromuscular disorders.

Infection of surgical wounds with acid-fast bacilli, including tubercle bacilli, is rare, and is poorly described in the literature. We present the case of a 74-year-old male who developed a sternal wound infection after cardiac surgery due to Mycobacterium tuberculosis complex, diagnosed post-mortem. SARS-CoV-2 infection contributed to worsened clinical conditions and surgical site infection. A high degree of suspicion to avoid unnecessary treatments and progression to severe disease with dismal prognosis is necessary in these types of infections.

Abstract Introduction Transplantation among HIV positive patients may be a valuable therapeutic intervention. This study involves an HIV D+/R+ kidney–liver transplantation, where PBMC-associated HIV quasispecies were analyzed in donor and transplant recipients (TR) prior to transplantation and thereafter, together with standard viral monitoring. Methods The donor was a 54 year of age HIV infected woman: kidney and liver recipients were two HIV infected men, aged 49 and 61. HIV quasispecies in PBMC was analyzed by ultra-deep sequencing of V3 env region. During TR follow-up, plasma HIV-1 RNA, HIV-1 DNA in PBMC, analysis of proviral integration sites and drug-resistance genotyping were performed. Other virological and immunological monitoring included CMV and EBV DNA quantification in blood and CD4 T cell counts. Results Donor and TR were all ART-HIV suppressed at transplantation. Thereafter, TR maintained a nearly suppressed HIV-1 viremia, but HIV-1 RNA blips and the increase of proviral integration sites in PBMC attested some residual HIV replication. A transient peak in HIV-1 DNA occurred in the liver recipient. No major changes of drug-resistance genotype were detected after transplantation. CMV and EBV transient reactivations were observed only in the kidney recipient, but did not require specific treatment. CD4 counts remained stable. No intermixed quasispecies between donor and TR was observed at transplantation or thereafter. Despite signs of viral evolution in TR, HIV genetic heterogeneity did not increase over the course of the months of follow up. Conclusions No evidence of HIV superinfection was observed in the donor nor in the recipients. The immunosuppressive treatment administrated to TR did not result in clinical relevant viral reactivations.

PurposeQuantitative Muscle MRI (qMRI) is a valuable and non-invasive tool to assess disease involvement and progression in neuromuscular disorders being able to detect even subtle changes in muscle pathology. The aim of this study is to evaluate the feasibility of using a conventional short-tau inversion recovery (STIR) sequence to predict fat fraction (FF) and water T2 (wT2) in skeletal muscle introducing a radiomic workflow with standardized feature extraction combined with machine learning algorithms.MethodsTwenty-five patients with facioscapulohumeral muscular dystrophy (FSHD) were scanned at calf level using conventional STIR sequence and qMRI techniques. We applied and compared three different radiomics workflows (WF1, WF2, WF3), combined with seven Machine Learning regression algorithms (linear, ridge and lasso regression, tree, random forest, k-nearest neighbor and support vector machine), on conventional STIR images to predict FF and wT2 for six calf muscles.ResultsThe combination of WF3 and K-nearest neighbor resulted to be the best predictor model of qMRI parameters with a mean absolute error about ± 5 pp for FF and ± 1.8 ms for wT2.ConclusionThis pilot study demonstrated the possibility to predict qMRI parameters in a cohort of FSHD subjects starting from conventional STIR sequence.

ObjectiveTo describe a study protocol for investigating the functional association between posture, spinal balance, ambulatory biomechanics, paraspinal muscle fatigue, paraspinal muscle quality and symptoms in patients with symptomatic lumbar spinal stenosis (sLSS) before and 1-year after elective surgical intervention.DesignSingle-centre prospective, experimental, multimodal (clinical, biomechanical, radiological) study with three instances of data collection: baseline (study visit 1), 6-month follow-up (remote) and 1-year follow-up (study visit 2). Both study visits include an in vivo experiment aiming to elicit paraspinal muscle fatigue for postural assessment in a non-fatigued and fatigued state.Experimental protocolAt baseline and 1-year follow-up, 122 patients with sLSS will be assessed clinically, perform the back-performance scale assessment and complete several patient-reported outcome measure (PROMs) questionnaires regarding overall health, disease-related symptoms and kinesiophobia. Posture and biomechanical parameters (joint kinematics, kinetics, surface electromyography, back curvature) will be recorded using an optoelectronic system and retroreflective markers during different tasks including overground walking and movement assessments before and after a modified Biering-Sørensen test, used to elicit paraspinal muscle fatigue. Measurements of muscle size and quality and the severity of spinal stenosis will be obtained using magnetic resonance imaging (MRI) and sagittal postural alignment data from EOS radiographies. After each study visit, physical activity level will be assessed during 9 days using a wrist-worn activity monitor. In addition, physical activity level and PROMs will be assessed remotely at 6-month follow-up.ConclusionThe multimodal set of data obtained using the study protocol described in this paper will help to expand our current knowledge on the pathophysiology, biomechanics, and treatment outcome of degenerative sLSS. The results of this study may contribute to defining and/or altering patient treatment norms, surgery indication criteria and post-surgery rehabilitation schedules.Trial registrationThe protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT05523388).

