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Summary Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.

Aims Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine transaminase aminotransferase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) in NAFLD patients treated or not treated with statins. Methods We performed a systematic review of MEDLINE via PubMed and EMBASE databases and metanalysis of clinical studies investigating levels of ALT, AST and GGT in NAFLD according to statin treatment. Mean difference (MD) and percentage MD were calculated between the two groups. Results We included 22 studies with 2345 NAFLD patients. Overall, 16 were before-after interventional, five were cross-sectional and one was combined cross-sectional/interventional study. In all interventional studies, except one, patients had raised ALT, AST and GGT at baseline. Interventional studies showed reduced ALT values with an MD reduction of -27.2 U/L (95% CI -35.25/-19.15) and a percentage MD reduction of -35.41% (95% CI -44.78/-26.04). Also, AST values were reduced after statin treatment in interventional studies with an MD of -18.82 U/L (95% CI -25.63/-12.02) (percentage -31.78%, 95% CI -41.45/-22.11). Similarly, GGT levels were reduced after statin treatment with an MD of -19.93 U/L (95% CI -27.10/-12.77) (percentage -25.57%, 95% CI -35.18/-15.97). Cross-sectional studies showed no difference in AST and GGT values between patients treated with and without statins. Conclusion In interventional studies, ALT, AST and GGT were reduced after statin treatment with a percentage mean difference of -35.41%, -31.78% and -25.57%, respectively, while observational studies showed a null effect, suggesting liver safety of statins in NAFLD patients.

Background: Early diagnosis of Parkinson's disease (PD) is of primary importance. The delayed (3-4 h after injection) Iodine-123-Metaiodobenzylguanidine (123I-mIBG) scintigraphy has been proven to be effective in early differential diagnosis for Lewy body disease. But early imaging (15-30 min after injection) has only been marginally studied for its possible diagnostic role. In this prospective study, a threshold for the early Heart-to-Mediastinum (H/M) count ratio has been investigated, obtaining a diagnostic accuracy analogous to conventional, delayed imaging. Methods: One hundred and eight patients with suspected Parkinson's disease (PD) were acquired after 15 and 240 minutes from the injection of 150-185 MBq of 123I-mIBG. The early and late H/M (He/Me and Hl/Ml) were evaluated by drawing Region-of-Interests on the heart and the upper half of the mediastinum. Optimal threshold (Youden index) and overall predictive performance were determined by receiver operating characteristic curve, classifying tentatively patients having an Hl/Ml lower than 1.6 as suffering from PD. Results: He/Me was not significantly different from Hl/Ml (p-value=0.835). The Area-under-curve was 0.935 (95%CI: 0.845-1.000). The He/Me optimal threshold was 1.66, with sensitivity, specificity, and diagnostic accuracy of 95.5%, 85.7 and 90.7% respectively. Conclusions: The He/Me Ratio is almost as accurate as the widely used delayed 123I-mIBG imaging, reducing the burden of delayed imaging but preserving the diagnostic accuracy of the method. Moreover the differential diagnosis in Parkinson's disease can be made in just 25 minutes against the 4 hours currently needed, lowering costs of the healthcare system and improving patients compliance.

This systematic review aimed to evaluate the prognostic value of Iodine123 Metaiodobenzylguanidine (123I-mIBG) SPECT myocardial imaging in patients with heart failure (HF) and to assess whether semi-quantitative SPECT scores can be useful for accurate risk stratification concerning arrhythmic event (AE) and sudden cardiac death (SCD) in this cohort. A systematic literature search of studies published until November 2020 regarding the application of 123I-mIBG SPECT in HF patients was performed, in Pubmed, Scopus, Medline, Central (Cochrane Library) and Web Of Science databases, including the words “MIBG”, “metaiodobenzylguanidine”, “heart”, “spect”, and “tomographic”. The included studies had to correlate 123I-mIBG SPECT scores with endpoints such as overall survival and prevention of AE and SCD in HF patients. According to the sixteen studies included, the analysis showed that 123I-mIBG SPECT scores, such as summed defect score (SDS), regional wash-out (rWO), and regional myocardial tracer uptake, could have a reliable prognostic value in patients with HF. An increased SDS or rWO, as well as a reduced 123I-mIBG myocardial uptake, have proven to be effective in predicting AE- and SCD-specific risk in HF patients. Despite achieved results being promising, a more reproducible standardized method for semi-quantitative analysis and further studies with larger cohort are needed for 123I-mIBG SPECT myocardial imaging to be as reliable and, thus, accepted as the conventional 123I-mIBG planar myocardial imaging.

Radium-223 has demonstrated efficacy in improving overall survival (OS) and in delaying symptomatic skeletal-related events (SREs). Bone Health Agents (BHA), i.e. RANK ligand inhibitor (Denosumab) and bisphosphonate such as zoledronic acid, are indicated to prevent SREs without a clear survival benefit. SREs on patient health have a high impact and it is, therefore, important to consider the role of new therapies with BHA to better understand the involvement of combination therapy. The primary aim of this multicentric study is to assess OS in mCRPC patients treated with Radium-223 in combination with BHA.430 consecutive patients treated with Radium-223 alone or in combination with BHA, affected by mCRPC, from January 2015 to July 2019 in six Italian Nuclear Medicine Units, were included. Furthermore, data were collected at baseline, after every Radium-223 administration, and during follow-up, at 3 and 6 months and 1 year after the 6th cycle. Clinical data have been evaluated before starting treatment with Radium-223 and at the end of treatment and/or at progression. Patients who received target bone therapy with BHA before Radium-223 treatment together with patients who did not receive this therapy at all (NO BHA GROUP), were compared to patients treated with concomitant Radium-223 and BHA (BHA GROUP).In univariate models (At univariate analysis, our data showed that NO BHA GROUP and BHA GROUP differ in OS by 7 months (95%CI: (1-16.4)

Socotra Island, in the western Indian Ocean, harbors high biodiversity and endemism and makes up the largest part of the Socotra archipelago UNESCO World Heritage site. Its climatic, pedological, and geomorphological characteristics, together with the long geological isolation and inaccessibility, led to the flourishing of unique tree diversity, with great cultural and ecological value. Lately, trees on Socotra are facing new threats linked to the abandonment of traditional management practices, climate change impacts, and growing human pressure. This study assesses the relative influence of environmental factors and human activity as drivers of tree cover and density, which can be used to support land management policies for the conservation of this key local resource. Tree cover and density were assessed on a total of 3600 plots of 0.5 ha each, laid on a regular grid covering the entire area of the island through Collect Earth, a free open source software tool that allows an augmented visual interpretation of high-resolution satellite images. A total of 770,000 trees, with an average of 2.14 trees/ha, were estimated on the island. The collected data was validated by ground surveys in 26 plots. The relative influence of selected predictors (seven environmental, two anthropic) on tree cover and density was analyzed through logistic and survival regression. Tree cover and density were found to be impacted positively by steeper slopes, higher rainfall, and marked precipitation seasonality and negatively by relatively warmer temperatures and a higher sand content in the soil. Distance of each plot from the nearest road and settlement was calculated and neither of these anthropic predictors emerged as significant, indicating that the limited number of trees present are not currently as affected by anthropic pressure, but, instead, their presence is mostly limited by the harsh climatic and pedological factors. However, as human population and development increase, periods of drought rise, and extreme and random climatic events intensify, these additional stresses on the environment could negatively impact the availability of natural resources in the terrestrial environment. Lastly, potential recommendations to the existing conservation policies and Socotra Conservation Zoning Plan are discussed based on the results.

