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Background and purpose: Treatment of freezing of gait (FoG) and other Parkinson disease (PD) axial symptoms is challenging. Systematic assessments of axial symptoms at progressively increasing levodopa doses are lacking. We sought to analyze the resistance to high levodopa doses of FoG, posture, speech, and altered gait features presenting in daily-ON therapeutic condition. Methods: We performed a pre-/postinterventional study including patients treated with levodopa/carbidopa intestinal gel infusion (LCIG) with disabling FoG in daily-ON condition. Patients were evaluated at their usual LCIG infusion rate (T1), and 1 h after 1.5× (T2) and 2× (T3) increase of the LCIG infusion rate by quantitative outcome measures. The number of FoG episodes (primary outcome), posture, speech, and gait features were objectively quantified during a standardized test by a blinded rater. Changes in motor symptoms, dyskinesia, and plasma levodopa concentrations were also analyzed. Results: We evaluated 16 patients with a mean age of 69 ± 9.4 years and treated with LCIG for a mean of 2.2± 2.1 years. FoG improved in 83.3% of patients by increasing the levodopa doses. The number of FoG episodes significantly decreased (mean=2.3 at T1, 1.7 at T2, 1.2 at T3; p= 0.013). Posture and speech features did not show significant changes, whereas stride length (p= 0.049), turn duration (p= 0.001), and turn velocity (p= 0.024) significantly improved on doubling the levodopa infusion rate. Conclusions: In a short-term evaluation, the increase of LCIG dose can improve "dopa-resistant" FoG and gait issues in most advanced PD patients with overall good control of motor symptoms in the absence of clinically significant dyskinesia.

Supplementary Figure Legends 1-5 from Ectopic Runx2 Expression in Mammary Epithelial Cells Disrupts Formation of Normal Acini Structure: Implications for Breast Cancer Progression

Supplementary Figures 1-5 from Ectopic Runx2 Expression in Mammary Epithelial Cells Disrupts Formation of Normal Acini Structure: Implications for Breast Cancer Progression

The transcription factor Runx2 is highly expressed in breast cancer cells compared with mammary epithelial cells and contributes to metastasis. Here we directly show that Runx2 expression promotes a tumor cell phenotype of mammary acini in three-dimensional culture. Human mammary epithelial cells (MCF-10A) form polarized, growth-arrested, acini-like structures with glandular architecture. The ectopic expression of Runx2 disrupts acini formation, and electron microscopic ultrastructural analysis revealed the absence of lumens. Characterization of the disrupted acini structures showed increased cell proliferation (Ki-67 positive cells), decreased apoptosis (Bcl-2 induction), and loss of basement membrane formation (absence of β4 integrin expression). In complementary experiments, inhibition of Runx2 function in metastatic MDA-MB-231 breast cancer cells by stable expression of either short hairpin RNA-Runx2 or a mutant Runx2 deficient in subnuclear targeting resulted in reversion of acini to more normal structures and reduced tumor growth in vivo. These novel findings provide direct mechanistic evidence for the biological activity of Runx2, dependent on its subnuclear localization, in promoting early events of breast cancer progression and suggest a molecular therapeutic target. [Cancer Res 2009;69(17):6807–14]

Introduction: Antiarrhythmic drugs (AADs) show a narrow therapeutic range and marked intersubject variability in pharmacokinetics (PK), which may lead to inappropriate dosing and drug toxicity. Areas covered: The aim of the present review is to describe PK properties of AADs, discussing the main changes in different clinical scenarios, such as the elderly and patients with obese, chronic kidney, liver, and cardiac disease, in order to guide their right prescription in clinical practice. Expert opinion: There are few data about PK properties of AADs in a special population or challenging clinical setting. The use and dose of AADs is commonly based on physicians’ clinical experience observing the clinical effects rather than being personalized on the individual patients PK profiles. More and updated studies are needed to validate a patient centered approach in the pharmacological treatment of arrhythmias based on patients’ clinical features, including pharmacogenomics, and AAD pharmacokinetics.