Sonosensitive perfluorocarbon F8TAC18-PFOB emulsion is under development to enhance heating, increase thermal contrast, and reduce treatment times during focused ultrasound tumor ablation of highly perfused tissue. The emulsion previously showed enhanced heating during ex vivo and in vitro studies. Experiments were designed to observe the response in additional scenarios by varying focused ultrasound conditions, emulsion concentrations, and surfactants. Most notably, changes in acoustic absorption were assessed with MR-ARFI. Phantoms were developed to have thermal, elastic, and relaxometry properties similar to those of ex vivo pig tissue. The phantoms were embedded with varying amounts of F8TAC18-PFOB emulsion or lecithin-PFOB emulsion, between about 0.0-0.3% v:w, in 0.05% v:w increments. MR-ARFI measurements were performed using a FLASH-ARFI-MRT sequence to obtain simultaneous displacement and temperature measurements. A Fabry-Perot hydrophone was utilized to observe the acoustic emissions. Susceptibility-weighted imaging and relaxometry mapping were performed to observe concentration-dependent effects. 19F diffusion-ordered spectroscopy NMR was used to measure the diffusion coefficient of perfluorocarbon droplets in a water emulsion. Increased displacement and temperature were observed with higher emulsion concentration. In semi-rigid MR-ARFI phantoms, a linear response was observed with low-duty cycle MR-ARFI sonications and a mono-exponential saturating response was observed with sustained sonications. The emulsifiers did not have a significant effect on acoustic absorption in semi-rigid gels. Stable cavitation might also contribute to enhanced heating.

Type A acute aortic dissection is associated with significant morbidity and mortality, with prompt referral imaging and management to tertiary referral centers needed urgently. Surgery is usually needed emergently, but the choice of surgery often varies depending on the patient and the presentation. Staff and center expertise also play a major role in determining the surgical strategy employed. The aim of this study was to compare the early- and medium-term outcomes of patients undergoing a conservative approach extended only to the ascending aorta and the hemiarch to those of patients subjected to extensive surgery (total arch reconstruction and root replacement) across three European referral centers. A retrospective study was conducted across three sites between January 2008 and December 2021. In total, 601 patients were included within the study, of which 30% were female, and the median age was 64.4 years. The most common operation was ascending aorta replacement (n = 246, 40.9%). The aortic repair was extended proximally (i.e., root n = 105; 17.5%) and distally (i.e., arch n = 250; 41.6%). A more extensive approach, extending from the root to the arch, was employed in 24 patients (4.0%). Operative mortality occurred in 146 patients (24.3%), and the most common morbidity was stroke (75, 12.6%). An increased length of ICU admission was noted in the extensive surgery group, which comprised younger and more frequently male patients. No significant differences were noted in surgical mortality between patients managed with extensive surgery and those managed conservatively. However, age, arterial lactate levels, “intubated/sedated” status on arrival, and “emergency or salvage” status at presentation were independent predictors of mortality both within the index hospitalization and during the follow-up. The overall survival was similar between the groups.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.)