Radium-223 prolongs overall survival (OS) and delays time to the first symptomatic skeletal events in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC). There is a lack of evidence on the safety and efficacy of Radium-223 treatment in the very elderly population. Aim of this multicentre study is to analyze mCRPC patients treated with Radium-223 in terms of OS and to assess whether there are differences between young and elderly, as well as to verify efficacy and safety in patients ≥ 75 years of age. 430 mCRPC patients of six Italian Centres were analyzed in this multicenter retrospective study. At baseline and after each cycle were collected clinical and diagnostic patients’ parameters. The whole cohort was divided into two groups based on the age of the patients (

Background Data on the prognostic role of D-dimer in patients with acute coronary syndrome (ACS) are controversial. Our aim was to summarize current evidence on the association between D-dimer levels and short/long-term poor prognosis of ACS patients. We also investigated the association between D-Dimer and no-reflow (NR) phenomenon.Methods Systematic review and metanalysis of observational studies including ACS patients and reporting data on D-Dimer levels. PubMed and SCOPUS databases were searched. Data were combined with hazard ratio (HR) and metanalysed. The principal endpoint was a composite of cardiovascular events (CVEs) including myocardial infarction, all-cause and cardiovascular mortality. Results Overall, 32 studies included in the systematic review with 28,869 patients. Of them, 6 studies investigated in-hospital and 26 studies long-term outcomes. Overall, 23 studies showed positive association of high D-Dimer levels with CVEs. D-Dimer levels predicted poor prognosis in all studies reporting in-hospital outcomes. Five studies satisfied inclusion criteria and were included in the metanalysis, with a total of 8,616 patients. Median follow-up was 13.2 months with 626 CVEs. The pooled HR for D-dimer levels and CVEs was 1.264 (95% CI 1.134-1.409). Five out of 7 studies (4,195 STEMI patients) investigating the association between D-Dimer levels and NR showed a positive correlation of D-dimer levels with NR. Conclusions In patients with ACS D-Dimer was associated with higher in-hospital and short/long-term complications. D-Dimer was also higher in patients with NR phenomenon. The use of D-Dimer may help to identify patients with residual thrombotic risk after ACS.Trial registration: the review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews: CRD42021267233.

Background Aim of our study was to assess the load of bone disease at starting and during Ra-223 treatment as an overall survival (OS) predictor in metastatic castration-resistant prostate cancer (mCRPC) patients. Bone scan index (BSI) is defined as the percentage of total amount of bone metastasis on whole-body scintigraphic images. We present a specific software (DASciS) developed by an engineering team of “Sapienza” University of Rome for BSI calculation. Patients and methods 127 mCRPC patients bone scan images were processed with DASciS software, and BSI was tested as OS predictor. Results 546 bone scans were analyzed revealing that the extension of disease is a predictor of OS (0–3% = 28 months of median survival (MoMS]; 3%–5% = 11 MoMS, > 5% = 5 MoMS). BSI has been analyzed as a single parameter for OS, determining an 88% AUC. Moreover, the composition between the BSI and the 3-PS (3-variable prognostic score) determines a remarkable improvement of the AUC (91%), defining these two parameters as the best OS predictors. Conclusions This study suggests that OS is inversely correlated with the load of bone disease in mCRPC Ra-223-treated subjects. DASciS software appears a promising tool in identifying mCRPC patients that more likely take advantage from Ra-223 treatment. BSI is proposed as a predictive variable for OS and included to a multidimensional clinical evaluation permits to approach the patients’ enrollment in a rational way, allowing to enhance the treatment effectiveness together with cost optimization.

Background Alterations in health-related quality of life (HRQoL) and neuropsychological disorders were described in the hepatitis C virus (HCV) patients. Although several studies investigated the modifications of HRQoL after HCV eradication, no data exists on the modifications of neuropsychological symptoms. Aim To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms. Methods Thirty nine patients with HCV infection underwent a neuropsychological assessment, including Zung-Self Depression-Rating-Scale, Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs treatment. HRQoL was detected by Short-Form-36 (SF-36). Results All HRQoL domains, but role limitation physical and bodily pain, significantly improved after treatment. Interestingly, after DAAs treatment, all domains of HRQoL returned similar to those of controls. Each neuropsychological test significantly improved after HCV eradication. A significant correlation was observed among each psychological test and the summary components of SF-36. At multiple linear regression analysis including each psychological test as possible covariates, Zung-Self Depression Rating Scale (Zung-SDS) score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the treatment. Conclusion Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.

Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications including overt hepatic encephalopathy (HE). The aim of our study was to investigate the relationship between muscle alterations and minimal HE (MHE) and their role in the risk of overt HE. Sixty-four patients with cirrhosis were administered the Psychometric Hepatic Encephalopathy Score and animal naming test to detect MHE. Computed tomography was used to analyze the skeletal muscle index and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%), and MHE in 32 (50%). Both myosteatosis (62.5% versus 12.5%, P < 0.001) and sarcopenia (84% versus 31%, P < 0.001) were more frequent in patients with MHE. The variables independently associated with the presence of MHE were sarcopenia, previous overt HE, and myosteatosis. Thirty-one (48%) patients developed overt HE over 16.1 ± 13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated with the development of overt HE. Venous ammonia was significantly higher in patients with sarcopenia (62.6 ± 17.7 versus 41.4 ± 16.1 μg/dL, P < 0.001) and in patients with myosteatosis (65.2 ± 19.2 versus 46.7 ± 17.1 μg/dL, P < 0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared to patients without myosteatosis or sarcopenia (P < 0.001). Conclusion: Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE and the risk of overt HE in patients with cirrhosis; in malnourished patients, the amelioration of nutritional status may be a goal to decrease both the prevalence of MHE and the incidence of overt HE.

Background The incidence of atrial fibrillation (AF) is increasing, conferring a major health-care issue in Asia. No risk score for predicting incident AF has been specifically developed in Asian subjects. Our aim was to investigate risk factors for incident AF in Asian subjects and to combine them into a simple clinical risk score. Methods Risk factors for incident AF were analyzed in 471,446 subjects from the Chinese Yunnan Insurance Database (internal derivation cohort) and then combined into a simple clinical risk score. External application of the new score was performed in 451,199 subjects from the Korean National Health Insurance Service (external cohort). Results In the internal cohort, structural heart disease (SHD), heart failure (HF), age ≥ 75 years, coronary artery disease (CAD), hyperthyroidism, COPD, and hypertension were associated with incident AF. Given the low prevalence and the strong association of SHD with incident AF (hazard ratio, 26.07; 95% CI, 18.22-37.30; P Conclusions We have developed and validated the C2HEST score as a simple clinical tool to assess the individual risk of developing AF in the Asian population without SHD.

Aims To analyse the safety and efficacy of direct oral anticoagulants (DOACs) in real-world studies including atrial fibrillation (AF) patients. Methods and results Systematic review and meta-analysis of observational studies including AF patients on DOACs. Primary endpoints: any, major, gastrointestinal (GI), intracranial haemorrhage (ICH), and haemorrhagic stroke (HS). Secondary endpoints: ischaemic stroke (IS), systemic embolism (SE), myocardial infarction (MI), and all-cause of death. A set of pair-wise meta-analyses using a random effect model and a random effect network meta-analysis under a Bayesian framework were performed. Prospero registration number: CRD42019137111. We included 21 studies with 605 771 AF patients. Apixaban was associated with lower major and GI bleeding compared with Rivaroxaban [hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.6–2.5] and Dabigatran (HR 1.6, 95% CI 1.3–2.1). The latter drug performed better than Rivaroxaban (HR 1.2, 95% CI 1.0–1.5). Dabigatran and Apixaban had a similar association with HS, but Apixaban performed better than Rivaroxaban (HR 1.8, 95% CI 1.1–3.0). Apixaban had a similar association with Rivaroxaban and Dabigatran for ICH, the latter drug performing better than Rivaroxaban (HR 1.3, 95% CI 1.0–1.7). Rankograms showed that Apixaban was likely to be the first-choice treatment in relation to any (65%) major (100%) and GI bleeding (100%) followed by Dabigatran (46%, 100%, 99%, respectively). Dabigatran and Apixaban had similar rank as first choice for ICH (44% and 55%) and HS (52% and 48%). DOACs showed similar association with IS/SE, MI, all-cause of death. Conclusions Analysis of real-world studies shows significant differences for safety among DOACs.