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

Purpose We sought to estimate the impact of cardiovascular autonomic neuropathy (cAN) on informal caregivers of patients with Parkinson’s disease (PD), defined as individuals providing regular care to a friend, partner, or family member with PD, and to evaluate the mutual relationship between caregiver burden and patient health-related quality of life (HRQoL). Methods We enrolled 36 consecutive patients with PD and their informal caregivers. Patients underwent a detailed motor, autonomic, cognitive, and functional assessment. Caregivers were assessed using the Zarit Burden Interview (ZBI). Differences in caregiver burden, expressed by the ZBI score, and strength of association between caregiver burden, cAN, and HRQoL were assessed using analysis of covariance (ANCOVA), logistic regression, and linear regression analyses. Analyses were adjusted for patients’ age, PD duration, and motor and cognitive disability, as well as caregivers’ age. Results Moderate-severe caregiver burden was reported in 41.7% of PDcAN+ versus 8.7% of PDcAN− (p < 0.001). The ZBI score was increased in PDcAN+ versus PDcAN− (31.5 ± 3.4 versus 15.2 ± 2.3; p p = 0.012) of moderate-severe caregiver burden in PDcAN+, even after adjusting for potential confounders. The ZBI score correlated with cAN severity (p = 0.005), global autonomic impairment (p = 0.012), and HRQoL impairment (p Conclusion These results highlight the significant impact of cAN on PD caregivers and the need for targeted interventions addressing this frequently overlooked and insufficiently treated source of nonmotor disability in PD.

Statins possess antithrombotic and profibrinolytic properties. The association between statin use and short-term outcomes in patients with acute pulmonary embolism (PE) remains unknown.We used the data from the Registro Informatizado de Pacientes con Enfermedad TromboEmbólica registry to compare the 30-day all-cause mortality in patients with acute PE according to the use of statins. Secondary outcome was fatal PE. We used cancer-related mortality as a falsification endpoint.From January 2009 to April 2021, 31 169 patients with PE were recruited. Of these, 5520 (18%) were using statins at baseline: low intensity: 829, moderate: 3636, high intensity: 1055. Statin users were older and had a higher frequency of diabetes, hypertension, or atherosclerotic disease than non-users (P0.001 for all comparisons). During the first 30 days, 1475 patients died (fatal PE, 255). On multivariable analysis, statin users had a lower risk of all-cause death (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.56-0.76) and fatal PE (OR: 0.42; 95% CI: 0.28-0.62) than non-users. The risk for death was lower in patients using either low- (OR: 0.51; 95% CI: 0.34-0.77), moderate- (OR: 0.68; 95% CI: 0.57-0.81), or high-intensity statins (OR: 0.68; 95% CI: 0.51-0.92). Results did not change in mixed effects logistic regression models with hospitals as a random effect. Statins were not associated with a significant chance in cancer mortality (falsification endpoint).PE patients using statins at baseline had a significantly lower risk of dying within the first 30 days than non-users. Randomized trials are needed to confirm these data.

Nattokinase (NK) is a protease derived from food used mainly in the Japanese diet that has several properties. The main activity is related to improving fibrinolytic activities. Other activities have been demonstrated in the regulation of blood pressure by the action toward angiotensin proteases and in the antiplatelet activities. NK can be given orally and reaches its maximal concentration after 12 hours. In addition, an antithrombotic activity based on various NK activities has been proposed. First, increased fibrinolytic activity increases thrombus dissolution and/or the formation of atherosclerotic plaques; second, its enhanced antiplatelet action adds to clot dissolution. All activities have been studied in animals and humans in vitro and in vivo. Relevant adverse effects of NK therapy have not been described, however clinical experience is restricted to case series and volunteers and is not based on clinical studies, thus clinical trials are required to confirm.

IntroductionIn addition to healthy lifestyle and balanced diet, nutraceuticals supplementation may be useful to maintain overall metabolic wellness. The aim of the current study was to assess the metabolic and vascular effects of a new highly standardized bergamot phytocomplex supplementation in healthy volunteers with the features of the metabolic syndrome.Material and methodsWe carried out a double-blind, randomized, placebo-controlled, three-arm, parallel-group clinical trial in 90 adult subjects treated for 12 weeks with two different dosages of a highly standardized bergamot phytocomplex (Endoberg by AKHYNEX and as Kalita®) or placebo. Lipid plasma levels of lipids, glycaemia, plasma hs-CRP, HOMA-IR, body fat, endothelial reactivity and fatty liver index were assessed at baseline, after 6 weeks and at the end of treatment in all subjects.ResultsAt the end of treatment, both tested bergamot extract doses were able to significantly improve atherogenic dyslipidaemia and insulin-sensitivity (pConclusionsThe tested bergamot phytocomplex was able to significantly improve glucose and lipid metabolism, as well as inflammation and might represent a novel multi-target approach to control metabolic syndrome.