Abstract Background Phase contrast magnetic resonance imaging, PC MRI, is a valuable tool allowing for non-invasive quantification of CSF dynamics, but has lacked adoption in clinical practice for Chiari malformation diagnostics. To improve these diagnostic practices, a better understanding of PC MRI based measurement agreement, repeatability, and reproducibility of CSF dynamics is needed. Methods An anatomically realistic in vitro subject specific model of a Chiari malformation patient was scanned three times at five different scanning centers using 2D PC MRI and 4D Flow techniques to quantify intra-scanner repeatability, inter-scanner reproducibility, and agreement between imaging modalities. Peak systolic CSF velocities were measured at nine axial planes using 2D PC MRI, which were then compared to 4D Flow peak systolic velocity measurements extracted at those exact axial positions along the model. Results Comparison of measurement results showed good overall agreement of CSF velocity detection between 2D PC MRI and 4D Flow (p = 0.86), fair intra-scanner repeatability (confidence intervals ± 1.5 cm/s), and poor inter-scanner reproducibility. On average, 4D Flow measurements had a larger variability than 2D PC MRI measurements (standard deviations 1.83 and 1.04 cm/s, respectively). Conclusion Agreement, repeatability, and reproducibility of 2D PC MRI and 4D Flow detection of peak CSF velocities was quantified using a patient-specific in vitro model of Chiari malformation. In combination, the greatest factor leading to measurement inconsistency was determined to be a lack of reproducibility between different MRI centers. Overall, these findings may help lead to better understanding for application of 2D PC MRI and 4D Flow techniques as diagnostic tools for CSF dynamics quantification in Chiari malformation and related diseases.

Background: Type A Acute Aortic Dissection (TAAAD) repair is a surgical emergency associated with high morbidity and mortality. Registry data have noted several sex-specific differences in presentation with TAAAD which may account for the differences in men and women undergoing surgery for this condition. Methods: A retrospective review of data from three departments of cardiac surgery (Centre Cardiologique du Nord, Henri-Mondor University Hospital, San Martino University Hospital, Genoa) between January 2005 and 31 December 2021 was conducted. Confounders were adjusted using doubly robust regression models, a combination of regression models with inverse probability treatment weighting by propensity score. Results: 633 patients were included in the study, of which 192 (30.3%) were women. Women were significantly older with reduced haemoglobin levels and pre-operative estimated glomerular filtration rate compared to men. Male patients were more likely to undergo aortic root replacement and partial or total arch repair. Operative mortality (OR 0.745, 95% CI: 0.491–1.130) and early postoperative neurological complication results were comparable between the groups. The adjusted survival curves using IPTW by propensity score confirmed the absence of a significant impact of gender on long-term survival (HR 0.883, 95% CI 0.561–1.198). In a subgroup analysis of women, preoperative levels of arterial lactate (OR 1.468, 95% CI: 1.133–1.901) and mesenteric ischemia after surgery (OR 32.742, 95% CI: 3.361–319.017) were significantly associated with increased operative mortality. Conclusions: The advancing age of female patients alongside raised preoperative level of arterial lactate may account for the increasing preponderance among surgeons to perform more conservative surgery compared to their younger male counterparts although postoperative survival was similar between the groups.

Objectives. The current guidelines still do not include specific recommendations on the use of subvalvular repair (SV-r) for treatment of ischemic mitral regurgitation (IMR). Therefore, the objective of our study was to evaluate the clinical impact of mitral regurgitation (MR) recurrence and ventricular remodeling on long-term outcomes after SV-r combined with restrictive annuloplasty (RA-r). Methods. We performed a subanalysis of the papillary muscle approximation trial, studying 96 patients with severe IMR and coronary artery disease undergoing restrictive annuloplasty alongside subvalvular repair (SV-r + RA-r group) or restrictive annuloplasty alone (RA-r group). We analyzed treatment failure differences, the influence of residual MR, left ventricular remodeling, and clinical outcomes. The primary endpoint was treatment failure (composite of death; reoperation; or recurrence of moderate, moderate-to-severe, or severe MR) within 5 years of follow-up after the procedure. Results. A total of 45 patients showed failure of the treatment within 5 years, of which 16 patients underwent SV-r + RA-r (35.6%) and 29 underwent RA-r (64.4%, p = 0.006). Patients with significant residual MR presented with a higher rate of all-cause mortality at 5 years compared with trivial MR (HR 9.09, 95% CI 2.08–33.33, p = 0.003). MR progression occurred earlier in the RA-r group, as 20 patients in the RA-r group vs. 6 in SV-r + RA-r group had a significant MR 2 years after surgery (p = 0.002). Conclusions. RA-r remains a surgical mitral repair technique with an increased risk of failure and mortality at 5 years compared with SV-r. The rates of recurrent MR are higher, and recurrence occurs earlier, with RA-r alone compared to SV-r. The addition of the subvalvular repair increases the durability of the repair, thus extending all of the benefits of preventing MR recurrence.

