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Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P

Objectives Stereotactic ablative radiotherapy (SABR) has been reported to be an effective treatment for oligometastatic disease from different primary cancer sites. Here we assess the effectiveness and safety of SABR for oligometastatic breast cancer patients by performing a meta-analysis. Methods Following PRISMA and MOOSE guidelines, a systematic review and meta-analysis was performed. Eligible studies were identified on Medline, Embase, Cochrane Library, and annual meetings proceedings from 1990 to June 2021. A meta-regression analysis was performed to assess if there was a correlation between moderator variables and outcomes, and a p-value Results Ten studies met criteria for inclusion, comprising 467 patients and 653 treated metastases. The 1- and 2-year local control rates were 97% (95% CI 95–99%), and 90% (95% CI 84–94%), respectively. Overall survival (OS) was 93% (95% CI 89–96%) at 1 year, 81% (95% CI 72–88%) at 2 years. The rate of any grade 2 or 3 toxicity was 4.1 % (95% CI 0.1–5%), and 0.7% (0–1%), respectively. In the meta-regression analysis, only prospective design (p = 0.001) and bone-only metastases (p = 0.01) were significantly associated with better OS. In the subgroup analysis, the OS at 2y were significantly different comparing HER2+, HR+/HER2(-) and triple negative breast cancer 100%, 86% and 32%, p = 0.001. For local control outcomes, hormone receptor status (p = 0.01) was significantly associated on meta-regression analysis. Conclusion SABR for oligometastatic breast cancer is safe and associated with high rates of local control. Longer follow-up of existing data and ongoing prospective trials will help further define the role of this management strategy.

Abnormal coagulation parameters are often observed in patients with coronavirus disease 2019 (COVID-19) and the severity of derangement has been associated with a poor prognosis. The COVID-19 associated coagulopathy (CAC) displays unique features that include a high risk of developing thromboembolic complications. Viscoelastic tests (VETs), such as thromboelastometry (ROTEM), thromboelastography (TEG) and Quantra Hemostasis Analyzer (Quantra), provide “dynamic” data on clot formation and dissolution; they are used in different critical care settings, both in hemorrhagic and in thrombotic conditions. In patients with severe COVID-19 infection VETs can supply to clinicians more information about the CAC, identifying the presence of hypercoagulable and hypofibrinolysis states. In the last year, many studies have proposed to explain the underlying characteristics of CAC; however, there remain many unanswered questions. We tried to address some of the important queries about CAC through VETs analysis.

PURPOSE Intensity-modulated radiotherapy with simultaneous integrated boost (SIB) presents several attractive advantages to be employed in clinical practice. Its secure application demands a rigorous quality assurance (QA) procedure, ideal for three-dimensional (3D) dose distribution measurements. Thus, a gel dosimetry methodology to evaluate the dose delivery of SIB treatments is presented and compared to conventional gamma evaluation. METHODS MAGIC-f gel dosimeter with magnetic resonance images for dose reading were used following its standard procedures. Four SIB QA plans created in gel dosimeter phantoms were used. The gel measured and treatment planning system (TPS) calculated doses were compared using 3D gamma analyses (3%/3mm/15% threshold). Two structures were artificially on the TPS dose distribution expected on the phantom by converting the 1.7 and 2.0 Gy isodose levels into structures to represent the treatment. The gel and TPS dose-volume histogram (DVH) were compared based on five dose points: D95%, D90%, D50%, D10%, and D5%. RESULTS Approvals of 93%, 96%, 98%, and 92% were achieved in the 3D gamma analyses for the plans QA 1, 2, 3, and 4. In the DVH analyses, QA plan 1 measured and expected curves showed a good agreement. QA plan 2 showed deviations in the highest doses for both structures with a maximum deviation (Δmax ) of 8.0%. QA plans 3 and 4 showed the highest dose variation between the gel and TPS in the smaller doses of the DVH (Δmax of 7.2% and -8.9%, respectively). For QA plan 4, the curves of the 1.7 Gy structure presented a good agreement, but deviations in the smaller dose region of the DVH occurred for the 2 Gy structure (Δmax of 7.7%). CONCLUSIONS A methodology for 3D dose evaluation of complex SIB treatments was proposed. It provided an important overview of the dose distributions. Their results significantly complemented the usual gamma analysis results.

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

BACKGROUND: The aim of this study was to evaluate the effectiveness of prophylactic corticosteroids to prevent pain flare (PF) in bone metastases treated with radiotherapy performing a meta-analysis of randomized clinical trials (RCT). MATERIALS AND METHODS: RCTs were identified on Medline, Embase, the Cochrane Library, and the proceedings of annual meetings through June 2020. We followed the PRISMA and MOOSE guidelines. A meta-analysis was performed to assess if corticosteroids reduce the PF, pain progression, and the mean of days with PF compared with the placebo. A p-value < 0.05 was considered significant. RESULTS: Three RCTs with a total of 713 patients treated were included. The corticosteroids reduced the occurrence of early PF 20.5% (51/248) versus 32% (80/250) placebo, OR= 0.55 (95% CI: 0.36–0.82, p = 0.002). The mean days of PF were reduced to 1.6 days (95% CI: 1.3–1.9, p = 0.0001). Prophylactic corticosteroids had more patients with no PF and no pain progression, OR = 1.63 (95% CI: 1.14–2.32, p = 0.007). No significant corticosteroids effect was observed for pain progression (p = ns) and late PF occurrence (p = ns). CONCLUSION: Prophylactic corticosteroids reduced the incidence of early PF, the days with PF, resulting in a superior rate of patients with no PF and no pain progression, but with no significant benefit for reducing pain progression or late PF occurrence.

Hepatitis E virus (HEV) is the causative agent of hepatitis E, an emerging public health infection which has an increasing incidence across Europe. Because of the apparent lack of species barriers, HEV was characterized as a zoonotic agent. Swine are recognized as the main reservoir, but HEV is also found in wild animals such as ungulates, lagomorphs, and bats. Our work aimed at detecting the HEV presence in wild fauna in two hunting areas of Northern Italy (Parma and Sondrio areas) with different environmental and anthropic characteristics to investigate its possible role as reservoir. Liver samples were collected from wild boars, red deer, roe deer and chamois, and viral identification was carried out by One-Step RT Real-time PCR. Positive samples were genotyped, and phylogenetic analysis was performed. The virus was found only in the wild boar population, with different prevalence and subtypes in the two areas (14% HEV3a and 1.2% close to HEV3f in Parma and Sondrio, respectively). Wild ruminants seem otherwise to pose a marginal risk. Given the high pig farm density in the Parma area, and expansion of the wild boar population, continuous monitoring of the strains circulating in wildlife is crucial.

Objectives To evaluate tooth movements during maxillary arch expansion with clear aligner treatment. Materials and Methods The study group included 28 subjects (16 females, 12 males, mean age 31.9 ± 5.4 years) collected prospectively from January 2018 to May 2019. Inclusion criteria were European ancestry, posterior transverse discrepancy of 3–6 mm, permanent dentition stage, presence of second permanent molars, mild or moderate crowding, and good compliance with aligners. Treatment protocol included nonextraction strategies, application of Invisalign clear aligner system, and no auxiliaries other than Invisalign attachments. Linear and angular measurements were performed before treatment (T1), at the end of treatment (T2), and on final virtual models (T2 ClinCheck). A paired t-test was used to compare T2-T1 and T2-T2 ClinCheck changes. The level of significance was set at 5%. Results Statistically significant differences were found for all measurements, except for ones at the upper second molars. The greatest increase in maxillary width was detected at the upper first and second premolars: +3.5 mm for the first premolar and +3.8 mm for the second premolar at T2. Comparison of T2-T1 angular outcomes showed statistically significant changes in the inclinations of all teeth except for the second permanent molars. T2-T2 ClinCheck showed significant differences for both linear and angular measurements for maxillary canines, resulting in poor predictability. Conclusions Maxillary arch development revealed a progressive reduction of the expansion rate and buccal tipping in the anterior, lateral, and posterior regions, with the greatest net increase at the first and second premolars. Clinical attention should be paid to maxillary canine movements, and overcorrection should be planned for them during dentoalveolar expansion.

Background Although polychlorinated biphenyls (PCBs) have been classified as human carcinogens for their association with melanoma, few data are available for other skin lesions. Objectives To investigate the prevalence of skin disorders in a highly PCB polluted area in northern Italy, with locally produced food as the main source of human contamination, and evaluate the association between skin lesions and PCB serum levels, taking account of possible confounders. Materials & methods Thirty-three PCB congeners were quantitatively assessed and a total of 189 subjects were equally divided into three groups using the tertiles of total PCB serum concentrations. All subjects underwent a clinical examination and were interviewed on their risk factors and history of skin diseases. Results No statistically significant difference was found in the prevalence of skin cancer, nevi, pigmentary disorders as well as inflammatory and infectious skin diseases among the three PCB exposure groups. It should be noted that the use of questionnaires to assess subjects' past sun exposure and photoprotection is intrinsically flawed due to random error. Conclusions Our study does not support the hypothesis that chronic PCB exposure, through the ingestion of contaminated food, determines an increased risk of developing skin diseases.

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p &lt, 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p &lt, 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation, including pulmonary hypertension (PH). PH may complicate bronchopulmonary dysplasia (BPD) course. Aims of this retrospective study were to assess the feasibility of NPE follow-up of infants with BPD and to describe the course of PH of infants with moderate/severe BPD. Preterm infants32 gestational weeks or birthweight ≤1500 g with moderate/severe BPD underwent NPE follow-up, from 36 weeks postmenstrual age up to 8 months postnatal age. Twenty-three preemies were included (birth weight 840 (213) g, gestational age 26.8 (2.3) weeks); 12/23 developed mild PH, 2/12 after discharge. PH resolved at 8.9 (3.9) months. Clinical and echocardiographic variables did not differ between infants with and without PH, except pulmonary artery acceleration time (PAAT) and PAAT/right ventricle ejection time (RVET) ratio (PAAT: 36 weeks, 68.9 (11.9) vs 52.0 (19.1), p = 0.0443; 6 months: 83.9 (38.9) vs 74.8 (16.9), p = 0.0372). No deaths or admissions for PH were reported. Neonatologist's Image Quality Assessment score attributed by the cardiologist assumed as gold standard was adequate or optimal (9.5/14 total score); inter-rater agreement was excellent (ICC 0.974).Conclusions: NPE follow-up seems to be feasible and safe in both intensive care and outpatient clinic. Mild PH is frequently detected in moderate/severe BPD, with good prognosis. What is Known: • Preterm infants with bronchopulmonary dysplasia (BPD) may develop pulmonary hypertension (PH) and have a late diagnosis. • Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation of the neonate. What is New: • To our knowledge this is the first study of NPE follow-up of moderate/severe BPD, describing the course of mild PH from diagnosis to its resolution. • NPE follow-up of BPD seems to be safe and practicable, in both intensive care and outpatient clinic, as long as neonatologists maintain a sound collaboration with pediatric cardiologists.

Background Recently, low dose radiotherapy delivered to the whole lung has been proposed as treatment for the pneumonia due to COVID-19. Although there is biological plausibility for its use, the evidence supporting its effectiveness is scarce, and the risks associated with it may be significant. Thus, based on a virtual case simulation, we estimated the risks of radiation-induced cancer (RIC) and cardiac disease. Methods Lifetime attributable risks (LAR) of RIC were calculated for the lung, liver, esophagus, and breast of female patients. The cardiovascular risk of exposure-induced death (REID) due to ischemic heart disease was also calculated. The doses received by the organs involved in the treatment were obtained from a simulation of conformal radiotherapy (RT) treatment, delivering a dose of 0.5 Gy–1.5 Gy to the lungs. We considered a LAR and REID 2% unacceptable. Results The lung was at the highest risk for RIC (absolute LAR below 5200 cases/100,000 and 2250 cases/100,000 for women and men, respectively). For women, the breast had the second-highest LAR, especially for young women. The liver and esophagus had LARs below 700/100,000 for both sexes, with a higher incidence of esophageal cancer in women and liver cancer in men. Regarding the LAR cutoff, we observed an unacceptable or cautionary LAR for lung cancer in all women and men 1 Gy. LAR for lung cancer with an RT dose of 1 Gy was cautionary for women >60 years of age and men

Highlights • SARS-CoV-2 cause a wide spectrum of clinical manifestations including acute respiratory distress syndrome (ARDS) manifestation. • Continuous positive airway pressure, or non-invasive ventilation, and invasive ventilatory support are often required to manage the acute respiratory failure in COVID-19 patients. • Temperature >38 °C, LDH > 250 U/L and d-dimer >1000 ng/ml resulted to be indipendent risk factors for non invasive/invasive ventilator support requirement. • An early inflammatory screening should be warranted in order to stratify the illness severity and provide an appropriate treatment., Objectives To investigate risk factors for non-invasive/invasive-ventilatory support (NI/I-VS) in Coronavirus diseases 2019 (COVID-19) patients. Methods All consecutive patients admitted, from February 25 to April 25, 2020, to the Infectious Diseases Unit and Intensive Care Unit of Santa Maria Annunziata Hospital (Florence, Italy) with confirmed COVID-19 diagnosis were enrolled in this retrospective cohort study. NI/I-VS was defined as need for continuous positive airway pressure (CPAP) or bilevel positive pressure non-invasive ventilation (BPAP) or mechanical ventilation (MV) than low-flow systems oxygen-therapy as Venturi Mask (VM) or nasal cannula. Results Ninety-seven patients were enrolled; 61,9% (60/97) were male, median age was 64 years; intra-hospital mortality was 9.3%. Thirty five out of 97 (36%) patients required ICU admission and 94.8% (92/97) were prescribed oxygen-therapy: 10.8% (10/92) with nasal cannula, 44.5% (41/92) with VM, 31.5% (29/92) with CPAP, 2.2% (2/92) with BPAP and 10.8% (10/92) underwent intubation for MV. Patients with body mass index >30, type II diabetes mellitus and presenting at the admission with dyspnoea, asthenia, SOFA score ≥2 points, PaO2/FiO2 38 °C, increased levels of lactate dehydrogenase (LDH), alanine aminotransferase, C-reactive protein and a d-dimer >1000 ng/ml underwent more frequently NI/I-VS at the univariate analysis. Multivariate logistic regression analysis confirmed temperature >38 °C (odds ratio [OR] 21.2, 95% confidential interval [95%CI] 3.5-124.5, p = 0.001), LDH > 250 U/L (OR 15.2, 95%CI 1.8-128.8, p = 0.012) and d-dimer >1000 ng/ml (OR 4.5, 95%CI 1.2-17.3, p = 0.027) as significantly associated with NI/I-VS requirement. A non-significant trend (p = 0.051) was described for PaO2/FiO2 38 °C, LDH > 250 U/L and d-dimer >1000 ng/ml resulted to be indipendent risk factors for NI/I-VS in COVID-19 patients. In order to quickly recognize patients likely at risk to develop a critical illness, inflammatory markers assessment should be warranted upon hospital admission.

The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

Biodegradable chitosan films were produced using lactic and acetic acid solutions and glutaraldehyde as crosslinking agent by casting technique. The aim of this study was to evaluate the influence of different acids and the crosslinking on the characteristics and biodegradability of chitosan films. The films were analyzed through thickness, swelling degree, mechanical and thermal properties, chemical structure and biodegradability. The glutaraldehyde release was also evaluated. All films’ properties are deeply affected by the acid type and glutaraldehyde crosslinking. Crosslinking reduced the swelling degree of films, also increasing their fragility. The glutaraldehyde release from the films to the simulant solutions was not observed after the incubation period. Through biodegradation tests, it was observed that the crosslinking does not prevent films’ degradability but longer time is required. The qualitative analysis of ecotoxicity of the films suggests the possibility of composting the developed films. The films presented potential for application as membranes and in packaging, and different formulations can be used according to the desired final characteristics.

PURPOSE To investigate the role of consolidation radiotherapy (cRT) in advanced-stage Hodgkin lymphoma (HL) presenting at baseline with a large nodal mass (LNM) in complete metabolic response after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. PATIENTS AND METHODS Advanced-stage (IIB-IVB) HL patients, enrolled in the HD 0607 trial (Clinicaltrial.gov identifier NCT00795613 ), with both a negative PET after two (PET-2) and six (PET-6) ABVD cycles, who presented at baseline with an LNM, defined as a nodal mass with the largest diameter ≥ 5 cm, were prospectively randomly assigned to receive cRT over the LNM or no further treatment (NFT). RESULTS Among 296 randomly assigned patients, the largest diameter of LNM at baseline was 5-7 cm in 101 (34%; subgroup A) and 8-10 cm in 96 (32%; subgroup B), whereas classic bulky (diameter > 10 cm) was detected in 99 (33%; subgroup C). Two hundred eighty patients (88%) showed a postchemotherapy RM. The median dose of cRT was 30.6 Gy (range, 24-36 Gy). After a median follow-up of 5.9 years (range, 0.5-10 years), the 6-year progression-free survival rate of patients who underwent cRT or NFT was, respectively, 91% (95% CI, 84% to 99%) and 95% (95% CI, 89% to 100%; P = .62) in subgroup A; 98% (95% CI, 93% to 100%) and 90% (95% CI, 80% to 100%; P = .24) in subgroup B; 89% (95% CI, 81% to 98%) and 86% (95% CI, 77% to 96%; P = .53) in subgroup C (classic bulky). CONCLUSION cRT could be safely omitted in patients with HL presenting with an LNM and a negative PET-2 and PET-6 scan, irrespective from the LNM size detected at baseline.

Background/Aims: Curing Helicobacter pylori infection remains challenging for clinicians, as no proposed first-line therapy achieves bacterial eradication in all treated patients so that several patients need two or more consecutive treatments. Bacterial culture with antibiotics susceptibility testing is largely unachievable in Italy, and empiric second-line and rescue therapies are generally used. This study aimed to identify what eradication regimens perform better in Italy, following first-line therapy failure. Methods: We performed a literature search on PubMed for studies on standard therapy regimens used as second-line or rescue treatments performed in adult patients. Studies including modified drug combinations were not considered. Both intention-to-treat and per- protocol analyses were computed for each therapy subgroup. Results: Data from 35 studies with a total of 4830 patients were eventually considered. As a second-line therapy, Pylera® (90.6%) and a sequential regimen (89.8%) achieved eradication rates significantly higher than other therapies. For third-line therapy, a levofloxacin-based regimen and Pylera® achieved comparable eradication rates (88.2% vs. 84.7%; p = 0.2). Among therapies used as fourth (or more) attempts, Pylera® and a rifabutin-based therapy achieved 77.4% and 66.4% cure rates, respectively (p = 0.013). A therapy sequence based on the type of first-line therapy used was proposed. Conclusions: Data obtained through our review indicate that standard therapies for H. pylori eradication can be used when following an appropriate sequence, allowing clinicians to improve the cure rate without resorting to bacterial culture.

Background Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested. Methods We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters. Results We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV. Conclusions HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations. Trial registration NCT04411459.

Background Prone positioning (PP) has been used to improve oxygenation in patients affected by the SARS-CoV-2 disease (COVID-19). Several mechanisms, including lung recruitment and better lung ventilation/perfusion matching, make a relevant rational for using PP. However, not all patients maintain the oxygenation improvement after returning to supine position. Nevertheless, no evidence exists that a sustained oxygenation response after PP is associated to outcome in mechanically ventilated COVID-19 patients. We analyzed data from 191 patients affected by COVID-19-related acute respiratory distress syndrome undergoing PP for clinical reasons. Clinical history, severity scores and respiratory mechanics were analyzed. Patients were classified as responders (≥ median PaO2/FiO2 variation) or non-responders (2/FiO2 variation) based on the PaO2/FiO2 percentage change between pre-proning and 1 to 3 h after re-supination in the first prone positioning session. Differences among the groups in physiological variables, complication rates and outcome were evaluated. A competing risk regression analysis was conducted to evaluate if PaO2/FiO2 response after the first pronation cycle was associated to liberation from mechanical ventilation. Results The median PaO2/FiO2 variation after the first PP cycle was 49 [19–100%] and no differences were found in demographics, comorbidities, ventilatory treatment and PaO2/FiO2 before PP between responders (96/191) and non-responders (95/191). Despite no differences in ICU length of stay, non-responders had a higher rate of tracheostomy (70.5% vs 47.9, P = 0.008) and mortality (53.7% vs 33.3%, P = 0.006), as compared to responders. Moreover, oxygenation response after the first PP was independently associated to liberation from mechanical ventilation at 28 days and was increasingly higher being higher the oxygenation response to PP. Conclusions Sustained oxygenation improvement after first PP session is independently associated to improved survival and reduced duration of mechanical ventilation in critically ill COVID-19 patients.

Background and aims Helicobacter pylori prevalence remains high worldwide, especially in developing areas where infection acquisition occurs in early childhood. H. pylori eradication fails in a definite number of patients, despite one or more therapeutic attempts. Curing these patients is progressively more difficult, due to development of antibiotic resistance. While the cure rate of first-line therapies in foreigners was found to be different from that of Italians, no data are available on rescue therapies. Materials and methods Consecutive foreigner patients with H. pylori infection following at least one therapy failure were enrolled. All patients underwent upper endoscopy with gastric biopsies used for both histologic examination and culture/susceptibility test. Rescue therapies administered accordingly to susceptibility testing were rifabutin-based therapy, levofloxacin-based therapy, sequential. Pylera was prescribed regardless the resistance pattern. Results A total of 103 (M/F: 27/76, mean age: 41.9 y, range: 18 to 85) were enrolled. The overall resistance rates toward clarithromycin, metronidazole, and levofloxacin were 76.7%, 66%, and 42.7%, respectively, with triple resistance present in 33.9% of bacterial isolates. Eradication rates were 71.4% on 40 patients for rifabutin-based therapy, 82.8% on 42 cases for levofloxacin-based therapy, 75% on 11 patients treated with sequential therapy, and 100% on 10 cases who received Pylera regimen. Conclusions To our knowledge, this is the first study assessing H. pylori eradication rates in foreigner patients, who failed at least one therapeutic attempt, managed in Italy. Even by using a culture-based approach, the infection was not cured in a definite number of patients.

Introduction: Few data on the diagnostic performance of serological tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are currently available. We evaluated sensitivity and specificity of five different widely used commercial serological assays for the detection of SARS-CoV-2–specific IgG, IgM, and IgA antibodies using reverse transcriptase-PCR assay in nasopharyngeal swab as reference standard test.Methods: A total of 337 plasma samples collected in the period April–June 2020 from SARS-CoV-2 RT-PCR positive (n = 207) and negative (n = 130) subjects were investigated by one point-of-care lateral flow immunochromatographic assay (LFIA IgG and IgM, Technogenetics) and four fully automated assays: two chemiluminescence immunoassays (CLIA-iFlash IgG and IgM, Shenzhen YHLO Biotech and CLIA-LIAISON® XL IgG, DiaSorin), one electrochemiluminescence immunoassay (ECLIA-Elecsys® total predominant IgG, Roche), and one enzyme-linked immunosorbent assay (ELISA IgA, Euroimmune).Results: The overall sensitivity of all IgG serological assays was >80% and the specificity was >97%. The sensitivity of IgG assays was lower within 2 weeks from the onset of symptoms ranging from 70.8 to 80%. The LFIA and CLIA-iFlash IgM showed an overall low sensitivity of 47.6 and 54.6%, while the specificity was 98.5 and 96.2%, respectively. The ELISA IgA yielded a sensitivity of 84.3% and specificity of 81.7%. However, the ELISA IgA result was indeterminate in 11.7% of cases.Conclusions: IgG serological assays seem to be a reliable tool for the retrospective diagnosis of SARS-CoV-2 infection. IgM assays seem to have a low sensitivity and IgA assay is limited by a substantial rate of indeterminate results.

Mercury (Hg) contamination in the Gulf of Trieste (northern Adriatic Sea) due to mining activity in Idrija (Slovenia) still represents an issue of environmental concern. The Isonzo/Soča River’s freshwater inputs have been identified as the main source of Hg into the Gulf, especially following periods of medium-high discharge. This research aims to evaluate the occurrence and distribution of dissolved (DHg) and particulate (PHg) Hg along the water column in the northernmost sector of the Gulf, a shallow and sheltered embayment suitable for the accumulation of fine sediments. Sediment and water samples were collected under unperturbed and perturbed environmental conditions induced by natural and anthropogenic factors. Mercury in the sediments (0.77–6.39 µg g−1) and its relationship to grain size were found to be consistent with previous research focused on the entire Gulf, testifying to the common origin of the sediment. Results showed a notable variability of DHg (&lt, LOD–149 ng L−1) and PHg (0.39–12.5 ng L−1) depending on the interaction between riverine and marine hydrological conditions. Mercury was found to be mainly partitioned in the suspended particles, especially following periods of high discharge, thus confirming the crucial role of the river inputs in regulating PHg distribution in the Gulf.

Highlights • Narsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage, reducing thrombotic risk. • All patients treated with narsoplimab, a lectin-pathway inhibitor, improved and survived without any drug-related adverse events., In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway’s effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.

Helicobacter pylori (H. pylori) eradication fails in a definite amount of patients despite one or more therapeutic attempts. Curing these patients is progressively more difficult, due to development of antibiotic resistance. Current guidelines suggest testing antibiotic susceptibility in H. pylori isolates following two therapeutic attempts. Aim: to evaluate the development of antibiotic resistance, MIC values trends and therapeutic outcomes in patients who failed at least one H. pylori eradication therapy. Methods: consecutive patients, referred to perform upper gastrointestinal endoscopy (UGIE) to our Unit from January 2009 to January 2019 following at least one therapeutic attempt were considered. Bacterial resistance towards clarithromycin, metronidazole and levofloxacin was tested. Patients received either a susceptibility-guided therapy or Pylera&reg, Results: a total of 1223 patients were H. pylori positive, and antibiotic susceptibility was available for 1037. The rate of antibiotic resistance and MIC values significantly increased paralleling the number of previous therapeutic attempts. Eradication rates of antibiogram-tailored therapies remained stable, except for the sequential therapy if used as a third line. As a rescue treatment, the Pylera&reg, therapy achieved cure rates comparable to those of the other culture-guided therapies. Conclusions: A significant increase in the secondary resistance towards the three tested antibiotics was observed, both as rate and MIC values, in correlation with the number of therapy failures. These findings should be considered when administering an empirical second-line therapy. Pylera&reg, therapy eradication rates are comparable to culture-tailored therapies.

There are no evidence-based recommendations for performing upper gastrointestinal endoscopy (UGIE) in patients with extra-oesophageal symptoms of gastro-oesophageal reflux disease (GORD). However, UGIEs are often performed in clinical practice in these patients. We aimed to assess the prevalence of gastro-oesophageal lesions in patients with atypical GORD symptoms.Patients complaining of at least one extra-oesophageal GORD symptom and undergoing UGIE in seven centres were prospectively enrolled. Clinically relevant lesions (Barrett's oesophagus, erosive oesophagitis, gastric precancerous conditions, peptic ulcer, cancer, andTwo hundred eleven patients were enrolled (male/female: 74/137; mean age: 55.5 ± 14.7 years). Barrett's oesophagus was detected in 4 (1.9%), erosive oesophagitis in 12 (5.7%), gastric precancerous conditions in 22 (10.4%), andClinically relevant lesions are uncommon among young (≤50 years) patients with extra-oesophageal GORD symptoms. Hiatal hernia is not more prevalent in patients with cardiologic symptoms and suspicion of GORD. The usefulness of UGIE in these patients is questionable.Não existem recomendações baseadas na evidencia para realização de endoscopia digestiva alta (EDA) em doentes com sintomas extra-esofágicos da doença de refluxo gastroesofágico (DRGE). No entanto, EDAs são frequentemente realizadas na orientação clínica destes doentes. O nosso objectivo foi a valiar a prevalência de lesões gastro-esofágicas em doentes com sintomas atípicos de DRGE.Doentes com pelo menos um sintoma extra-esofágico de DRGE e que realizaram EDA em 7 centros foram prospectivamente recrutados. Lesões clinicamente relevantes (esófago de Barrett, esofagite erosiva, condições pré-malignas gástricas, úlcera péptica, cancro e infecção H. pylori) foram estatisticamente comparadas entre os grupos tendo em conta sintomas de DRGE (atípicos vs. quer típicos e atípicos), tipo de sintomas atípicos, idade e presenta de hérnia do hiato.Duzentos e onze doentes foram recrutados (H/M: 74/137; Idade média: 55.5 ± 14.7 anos). Esófago de Barrett foi detetado em 4 (1.9%), esofagite erosiva em 12 (5.7%), condições pré-malignas gástricas em 22 (10.4%) e infeção H. pylori em 38 (18%) doentes. A prevalência de lesões clinicamente relevantes foi inferior em doentes com apenas sintomas atípicos (28.6 vs. 42,5%; p = 0.046; teste de qui-quadrado), doentes com50 anos (20 vs. 44.8%; p = 0.004; teste de qui-quadrado), e nos doentes medicados com iniciadores da bomba de protões (IBP) (21.1 vs.40.2%; p = 0.01; teste de qui-quadrado). Nenhuma lesáo clinicamente relevante foi detectada nos doentes com50 anos, sem sintomas de alarme e medicados com IBP. Hérnia do hiato foi diagnosticada apenas em 6 doentes com sintomas do tipo cardíaco e em 41 com sintomas ORLs (11.3 vs. 35.1%; p = 0.03; teste de qui-quadrado).Lesões clinicamente relevantes são incomuns em doentes jovens com sintomas extra-esofágicos de DRGE. Hérnia do hiato não é mais prevalente em doentes com sintomas do tipo cardíaco e suspeita de DRGE. A utilidade da EDA nestes doentes é discutível.

Bacterial resistance toward the most used antibiotics is increasing in Helicobacter pylori strains worldwide. Emergence of multidrug resistance significantly affects the efficacy of standard therapy regimens. Therefore, monitoring for primary antimicrobial resistance is essential for H. pylori management in clinical practice.H. pylori isolates obtained from patients consecutively observed in a single center were tested for primary resistance by using E-test method. Bacterial strains showing MIC values 0.5, 8 and 1 mg/L toward clarithromycin, metronidazole and levofloxacin, respectively, were considered resistant. The trend of antibiotic prevalence, either single or combined, during 2010-2016 was assessed.Antibiotic susceptibility data were available in 1424 (82.3%) out of 1730 tested patients. The overall resistance for all the three antibiotics showed an increasing trend from 2010 to 2013 (clarithromycin: from 19% to 35.6%; metronidazole: from 33.6% to 45.3%; levofloxacin: from 19% to 29.7%; p .001), when a plateau until 2016 was observed (clarithromycin: 35.9%; metronidazole: 40.2%; levofloxacin: 29.3%). A similar trend occurred for clarithromycin-metronidazole combined resistance rate (2010: 11.4%; 2013: 28.2%; 2016: 21.9%).Our data suggest that prevalence of primary resistance in H. pylori isolates toward the most frequently used antibiotics probably reached a plateau in the last years.

Sars-Cov-2 has been the subject of study in the most diverse medical fields, since the pandemic began in China in late 2019. According to the American College of Cardiology, individuals with comorbid conditions have a hospitalization rate of 50%, when affected by COVID-19. It is observed that patients with comorbidities, such as arterial hypertension and diabetes, in addition to elderly individuals, have a higher rate of hospitalization due to the infection of the new coronavirus, as well as the aforementioned case. In view of the current pandemic and a disease still under investigation, all information about the clinic, treatment, complementary exams and patient monitoring can generate better knowledge about the characteristics of the infection and the development of treatment protocols. Therefore, with pharmacological management still uncertain, the use of antivirals, such as Oseltamivir, anticoagulants and 3rd generation cephalopsorins, have created positive perspectives regarding the prognosis of patients infected with Sars-Cov-2. Therefore, with pharmacological management still uncertain, the use of antivirals, such as Oseltamivir, anticoagulants and 3rd generation cephalopsorins, have created positive perspectives regarding the prognosis of patients infected with Sars-Cov-2.

We assessed the prognostic meaning of very early (

OBJECTIVE To assess the overall survival (OS) and prognostic factors in patients with cervix cancer treated by different modalities. MATERIAL AND METHODS The authors studied a cohort of patients with cervix cancer International Federation of Gynecology and Obstetrics stage I-IVa treated in the last 15 years. Patients were treated with surgery followed by radiotherapy (S+RT), or surgery plus chemoradiation (S+CRT), or radiotherapy alone (RT), or chemoradiation alone (CRT). Univariate and multivariate analyses were conducted to identify significant prognostic factors (P

Background Infectious bursal disease (IBD), also known as Gumboro disease, is a viral infection that causes mortality and immunosuppression in chickens (Gallus gallus). VP2 and VP3 are the major structural viral capsid components and are the most immunogenic proteins of IBD virus (IBDV). Reliable diagnostic tests using VP2 and VP3 produced in heterologous systems are important tools to control this infection. One advantage of an IBD diagnostic based on VP3, over those that use VP2, is that VP3 has linear epitopes, enabling its production in bacteria. Results We tested the suitability of recombinant VP3 (rVP3) as a diagnostic reagent in an enzyme-linked immunosorbent assay (ELISA). Compared with a commercial test, rVP3 ELISA showed high sensitivity and specificity as a diagnostic tool for vaccinated animals. In addition, rVP3, but not the commercial ELISA, was able to detect antibodies in nonvaccinated chickens, probably developed against circulating IBDV strains. It was possible the assessment of VP3 regions antigenicity using chicken antisera. Conclusions The full-length recombinant VP3 can be used to assess post vaccination immunological status of chickens and its production is feasible and inexpensive. The evaluation of VP3 regions as candidates for general use in the diagnosis of IBD in chickens should be conducted with caution. Our work was the first to identify several regions of VP3 recognized by chicken antibodies.

The SARS-CoV-2 spike (S) protein is exposed on the viral surface and is the first point of contact between the virus and the host. For these reasons it represents the prime target for Covid-19 vaccines. In recent months, variants of this protein have started to emerge. Their ability to reduce or evade recognition by S-targeting antibodies poses a threat to immunological treatments and raises concerns for their consequences on vaccine efficacy.To develop a model able to predict the potential impact of S-protein mutations on antibody binding sites, we performed unbiased multi-microsecond molecular dynamics of several glycosylated S-protein variants and applied a straightforward structure-dynamics-energy based strategy to predict potential changes in immunogenic regions on each variant. We recover known epitopes on the reference D614G sequence. By comparing our results, obtained on isolated S-proteins in solution, to recently published data on antibody binding and reactivity in new S variants, we directly show that modifications in the S-protein consistently translate into the loss of potentially immunoreactive regions. Our findings can thus be qualitatively reconnected to the experimentally characterized decreased ability of some of the Abs elicited against the dominant S-sequence to recognize variants. While based on the study of SARS-CoV-2 Spike variants, our computational epitope-prediction strategy is portable and could be applied to study immunoreactivity in mutants of proteins of interest whose structures have been characterized, helping the development/selection of vaccines and antibodies able to control emerging variants.

Specific memory B cells and antibodies are reliable read-out of vaccine efficacy. We analyzed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly-specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase thus predicting a sustained protection from COVID-19. Graphical Abstract

Summary Objective The objective of this study was to analyse the soft tissue changes produced by the functional treatment of mandibular advancement in growing Class II patients. Materials The treated group consisted of 25 Caucasian patients (12 females and 13 males) with dento-skeletal Class II malocclusion treated with functional therapy (Activator). All patients were evaluated before treatment (T1; mean age, 9.9 years), at the end of functional treatment phase (T2; mean age, 11.9 years), and at a post-pubertal follow-up observation (T3; mean age, 18.5 years). The treated group was compared with a matched control group of 25 untreated subjects (13 females, 12 males) with untreated Class II division 1 malocclusion. Statistical comparisons between the two groups were performed with independent samples t-tests (P < 0.05). Results Significant improvements were found during the long-term interval for mandibular sulcus (9.9°) and the profile facial angle (9.8°) in the treated group. No significant effects were found in terms of lower face percentage between the two groups. Conclusion Removable functional appliances induced positive effects on the soft tissue profile in Class II growing subjects with good stability in the long-term.

To observe the prevalence of contamination by hepatitis A virus (HAV) and norovirus (NoV) in different food types, 9242 samples were analyzed over a 6-year period (January 2014–December 2019). Samples were from routine official activities by Competent Authorities (CAs) and Food Business Operators, according to Hazard Analysis and Critical Control Points plans. Analyses were performed in accordance with European and Italian regulations. Food types were obtained from different production areas of Italy, and ranged from mollusks, ready-to-eat (RTE) and packaged vegetables, frozen berries, tap water, fruit and RTE fruit salads, and processed and preserved foods. No risk management plans were set by the authors’ laboratory, because they were still adopted by conferring customers. Analyses were conducted according to ISO/TS 15216-2:2013 (ISO in Part 2: Method for Qualitative Detection. International Organization for Standardization, Geneva, 2013). The data showed that 2.25% (95% CI: 2.0–2.6) of samples were contaminated by at least one virus type, and that the most detected pathogen was NoV GII (89.50% of all positives). Mollusks (filter-feeding animals) were the most contaminated category (92.31% of all positives) not only by NoV or HAV individually, but also by multiple HAV/NoV contaminations consisting of 22.59% of all positives. For NoV, there was a significant correlation between shellfish positivity and season, with the autumn–winter period being the most associated with risk. Conversely, berries, drinking water and RTE vegetables, previously linked to several outbreaks, showed a low rate of contamination. These results from data collection have implications for the improvement of sampling plans for HAV and NoV by Italian CAs, and by food-producing and distribution operators. Moreover, these findings obtained by a standardized qualitative method contribute the collection of data aimed at establishing new microbiological criteria not yet foreseen (but advocated) by current European rules.

In this ecological study, we investigated spatial patterns of human visceral leishmaniasis (VL) incidence, its correlation with socioeconomic aspects, environmental indices (obtained through remote sensing) and canine VL during 2011–2016 in the municipality of Rondonopolis, a relevant endemic area for VL in Central-Western Brazil. Human VL cases were georeferenced and point patterns were analyzed by univariate Ripley's K function and Kernel density estimation (KDE). Poisson-based scan statistics were used to investigate spatial and spatiotemporal clusters of human VL incidence at the neighborhood level. Socioeconomic and environmental characteristics were compared between neighborhoods within and outside spatial human VL clusters. Also, we assessed the correlation between smoothed human VL incidence and canine VL seropositivity rates within and between neighborhoods. Human VL cases were clustered up to 2000 m; four hotspots were identified by KDE in peripheral areas. Spatial and spatiotemporal low-risk clusters for human VL were identified in central and southern areas. Neighborhoods within spatial low-risk cluster presented higher mean income, literacy rate, sanitary sewage service coverage and lower altitude, compared to the rest of the municipality. A positive correlation was found between the occurrence of human and canine VL. On the northern outskirts, high human VL incidence was spatially correlated with high canine VL seropositivity in surrounding neighborhoods. In conclusion, human VL demonstrated a heterogeneous, aggregated and peripheral spatial pattern. This distribution was correlated with intra-urban socioeconomic differences and canine VL seropositivity at the neighborhood level.