Rehabilitation of Post-COVID Patients: A Virtual Reality Home-Based Intervention Including Cardio-Respiratory Fitness Training

The post-COVID syndrome is emerging as a new chronic condition, characterized by symptoms of breathlessness, fatigue, and decline of neurocognitive functions. Rehabilitation programs that include physical training seem to be beneficial to reduce such symptoms and improve patients' quality of life. Given this, and considering the limitations imposed by the pandemic on rehabilitation services, it emerged the need to integrate telerehabilitation programs into clinical practice. Some telerehabilitation solutions, also based on virtual reality (VR), are available in the market. Still, they mainly focus on rehabilitation of upper limbs, balance, and cognitive training, while exercises like cycling or walking are usually not considered. The presented work aims to fill this gap by integrating a VR application to provide cardio-respiratory fitness training to post-COVID patients in an existing telerehabilitation platform. The ARTEDIA application allows patients to perform a cycling exercise and a concurrent cognitive task. Patients can cycle in a virtual park while performing a "go/no-go" task by selecting only specific targets appearing along the way. The difficulty of the practice can be adjusted by the therapists, while the physiological response is continuously monitored through wearable sensors to ensure safety. The application has been integrated into the VRRS system by Khymeia. In the next months, a study to assess the feasibility of a complete telerehabilitation program based on physical and cognitive training will take place. Such a program will combine the existing VRRS exercises and the cardio-respiratory fitness exercise provided by the ARTEDIA application. Feasibility, acceptance, and usability will be assessed from both the patients' and the therapists' sides

Sacubitril/Valsartan in heart failure with reduced ejection fraction: clinical and echocardiographic insights from a real world population

Abstract Background Following the PARADIGM trial, some studies have identified cardiac remodeling as major background for hard end point benefits of Sacubitril/Valsartan (S/V), but few adopted a well described definition in the literature. Purpose We aimed at a comprehensive evaluation of the effects of S/V on echo-derived measures of cardiac remodeling along with clinical and laboratory data over a medium-term follow-up pointing to a real-world HFrEF population. Methods This is a prospective observational study of HFrEF patients on optimal medical therapy (OMT) initiated with S/V at Heart Failure Clinic of our institute (January 2017-January 2020). In 62 HFrEF, echocardiographic, laboratory and clinical data were collected at baseline and over 10 (Q1-Q3 8–13) months after S/V initiation. Mean age was 68±12 years, 79% men. Left ventricular reverse remodeling (LVRR) was defined as: 1) an absolute increase in LVEF ≥10 points or a LVEF ≥50% at follow-up and 2) a relative decrease in indexed left ventricular end-diastolic diameter of at least 10% or an indexed left ventricular end-diastolic diameter ≤33 mm/m2. Results Compared to baseline, S/V promoted a significant improvement of LV ejection fraction (LVEF, from 30% to 37%; p<0,0001) with an absolute median increase in LVEF of 8 points. Parallel significant reductions in left ventricular and atrial volumes, lower mitral regurgitation degree and a better diastolic dysfunction along with clinical improvement (NYHA class and NT-proBNP values) were observed at follow up. sPAP (systolic Pulmonary Arterial Pressure) was significantly decreased at follow-up evaluation (37 mmHg vs 31 mmHg p=0,005) (Table 1). Overall, LVRR as defined above was observed in 30% of patients. Younger age (64 vs 74 years, p=0,007), a shorter duration of the disease (7 vs 23 months, p=0,009), and non ischaemic etiology (79% vs 33% p=0,003), along with a smaller baseline LAESVi (Left Atrial End Systolic Volume, 41 vs 48 ml/m2 p=0,012) were more common in patients with LVRR. sPAP and Right Ventricular (RV) function estimated by tricuspid annular plane systolic excursion (TAPSE) were significantly better in LVRR patients along with TAPSE/sPAP ratio (Table 2). Conclusions Our data point to a remarkable medium-term reverse remodeling effect by S/V in HFrEF. Findings reinforce the concept that the main benefits of S/V on hard end-points are mediated by its cardiac-related effects. Both a left and right reverse remodeling occur in HFrEF patients who start S/V in the most adaptable phase of the disease supporting an early administration. Funding Acknowledgement Type of funding sources: None

