Heart rate variability (HRV) is a biomarker which is strictly related to the activity of the autonomic nervous system (ANS). It has also been demonstrated that HRV is strictly related to human psycho-physical resilience and, more generally, to human health and aging. The analysis of HRV through different methods, mostly of photoplethysmographic type, is being increasingly employed in several medical disciplines, both as a diagnostic tool and as a prognostic mean to monitor a number of treatments. ANS notoriously influences a wide spectrum of human physiological processes and its unbalance brings several alterations in a number of pathophysiology processes related to cardiovascular diseases and psycho-neuro-biology in general. The HRV analysis technique includes a basal and under "stress"examination, to elicit a series of time-domain and frequency-domain-based parameters which highlight the orthosympathetic and parasympathetic (vagal) activities. The usage of HRV analysis in vascular diseases may be of interest in a few cases, such as: the diabetic dysautonomia and microangiopathy, the vaso-dystonic acro-syndromes (e.g. Raynaud phenomenon), the autoimmune disease-based "vasculitis" and more generally any vascular ulcer, lymphedema and all types of microangiopathies and cardiovascular diseases. This mini-review describes the basic principles of HRV analysis and its applications in the diagnostic-therapeutic approach to vascular diseases.

Limb phlebolymphedema (PLE) is characterized by an accumulation of fluid in the interstitial space and it is caused by an impairment of venous and lymphatic flow. From the pathophysiology point of view, PLE may be of primary and (more frequently) secondary type; it mostly occurs in post-thrombotic syndrome, after trauma, in varicose veins with dysfunctional centripetal flow pumping mechanisms, in proximal vein obstruction syndromes (e.g. May-Thurner syndrome), in phlebolymphatic congenital malformations (e.g. Klippel Trenaunay syndrome). To improve diagnostics of limb PLE, bioimpedance technology has been proposed, both under the form of bioimpedance analysis and under the form of the more accurate bioimpedance spectroscopy (BIS); the latter is based on multiple frequencies which investigate tissues with a higher degree of accuracy, compared to bioimpedance analysis which is usually based on one or two frequencies. By means of BIS it is possible to measure and monitor the variations in the extracellular (interstitial) and intracellular fluids as well as in the tissue composition. More importantly, this biotechnology permits a segmental assessment of the edema, thus both limbs may be individually investigated, as well as the fluid accumulation/tissue conditions of the single limb or part of it may be assessed. Similarly, this method may contribute to monitor therapy outcomes and it may also have a relevant prognostic role after oncologic therapy (e.g. breast cancer treatment) to anticipate the risk of lymphedema/PLE onset. Beside the classical L-Dex index which compares the two limbs in terms of impedance, the analysis of raw data permits to extrapolate absolute figures concerning a series of relevant parameters such as: a) resistance which is the expression of the extracellular fluids, b) reactance and c) cell membrane capacitance (CMC) which are both indexes of tissue composition/health. Furthermore, BIS provides a wide range of data concerning body composition in terms of fat and lean mass, water and general health (for example through phase angle index); this way, a more comprehensive approach to the possible concomitant chronic diseases (e.g. obesity, cardiovascular diseases, diabetes, cancer) in the PLE patient is pursued.

