Sacubitril/valsartan in COVID-19 patients: the need for trials

We thank Luigi Petramala and Claudio Letizia for their comment1 on our letter about the possible role of sacubitril/valsartan in patients with coronavirus disease 2019 (COVID-19).2 The authors rightly affirm the need for continuing previous therapies with angiotensinconverting enzyme inhibitors (ACE-Is) or sartans in patients with COVID-19, as outlined by recent international consensus papers.3 There is no definite evidence about the harmful or protective use of ACE-Is/sartans in COVID-19 patients.4,5 Dedicated, randomized controlled trials are needed in order to verify the possible worsening of lung infection and/or systemic involvement in patients with COVID-19 who are chronically treated with ACE-Is/sartans. Furthermore, we do not intend to pressurize the indiscriminate change of previous treatments towards sacubitril/valsartan in the absence of evidence from randomized trials. The COVID-19 pandemic forced the scientific community to think about possible, alternative solutions to counteract the multiorgan damage by the virus. We do agree that interrupting specific treatments would increase adverse clinical outcomes in patients, independently from the course of COVID-19, but trying to improve therapeutic solutions is challenging. Sacubitril/ valsartan has already demonstrated superiority over standard therapies in patients suffering from heart failure with reduced ejection fraction (HFrEF), regardless of any comorbidities.6 Moreover, post-hoc analysis from the Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) trial revealed a 42% relative risk reduction in the composite endpoint of death from any cause, re-hospitalization for heart failure, left ventricular assist device implantation, or listing for cardiac transplant, a 42% relative risk reduction in the composite endpoint of cardiovascular death or re-hospitalization for heart failure, and a 39% relative risk reduction in re-hospitalization for heart failure after 8 weeks of treatment with sacubitril/valsartan administered early in patients stabilized during hospitalization for acute decompensated heart failure.7 Furthermore, a significant 50% reduction in NT-proBNP is evident after the first week of treatment with sacubitril/valsartan.8 The need for early administration of sacubitril/valsartan in acute heart failure is probably becoming mandatory in pharmacological management of heart failure patients, although not yet covered by the guidelines. In recent days, the characteristics of cardiac injury during COVID-19 infection have been made available to the medical and scientific community.9,10 In COVID-19 patients, with and without symptoms attributable to pneumonia, there is evidence of a significant increase in NTproBNP, regardless of left ventricular dysfunction. NT-proBNP levels are also the results of acute renal injury and pro-inflammatory molecules such as interleukin-1 and C-reactive protein, which are independent of cardiac function. Shi et al. showed that patients with cardiac injury had a higher rate of mortality during the interval both from symptom onset to admission and from admission to clinical endpoint. Increased death rates were associated with higher levels of NT-proBNP. 9 Gao et al. reported that higher NT-proBNP was an independent risk factor for in-hospital death in patients with severe COVID-19 after adjusting for sex, age, hypertension, coronary heart disease, chronic obstructive pulmonary disease, myoglobin, creatin kinase-MB, high sensitivity troponin-I, white blood cell count, lymphocyte count, C-reactive protein, and procalcitonin.10 Based on the evidence and in relation to the hypotheses generated from our previous correspondence,2 we thought about the possibility of early adoption of sacubitril/valsartan in patients with COVID-19, to maximize the antiinflammatory effects of an enhanced natriuretic peptide system and contain the effects of angiotensin II. Clinical trials in COVID-19 patients are needed in order to validate our hypothesis

Application of an Additive Manufactured Hybrid Metal/Composite Shock Absorber Panel to a Military Seat Ejection System

