Cardiovascular events after exacerbations of chronic obstructive pulmonary disease: Results from the EXAcerbations of COPD and their OutcomeS in CardioVascular diseases study in Italy.

INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease (COPD) can increase the risk of severe cardiovascular events. OBJECTIVE: Assess the crude incidence rates (IR) of cardiovascular events and the impact of exacerbations on the risk of cardiovascular events within different time periods following an exacerbation. METHODS: COPD patients aged ≥45 years between 01/01/2015 and 12/31/2018 were identified from the Fondazione Ricerca e Salute administrative database. IRs of severe non-fatal and fatal cardiovascular events were obtained for post-exacerbation time periods (1-7, 8-14, 15-30, 31-180, 181-365 days). Time-dependent Cox proportional hazard models compared cardiovascular risks between periods with and without exacerbations. RESULTS: Of 216,864 COPD patients, >55 % were male, mean age was 74 years, frequent comorbidities were cardiovascular, metabolic and psychiatric. During an average 34-month follow-up, 69,620 (32 %) patients had ≥1 exacerbation and 46,214 (21 %) experienced ≥1 cardiovascular event. During follow-up, 55,470 patients died; 4,661 were in-hospital cardiovascular-related deaths. Among 10,269 patients experiencing cardiovascular events within 365 days post-exacerbation, the IR was 15.8 per 100 person-years (95 %CI 15.5-16.1). Estimated hazard ratios (HR) for the cardiovascular event risk associated with periods post-exacerbation were highest within 7 days (HR: 34.3, 95 %CI: 33.1-35.6), especially for heart failure (HR 50.6; 95 %CI 48.6-52.7) and remained elevated throughout 365 days (HR 1.1, 95 %CI 1.02-1.13). CONCLUSIONS: COPD patients in Italy are at high risk of severe cardiovascular events following exacerbations, suggesting the need to prevent exacerbations and possible subsequent cardiovascular events through early interventions and treatment optimization.

Identification of hemodynamically stable patients with acute pulmonary embolism at high risk for death: external validation of different models.

BACKGROUND: The optimal strategy for identification of hemodynamically stable patients with acute pulmonary embolism (PE) at risk for death and clinical deterioration remains undefined. OBJECTIVES: We aimed at assessing the performances of currently available models/scores for identifying hemodynamically stable patients with acute, symptomatic PE at risk of death and clinical deterioration. METHODS: Prospective multicentre cohort study including patients with acute PE (COPE, NCT03631810). Primary study outcome was in-hospital death within 30 days or clinical deterioration. Other outcomes were in-hospital death, death and PE-related death all at 30 days. We calculated positive and negative predictive values, c-statistics of ESC-2014, ESC-2019, PEITHO, Bova, TELOS, FAST and NEWS2 for the study outcomes. RESULTS: In 5,036 hemodynamically stable patients with acute PE, positive predictive values for the evaluated models/scores were all below 10%, except for TELOS and NEWS2; negative predictive values were above 98% for all the models/scores, except for FAST and NEWS-2. ESC-2014 and TELOS had good performances for in-hospital death or clinical deterioration (c-statistic 0.700 and 0.722, respectively), in-hospital death (c-statistic 0.713 and 0.723, respectively) and PE-related death (c-statistic 0.712 and 0.777, respectively); PEITHO, Bova and NEWS2 also had good performances for PE-related death (c-statistic 0.738, 0.741 and 0.742, respectively). CONCLUSION: In hemodynamically stable patients with acute PE, the accuracy for identification of hemodynamically stable patients at risk for death and clinical deterioration varies across the available models/scores; TELOS seems to have the best performances. These data can inform management studies and clinical practice.

