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The aim of this study was to assess the incidence of deep vein thrombosis (DVT) of the lower limbs, using serial compression ultrasound (CUS) surveillance, in acutely ill patients with COVID-19 pneumonia admitted to a non-ICU setting. Multicenter, prospective study of patients with COVID-19 pneumonia admitted to Internal Medicine units. All patients were screened for DVT of the lower limbs with serial CUS. Anticoagulation was defined as: low dose (enoxaparin 20-40 mg/day or fondaparinux 1.5-2.5 mg/day); intermediate dose (enoxaparin 60-80 mg/day); high dose (enoxaparin 120-160 mg or fondaparinux 5-10 mg/day or oral anticoagulation). The primary end-point of the study was the diagnosis of DVT by CUS. Over a two-month period, 227 consecutive patients with moderate-severe COVID-19 pneumonia were enrolled. The incidence of DVT was 13.7% (6.2% proximal, 7.5% distal), mostly asymptomatic. All patients received anticoagulation (enoxaparin 95.6%) at the following doses: low 57.3%, intermediate 22.9%, high 19.8%. Patients with and without DVT had similar characteristics, and no difference in anticoagulant regimen was observed. DVT patients were older (mean 77±9.6 vs 71±13.1 years; p = 0.042) and had higher peak D-dimer levels (5403 vs 1723 ng/mL; p = 0.004). At ROC analysis peak D-dimer level >2000 ng/mL (AUC 0.703; 95% CI 0.572-0.834; p = 0.004) was the most accurate cut-off value able to predict DVT (RR 3.74; 95%CI 1.27-10, p = 0.016). The incidence of DVT in acutely ill patients with COVID-19 pneumonia is relevant. A surveillance protocol by serial CUS of the lower limbs is useful to timely identify DVT that would go otherwise largely undetected.

The role of noninvasive positive pressure ventilation (NIPPV) in COVID-19 patients with acute hypoxemic respiratory failure (AHRF) is uncertain, as no direct evidence exists to support NIPPV use in such patients. We retrospectively assessed the effectiveness and safety of NIPPV in a cohort of COVID-19 patients consecutively admitted to the COVID-19 general wards of a medium-size Italian hospital, from March 6 to May 7, 2020. Healthcare workers (HCWs) caring for COVID-19 patients were monitored, undergoing nasopharyngeal swab for SARS-CoV-2 in case of onset of COVID-19 symptoms, and periodic SARS-CoV-2 screening serology. Overall, 50 patients (mean age 74.6 years) received NIPPV, of which 22 (44%) were successfully weaned, avoiding endotracheal intubation (ETI) and AHRF-related death. Due to limited life expectancy, 25 (50%) of 50 NIPPV-treated patients received a “do not intubate” (DNI) order. Among these, only 6 (24%) were weaned from NIPPV. Of the remaining 25 NIPPV-treated patients without treatment limitations, 16 (64%) were successfully weaned, 9 (36%) underwent delayed ETI and, of these, 3 (33.3%) died. NIPPV success was predicted by the use of corticosteroids (OR 15.4, CI 1.79–132.57, p 0.013) and the increase in the PaO2/FiO2 ratio measured 24–48 h after NIPPV initiation (OR 1.02, CI 1–1.03, p 0.015), while it was inversely correlated with the presence of a DNI order (OR 0.03, CI 0.001–0.57, p 0.020). During the study period, 2 of 124 (1.6%) HCWs caring for COVID-19 patients were diagnosed with SARS-CoV-2 infection. Apart from patients with limited life expectancy, NIPPV was effective in a substantially high percentage of patients with COVID-19-associated AHRF. The risk of SARS-CoV-2 infection among HCWs was low.

Development of autoantibodies against coagulation factors is an uncommon bleeding disorder associated with cancer, autoimmune conditions, pregnancy, or no apparent disease. Spontaneous FVIII inhibitors are the most frequently encountered; those against FXI have been only anecdotally reported. We report a case of acquired FXI inhibitor presenting as fatal intracranial spontaneous bleeding in an elderly patient with history of cancer and previous transfusions. Few cases of acquired FXI inhibitor have been reported in association with connective tissue disease, cancer, or surgery. Bleeding includes mucocutaneous bleeding, postsurgical hemorrhage, or life-threatening events. Treatment consists of arresting the bleeding and inhibitor eradication. High degree of suspicion is essential to promptly diagnose and treat this uncommon condition.

Background: The aim of this study was to investigate whether human mast cells express functional active CCR3 receptors, which are activated by CC chemokines. These ligands include the CCR3-selective chemokines eotaxin and eotaxin-2 and the more promiscuous CC chemokines, MCP-4, MCP-3, MCP-2 and RANTES. Methods: Immunohistochemical analysis was performed on skin, gut and lung specimens. Double immunostaining was performed with anti-CCR3 and antitryptase, and anti-CCR3 and antichymase antibody (Ab) by using the avidin-biotin-peroxidase system with two different substrates. Mast cells were isolated and purified from human lung parenchyma (HLMC) by countercurrent elutriation followed by discontinuous Percoll density gradient. Flow-cytometric analysis of HLMC surface CCR3 expression was performed with the monoclonal Ab anti-CCR3 (7B11). Functional activation of HLMC was verified by the ability of cells to release histamine and/or migrate in response to eotaxin. Results: High percentages (>70%) of tryptase-positive cells showing CCR3 expression were found in the skin and in the intestinal submucosa, whereas much lower percentages (≤20%) were found in the intestinal mucosa and in the lung interstitium. Eotaxin (1–100 nM) neither induced histamine release from HLMC nor enhanced anti-IgE-induced histamine release. In contrast, eotaxin (10–100 nM) and RANTES (10–100 nM) induced HLMC chemotaxis in vitro. Preincubation of HLMC with antibody anti-CCR3 (5 µg/ml) before loading into the chemotaxis chamber abrogated chemotaxis elicited by eotaxin. Double immunostaining with anti-CCR3 and anti-chymase antibody showed that the vast majority of CCR3-expressing mast cells in the various human tissues examined were tryptase-chymase double-positive. Conclusions: These results indicate that CCR3 is expressed on human mast cells and that these cells are attracted by CCR3-binding chemokines.

Eosinophils, basophils, and Th2 cells express the chemokine receptor CCR3, which binds eotaxin, RANTES, and some other chemokines. Using immunohistochemistry and flow cytometry, we demonstrate that CCR3 is also expressed by a variable proportion of human mast cells in gut, skin, and lung tissue. By contrast, with the same anti-CCR3 antibody (B711), CCR3 was poorly if at all detectable on human Th2 cells in vitro and in vivo . Eotaxin neither induced histamine release from purified human mast cells nor increased anti-IgE-stimulated histamine secretion. However, both eotaxin and RANTES elicited mast cell migration in vitro with a similar efficacy. High percentages of CCR3-expressing mast cells were present in the skin and in the intestinal submucosa; much lower percentages were found in the intestinal mucosa and in lung interstitium. Double immunostaining with anti-CCR3 and anti-chymase antibody showed that the vast majority of CCR3-expressing mast cells in the various tissues examined were tryptase-chymase double-positive. Therefore, tryptase-chymase double-positive mast cells express CCR3 and are attracted by CCR3-binding chemokines, eotaxin, and RANTES. Our findings indicate that these chemokines may play an important role in the differentiation and/or migration of this mast cell subset in connective tissues, as well as in sites of allergic inflammation.

Understanding the cause of sex disparities in COVID-19 outcomes is a major challenge. We investigate sex hormone levels and their association with outcomes in COVID-19 patients, stratified by sex and age. This observational, retrospective, cohort study included 138 patients aged 18 years or older with COVID-19, hospitalized in Italy between February 1 and May 30, 2020. The association between sex hormones (testosterone, estradiol, progesterone, dehydroepiandrosterone) and outcomes (ARDS, severe COVID-19, in-hospital mortality) was explored in 120 patients aged 50 years and over. STROBE checklist was followed. The median age was 73.5 years [IQR 61, 82]; 55.8% were male. In older males, testosterone was lower if ARDS and severe COVID-19 were reported than if not (3.6 vs. 5.3 nmol/L, p =0.0378 and 3.7 vs. 8.5 nmol/L, p =0.0011, respectively). Deceased males had lower testosterone (2.4 vs. 4.8 nmol/L, p =0.0536) and higher estradiol than survivors (40 vs. 24 pg/mL, p = 0.0006). Testosterone was negatively associated with ARDS (OR 0.849 [95% CI 0.734, 0.982]), severe COVID-19 (OR 0.691 [95% CI 0.546, 0.874]), and in-hospital mortality (OR 0.742 [95% CI 0.566, 0.972]), regardless of potential confounders, though confirmed only in the regression model on males. Higher estradiol was associated with a higher probability of death (OR 1.051 [95% CI 1.018, 1.084]), confirmed in both sex models. In males, higher testosterone seems to be protective against any considered outcome. Higher estradiol was associated with a higher probability of death in both sexes.

International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer (EOC) has a significantly better prognosis than stage III/IV EOC, with about 80% of patients surviving at 5 years (compared with about 20% of those with stage III/IV EOC). However, 20% of patients with stage I EOC relapse within 5 years. It is therefore crucial that the biological properties of stage I EOCs are further elucidated. MicroRNAs (miRNAs) have shown diagnostic and prognostic potential in stage III and IV EOCs, but the small number of patients diagnosed with stage I EOC has so far prevented an investigation of its molecular features. We profiled miRNA expression in stage I EOC tumours to assess whether there is a miRNA signature associated with overall and progression-free survival (PFS) in stage I EOC. We analysed tumour samples from 144 patients (29 of whom relapsed) with stage I EOC gathered from two independent tumour tissue collections (A and B), both with a median follow-up of 9 years. 89 samples from tumour tissue collection A were stratified into a training set (51 samples, 15 of which were from patients who relapsed) for miRNA signature generation, and into a validation set (38 samples, seven of which were from patients who relapsed) for signature validation. Tumour tissue collection B (55 samples, seven of which were from patients who relapsed) was used as an independent test set. The Cox proportional hazards model and the log-rank test were used to assess the correlation of quantitative reverse transcription PCR (qRT-PCR)-validated miRNAs with overall survival and PFS. A signature of 34 miRNAs associated with survival was generated by microarray analysis in the training set. In both the training set and validation set, qRT-PCR analysis confirmed that 11 miRNAs (miR-214, miR-199a-3p, miR-199a-5p, miR-145, miR-200b, miR-30a, miR-30a*, miR-30d, miR-200c, miR-20a, and miR-143) were expressed differently in relapsers compared with non-relapsers. Three of these miRNAs (miR-200c, miR-199a-3p, miR-199a-5p) were associated with PFS, overall survival, or both in multivariate analysis. qRT-PCR analysis in the test set confirmed the downregulation of miR-200c in relapsers compared with non-relapsers, but not the upregulation of miR-199a-3p and miR-199a-5p. Multivariate analysis confirmed that downregulation of miR-200c in the test set was associated with overall survival (HR 0·094, 95% CI 0·012–0·766, p=0·0272) and PFS (0·035, 0·004–0·311; p=0·0026), independent of clinical covariates. miR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC. Nerina and Mario Mattioli Foundation, Cariplo Foundation (Grant Number 2010-0744), and the Italian Association for Cancer Research.

Microarray technology was used to profile miRNA expression in primary tumor and stromal tissue from paraffin embedded material of 51 patients with colorectal cancer. 26 miRNAs resulted differentially expressed with at least 2-fold change in tumor tissue with respect to stroma (16 more expressed in the tumor and 10 more expressed in the stroma). 10/26 were confirmed as differentially expressed at qRTPCR: miR-200c-3p, miR-141-3p, miR-200b-3p, miR-200a-3p, miR-1246, miR-92a-3p, miR-194-5p, miR-192-5p, miR-3651-5p, and miR-574-3p. No significant association was found between miRNA expressions and stage at diagnosis, site of primary tumor, first site of metastasis, progression-free, or overall survival.

In Italy, the epidemiology of tick-borne pathogens is still poorly characterized. This prospective study was conducted at the IRCCS Sacro Cuore Don Calabria Hospital in Negrar di Valpolicella (Verona), northeastern Italy, from 2018 to 2022. Ticks from asymptomatic individuals visiting the hospital after a recent tick bite were characterized using microscopy and tested for pathogens using molecular tests. A total of 317 ticks collected from 280 subjects were analyzed, with most identified as Ixodes species (95.6%), followed by Rhipicephalus spp. (0.6%) and Dermacentor spp. (0.3%). Molecular analysis was performed on 257 single ticks and 23 pooled samples. Overall, 15.4% tested positive for at least one pathogen. The most frequently detected pathogen was Borrelia spp. (n = 22, 7.8%), including B. afzeli (n = 8), B. miyamotoi (n = 6), B. valaisiana (n = 2), B. garinii (n = 2), Borrelia spp. (n = 2), B. burgdorferi sensu stricto (n = 1), and B. spielmanii (n = 1). Rickettsia spp. was detected in 20 samples (7.1%), comprising R. helvetica (n = 11), R. monacensis (n = 7), and Rickettsia spp. (n = 2). Other pathogens included Anaplasma phagocytophilum (n = 5, 1.8%), Babesia venatorum (n = 2, 0.7%), and tick-borne encephalitis virus (n = 1, 0.4%). This study calls for enhanced surveillance in the province of Verona to clarify these pathogens’ clinical impact.

BACKGROUND:Hepatic encephalopathy (HE) occurs in 20%–50% of patients after transjugular intrahepatic portosystemic shunt (TIPS). While indices such as an older age, a history of overt HE and severe liver failure have been associated with post-TIPS HE, it remains difficult to identify patients at risk. The aim of this study was to evaluate the predictive value of a large set of clinical, laboratory and neuropsychiatric parameters, both at baseline and after the induction of hyperammonaemia, in relation to the development of post-TIPS HE for 12 months in a group of well-characterised TIPS candidates.METHODS:18 TIPS candidates (58 ± 8 yrs, MELD 11 ± 3; 13 refractory ascites, 1 hydrothorax, 4 uncontrolled bleeding) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan test], capillary ammonia and subjective sleepiness assessment both at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC).RESULTS:At baseline, 3 (17%) patients had abnormal EEG, 1 (5%) abnormal PHES, and 6 (33%) abnormal Scan performance; fasting capillary ammonia concentrations were 199 ± 88 μg/dL and subjective sleepiness 2.5 ± 1.2 (1–9 scale). Post-AAC, 3 (17%) patients had abnormal EEG, none abnormal PHES, and 3 (17%) abnormal Scan performance. Post-AAC, patients exhibited the expected increase in ammonia [F(4, 56) = 2.7213, P = 0.038] and subjective sleepiness [F(4, 52) = 5.4002, P = 0.001]. Six months after TIPS, 3 patients had had an HE-related hospitalization. Compared to their counterparts who had not, they showed significantly lower, pre-AAC fasting ammonia concentrations (96 ± 93 vs. 225 ± 58 μg/dL, P = 0.017). They also showed worse PHES and Scan performance at baseline, as well as worse Scan performance and slower EEG post-AAC. Twelve months post-TIPS, 5 patients had had an HE-related hospitalization, and comparisons between the two groups confirmed the findings at 6 months.CONCLUSIONS:TIPS candidates, who are by definition at low risk of HE, seem to encompass two different populations: i) those who are well and have not had overt HE because their ammonia levels are near-normal, ii) those who are well and have not had overt HE despite hyperammonaemia, either because of habituation or a personal inclination not to exhibit the HE phenotype. Fasting ammonia may be a promising and easily obtained parameter for future validation and inclusion in models for the prediction of post-TIPS HE.