Several neurological complications have been reported following SARS-Cov-2 vaccination, without a clear causal relationship ever being verified, including some cases of worsening of Parkinson's disease (PD) symptoms and new onset of movement disorders in non-parkinsonian patients.We describe two new cases of PD patients treated with device-aided therapy who developed worsening of parkinsonian symptoms after receiving the third vaccine dose (booster). We also conducted a short review of the cases reported in literature of PD symptoms worsening and new onset of movement disorders in non-parkinsonian patients after SARS-Cov-2 vaccination.The first patient, a 46-year-old man implanted with bilateral Subthalamic Deep Brain Stimulation, experienced temporary motor and non-motor symptoms worsening after mRNA-1273 booster, improved after stimulation settings modification. The second patient, a 55-year-old man implanted with percutaneous endoscopic transgastric jejunostomy (PEG-J) for levodopa-carbidopa intestinal gel (LCIG) infusion experienced severe temporary worsening of dyskinesia and managed through temporary LCIG dose reduction. Other seven cases of vaccine-related movement disorder are currently reported in literature, four describing PD symptoms worsening and three the onset of new movement disorders in otherwise healthy people.Both our patients and the cases described so far completely recovered after few days with parkinsonian therapy modification, symptomatic treatment, or even spontaneously, underlining the transient and benign nature of side effects from vaccine. Patients should be reassured about these complications, manageable through a prompt evaluation by the reference neurologist.

Two-dimensional strain echocardiography (2D-SE) is a reliable method for measuring deformation of the left ventricle.Aim of the study was to determine changes in 2D-SE parameters over time collected during dipyridamole stress echo-cardiography (dipy-stress) and prognosis of patients with non-diagnostic dipy-stress results.In the first phase of the study, assessment of a prospective enrolled population with a non-diagnostic dipy-stress test result was conducted, checking through coronary CT angiography (CCTA) the presence of coronary artery disease (CAD). In the follow-up phase, an echocardiographic re-evaluation and outcome analysis during a mean follow-up of 78 months was carried out.In the first phase, Global Circumferential Strain (GCS) values were similar in the CCTA positive and CCTA negative groups at rest and after stress. For Global Longitudinal Strain (GLS), there was a significant reduction (p.0001) in the CCTA positive group compared to the CCTA negative group. After 78 ± 9 months none of the enrolled patients experimented cardiac events. Values of GCS, both at rest and after stress, did not differ statistically comparing follow-up values with baseline ones. No statistically significant changes were seen in the same analysis for GLS rest and stress values, between baseline and follow-up in the two groups.Performing 2D-SE during dipy-stress can detect mild CAD that conventional stress-tests miss. Patients with mild coronary stenosis may have a favorable mid-term prognosis, but efforts should be made to investigate the decrease trend in GLS, at rest and after stress, reported in this patient group.

Purpose: We aimed to investigate the clinical performance of edoxaban for the treatment of pulmonary embolism (PE) in hospitalized COVID-19 patients. Methods: We conducted a retrospective analysis selecting hospitalized patients with COVID-19 admitted to our Institution from 20 May 2020 to 20 November 2020 with computer tomography (CT) detected PE at admission, treated with edoxaban after initial parenteral therapy. Clinical outcomes were compared between patients with and without ARDS at admission and between those with and without CT confirmed PE resolution. Results: 50 patients were included. Mean follow-up was 42.5±10days. No baseline differences were found between patients with ARDS (30%) and those without ARDS at admission. Patients with PE resolution (84%) were younger (P =0.03), had a shorter duration of fondaparinux therapy (9.9±3.8 vs 15.8±7.5days; P =0.0015) and length of hospitalization (36±8 vs 46±9days: P =0.0023) compared with those without PE resolution. 2 patients experienced major bleedings. At multivariate analysis the time to edoxaban switch was the only predictor of the PE resolution (HR: 0.92; 95% C.I. 0.86 to 0.99). Conclusion: Edoxaban was an effective and safe treatment for acute PE in COVID-19 setting.

Objective To evaluate the specific effects of PCSK9 inhibitors (i.e. alirocumab and evolocumab) on major cardiovascular events (MACE) and lipid profile in patients with diabetes. Methods and results We conducted a systematic review of literature according to the PRISMA statement. A total of eight randomized control trials (RCTs) enrolling 20 651 patients with diabetes were included. The mean follow-up was 51 weeks. We included RCTs that had compared the subtilisin–kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab with placebo in subjects with hypercholesterolaemia and diabetes mellitus. MACE occurred in 8.7% of patients with diabetes randomized to PCSK9i vs. 11.0% of those randomized to placebo. Thus, the use of alirocumab or evolocumab reduced MACE by 18% [odds ratio (OR): 0.82; 95% confidence interval (CI): 0.74–0.90]. Compared with control group, the use of PCSK9 inhibitors was associated with a significant percentage change from baseline in low-density lipoprotein cholesterol [mean difference (MD) –58.48%; 95% CI: –63.73 to –53.22%, P Conclusion PCSK9i appear to be effective in reducing the risk of MACE and in improving lipid profiles of subjects with diabetes and dyslipidaemia.

Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodeling enzymes that are critical for normal cellular functions and that are mis-regulated in ∼20% of human cancers. These enzymes exhibit significant diversity in the composition of individual enzyme complexes. mSWI/SNF enzymes are classified into three general sub-families based on the presence or absence of specific subunit proteins. The three sub-families are called BAF (BRM or BRG1-associated factors), ncBAF (non-canonical BAF), and PBAF (Polybromo-associated BAF). The biological roles for the different subfamilies of mSWI/SNF enzymes are poorly described. We knocked down (KD) the expression of genes encoding subunit proteins unique to each of the three subfamilies,Baf250A, Brd9, andBaf180, which mark the BAF, ncBAF, and PBAF sub-families, respectively, and examined the requirement for each in myoblast differentiation. We found that BAF250A and the BAF complex was required to drive lineage-specific gene expression during myoblast differentiation. KD ofBaf250Areduced the expression of the lineage determinantMyogeninand other differentiation markers, due to decreased binding of BAF250A to myogenic gene promoters. KD ofBrd9delayed myoblast differentiation. However, RNA-seq analysis revealed that while theBaf250A-dependent gene expression profile included genes involved in myogenesis, theBrd9-dependent gene expression profile did not. Moreover, no-colocalization of Baf250A and Brd9 was observed in differentiating cells, suggesting independent mechanisms of action for BAF and ncBAF complexes in myogenesis. The PBAF complex was dispensable for myoblast differentiation. The results distinguish between the roles of the mSWI/SNF enzyme subfamilies during myoblast differentiation.

Background Botulinum toxin (BoNT) is a valuable treatment in movement disorders; however, time to onset and duration of efficacy may widely differ among patients. We aimed to clarify the impact of main demographic and clinical features on time to onset and duration of BoNT efficacy. Methods We analyzed time-to-onset and duration of BoNT efficacy in 186 consecutive patients treated with BoNT for blepharospasm, cervical dystonia, facial hemispasm, oromandibular dystonia, limb dystonia, and sialorrhea due to Parkinsonism. The following factors were considered as potential efficacy predictors: doses and types of toxin, sex, age, years of treatment, and clinical condition. Kruskall–Wallis, Spearman correlation, and multivariate linear regression were used for statistical analysis. Results The average time to onset was 6.7 ± 5 days and duration of BONT efficacy 78.5 ± 28.4 days. Both time to onset and duration of efficacy were correlated with BoNT doses (p: 0.007 and p: 0.02). The multiple regression analysis showed that sex, age, years of BoNT treatment, doses, type of toxin, and clinical condition significantly predicted time to onset (F(11, 171) = 2.146, p: 0.020) with age being the strongest predictor (p: 0.004). The same model explained 20.1% of the variance of duration of BoNT efficacy, showing a significant prediction of the outcome (F(11, 164) = 3.754, p p p: 0.017), and clinical condition (p Conclusion Our findings suggest that age, type of toxin, clinical condition and especially doses may account for the variability of BoNT efficacy in terms of time to onset and duration.

Objective To evaluate the specific effects of alirocumab and evolocumab on major cardiovascular events (MACE) and lipid profile in patients with diabetes. Methods We conducted a systematic review of literature according to the PRISMA statement. A total of 8 randomized control trials (RCTs) enrolling 20651 patients with diabetes were included. Mean follow–up was 51 weeks. We included RCTs which had compared the PCSK9i alirocumab and evolocumab with placebo in subjects with hypercholesterolemia and diabetes mellitus. Results MACE occurred in 8.7% of patients with diabetes randomized to PCSK9i vs. 11.0% of those randomized to placebo. Thus, the use of alirocumab or evolocumab reduced MACE by 18% (relative risk [RR] 0.82, 95% confidence interval [CI] 0.74–0.90), without differences between PCSK9i compounds (p= 0.70, I2 0.0%). Compared to control group, the use of PCSK9 inhibitors was associated with a significant % change from baseline in LDL–C (mean difference [MD]–58.48%; 95% CI: –63.73 to –53.22%), p Conclusions Alirocumab and evolocumab appear to be effective in reducing the risk of MACE in subject with diabetes. Moreover, the use of PCSK9 inhibitors provides enhancement of lipid profile of patients with diabetes and dyslipidemia by reducing LDL–c and Lp(a) values.

COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease, and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years.

Supplemental material, sj-docx-2-vmj-10.1177_1358863X231175185 for Risk for recurrence of symptomatic upper-extremity deep vein thrombosis in patients without cancer: Analysis of three RIETE cohorts by Manuel J Núñez Fernández, Emilio M Padín Paz, Nuria Vázquez Temprano, José A Nieto Rodríguez, Pablo J Marchena Yglesias, Egidio Imbalzano, Ana Cristina Montenegro, Begoña Fernández Jiménez, Alberto Rivera, Olivier Espitia and Manuel Monreal in Vascular Medicine

Supplemental material, sj-docx-2-vmj-10.1177_1358863X231175185 for Risk for recurrence of symptomatic upper-extremity deep vein thrombosis in patients without cancer: Analysis of three RIETE cohorts by Manuel J Núñez Fernández, Emilio M Padín Paz, Nuria Vázquez Temprano, José A Nieto Rodríguez, Pablo J Marchena Yglesias, Egidio Imbalzano, Ana Cristina Montenegro, Begoña Fernández Jiménez, Alberto Rivera, Olivier Espitia and Manuel Monreal in Vascular Medicine

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X231175185 for Risk for recurrence of symptomatic upper-extremity deep vein thrombosis in patients without cancer: Analysis of three RIETE cohorts by Manuel J Núñez Fernández, Emilio M Padín Paz, Nuria Vázquez Temprano, José A Nieto Rodríguez, Pablo J Marchena Yglesias, Egidio Imbalzano, Ana Cristina Montenegro, Begoña Fernández Jiménez, Alberto Rivera, Olivier Espitia and Manuel Monreal in Vascular Medicine

Supplemental material, sj-docx-3-vmj-10.1177_1358863X231175185 for Risk for recurrence of symptomatic upper-extremity deep vein thrombosis in patients without cancer: Analysis of three RIETE cohorts by Manuel J Núñez Fernández, Emilio M Padín Paz, Nuria Vázquez Temprano, José A Nieto Rodríguez, Pablo J Marchena Yglesias, Egidio Imbalzano, Ana Cristina Montenegro, Begoña Fernández Jiménez, Alberto Rivera, Olivier Espitia and Manuel Monreal in Vascular Medicine

Supplemental material, sj-docx-3-vmj-10.1177_1358863X231175185 for Risk for recurrence of symptomatic upper-extremity deep vein thrombosis in patients without cancer: Analysis of three RIETE cohorts by Manuel J Núñez Fernández, Emilio M Padín Paz, Nuria Vázquez Temprano, José A Nieto Rodríguez, Pablo J Marchena Yglesias, Egidio Imbalzano, Ana Cristina Montenegro, Begoña Fernández Jiménez, Alberto Rivera, Olivier Espitia and Manuel Monreal in Vascular Medicine

The link between alarmins and atrial fibrillation is clear and well known in the literature. We performed a non-systematic review about role of alarmins in pathophysiological mechanism of AF, hypothesizing their role in potential novel therapeutic targets for arrhythmia. Several studies have shown a key role of HMGB1 in AF physiopathology. We have seen an almost direct correlation between HMGB1 and oxidative stress in the inflammatory process of AF. Wu et al. observed that HMGB1 is higher in patients with permanent AF, because they experienced a continuous inflammatory tissue damaging impulse. It was shown a prothrombotic and procoagulative role of HMGB1, increased in patients with AF and atrial thrombosis. Scherschel et al. showed higher concentration of S100β protein in AF patients undergoing catheter ablation. Neuronal injury by intrinsic cardiac autonomic nervous system (ICSN) upon catheter treatment released damage-associated molecular pattern proteins (DAMPs) as S100β protein. In vitro studies dealing with murine intracardiac neuros showed that S100β decreased potential action and increased neuronal cells growth. Many studies demonstrate HSP70 protective role when intracellular, at high concentrations in patients who do not develop arrhythmia after cardiac injury, such as bypass, and low concentrations preoperatively in patients who later develop arrhythmia. At the serum level, on the other hand, it becomes an important marker of cellular damage and oxidative stress, also related to increased IL-2 AND IL-4. Conclusions These results could be considered for new therapeutic strategies, as inhibition of oxidative stress, novel therapeutic targets of anticoagulant drugs and considering alarmins as predictive or prognostic biomarkers of disease.