The Clinical Impact of the Pulmonary Embolism Severity Index on the Length of Hospital Stay of Patients with Pulmonary Embolism: A Randomized Controlled Trial.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) is an extensively validated prognostic score, but impact analyses of the PESI on management strategies, outcomes and health care costs are lacking. Our aim was to assess whether the adoption of the PESI for patients admitted to an internal medicine ward has the potential to safely reduce the length of hospital stay (LOS). METHODS: We carried out a multicenter randomized controlled trial, enrolling consecutive adult outpatients diagnosed with acute PE and admitted to an internal medicine ward. Within 48 h after diagnosis, the treating physicians were randomized, for every patient, to calculate and report the PESI in the clinical record form on top of the standard of care (experimental arm) or to continue routine clinical practice (standard of care). The ClinicalTrials.gov identifier is NCT03002467. RESULTS: This study was prematurely stopped due to slow recruitment. A total of 118 patients were enrolled at six internal medicine units from 2016 to 2019. The treating physicians were randomized to the use of the PESI for 59 patients or to the standard of care for 59 patients. No difference in the median LOS was found between the experimental arm (8, IQR 6-12) and the standard-of-care arm (8, IQR 6-12) (p = 0.63). A pre-specified secondary analysis showed that the LOS was significantly shorter among the patients who were treated with DOACs (median of 8 days, IQR 5-11) compared to VKAs or heparin (median of 9 days, IQR 7-12) (p = 0.04). CONCLUSIONS: The formal calculation of the PESI in the patients already admitted to internal medicine units did not impact the length of hospital stay.

No contraindication to internal jugular central venous catheter insertion in patients at increased risk of bleeding: Results from a prospective observational study in a internal medicine department.

Implantation of centrally inserted central venous catheter (CICC) may be complicated by bleedings particularly in patients with severe coagulopathy or taking antithrombotic drugs. It has been shown that the application of the Italian Group for Venous Access Devices (GAVeCeLT) bundle reduces the incidence of bleeding in patients admitted to intensive care units (ICU), but its effectiveness has never been demonstrated in different contexts. In this study we evaluated the incidence of bleeding after urgent internal jugular CICC (J-CICC) implantation in patients with increased or no risk of bleeding complications when recommended preventive strategies are applied systematically. We included 185 patients admitted to Internal Medicine Units who underwent urgent J-CICC implantation from April 2016 to December 2018. The incidence of major and minor bleeding immediately after the procedure and in the following 30 days was recorded. None of the enrolled patients showed major bleeding. The incidence of minor bleedings was 2.1% (95% IC: 0.03-4.2) with two patients requiring line removal and repositioning (1.1%; 95% IC: -0.45 to 2.6). Bleeds were not correlated with age or sex, although they all occurred in female subjects. The incidence of bleeds was not increased in patients with increased risk of bleeding compared with those without (5.0% vs 1.3%; p = 0.16). The use of anti-thrombotic medications was significantly associated with increased risk of minor bleedings (p = 0.03). In this study we demonstrated that the application of the GAVeCeLT suggested bundle can minimize the number of bleeding complications even in patients hospitalized in Internal Medicine Units. Further data are needed in patients taking antithrombotic drugs who appear to be more prone to minor bleeding, however the benefit of completing the procedure appears to significantly outweigh the risk of mechanical complications.

Rates of venous thromboembolism and use of thromboprophylaxis after major orthopedic surgery in patients with congenital hemophilia A or B: a systematic review.

BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication after total joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies, and administering pharmacologic thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk. OBJECTIVES: To analyze best available evidences of VTE rates in persons with hemophilia A or B undergoing lower limb TJR and the use of postoperative pharmacologic thromboprophylaxis. METHODS: We systematically screened 4 online biomedical databases to identify studies reporting VTE rates in patients with hemophilia after TJR. Case reports and case series with less than 10 patients were excluded. RESULTS: Twenty-six observational studies were included in this systematic review, reporting 1181 TJRs in patients with hemophilia A or B. Eight studies had VTE rates as the primary outcome. Five studies reported screen-detected VTE, while 21 reported symptomatic VTE events. Overall, 17 VTE events were reported (1.4%; 95% CI, 0.9%-2.3%), including 10 (6.6%) after 151 surgeries with postoperative VTE screening and 7 (0.7%) after 1080 surgeries without postoperative screening. Thromboprophylaxis protocols were specified in 21 studies; postoperative thromboprophylaxis was used in 15 (1.3%) surgeries. This information was not available for 29.0% of the analyzed population. CONCLUSION: Despite the low thromboprophylaxis use in patients with hemophilia, rates of symptomatic VTE after TJR appeared to be low. We also highlighted the need to better report the thrombotic outcome in persons with hemophilia to face the ongoing changes in the hemophilia landscape.

The Use of Risk Scores for Thromboprophylaxis in Medically Ill Patients-Rationale and Design of the RICO trial.

Background Venous thromboembolism (VTE) in hospitalized medically ill patients is a significant cause of morbidity and mortality. Guidelines suggest that VTE and bleeding risk assessment models (RAMs) should be integrated into the clinical decision-making process on thromboprophylaxis. However, poor evidence is available comparing the use of a RAM versus clinical judgement in evaluating VTE and bleeding occurrence. Methods Reducing Important Clinical Outcomes in hospitalized medical ill patients (RICO) is a multicenter, cluster-randomized, controlled clinical trial (ClinicalTrials.gov Identifier: NCT04267718). Acutely ill patients hospitalized in Internal Medicine wards are randomized to the use of RAMs-namely the Padua Prediction Score and the International Medical Prevention Registry on Venous Thromboembolism Bleeding Score-or to clinical judgement. The primary study outcome is a composite of symptomatic objectively confirmed VTE and major bleeding at 90-day follow-up. Secondary endpoints include the evaluation of clinical outcomes at hospital discharge and the assessment of VTE prophylaxis prescription during the study period. In order to demonstrate a 50% reduction in the primary outcome in the experimental group and assuming an incidence of the primary outcome of 3.5% in the control group at 90-day; 2,844 patients across 32 centers will be included in the study. Discussion The RICO trial is a randomized study of clinical management assessing the role of RAMs in hospitalized medical ill patients with the aim of reducing VTE and bleeding occurrence. The study has the potential to improve clinical practice since VTE still represents an important cause of morbidity and mortality in this setting.

Recommendations for the management of hyperkalemia in patients receiving renin-angiotensin-aldosterone system inhibitors.

Hyperkalemia is common in clinical practice and can be caused by medications used to treat cardiovascular diseases, particularly renin-angiotensin-aldosterone system inhibitors (RAASis). This narrative review discusses the epidemiology, etiology, and consequences of hyperkalemia, and recommends strategies for the prevention and management of hyperkalemia, mainly focusing on guideline recommendations, while recognizing the gaps or differences between the guidelines. Available evidence emphasizes the importance of healthcare professionals (HCPs) taking a proactive approach to hyperkalemia management by prioritizing patient identification and acknowledging that hyperkalemia is often a long-term condition requiring ongoing treatment. Given the risk of hyperkalemia during RAASi treatment, it is advisable to monitor serum potassium levels prior to initiating these treatments, and then regularly throughout treatment. If RAASi therapy is indicated in patients with cardiorenal disease, HCPs should first treat chronic hyperkalemia before reducing the dose or discontinuing RAASis, as reduction or interruption of RAASi treatment can increase the risk of adverse cardiovascular and renal outcomes or death. Moreover, management of hyperkalemia should involve the use of newer potassium binders, such as sodium zirconium cyclosilicate or patiromer, as these agents can effectively enable optimal RAASi treatment. Finally, patients should receive education regarding hyperkalemia, the risks of discontinuing their current treatments, and need to avoid excessive dietary potassium intake.

Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

Contemporary anticoagulant treatment strategies in patients with acute pulmonary embolism at different risk for death.

INTRODUCTION: Availability of new treatment strategies for patients with acute pulmonary embolism (PE) have changed clinical practice with potential influence in short-term patients' outcomes. We aimed at assessing contemporary anticoagulation strategies and mortality in patients with acute PE included in the prospective, non-interventional, multicentre, COntemporary management of PE study. MATERIALS AND METHODS: Anticoagulant treatment at admission, during hospital-stay, at discharge and at 30-day are described in the overall population and by clinical severity. RESULTS: Overall, 5158 patients received anticoagulant treatment (99%); during the hospital-stay, 2298 received completely parenteral, 926 completely oral and 1934 parenteral followed by oral anticoagulation (1670 DOACs, 264 VKAs). Comorbidities and PE severity influenced the choice of in-hospital anticoagulation. The use of completely parenteral and completely oral anticoagulation varied based on PE severity. In patients treated with thrombolysis, DOACs were used in 46.4% and 80.1% during the hospital stay and at discharge, respectively. Death at 30 days occurred in 34.6% of patients not receiving anticoagulant treatment and in 1.5, 1.3, 3.4 and 8.1% of patients receiving completely oral, sequential with DOACs, sequential with VKAs and completely parenteral regimens, respectively. Increased mortality in patients receiving completely parenteral anticoagulation persisted after adjustment for PE severity. Completely oral anticoagulation was effective and safe also in patients at intermediate-high risk of death. CONCLUSIONS: Contemporary anticoagulation for acute PE includes parenteral agents in over 90% of patients; DOACs are used in the large majority of PE patients at discharge and their early use seems effective and safe also in selected intermediate-risk patients. TRIAL REGISTRATION NUMBER: NCT03631810.

