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Background The severe acute respiratory syndrome Coronarovirus-2 associated still causes a significant number of deaths and hospitalizations mainly by the development of respiratory failure. We aim to validate lung ultrasound score in order to predict mortality and the severity of the clinical course related to the need of respiratory support. Methods In this prospective multicenter hospital-based cohort study, all adult patients with diagnosis of SARS-CoV-2 infection, performed by real-time reverse transcription polymerase chain reaction were included. Upon admission, all patients underwent blood gas analysis and lung ultrasound by expert operators. The acquisition of ultrasound scan was performed on 12 peculiar anatomic landmarks of the chest. Lung ultrasound findings were classified according to a scoring method, ranging 0 to 3: Score 0: normal A-lines. Score 1: multiple separated B-lines. Score 2: coalescent B-lines, alteration of pleural line. Score 3: consolidation area. Results One thousand and seven patients were included in statistical analysis (male 62.4 %, mean age 66.3). Oxygen support was needed in 811 (80.5 %) patients. The median ultrasound score was 24 and the risk of having more invasive respiratory support increased in relation to higher values score computed. Lung ultrasound score showed negative strong correlation (rho: -0.71) with the P/F ratio and a significant association with in-hospital mortality (OR 1.11, 95 %CI 1.07–1.14; p < 0.001), even after adjustment with the following variables (age, sex, P/F ratio, SpO2, lactate, hypertension, chronic renal failure, diabetes, and obesity). Conclusions The novelty of this research corroborates and validates the 12-field lung ultrasound score as tool for predicting mortality and severity clinical course in COVID-19 patients. Baseline lung ultrasound score was associated with in-hospital mortality and requirement of intensive respiratory support and predict the risk of IOT among COVID-19 patients.

Performance of T-SPOT.TB™ (TS-TB) and QuantiFERON TB Gold- In tube (QFT-IT) assays was evaluated for detection of M. tuberculosis (Mtb) infection in patients with suspected extra-pulmonary or smear-negative pulmonary tuberculosis (TB) in a low prevalence country. Twenty-one out of 35 patients were affected by active TB. Mtb culture isolation was achieved in 76% of cases. Tuberculin skin testing (TST), TS-TB, and QFT-IT yielded a positive result in 67%, 95% and 81% of cases, respectively. Agreement of interferon-γ release assays and TST was 70% (κ=0.18 for TS-TB; κ=0.46 for QFT-IT). Increased sensitivity of blood assays (>80%) improved diagnostic evaluation of difficult TB cases.

Aims: Hyperglycaemic conditions increase cardiac stress, a common phenomenon associated with inflammation, aging, and metabolic imbalance. Sodium-glucose cotransporter 2 inhibitors, a class of anti-diabetic drugs, showed to improve cardiovascular functions although their mechanism of action has not yet been fully established. This study investigated the effects of empagliflozin on cardiomyocytes following high glucose exposure, specifically focusing on inflammatory and metabolic responses., Methods and Results: A three-part strategy was formulated: (i) a meta-analysis of selected randomized clinical trials was carried out to assess the anti-inflammatory effects of empagliflozin in diabetic patients; (ii) the impact of empagliflozin on human cardiomyocyte AC16 cells exposed to normal (5 mM) and high (33 mM) glucose concentrations for 2 and 7 days was explored by evaluating gene expression and protein levels of pivotal markers associated with cardiac inflammation, stress, endoplasmic reticulum damage, and calcium modulation; (iii) in silico data from bioinformatic analyses were exploited to construct an interaction map delineating the potential mechanism of action of empagliflozin on cardiac tissue. Empagliflozin reversed high-glucose mediated alterations at the transcriptional level, decreasing inflammatory, metabolic, and aging signatures. Specifically, in vitro experiments on human cardiomyocytes, meta-analyses of clinical data on inflammatory biomarkers from diabetic peripheral blood samples, and sequencing of pathological human heart tissues, all support that empagliflozin exerts anti-inflammatory effects both systemically and directly in cardiac tissue, on cardiomyocytes., Conclusion: Our study provides insights based on robust mechanistic data for optimizing heart failure management and highlights the intricate interplay between diabetes, inflammation, aging, and cardiovascular health., (© 2025 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

BACKGROUNDRecent studies conducted in individuals who survived COVID-19 suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is affecting the overall burden of cardiometabolic diseases.METHODSTo address these aspects, we conducted a 6-year longitudinal study to examine the broader effects of COVID-19 on dyslipidemia incidence in a real-world population (228,266 individuals) residing in Naples in southern Italy. The pre-COVID-19 and COVID-19 groups were balanced for demographic and clinical factors using propensity score matching.RESULTSOur analysis spans a period of 3 years during the COVID-19 pandemic (2020-2022), comparing dyslipidemia incidence with pre-pandemic data (2017-2019), with a follow-up of at least 1,095 days corresponding to 21,349,215 person-years. During the COVID-19 period, we detected an increased risk of developing any dyslipidemia when compared with the pre-COVID-19 triennium (OR = 1.29; 95% CI, 1.19-1.39). Importantly, these estimates were adjusted for comorbidities by a multivariate analysis.CONCLUSIONSTaken together, our data reveal a notable rise in dyslipidemia incidence during the COVID-19 pandemic, suggesting the utility of establishing specialized clinical monitoring protocols for patients who survive COVID-19 to mitigate the risk of developing dyslipidemia.