Background and Aims Obesity, a major risk factor for acute coronary syndrome (ACS), is a multifaced disease with different metabolic phenotypes and sex-specific features. We evaluated the long-term cardiovascular risk by different obesity/metabolic phenotypes and by sex in ACS patients. Methods The occurrence of the composite outcome of death, non-fatal re-infarction with or without PCI and/or stroke was evaluated in 674 patients (504 men; 170 women), consecutively hospitalized for ACS and followed-up for 7 years, who were stratified in metabolically healthy (MHNW) and unhealthy normal weight (MUNW), and in metabolically healthy (MHO) and unhealthy obese (MUO) groups, as shown in Figure 1. Results At baseline, 54,6% of patients were included in the MHNW group, 26,4% in the MUNW, 5,9% in the MHO and 13,1% in the MUO, with no sex-differences in the phenotypes distribution. The overall rate of major outcome (100 person-years) in the reference group (MHNW) was higher in men that in women (RR: 1.19 vs 0.6). The Kaplan-Meier curves (see Figure 2) for cumulative survival free from cardiovascular events according to obesity/metabolic status diverged significantly according to sex (long rank test, P= 0.006), being this effect more prominent in men (P=0.011), than in women (P=0.047). Compared to MHNW, the risk increased in obese men (RR: 2.2; 95% CI 1.11-1.54 in MUO group), whereas in women the risk was confined to the metabolically unhealthy subjects (RR: 3.2; 95% CI 1.23-9.98, MUNW group). Conclusions Our data show a sex-specific impact of obesity phenotypes on long-term cardiovascular risk in patients hospitalized for ACS. Thus, while MHO women seemed to be protected over time, in men, obesity had a stronger impact irrespective of metabolic status. These data emphasize the importance of assessing metabolic status and implementing systematic metabolic surveillance in patients undergoing coronary revascularization procedures, even if their weight is normal.

Introduction Dipyridamole stress echocardiography (Dipy-stress) compared to exercise ECG, has an higher specificity in non-invasive detection of coronary artery disease (CAD). Two-dimensional strain echocardiography (2D-SE) is able to detect even minimal abnormalities of systolic function. The aim of the study was to observe changes in 2D-SE parameters during dipy-stress and to assess prognosis in a group of patients who had previously a non-diagnostic dipy-stress test result. Methods In the first phase 71 patients were enrolled and a dipy-stress test was performed. Each patient was then studied by off-line measurement of 2D-SE and coronary computed tomography angiography (CCTA), to check the presence of CAD. In the follow-up phase, an echocardiographic re-evaluation and outcome analysis during a mean follow-up of 78 months was carried out. Results In the first phase, Global Longitudinal Strain (GLS) was reduced (p < .0001) in the CCTA positive group compared to the CCTA negative group (23±3 vs 26±2 at rest; 20±3 vs 26±2 after stress). CCTA negative group and the CCTA positive group did not differ in terms of clinical features, cardiovascular risk factors, or treatments. Despite a trend in reduction for positive CCTA group (23±3 vs 20±3 at rest; 20±3 vs 19±3 after stress), no statistically significant changes were seen in the analysis of GLS rest and stress values, between baseline and follow-up in the two groups. None of the enrolled patients experimented cardiac events during follow-up. Conclusions Left ventricular GLS analysis improves the accuracy of dipy-stress echocardiography in the detection of mild CAD compared with the assessment of Wall Motion changes, particularly in those with preserved left ventricular ejection fraction. Patients may have a better mid-term prognosis thanks to close follow-up and early treatment of all cardiovascular risk factors.