Direct oral anticoagulants for the treatment of cerebral venous thrombosis - a protocol of an international phase IV study.

Introduction: Current guidelines recommend that patients with cerebral venous thrombosis (CVT) should be treated with vitamin K antagonists (VKAs) for 3-12 months. Direct oral anticoagulants (DOACs), however, are increasingly used in clinical practice. An exploratory randomized controlled trial including 120 patients with CVT suggested that the efficacy and safety profile of dabigatran (a DOAC) is similar to VKAs for the treatment of CVT, but large-scale prospective studies from a real-world setting are lacking. Methods: DOAC-CVT is an international, prospective, observational cohort study comparing DOACs to VKAs for the prevention of recurrent venous thrombotic events after acute CVT. Patients are eligible if they are 18 years or older, have a radiologically confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 days of CVT diagnosis. Patients with an absolute contra-indication for DOACs, such as pregnancy or severe renal insufficiency, are excluded from the study. We aim to recruit at least 500 patients within a three-year recruitment period. The primary endpoint is a composite of recurrent venous thrombosis and major bleeding at 6 months of follow-up. We will calculate an adjusted odds ratio for the primary endpoint using propensity score inverse probability treatment weighting. Discussion: DOAC-CVT will provide real-world data on the comparative efficacy and safety of DOACs versus VKAs for the treatment of CVT. Clinical trial registration: ClinicalTrials.gov, NCT04660747.

Humoral and Cellular Immune Response Elicited by the BNT162b2 COVID-19 Vaccine Booster in Elderly.

Although the safety and efficacy of COVID-19 vaccines in older people are critical to their success, little is known about their immunogenicity among elderly residents of long-term care facilities (LTCFs). A single-center prospective cohort study was conducted: a total IgG antibody titer, neutralizing antibodies against Wild-type, Delta Plus, and Omicron BA.2 variants and T cell response, were measured eight months after the second dose of BNT162b2 vaccine (T0) and at least 15 days after the booster (T1). Forty-nine LTCF residents, with a median age of 84.8 ± 10.6 years, were enrolled. Previous COVID-19 infection was documented in 42.9% of the subjects one year before T0. At T1, the IgG titers increased up to 10-fold. This ratio was lower in the subjects with previous COVID-19 infection. At T1, IgG levels were similar in both groups. The neutralizing activity against Omicron BA.2 was significantly lower (65%) than that measured against Wild-type and Delta Plus (90%). A significant increase of T cell-specific immune response was observed after the booster. Frailty, older age, sex, cognitive impairment, and comorbidities did not affect antibody titers or T cell response. In the elderly sample analyzed, the BNT162b2 mRNA COVID-19 vaccine produced immunogenicity regardless of frailty.

A new score to predict Clostridioides difficile infection in medical patients: a sub-analysis of the FADOI-PRACTICE study.

Medical divisions are at high risk of Clostridioides difficile infection (CDI) due to patients' frailty and complexity. This sub-analysis of the FADOI-PRACTICE study included patients presenting with diarrhea either at admission or during hospitalization. CDI diagnosis was confirmed when both enzyme immunoassay and A and B toxin detection were found positive. The aim of this sub-analysis was the identification of a new score to predict CDI in hospitalized, medical patients. Five hundred and seventy-two patients with diarrhea were considered. More than half of patients was female, 40% on antibiotics in the previous 4 weeks and 60% on proton pump inhibitors (PPIs). CDI diagnosis occurred in 103 patients (18%). Patients diagnosed with CDI were older, more frequently of female sex, recently hospitalized and bed-ridden, and treated with antibiotics and PPIs. Through a backward stepwise logistic regression model, age > 65 years, female sex, recent hospitalization, recent antibiotic therapy, active cancer, prolonged hospital stay (> 12 days), hypoalbuminemia (albumin < 3 g/dL), and leukocytosis (white blood cells > 9 × 10^9/L) were found to independently predict CDI occurrence. These variables contributed to building a clinical prognostic score with a good sensitivity and a modest specificity for a value > 3 (79% and 58%, respectively; AUC 0.75, 95% CI 0.71-0.79, p < 0.001), that identified low-risk (score ≤ 3; 42.5%) and high-risk (score > 3; 57.5%) patients. Although some classical risk factors were confirmed to increase CDI occurrence, the changing landscape of CDI epidemiology suggests a reappraisal of common risk factors and the development of novel risk scores based on local epidemiology.