The dual anticytokine and antiviral actions of baricitinib reduce SARS-CoV-2 infectivity in organoids and morbidity in people., Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Introduction The role of diabetes mellitus in determining of major adverse outcomes in patients with atrial fibrillation (AF) is well-established. Little is known about fasting plasma glucose (FPG) visit-to-visit variability (VVV) and its impact on outcomes. Aim To analyse the role of FPG-VVV in determining major adverse outcomes in AF patients. Second, to evaluate the prognostic impact of history of diabetes mellitus and antidiabetic regimens. Methods Warfarin-treated patients from the SPORTIF trials were considered for analysis if they had FPG evaluation at baseline and at least 4 determinations throughout follow-up. Standard deviation (SD) of the mean of FPG throughout follow-up was the main measure of VVV, according to its quartiles (SD-Qs). A composite of cardiovascular events and the occurrence of all-cause death was the adverse outcome considered. Results Among the 3665 patients originally included, 3415 (93.2%) were included in this analysis. Throughout a mean (±SD) of 577.59 (±122.09) days of follow-up patients in the highest SD-Q (SD-Q4) had the highest rate of the composite outcome and all-cause death [Figure]. A Cox multi-regression analysis confirmed that SD-Q4 had a significant independent association with occurrence of composite outcome (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.10–2.35) [Figure, Upper Panel], with a non-significant trend for all-cause death, [Figure, Lower Panel]. If no significant impact of history of diabetes mellitus was found, there was a significant impact on the composite outcome of the various antidiabetic regimes: there was no difference found in patients treated with oral antidiabetics, compared to no antidiabetic treatment, but those patients treated with insulin (±oral antidiabetics) were independently associated with the occurrence of composite outcome (HR: 2.38, 95% CI: 1.05–5.38) (Table). Conclusion In AF patients treated with warfarin, patients with the highest FPG-VVV had an increased rate of outcomes and the largest FPG-VVV being significantly associated with the composite outcome of adverse clinical events. In diabetic patients, use of insulin is independently associated with an increased risk of the composite outcome, reflecting the more severe disease in determining adverse events amongst AF patients. Major Adverse Outcomes Funding Acknowledgement Type of funding source: None

Background Patients with atrial fibrillation (AF) experience a high mortality rate despite optimal antithrombotic treatment. Characteristics of AF patients at higher mortality risk have been barely described so far and no risk score has been specifically developed at this aim. Furthermore, a clinical approach based on risk scores present some limits such as to not consider some important risk factors for mortality, and many available scores have poor predictive value. Cluster analysis may play a role in overcoming limitations of risk scores, especially in the case of overlapping risk factors. Purpose To identify of clinical phenotypes by using an unbiased statistical approach, such as the cluster analysis. Methods Cluster analysis was used to identify clinical phenotypes of AF patients associated with all-cause mortality in 5,171 AF patients from the START registry. Clinical variables used for the analysis were age, sex, diabetes, previous cerebrovascular events, previous cardiovascular events, heart failure, peripheral artery disease, use of non-vitamin K oral anticoagulants, cancer, pulmonary disease, smoking habit, previous major bleeding. The risk of all-cause mortality in each cluster was analyzed. Results We identified 4 clusters (Figure 1). Cluster 1 was composed by youngest patients, with obesity and paroxysmal AF; Cluster 2 by patients with low cardiovascular risk factors and high proportion of cancer; Cluster 3 by men with diabetes and coronary and peripheral artery disease, a high proportion of thrombocytopenia, and a high use of aspirin, proton pump inhibitors, and statins; Cluster 4 included the oldest patients, mainly women, with previous cerebrovascular disease, persistent/ permanent AF, heart failure, kidney disease and anemia. In this cluster there was the highest use of digoxin and NOACs. During 9856,84 patient/years of observation, 386 deaths (3.92%/year) occurred. Mortality rates significantly increased across clusters: 0.42%/year (cluster 1, reference group), 2.12%/year (cluster 2, adjusted hazard ratio [aHR] 3.306, 95% confidence interval [CI] 1.204–9.077, p=0.020), 4.41%/year (cluster 3, aHR 6.702, 95% CI 2.433–18.461, p Conclusions We identified different clinical phenotypes of AF patients by cluster analysis which were specifically associated with mortality. This approach may help identify patients at higher risk of mortality. Figure 1 Funding Acknowledgement Type of funding source: None

Background Statins are guidelines recommended in patients with peripheral artery disease (PAD) for the prevention of cardiovascular (CV) events. Comprehensive meta-data on the impact of statins on major adverse limb events (MALE) in PAD patients are lacking. We examined the association of statin use with MALE in patients with PAD. Methods We performed a systematic review (registered at PROSPERO: number CRD42019137111) and metanalysis of studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of statin on MALE including amputation and graft occlusion/revascularization. Secondary endpoints were all-cause death, composite CV endpoints, CV death, and stroke. Results We included 51 studies with 138,060 PAD patients, of whom 48,459 (35.1%) were treated with statins. The analysis included 2 randomized controlled trials, 20 prospective, and 29 retrospective studies. Overall, 11,396 MALE events, 21,624 deaths, 4,852 composite CV endpoints, 4,609 CV deaths, and 860 strokes were used for the analysis. Statins reduced MALE incidence by 30% (pooled hazard ratio [HR]: 0.702; 95% confidence interval [CI]: 0.605–0.815) and amputations by 35% (HR: 0.654; 95% CI: 0.522–0.819), all-cause mortality by 39% (pooled HR: 0.608, 95% CI: 0.543–0.680), CV death by 41% (HR: 0.594; 95% CI: 0.455–0.777), composite CV endpoints by 34% (pooled HR: 0.662; 95% CI: 0.591–0.741) and ischemic stroke by 28% (pooled HR: 0.718; 95% CI: 0.620–0.831). Conclusion Statins reduce the incidence of MALE, all-cause, and CV mortality in patients with PAD. In PAD, a high proportion of MALE events and deaths could be prevented by implementing a statin prescription in this patient population.

Aims Many clinical scores for risk stratification in patients with atrial fibrillation have been proposed, and some have been useful in predicting all-cause mortality. We aim to analyse the relationship between clinical risk score and all-cause death occurrence in atrial fibrillation patients. Methods We performed a systematic search in PubMed and Scopus from inception to 22 July 2017. We considered the following scores: ATRIA-Stroke, ATRIA-Bleeding, CHADS2, CHA2DS2-VASc, HAS-BLED, HATCH and ORBIT. Papers reporting data about scores and all-cause death rates were considered. Results Fifty studies and 71 scores groups were included in the analysis, with 669,217 patients. Data on ATRIA-Bleeding, CHADS2, CHA2DS2-VASc and HAS-BLED were available. All the scores were significantly associated with an increased risk for all-cause death. All the scores showed modest predictive ability at five years (c-indexes (95% confidence interval) CHADS2: 0.64 (0.63–0.65), CHA2DS2-VASc: 0.62 (0.61–0.64), HAS-BLED: 0.62 (0.58–0.66)). Network meta-regression found no significant differences in predictive ability. CHA2DS2-VASc score had consistently high negative predictive value (≥94%) at one, three and five years of follow-up; conversely it showed the highest probability of being the best performing score (63% at one year, 60% at three years, 68% at five years). Conclusion In atrial fibrillation patients, contemporary clinical risk scores are associated with an increased risk of all-cause death. Use of these scores for death prediction in atrial fibrillation patients could be considered as part of holistic clinical assessment. The CHA2DS2-VASc score had consistently high negative predictive value during follow-up and the highest probability of being the best performing clinical score.