Background Sclerotherapy is a non-invasive procedure commonly used to treat superficial venous disease, vascular malformations and other ectatic vascular lesions. While extremely rare, sclerotherapy may be complicated by serious adverse events. Objectives To categorise contraindications to sclerotherapy based on the available scientific evidence. Methods An international, multi-disciplinary panel of phlebologists reviewed the available scientific evidence and developed consensus where evidence was lacking or limited. Results Absolute Contraindications to sclerotherapy where the risk of harm would outweigh any benefits include known hypersensitivity to sclerosing agents; acute venous thromboembolism (VTE); severe neurological or cardiac adverse events complicating a previous sclerotherapy treatment; severe acute systemic illness or infection; and critical limb ischaemia. Relative Contraindications to sclerotherapy where the potential benefits of the proposed treatment would outweigh the risk of harm or the risks may be mitigated by other measures include pregnancy, postpartum and breastfeeding; hypercoagulable states with risk of VTE; risk of neurological adverse events; risk of cardiac adverse events and poorly controlled chronic systemic illness. Conditions and circumstances where Warnings and Precautions should be considered before proceeding with sclerotherapy include risk of cutaneous necrosis or cosmetic complications such as pigmentation and telangiectatic matting; intake of medications such as the oral contraceptive and other exogenous oestrogens, disulfiram and minocycline; and psychosocial factors and psychiatric comorbidities that may increase the risk of adverse events or compromise optimal treatment outcomes. Conclusions Sclerotherapy can achieve safe clinical outcomes provided that (1) patient-related risk factors and in particular all material risks are (1a) adequately identified and the risk benefit ratio is clearly and openly discussed with treatment candidates within a reasonable timeframe prior to the actual procedure; (1b) when an individual is not a suitable candidate for the proposed intervention, conservative treatment options including the option of ‘ no intervention as a treatment option’ are discussed; (1c) complex cases are referred for treatment in controlled and standardised settings and by practitioners with more expertise in the field; (1d) only suitable individuals with no absolute contraindications or those with relative contraindications where the benefits outweigh the risks are offered intervention; (1e) if proceeding with intervention, appropriate prophylactic measures and other risk-mitigating strategies are adopted and appropriate follow-up is organised; and (2) procedure-related risk factors are minimised by ensuring the treating physicians (2a) have adequate training in general phlebology with additional training in duplex ultrasound, procedural phlebology and in particular sclerotherapy; (2b) maintain their knowledge and competency over time and (2c) review and optimise their treatment strategies and techniques on a regular basis to keep up with the ongoing progress in medical technology and contemporary scientific evidence.

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

Abstract Objectives To assess the immediate/short-term outcomes of a maqui berry-based nutraceutical (MBN) supplementation on the autonomic nervous system (ANS), resilience level, metabolism and body composition. Methods A randomized controlled single-blind study was performed on healthy subjects. Throughout 30 days, one group took 1,000 mg/day of an MBN (Maqui 500®), the control group had no supplementation. On day 0 (T0) and 30 (T3) all subjects performed blood tests, bioimpedance spectroscopy and questionnaires for resilience, perceived stress and short-form 12 (SF12). At T0, 75′ after T0 (T1), on day 7 and at T3 the subjects underwent biometric parameter measurement and heart rate variability (HRV) test to investigate psycho-physical resilience. Results Fifteen subjects per group were included; abnormal seasonal high temperatures altered individuals’ lifestyle and nutrition, influencing the trial’s outcomes. Biometric parameters, blood pressure, oxygen saturation and blood tests did not differ between T0 and T3 in both groups. In the MBN group the HRV analysis showed a significant increase of ANS coordination (p=0.05), parasympathetic activity at 75′, very low frequencies and total power at T3, whereas these parameters decreased in the control group. SF12 mental score improved in the maqui group (p=0.02); the questionnaire-based outcomes showed no further variations. In the control subjects bioimpedance showed an increase of resistance and fat mass, with decreased total body water and lean mass (p=n.s.). Conclusions The maqui-based nutraceutical improved HRV, namely ANS activation/coordination, and SF12 mental component. Blood tests and bioimpedance/biometric parameters mildly varied. The elapsed hot weather likely biased many investigated variables.