Impact of loop diuretic dosage in a population of patients with acute heart failure: a retrospective analysis

BackgroundLoop diuretics are essential for managing congestion in acute heart failure (AHF) patients, but concerns exist about their dosing and administration. This study aims to explore the relationship between aggressive diuretic treatment and clinical outcomes in AHF patients.MethodsWe randomly selected 370 AHF patients from admissions at Maastricht University Medical Center between January 2011 and March 2017. Patients were divided into four quartiles based on diuretic doses administrated during index hospitalization. The primary endpoint was a composite of cardiovascular (CV) rehospitalization or death at 1 year.Results42.4% of patients experimented the primary outcome The composite endpoint rates were 35.4%, 41.6%, 38.5%, and 54.9%, respectively, from lowest to highest dose quartiles (p = 0.033). In univariate analysis, the outcome was significantly lower in the first three quartiles as compared to the fourth quartile. One-year CV mortality was 9.1%, 10.1%, 20.9% and 27.2%, respectively (p = 0.002). After adjusting for confounders, the association between loop diuretic dosage disappeared for both the primary outcome and one-year CV mortality. Most secondary outcomes and endpoints at 3 months, including worsening renal function, showed no significant differences between groups, while hypokaliemia occurrence, length of hospital stay and weight loss at index admission were higher in the fourth quartile compared to the first one.ConclusionsHigh loop diuretic doses are associated with poor outcomes in AHF patients, reflecting disease severity rather than harm from aggressive diuretic use. Furthermore, high diuretic doses do not seem to negatively affect kidney function

Activated Leukocyte Cell Adhesion Molecule Expression and Shedding in Thyroid Tumors

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is expressed in various tissues, cancers, and cancer-initiating cells. Alterations in expression of ALCAM have been reported in several human tumors, and cell adhesion functions have been proposed to explain its association with cancer. Here we documented high levels of ALCAM expression in human thyroid tumors and cell lines. Through proteomic characterization of ALCAM expression in the human papillary thyroid carcinoma cell line TPC-1, we identified the presence of a full-length membrane-associated isoform in cell lysate and of soluble ALCAM isoforms in conditioned medium. This finding is consistent with proteolytically shed ALCAM ectodomains. Nonspecific agents, such as phorbol myristate acetate (PMA) or ionomycin, provoked increased ectodomain shedding. Epidermal growth factor receptor stimulation also enhanced ALCAM secretion through an ADAM17/TACE-dependent pathway. ADAM17/TACE was expressed in the TPC-1 cell line, and ADAM17/TACE silencing by specific small interfering RNAs reduced ALCAM shedding. In addition, the CGS27023A inhibitor of ADAM17/TACE function reduced ALCAM release in a dose-dependent manner and inhibited cell migration in a wound-healing assay. We also provide evidence for the existence of novel O-glycosylated forms and of a novel 60-kDa soluble form of ALCAM, which is particularly abundant following cell stimulation by PMA. ALCAM expression in papillary and medullary thyroid cancer specimens and in the surrounding non-tumoral component was studied by western blot and immunohistochemistry, with results demonstrating that tumor cells overexpress ALCAM. These findings strongly suggest the possibility that ALCAM may have an important role in thyroid tumor biology

Design of serious games in engineering education: An application to the configuration and analysis of manufacturing systems

Higher education has to cope with current trends in digital technologies, in particular in the field of industrial engineering, where digital competencies are required more and more. Digital technologies, combined with serious gaming, offer new opportunities for teaching engineering in higher education, with a twofold objective: 1) offering students a rich and realistic experience exploiting advanced digital tools; 2) supporting and complementing traditional education schemes by increasing participation and involvement via serious gaming, enhanced by digital/virtual technologies. Herein, we present a framework for the design of serious games in engineering education, with a specific focus on the definition of intended learning outcomes and the development of the corresponding game activities. This framework was applied to develop a serious game application for the design and analysis of manufacturing systems. The approach was tested thanks to the cooperation of 60 bachelor engineering students and the results extensively analyzed in both quantitative and qualitative terms