Abstract Background The aim of this study is to quantify the frequency content of the blood velocity waveform in different body regions by means of phase contrast (PC) cardiovascular magnetic resonance (CMR) and Doppler ultrasound. The highest frequency component of the spectrum is inversely proportional to the ideal temporal resolution to be used for the acquisition of flow-sensitive imaging (Shannon-Nyquist theorem). Methods Ten healthy subjects (median age 33y, range 24–40) were scanned with a high-temporal-resolution PC-CMR and with Doppler ultrasound on three body regions (carotid arteries, aorta and femoral arteries). Furthermore, 111 patients (median age 61y) with mild to moderate arterial hypertension and 58 patients with aortic aregurgitation, atrial septal defect, or repaired tetralogy of Fallot underwent aortic CMR scanning. The frequency power distribution was calculated for each location and the maximum frequency component, fmax, was extracted and expected limits for the general population were inferred. Results In the healthy subject cohort, significantly different fmax values were found across the different body locations, but they were nonsignificant across modalities. No significant correlation was found with heart rate. The measured fmax ranged from 7.7 ± 1.1 Hz in the ascending aorta, up to 12.3 ± 5.1 Hz in the femoral artery (considering PC-CMR data). The calculated upper boundary for the general population ranged from 11.0 Hz to 27.5 Hz, corresponding to optimal temporal resolutions of 45 ms and 18 ms, respectively. The patient cohort exhibited similar values for the frequencies in the aorta, with no correlation between blood pressure and frequency content. Conclusions The temporal resolution of PC-CMR acquisitions can be adapted based on the scanned body region and in the adult population, should approach approximately 20 ms in the peripheral arteries and 40 ms in the aorta. Trial registration This study presents results from a restrospective analysis of the clinical study NCT01870739 (ClinicalTrials.gov).

In his pioneering work on Abstract Argumentation, P.M. Dung set a wide scenario by connecting stable models in Logic and Game Theory to simple Abstract Argumentation Frameworks (AAF), which are essentially directed graphs in which arguments are represented as nodes, and the attack relation is represented by arrows. From such abstraction and simplicity, it is possible to capture important properties in many different fields. The Stable Marriage (SM) problem is exactly one of such representable problems. Given two sets of individuals partitioned into men and women, a matching is stable when there does not exist any man-woman match by which both man and woman would be individually better off than they are with the person to which they are currently matched. Stable matchings correspond to stable extensions if an AAF is correctly generated from the given SM problem. In this paper we elaborate on the original formulation by Dung, by also encoding SM problems with ties and incomplete preference lists into AAFs. Moreover, we use Weighted Abstract Argumentation to represent optimality criteria in the optimal extension of SM problems, where some matchings are better than others: criteria may consider only the preference of either men, or women, or a more global view obtained by combining the preferences of both.

Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.

Background: Biomarkers of disease progression and outcome measures are still lacking for patients with amyotrophic lateral sclerosis (ALS). Muscle MRI can be a promising candidate to track longitudinal changes and to predict response to the therapy in clinical trials.Objective: Our aim is to apply quantitative muscle MRI in the evaluation of disease progression, focusing on thigh and leg muscles of patients with ALS, and to explore the correlation between radiological and clinical scores.Methods: We enrolled newly diagnosed patients with ALS, longitudinally scored using the ALS Functional Rating Scale-Revised (ALSFRS-R), who underwent a 3T muscle MRI protocol including a 6-point Dixon gradient-echo sequence and multi-echo turbo spin echo (TSE) T2-weighted sequence for quantification of fat fraction (FF), cross-sectional area (CSA), and water T2 (wT2). A total of 12 muscles of the thigh and six muscles of the leg were assessed by the manual drawing of 18 regions of interest (ROIs), for each side. A group of 11 age-matched healthy controls (HCs) was enrolled for comparison.Results: 15 patients (M/F 8/7; mean age 62.2 years old, range 29–79) diagnosed with possible (n = 2), probable (n = 12), or definite (n = 1) ALS were enrolled. Eleven patients presented spinal onset, whereas four of them had initial bulbar involvement. All patients performed MRI at T0, nine of them at T1, and seven of them at T2. At baseline, wT2 was significantly elevated in ALS subjects compared to HCs for several muscles of the thigh and mainly for leg muscles. By contrast, FF was elevated in few muscles, and mainly at the level of the thigh. The applied mixed effects model showed that FF increased significantly in the leg muscles over time (mainly in the triceps surae) and that wT2 decreased significantly in line with worsening in the leg subscore of ALSFRS-R, mainly at the leg level and in the anterior and medial compartment of the thigh.Conclusions: Quantitative MRI represents a non-invasive tool that is able to outline the trajectory of pathogenic modifications at the muscle level in ALS. In particular, wT2 was found to be increased early in the clinical history of ALS and also tended to decrease over time, also showing a positive correlation with leg subscore of ALSFRS-R.