Psycho-biological resilience is considered one of the most important factors in the epigenetics of aging. Cell senescence exhibits a series of possible biochemical derangements concerning mitochondria, proteasome, genome and membranes. Research has shown that resilience can be acquired through hormesis, a set of conservative and adaptive processes based on biphasic dose-response to specific mild stressors, such as fasting, intake of polyphenols, exercising, physical and chemical stress and mental engagement. These stimuli were shown to elicit beneficial cellular metabolic pathways, such as sirtuin activation, mechanistic target of rapamycin and insulin growth factor-1 downregulation, nuclear related factor 2 upregulation and autophagy. The complex of these resilience-building processes plays a documented role in longevity. Mitochondria are regarded as one of the core actors of aging processes and represent the main target of hormetic approaches [mitohormesis]; furthermore, the influence of the mind on mitochondria, and thus on the balance of health and disease has been recently established , leading to the so-called mitochondria psychobiology. Hence, psychologic and physical stress that reflects on these organelles may be regarded as a relevant factor in cell senescence and thus the proposed "mitoresilience" denomination may be pertinent within the biomedical science of aging. Finally, the quantification of individual resilience is becoming increasingly important in aging science and the investigation of the autonomic nervous system through heart rate variability [HRV] proved to be a valid method to quantify this parameter. In conclusion, an integrated approach targeting hormetic pathways to improve psycho-physical resilience [namely mitoresilience], supported by the monitoring of HRV may represent a valuable option in longevity medicine.

Biomedical science is experiencing a reassessment of its practices of healthcare management where more appropriate cost-benefit profiles are being combined with improvements in knowledge, effectiveness, and safety of diagnostic/therapeutic procedures to drive the advances in medicine. This review aims to assess: (a) possible biases of the scientific literature and research, (b) the clinical value and the cost-effectiveness of the principal medical practices and (c) the possible contribution of integrative and translational medicine. Literature shows that current medical research has cognitive (mostly industry-induced) biases that negatively impact clinical practice: the ever-increasing use of drugs and technologies, united with a certain inattention to the basic mechanisms of pathophysiology are paving the way of reductionism in medical practice. A critical view of innovations in medicine, together with a sound understanding and application of the scientific method, would improve the effectiveness, safety and sustainability of therapies. Translational and integrative medicine can contribute to develop a new patient-centered approach. Conversely, reductionism, eminence/reimbursement-based medical decisions, lack of patient education, industry-influenced science, and limited awareness from physicians may compromise the efficacy, safety, appropriateness, and cost-effectiveness of diagnostic and therapeutic processes.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

BACKGROUND:Both natural immunity and vaccine-induced immunity to COVID-19 may be useful to reduce the mortality/morbidity of this disease, but still a lot of controversy exists.AIMS:This narrative review analyzes the literature regarding these two immunitary processes and more specifically: (a) the duration of natural immunity; (b) cellular immunity; (c) cross-reactivity; (d) the duration of post-vaccination immune protection; (e) the probability of reinfection and its clinical manifestations in the recovered patients; (f) the comparisons between vaccinated and unvaccinated as to the possible reinfections; (g) the role of hybrid immunity; (h) the effectiveness of natural and vaccine-induced immunity against Omicron variant; (i) the comparative incidence of adverse effects after vaccination in recovered individuals vs. COVID-19-naïve subjects.MATERIAL AND METHODS:through multiple search engines we investigated COVID-19 literature related to the aims of the review, published since April 2020 through July 2022, including also the previous articles pertinent to the investigated topics.RESULTS:nearly 900 studies were collected, and 246 pertinent articles were included. It was highlighted that the vast majority of the individuals after suffering from COVID-19 develop a natural immunity both of cell-mediated and humoral type, which is effective over time and provides protection against both reinfection and serious illness. Vaccine-induced immunity was shown to decay faster than natural immunity. In general, the severity of the symptoms of reinfection is significantly lower than in the primary infection, with a lower degree of hospitalizations (0.06%) and an extremely low mortality.CONCLUSIONS:this extensive narrative review regarding a vast number of articles highlighted the valuable protection induced by the natural immunity after COVID-19, which seems comparable or superior to the one induced by anti-SARS-CoV-2 vaccination. Consequently, vaccination of the unvaccinated COVID-19-recovered subjects may not be indicated. Further research is needed in order to: (a) measure the durability of immunity over time; (b) evaluate both the impacts of Omicron BA.5 on vaccinated and healed subjects and the role of hybrid immunity.

