Clinical Outcomes in Patients Aged 80 Years or Older Receiving Non-Invasive Respiratory Support for Hypoxemic Acute Respiratory Failure Consequent to COVID-19

: As the clinical outcome of octogenarian patients hospitalised for COVID-19 is very poor, here we assessed the clinical characteristics and outcomes of patients aged 80 year or older hospitalised for COVID-19 receiving non-invasive respiratory support (NIRS). A multicentre, retrospective, observational study was conducted in seven hospitals in Northern Italy. All patients aged ≥80 years with COVID-19 associated hypoxemic acute respiratory failure (hARF) undergoing NIRS between 24 February 2020, and 31 March 2021, were included. Out of 252 study participants, 156 (61.9%) and 163 (64.6%) died during hospital stay and within 90 days from hospital admission, respectively. In this case, 228 (90.5%) patients only received NIRS (NIRS group), while 24 (9.5%) were treated with invasive mechanical ventilation (IMV) after NIRS failure (NIRS+IMV group). In-hospital mortality did not significantly differ between NIRS and NIRS+IMV group (61.0% vs. 70.8%, respectively; p = 0.507), while survival probability at 90 days was significantly higher for NIRS compared to NIRS+IMV patients (0.379 vs. 0.147; p = 0.0025). The outcome of octogenarian patients with COVID-19 receiving NIRS is quite poor. Caution should be used when considering transition from NIRS to IMV after NIRS failure

Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint

Introduction: Evaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-\u3b1 blockers in psoriatic arthritis (PsA). Methods: Systemic and local disease activity indexes (disease activity score [DAS]; the Ritchie articular index [mRAI], erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular [THOMP] and joint articular [KJAI]-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml - 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a ten week period. Total SF white blood cell (WBC) counts (WBC/ \u3bcl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8/14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105. Results: At baseline, CRP and/or ESR were significantly correlated with SF-CK (IL-1\u3b2, IL-1Ra, IL-6, IL-8) and CCK (CCL2, CCL3 and CCL4). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/\u3bcl and in SF-CK (TNF-\u3b1, IL- 1\u3b2, IL-1Ra, IL-6 and IL-22). Pre- and post- IAE injections, there were significant correlations between ST markers and SF-CK (IL-1\u3b2 with CD45; IL-1\u3b2 and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3)