Backgrounds Psoriasis is a chronic skin inflammatory disease, characterized by immune-mediated reaction and hyperproliferation of keratinocytes. It is typically associated with several comorbidities; in particular, there are numerous evidence of a link between this condition and cardiovascular (CV) disease. Nevertheless, little is known about its role as an independent cardiovascular risk factor. Purpose The aim of this longitudinal study is to evaluate the role of Psoriasis as an independent CV risk factor, to establish the relationship between severity and duration of Psoriasis and CV damage and to find reliable markers to stratify CV risk in these patients. Methods 33 patients affected by mild Psoriasis without comorbidities were enrolled in this longitudinal study and were compared with 33 healthy subjects. The severity of Psoriasis was assessed with the PASI (Psoriasis Area and Severity Index) score: a score Results A total of 66 patients was included: 33 (50%) with mild psoriasis without comorbidities and 33 (50%) healthy subjects. Comparable clinical and echocardiographic baseline characteristics were observed between the two groups, except for Global Longitudinal Strain (GLS), which was significantly lower (p=0.002) in the Psoriasis group (22.39 ± 2.28%) than in controls (24.15 ± 2.17%), and PWV, that was significantly lower (p=0.004) in controls (8.06±1.68 m/sec) than in the psoriasis group (9.23 ± 1.53 m/sec). Significant correlations between GLS, disease duration and patient age at diagnosis were found, as in coronary artery disease (CAD) and cardiomyopathies. At 2-year follow-up, no significant changes in demographic or clinical characteristics were found within the Psoriasis group. The PASI score did not change significantly, no patient needed any systemic therapy (6 needed an increase in topical drugs) and none of the patients developed any conventional cardiovascular risk factor. There were no significant differences in echocardiographic parameters and no CV events occurred. Conclusions According to our data, mild Psoriasis determines subclinical cardiac and vascular damage. However, at two-year follow-up, no CV changes in initially healthy patients were found.

The skeletal muscle plays a key role in systemic energy homeostasis besides its canonical contractile function, but what couples these functions is poorly defined. Protein Arginine MethylTransferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels ofPrmt5, we generated myocyte-specificPrmt5knockout (Prmt5MKO) mice. We observed reduced muscle mass, oxidative capacity, force production and exercise performance inPrmt5MKOmice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and degradation. First,Prmt5MKOreduced demethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator ofde novolipogenesis. Second,Prmt5MKOimpaired the repressive H4R3Me2s (histone H4 arginine-3 symmetric demethylation) at thePnpla2gene, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, myocyte-specific double knockout ofPnpla2andPrmt5normalized muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

Introduction Some local protocols suggest using intermediate or therapeutic doses of anticoagulants for thromboprophylaxis in hospitalized patients with coronavirus disease 2019 (COVID‐19). However, the incidence of bleeding, predictors of major bleeding, or the association between bleeding and mortality remain largely unknown. Methods We performed a cohort study of patients hospitalized for COVID‐19 that received intermediate or therapeutic doses of anticoagulants from March 25 to July 22, 2020, to identify those at increased risk for major bleeding. We used bivariate and multivariable logistic regression to explore the risk factors associated with major bleeding. Results During the study period, 1965 patients were enrolled. Of them, 1347 (69%) received intermediate‐ and 618 (31%) therapeutic‐dose anticoagulation, with a median duration of 12 days in both groups. During the hospital stay, 112 patients (5.7%) developed major bleeding and 132 (6.7%) had non‐major bleeding. The 30‐day all‐cause mortality rate for major bleeding was 45% (95% confidence interval [CI]: 36%‐54%) and for non‐major bleeding 32% (95% CI: 24%‐40%). Multivariable analysis showed increased risk for in‐hospital major bleeding associated with D‐dimer levels >10 times the upper normal range (hazard ratio [HR], 2.23; 95% CI, 1.38–3.59), ferritin levels >500 ng/ml (HR, 2.01; 95% CI, 1.02–3.95), critical illness (HR, 1.91; 95% CI, 1.14–3.18), and therapeutic‐intensity anticoagulation (HR, 1.43; 95% CI, 1.01–1.97). Conclusions Among patients hospitalized with COVID‐19 receiving intermediate‐ or therapeutic‐intensity anticoagulation, a major bleeding event occurred in 5.7%. Use of therapeutic‐intensity anticoagulation, critical illness, and elevated D‐dimer or ferritin levels at admission were associated with increased risk for major bleeding.

Chronic kidney disease is a risk factor for cardiovascular events. Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for renal impairment. The aim of this study was to test the combined effect of smoking and COPD on renal function decline in hypertensives. We enrolled 1728 hypertensives stratified by smoking status and presence/absence of COPD. To test the mutual effect modification by both smoking and COPD and e-GFR, we performed crude and adjusted linear regression analyses, these latter taking into account potential confounders. Smokers displayed significantly lower e-GFR values than non-smokers (90 ± 24 vs. 121 ± 35 ml/min/1.73 m

The thrombosis-related diseases are one of the leading causes of illness and death in the general population, and despite significant improvements in long-term survival due to remarkable advances in pharmacologic therapy, they continue to pose a tremendous burden on healthcare systems. The oxidative stress plays a role of pivotal importance in thrombosis pathophysiology. The anticoagulant and antiplatelet drugs commonly used in the management of thrombosis-related diseases show several pleiotropic effects, beyond the antithrombotic effects. The present review aims to describe the current evidence about the antioxidant effects of the oral antithrombotic therapies in patients with atherosclerotic disease and atrial fibrillation.