In this work, a preliminary numerical assessment on the application of an additive manufactured hybrid metal/composite shock absorber panels to a military seat ejection system, has been carried out. The innovative character of the shock absorber concept investigated is that the absorbing system has a thickness of only 6 mm and is composed of a pyramid-shaped lattice core that, due to its small size, can only be achieved by additive manufacturing. The mechanical behaviour of these shock absorber panels has been examined by measuring their ability to absorb and dissipate the energy generated during the ejection phase into plastic deformations, thus reducing the loads acting on pilots. In this paper the effectiveness of a system composed of five hybrid shock absorbers, with very thin thickness in order to be easily integrated between the seat and the aircraft floor, has been numerically studied by assessing their ability to absorb the energy generated during the primary ejection phase. To accomplish this, a numerical simulation of the explosion has been performed and the energy absorbed by the shock-absorbing mechanism has been assessed. The performed analysis demonstrated that the panels can absorb more than 60% of the energy generated during the explosion event while increasing the total mass of the pilot-seat system by just 0.8%

Application of an Additive Manufactured Hybrid Metal/Composite Shock Absorber Panel to a Military Seat Ejection System

In this work, a preliminary numerical assessment on the application of an additive manufactured hybrid metal/composite shock absorber panels to a military seat ejection system, has been carried out. The innovative character of the shock absorber concept investigated is that the absorbing system has a thickness of only 6 mm and is composed of a pyramid-shaped lattice core that, due to its small size, can only be achieved by additive manufacturing. The mechanical behaviour of these shock absorber panels has been examined by measuring their ability to absorb and dissipate the energy generated during the ejection phase into plastic deformations, thus reducing the loads acting on pilots. In this paper the effectiveness of a system composed of five hybrid shock absorbers, with very thin thickness in order to be easily integrated between the seat and the aircraft floor, has been numerically studied by assessing their ability to absorb the energy generated during the primary ejection phase. To accomplish this, a numerical simulation of the explosion has been performed and the energy absorbed by the shock-absorbing mechanism has been assessed. The performed analysis demonstrated that the panels can absorb more than 60% of the energy generated during the explosion event while increasing the total mass of the pilot-seat system by just 0.8%

Dapped-End Beams: Experimental Tests and Capacity Models in the Literature

Half joints are very common construction details, often used for precast beams connections or bridge deck supports, since they allow the creation of an effective joint without increasing the height of the nodal region. If not adequately designed, dapped-end beams can show premature shear failure, due to the abrupt variation in the cross-section dimension. Given the very low shear span, preventing the application of the Bernoulli’s beam theory, strut and tie models need to be taken into account. In this context, experimental tests provide a powerful instrument to detect the stress flows and define the associated capacity models. The presented work supplies a wide literature review of experimental tests and numerical formulations, aiming to characterize the shear behavior of dapped-end beams. It can be a useful tool for design and assessment procedures of such beams

Impaired Vagal Activity in Long-COVID-19 Patients

Long-COVID-19 refers to the signs and symptoms that continue or develop after the “acute COVID-19” phase. These patients have an increased risk of multiorgan dysfunction, readmission, and mortality. In Long-COVID-19 patients, it is possible to detect a persistent increase in D-Dimer, NT-ProBNP, and autonomic nervous system dysfunction. To verify the dysautonomia hypothesis in Long-COVID-19 patients, we studied heart rate variability using 12-lead 24-h ECG monitoring in 30 Long-COVID-19 patients and 20 No-COVID patients. Power spectral analysis of heart rate variability was lower in Long-COVID-19 patients both for total power (7.46 ± 0.5 vs. 8.08 ± 0.6; p p p = 0.015; Cohens-d = 0.76) components. The LF/HF ratio was significantly higher in Long-COVID-19 patients (1.46 ± 0.27 vs. 1.23 ± 0.13; p = 0.001; Cohens-d = 1.09). On multivariable analysis, Long-COVID-19 is significantly correlated with D-dimer (standardized β-coefficient = 0.259), NT-ProBNP (standardized β-coefficient = 0.281), HF component of spectral analysis (standardized β-coefficient = 0.696), and LF/HF ratio (standardized β-coefficient = 0.820). Dysautonomia may explain the persistent symptoms in Long COVID-19 patients. The persistence of a procoagulative state and an elevated myocardial strain could explain vagal impairment in these patients. In Long-COVID-19 patients, impaired vagal activity, persistent increases of NT-ProBNP, and a prothrombotic state require careful monitoring and appropriate intervention

Safety and Feasibility of Treatment with Rivaroxaban for Non-Canonical Indications: A Case Series Analysis.