Background: Left bundle branch (LBB) pacing could achieve cardiac resynchronization therapy (CRT) in patients who cannot be resynchronized via the placement of the left ventricle (LV) lead into the coronary sinus. LBB pacing could improve cardiovascular outcomes in heart failure (HF) patients with LBB block who are affected by type 2 diabetes mellitus (T2DM)., Study Hypothesis: LBB pacing could increase the number of CRT responders and lead to the best clinical outcomes in HF patients with T2DM, inducing cardiac remodeling and improving left ventricle ejection fraction (LVEF) via microRNA (miR) modulation., Methods: In a multicenter observational study, we enrolled 334 HF patients with LBB block and an indication to receive LBB pacing for CRT. In these patients, we evaluated the CRT responder rate, clinical outcomes, and miR expression at 1 year of follow-up., Results: At 1 year of follow-up, we had 223 responders (66.8%), 132 hospitalizations for HF (39.5%), 24 cardiac deaths (7.2%), and 37 all-cause deaths (11.1%), with a higher rate of HF hospitalizations (77 (69.4%) vs 55 (24.7%), p < 0.05), and cardiac deaths (13 (11.7% vs 11 (4.9%), p < 0.05) in non-responders vs responders. At the end of follow-up, we found the lowest expression of miR-26, miR-29, miR-30, miR-92, and miR-145 in LBB-pacing non-responders vs responders ( p < 0.05), and a direct correlation between miR-30 (0.340, [0.833-1.915]; p 0.001), the 6-minute-walking test (6MWT; 0.168, [0.008-0.060]; p 0.011), angiotensin-receptor-neprilysin inhibitors (ARNI; 0.157, [0.183-4.877]; p 0.035), sodium-glucose-transporter-2 inhibitors (0.245, [2.242-7.283]; p 0.001), and LVEF improvements. C reactive protein (CRP) inversely correlated with LVEF improvement (-0.220, [-(0.066-0.263)]; p 0.001). ARNI (1.373, CI 95% [1.007-1.872], p 0.045), miR-30 (2.713, CI 95% [1.543-4.769], p 0.001), and 6MWT (1.288, CI 95% [1.084-1.998], p 0.001) were predictors of LBB pacing responders at 1 year of follow-up., Conclusion: LBB-pacing responders evidenced miR modulation, which was linked to significant improvement of the cardiac pump. Specifically, miR-30 was linked to cardiac pump improvement and predicted responders at 1 year of follow-up in patients with T2DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sardu, Vittoria Marfella, Giordano, Lepre, D’Amico, Volpicelli, Contaldi, Galiero, Caturano, Casolaro, Sasso, Uran, Cozzolino, Nicoletti, Signoriello, Paolisso and Marfella.)

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist., Methods: A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT., Results: Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40-0.79, Heterogeneity: r 2  = 0.01, I 2  = 23.45%, H 2  = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure., Conclusion: Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT., (© 2024. The Author(s).)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing COVID-19, has spread across the globe. To limit the spread of COVID-19, the Italian government imposed various restrictions (lockdowns). These restrictions had an impact on the flow of patients accessing hospital care. Our aim in this study was to analyze the impact of lockdowns on the epidemiology of patients suffering from hand trauma. Our work analyzed the variation in the number and characteristics of hand trauma patients during the lockdown and half-lockdowns in 2020 compared to the same periods in the previous and subsequent years. In 2020, during the lockdown period, 107 patients were treated by our department for hand trauma, amounting to a 2% increase compared to the average number of patients treated in the pre-pandemic period. In 2020, during the half-lockdown period, 158 patients were treated, amounting to a 6.8% increase in comparison to the pre-pandemic period. During the lockdown period in Italy, the flow of patients suffering from hand trauma referred to our hub center remained stable. Given the restrictions imposed by the lockdown, we expected a consequent reduction in the number of work-related injuries, which did occur, while there was a surprising increase in the number of traffic-related injuries. The number of domestic accidents remained stable.

Background: Hepcidin is one of the major negative regulators of iron balance. Periodic blood donors are highly susceptible to iron deficiency. Our goal was to evaluate the possible association between serum hepcidin levels and iron homeostasis parameters in periodic blood donors., Materials and Methods: We enrolled a total of n = 39 periodic healthy blood donors (n = 24 M and n = 15 F). A solid phase enzyme-linked immunosorbent assay (ELISA) was performed to measure endogenous hepcidin-25 levels in serum biospecimens collected from each study participant. Statistical analysis evaluated possible associations between hepcidin levels and ferritin, transferrin, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), transferrin saturation (TSAT), and number of previous donations., Results: Reduced serum hepcidin levels significantly correlated with lower ferritin concentration (r = 0.56, IC 95%: 0.51-0.60, p < 0.01). A multiple linear regression analysis showed that hepcidin levels were independently and negatively correlated with ferritin (p < 0.01). In addition, the number of previous blood donations was significantly associated with reduced hepcidin levels, independently of the other covariates (p < 0.01)., Conclusion: Reduced serum hepcidin levels were significantly associated with reduced levels of ferritin and with increased number of previous donations suggesting its possible clinical role as non-invasive "point-of-care" in predicting iron deficiency among periodic blood donors., (Copyright © 2023 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate the expression of sodium-glucose transporter 2 (SGLT2), inflammatory cytokines, and sirtuins in breast fat tissue at baseline, and serum cytokines of fatty vs. non-fatty pre-menopausal women at baseline, and at 12 months of follow-up. To correlate SGLT2/cytokines/sirtuins expression to clinical variables, and their changes (Δ) at follow-up, as intima-media wall thickness (IMT), left ventricle mass (LVM), left ventricle ejection fraction (LVEF), and myocardial performance index (MPI), and its normalization., Background: Pre-menopausal women with the lowest breast fat density (fatty breast) vs. higher breast fat density (non-fatty breast) are a high-risk population for cardiovascular diseases and worse prognosis., Methods: We analyzed SGLT2/cytokines/sirtuins of excised fatty breasts of fatty vs. non-fatty pre-menopausal women. We correlated SGLT2/cytokines/sirtuins to Δ IMT, Δ LVM, Δ LVEF, and Δ MPI, and normal cardiac performance (NCP) at 1 year of follow-up., Results: fatty vs. non-fatty breast over-expressed SGLT2/inflammatory cytokines, with lowest values of sirtuins (p<0.05). We found a direct correlation between SGLT2 (R2 0.745), TNFα (R2 0.262), and ΔMPI (p<0.05), and an inverse correlation between breast density (R2 -0.198), SIRT-3 (R2-0.181), and ΔMPI (p<0.05). Fatty breast (0.761, CI 95% [0.101-0.915]), SGLT2 (0.812, CI 95% [0.674-0.978]) and SIRT-3 (1.945, CI 95% [1.201-3.148]) predicted NCP at 1 year of follow-up., Conclusions: fatty vs. non-fatty breast women over-expressed SGLT2/inflammatory cytokines, and down-regulated breast sirtuins. SGLT2/inflammatory cytokines expression and inversely the tissue sirtuin 3 (tSIRT3) and breast percentage density linked to ΔMPI at 1 year of follow-up. Fatty breast and SGLT2 inversely predicted NCP; SIRT-3 increased the probability of NCP at 1 year of follow-up., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Aims: To evaluate cognitive function in subjects with type 2 diabetes (T2D) treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) plus metformin or metformin alone and its association with endothelial progenitor cells (EPCs)., Methods: Adults with T2D treated with GLP-1RA plus metformin (GLP-1RA + MET) or MET alone for at least 12 months were included. Montreal Cognitive Assessment test (MoCA), Mini-Mental State Examination (MMSE), Mini Nutritional Assessment (MNA) and disability tests were administered. Circulating levels of seven EPCs phenotypes were measured by flow cytometry., Results: A total of 154 elderly patients were included, of whom 78 in GLP-1RA + MET group and 76 in MET group. The GLP-1RA + MET group showed better cognitive function as indicated by a significant higher MoCA and MMSE scores, and higher levels of CD34 + CD133 + , CD133 + KDR + , and CD34 + CD133 + KDR + as compared with MET group. The number of CD34 + CD133 + KDR + cells was an independent predictor of higher MoCA, MMSE and MNA scores., Conclusions: People with T2D on GLP-1RA + MET treatment had better cognitive function and higher circulating levels of EPCs as compared with those on MET alone warranting further studies to understand the interrelationship between EPCs, GLP-RA treatment and cognitive health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Ileoanal pouch related fistulae (PRF) are a complication of restorative proctocolectomy often requiring repeated surgical interventions and with a high risk of long-term recurrence and pouch failure., Aims: To assess the incidence of PRF and to report on the outcomes of available surgical treatments., Methods: A PRISMA-compliant systematic literature search for articles reporting on PRF in patients with inflammatory bowel diseases (IBD) or familial adenomatous polyposis (FAP) from 1985 to 2020., Results: 34 studies comprising 770 patients with PRF after ileal-pouch anal anastomosis (IPAA) were included. Incidence of PRF was 1.5-12%. In IBD patients Crohn's Disease (CD) was responsible for one every four pouch-vaginal fistulae (PVF) (OR 24.7; p=0.001). The overall fistula recurrence was 49.4%; procedure-specific recurrence was: repeat IPAA (OR 42.1; GRADE +); transvaginal repair (OR 52.3; GRADE ++) and transanal ileal pouch advancement flap (OR 56.9; GRADE ++). The overall failure rate was 19%: pouch excision (OR 0.20; GRADE ++); persistence of diverting stoma (OR 0.13; GRADE +) and persistent fistula (OR 0.18; GRADE +)., Conclusion: PVFs are more frequent compared to other types of PRF and are often associated to CD; surgical treatment has a risk of 50% recurrence. Repeat IPAA is the best surgical approach with a 42.1% recurrence rate., (Copyright © 2022. Published by Elsevier Ltd.)

Background: No study evaluated the incidence of intra-stent restenosis (ISR)-related events in patients with type 2 diabetes (T2DM) and acute myocardial infarction (AMI) treated or not with sodium/glucose cotransporter 2 inhibitors (SGLT2i)., Methods: We recruited 377 patients with T2DM and AMI undergoing percutaneous coronary intervention (PCI). Among them, 177 T2DM were treated with SGLT2 inhibitors before PCI. The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, re-infarction, and heart failure related to ISR. In patients without ISR, minimal lumen area and minimal lumen diameter were assessed by coronary CT-angiography at 1-year follow-up., Results: Glycemic control was similar in SGLT2i-treated patients and never SGLT2i-users. The incidence of ISR-related MACE was higher in never SGLT2i-users compared with SGLT2i-treated patients, an effect independent of glycemic status (HR = 0.418, 95% CI = 0.241-0.725, P = 0.002) and observed also in the subgroup of patients with HbA1c < 7% (HR = 0.393, 95% CI = 0.157-0.984, P = 0.027). In patients without the event, the stent patency was greater in SGLT2i-treated patients compared with never SGLT2i-users at 1-year follow-up., Conclusions: SGLT2i treatment in T2DM is associated with a reduced incidence of ISR-related events, independently of glycemic control., (© 2023. The Author(s).)

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum levels. We designed a prospective multi-center study with a 1-year follow-up to evaluate ED, ET-1, and miR-130a-5p in CRTd patients with ED (ED-CRTd) vs. patients without ED (NED-CRTd). Clinical outcomes were CRTd response, HF hospitalization, cardiac death, and all-cause death. At 1-year follow-up, NED-CRTd (n = 541) vs. ED-CRTd (n = 326) patients showed better clinical statuses, lower serum values of B type natriuretic peptide (BNP: 266.25 ± 10.8 vs. 297.43 ± 16.22 pg/mL; p < 0.05) and ET-1 (4.57 ± 0.17 vs. 5.41 ± 0.24 pmol/L; p < 0.05), and higher values of miR-130a-5p (0.51 ± 0.029 vs. 0.41 ± 0.034 A.U; p < 0.05). Compared with NED-CRTd patients, ED-CRTd patients were less likely to be CRTd responders (189 (58%) vs. 380 (70.2%); p < 0.05) and had higher rates of HF hospitalization (115 (35.3%) vs. 154 (28.5%); p < 0.05) and cardiac deaths (30 (9.2%) vs. 21 (3.9%); p < 0.05). Higher miR-130a-5p levels (HR 1.490, CI 95% [1.014−2.188]) significantly predicted CRTd response; the presence of hypertension (HR 0.818, CI 95% [0.669−0.999]), and displaying higher levels of ET-1 (HR 0.859, CI 98% [0.839−0.979]), lymphocytes (HR 0.820, CI 95% [0.758−0.987]), LVEF (HR 0.876, CI 95% [0.760−0.992]), and ED (HR 0.751, CI 95% [0.624−0.905]) predicted CRTd non-response. Higher serum miR-130a-5p levels (HR 0.332, CI 95% [0.347−0.804]) and use of ARNI (HR 0.319, CI 95% [0.310−0.572]) predicted lower risk of HF hospitalization, whereas hypertension (HR 1.818, CI 95% [1.720−2.907]), higher BNP levels (HR 1.210, CI 95% [1.000−1.401]), and presence of ED (HR 1.905, CI 95% [1.238−2.241]) predicted a higher risk of HF hospitalization. Hence, serum miR-130a-5p could identify different stages of ED and independently predict CRTd response, therefore representing a novel prognostic HF biomarker.

Obesity, through adipose tissue (AT) inflammation and dysregulation, represents a critical factor for COVID-19; here, we investigated whether serum levels of adiponectin, HMW oligomers, leptin, and resistin are modulated and/or correlated with clinical and biochemical parameters of severe COVID-19 patients. This study included 62 severe COVID-19 patients; 62 age and sex-matched healthy subjects were recruited as a control group. Anthropometric and biochemical parameters were obtained and compared. Adiponectin, HMW oligomers, leptin, and resistin were analyzed by ELISA. The adiponectin oligomerization state was visualized by Western blotting. When compared to healthy subjects, total adiponectin levels were statistically lower in severe COVID-19 while, in contrast, the levels of leptin and resistin were statistically higher. Interestingly, HMW adiponectin oligomers negatively correlated with leptin and were positively associated with LUS scores. Resistin showed a positive association with IL-6, IL-2R, and KL-6. Our data strongly support that adipose tissue might play a functional role in COVID-19. Although it needs to be confirmed in larger cohorts, adiponectin HMW oligomers might represent a laboratory resource to predict patient seriousness. Whether adipokines can be integrated as a potential additional tool in the evolving landscape of biomarkers for the COVID-19 disease is still a matter of debate. Other studies are needed to understand the molecular mechanisms behind adipokine's involvement in COVID-19.

Background: In patients with unexplained syncope, bifascicular block (BFB) is considered associated with syncope due to either heart block or sinus arrest. Immediate or delayed pacemaker (PM) implantation after ECG documentation of syncopal recurrence by means of implantable cardiac monitors (ICM) is still debated. We aimed to assess the incidence of recurrent syncope and guideline-based PM implantation in patients with syncope and BFB implanted with ICM., Methods: Consecutive patients with syncope and BFB followed at two tertiary care syncope units and implanted with ICM from 2012 to 2020 were retrospectively reviewed. Only patients with ≥2 clinical visits and ≥ 18 years of age were included. Incidence of a Class I indication for PM implantation was the primary outcome., Results: Of 635 syncope patients implanted with an ICM, 55 (8.7%) had a BFB and were included. Median age at implantation was 75 [interquartile range, IQR:64-81] years, and 28(49.1%) were women. At 26 [IQR:12-41] months follow-up, 20 (36.3%,16.3%/year) patients experienced syncope: in 6(10.9%) patients syncope was classified 'arrhythmic' with a higher prevalence in older individuals (p = 0.048). PM implantation (N = 14,25.5%) was more frequent in patients ≥75 years (p = 0.024). At survival analysis, patients ≥75 years were at highest risk of arrhythmic syncope and guideline directed PM implantation (Hazard Ratio: 4.5, 95% Confidence Intervals 1.5-13.3)., Conclusions: Most older patients with syncope who received an ICM did not have events during follow-up. One-in-three experienced syncope, and an even smaller number had an arrhythmic syncope with indication for PM implantation. Older age was strongly associated with PM implantation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In patients with type 2 diabetes mellitus (T2DM) the vaso-vagal syncope (VVS) recurrence could be due to the alteration of autonomic system function, evaluated by heart rate variability (HRV), and by 123I-metaiodobenzylguanidine (123I-mIBG) myocardial scintigraphy indexes: Heart to Mediastinum ratio (H/M late ), and Washout rate (WR). The SGLT2-I could modulate/reduce autonomic dysfunction in T2DM patients with VVS. This effect could reduce the VVS recurrence in T2DM patients., Methods: In a prospective multicenter study, after propensity score matching, we studied a population of 324 T2DM patients with VVS, divided into 161 SGLT2-I-users vs. 163 Non-SGLT2-I users. In these patients as SGLT2-I-users vs. Non-SGLT2-I users, we investigated the HRV and 123I-MIBG modifications and VVS recurrence at 12 months of follow-up., Results: At follow-up end, the SGLT2-I-users vs. Non-SGLT2-I users had best glucose homeostasis and lower values of inflammatory markers, and resting heart rate (p < 0.05). The SGLT2-I-users vs. Non-SGLT2-I users evidenced the lowest low frequency/high frequency ratio (LF/HFr), a significant difference for all the indexes of autonomic dysfunction via ECG Holter analysis, and higher values of H/M late (p < 0.05). Finally, comparing SGLT2-I-users vs. Non-SGLT2-I users, we found a higher rate of VVS recurrence events, specifically of the vasodepressor VVS recurrence at 1-year follow-up (p < 0.05). We did not find a significant difference of mixed and cardio-inhibitory VVS recurrence events at 1 year of follow-up in the study cohorts (p > 0.05). At the Cox regression analysis H/M late (0.710, [0.481-0.985]), and SGLT2-I therapy (0.550, [0.324-0.934]) predicted all causes of syncope recurrence at 1 year of follow-up., Conclusions: Non-SGLT2-I users vs. SGLT2-I-users had alterations of the autonomic nervous system, with a higher rate of VVS recurrence at 1 year of follow-up. The indexes of cardiac denervation predicted the VVS recurrence, while the SGLT2-I reduced the risk of VVS recurrence., Clinical Trial Registration Number: NCT03717207., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Hidradenitis suppurativa (HS) is a severe chronic skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokine dysregulation is crucial in HS severity and progression., Objectives: The aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomers in HS patients compared to both obese and healthy subjects., Methods: The concentrations of adiponectin and cytokines were measured using enzyme-linked immunosorbent assay (ELISA); the oligomeric distribution of adiponectin (low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers)was evaluated through Western Blotting analysis., Results: Total adiponectin is statistically higher in HS patients compared to matched controls and obese subjects. Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1β, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFγ, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13., Conclusions: Our data confirmed that the complex network that links metabolism to immune homeostasis is dysregulated in HS and that adiponectin and its HMW oligomers are actively involved in this disease. In addition, the correlation between adiponectin and PDGF-BB, and IL-13 extends the role of this adipokine in modulation of the immune response, in particular regulating the innate immune system rather that the adaptive one. Further researches are needed to clarify the complex inflammatory milieu that characterizes HS syndrome., Competing Interests: Competing interests: None., (©2022 Nigro et al.)

Background: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control., Objectives: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts., Methods: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis., Results: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression., Conclusion: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition., Trial Registration: https://clinicaltrials.gov/ NCT03546062., (© 2022. The Author(s).)

Objectives: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling., Background: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy., Methods: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users., Results: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users., Conclusions: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the present study, our aim was to evaluate the clinical and microbiological characteristics of a cohort of patients with bloodstream infections (BSI) due to Carbapenem-Resistant Enterobacteriaceae (CRE) and investigate the independent predictors of mortality., Methods: All episodes of carbapenem-resistant E. coli (CREc) or K. pneumoniae (CRKp) BSI that were subject to a mandatory notification from January to December 2020 in all acute care hospitals and long-term care facilities of the Campania region in southern Italy were enrolled. All carbapenem-resistant strains were assessed through molecular tests for the presence of five carbapenemase gene families, i.e., K. pneumoniae Carbapenemase (KPC), oxacillinase-48 (OXA-48), New Delhi Metallo-β-lactamase (NDM), Verona integron encoded metallo-β-lactamase (VIM) and Imipenemase (IMP)., Results: During the study period, a total of 154 consecutive non-repeated CRE BSI, all due to CRKp, were reported. The most frequently identified genes were KPC in 108 cases (70.1%), followed by metallo-betalactamases (MBL) (16.2%), and OXA-48 (2.6%); in 17 isolates (11%) no carbapenemase was detected. The overall mortality at 90 days was 41.9%. Using a log-rank test, patients without risk factors for CRE infections showed a significantly lower cumulative mortality ( p = 0.001). After multivariate logistic regression analysis, the presence of at least one risk factor was the only predictor of mortality (OR: 1.7, 95% CI 1.2-6.1, p = 0.015)., Conclusions: The study reported a non-negligible prevalence of MBL-producing organisms among CRKp isolated from blood cultures in our region. This data highlights the importance of molecular characterization of all clinical isolates of carbapenem-resistant organisms.

Background: External rectal prolapse (ERP) is a debilitating condition in which surgery plays an important role. The aim of this study was to evaluate the outcomes of abdominal approaches (AA) and perineal approaches (PA) to ERP., Methods: This was a PRISMA-compliant systematic review with meta-analysis. Studies published between 1990 and 2021 were retrieved. The primary endpoint was recurrence at the last available follow-up. Secondary endpoints included factors associated with recurrence and function. All studies were assessed for bias using the Newcastle-Ottawa Scale and Cochrane tool., Results: Fifteen studies involving 1611 patients (AA = 817; PA = 794) treated for ERP were included, three of which were randomized controlled trials (RCTs; 114 patients (AA = 54; PA = 60)). Duration of follow-up ranged from 12 to 82 months. Recurrence in non-randomized studies was 7.7 per cent in AA versus 20.1 per cent in PA (odds ratio (OR) 0.29, 95 per cent confidence interval (c.i.) 0.17 to 0.50; P < 0.001, I2 = 45 per cent). In RCTs, there was no significant difference (9.8 per cent versus 16.3 per cent, AA versus PA (OR 0.82, 95 per cent c.i. 0.29 to 2.37; P = 0.72, I2 = 0.0 per cent)). Age at surgery and duration of follow-up were risk factors for recurrence. Following AA, the recurrence rates were 10.1 per cent and 6.2 per cent in patients aged 65 years and older and less than 65 years of age, respectively (effect size [e.s.] 7.7, 95 per cent c.i. 4.5 to 11.5). Following PA, rates were 27 per cent and 16.3 per cent (e.s. 20.1, 95 per cent c.i. 13 to 28.2). Extending follow-up to at least 40 months increased the likelihood of recurrence. The median duration of hospital stay was 4.9 days after PA versus 7.2 days after AA. Overall, incontinence was less likely after AA (OR 0.32), but constipation occurred more frequently (OR 1.68). Most studies were retrospective, and several outcomes from RCTs were not consistent with those observed in non-RCTs., Conclusion: The overall risk of recurrence of ERP appears to be higher with PA versus AA. Incontinence is less frequent after AA but at the cost of increased constipation. Age at surgery and duration of follow-up are associated with increased risk of recurrence, which warrants adequate reporting of future studies on this topic., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Innate immune mechanisms are central players in response to the binding of pathogens to pattern-recognition receptors providing a crucial initial block on viral replication. Moreover, innate immune response mobilizes cells of the cellular-mediated immune system, which develop into effector cells that promote viral clearance. Here, we observed circulating leukocyte T cell response in healthy subjects, COVID-19 infected, and in healthy vaccinated subjects. We found a significant CD8 + T cells (p < 0,05) decrease and an augmented CD4 + /CD8 + ratio (p < 0,05) in COVID-19 infected group compared with vaccinated subjects. In addition, healthy vaccinated subjects have a significant increased expression of CD8 + T cells, and a reduction of CD4 + /CD8 + ratio with respect to subjects previously COVID-19 infected. Central Memory and Terminal Effector Memory cells (TEMRA) increased after vaccine but not among groups., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The first pandemic phase of COVID-19 in Italy was characterized by high in-hospital mortality ranging from 23% to 38%. During the third pandemic phase there has been an improvement in the management and treatment of COVID-19, so mortality and predictors may have changed. A prospective study was planned to identify predictors of mortality during the third pandemic phase., Patients and Methods: From 15 December 2020 to 15 May 2021, 208 patients were hospitalized (median age: 64 years; males: 58.6%); 83% had a median of 2 (IQR,1-4) comorbidities; pneumonia was present in 89.8%. Patients were monitored remotely for respiratory function and ECG trace for 24 hours/day. Management and treatment were done following the timing and dosage recommended by international guidelines., Results: 79.2% of patients necessitated O2-therapy. ARDS was present in 46.1% of patients and 45.4% received non-invasive ventilation and 11.1% required ICU treatment. 38% developed arrhythmias which were identified early by telemetry and promptly treated. The in-hospital mortality rate was 10%. At multivariate analysis independent predictors of mortality were: older age (R-R for≥70 years: 5.44), number of comorbidities ≥3 (R-R 2.72), eGFR ≤60 ml/min (RR 2.91), high d-Dimer (R-R for≥1,000 ng/ml:7.53), and low PaO2/FiO2 (R-R for <200: 3.21)., Conclusions: Management and treatment adherence to recommendations, use of telemetry, and no overcrowding appear to reduce mortality. Advanced age, number of comorbidities, severe renal failure, high d-Dimer and low P/F remain predictors of poor outcome. The data help to identify current high-risk COVID-19 patients in whom management has yet to be optimized, who require the greatest therapeutic effort, and subjects in whom vaccination is mandatory.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1 , and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband's mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

Background: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment., Methods: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX., Results: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment., Conclusion: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The diagnosis of metastatic cutaneous melanoma (CM) on lymph node fine needle aspiration samples may be challenging and usually requires confirmation by immunocytochemistry. However, the cytological material could be too scant to order a broad panel of markers. In this case, the pathologist is forced to choose the most advantageous antibodies. The most commonly used melanocytic markers include S100, Melan-A, HMB45 and SOX10 but their diagnostic yield on cytological samples has been poorly studied. The current work aimed to evaluate the diagnostic performance of melanocytic markers when applied to cell blocks obtained from fine needle aspiration cytology (FNAC) of lymph node metastases from CM., Methods: S100, Melan-A, HMB45 and SOX10 were tested on cell block sections of 38 lymphnode metastases from CM diagnosed by cytology. A combined score was built to evaluate each immunostaining, considering the intensity of the staining and the percentage of stained neoplastic cells., Results: S100 and SOX10 revealed a higher sensitivity (100%) than Melan-A and HMB45 for the diagnosis of metastatic CM. Furthermore, SOX10 emerged as the melanocytic marker with the best staining performance., Conclusion: SOX10 has a 100% detection rate and the most easily interpretable staining pattern compared with other melanocytic markers. Therefore, it is strongly recommended that SOX10 is included in the minimal immunocytochemical panel for the diagnostic evaluation of lymph node FNAC in patients with suspected CM metastasis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We evaluated the effect of the pandemic on the disruption of a persuasive educational antimicrobial stewardship program (ASP) conducted in a university hospital in southern Italy., Methods: In March 2020, the ASP, which began in January 2017 and was carried out at different times in 10 wards, was stopped due to the COVID-19 pandemic. We conducted an observational study with interrupted time series analysis to compare the antibiotic consumption and costs, average length of hospital stay and in-hospital mortality between 12 months before and 9 months after the interruption., Results: Four medical, four surgical wards and two ICUs were included in the study, for a total of 35,921 patient days. Among the medical wards we observed after the interruption a significant increase in fluoroquinolone use, with a change in trend (CT) of 0.996, p = 0.027. In the surgical wards, we observed a significant increase in the overall consumption, with a change in level (CL) of 24.4, p = 0.005, and in the use of third and fourth generation cephalosporins (CL 4.7, p = 0.003). In two ICUs, we observed a significant increase in piperacillin/tazobactam and fluoroquinolone consumption (CT 9.28, p = 0.019, and 2.4, p = 0.047). In the wards with a duration of ASP less than 30 months, we observed a significant increase in antibiotic consumption in the use of piperacillin/tazobactam and fluoroquinolones (CT 12.9, p = 0.022: 4.12, p = 0.029; 1.004, p = 0.011)., Conclusions: The interruption of ASP during COVID-19 led to an increase in the consumption of broad-spectrum antibiotics, particularly in surgical wards and in those with a duration of ASP less than 30 months.

Background: The DyeVert™ system (Osprey Medical Inc., Minnesota, MN) may reduce contrast media (CM) volume during coronary procedures while maintaining fluoroscopic image quality. Here, we assessed whether the use of the DyeVert system reduces acute kidney injury (AKI) rate in patients with acute coronary syndrome (ACS) undergoing invasive coronary procedures., Methods: ACS patients scheduled for coronary procedure from January 2017 to December 2019 were included. Two groups were identified: (a) Control group (n = 339), including patients in which a conventional manual injection syringe was used; and (b) DyeVert group (n = 112), in which CM injection was handled by the DyeVert™ system. A propensity score matching was performed to reduce the effect of treatment selection bias and potential confounders. In all cases, a low-osmolar, nonionic CM was administered. The primary objective was the rate of AKI, defined as a serum creatinine increase ≥0.3 mg/dl within 72 hr after CM exposure., Results: CM volume was higher in the Control group than in the DyeVert group (130 [120-188] ml vs. 99 [69-136] ml; p <.001). In the DyeVert group the mean percent CM volume saved was 38 ± 13%. AKI occurred in 7/90 patients (8%) in the DyeVert group and in 17/90 (19%) patients in the Control group (odds ratio = 0.37; 95% confidence interval 0.14-0.95; p =.047)., Conclusions: This preliminary result suggests that CM volume reduction obtained by the DyeVert™ system is an effective strategy to prevent AKI in ACS patients undergoing invasive procedure., (© 2020 Wiley Periodicals LLC.)

Background: The aim of the study was to compare coronavirus disease 2019 (COVID-19) severity presentation between oncologic and non-oncologic patients and to evaluate the impact of cancer type and stage on COVID-19 course., Methods: We performed a multicentre, retrospective study involving 13 COVID-19 Units in Campania region from February to May 2020. We defined as severe COVID-19 presentation the cases that required mechanical ventilation and/or admission to Intensive Care Units (ICU) and/or in case of death., Results: We enrolled 371 COVID-19 patients, of whom 34 (9.2%) had a history or a diagnosis of cancer (24 solid, 6 onco-hematological). Oncologic patients were older (p<0.001), had more comorbidities (p<0.001) and showed a higher rate of severe COVID-19 presentation (p=0.001) and of death (p<0.001). Compared to 12 patients with non-active cancer and to 337 without cancer, the 17 patients with active cancer had more comorbidities and showed a higher rate of severe COVID-19 and of mortality (all p values <0.001). Compared to the 281 non-severe patients, the 90 subjects with a severe presentation of COVID-19 were older (p<0.01), with more comorbidities (p<0.001) and with a higher rate of cancer (p=0.001). At multivariate analysis, age (OR 1.08, 95% CI: 1.04-1.11) and suffering from cancer in an active stage (OR 5.33, 95% CI: 1.77-16.53) were independently associated with severe COVID-19., Conclusions: Since the higher risk of severe evolution of COVID-19, cancer patients, especially those with an active malignancy, should be candidates for early evaluation of symptoms and early treatment for COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Monari, Sagnelli, Maggi, Sangiovanni, Numis, Gentile, Masullo, Rescigno, Calabria, Megna, Gambardella, Manzillo, Russo, Esposito, Camaioni, Messina, Pisaturo, Allegorico, Pinchera, Pisapia, Catalano, Salzillo, Porta, Signoriello and Coppola.)

Aim: To investigate the rate of antibiotic resistance and its main risk factors in a population of patients with diabetic foot infection (DFI) during the COVID-19 pandemic, in comparison with the population of 2019., Methods: Two hundred and twenty-five patients with DFI were admitted in a tertiary care center from January 2019 to December 2020. Antibiotic resistance was evaluated by microbiological examination of soft tissues' or bone's biopsy., Results: Compared with 2019 group (n = 105), 2020 group (n = 120) had a significantly higher prevalence of antibiotic resistance [2019 vs 2020, 36% vs 63%, P <0.001] and more often was admitted with recent or current antibiotic therapy (18% vs 52%, P <0.001), which was frequently self-administered (5% vs 30%, P = 0.032). The risk of antibiotic resistance was also higher in 2020 group [OR 95% CI, 2.90 (1.68 to 4.99)]. Prior hospitalization, antibiotic self-administration and antibiotic prescription by general practitioners resulted as independent predictors of antibiotic resistance., Conclusions: In a population of people with DFI admitted in a tertiary care center during the COVID-19 pandemic the prevalence of antibiotic resistance was higher than 2019. Previous hospitalization, antibiotic self-administration /prescription by general practitioners were related to higher risk of antibiotic resistant infections., Competing Interests: Declaration of Competing Interest M.I.M. received honoraria for speaking at meetings from Astra-Zeneca, Novo Nordisk, Sanofi-Aventis, Mundi Pharma, Merck. G.B. received honoraria for speaking at meetings for Roche and Novo Nordisk. K.E. received honoraria for speaking at meetings from Sanofi-Aventis, Lilly, AstraZeneca, Abbott, Boehringer Ingelheim, Novo Nordisk, Mundi Pharma. Other authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cystic fibrosis (CF) is one of the most common inherited diseases. It is characterised by a severe decline in pulmonary function associated with metabolic perturbations and an increased production of inflammatory cytokines. The key role of physical activity (PA) in improving the health status of CF patients and reducing lung function decline has recently been demonstrated. This study evaluated interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) expression in two subgroups of CF patients classified based on PA., Methods: We selected 85 CF patients; half of them regularly undertook supervised PA in the three years leading up to the study and half of them were not physically active. Patients were analysed for serum IL-6 and TNFα levels using enzyme-linked immunosorbent assays., Results: We found that the expression levels of IL-6 and TNFα differed in terms of their regulation by PA. In particular, TNFα levels negatively correlated with FEV1% decrease/year and FEV1% decrease ( p = 0.023 and p = 0.02, respectively), and positively correlated with serum fasting glucose ( p = 0.019) in PA CF patients. In contrast, in the NPA subgroup, TNFα levels were positively correlated with IL-6 ( p = 0.001) and negatively correlated with adiponectin ( p = 0.000). In addition, multiple logistic regression analysis confirmed that PA is an independent modulator of the inflammatory state., Conclusions: PA modulates inflammatory processes in CF patients by regulating the secretion of pro-inflammatory cytokines and thus ameliorating lung function. Our data show that PA is a useful complementary strategy in the management of CF and that TNFα may be a marker of these effects of PA.

Background: The global active prevalence of migraines is approximately 14.7%. Oxygen therapy may reduce the use of non-steroidal anti-inflammatory drugs (NSAIDs) which often have various negative side effects. The purpose of this systematic review is to analyze the literature on the efficacy of high flow oxygen for the management of headache disorders, compared to placebo treatment., Methods: Studies were identified by PubMed, Web of Science and Scopus database from 1980 to the 30 October 2020. The search included the following terms: "oxygen therapy" and "headache" and "migraine". Studies were included if high flow oxygen was used in the treatment of headache disorders. All selected studies were qualitatively analyzed., Results: Our literature search identified 71 studies, of which 65 were discarded and 6 were included in the meta-analysis. The random effect model did not show a pooled significant resolution of headache disorders (OR 2.08 (95% CI 0.92-4.70), p < 0.0001) in the oxygen therapy group compared to the placebo group., Conclusion: In our systematic review of six studies, there were no significant differences between high flow oxygen and placebo treatment groups.

The diagnosis of cutaneous melanoma and melanocytic neoplasms in general is one of the most challenging fields in pathology, and the reported interobserver diagnostic agreement in the evaluation of melanocytic lesions is poor. Nevertheless, a correct histopathological diagnosis is crucial to ensure a good clinical management of the patients. The institution of multidisciplinary teams has recently modified the approach to the patients with cutaneous melanoma. Patients referred to a multidisciplinary melanoma unit after receiving a diagnosis of melanoma elsewhere are encouraged to have their histopathological diagnosis confirmed by a second opinion from the experienced pathologist of the team before any treatment is initiated. We performed a retrospective analysis on a series of 121 histopathological revisions required for melanocytic neoplasms in the context of a multidisciplinary team, in order to evaluate the effects of second diagnostic opinion (SDO) on the clinical management of the patients. We defined three types of diagnostic discrepancies between the first diagnosis and the second opinion, according to the greatness of their clinical impact. Overall, the incidence of diagnostic discrepancies of any type was quite high in our series (56%). Interestingly, the SDO determined relevant changes in the clinical management of the patients in 33 out of 121 (27.3%) cases. This study confirms that SDO by expert pathologists significantly affects the course of treatment of melanoma patients and helps improving the diagnostic accuracy and clinical outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ronchi, Pagliuca, Zito Marino, Argenziano, Brancaccio, Alfano, Signoriello, Moscarella and Franco.)

Background: RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC., Methods: AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR-based therapy; RAS mutant patients (N = 171) received anti-angiogenic-based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset., Results: AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients., Conclusions: AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients., Competing Interests: Conflict of interest statement TT reports advisory board for Amgen, Bayer, Merck, Novartis, Roche and Sanofi. FM reports advisory board for Lilly and MSD. ChCr reports personal fees from Roche, Amgen, Bayer and Servier, research funding from Merck Serono and consulting or advisory role for Roche, Bayer and Amgen. FP reports honoraria/speaker bureau from Amgen, Roche, Merck Serono, Lilly, Sanofi, Bayer and Servier and research grants from BMS. GWP reports personal fees from advisory boards and/or speaker's honorarium: Amgen, Bayer, BMS, Boston Biomedical, Celgene, Halozyme, Lilly, Merck Serono, Roche, Sanofi, Servier, Shire, MSD, Taiho and CECOG. NN reports personal financial interests as speaker's fee and/or advisory boards from MSD, Qiagen, Bayer, Biocartis, Incyte, Roche, BMS, Merck, Thermo Fisher, Boehringer Ingelheim, AstraZeneca, Sanofi and Eli Lilly; institutional financial interests (financial support to research projets) from Merck, Sysmex, Thermo Fisher, Qiagen, Roche, AstraZeneca and Biocartis; non-financial interests: President, International Quality Network for Pathology (IQN Path), President Elect, Italian Cancer Society (SIC). EvMa reports personal financial interests honoraria for advisory role for advisory board from: Astra Zeneca, Sanofi Genzyme, Servier, Celgene, Merck, Lilly and Roche; research grants from MSD and BSD; travel grants from Merck and Roche; institutional financial interests as financial support for clinical trials from Roche, Sanofi Genzyme, Teva and Merck. GA reports personal financial interests from Hoffman-La Roche, Bristol Myers Squibb, Bayer, Servier, Amgen, Merck Serono and Menarini; institutional financial interests from Bayer, Servier, Novartis, Boehringer Ingelheim, Boston Pharmaceuticals, Hoffman-La Roche and Genentech. EE reports personal financial interests, honoraria for advisory role, travel grants, research grants from Hoffman-La Roche, Sanofi Aventis, Amgen, Merck Serono and Servier, MSD; institutional financial interests from Hoffman-LaRoche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre Fabre and Novartis. AF reports personal financial interests (advisory role/honoraria): Bayer, Bristol, Lilly, Merck, Pierre Fabre, Roche, Servier; institutional financial interests as financial support for clinical trials from AstraZeneca, Bayer, Bristol, Lilly, Merck, MSD, Novartis, Roche, Sanofi and Servier. JT reports scientific consultancy roles for Bayer, Boehringer Ingelheim, Chugai, Genentech, Inc., Ipsen, Lilly, MSD, Merck Serono, Merrimack, Merus, Novartis, Peptomyc, Pfizer, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, Seattle Genetics, Symphogen and Taiho. FC reports being in the advisory boards for Merck, Roche, Amgen, Bayer, Servier, Symphogen and Pfizer and research funding from Roche, Merck, Amgen, Bayer and Ipsen. ErMa reports being in the advisory boards for Amgen, Bayer, Merck, Roche, Sanofi and Servier and giving expert opinion for ESMO (European Society of Medical Oncology). ClCa, BB, VMV, GM, VS, PPV, DC, VB, NM, FZ, MD, AN, AB, CA, GS, RF and MS report no competing conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: This study compared left ventricular end-diastolic pressure (LVEDP)-guided and urine flow rate (UFR)-guided hydration., Background: Tailored hydration regimens improve the prevention of contrast-associated acute kidney injury (CA-AKI)., Methods: Between July 15, 2015, and June 6, 2019, patients at high risk for CA-AKI scheduled for coronary and peripheral procedures were randomized to 2 groups: 1) normal saline infusion rate adjusted according to the LVEDP (LVEDP-guided group); and 2) hydration controlled by the RenalGuard System in order to reach UFR ≥300 ml/h (UFR-guided group). The primary endpoint was the composite of CA-AKI (i.e., serum creatinine increase ≥25% or ≥0.5 mg/dl at 48 h) and acute pulmonary edema (PE). Major adverse events (all-cause death, renal failure requiring dialysis, PE, and sustained kidney injury) at 1 month were assessed., Results: The primary endpoint occurred in 20 of 351 (5.7%) patients in the UFR-guided group and in 36 of 351 (10.3%) patients in the LVEDP-guided group (relative risk [RR]: 0.560; 95% confidence interval [CI]: 0.390 to 0.790; p = 0.036). CA-AKI and PE rates in the UFR-guided group and LVEDP-guided group were 5.7% and 10.0% (RR: 0.570; 95% CI: 0.300 to 0.960; p = 0.048), and, respectively, 0.3% and 2.0% (RR: 0.070; 95% CI: 0.020 to 1.160; p = 0.069). Three patients in the UFR-guided group experienced complications related to the Foley catheter. Hypokalemia rate was 6.2% in the UFR-guided group and 2.3% in the LVEDP-guided group (p = 0.013). The 1-month major adverse events rate was 7.1% in the UFR-guided group and 12.0% in the LVEDP-guided group (p = 0.030)., Conclusions: The study demonstrates that UFR-guided hydration is superior to LVEDP-guided hydration to prevent the composite of CA-AKI and PE., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The indications to LT are changing rapidly in Europe and the U.S. mainly due to the extensive use of direct-acting antiviral agents (DAA) against HCV. Italy was an endemic area for viral hepatitis. Methods: The study reviewed liver transplant registry of a leading Italian centre from the year 2014 (the year before the extensive use of DAA in Italy) to December 2018, with the scope of recording trends in indications. The indications were categorised as: HCV; HBV ± HDV; alcohol-dependent liver disease (ALD); NASH; mescellaneous. Transplants for decompensation or hepatocellular carcinoma were analysed separately. The data were analysed using standard statistical methods. Results: During the study period 463 LTs were accomplished. For the scope of the present study second transplants and transplant in patients <18 years were eliminated; in all, 397 patients were analysed. Overall, HCV infection was the main aetiological factor leading to transplant (139/397, 35%) followed by alcohol use (20.9%), HBV ± HDV (15.8%) and NASH (12.8%). In the decompensation group HCV decreased from 41.9% in 2014 to 14.3% in 2018 while alcohol increased ( p  < .001); in the HCC group, HCV decreased from 52.6% to 34% and alcohol and NASH increased; the number and proportion of HBV infections remained stable over time, with a 56% prevalence of HDV among decompensated patients. Conclusion: LT landscape is rapidly evolving; hepatitis virus infections still maintain a remarkable proportion among the indications for LT in an area that reached in the past high endemic levels for hepatitis C and B.