Efficacy and safety of the sofosbuvir/velpatasvir combination for the treatment of patients with early mild to moderate COVID-19

: SARS-CoV-2 is still a health problem worldwide despite the availability of vaccines. Therefore, there is a need for effective and safe antiviral. SARS-CoV-2 and HCV necessitate RNA-dependent RNA polymerase (RdRp) for replication; therefore, it has been hypothesized that RdRp inhibitors used to treat HCV may be effective treating SARS-CoV-2. Accordingly, we evaluated the effect of the sofosbuvir/velpatasvir (SOF/VEL) combination in early SARS-CoV-2 infection. A multicenter case-control study was conducted, enrolling 120 patients with mild or moderate COVID-19, of whom 30, HCV coinfected or not, received SOF/VEL tablets (400/100 mg) once daily for 9 days within a median of 6 days from the beginning of infection and 90 controls were treated with standard care. The primary endpoint was the effect on viral clearance, and the secondary endpoint was the improvement of clinical outcomes. Nasal swabs for SARS-CoV-2 by PCR were performed every 5-7 days. Between 5-14 days after starting SOF/VEL treatment, SAS-CoV-2 clearance was observed in 83% of patients, while spontaneous clearance in the control was 13% (p < 0.001). An earlier SARS-CoV-2 clearance was observed in the SOF/VEL group than in the control group (median 14 vs 22 days, respectively, p < 0.001) also when the first positivity was considered. None of the patients in the SOF/VEL group showed disease progression, while in the control group, 24% required more intensive treatment (high flow oxygen or noninvasive/invasive ventilation), and one patient died (p < 0.01). No significant side effects were observed in the SOF/VEL group. Early SOF/VEL treatment in mild/moderate COVID-19 seems to be safe and effective for faster elimination of SARS-CoV-2 and to prevent disease progression

AIM2 Inflammasome Activation Leads to IL-1α and TGF-β Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells

Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide and its prevalence is increasing. The progressive decline of lung function and airway remodelling are a consequence of chronic inflammatory responses. It was recently postulated the involvement of the inflammasome in COPD, although the underlying mechanism/s still need to be elucidated. Therefore, we isolated peripheral blood mononuclear cells (PBMCs) from exacerbated/unstable COPD patients. The stimulation of PBMCs with an AIM2 inflammasome activator, Poly dA:dT, led to IL-1α, but not IL-1β, release. The release of this cytokine was caspase-1- and caspase-4-dependent and correlated to higher levels of 8-OH-dG in COPD compared to non-smoker and smoker-derived PBMCs. Interestingly, AIM2-depedent IL-1α release was responsible for higher TGF-β levels, crucial mediator during pro-fibrotic processes associated to COPD progression. In conclusion, our data highlight the involvement of AIM2/caspase-1/caspase-4 in IL-1α-induced TGF-β release in unstable COPD-derived PBMCs, opening new therapeutic perspectives for unstable COPD patients

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN)

Background Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. Methods This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed >= 12, and proximal and distal free resection margins length >= 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. Results A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to infinity). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to infinity). Conclusions Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection

Etest® versus broth microdilution for ceftaroline MIC determination with Staphylococcus aureus: results from PREMIUM, a European multicentre study

Objectives: To compare the concordance of ceftaroline MIC values 24 by reference broth microdilution (BMD) and Etest (BioMérieux, France) for MSSA and MRSA isolates, respectively, in isolates from PREMIUM (D372SL00001), a European multi-centre study.  Methods: Ceftaroline MICs were determined by reference BMD and by Etest for 1,242 MSSA and MRSA from adult patients with community-acquired pneumonia or complicated skin and soft tissue infections collected between February and May 2012; tests were performed across six European laboratories. Selected isolates with ceftaroline resistance in broth (MIC >1 mg/L) were retested in three central laboratories to confirm their behaviour.  Results: Overall concordance between BMD and Etest was good, with >97% essential agreement and >95% categorical agreement. Nevertheless, 12 of the 26 MRSA isolates found resistant by BMD scored as susceptible by Etest, with MICs ≤1 mg/L, thus counting as very major errors, whereas only five of 380 MRSA found ceftaroline susceptible in BMD were mis-categorised as resistant by Etest. Twenty-one of the 26 isolates with MICs of 2 mg/L by BMD were then re-tested twice by each of three central laboratories: BMD MICs of 2 mg/L were consistently found for 19 of the 21 isolates. Among 147 Etest results for these 21 isolates (original plus six repeats per isolate) 112 were >1 mg/L.  Conclusions: BMD and Etest have good overall agreement for ceftaroline against Staphylococcus aureus; nevertheless, reliable Etest-based discrimination of the minority of ceftaroline-resistant (MIC 2 mg/L) MRSA is extremely challenging, requiring careful reading of strips, ideally with duplicate testing

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Quantum mechanical computations and spectroscopy: From small rigid molecules in the gas phase to large flexible molecules in solution

Interpretation of structural properties and dynamic behavior of molecules in solution is of fundamental importance to understand their stability, chemical reactivity, and catalytic action. While information can be gained, in principle, by a variety of spectroscopic techniques, the interpretation of the rich indirect information that can be inferred from the analysis of experimental spectra is seldom straightforward because of the subtle interplay of several different effects, whose specific role is not easy to separate and evaluate. In such a complex scenario, theoretical studies can be very helpful at two different levels: (i) supporting and complementing experimental results to determine the structure of the target molecule starting from its spectral properties; (ii) dissecting and evaluating the role of different effects in determining the observed, spectroscopic properties. This is the reason why computational spectroscopy is rapidly evolving from a highly specialized research field into a versatile and widespread tool for the assignment of experimental spectra and their interpretation in terms of chemical physical effects. In such a situation, it becomes important that both computationally and experimentally oriented chemists are aware that new methodological advances and integrated computational strategies are available, providing reliable estimates of fundamental spectral parameters not only for relatively small molecules in the gas phase but also for large and flexible molecules in condensed phases.In this Account, we review the most significant methodological contributions from our research group in this field, and by exploiting some recent results of their application to the computation of IR, UV-vis, NMR, and EPR spectral parameters, we discuss the microscopic mechanisms underlying solvent and vibrational effects on the spectral parameters.After reporting some recent achievements for the study of excited states by first principle quantum mechanical approaches, we focus on the treatment of environmental effects by means of mixed discrete-continuum solvent models and on effective methods for computing vibronic contributions to the spectra. We then discuss some new developments, mainly based on time-dependent approaches, allowing us to go beyond the determination of spectroscopic parameters toward the simulation of line widths and shapes.Although further developments are surely needed to improve the accuracy and effectiveness of several items in the proposed approach, we try to show that the first important steps toward a direct. comparison between the results obtained in vitro and those obtained in silico have been made, making easier fruitful crossovers among experiments, computations and theoretical models, which would be decisive for a deeper understanding of the spectral behavior associated with complex systems and processes

Experiences of Italian surgical residents in low-income countries: an analysis from the Italian Polyspecialistic Society of Young Surgeons (SPIGC)

BACKGROUND: Surgery is a developing sector of global health; the insufficient number of surgeons seems to be the primary problem in low-income countries. International experiences in low-income countries are advocated from students and residents, lack of tutoring and different kind of surgeries represent obstacles for the training. The Italian Polyspecialistic Society of Young Surgeons (SPIGC) administered a survey to young surgeons and surgical residents, to examine the reasons they become involved in global surgery during residency and the impact of their experiences on the surgical training. METHODS: A 23-item, anonymous electronic questionnaire was administered to Italian surgical residents and young surgeons (≤40 years of age), coming from any surgical specialty. The study was conducted during January 2020. The study design guaranteed anonymity. RESULTS: All respondents (100%) recommended the experience in the low-income country, and none recommended spending time during the residency in a different way. Moreover, 83% of respondents judged their training as improved. CONCLUSIONS: This is the first Italian survey regarding global surgery experiences in relation to surgical residency. Our results show how Italian medical doctors who travelled in low-income countries during residency recommend this experience to improve knowledge. Surgical residents’ experience in low-income countries should grow, Italian residents are satisfied, and the training should be standardized

Radiological assessment of anal cancer: an overview and update

Anal cancer is uncommon neoplasm with an incidence of 2 new cases per 100,000 per year in the USA, accounting approximately 0.4 % of all tumors and 2.5 % of gastrointestinal malignancies. An early detection of the anal cancer is crucial for the patient management, whereas the diagnosis at an early stage allows conservative management with sphincter sparing, on the contrary a delays in diagnosis might lead to an advance cancer stage at presentation with worst survival. According to National Comprehensive Cancer Network (NCCN) Anal Carcinoma guidelines the patients should be subjected to a careful clinical examination, including a digital rectal examination (DRE), an anoscopic examination, and palpation of inguinal nodes. The guidelines recommended for the assessment of T stage, only a clinical examination, while the role of imaging techniques, as Magnetic Resonance imaging (MRI) is limited to the identification of regional nodes. Instead, the endoanal ultrasound (EAUS) is not recommended. This paper presents an overview and some updates about 3D EAUS and MRI in detection, staging and assessment post therapy of anal cancer patients

Radiological patterns and pulmonary function values of lung involvement in primary Sjögren's syndrome: A pilot analysis

Background: Lung involvement in primary Sjögren's syndrome (pSS) may vary from 9 to 90%. Interstitial lung disease and tracheobronchial alterations are the most typical findings. The evidence of primarily emphysematous changes at computed tomography of the chest of pSS patients has occasionally been described but poorly characterized. This study aims to assess pulmonary involvement and the impact on respiratory function in a cohort of pSS patients. Materials and methods: A total of 22 consecutive patients diagnosed with pSS underwent pulmonary function tests to investigate the presence of ventilatory impairment and evaluate the exchanges of alveolar gases. All patients underwent a chest high-resolution computed tomography (HRTC). Results: Dynamic volumes were within the normal range in 21 patients (95.4%). A reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) was observed in 18 patients (81.8%). Ten (45.5%) patients showed a mild degree deficit, while 8 patients (36%) showed a moderate degree deficit. Analysis of DLCO revealed a significant difference between pSS patients and controls [t(30.98) = -10.77; p < 0.001], showing a higher DLCO value for the healthy controls (mean ± SE; 101.27 ± 6.08) compared to pSS patients (mean ± SE; 65.95 ± 12.78). Emphysema was found in 21 (94.5%) patients and was the most widespread pulmonary injury. Tracheal thickness was reduced in 15 (67%) patients. Micronodules were observed in 10 (45%) patients in all the pulmonary fields. Bronchial wall thickening and bronchiectasis were observed in 8 (36%) patients, mainly in the lower lobes. Ground glass was found in 5 (22.5%) patients in lower and higher lobes. Cysts were observed in two patients (9%). Conclusion: The reduction of the DLCO could be related to early emphysematous alterations in the absence of spirometric alterations and relevant respiratory symptoms. In conclusion, emphysema might be seen as an early pulmonary involvement mark in patients suffering from pSS