Real-world use of remdesivir for the treatment of patients admitted to Italian hospitals with COVID-19: the nationwide retrospective FADOI-RECOVER study.

BACKGROUND: Remdesivir is widely used for treatment of SARS-CoV-2 pneumonia. The aim of this study was to evaluate the characteristics of patients with moderate-to-severe COVID-19 treated with remdesivir, and their outcomes during hospitalization. METHODS: This retrospective observational multicenter study included consecutive patients, hospitalized for moderate-to-severe COVID-19 (September 2020-September 2021), who were treated with remdesivir. RESULTS: One thousand four patients were enrolled, all with onset of symptoms occurring less than 10 days before starting remdesivir; 17% of patients had 4 or more concomitant diseases. Remdesivir was well tolerated, adverse drug reactions (ADRs) being reported in 2.3% of patients. In-hospital death occurred in 80 patients (8.0%). The median timing of the first remdesivir dose was 5 days after symptom onset. The following endpoints did not differ according to the time span from the onset of symptoms to the first dose: length of hospitalization, in-hospital death, composite outcome (in-hospital death and/or endotracheal intubation). Advanced age, number of comorbidities ≥ 4, and severity of respiratory failure at admission were associated with poor in-hospital outcomes. CONCLUSION: In a real-world setting, remdesivir proved to be a safe and well-tolerated treatment for moderate-to-severe COVID-19. In patients receiving remdesivir less than 3 or 5 days from the onset of SARS-CoV-2 symptoms, mortality and the need for mechanical ventilation did not differ from the rest of the sample.

Enhanced Carotid Plaque Echolucency Is Associated with Reduced Cognitive Performance in Elderly Patients with Atherosclerotic Disease Independently on Metabolic Profile.

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled 113 patients aged 65 years or more (72.4 ± 5.9 years) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by grey-scale median (GSM) and neuropsychological tests to assess cognitive function. The GSM values at baseline were inversely correlated with the number of seconds required to complete Trail Makin Test (TMT) A (rho: -0.442; p < 0.0001), TMT B (rho: -0.460; p < 0.0001) and TMT B-A (rho: -0.333; p < 0.0001) and directly correlated with Mini Mental State Examination (MMSE) and Verbal Fluency Test (VFT) score (rho: 0.217; p = 0.021 and rho: 0.375; p < 0.0001, respectively) and the composite cognitive z-score (rho: 0.464; p < 0.0001). After a mean period of 3.5 ± 0.5 years, 55 patients were reevaluated according to the same baseline study protocol. Patients with baseline GSM value higher than the median value of 29 did not show any significant variation in the z-score. Instead, those with GSM ≤ 29 showed a significant worsening of z-score (-1.2; p = 0.0258). In conclusion, this study demonstrates the existence of an inverse relationship between the echolucency of carotid plaques and cognitive function in elderly patients with atherosclerotic carotid disease. These data suggest that the assessment of plaque echogenicity if used appropriately, might aid in identifying subjects at increased risk for cognitive dysfunction.

Contemporary Management and Clinical Course of Acute Pulmonary Embolism: The COPE Study.