The recent research on chronic degenerative diseases (CDD), such as obesity, diabetes, neurodegeneration, atherosclerosis, autoimmune diseases, cancer and aging itself, has shown that Venous and Lymphatic Diseases (VLD) may play an important role in their development, de facto pushing phlebology and especially lymphology under a spotlight in biomedical research [...].

Aims To highlight the relationship among compression therapy (CT), the autonomic nervous system (ANS) (parasympathetic and sympathetic system), and the heart rate variability (HRV) analysis. Background Beyond the typical analgesic and anti-inflammatory effects of CT in patients affected by venous and/or lymphatic diseases, some literature about CT influence on wellbeing has been published as well. More specifically, CT influence on the ANS has been elucidated mostly through HRV application, providing useful quali-quantitative data for scientific and clinical purposes. Material and Methods A literature search was performed through several web-based search engines to investigate the available evidence concerning the possible influence of CT on the ANS and on psychoneuroendocrineimmunology. Moreover, we examined literature data regarding HRV use in the assessment of CT. Lastly, a preliminary cross-over study was performed on 10 patients affected by phlebolymphedema of the lower limbs, undergoing CT with 18–21 mmHg stockings for 10 h and investigated by means of HRV. Results A CT-based increase of the anti-inflammatory activity of the parasympathetic (vagal) system has been elucidated in most scientific literature. Similarly, CT application has generally resulted in an improvement of HRV, which indicates a beneficial influence on the ANS. In our preliminary experience with compression stockings and HRV, two parasympathetic-based parameters improved by 22.8% and 68.0% after 10 h, whereas they decreased in the same subjects without stockings by 2.7% and 8.2%, during normal breathing. The remaining HRV parameters did not show relevant variations, especially during diaphragmatic breathing. Conclusions From literature data and based on our very preliminary experience, it is possible to deduce that CT exerts different effects on the psychobiological parameters of the individual, overall improving HRV and parasympathetic activity. Incorporating both HRV/ANS assessment in phlebolymphology and the beneficial neural action of CT in health care may represent viable options in the future biomedical science.

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

Literature concerning the causative factors of atherosclerotic cardiovascular disease shows complex and sometimes contrasting evidence. Most guidelines suggest a strategy aimed at lowering circulating low density lipoproteins (LDL) and ApoB lipoprotein levels. The use of statins and of cholesteryl ester transfer protein inhibitors has led to a number of controversial outcomes, generating a certain degree of concern about the real efficacy and especially safety of these drugs. Literature data show that the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors results in a dramatic reduction of various markers of lipid metabolism (namely LDL); however, several critical scientific papers have questioned the value, the need and especially the safety of these innovative drugs. LDL are a protective factor against lipopolysaccharides and other microbial derivatives. Similarly, these gram-negative bacteria-derived compounds have been identified as probable culprits of cardiovascular atherogenesis; moreover, lipopolysaccharides increase hepatic synthesis of PCSK9, as defense mechanism. This enzyme modulates LDL receptors level in the liver, as well as in other organs, such as adrenal gland and reproductive organs. Hence, PCSK9 inhibition may influence glucocorticoid secretion and fertility. Lastly, the consequent reduction of circulating LDL may relevantly hindrance immune system and favor lipopolysaccharides diffusion.

By calculating the centrality measures of the nodes of the SARS-CoV-2 protein interactome network, we have identified the viral proteins of potential greatest interest for further experimental investigation to understand the mechanisms by which SARS-CoV-2 attacks cells and to identify possible therapeutic targets. The proteins identified in this study including NSP13, NSP7, ORF3a, ORF8a, and ORF8b, were found to be involved in crucial processes of the viral life cycle, and some of them are currently suspected to be antiviral targets. These results thus demonstrate the importance - and the predictive power- of the in silico analysis of the viral interactome to guide and support experimental investigation, which could otherwise be too complex and time-consuming to carry out in clinical and experimental research, given the size and interaction density of the viral protein network and the current still partial knowledge of this new virus.

More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan (China), rapidly evolving into a global pandemic. This infectious disease has become a major public health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to be effective against COVID-19, and although a few vaccines are available, the mortality rate is not decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention and control measures. In this regard, the use of nutraceutical supports may play a role against some aspect of the infection, particularly the inflammatory state and the immune system function of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this reason, we performed an overview including meta-analyses and systematic reviews to assess the association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation showed positive results in CRP. Based on the data reported in this review, the public health system could consider whether it is possible to supplement the current limited preventive measures through targeted nutraceutical large-scale administration.

Lymphology is evolving in search of a better management of lymphedema patients, both as to the diagnostic pathway and as to the therapeutic options. Similarly, lymphatic system is involved in a wide spectrum of pathophysiologic processes of most chronic degenerative diseases. Translational medicine integrates the interdisciplinary scientific knowledge to improve diagnostic and therapeutic options in the biomedical field. Inflammation and lymphatic function are regarded as the connecting biochemical factors in most diseases. This review focuses on the scientific publications regarding lymphatic system in connection to psycho-neuroendocrine immunology, hormesis, epigenetics and more generally nutrition and lifestyle. The interaction between lymphology and translational medicine may play a relevant role to improve management of lymphedema on the one hand, and of chronic degenerative diseases on the other.

Aims To assess (a) immediate/short-term outcomes of intensive complex decongestive treatment of lower limb lymphedema, by means of bioimpedance spectroscopy and tape measurement-based volumetry, and (b) correlation between these two methods. Patients and methods Cohort study on patients affected by unilateral primary or secondary lymphedema, stage II or III. Patients underwent complex decongestive treatment (manual and electro-sound lymphatic drainage, compression bandage, exercises, low-carb nutrition, and dietary supplements) for six days. Before (D0), three and six days after complex decongestive treatment (D3 and D6), volumetry and bioimpedance spectroscopy data of the total limb and lower leg were collected. Statistical analysis was applied to pre–post treatment outcomes and to the volumetry/bioimpedance spectroscopy correlation. Results Forty-one patients (15 males and 26 females, mean age: 50.7 years) were included. A progressive improvement of volumetry and bioimpedance spectroscopy figures was recorded. Total limb and leg volumetry (mean value in cc) was, respectively, 11,072.9 and 3150.8 at D0, 10,493 (−5.2%, p = 0.001) and 2980.2 (−5.4%, p < 0.001) at D6. Total limb lymphatic index at D0 and D6 was 18.9 and 14.8 (−21.5%, p < 0.001). Total limb resistance at D0, D3, and D6 was 200.4, 225.7, and 237.5 (+18.5%, p < 0.001), respectively; leg resistance at D0 and D6 was 117.5 and 150 (+27.7%, p < 0.001), respectively. Total limb reactance at D0, D3, and D6 was 12.2, 15, and 16.6 (+35.5%, p < 0.001), respectively. Leg reactance at D0 and D6 was 7.7 and 11.5 (+ 49.6%, p < 0001), respectively. Correlation volumetry/bioimpedance spectroscopy data were (a) total limb volumetry/resistance rho = −0.449, p < 0.01; volumetry/reactance rho=−0.466, p < 0.01; volumetry/lymphatic index rho = 0.581, p < 0.01; (b) leg volumetry/resistance rho=−0.579, p < 0.01; volumetry/reactance rho=−0.469, p < 0.01; volumetry/lymphatic index rho = 0.466, p < 0.05. Conclusions Complex decongestive treatment on lymphedematous limbs was effective at short term; both volumetry and bioimpedance spectroscopy showed a statistically significant improvement. Resistance and reactance increase, with lymphatic index decrease, correlated with volumetry decrease. Bioimpedance spectroscopy proved to help to assess fluid decrease and the tissue-related parameters variations.

Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicine-based narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.