Abstract Background Sortilin is a 95-kDa protein which has recently been linked to circulating cholesterol concentration and lifetime risk of developing significant atherosclerotic disease. Sortilin is found inside different cell types and circulating in blood. Higher circulating sortilin concentration has been found in patients with coronary atherosclerosis compared to control subjects. Sortilin concentration is influenced by statin therapy. Methods We enrolled statin-naïve subjects with type 2 diabetes mellitus and we performed a cross-sectional study to evaluate the association between sortilin levels and the presence of clinically significant lower limb peripheral artery disease (PAD) in a population of statin-free diabetic subjects. Results Out of the 154 patients enrolled in our study, 80 patients were free from PAD, while 74 had clinically significant PAD. Sortilin concentration was significantly higher in the latter group compared to the former (1.61 ± 0.54 ng/mL versus 0.67 ± 0.30 ng/mL, P

Background: Muscles from patients with cerebral palsy (CP) are often spastic and form contractures that limit the range of motion. Injections of botulinum toxin A (BTX) into the calf muscles are an important treatment for functional equinus; however, improvement in gait function is not always achieved. BTX is also used to test muscle weakening for risk evaluation of muscle lengthening surgery. Our aim was to assess the effect of BTX over time on calf muscle properties in pediatric CP patients with MRI.Material and Methods: Six toe-walking CP patients (mean age 11.6 years) with indication for lengthening surgery were prospectively enrolled and received BTX injections into the gastrocnemius and soleus muscles. MRI scans at 3T of the lower legs and clinical examinations were performed pre-BTX, 6 weeks (6w), and 12 weeks (12w) post-BTX. A fat-suppressed 2D multi-spin-echo sequence was used to acquire T2 maps and for segmentation. Fat fraction maps were calculated from 3D multi-echo Dixon images. Diffusion tensor imaging (DTI) with a 2D echo-planar imaging (EPI) sequence yielded maps of the mean apparent diffusion coefficient (ADC) and of the fractional anisotropy (FA). Hyperintense regions of interest (ROIs) on the T2-weighted (T2w) images at 6w were segmented in treated muscles. Mean values of T2, fat fraction, ADC, and FA were calculated in hyperintense ROIs and in reference ROIs in non-treated muscles.Results: Hyperintensity on T2w scans and increased T2 (group mean ± standard deviation: 35 ± 1 ms pre-BTX, 45 ± 2 ms at 6w, and 44 ± 2 ms at 12w) were observed in all patients at the injection sites. The T2 increase was spatially limited to parts of the injected muscles. FA increased (0.30 ± 0.03 pre-BTX, 0.34 ± 0.02 at 6w, and 0.36 ± 0.03 at 12w) while ADC did not change in hyperintense ROIs, indicating a BTX-induced increase in extracellular space and a simultaneous decrease of muscle fiber diameter. Fat fraction showed a trend for increase at 12w. Mean values in reference ROIs remained unchanged.Conclusion: MRI showed limited spatial distribution of the BTX-induced effects in pediatric CP patients. It could be a promising non-invasive tool for future studies to test BTX treatment protocols.