BACKGROUND: New diagnosis, risk stratification, and treatment strategies became recently available for patients with acute pulmonary embolism (PE) leading to changes in clinical practice and potentially influencing short-term patients' outcomes. RESEARCH QUESTION: The COntemporary management of PE (COPE) study is aimed at assessing the contemporary clinical management and outcomes in patients with acute symptomatic PE. STUDY DESIGN AND METHODS: Prospective, noninterventional, multicenter study. The co-primary study outcomes, in-hospital and 30-day death, were reported overall and by risk categories according to the European Society of Cardiology (ESC) and American Heart Association guidelines. RESULTS: Among 5,213 study patients, PE was confirmed by computed tomography in 96.3%. In-hospital, 289 patients underwent reperfusion (5.5%), 92.1% received parenteral anticoagulants; at discharge, 75.6% received direct oral anticoagulants and 6.7% vitamin K antagonists. In-hospital and 30-day mortalities were 3.4 and 4.8%, respectively. In-hospital death occurred in 20.3% high-risk patients (n = 177), in 4.0% intermediate-risk patients (n = 3,281), and in 0.5% low-risk patients (n = 1,702) according to ESC guidelines. Further stratification in intermediate-high and intermediate-low risk patients did not reach statistical significance, but intermediate-risk patients with sPESI > 0 alone had lower mortality compared to those with one or both among right ventricular dilation at echocardiography or increased troponin. Death or clinical deterioration occurred in 1.5, 5.0, and 9.4% of patients at low, intermediate-low, and intermediate-high risk for death according to ESC guidelines. CONCLUSION: For the majority of patients with PE, contemporary initial management includes risk stratification and treatment with direct oral anticoagulants. In-hospital mortality remains high in intermediate and high-risk patients calling for and informing research focused on its reduction. TRIAL REGISTRATION NUMBER: NCT03631810.

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine.

BACKGROUND: To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination. METHODS: Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. FINDINGS: After eight months from the second dose, IgG decreased in both serum (T2GMC: 23,838.5 ng/ml; T3GMC: 1473.8 ng/ml) and saliva (T2GMC: 12.9 ng/ml; T3GMC: 0.3 ng/ml). Consistently, serum IgA decreased (T2GMC: 48.6 ng/ml; T3GMC: 6.4 ng/ml); however, salivary IgA showed a different behaviour and increased (T2GMC: 0.06 ng/ml; T3GMC: 0.41 ng/ml), indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum (IgG T4GMC: 98,493.9 ng/ml; IgA T4GMC: 187.5 ng/ml) and saliva (IgG T4GMC: 21.9 ng/ml; IgA T4GMC: 0.65 ng/ml). Moreover, the booster re-established the neutralizing activity in the serum of all individuals, not only against the Wuhan wild-type antigen (N = 50; INH: 91.6%) but also against the variants (Delta INH: 91.3%; Delta Plus INH: 89.8%; Omicron BA.1 INH: 85.1%). By contrast, the salivary neutralizing activity was high against the Wuhan antigen in 72% of individuals (N = 36, INH: 62.2%), but decreased against the variants, especially against the Omicron BA.1 variant (Delta N = 27, INH: 43.1%; Delta Plus N = 24, INH: 35.2%; Omicron BA.1 N = 4; INH: 4.7%). This was suggestive for a different behaviour of systemic immunity observed in serum with respect to mucosal immunity described in saliva (Wald chi-square test, 3 df of interaction between variants and sample type = 308.2, p < 0.0001). INTERPRETATION: The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant. FUNDING: This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020), Italy.

Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial.

OBJECTIVE: To compare two different treatment durations of rivaroxaban in patients with symptomatic isolated distal deep vein thrombosis (DVT). DESIGN: Randomised, double blind, placebo controlled clinical trial. SETTING: 28 outpatient clinics specialising in venous thromboembolism. PARTICIPANTS: 402 adults (≥18 years) with symptomatic isolated distal DVT. INTERVENTIONS: After receiving standard dose rivaroxaban for six weeks, participants were randomly assigned to receive rivaroxaban 20 mg or placebo once daily for an additional six weeks. Follow-up was for 24 months from study inclusion. MAIN OUTCOMES MEASURES: The primary efficacy outcome was recurrent venous thromboembolism during follow-up after randomisation, defined as the composite of progression of isolated distal DVT, recurrent isolated distal DVT, proximal DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. The primary safety outcome was major bleeding after randomisation until two days from the last dose of rivaroxaban or placebo. An independent committee adjudicated the outcomes. RESULTS: 200 adults were randomised to receive additional rivaroxaban treatment and 202 to receive placebo. Isolated distal DVT was unprovoked in 81 (40%) and 86 (43%) patients, respectively. The primary efficacy outcome occurred in 23 (11%) patients in the rivaroxaban arm and 39 (19%) in the placebo arm (relative risk 0.59, 95% confidence interval 0.36 to 0.95; P=0.03, number needed to treat 13, 95% confidence interval 7 to 126). Recurrent isolated distal DVT occurred in 16 (8%) patients in the rivaroxaban arm and 31 (15%) in the placebo arm (P=0.02). Proximal DVT or pulmonary embolism occurred in seven (3%) patients in the rivaroxaban arm and eight (4%) in the placebo arm (P=0.80). No major bleeding events occurred. CONCLUSIONS: Rivaroxaban administered for six additional weeks in patients with isolated distal DVT who had an uneventful six week treatment course reduces the risk of recurrent venous thromboembolism, mainly recurrent isolated distal DVT, over a two year follow-up without increasing the risk of haemorrhage. TRIAL REGISTRATION: EudraCT 2016-000958-36; ClinicalTrials.gov NCT02722447.

