Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: Results from a single Italian Centre study on tocilizumab versus standard of care

Objective: Approximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or \u201ccytokine storm\u201d. Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear, and the aim of our study is to address this point. Methods: Between February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). Results: In the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were three deaths (17.8 \ub1 10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and one serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p < 0.0001 for both) and higher neutrophils and lower lymphocyte levels (p = 0.04 and p = 0.001, respectively) with the TOCI ventilated patients having higher markers than non-ventilated TOCI patients. Conclusion: Higher inflammatory markers, more infections and worse outcomes characterized ventilated TOCI cases compared to ward based TOCI. Despite the confounding factors, this suggests that therapy time in anti-cytokine randomized trials will be key

High Throughput Genetic Characterisation of Caucasian Patients Affected by Multi-Drug Resistant Rheumatoid or Psoriatic Arthritis

Rheumatoid and psoriatic arthritis (RA and PsA) are inflammatory rheumatic disorders characterised by a multifactorial etiology. To date, the genetic contributions to the disease onset, severity and drug response are not clearly defined, and despite the development of novel targeted therapies, ~10% of patients still display poor treatment responses. We characterised a selected cohort of eleven non-responder patients aiming to define the genetic contribution to drug resistance. An accurate clinical examination of the patients was coupled with several high-throughput genetic testing, including HLA typing, SNPs-array and Whole Exome Sequencing (WES). The analyses revealed that all the subjects carry very rare HLA phenotypes which contain HLA alleles associated with RA development (e.g., HLA-DRB1*04, DRB1*10:01 and DRB1*01). Additionally, six patients also carry PsA risk alleles (e.g., HLA-B*27:02 and B*38:01). WES analysis and SNPs-array revealed 23 damaging variants with 18 novel “drug-resistance” RA/PsA candidate genes. Eight patients carry likely pathogenic variants within common genes (CYP21A2, DVL1, PRKDC, ORAI1, UGT2B17, MSR1). Furthermore, “private” damaging variants were identified within 12 additional genes (WNT10A, ABCB7, SERPING1, GNRHR, NCAPD3, CLCF1, HACE1, NCAPD2, ESR1, SAMHD1, CYP27A1, CCDC88C). This multistep approach highlighted novel RA/PsA candidate genes and genotype-phenotype correlations potentially useful for clinicians in selecting the best therapeutic strategy

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml−1 has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin–antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group

Rilevamento geomagnetico degli apparati vulcanici Vicano e Sabazio

A geomagnetic survey for the vertical component ofthe earth's field has been made in the region of lakes Vico and Bracciano,i. e., in the areas interested by the Vican and Sabatian volcanic structures,in view of a more detailed study of the magmatic masses that have alimentedthese structures.Interpretations of the results have led to following conclusion: a) adiscontinuity exists between tlie magmatic mass that has alimented the Vican and Sabatian volcanism and the magmatic masses responsible for the volcanismin the area of lake Bolsena and of the Colli Albani; b) this magmaticmass may be assimilated to a rougly ellipsoidal body with the central pointat approximately 7 to 10 km depth and the upper level very near to surface,and with lateral dimensions of the order of about 12-15 km, presentingupward protuberances that correspond to the crater of the Vico lake andto the area on the northwest of the Bracciano lake basin; c) there exista lateral apophysis, connected with the main mass, which interests the cratersof I'olline, Martignano, Baccano, and Sacrofano; it consists of a kind ofplate of minor thickness, extending eastward at a depth of about 1-2 km,and roughly 5 km large

Development of a stereoselective Ugi reaction starting from an oxanorbornene beta-amino acid derivative

We have synthesised a novel oxanorbornene beta-aminoacid derivative and employed it in a stereoselective Ugi reaction. Hypothesis regarding the mechanism taking place during the reaction have been made and validated through the determination of the relative and absolute configuration of the Ugi adducts. Use of the correct choice of solvents can increase stereoselection. The resulting bicyclic peptidomimetics can be used as a novel class of pluripotent substrates to be elaborated according to the synthetic strategies previously elaborated in our laboratories

Interleukin 6, soluble interleukin 2 receptor alpha (CD25), monocyte colony-stimulating factor, and hepatocyte growth factor linked with systemic hyperinflammation, innate immunity hyperactivation, and organ damage in COVID-19 pneumonia

Background: Patients infected by SARS-CoV-2 can develop interstitial pneumonia, requiring hospitalisation or mechanical ventilation. Increased levels of inflammatory biomarkers are associated with development of acute respiratory distress syndrome (ARDS). The aim of the present study was to determine which cytokines are associated with respiratory insufficiency in patients hospitalised for COVID-19. Patients and methods: Data on 67 consecutive patients were collected between March 8 and March 30, 2020. PaO2/FiO2 ratio (P/F) was calculated at hospital admission. The following cytokines were analysed: interleukin (IL)-6, IL-1\u3b1, IL-18, tumour necrosis factor (TNF)-\u3b2, macrophage colony-stimulating factor (M-CSF), macrophage migration inhibitory factor (MIF), soluble IL-2 receptor alpha (sIL-2R\u3b1; CD25), IL-12\u3b2, IL-3, interferon (IFN) \u3b12a, monokine induced by gamma interferon (MIG), monocyte-chemotactic protein 3 (MCP3) and hepatocyte growth factor (HGF). Results: P/F lower than 300 was recorded in 22 out of 67 patients (32.8%). P/F strongly correlated with IL-6 (r = 120.62, P < 0.0001), M-CSF (r = 120.63, P < 0.0001), sIL-2R\u3b1 (r = 120.54, P < 0.0001), and HGF (r = 120.53, P < 0.0001). ROC curve analyses for IL-6 (AUC 0.83, 95% CI 0.73\u20130.93, P < 0.0001), M-CSF (AUC 0.87, 95% CI 0.79\u20130.96, P < 0.0001), HGF (AUC 0.81, 95% CI 0.70\u20130.93, P < 0.0001), and sIL-2R\u3b1 (AUC 0.80, 95% CI, 0.69\u20130.90, P < 0.0001) showed that these four soluble factors were highly significant. All four soluble factors correlated with LDH, white blood cell count, neutrophil count, lymphocyte count, and CRP. Conclusion: IL-6, M-CSF, sIL-2R\u3b1, and HGF are possibly involved in the main biological processes of severe COVID-19, mirroring the level of systemic hyperinflammatory state, the level of lung inflammation, and the severity of organ damage

Hypertension and chronic exposure to noise.

ABSTRACT

Acute experimental exposure to noise and hormonal modification.

ABSTRAC