Background: Cerebral palsy (CP) is the most common cause of physical disability in childhood. Muscle pathologies occur due to spasticity and contractures; therefore, diagnostic imaging to detect pathologies is often required. Imaging has been used to assess torsion or estimate muscle volume, but additional methods for characterizing muscle composition have not thoroughly been investigated. MRI fat fraction (FF) measurement can quantify muscle fat and is often a part of standard imaging in neuromuscular dystrophies. To date, FF has been used to quantify muscle fat and assess function in CP. In this study, we aimed to utilize a radiomics and FF analysis along with the combination of both methods to differentiate affected muscles from healthy ones.Materials and Methods: A total of 9 patients (age range 8–15 years) with CP and 12 healthy controls (age range 9–16 years) were prospectively enrolled (2018–2020) after ethics committee approval. Multi-echo Dixon acquisition of the calf muscles was used for FF calculation. The images of the second echo (TE = 2.87 ms) were used for feature extraction from the soleus, gastrocnemius medialis, and gastrocnemius lateralis muscles. The least absolute shrinkage and selection operator (LASSO) regression was employed for feature selection. RM, FF model (FFM), and combined model (CM) were built for each calf muscle. The receiver operating characteristic (ROC) curve and their respective area under the curve (AUC) values were used to evaluate model performance.Results: In total, the affected legs of 9 CP patients and the dominant legs of 12 healthy controls were analyzed. The performance of RM for soleus, gastrocnemius medialis, and gastrocnemius lateralis (AUC 0.92, 0.92, 0.82, respectively) was better than the FFM (AUC 0.88, 0.85, 0.69, respectively). The combination of both models always had a better performance than RM or FFM (AUC 0.95, 0.93, 0.83). FF was higher in the patient group (FFS 9.1%, FFGM 8.5%, and FFGL 10.2%) than control group (FFS 3.3%, FFGM 4.1%, FFGL 6.6%).Conclusion: The combination of MRI quantitative fat fraction analysis and texture analysis of muscles is a promising tool to evaluate muscle pathologies due to CP in a non-invasive manner.

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA.Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally.Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content.Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

Imaging has become a valuable tool in the assessment of neuromuscular diseases, and, specifically, quantitative MR imaging provides robust biomarkers for the monitoring of disease progression. Quantitative evaluation of fat infiltration and quantification of the T2 values of the muscular tissue's water component (wT2) are two of the most essential indicators currently used. As each voxel of the image can contain both water and fat, a two-component model for the estimation of wT2 must be used. In this work, we present a fast method for reconstructing wT2 maps obtained from conventional multi-echo spin-echo (MESE) acquisitions and released as Free Open Source Software. The proposed software is capable of fast reconstruction thanks to extended phase graphs (EPG) simulations and dictionary matching implemented on a general-purpose graphic processing unit. The program can also perform more conventional biexponential least-squares fitting of the data and incorporate information from an external water-fat acquisition to increase the accuracy of the results. The method was applied to the scans of four healthy volunteers and five subjects suffering from facioscapulohumeral muscular dystrophy (FSHD). Conventional multi-slice MESE acquisitions were performed with 17 echoes, and additionally, a 6-echo multi-echo gradient-echo (MEGE) sequence was used for an independent fat fraction calculation. The proposed reconstruction software was applied on the full datasets, and additionally to reduced number of echoes, respectively, to 8, 5, and 3, using EPG and biexponential least-squares fitting, with and without incorporating information from the MEGE acquisition. The incorporation of external fat fraction maps increased the robustness of the fitting with a reduced number of echoes per datasets, whereas with unconstrained fitting, the total of 17 echoes was necessary to retain an independence of wT2 from the level of fat infiltration. In conclusion, the proposed software can successfully be used to calculate wT2 maps from conventional MESE acquisition, allowing the usage of an optimized protocol with similar precision and accuracy as a 17-echo acquisition. As it is freely released to the community, it can be used as a reference for more extensive cohort studies.

Quantification of skeletal muscle contraction in Magnetic Resonance Imaging (MRI) is a non-invasive method for studying muscle motion and deformation. The aim of this study was to evaluate the repeatability of quantitative measures such as strain, based on single slice dynamic MRI synchronized with neuromuscular electrical stimulation (NMES) and standardized to a similar relative force level across various individuals. Unilateral electrical stimulation of the triceps surae muscles was applied in eight volunteers during single-slice, three-directional phase contrast MRI acquisition at a 3T MRI scanner. To assess repeatability, the same process was executed on two different days by standardizing the stimulation aiming at evoking a fixed percentage of their maximal voluntary force in the same position. Except from the force, the effect of using the current as reference was evaluated on day two as a secondary acquisition. Finally, the presence of fatigue induced by NMES was assessed (on day one) by examining the difference between consecutive measurements. Strain maps were derived from the acquired slice at every time point; distribution of strain in the muscle and peak strain over the muscle of interest were evaluated for repeatability. It was found that fatigue did not have an appreciable effect on the results. The stimulation settings based on evoked force produced more repeatable results with respect to using the current as the only reference, with an intraclass correlation coefficient between different days of 0.95 for the former versus 0.88 for the latter. In conclusion, for repeatable strain imaging it is advisable to record the force output of the evoked contraction and use that for the standardization of the NMES setup rather than the current.