Background: The use of 123I-mIBG has been approved for decades for Parkinson’s disease (PD) diagnosis and as a predictor of mortality and potentially fatal events in patients with Heart Failure (HF). The standardized technique includes an early acquisition (15 minutes from injection), and a late acquisition (240 minutes). Early images mainly represent interstitial uptake, whereas delayed images represent actual neuronal uptake, however, it is reasonable to affirm that different pathological situations, such as PD and HF, imply a different meaning for early and late imaging. Objective: This prospective study aims to investigate the clinical usefulness of an immediate planar 123I-mIBG image acquisition (5 minutes) both in patients with PD and in patients with HF. Methods: 115 patients referred to 123I-mIBG cardiac imaging in Nuclear Medicine Center have been enrolled (60 patients with PD, absence of diabetes and/or cardiologic pathology, Hoehn e Yahr classification ≤ 1.5; 55 patients with cardiomyopathy, diagnosis of HF, NYHA class I–III). 123I-mIBG planar anterior thoracic acquisitions were performed after 5 (immediate), 15 (early) and 240 (late) minutes from injection and H/M ratios were calculated. Results: In PD group H/M mean values resulted in 1.58±0.22 for immediate (5 min), 1.61±0.26 for early (15 min) and 1.59±0.37 for late (240 min) acquisitions. In the HF group, H/M mean values resulted in 1.63±0.24 for immediate (5 min), 1.65±0.22 for early (15 min) and 1.57±0.17 for late (240 min) acquisitions, respectively. H/M values obtained at 5 min and 15 min are provided similar results, with no statistical difference (p = ns) regardless of the pathology examined (PD or HF groups). The statistical analyses validated the diagnostic role of immediate acquisition (5 min) and early acquisition (15 min) in PD group as compared to the standardized late acquisition (240 min). On the contrary, in HF group, immediate and early acquisition, as compared to late acquisition (240 min), is not validated as a major cardiac events predictor. Conclusion: Our results indicate the potential role of immediate (5 min) or early (15 min) acquisition in replacement of standardized 240 minutes acquisition in PD patients, but this result is not confirmed in HF patients, in which the acquisition at 240 min is confirmed as the most affordable timing for image interpretation, emphasizing the different pathophysiology that underlies these two pathologies.

Objective To estimate the prevalence of nonalcoholic fatty liver disease (NAFLD) and its impact on bleeding and thrombotic events in patients with atrial fibrillation (AF). Patients and Methods Prospective multicenter cohort study including patients with nonvalvular AF receiving vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) from February 2008 for patients on VKA and from September 2013 for patients on NOACs. NAFLD was diagnosed using the validated fatty liver index, with a cutoff score of 60 or higher. Primary end points were the occurrence of major bleedings and cardiovascular events (CVEs). Results NAFLD was diagnosed in 732 of 1735 (42.2%) patients. Patients with NAFLD were younger, less frequently women, and more likely to be treated with NOACs and to have obesity, dyslipidemia, and persistent/permanent AF. During a median follow-up of 18.7 months (3155 patient-years), we recorded 78 major bleedings (incidence rate, 2.5% per year): 29 (2.1% per year) in patients with and 49 (2.7% per year) in patients without NAFLD (log-rank test P=.23). Univariate Cox proportional regression analysis showed no association of NAFLD with major bleedings (hazard ratio, 0.75; 95% CI, 0.47-1.20; P=.23). One hundred fifty-five CVEs occurred (incidence rate, 3.1% per year). No significant association was found between NAFLD and CVEs (log-rank test P=.12). In the entire population, NOAC use was associated with lower CVEs compared with VKAs (hazard ratio, 0.61; 95% CI, 0.42-0.89; P=.01). Conclusion NAFLD is highly prevalent in AF but is not associated with higher bleeding or thrombotic risk.

Background We investigated, in a real-life setting, the prognostic relevance of previous primary treatment (radical prostatectomy [RP] or external beam radiotherapy [EBRT]) on overall survival for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (223Ra). Materials and Methods In the present multicenter retrospective study, we enrolled 275 consecutive patients. The demographic and clinical data and mCRPC characteristics were recorded and evaluated at baseline and at the end of treatment or progression. 223Ra was administered according to the current label authorization until disease progression or unacceptable toxicity. We divided the whole cohort into 2 groups: those who had undergone primary radical prostatectomy or ablative radiotherapy (RP/EBRT) and those who had not received previous primary treatment (NO). Results Of the 275 patients, 128 (46.5%) were alive and undergoing monitoring at the last follow-up examination, 103 (37.4%) had stopped treatment because of disease progression or the onset of comorbidities, and 147 (53.5%) had died during the study period. Of the 275 patients, 132 were in the RP/EBRT group (48%), of whom 93 had undergone RP and 76 had undergone ablative EBRT, and 143 patients were in the NO group (52%). The data showed a clear advantage for the patients in the RP/EBRT group compared with those in the NO group, with an estimated median survival of 18 versus 11 months, respectively (P Conclusions Previous radical treatment provides a protective role for patients with mCRPC undergoing 223Ra treatment.

BACKGROUND: Patients with atrial high-rate episodes (AHREs) are at higher risk of thromboembolic events and mortality. The risk of major adverse cardiovascular events (MACE) in these patients is unknown.OBJECTIVE: To investigate the risk of MACE in patients implanted with cardiac implantable electronic devices (CIEDs) developing AHREs METHODS AND RESULTS: We included 852 consecutive patients undergoing CIEDs implantation. Primary outcome was a composite endpoint of MACEs occurring after AHREs ≥ 5 min. AHRE was defined as > 175 bpm and lasting ≥ 5 min. We also performed a subgroup analysis in patients with the longest AHRE lasting ≥ 24 h. Cox regression analysis with time-dependent covariates was used to investigate the relationship between AHREs and MACEs. Mean age was 70.0 ± 13.6 years, and 39.3% were women: 325 patients developed AHREs ≥ 5 min [incidence rate (IR) 13.1% year 95% confidence interval (CI) 11.7-14.6] and 124 patients developed AHREs ≥ 24 h (IR 3.7%/year 95% CI 3.1-4.5). During a median follow-up of 37.0 months (IQR 19.0-64.3, 316,132 patient-years), 152 MACEs occurred (IR 4.85%/year, 95% CI 4.11-5.68). The IR of MACE occurring after AHREs onset was higher in patients developing AHREs ≥ 24 h (IR 1.13%/year) than AHREs ≥ 5 min (IR 0.63%/year, p = 0.030). Multivariable Cox regression analysis showed that AHREs ≥ 5 min (HR 1.788, 95% CI 1.247-2.562, p = 0.002), diabetes (HR 1.909, 95% CI 1.358-2.683, p CONCLUSIONS: Patients implanted with CIEDs developing AHREs show a significant risk for MACE, which is dependent on AHREs burden. Cardiovascular prevention strategies in this patient population are warranted.

Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible

Summary Introduction To systematically review clinical and biochemical characteristics associated with the severity of the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐related disease (COVID‐19). Materials and methods Systematic review of observational studies from PubMed, ISI Web of Science, SCOPUS and Cochrane databases including people affected by COVID‐19 and reporting data according to the severity of the disease. Data were combined with odds ratio (OR) and metanalysed. Severe COVID‐19 was defined by acute respiratory distress syndrome, intensive care unit admission and death. Results We included 12 studies with 2,794 patients, of whom 596 (21.33%) had severe disease. A slightly higher age was found in severe versus non‐severe disease. We found that prevalent cerebrovascular disease (Odds Ratio [OR] 3.66, 95% Confidence Interval [CI] 1.73‐7.72), chronic obstructive pulmonary disease (OR: 2.39, 95%CI 1.10‐5.19), prevalent cardiovascular disease (OR: 2.84, 95%CI 1.59‐5.10), diabetes (OR: 2.78, 95%CI 2.09‐3.72), hypertension (OR: 2.24, 95%CI 1.63‐3.08), smoking (OR: 1.54, 95%CI 1.07‐2.22), and male sex (OR: 1.22, 95%CI 1.01‐1.49) were associated with severe disease. Furthermore, increased procalcitonin (OR: 8.21, 95%CI 4.48‐15.07), increased D‐Dimer (OR: 5.67, 95%CI 1.45‐22.16) and thrombocytopenia (OR: 3.61, 95%CI 2.62‐4.97) predicted severe infection. Discussion Characteristics associated with the severity of SARS‐CoV‐2 infection may help to guide the early identification and management of patients with poor outcomes.

Background Bloodstream infections (BSIs) by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) are associated with high mortality. The aim of this study is to assess the relationship between time to administration of appropriate antibiotic therapy and the outcome of patients with BSI due to KPC-Kp hospitalized in intensive care unit (ICU). Methods An observational study was conducted in the ICUs of two academic centers in Italy. Patients with KPC-Kp bacteremia hospitalized between January 2015 to December 2018 were included. The primary outcome was the relationship between time from blood cultures (BC) collection to appropriate antibiotic therapy and 30-day mortality. The secondary outcome was to evaluate the association of different treatment regimens with 30-day mortality and a composite endpoint (30-day mortality or nephrotoxicity). A Cox regression analysis to identify factors independently associated with 30-day mortality was performed. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. Results A total of 102 patients with KPC-Kp BSI were included. The most common sources of infection were intra-abdominal (23.5%), urinary tract (20.6%), and skin and skin structure (17.6%). The 30-day mortality was 45%. Median time to appropriate antibiotic therapy was shorter in patients who survived (8.5 h [IQR 1–36]) versus those who died (48 h [IQR 5–108], p = 0.014). A propensity score matching showed that receipt of an in vitro active therapy within 24 h from BC collection was associated with lower 30-day mortality (HR = 0.36, 95% CI: 0.188–0.690, p = 0.0021). At Cox regression analysis, factors associated with 30-day mortality were primary bacteremia (HR 2.662 [95% CI 1.118–6.336], p = 0.027), cardiovascular disease (HR 2.196 [95% CI 1.082–4.457], p = 0.029), time (24-h increments) from BC collection to appropriate therapy (HR 1.382 [95% CI 1.132–1.687], p = 0.001), SOFA score (HR 1.122 [95% CI 1.036–1.216], p = 0.005), and age (HR 1.030 [95% CI 1.006–1.054], p = 0.012). Ceftazidime-avibactam-containing regimens were associated with reduced risk of composite endpoint (30-day mortality OR nephrotoxicity) (HR 0.231 [95% CI 0.071–0.745], p = 0.014) compared to colistin-containing regimens. Conclusions Time to appropriate antibiotic therapy is an independent predictor of 30-day mortality in patients with KPC-Kp BSI. Appropriate antibiotic therapy should begin within 24 h from the collection of BC.

Objective The central nervous system (CNS) may be involved in a variety of inflammatory diseases of the blood vessels, generally known as vasculitis. The clinical diagnosis of such involvement in early stages is difficult, since a mild cognitive impairment can be the only symptom. It was hypothesized that brain-perfusion SPECT would be able to reveal CNS involvement and to monitor the course of the disease. The purpose of this study was assess if and when an improvement of cerebral perfusion can be registered by SPECT during the follow-up of these diseases. Material and methods Eighteen patients affected by Systemic Lupus Erythematosus (SLE), 22 by undifferentiated vasculitis (UV), 5 by Behcet's disease (BD) and 5 by primary Sjogren's Syndrome (pSS) were enrolled in this prospective study. A 99mTc-HMPAO brain perfusion SPECT was performed before the treatment and was repeated during the follow-up at different time intervals. Image analysis was performed on 10 cerebral areas using a specific software. Results In the SLE patients, no significant improvement of brain perfusion was found. On the contrary, in the UV the cerebral uptake of the tracer significantly improved from the twenty-fourth month (18/22 patients). Patients with BD showed an improvement of scintigraphic findings (5/5 patients), while a similar result was obtained only in 2 of the patients with pSS. Conclusions In conclusion, brain SPECT seems to be able to monitor the disease in UV, indicating the moment when an improvement of the cerebral perfusion is achieved. In SLE patients this scintigraphic technique did not show a significant improvement in CNS perfusion.

Background: Use of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) is associated with an inherited risk of bleeding. Benefits and risks of OAC restarting after a major bleeding are still uncertain. We aimed to assess effectiveness and safety of restarting OAC in AF patients after a major bleeding event. Methods: We performed a systematic review and meta-analysis of all studies reporting data about AF patients that sustained a major bleeding, reporting data on restarting or not restarting OAC therapy. Results: A total of seven studies were included, involving 5685 patients. No significant difference was found in “any stroke” occurrence between OAC restarters and non-restarters (odds ratio [OR]: 0.75, 95% confidence interval [CI]: 0.37–1.51), with a significant 46% relative risk reduction (RRR) (p < 0.00001) for “any thromboembolism” in OAC restarters, with consistent results when the index bleeding event was an intracranial or gastrointestinal bleeding. A significantly higher risk of recurrent major bleeding was seen (OR: 1.85, 95% CI: 1.48–2.30), but no difference in risk for recurrence of index event. OAC restarters had a 10.8% absolute risk reduction for all-cause death (OR: 0.38, 95% CI: 0.24–0.60); p < 0.00001). Net clinical benefit (NCB) analysis demonstrated that restarting OAC therapy after a major bleeding was significantly associated with a clinical advantage (NCB: 0.11, 95% CI: 0.09–0.14; p < 0.001). Conclusions: Restarting OAC therapy after a major bleeding event in AF was associated with a positive clinical benefit when compared to non-restarting OAC, with a significant reduction in any thromboembolism and all-cause mortality.

Background: Despite therapeutic improvement, the prognosis of chronic heart failure (CHF) remains unfavorable partly due to arrhythmia and sudden cardiac death (SCD). This prospective study evaluated myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy as a predictor of arrhythmic events (AE) in CHF patients. Methods: 170 CHF patients referred for implantable cardioverter-defibrillator (ICD) implantation for both primary and secondary prevention were enrolled. All patients underwent planar and SPECT imaging. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO), early and late summed SPECT scores were calculated The primary endpoint was an AE: sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD therapy or SCD. The secondary endpoint was appropriate ICD therapy. Results: During a median follow-up of 23.3 months, 69 patients experienced an AE. Early summed score (ESS) was the only independent predictor of AE [HR 1.023 (1.003-1.043)]. Focussing on only patients with an ICD for primary prevention, ESS was the only independent predictor of AE [HR 1.028 (1.007-1.050)]. 123I-mIBG-derived parameters failed to be independent predictors of appropriate ICD therapy. However there was a “bell-shaped” relation between 123I-mIBG scintigraphy-derived parameters and AE and appropriate ICD therapy, i.e., those with intermediate 123I-mIBG abnormalities tended to be at higher risk of events. Conclusion: Although SPECT 123I-mIBG scintigraphy was associated with AE in CHF patients with ICD implantation for primary and secondary prevention, no association was found between 123I-mIBG scintigraphy-derived parameters and appropriate ICD therapy.