Detection of Torquetenovirus and Redondovirus DNA in Saliva Samples from SARS-CoV-2-Positive and -Negative Subjects.

OBJECTIVES: Torquetenovirus (TTV) and Redondovirus (ReDoV) are the most prevalent viruses found in the human respiratory virome in viral metagenomics studies. A large-scale epidemiological study was performed to investigate their prevalence and loads in saliva samples according to SARS-CoV-2 status. METHODS: Saliva samples from 448 individuals (73% SARS-CoV-2 negative and 27% SARS-CoV-2 positive) aged 23-88 years were tested. SARS-CoV-2 and TTV were determined in saliva by specific qualitative and quantitative real-time PCRs, respectively. A sub-cohort of 377 subjects was additionally tested for the presence and load of ReDoV in saliva, and a different sub-cohort of 120 subjects for which paired saliva and plasma samples were available was tested for TTV and ReDoV viremia at the same timepoints as saliva. RESULTS: TTV in saliva was 72% prevalent in the entire cohort, at a mean DNA load of 4.6 log copies/mL, with no difference regardless of SARS-CoV-2 status. ReDoV was found in saliva from 61% of the entire cohort and was more prevalent in the SARS-CoV-2-negative subgroup (65% vs. 52%, respectively). In saliva, the total mean load of ReDoV was very similar to the one of TTV, with a value of 4.4 log copies/mL. The mean viral loads in subjects infected with a single virus, namely, those infected with TTV or ReDoV alone, was lower than in dually infected samples, and Tukey's multiple-comparison test showed that ReDoV single-infected samples resulted in the only true outlier (p = 0.004). Differently from TTV, ReDoV was not detected in any blood samples. CONCLUSIONS: This study establishes the prevalence and mean value of TTV and ReDoV in saliva samples and demonstrates the existence of differences between these two components of the human virome.

Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.

Rivaroxaban Monotherapy in Patients with Pulmonary Embolism: Off-Label vs. Labeled Therapy.

Background: The use of rivaroxaban in clinical practice often deviates from manufacturer prescribing information. No studies have demonstrated an association between this practice and improved outcomes. Methods: We used the RIETE registry to assess the clinical characteristics of patients with pulmonary embolism (PE) who received off-label rivaroxaban, and to compare their 3-month outcomes with those receiving the labeled therapy. The patients were classified into four subgroups: (1) labeled therapy; (2) delayed start; (3) low doses and (4) both conditions. Results: From May 2013 to May 2022, 2490 patients with PE received rivaroxaban: labeled therapy­1485 (58.6%); delayed start­808 (32.5%); low doses­143 (5.7%); both conditions­54 (2.2%). Patients with a delayed start were more likely to present with syncope, hypotension, raised troponin levels and more severe abnormalities on the echocardiogram than those on labeled therapy. Patients receiving low doses were most likely to have cancer, recent bleeding, anemia, thrombocytopenia or renal insufficiency. During the first 3 months, 3 patients developed PE recurrence, 4 had deep-vein thrombosis, 11 had major bleeding and 16 died. The rates of major bleeding (11 vs. 0; p < 0.001) or death (15 vs. 1; OR: 22.5; 95% CI: 2.97−170.5) were higher in patients receiving off-label rivaroxaban than in those on labeled therapy, with no differences in VTE recurrence (OR: 1.11; 95% CI: 0.25−6.57). Conclusions: In patients with severe PE, the start of rivaroxaban administration was often delayed. In those at increased risk for bleeding, it was often prescribed at low doses. Both subgroups had a worse outcome than those on labeled rivaroxaban.