Abstract BACKGROUND AND OBJECTIVES: The new oral anticoagulants (NOACs) are used for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (AF) and those at risk of deep venous thrombosis. Their rapid onset of action and predictable pharmacokinetic and pharmacodynamic profiles make them the optimal alternative to warfarin in the treatment of these two categories of patients. Unfortunately, however, NOACs cannot be used in patients with valvular AF or valvular cardiac prostheses. Although mechanical valves are effectively a contraindication to NOAC use due to several pathophysiological mechanisms that promote the use of warfarin rather than NOACs, few data exist regarding the use of such new pharmacological compounds on patients with cardiac biological valves or those who have undergone mitral repair or tubular aortic graft implantation. METHODS: Our case series involved 27 patients [mean age 70 ± 10 years; mean CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years (doubled), Diabetes mellitus, Stroke/transient ischemic attack (doubled), Vascular disease, Age 65-74 years, Sex category): 6 ± 1.4; and mean HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratios, Elderly, Drugs or alcohol): 4 ± 1] with AF and biological prostheses, repaired mitral valves, or tubular aortic graft who were treated with the factor Xa inhibitor rivaroxaban due to inefficacy or adverse effects of warfarin. RESULTS: The mean left ventricular ejection fraction was 48 ± 9 %, the left atrial diameter was 46.5 ± 7 mm, and the estimated glomerular filtration rate was 45 ± 21 mL/min/1.73 m2. The mean duration of treatment was 15 ± 2 months. No relevant complications or recurrent thromboembolic events occurred. Three patients had recurrent nose bleeding and two had hematuria that led to reduction of the rivaroxaban dose by the treating physician to 15 mg once a day after 4 months of therapy. No further bleeding episode was recorded after escalating the dose. CONCLUSIONS: Rivaroxaban is a valuable treatment option for patients with biological prostheses, repaired mitral valves, or a tubular aortic graft in order to prevent thromboembolic complications

Post-Procedural Follow-Up of the Interventional Radiology’s Management of Osteoid Osteomas and Osteoblastomas

The family of painful osteocytic tumors includes osteoblastomas and osteoid osteomas—these lesions are considered benign, but they could produce a significant painful symptomatology. Usually, people affected are between 20 s and 30 s. When symptomatic, an effective treatment is mandatory for the management of these lesions to allow for a ful quality of life. The possibilities of treatment range from chirurgical en-block resection (procedure of surgical oncology aiming to remove a tumoral mass in its entirety, completely surrounded by a continuous layer of healthy tissue) to interventional approaches that, nowadays, are considered the most affordable and sustainable in terms of effectiveness, recovery after procedure, and for bone structure sparing. The main techniques used for osteoid osteomas and osteoblastomas are radio frequency ablation (RFA) and magnetic resonance-guided focused ultrasound (MRgFUS): the most important difference between these approaches is the needleless approach of MRgFUS, which further reduces the minimal invasiveness of RFA (and the related consequences) and the absence of exposure to ionizing radiation. Despite their high efficacy, a recurrence of pathology may occur due to a failure in therapy. In light of this, describing the various possibilities of follow up protocols and the imaging aspects of recurrence or incomplete treatment is mandatory. In the scenario given in the literature, many authors have tried to asses an organized follow up protocol of these patients, but many of them did not undergo periodical magnetic resonance (MR) or computerized tomography (CT) because of the lack of symptomatology. However, even if it seems that clinical evolution is central, different papers describe the protocol useful to detect eventual relapse. The aim of our manuscript is to review the various possibilities of follow-up of these patients and to bring together the most salient aspects found during the management of these osteocytic bone lesions