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients

Studio dei biomarcatori della sinovite

Introduction: Synovitis is a chronic inflammation concerning all early inflammatory arthritis. It is often resistent to standard pharmacological treatment and local therapy , and if not treated , the process becames irreversible. Aim of the study: To identify biomarkers useful to determine the disease activity level, to evaluate the responses to therapies and to delineate the mechanisms involved in the synovitis process, in order to find new potential therapeutic targets for this severe disease. Methods: Synovial fluid (SF), synovial tissue (ST) and/or peripheral bood (PB) samples were obtained from patients affected by psoriatric arthritis (PsA) and pigmented villonodular synovitis (PVNS). Local and sistemic disease activity indexes: knee Thompson articular index (THOMP: range 0 -9), Knee Joint Articular Index (KJAI: range 0 -14), erythrocytes sedimentation rate(ERS: norm 0–20 mm/hr), C-reactive protein (CRP: norm<10), and SF cytokine/chemokine expression levels were mesured before and after IA TNF α blockade.Characterization of synovial mononclear cell infiltration and synovial vessels, and the evaluation of the different cellular subset expression (T regulatory and Thelper 17 cells) was carried out in consecutive serial sections obtained from synovial biopsies or in mononuclear cells obtained from SF or PB. Proper antibodies were used for immunostaining. Analysis were carried out by cellular and molecular biology techniques, cytofluorimetry and immunoistochemistry. Data obtained from the patients were compared to data obtained from proper control groups. Results: SF biomarkers correlate with synovial tissue inflammation and with local and systemic indexes of disease activity in PsA. The IA TNF α blockade lead to a synovial effusion regression and a ST and SF biomarkers significant reduction compared to baseline. In PVNS affected patients, knee injectons lead to a reduction in local indexes of disease activity and in immunohistological alterations. We detected higher CSF-1mRNA expression level in PVNS compared to chronic inflammatory synovitis. The evaluation of Treg and TH17 subset cells phenotype in PsA affected patients showed an increased expression of TH17 cells both at local and systemic level. Moreover, we found some correlations between cell markers both at local and systemic level. Conclusions: Synovial effusion regression is a reliable indicator of the response to IA TNFα blockers in PsA patients and it is confirmed by the correlation between SF biomarkers to disease activity and synovial tissue inflammation. Changes following IA treatment, indicate that ST CD45+ MNC and CD31+ vessels, along with SF IL-6 and -IL-1β, may represent candidate biomarkers of the knee synovitis response to IA TNF-α blockade. The new therapeutic approach concerning serial intraarticular anti-TNF-α injections in pigmented villonodular synovitis resulted in a local clinical improvement accompanied by a rapid regression in synovial stromal fibrosis and vasculogenesis. Moreover, it was ineffective in reducing synovial CSF-1 expression. The detection of higher level of colony-stimulating factor-1 (CSF-1) in synovial tissue of pigmented villonodular synovitis (PVNS) suggests that CSF-1 play an important role in PVNS disease process and supports the idea that CSF-1/CSF-1R interaction may represent a potential therapeutic target of this disease. The higher expression of TH17 cells in contrast to the lower expression of Treg cells detected in the SF and PB of PsA patients, highlights new specific molecular targets for the development of different pharmacological approches able to inhibit the effector response, preventing TH17 activity, or enhancing the regulatory response, inducing the differentiation of Treg cells.Introduzione: Le sinoviti sono infiammazioni croniche che riguardano tutte le artriti infiammatorie primitive. Spesso resistenti al trattamento farmacologico tradizionale ed alla terapia locale, se non curate, si dimostrano irreversibili. Scopo dello studio: Individuare biomarcatori utili a determinare il grado di attività di malattia, le risposte ai trattamenti e chiarire i meccanismi coinvolti nel mantenimento della sinovite al fine di poterli considerare nuovi possibili bersagli terapeutici per questa grave patologia. Materiali e metodi: Campioni di liquido sinoviale (LS), tessuto sinoviale (TS) e/o sangue periferico (SP) sono stati ottenuti da pazienti affetti da artrite psoriasica (AP) e sinovite villonodulare pigmentosa diffusa (PVNS). Sono stati valutati gli indici di attività di malattia locali: knee Thompson articular index (THOMP: range 0 -9), Knee Joint Articular Index (KJAI: range 0 -14) e sistemici: velocità di eritrosedimantazione (VES: norm 0–20 mm/hr), proteina C-reattiva (PCR: norm<10), e sono stati misurati i livelli di citochine/chemochine nel LS prima e dopo trattamento intra-articolare (IA) con anti-TNFα (E). La caratterizzazione dell’infiltrato cellulare sinoviale e dei vasi sinoviali e la valutazione dell’espressione di frazioni cellulari ad attività funzionale opposta (Treg e TH17) è stata ottenuta marcando con opportuni anticorpi sezioni seriali di biopsie sinoviali e cellule mononucleate separate da SP e LS rispettivamente. Tutte le analisi sono state eseguite mediante l’utilizzo di tecniche di citofluorimetria, di biologia cellulare e molecolare e di immunoistochimica e i dati raccolti dai gruppi di pazienti sono stati confrontati con quelli raccolti da opportuni gruppi di controllo. Risultati: Abbiamo dimostrato che nell’AP i biomarcatori del liquido sinoviale correlano con l’infiammazione del tessuto sinoviale e gli indici sistemici di attività di malattia e che in risposta al trattamento IA con anti-TNFα il versamento sinoviale e i biomarcatori del liquido e del tessuto sinoviale sono significativamente ridotti rispetto ai livelli basali. Nella PVNS le iniezioni IA hanno portato ad un effettivo miglioramento degli indici locali di attività di malattia e ad una riduzione delle alterazioni immunoistologiche. Lo studio di espressione del CSF-1 ha evidenziato che esso è maggiormente espresso nelle sinoviti villonodulari rispetto alle sinoviti infiammatorie croniche. La valutazione dei profili fenotipici delle frazioni cellulari Treg e TH17 nei pazienti affetti da AP ha mostrato che sia a livello sistemico che locale l’equilibrio tra le due frazioni è significativamente spostato verso il fenotipo proinfiammatorio TH17 e che vi sono correlazioni tra l’espressione di alcuni marcatori a livello locale e sistemico. Conclusioni: La regressione del versamento sinoviale è un indicatore reale della risposta ai farmaci bloccanti il TNFα nei pazienti affetti da AP ed è confermata dalle correlazioni tra i biomarcatori del LS con l’attività di malattia e l’infiammazione del tessuto sinoviale. Le alterazioni conseguenti al trattamento indicano che specifici marcatori sinoviali studiati (CD45+, CD31+, IL-1β; IL-6) possano rappresentare potenziali biomarcatori sinoviali della risposta al trattamento con tali farmaci. Il nuovo approccio terapeutico IA anti TNFα nel trattamento della PVNS ha portato ad una rapida regressione della fibrosi e della vasculogenesi. Inoltre si è dimostrato inefficace nel ridurre l’espressione del CSF-1. I più alti livelli di espressione dell’mRNA-CSF-1 riscontrati nella PVNS suggeriscono che il CSF-1 svolge un ruolo chiave nello sviluppo della malattia e che l’interazione tra CSF-1/CSF-1R possa rappresentare un potenziale bersaglio terapeutico per la sinovite villonodulare. L’elevata espressione della frazione cellulare TH17 rispetto alla frazione Treg riscontrata sia nel liquido sinoviale che nel sangue periferico dei pazienti affetti da AP ci permette di pensare a specifici bersagli molecolari per lo sviluppo di nuovi composti capaci sia di inibire la risposta effettrice, per esempio prevenendo l'attivazione antigene-specifica delle cellule TH17, sia di aumentare quella regolatoria, per esempio inducendo il differenziamento delle cellule Treg