Background Spleen and liver stiffness measured by Acoustic radiation force impulse (ARFI) imaging has been showed to be useful in identifying patients with portal hypertension. Aim to establish if the modification of portal pressure induced by a TIPS parallels the modification of spleen or liver stiffness measured by ARFI in order to understand if ARFI may be used to monitor the modification of portal pressure in patients with cirrhosis. Patients and Methods 38 patients with severe portal hypertension underwent liver stiffness (LS) and spleen stiffness (SS) before TIPS and one week after TIPS. Portal atrial gradient (PAG) was measured before and after the shunt opening. Results PAG decreased significantly from 19.5 mmHg to 6 mmHg (p

Background: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No...

Sarcopenia is a frequent complication in liver transplant (LT) recipients. &beta, hydroxy-&beta, methyl-butyrate (HMB) has the potential to increase muscle-performance and tropism. Our study aims at evaluating the effect on muscle mass and functioning, and the safety of 12 weeks of HMB supplementation in patients after LT. This is a pilot, randomized study. Male patients undergoing LT were randomly assigned to the HMB or control group. A diet interview, anthropometry and body composition by dual energy X-ray absorptiometry (DEXA) were performed at enrollment (T0), after 12 weeks (T1) and after 12 months (T12). Twenty-two liver transplant male patients were enrolled in the study: 12 in the HMB group and 10 as the control group. At enrollment, demographic, clinical and nutritional data were similar. According to the appendicular skeletal muscle index, sarcopenia was present in 50% of patients. The appendix skeletal muscle mass index (ASMI) showed a significant increase at T1 and T12 in HMB patients, but not in controls. The mid-arm muscle-circumference and hand grip strength also increased at T1 and T12 versus T0 only in the HMB group. No side effects were reported in either group. The study showed a positive effect of HMB in the recovery of muscle mass and strength after LT. HMB supplement in patients after LT was safe and well tolerated.

We discuss Bayesian log-linear models for incomplete contingency tables with both missing and interval censored cells, with the aim of obtaining reliable population size estimates. We also discuss use of external information on the censoring probability, which may substantially reduce uncertainty. We show in simulation that information on lower bounds and external information can each improve the mean squared error of population size estimates, even when the external information is not completely accurate. We conclude with an original example on estimation of prevalence of multiple sclerosis in the metropolitan area of Rome, where five out of six lists have interval censored counts. External information comes from mortality rates of multiple sclerosis patients.

Italian Group for Antimicrobial Stewardship, GISA., [Background] Echinocandins are recommended as firstline therapy in patients with candidemia. However, there is debate on their efficacy in survival outcomes. The aim of this study is to evaluate whether the choice of initial antifungal therapy improves mortality in patients with candidemia in relation to the presence of septic shock., [Methods] Patients with candidemia hospitalized in internal medicine wards of 5 tertiary care centers were included in the study (December 2012–December 2014). Patient characteristics, therapeutic interventions, and outcome were reviewed. Propensity score (PS) was used as a covariate of the multivariate analysis to perform a stratified analysis according to PS quartiles and to match patients receiving “echinocandins” or “azoles.”, [Results] Overall, 439 patients with candidemia were included in the study. A total of 172 (39.2%) patients had septic shock. Thirty-day mortality was significantly higher in patients with septic shock (45.3%) compared with those without septic shock (31.5%; P = .003). Among patients with septic shock, the use of echinocandins in the first 48 hours, compared with azoles, did not affect 30-day mortality in the PS-adjusted Cox regression analysis (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.37–1.59; P = .48), the PS-stratified analysis, or the logistic regression model in matched cohorts (adjusted HR, 0.92; 95% CI, 0.51–1.63; P = .77)., [Conclusions] Echinocandin therapy seems not to improve the outcome of non–intensive care unit patients with septic shock due to candidemia. These findings support the urgent need of further studies in this patient population.

The predictive role of serum albumin (SA) has been evaluated in primary prevention studies. We want to assess the association of SA with the subsequent risk of cardiovascular events (CVE) in primary and secondary prevention studies. We performed a systematic review and Bayesian meta-regression analysis. Studies were identified by PubMed and EMBASE database using a combination of the following terms and MeSH terms: “serum albumin”, “myocardial infarction, “cardiovascular events”, “percutaneous coronary intervention” and “coronary restenosis”. No time restriction of the research was applied. Two experienced physicians reviewed data on outcome measures and assessed the quality rating. The main outcomes were CVE including myocardial infarction, coronary heart disease, percutaneous coronary intervention and coronary restenosis. 15 studies of SA and CVE were identified involving 65,077 subjects with a mean age of 57.89 ± 6.05 years and a mean follow-up of 9.4 (±5.56) years. Subjects under SA cut-off of 3.8 g/dL had a combined hazard ratio (HR) for CVE of 2.16 [95% confidence interval (CI) 1.93–2.45]. An increased risk for CVE was also evident using SA as a continuous variable (HR = 1.89, 95% CI 1.5–2.39). Females and males had a similar risk for CVE (HR 2.46, 95% CI 1.92–3.16, and HR 1.46, 95% CI 1.27–1.69, respectively). We found a similar risk of CVE between primary and secondary prevention studies (HR 1.79, 95% CI 1.5–2.17, and HR 2.47, 95% CI 2.24–2.75, respectively). Low SA levels are associated with an increased risk of CVE, not only in subjects free from CVE, but also in patients who already experienced a CVE.

Aims Overall, 40% of patients with atrial fibrillation are asymptomatic. The usefulness and cost-effectiveness of atrial fibrillation screening programmes are debated. We evaluated whether an atrial fibrillation screening programme with a handheld electrocardiogram (ECG) machine in a population-wide cohort has a high screening yield and is cost-effective. Methods We used a Markov-model based modelling analysis on 1000 hypothetical individuals who matched the Belgian Heart Rhythm Week screening programme. Subgroup analyses of subjects ≥65 and ≥75 years old were performed. Screening was performed with one-lead ECG handheld machine Omron® HeartScan HCG-801. Results In both overall population and subgroups, the use of the screening procedure diagnosed a consistently higher number of diagnosed atrial fibrillation than not screening. In the base-case scenario, the screening procedure resulted in 106.6 more atrial fibrillation patient-years, resulting in three fewer strokes, 10 more life years and five more quality-adjusted life years (QALYs). The number needed-to-screen (NNS) to avoid one stroke was 361. In subjects ≥65 years old, we found 80.8 more atrial fibrillation patient-years, resulting in three fewer strokes, four more life-years and five more QALYs. The NNS to avoid one stroke was 354. Similar results were obtained in subjects ≥75 years old, with a NNS to avoid one stroke of 371. In the overall population, the incremental cost-effectiveness ratio for any gained QALY showed that the screening procedure was cost-effective in all groups. Conclusions In a population-wide screening cohort, the use of a handheld ECG machine to identify subjects with newly diagnosed atrial fibrillation was cost-effective in the general population, as well as in subjects ≥65 and subjects ≥75 years old.

OBJECTIVE Painful bone metastases cause reduced quality of life (QoL) in patients with castration-resistant prostate cancer (CRPC). Alpha-emitter 223Radium is associated with a clear survival benefit and significant bone pain palliation in CRPC patients with symptomatic bone metastases. The aim of this study was to evaluate the association between pain relief and psychological distress during the time course of therapy in patients treated with 223Radium. METHODS A total of 63 patients with mCRPC undergoing 223Radium treatment in our Nuclear Medicine Unit, carefully instructed on the possibility of improving the pain and increasing the survival by the treatment, were retrospectively evaluated. Pain response during treatment was assessed with the Brief Pain Inventory Numeric Rating Scale. Psychological distress was evaluated through the analysis of specific items from EORTC QoL questionnaires C30 and BM22, submitted to patients at baseline and after each 223Radium cycle. RESULTS Pain intensity showed a significant decrease after first 223Radium administration (-1.03 points, p = 0.0032), with a subsequent stability through the course of treatment (-1.30 points, p =

Introduction In recent years the hypothesis that gut microbiota associates with Parkinson's disease (PD) has gained importance, although it has not been possible to define a specific microbiota composition as a predictive biomarker of this disease. We have investigated dysbiosis of gut microbiota in a selected population of PD patients from Central Italy, and examined the weight of specific confounders and predictors, in order to identify potential correlations with clinical phenotypes. Methods 152 fecal samples were collected from 80 patients and 72 healthy controls. Patients were enrolled according to tight inclusion criteria. Microbiota composition was studied through 16s ribosomal RNA gene amplicon sequencing analysis in combination with data on dietary/life habits. Age, loss of weight, and sex were recognized as confounding factors, whereas PD-status, age, Body Mass Index, “eat cereals”, “gain of weigth” and “physical activity” as predictors. The presence of Lactobacillaceae, Enterobacteriaceae and Enterococcaceae families was significantly higher in feces from PD patients compared to healthy controls, while Lachnospiraceae were significantly reduced. Lower levels of Lachnospiraceae and higher levels of Enterobacteriaceae families also correlated with increased disease severity and motor impairment (Hoehn & Yahr stage, MDS-UPDRS Part III). Predictive metagenomics indicated a significant variation of genes involved in the metabolism of short chain fatty acids and amino acids, and in lipopolysaccharide biosynthesis. Conclusions PD showed a distinctive microbiota composition. Functional predictions suggest changes in pathways favoring a pro-inflammatory environment in the gastrointestinal tract, and a reduction in the biosynthesis of amino acids acting as precursors of physiological transmitters.

Background & aims Little is known on nutritional parameters in patients with chronic portal vein thrombosis (PVT) and idiopathic non-cirrhotic portal hypertension (INCPH). The study aims to assess the prevalence and the clinical impact of sarcopenia in patients with non-cirrhotic portal hypertension (NCPH). A control group of cirrhotic patients was also studied. Both groups were followed up to establish the relationship between sarcopenia and clinical outcomes. Methods Sixty-seven patients with NCPH (51 PVT and 16 INCPH) were included in the study group and 104 patients with liver cirrhosis in the control group. The axial plane passing through the intersomatic disk between L3 and L4 was evaluated for the quantitative analysis of muscle mass and the skeletal muscle index (SMI) was calculated. The presence of sarcopenia was established according to SMI validated cut off. Results Sarcopenia was present in the 38% of patients with INCPH, 35% of patients with chronic PVT, 32% of patients with compensated cirrhosis and 54% of decompensated cirrhotics. During a mean follow-up of 51 ± 62 months, there was no difference in sarcopenic and non-sarcopenic patients with NCPH for incidence of ascites, hepatic encephalopathy, esophageal varices, variceal bleeding and death. However, the incidence of refractory variceal bleeding requiring TIPS placement was significantly higher in comparison with the non-sarcopenic ones (29% vs 7%, P = 0.01 at log-rank test). Conclusions In patients with NCPH sarcopenia is similar to that observed in cirrhotic patients. Moreover, the rate of refractory variceal bleeding was higher in sarcopenic patients suggesting a clinical negative impact of muscle depletion.

While the inflammatory response to severe pneumonia is paramount in limiting and resolving the infection, excessive inflammation can lead to deleterious effects. We theorized that patients with severe community-acquired pneumonia (CAP) who were treated with macrolides and aspirin would receive benefit beyond that of conventional antibiotic therapy. An observational study was conducted with patients with severe CAP. All patients were admitted to 5 teaching hospitals (in Italy, the United States, Japan, and China), and data were gathered from their electronic medical records. Severe pneumonia was defined according to Infectious Diseases Society of America/American Thoracic Society criteria. Patients were divided into 4 groups, i.e., (i) the aspirin-only group (ASG), (ii) the macrolide-only group (MG), (iii) the aspirin plus macrolide group (ASMG), or (iv) the neither aspirin nor macrolide group (NASMG). Survival rates for the 4 groups were evaluated after adjustment for confounders and after weighting by propensity score. A total of 1,295 patients were included in the analysis. There were 237 patients (18.3%) in the ASG, 294 (22.7%) in the MG, 148 (11.4%) in the ASMG, and 616 (47.6%) in the NASMG. The mortality rate at 30 days was 15.5% in the ASMG, compared to 28.2% in the NASMG, 23.8% in the MG, and 21.1% in the ASG. After propensity score analysis, receipt of aspirin plus macrolide (hazard ratio, 0.71 [95% confidence interval, 0.58 to 0.88]; P = 0.002) was associated with a higher 30-day survival rate. This is a hypothesis-generating study in which data suggest that the combination of aspirin plus a macrolide improves 30-day survival rates for patients with severe CAP. Further randomized studies will need to be undertaken to confirm this phenomenon.

Rosellina Margherita Mancina,1,* Flaminia Ferri,2,* Alessio Farcomeni,3 Antonio Molinaro,1 Angela Maffongelli,4 Monica Mischitelli,2 Edoardo Poli,2 Lucia Parlati,5 Maria Antonella Burza,6 Adriano De Santis,2 Fabio Attilia,2 Claudia Rotondo,2 Maria Margherita Rando,2 Maria Luisa Attilia,2 Mauro Ceccanti,2 Stefano Ginanni Corradini2 1Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Wallenberg Laboratory, Göteborg, Sweden; 2Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; 3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; 4Department of General Surgery, Urgency and Organ Transplantation, University Hospital “Paolo Giaccone”, University of Palermo, Palermo, Italy; 5Hepatology Department, Université Paris Descartes, Cochin Hospital, APHP, Paris, France; 6Department of Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden *These authors contributed equally to this work Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption.Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves.Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity.Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors. Keywords: alcoholic cirrhosis, PNPLA3, CD14, predictive score

Background Since the use of the Model for End-Stage Liver Disease (MELD) score for establishing the prognosis of cirrhotic patients has been introduced, questions have been raised whether complications of liver cirrhosis would provide additional information. Myosteatosis, sarcopenia and hepatic encephalopathy (HE) are frequent in cirrhosis and may affect prognosis. Aim of the study was analyzing if these factors are independently related to survival and may improve the accuracy of MELD. Methods 249 cirrhotics that underwent abdominal CT-scan were enrolled. For each patient, information about previous episodes of HE and muscle alterations were obtained. Patients were followed until transplantation or death. Results History of HE, MELD, sarcopenia and myosteatosis were independently associated with mortality. The MELD-Sarco-Myo-HE score added accuracy to the MELD score alone for 6- and 3-months mortality. By removing HE, as the only not quantifiable parameter of the model, no relevant decrease in accuracy for 6- and 3-months mortality detection was observed. Conclusions The accuracy of MELD in predicting 3- and 6-months mortality may be improved by considering the muscle alterations. A model considering the above parameters may classify more accurately over 30% of the patients.

BACKGROUND The Atrial fibrillation Better Care (ABC) pathway has been proposed to streamline patient management in an integrated, holistic manner. Compliance to ABC resulted in lower incidence of cardiovascular events, but its impact on health-related costs has not been evaluated. METHODS Exploratory analysis of costs related to cardiovascular events in the ATHERO-AF prospective cohort study including atrial fibrillation patients on vitamin K antagonists. A Diagnosis-Related Group code provided by the Italian Ministry of Health was assigned to each event to estimate the relative cost. The analysis was performed by dividing patients according to ABC pathway components. RESULTS Overall, 118 cardiovascular events incurred a cost of 1,017,354 euros (1,149,610 USD). The mean total costs were 13,050 (14,747 USD) and 11,218 euros (12,676 USD) for a non-fatal cardiac event or ischaemic stroke, respectively. The cost-saving was 719 euros (813 USD) per patient-year for patients in group A vs non-A, 703 euros (794 USD) for B vs non-B, 480 euros (542 USD) for C vs non-C and 2776 euros (3,137 USD) for ABC vs non-ABC. The cost per event increased with the number of uncontrolled ABC components: 507 euros (573 USD) for 1, 965 euros (1,091 USD) for 2 and 3,431 euros (3,877 USD) for patients not having any of the three components of the ABC. CONCLUSIONS Management of atrial fibrillation patients according to the ABC pathway was associated with significantly lower health-related costs. Application of the ABC pathway may help reduce healthcare costs related to cardiovascular events in this high-risk patient population.

Adults hospitalized for community-acquired pneumonia (CAP) have an increased risk of myocardial infarction. Corticosteroid treatment lowers CAP morbidity and mortality, but it is not known whether it influences in-hospital myocardial infarction.The aim of the present study was to investigate the potential interplay between corticosteroid treatment and in-hospital myocardial infarction in adults with CAP.We retrospectively analyzed adults with CAP referred to the University Hospital Policlinico Umberto I (Rome, Italy), consecutively recruited, and prospectively followed until discharge. The primary outcome was the occurrence of myocardial infarction during hospitalization. We used propensity score-adjusted Cox models to examine the association between corticosteroid use and myocardial infarction.Seven hundred fifty-eight patients (493 males, 265 females; mean ± standard deviation age, 71.7 ± 14.4 yr) were included in the study. Of these, 241 (32%) were treated with systemic corticosteroids (methylprednisolone, betamethasone, or prednisone). During follow-up, 62 (8.2%) had a myocardial infarction during their hospitalization (incidence, 0.72 per 100 person-days; 95% confidence interval [CI], 0.55 to 0.92). Those treated with corticosteroids had a lower incidence of myocardial infarction (0.42 per 100 person-days) than those not treated with corticosteroids (0.89 per 100 person-days; absolute rate difference, -0.48 per 100 person-days; 95% CI, -0.85 to -0.10). In a propensity score-adjusted Cox model, corticosteroid use was associated with a lower incidence of myocardial infarction (hazard ratio, 0.46; 95% CI, 0.24 to 0.88; P = 0.02).We found that in-hospital corticosteroid treatment was associated with a lower incidence of myocardial infarction in adults hospitalized with CAP.

Objective To evaluate the effect of hospitalization on deep venous thrombosis (DVT) rate by the cumulative incidence of DVT in the proximal venous tract of the lower limbs at admission and discharge. Methods The AURELIO (rAte of venoUs thRombosis in acutEly iLl patIents hOspitalized in internal medicine wards) multicenter observational study was carried out in hospital-university internal medicine wards including consecutive acutely ill medical patients. Patients underwent compression ultrasonography (CUS) of proximal lower limb veins at admission and discharge. The occurrence of DVT was the primary end point of the study. Results Among 1340 patients, 26 (1.9%; 95% CI, 1.3%-2.8%) had asymptomatic DVT at admission and were excluded. During the follow-up, 144 patients were excluded because of hospitalization less than 5 days. The remaining 1170 patients underwent a CUS at discharge. Two hundred fifty (21%) underwent prophylaxis with parenteral anticoagulants; the remaining 920 (79%) were not treated with anticoagulants. The mean length of hospitalization was 13±8 days. Compared with patients without prophylaxis, those treated with parenteral anticoagulants had a higher incidence of active cancer, heart and respiratory failure, pneumonia, renal failure, previous venous thromboembolism, reduced mobility, and elderly age. During the hospital stay, 3 patients with a negative CUS at admission experienced DVT in the proximal tract (0.025%, rate of 1 per 5017 patient-days); 2 of them were in prophylaxis with parenteral anticoagulants. Conclusion We provide evidence that in the real world acutely ill medical patients display more than 90% (1.9%) asymptomatic DVT at admission, whereas the intrahospital DVT occurrence is very low. This suggests a novel diagnostic workup and a careful reanalysis of anticoagulant prophylaxis.

Anticardiolipin antibodies of the immunoglobulin G isotype (IgG aCL) have been suggested as risk factor for arterial and venous thrombosis. No conclusive data in patients with coronary artery disease (CAD) do exist. We investigate the risk of recurrent CAD according to the presence of IgG aCL.We performed a systematic review and meta-analysis to evaluate the risk of recurrent major adverse cardiac events (MACE) associated with the presence of IgG aCL in patients with CAD. MEDLINE and Cochrane databases were searched. We conducted a meta-analysis of the relative risk (RR) both at 12 and 24 months.We included 11 eligible studies with a total of 2425 patients, 283 IgG aCL+ and 2142 IgG aCL-. The prevalence of IgG aCL+ ranged from 6.1% to 43.3%. A total of 341 cardiac events were reported: 71 (25.1%) in IgG aCL+ and 270 (12.6%) in IgG aCL- patients. We found an increased risk of recurrent MACE in patients with high IgG aCL both at 12 (RR 2.17, 2.5-97.5%CI, 1.54-3.00) and 24 months (RR 2.11, 2.5-97.5%CI, 1.62-2.66). This association was even stronger in patients with juvenile CAD (i.e.50 years) at both 12 (RR 3.21, 2.5-97.5%CI, 1.74-5.41) and 24 months (RR 3.24, 2.5-97.5%CI, 1.84-5.21).Patients with CAD and elevated IgG aCL have a doubled risk of recurrent MACE at 12 and 24 months. The presence of aCL should be suspected in patients with recurrent CAD events or in patients with juvenile CAD.

Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis. Proton pump inhibitors (PPIs) can contribute to small-bowel bacterial overgrowth, but no study has investigated the link between PPIs and MHE. We investigated the relationship between MHE and PPI use as well as the role of PPI use in the development of overt HE and survival. Consecutive patients with cirrhosis (n = 310) were included in the study and followed up for 14.1 ± 12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score was ≤-4. Data were analyzed by logistic regression for the factors associated with MHE and by time-related models for overt HE development and survival. At inclusion, 131 out of 310 patients with cirrhosis (42%) were affected by MHE. One hundred and twenty-five patients (40%) were using PPIs. The variables independently associated with the presence of MHE were PPI use, previous overt HE, low albumin, low sodium, and age. During follow-up, the development of overt HE was higher (64% versus 25%, P < 0.001) and overall survival lower (41% versus 81%, P < 0.001) in PPI users than in nonusers. Variables independently associated with the development of overt HE were PPIs, history of overt HE, low albumin, MHE, and age, while variables independently associated with mortality were PPIs, development of overt HE, Model for End-Stage Liver Disease score, low sodium, and age. Conclusion: The study identifies a potentially removable factor associated with the presence of MHE and related to the development of overt HE and survival in patients with liver cirrhosis.

Background and aims Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated. Methods We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs. Results Median PCSK9 and LPS were 1200 [900–1970] and 49.9 [15.0–108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p Patients with concomitant high PCSK9 and LPS (LPS ≥88 pg/ml and PCSK9 ≥1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS Conclusions This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.

Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p

Background Energy homeostasis is mediated by the hypothalamus, whose inflammation-induced functional derangements contribute to the onset of anorexia in cancer. By using functional magnetic resonance imaging (fMRI), we determined the patterns of hypothalamic activation after oral intake in anorexic (A), non-anorexic (NA) cancer patients, and in controls (C). Methods Lung cancer patients were considered. Hypothalamic activation was recorded in A and NA patients and in C by fMRI, before (T0), immediately after (T1) the administration of an oral nutritional supplement, and after 15 min (T2). The grey of the hypothalamus and Blood Oxygen Level Dependent (BOLD) intensity were calculated and normalized for basal conditions. Interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, ghrelin, and leptin plasma levels were measured. A statistical parametric mapping was used. Results Thirteen lung cancer patients (7 M, 6 F; 9A, 4NA) and 2 C (1 M, 1 F) were enrolled. Controls had the lowest BOLD intensity. At all-time points, anorexic patients showed lower hypothalamic activity compared with NA (P