Post-Procedural Follow-Up of the Interventional Radiology’s Management of Osteoid Osteomas and Osteoblastomas

The family of painful osteocytic tumors includes osteoblastomas and osteoid osteomas—these lesions are considered benign, but they could produce a significant painful symptomatology. Usually, people affected are between 20 s and 30 s. When symptomatic, an effective treatment is mandatory for the management of these lesions to allow for a ful quality of life. The possibilities of treatment range from chirurgical en-block resection (procedure of surgical oncology aiming to remove a tumoral mass in its entirety, completely surrounded by a continuous layer of healthy tissue) to interventional approaches that, nowadays, are considered the most affordable and sustainable in terms of effectiveness, recovery after procedure, and for bone structure sparing. The main techniques used for osteoid osteomas and osteoblastomas are radio frequency ablation (RFA) and magnetic resonance-guided focused ultrasound (MRgFUS): the most important difference between these approaches is the needleless approach of MRgFUS, which further reduces the minimal invasiveness of RFA (and the related consequences) and the absence of exposure to ionizing radiation. Despite their high efficacy, a recurrence of pathology may occur due to a failure in therapy. In light of this, describing the various possibilities of follow up protocols and the imaging aspects of recurrence or incomplete treatment is mandatory. In the scenario given in the literature, many authors have tried to asses an organized follow up protocol of these patients, but many of them did not undergo periodical magnetic resonance (MR) or computerized tomography (CT) because of the lack of symptomatology. However, even if it seems that clinical evolution is central, different papers describe the protocol useful to detect eventual relapse. The aim of our manuscript is to review the various possibilities of follow-up of these patients and to bring together the most salient aspects found during the management of these osteocytic bone lesions

Exercise training effects on elderly and middle-age patients with chronic heart failure after acute decompensation: A randomized, controlled trial

Abstract Background The aim of this study was to evaluate the effect of exercise training on cardiac function in heart failure (HF) patients recently suffering from acute decompensation. Radionuclide ambulatory ventricular function monitoring (VEST) was used to detect variations in cardiac hemodynamics during training period. Methods This was a monocentric, randomized, controlled trial. We enrolled 72 HF patients [left ventricle ejection fraction (LVEF) < 40%] within two weeks after acute cardiogenic pulmonary edema: 40 in the elderly group, 32 in the middle-aged group. Trained patients underwent a specific four-weeks exercise program (closed-chain resistive activities and abdominal exercises) which was supervised by a therapist in agreement with patients' characteristics. Catecholamines at rest, echocardiography, right-heart catheterization, and bicycle ergometer were performed. VEST was performed at the end of the 4 weeks-training in all patients in order to assess patients' cardiac hemodynamics [LVEF, cardiac output (CO), stroke volume]. Results Exercise training significantly improved exercise duration, peak oxygen consumption, and ventilatory threshold both in elderly and middle-aged patients (p < 0.0001) after the 4-week controlled training. Despite age (F = 35.086, p < 0.0001; F = 16.967, p < 0.0001; F = 42.574, p = 0.03, respectively), training reliably influence previous cardiopulmonary parameters (F = 29.402, F = 16.421, F = 26.80, p < 0.0001, respectively). Norepinephrine and epinephrine were significantly reduced in both trained groups. Peak LVEF (37.3 ± 4.7% vs 34 ± 6.2%, p = 0.002), peak stroke volume (43.3 ± 3.9% vs 37.5 ± 4.3%, p = 0.001), and peak CO (63.4 ± 6.1% vs 48.2 ± 4.7%, p < 0.0001) increased in middle-aged patients after 4-week training. Conclusions Exercise training improves cardiac performance indexes and pulmonary function in both middle-aged and elderly HF patients early after an acute episode of cardiac decompensation

Additional file 4: of Relative lymphocyte count as an indicator of 3-year mortality in elderly people with severe COPD

Figure S3. Hazard ratio as a function of relative lymphocyte count threshold. (TIF 151 kb