Evaluating the effects of Virtual Reality on perceived effort during cycling: preliminary results on healthy young adults

Virtual Reality (VR) has proven effective in improving rehabilitation by providing engaging and customized inter-ventions. The application of VR in pulmonary rehabilitation is still limited, although it may increase patients' exercise tolerance. Studies on other target groups prove that VR can modify exercise performance and reduce perceived effort. Despite encouraging, the methodological differences among studies prevent reaching definitive conclusions on whether VR can influence exercise tolerance and which factors are more impactful. Our work aims to define and validate an experimental protocol for quantitative evaluation of the effects of VR on perceived effort. Secondary goals are to investigate whether a higher degree of immersion or interaction induces a lower perceived exertion. The experimental protocol consists of cycling at light/moderate intensity under four conditions: no VR, non-immersive VR, immersive VR with and without a dual-task. Heart rate, breathing response (breathing rate, tidal volume, and minute ventilation), cycling cadence, and rate of perceived exertion (RPE) are measured. Thirteen healthy adults (25.08pm 5.50 years) participated in the study. Results show that the protocol is sustainable and suitable for the aims set. All participants maintained the predefined exercise intensity and the desired cadence. RPE was not influenced by any VR factor (p = 0.224), although showing a tendency to decrease in the case of immersive VR (RPE = 11). In the future, a broader sample will allow drawing more definitive results. Further investigations include more factors in the analysis and replicate the study to healthy elderly and respiratory patients

Evaluating the effects of Virtual Reality on perceived effort during cycling: preliminary results on healthy young adults

Virtual Reality (VR) has proven effective in improving rehabilitation by providing engaging and customized inter-ventions. The application of VR in pulmonary rehabilitation is still limited, although it may increase patients' exercise tolerance. Studies on other target groups prove that VR can modify exercise performance and reduce perceived effort. Despite encouraging, the methodological differences among studies prevent reaching definitive conclusions on whether VR can influence exercise tolerance and which factors are more impactful. Our work aims to define and validate an experimental protocol for quantitative evaluation of the effects of VR on perceived effort. Secondary goals are to investigate whether a higher degree of immersion or interaction induces a lower perceived exertion. The experimental protocol consists of cycling at light/moderate intensity under four conditions: no VR, non-immersive VR, immersive VR with and without a dual-task. Heart rate, breathing response (breathing rate, tidal volume, and minute ventilation), cycling cadence, and rate of perceived exertion (RPE) are measured. Thirteen healthy adults (25.08pm 5.50 years) participated in the study. Results show that the protocol is sustainable and suitable for the aims set. All participants maintained the predefined exercise intensity and the desired cadence. RPE was not influenced by any VR factor (p = 0.224), although showing a tendency to decrease in the case of immersive VR (RPE = 11). In the future, a broader sample will allow drawing more definitive results. Further investigations include more factors in the analysis and replicate the study to healthy elderly and respiratory patients

Frequent Activation of Ret Protooncogene By Fusion With A New Activating Gene In Papillary Thyroid Carcinomas

Tumor specific rearrangements of ret gene are frequently detected in papillary thyroid carcinomas. These rearrangements result in the formation of chimeric genes showing the tyrosine kinase domain of ret fused with the 5' end sequences of different genes. We examined a series of 52 patients and identified 10 cases of ret fusion with D10S170 locus resulting in the generation of ret/PTC1 oncogene, 2 cases with the gene encoding the regulatory subunit RI alpha of PKA (ret/PTC2), and finally 6 cases, here described, with a newly discovered gene called ele1 localized on chromosome 10 and leading to the formation of ret/PTC3 oncogene. Our results show the expression of the ret/PTC3 hybrid gene in all the 6 cases and demonstrated its association with the synthesis of 2 constitutively phosphorylated isoforms of the oncoprotein (p75 and p80). The chromosome 10 localization of both ret and ele1 and the detection, in all cases, of a sequence reciprocal to that generating the oncogenic rearrangements, strongly suggest that ret/PTC3 formation is a consequence of an intrachromosomal inversion of chromosome 10

Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A.

The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement