Intermediate dose enoxaparin in hospitalized patients with moderate-severe COVID-19: a pilot phase II single-arm study, INHIXACOVID19.

BACKGROUND: Randomized clinical trials in non-critically ill COVID-19 patients showed that therapeutic-dose heparin increased survival with reduced organ support as compared with usual-care thromboprophylaxis, albeit with increased bleeding risk. The purpose of the study is to assess the safety of intermediate dose enoxaparin in hospitalized patients with moderate to severe COVID-19. METHODS: A phase II single-arm interventional prospective study including patients receiving intermediate dose enoxaparin once daily according to body weight: 60 mg for 45-60 kg, 80 mg for 61-100 kg or 100 mg for > 100 kg for 14 days, with dose adjustment according to anti-factor Xa activity (target range: 0.4-0.6 UI/ml); an observational cohort (OC) included patients receiving enoxaparin 40 mg day for comparison. Follow-up was 90 days. Primary outcome was major bleeding within 30 and 90 days after treatment onset. Secondary outcome was the composite of all-cause 30 and 90-day mortality rates, disease severity at the end of treatment, intensive care unit (ICU) admission and length of ICU stay, length of hospitalization. All outcomes were adjudicated by an independent committee and analyzed before and after propensity score matching (PSm). RESULTS: Major bleeding was similar in IC (1/98 1.02%) and in the OC (none), with only one event observed in a patient receiving concomitantly anti-platelet therapy. The composite outcome was observed in 53/98 patients (54%) in the IC and 132/203 (65%) patients in the OC (p = 0.07) before PSm, while it was observed in 50/90 patients (55.6%) in the IC and in 56/90 patients (62.2%) in the OC after PSm (p = 0.45). Length of hospitalization was lower in the IC than in OC [median 13 (IQR 8-16) vs 14 (11-21) days, p = 0.001], however it lost statistical significance after PSm (p = 0.08). At 30 days, two patients had venous thrombosis and two pulmonary embolism in the OC. Time to first negative RT-PCR were similar in the two groups. CONCLUSIONS: Weight adjusted intermediate dose heparin with anti-FXa monitoring is safe with potential positive impact on clinical course in COVID-19 non-critically ill patients. TRIAL REGISTRATION: The study INHIXACOVID19 was registred on ClinicalTrials.gov with the trial registration number (TRN) NCT04427098 on 11/06/2020.

Predictive comorbidities of hospital admission in 1,571 SARS- CoV-2 positive patients: analysis of administrative data from an Italian Local Health Autority.

Purpose: Globally, age and some comorbidities have been associ-ated with the risk of more severe outcomes of COVID-19. The purpose of this research is to calculate the hospitalization rate of SARS-CoV-2 positive patients in an Italian Local health Authority (LHA) and to examine whether medical comorbidities encoded through pharmaceutical administrative data are predictors of hospital admission in patients with a positive SARS-CoV-2 naso-pharyngeal swab. Methods: This retrospective observational study was conducted in a LHA of Pescara. Comorbidities were coded through the consumption of drugs, using the WHO's Anatomical Therapeutic Chemical (ATC) classification System. The admission was ascertained by checking the hospital discharge records where generated. Results: During the study period, 1571 patients were tested positive for SARS-CoV-2 oro-and-nasopharyngeal swab. Multivariable logistic analisys showed as predictors of admission an age ≥65 in the total sample (aOR 10.91; 95%CI 6.86-17.36) as well as in the male (aOR 12.64;95%CI 6.42-24.87) and female. (aOR 9.27; 95%CI 4.87-17.66) in SARS-CoV-2 positive patients. Comorbidities assiociated with admission were (GERD) in overall (AdjOR 1.58; 95% CI 1.06-2.34) and male (AdjOR 2.30; 95%CI 1.12-4.72) samples and anticoagulants drugs use in male (AdjOR 3.90; 95% 1.11-13.65) sample, the presence of congestive heart failure (CHF) in female (AdjOR 0.47;95%CI 0.27-0.83) sample results as protective factor. Conclusion: In conclusion, increasing age, male gender and PPI use are positively associated while female gender and CHF-related drug use are negatively associated with hospitalization in SARS-CoV-2 positive patients.

Utilization of endovascular and open surgical repair in the United States: A 10-year analysis of the National Trauma Databank (NTDB).

BACKGROUND: Endovascular therapy provides a less invasive alternative to open surgery for critically ill patients who have sustained arterial injuries. The purpose of this study was to evaluate recent trends in the management of arterial injuries in the United States with specific reference to the use of endovascular strategies and to examine the outcomes of endovascular vs open therapy for the treatment of civilian arterial traumatic injuries. METHODS: We performed a 10-year (2004-2014) analysis of ACS-NTDB and identified all adult trauma patients who had arterial injuries. Data regarding demographics, injury parameters, endovascular or open vascular repair and outcomes were extracted. Cochran-Armitage trend analysis and multivariate logistic regression analysis were performed. RESULTS: A total of 111,061 patients with arterial injuries were identified and included in our analysis. Mean age was 39 ± 19y, 82% were male and 79% were white. The most common artery injured was iliac artery followed by brachial artery and thoracic aorta. Overall 6.7% (7434) patients underwent endovascular repair while 38.8% (42,495) had open vascular repair. The rate of endovascular repair increased from 3.1% to 8.9% while the incidence of open vascular repair decreased from 47% to 32% over the study period. Patients in endovascular group had lower ISS compared to patients in open vascular repair group (17 + 10 vs 24 + 10, p < 0.001). Patients who underwent endovascular repair had shorter hospital length of stay (days: 10 + 17 vs 11 + 15, p < 0.001), lower mortality (8% vs 14%, p = 0.01). On multivariate regression analysis after controlling for confounding variables, endovascular repair was independently associated with improved survival (OR: 2.45[1.84-4.26], p = 0.01). CONCLUSIONS: The use of endovascular modalities to repair arterial injuries in the setting of acute trauma is increasing in a dramatic fashion. Endovascular repair of trauma arterial injuries is associated with shorter length of stay and improved survival compared to open vascular procedures.

Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains.

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

Modification of translation factor aIF5A from Sulfolobus solfataricus.

Eukaryotic eIF5A and its bacterial orthologue EF-P are translation elongation factors whose task is to rescue ribosomes from stalling during the synthesis of proteins bearing particular sequences such as polyproline stretches. Both proteins are characterized by unique post-translational modifications, hypusination and lysinylation, respectively, which are essential for their function. An orthologue is present in all Archaea but its function is poorly understood. Here, we show that aIF5A of the crenarchaeum Sulfolobus solfataricus is hypusinated and forms a stable complex with deoxyhypusine synthase, the first enzyme of the hypusination pathway. The recombinant enzyme is able to modify its substrate in vitro resulting in deoxyhypusinated aIF5A. Moreover, with the aim to identify the enzyme involved in the second modification step, i.e. hypusination, a set of proteins interacting with aIF5A was identified.

AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1.

Damaged mitochondria are eliminated by mitophagy, a selective form of autophagy whose dysfunction associates with neurodegenerative diseases. PINK1, PARKIN and p62/SQTMS1 have been shown to regulate mitophagy, leaving hitherto ill-defined the contribution by key players in 'general' autophagy. In basal conditions, a pool of AMBRA1 - an upstream autophagy regulator and a PARKIN interactor - is present at the mitochondria, where its pro-autophagic activity is inhibited by Bcl-2. Here we show that, upon mitophagy induction, AMBRA1 binds the autophagosome adapter LC3 through a LIR (LC3 interacting region) motif, this interaction being crucial for regulating both canonical PARKIN-dependent and -independent mitochondrial clearance. Moreover, forcing AMBRA1 localization to the outer mitochondrial membrane unleashes a massive PARKIN- and p62-independent but LC3-dependent mitophagy. These results highlight a novel role for AMBRA1 as a powerful mitophagy regulator, through both canonical or noncanonical pathways.

[Clinical indications for the use of cardiac MRI. By the SIRM Study Group on Cardiac Imaging]. / Indicazioni cliniche per l'utilizzo della cardio RM. A cura del Gruppo di lavoro della Sezione di Cardio-Radiologia della SIRM.

Cardiac magnetic resonance (CMR) is considered an useful method in the evaluation of many cardiac disorders. Based on our experience and available literature, we wrote a document as a guiding tool in the clinical use of CMR. Synthetically we describe different cardiac disorders and express for each one a classification, I to IV, depending on the significance of diagnostic information expected.

Optimisation of low-dose CT with adaptive statistical iterative reconstruction in total body examination.

PURPOSE: The aim of this study was to assess the feasibility of low-dose computed tomography (CT) with the adaptive statistical iterative reconstruction (ASIR) algorithm in whole-body imaging with low tube voltage and current. MATERIALS AND METHODS: Twenty-three patients underwent whole-body CT with 40% of ASIR and parameters modulated according to body mass index (BMI). All had previously undergone conventional-dose CT with 100% filtered back projection (FBP). Two radiologists jointly assessed image quality (sharpness, noise, artefacts) and diagnostic quality blinded to the scanning technique. The effective dose and image quality obtained with the ASIR protocol were compared with those obtained with the FBP algorithm. RESULTS: The mean effective dose achieved with ASIR was 15.6 ± 5 mSv versus 21.8 ± 5.3 mSv with the FBP protocol (p<0.0001). Image quality was good in all low-dose CT scans, and diagnostic quality was comparable with or superior to that of conventional-dose CT. CONCLUSIONS: Low-dose CT with the ASIR algorithm is feasible and ensures significant reduction in effective dose.

Clinical indications for cardiac computed tomography. From the Working Group of the Cardiac Radiology Section of the Italian Society of Medical Radiology (SIRM).

Cardiac computed tomography (CCT) has grown as a useful means in different clinical contexts. Technological development has progressively extended the indications for CCT while reducing the required radiation dose. Even today there is little documentation from the main international scientific societies describing the proper use and clinical indications of CCT; in particular, there are no complete guidelines. This document reflects the position of the Working Group of the Cardiac Radiology Section of the Italian Society of Radiology concerning the indications for CCT.

Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response.

Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program.

VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria.

Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca(2+) loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca(2+) signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP(3) receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca(2+) signals to mitochondria in apoptosis.

Multidetector computed tomographic coronary angiography as an alternative to conventional coronary angiography in non-coronary surgical patients.

AIM: Aim of our study was to evaluate multidetector 64-slice spiral computed tomography (MSCT) as an alternative to traditional coronary angiography (CA) to detect concomitant coronary artery disease (CAD) in patients initially admitted for non-coronary surgical procedures. METHODS: We have analyzed data of 380 consecutive patients operated from 2006 to 2008 initially admitted for aortic (N.=170) or mitral (N.=67) valve disease, ascending aorta aneurysm ± aortic valve disease (N.=99), and other (combined valve diseases, tumors; N.=44). These patients were submitted either to MSCT (Group CT, N.=112) or to CA (Group A, N.=268). Inclusion criteria to perform MSCT were no previous myocardial infarction or documented CAD, normal left ventricular function, sinus rhythm, less than 2-3 premature ventricular or atrial contractions /min. RESULTS: In Group CT, CAD was definitively excluded in 95 patients (85%) and was detected in 17; 8 of those 17 patients were subsequently submitted to CA and coronary artery bypass surgery for significant CAD. As compared to those in Group A, patients in Group CT were younger (64±15 vs. 70±10 years, P<0.0001), had less hypertension (P=0.0001), chest pain (P<0.05), peripheral vascular disease (P<0.05). NYHA class, incidence of diabetes, smoking habit, family history of CAD were similar. The incidence of operative mortality, postoperative myocardial infarction was not significantly different in both Group CT (0%) and A (0.4%) (P=NS). CONCLUSION: In selected cardiac surgical patients less invasive 64-slice MSCT can be with some limits an alternative to CA to rule out CAD, as confirmed by the absence of postoperative ischemic complications.

Anatomical and functional evaluation of the myocardium in patients with acute coronary syndrome (NSTEMI) using MR imaging.

PURPOSE: The aim of our study was to evaluate the role of magnetic resonance (MR) imaging in identifying the location and extent of acute ischaemic injury to predict reversibility and distinguish areas of acute from chronic ischaemia in patients with acute coronary syndrome non- ST-elevation myocardial infarction (NSTEMI). MATERIALS AND METHODS: We evaluated 22 patients with NSTEMI acute coronary syndrome confirmed by coronary angiography (CA). We studied ventricular function indices and segmental changes in wall thickness and kinetics by cine-MR imaging sequences. Subsequently, we evaluated myocardial wall oedema with T2-weighted black-blood short-tau inversion recovery turbo spin echo (T2 BB-STIRTSE) sequences and identified areas of myocardial necrosis using T1-weighted turbo field-echo inversion recovery (T1 TFE-IR) sequences after contrast material administration. RESULTS: The results obtained with the single sequences were as follows: T2 BB-STIR-TSE: 96.8% sensitivity, 100% specificity, 99.7% negative predictive value, 99.7% positive predictive value; T1 TFE-IR: 45.8% sensitivity, 96.9% specificity, 92.3% negative predictive value, 90.3% positive predictive value; systolic wall thickening: 87.5% sensitivity, 91.8% specificity, 98.7% negative predictive value, 50% positive predictive value, 91.4% accuracy. CONCLUSIONS: Our study suggests that the sequences used for evaluating oedema and assessing viability allow for precise localisation and differentiation of areas of acute and chronic ischaemia by quantifying the possible mismatch between ischaemia and necrosis.

Evaluation with 64-slice CT of the prevalence of coronary artery variants and congenital anomalies: a retrospective study of 3,236 patients.

PURPOSE: This study retrospectively evaluated the prevalence of anatomical coronary artery variants and congenital anomalies in 3,236 patients imaged with 64-slice computed tomography (CT). MATERIALS AND METHODS: Over a period of 4 years, 3,236 patients underwent CT coronary angiography performed with the standard protocol. We assessed coronary artery dominance, presence of the intermediate branch, presence and number of diagonal and marginal branches and coronary anomalies subdivided into anomalies of origin and course, intrinsic anomalies and termination anomalies. RESULTS: Coronary dominance was right-sided in 88.1% of patients; the intermediate branch was present in 21.3%, the number of diagonal and marginal branches was one to two in >90%, and the number of coronary anomalies was 224 (89 of origin and course, 129 intrinsic anomalies and six termination anomalies). CONCLUSIONS: Sixty-four-slice CT coronary angiography provides accurate three-dimensional evaluation of the coronary artery tree with correct visualisation of any coronary anomalies, a relatively common finding that had a prevalence of 5.7% in our study population.

Diagnostic accuracy of 64-slice CT in evaluating coronary artery bypass grafts and of the native coronary arteries.

PURPOSE: Our aim was to evaluate the accuracy, sensitivity and specificity of 64-slice multidetector computed tomography (MDCT) in the assessment of occlusions and stenoses of arterial and venous bypass grafts and disease progression in the native vessels distal to the graft, and to compare the results with those of conventional coronary angiography. MATERIALS AND METHODS: We enrolled 78 individuals (45 men, 33 women; mean age 59) and evaluated 213 bypass grafts using a 64-slice MDCT scanner. All patients underwent conventional coronary angiography with a mean time interval between the two examinations of 2 days. RESULTS: One patient was excluded due to arrhythmia during the examination. The 212 bypass grafts in the remaining 77 patients (98.7%) consisted of 115 (54%) venous grafts and 97 (46%) arterial grafts. In the 115 venous grafts, MDCT showed a sensitivity, specificity and accuracy of 100% in evaluating occluded grafts and a sensitivity of 94.4%, specificity of 98.4% and accuracy of 96.9% in evaluating significant stenoses. In evaluating occluded arterial grafts, sensitivity was 83.3%, specificity 100% and accuracy 98.9%, whereas in evaluating stenoses of arterial grafts, sensitivity was 100%, specificity 97.7% and accuracy 98%. CONCLUSIONS: Sensitivity, specificity and accuracy in evaluating native coronary vessels distal to the graft allow for a complete assessment of the surgical and native circulation. The examination appears therefore to be exhaustive in ruling out or confirming the presence of diseased vessels in the postoperative follow-up.

Role of 64-slice cardiac computed tomography in the evaluation of patients with non-ST-elevation acute coronary syndrome.

PURPOSE: This study was done to evaluate the feasibility, sensitivity and specificity of 64-slice computed tomography (CT) in identifying haemodynamically significant (>50%) coronary artery stenoses in patients with suspected acute coronary syndrome (ACS) by correlating the CT findings with the clinical event and data provided by conventional coronary angiography (CCA). MATERIALS AND METHODS: Sixty-four patients (38 men and 26 women; mean age 65 years; range+/-10 years) presenting to our hospital's emergency department with a clinical suspicion of ACS were studied with 64-slice CT followed by CCA within 24 h of arrival. RESULTS: Two patients (3.1%) were excluded from the analysis due to artefacts. Per-patient analysis in the remaining 62 patients identified 24 cases (38.7%) of negative CT findings (no stenoses or stenoses <50%), 35 cases of positive CT findings (56.4%) with identification of the culprit lesion, two cases in which the culprit lesion was not identified and one patient with unconfirmed stenosis. Sensitivity and specificity were 94.6% and 96%, respectively. Per-vessel analysis (186 vessels) revealed 17 non-evaluable vessels (9.1%) due to motion artefacts, 61 vessels (32.8%) with stenosis >50%, seven overestimated vessels (3.7%) due to extensive calcifications, three vessels (1.6%) with underestimated stenosis and 98 vessels (52.6%) without stenosis. Sensitivity and specificity were 95.3% and 93.3%, respectively. CONCLUSIONS: In this type of emergency, coronary CT angiography could lead to considerably lower healthcare costs by identifying patients without coronary disease and allowing immediate discharge without any need for further diagnostic procedures.

Bone turnover, osteopenia and vascular calcifications in hemodialysis patients. A histomorphometric and multislice CT study.

BACKGROUND: Several classical risk factors are at the base of vascular calcifications in hemodialysis patients. Among these, according to a general opinion, also bone turnover plays a role, which, however, requires a better definition. In addition, it has been suggested that there is a relationship between primary osteoporosis and vascular calcifications. This bone biopsy-based study on a hemodialysis patient cohort is a contribution to the evaluation of these alleged relations. METHODS: This study has been carried out on a cohort of 32 patients on maintenance hemodialysis, who were subjected to transiliac bone biopsy for histomorphometric, histodynamic and bone aluminum deposit evaluation. The patients were also examined with multislice computerized tomography for quantitation of heart and coronary calcifications. RESULTS: The patients were affected by renal osteodystrophy with a wide range of bone formation rate values. A significant negative correlation was found between the rate of bone turnover and log-transformed cardiac calcification score (p < 0.003). There were also negative significant correlations between the cardiac and coronary calcification score log and trabecular number (p < 0.02 and p < 0.05, respectively), while the correlations were positive with trabecular separation (p < 0.03 and p < 0.05, respectively). However, multiregression analysis, forward method, selected only age, hemodialysis age and serum Ca as predictive variables of cardiac and coronary calcification score log, while the histomorphometric and histodynamic variables were excluded. CONCLUSIONS: In this study, in spite of the suggestive findings of the univariate statistical approach, a further multivariate analysis was indicative of a spurious association between calcification scores and both bone turnover and histomorphometric parameters of trabecular mass and connectivity. Bone turnover and trabecular mass do not appear to be prominently connected with the extent of cardiac and coronary calcifications in hemodialysis patients.

[Disease progression in bladder cancer: which developments since 1994].

Objectives The introduction of PSA in clinical practice has resulted in decreasing the death rate form prostate cancer and in a downward shift of the pathological stage in radical prostatectomy specimens. This seems not to be the case for bladder cancer. In order to verify this assumption, we have reviewed the charts of the patients operated on of radical prostatectomy and radical cystectomy between 1994 and 2006. METHODS 456 and 491 consecutive patients, respectively, underwent radical cystectomy and radical prostatectomy with bilateral lymph nodes dissection. We excluded all the patients who had received neoadjuvant treatment or did not undergo node dissection. The patients were divided into two consecutive groups according to the year of treatment: group 1 included pts treated from 1994 to 2000, and group 2 pts from 2001 to 2006. The histopathological findings of the two groups of pts were compared. The difference among TNM systems has been balanced evaluating histopathological reports critically and converting them to the 2002 edition. RESULTS. For patients with prostate cancer, those in group 2 had a decrease in the incidence of extracapsular extension and lymph nodes invasion. The bladder cancer patients belonging to group 2 had a greater number of T2, but there was an increased number of pN+ in this group. CONCLUSIONS Even if there is a decline in locally advanced disease in patients with bladder cancer, our retrospective analysis did not show a comparable success in early diagnosis as it did for prostate cancer. There is undoubtedly an increase in the lymph node dissemination, whether this is due to a more extended lymph node dissection or to a premature dissemination remains questionable. Public awareness regarding bladder cancer and its risk factors is limited, but several studies have reported that a delay in diagnosis of invasive bladder cancer is an adverse prognostic factor. A higher care in the development of new diagnostic markers for bladder tumors and especially in the screening protocols together with an earlier radical therapy could hopefully improve the management of such a pathology, as it happened for prostate cancer.