The data presented here are related to the research paper entitled “Thrombin induces protease-activated receptor 1 signaling and activation of human atrial fibroblasts and dabigatran prevents these effects” (Altieri et al., 2018) [1]. Data show that silencing of protease-activated receptor 1 (PAR1) prevents the activation of Fib isolated from atrial appendages of patients without atrial fibrillation (AF), as assessed by immunofluorescence for α-smooth muscle actin (αSMA) and Picro-Sirius red staining. Moreover, it is reported that primary atrial Fib obtained from two subjects with permanent AF express PAR1 and PAR2 and display enhanced αSMA immunoreactivity and collagen synthesis in response to thrombin, but not to dabigatran-bound thrombin, alike Fib from non-fibrillating atria.

One of the mechanisms that characterizes the aging process of different organs is the accumulation of fat. Different authors have demonstrated that adipose tissue replaces the loss of other cell types, deriving from mesenchymal cells. During aging, there is substitution or trans-differentiation of mesenchymal cells with other cells having the same embryological origin. Newly formed adipocytes were also observed in the trabecular matrix of elderly people’s bones, associated with myeloid cells. In this study, we have investigated the relationship between immature myeloid-derived suppressor cells (I-MDSCs) and mesenchymal stem cells (MSCs) in bone marrow (BM) samples harvested from 57 patients subjected to different orthopedic surgeries. Patients aged from 18 to 92 years were considered in order to compare the cellular composition of bone marrow of young and elderly people, considered a biomarker of immunity, inflammation, and bone preservation. The I-MDSC percentage was stable during aging, but in elderly people, it was possible to observe a strong basal immunosuppression of autologous and heterologous T cells’ proliferation. We hypothesized that this pattern observed in elders depends on the progressive accumulation in the BM of activating stimuli, including cell–cell contact, or the production of different cytokines and proteins that induce the differentiation of bone marrow mesenchymal stem cells in adipocytes. The collected data provided underline the importance of specific biomarkers of aging that promote a reduction in immune response and incremented inflammatory pathways, leading to bone reabsorption in elderly people.

The data and information presented here refer to the research article entitled: “Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting with the human amniotic fluid stem cell secretome” (Balbi et al., 2019, Apr 04). This dataset illustrates the in vitro paracrine effect exerted by the human amniotic fluid stem cell secretome on rodent neonatal cardiomyocytes, human endothelial progenitors and different subsets of cardiac progenitor cells. Cytokine/chemokine profiling of the human amniotic fluid stem cell secretome is provided as well. This data can provide useful insights in regenerative medicine as demonstrating the in vitro cardioprotective and proliferative secretory paracrine potential of human fetal stem cells. Keywords: Paracrine effect, Human amniotic fluid stem cells, Cardiac progenitor cells, Neonatal cardiomyocytes, Endothelial progenitors, Proliferation, Cardioprotection, Angiogenesis

Our goal is to provide different semiring-based formal tools for the specification of security requirements: we quantitatively enhance the open-system approach, according to which a system is partially specified. Therefore, we suppose the existence of an unknown and possibly malicious agent that interacts in parallel with the system. Two specification frameworks are designed along two different (but still related) lines. First, by comparing the behaviour of a system with the expected one, or by checking if such system satisfies some security requirements: we investigate a novel approximate behavioural-equivalence for comparing processes behaviour, thus extending the Generalised Non Deducibility on Composition (GNDC) approach with scores. As a second result, we equip a modal logic with semiring values with the purpose to have a weight related to the satisfaction of a formula that specifies some requested property. Finally, we generalise the classical partial model-checking function, and we name it as quantitative partial model-checking in such a way to point out the necessary and sufficient conditions that a system has to satisfy in order to be considered as secure, with respect to a fixed security/functionality threshold-value.