The Safety of a High-Flow Nasal Cannula in Neuromuscular Disease Patients with Acute Respiratory Failure: A Retrospective Case-Series Study

(1) Background: Although Non-Invasive Ventilation (NIV) is effective in preventing mortality and endotracheal intubation in patients with Acute Respiratory Failure (ARF) linked to a neuromuscular disorder, its efficacy can be affected by patient intolerance. A High-Flow Nasal Cannula (HFNC) appears to have a significant advantage over NIV as far as patient tolerance is concerned. The aim of the study was to investigate HFNC’s safety profile in a group of consecutive Neuromuscular Disease (NMD) patients intolerant to NIV who were admitted to an Intermediate Respiratory Care Unit (IRCU) for ARF. (2) Methods: The clinical course of nine NMD patients intolerant to NIV and switched to HFNC was reported. HFNC was provided during daytime hours and NIV during the night-time to the NIV-intolerant patients. HFNC was utilized 24 h a day in those patients who were intolerant of even nocturnal NIV. (3) Results: HFNC was simple to use and it was well tolerated by all of the patients. Three out of nine patients experienced treatment failure, consisting of the need for ETI and/or death during their IRCU stay. The remaining 6 had a favorable outcome. Treatment failure was linked to the utilization of HFNC 24 h a day. (4) Conclusion: HFNC during the daytime hours, together with nocturnal NIV, seems to be a safe therapeutic approach for NMD patients with ARF. A round-the-clock use of HFNC tends to be linked to a high likelihood of failure

High-flow nasal cannula oxygen therapy to treat patients with hypoxemic acute respiratory failure consequent to SARS-CoV-2 infection

This observational study aims to assess the outcome and safety of O2-therapy by high-flow nasal cannula (HFNC) in 28 consecutive patients with severe hypoxemic acute respiratory failure (hARF) consequent to SARS-CoV-2 infection, unresponsive to conventional O2-therapy. Nineteen patients had a positive response. Nine patients required escalation of treatment to non-invasive ventilation (five subsequently intubated). None of the staff had a positive swab testing during the study period and the following 14 days. Severity of hypoxemia and C reactive protein level were correlated with HFNC failure. These data suggest HFNC to be a safe treatment for less severe patients with SARS-CoV-2 hARF and efficacy will need to be assessed as part of a clinical trial

Effect of \u3b11 Antitrypsin Deficiency on lung volume decline in severe asthmatic patients undergoing biologic therapy

Effect of \u3b1 1 Antitrypsin Deficiency on Lung Volume Decline in Severe Asthmatic Patients Undergoing Biologic Therap

Functional VEGF and VEGF receptors are expressed in human medulloblastomas

Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms–related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF121 and VEGF189 were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF165 was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF165 induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma