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Background Severe acute respiratory syndrome coronavirus 2 infection is associated with hypercoagulability, which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in patients with coronavirus disease 2019 (COVID-19) and their association with VTE. Methods Hospitalized patients with COVID-19 and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase 9, a neutrophil-released enzyme, were measured. Four patients were restudied after recovery. The activating effect of plasma from patients with COVID-19 on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied. Results A total of 36 patients with COVID-19 and 31 healthy controls were studied; VTE developed in 8 of 36 patients with COVID-19 (22.2%). Platelets and neutrophils were activated in patients with COVID-19. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic matrix metalloproteinase 9 was significantly increased in patients with COVID-19. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from patients with COVID-19 triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic-dose low-molecular-weight heparin, but not by aspirin or dypiridamole. Conclusions Platelet and neutrophil activation are key features of patients with COVID-19. NET biomarkers may help to predict clinical worsening and VTE and may guide low-molecular-weight heparin treatment.

Massimo Mammucari,1 Teresa Paolucci,2 Domenico Russo,3 Enrica Maggiori,1 Raffaele Di Marzo,4 Alberto Migliore,5 Umberto Massafra,5 Gianpaolo Ronconi,6 Paola Emilia Ferrara,6 Fabio Gori,7 Barbara Bifarini,7 Stefano Brauneis,8 Renato Vellucci,9 Rocco Domenico Mediati,9 Bartolomeo Violo,10 Silvia Natoli,11 Carmen Pediliggieri,12 Cristiana Di Campli,12 Maria Chiara Collina12 1Primary Care Unit, ASL RM 1, Rome, Italy; 2Unit of Physical Medicine and Rehabilitation, G. D’ Annunzio University of Chieti-Pescara, Department of Oral Medical Science and Biotechnology (DSMOB), Chieti, Italy; 3“San Marco” Hospice and Palliative Care, Latina, Italy; 4Member of the Italian Society of Mesotherapy, Rome, Italy; 5Unit of Rheumatology, San Pietro Fatebenefratelli Hospital, Rome, Italy; 6Physical Medicine and Rehabilitation Unit, IRCCS, Catholic University of Sacred Heart, Rome, Italy; 7Section of Anaesthesia, Intensive Care, and Pain Medicine, University Hospital Santa Maria Della Misericordia, Perugia, Italy; 8Pain Centre “Enzo BorzomatI”, University Hospital of Rome “Policlinico Umberto I”, Rome, Italy; 9Anaesthesiology Department, University Hospital Careggi, Florence, Italy; 10Pain Therapy Unit, S. Spirito Nuovo Regina Margherita Hospital, Rome, Italy; 11Department of Clinical Science and Translational Medicine, Tor Vergata University, Rome, Italy; 12Department of Vascular Surgery, Limb Salvage and Diabetic Foot, IDI-IRCCS, Rome, ItalyCorrespondence: Massimo MammucariPrimary Care Unit, Local Health, ASL RM 1, Rome, 00165, ItalyTel +39-06-61560695 Email massimo.mammucari@libero.itAbstract: Mesotherapy (local intradermal therapy, LIT) is a technique used to slowly spread drugs in tissues underlying the site of injection to prolong the pharmacological effect with respect to intramuscular injection. Recommendations for proper medical use of this technique have been made for pain medicine and rehabilitation, chronic venous disease, sport medicine, musculoskeletal disorders, several dermatological conditions, skin ageing, and immune-prophylaxis. Although mesotherapy is considered a valid technique, unresolved questions remain, which should be answered to standardize methodology and dosing regimen as well as to define the right indications in clinical practice. New randomized controlled trials are needed to test single products (dose, frequency of administration, efficacy and safety). Even infiltration of substances for dermo-cosmetic purposes must be guided by safety and efficacy tests before being proposed by mesotherapy. In this article, we put forth a preclinical and clinical research plan and a health technology assessment as a call to action by doctors, researchers and scientific societies to aid national health authorities in considering mesotherapy for prevention, treatment and rehabilitation paths.Keywords: mesotherapy, intradermal therapy, research plan

Coronavirus Disease Research Community – COVID-19 ZENODO CERN, May 13th, 2020 Publication date: May 12th, 2020 Title: Forecast of COVID19 infections, UK Authors: Gori Fabio, University of Rome Tor Vergata ORCID 0000-0002-3927-2834 I have updated the COVID19 infections data in UK on May 11th, forecasting the evolutions of the new cases and deaths, publishing the graphs on the following free blogs: https://covid19forecast.blogspot.com/ https://eucovid19.blogspot.com/ The same figures are reported here. The forecast of the total positive cases, according to the Verhulst equation is over 240,000 cases, with a ratio per 1000 capita of 3.7, while the forecast of the total deaths is over 34,000. The data of the new cases are still along a plateau but a forecast has been done. The data of the new deaths, on the contrary, are showing a trend to decrease and a forecast has been performed. Keywords: covid19; data analysis; forecast;Malthus equation; Verhulst equation.

Coronavirus Disease Research Community – COVID-19 ZENODO CERN, June 18th, 2020 Publication date: June 18th, 2020 Title: Forecast of COVID19 infections, Bangladesh Authors: Gori Fabio, University of Rome Tor Vergata ORCID 0000-0002-3927-2834 I have analyzed the COVID19 infections in Bangladeshon June 17th, publishing the graphs on the following free blog: https://covid19forecast.blogspot.com/ The same figures are reported in the attached file. Keywords: covid19; data analysis; forecast;Malthus equation; Verhulst equation.

Coronavirus Disease Research Community – COVID-19 ZENODO CERN, June 15th, 2020 Publication date: June 15th, 2020 Title: Forecast of COVID19 infections, India Authors: Gori Fabio, University of Rome Tor Vergata ORCID 0000-0002-3927-2834 I have analyzed the COVID19 infections in Indiaon June 14th, publishing the graphs on the following free blogs: https://india covid19 forecast.blogspot.com/ https://covid19forecast.blogspot.com/ The same figures are reported in the attached file. Keywords: covid19; data analysis; forecast;Malthus equation; Verhulst equation.

Coronavirus Disease Research Community – COVID-19 ZENODO CERN, June 15th, 2020 Publication date: June 15th, 2020 Title: Forecast of COVID19 infections, Chile Authors: Gori Fabio, University of Rome Tor Vergata ORCID 0000-0002-3927-2834 I have analyzed the COVID19 infections in Chileon June 14th, publishing the graphs on the following free blogs: https://covid19forecast.blogspot.com/ https://covid19southamerica.blogspot.com/ The same figures are reported in the attached file. Keywords: covid19; data analysis; forecast;Malthus equation; Verhulst equation.

Coronavirus Disease Research Community – COVID-19 ZENODO CERN, June 15th, 2020 Publication date: June 15th, 2020 Title: Forecast of COVID19 infections, Peru Authors: Gori Fabio, University of Rome Tor Vergata ORCID 0000-0002-3927-2834 I have analyzed the COVID19 infections in Peruon June 14th, publishing the graphs on the following free blogs: https://covid19forecast.blogspot.com/ https://covid19southamerica.blogspot.com/ The same figures are reported in the attached file. Keywords: covid19; data analysis; forecast;Malthus equation; Verhulst equation.

I have monitored the COVID19 infections in EU and USA from March 21st, reporting the graphs on the following free blogs: https://covid19forecast.blogspot.com/ https://eucovid19.blogspot.com/ https://usacovid19.blogspot.com/ https://forbigaio.blogspot.com/ The drawings of the data of the growth of the new infections, presented for Italy, EU27 and USA, has been forecasted with the exponential increase, or by using the Malthus equation of the rate of increase, as shown in the first figure of the attached file. On the other hand the data of the decrease of the new infections, has been forecasted for Italy, EU and USA, with a reasonable good agreement, up to now, by using the Verhulst equation, or logistic equation, which means that the rate of decrease is much slower than the rate of increase. The update of the forecast of decrease in Italy, EU27 and USA, on April 30this shown in the following three figures of the attached file. The different trend between increase and decrease is confirmed by the similar forecast/data of the deaths in Italy, shown in the lastfigure of the attached file. As a conclusion of this analysis, the first question is why the trend is different during the increase and the decrease of the new infections? And who can give the answer?