Purpose: To investigate the impact of continuous positive airway pressure (CPAP) applied by a full-face fitted mask at 15 cmH2O on total cerebral blood flow (tCBF), jugular venous flow (tJVF) and cerebrospinal fluid (CSF) flow. Materials and methods: Axial 2D phase-contrast MRI measurements were acquired at the C2–C3 vertebral level for 23 healthy male awake subjects at baseline (without) and with CPAP applied. CSF flow was quantified within the spinal subarachnoid space and tCBF was quantified based on the summation of blood flow within the left and right internal carotid and vertebral arteries. tJVF was quantified based on the summation of blood flow within the left and right jugular veins. Heart rate, transcutaneous carbon dioxide (PtcCO2) and oxygen saturation were continuously monitored during the MR protocol. Results: CPAP decreased the pulse amplitude (PtPPA) of tJVF by 21% (p = 0.004). CSF stroke volume (SV) and PtPPA also decreased by 20% (p = 0.003) and 15% (p = 0.005), respectively. Change in tCBF SV and PtPPA was not significant. However, the timing of maximum systolic tCBF occurred significantly earlier under CPAP. CSF flow and tJVF waveforms showed significant spatial and temporal differences in waveform feature points, and spectral analysis revealed a decrease in the first harmonic of tJVF under CPAP (p = 0.001). Under CPAP, a 5% decrease in PtcCO2 (p = 0.003) and 9% increase in HR (p = 0.006) were measured. However, these HR and PtcCO2 changes were not correlated with any changes in arterial, venous or CSF flow dynamics. Conclusion: Application of CPAP via a full-fitted mask at 15 cm H2O was found to have a significant effect on intracranial venous outflow and spinal CSF flow at the C2 vertebral level in healthy adult-age awake volunteers. CPAP can be used to non-invasively provoke changes in intracranial and CSF flow dynamics.

Infections due to carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are associated with increased mortality in cardiac surgery patients. In this short communication, we report on the changes in the incidence of CR-Kp colonization and CR-Kp infection in cardiac surgery patients from 2014 to 2018 in a teaching hospital in Italy, after the implementation of an antimicrobial stewardship project in 2014. During the study period, 2261 patients underwent open-heart surgery. Of them, 130 were found to be colonized by CR-Kp (5.7%) and 52 developed a postoperative CR-Kp infection (2.3%). The crude in-hospital mortality in patients with CR-Kp infections was 48% (25/52). The incidences of both CR-Kp colonization (incidence rate ratio (IRR) 0.82, 95% confidence intervals (CI) 0.78−0.86, p < 0.001) and CR-Kp infection (IRR 0.76, 95% CI 0.69−0.83, p < 0.001) considerably decreased over the study period. This encouraging result should prompt further concerted efforts, directed towards retaining the positive impact of stewardship and infection-control interventions on CR-Kp-related morbidity in the long term.

We propose the use of Soft Constraints as a natural way to model Service Oriented Architecture. In the framework, constraints are used to model components and connectors and constraint aggregation is used to represent their interactions. The "quality of a service" is measured and considered when performing queries to service providers. Some examples consist in the levels of cost, performance and availability required by clients. In our framework, the QoS scores are represented by the softness level of the constraint and the measure of complex (web) services is computed by combining the levels of the components.

Currently standard first line therapy for fit patients with B-CLL/SLL are fludarabine-based regimens. Elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl). However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m2 for the first course and 500 mg/m2 for subsequent cycles until the 6th cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3-4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3-4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL.

Ray-finned fishes constitute the dominant radiation of vertebrates with over 32,000 species. Although molecular phylogenetics has begun to disentangle major evolutionary relationships within this vast section of the Tree of Life, there is no widely available approach for efficiently collecting phylogenomic data within fishes, leaving much of the enormous potential of massively parallel sequencing technologies for resolving major radiations in ray-finned fishes unrealized. Here, we provide a genomic perspective on longstanding questions regarding the diversification of major groups of ray-finned fishes through targeted enrichment of ultraconserved nuclear DNA elements (UCEs) and their flanking sequence. Our workflow efficiently and economically generates data sets that are orders of magnitude larger than those produced by traditional approaches and is well-suited to working with museum specimens. Analysis of the UCE data set recovers a well-supported phylogeny at both shallow and deep time-scales that supports a monophyletic relationship between Amia and Lepisosteus (Holostei) and reveals elopomorphs and then osteoglossomorphs to be the earliest diverging teleost lineages. Our approach additionally reveals that sequence capture of UCE regions and their flanking sequence offers enormous potential for resolving phylogenetic relationships within ray-finned fishes.