Background and objectives: Pre-existing atrial fibrillation (AF) is a frequent comorbidity in hospitalized patients with COVID-19; however, little is still known about its prognostic role in infected patients. The aim of our study was to evaluate whether the pre-existing AF as comorbidity would contribute to increase the risk for severe forms of COVID-19, worse prognosis, or even higher mortality. Materials and Methods: We retrospectively evaluated all consecutive COVID-19 patients admitted to the emergency department of nine Italian Hospitals from 1 March to 30 April 2020.The prevalence and the type of pre-existing AF have been collected. The correlation between the history and type of AF and the development of severe ARDS and in-hospital mortality has been evaluated. Results: In total, 467 patients (66.88 ± 14.55 years; 63% males) with COVID-19 were included in the present study. The history of AF was noticed in 122 cases (26.1%), of which 12 (2.6%) with paroxysmal, 57 (12.2%) with persistent and 53 (11.3%) with permanent AF. Among our study population, COVID-19 patients with AF history were older compared to those without AF history (71.25 ± 12.39 vs. 65.34 ± 14.95 years; p < 0.001); however, they did not show a statistically significant difference in cardiovascular comorbidities or treatments. Pre-existing AF resulted in being independently associated with an increased risk of developing severe ARDS during the hospitalization; in contrast, it did not increase the risk of in-hospital mortality. Among patients with AF history, no significant differences were detected in severe ARDS and in-hospital mortality between patients with permanent and non-permanent AF history. Conclusions: Pre-existing AF is a frequent among COVID-19 patients admitted to hospital, accounting up to 25% of cases. It is independently associated with an increased risk of severe ARDS in hospitalized COVID-19 patients; in contrast, it did not affect the risk of death. The type of pre-existing AF (permanent or non-permanent) did not impact the clinical outcome.

We explored the variations in use of imaging modalities for confirming pulmonary embolism (PE) according to the trimester of pregnancy. We included all pregnant patients with confirmed acute PE from RIETE, a prospective registry of patients with PE (03/2001–02/2020). Imaging modalities included computed tomography pulmonary angiography (CTPA), ventilation-perfusion (V/Q) scan, or presence of signs of acute PE along with imaging-confirmed proximal deep vein thrombosis (pDVT) without pulmonary vascular imaging. We compared the imaging modalities to postpartum patients with PE, and other non-pregnant women with PE. There were 157 pregnant patients (age: 32.7 ± 0.5), 228 postpartum patients (age: 33.9 ± 0.5), and 23,937 non-pregnant non-postpartum women (age: 69.5 ± 0.1). CTPA was the most common modality for confirming PE, from 55.7% in first trimester to 58.3% in second trimester, and 70.0% in third trimester. From first trimester to third trimester, V/Q scanning was used in 21.3%, 16.7%, and 18.3% of cases, respectively. Confirmed pDVT along with the presence of signs/symptoms of PE was the confirmatory modality for PE in 21.3% of patients in first trimester, 19.4% in second trimester, and 6.7% in third trimester. The proportion of postpartum patients confirmed with CTPA (85.5%) was comparable to that of non-pregnant non-postpartum women (83.2%). From the first trimester of pregnancy to postpartum period, there was a linear increase in the proportion of patients with PE diagnosed with CTPA (p = 0.039). CTPA was the primary modality for confirming PE in all trimesters of pregnancy, although its proportional use was higher in later stages of pregnancy. • Computed tomography pulmonary angiography (CTPA) was the primary modality of diagnosis in all trimesters of pregnancy among patients with confirmed pulmonary embolism, even in the first trimester. • From the first trimester of pregnancy to postpartum period, there was a linear increase in the proportion of patients with pulmonary embolism who were diagnosed based on CTPA. • In the postpartum period, use of CTPA as the modality to confirm pulmonary embolism was comparable to non-pregnant patients.

The discrimination between heart failure with preserved ejection fraction (HFpEF) and pulmonary arterial hypertension (PAH) requires a multiparametric approach, eventually culminating in right heart catheterization. Solving this differential diagnosis is crucial in order to properly tailor patient treatment, with relevant clinical implications. However, it is not uncommon to be confronted with patients at intermediate or high risk of having HFpEF whose pulmonary artery wedge pressure (PAWP) falls in a grey zone in between 13 and 15 mmHg. In these patients, a provocative test in the cath lab might be considered, with the aim of unmasking an occult form of HFpEF with non-overt hemodynamic manifestations, or to definitely exclude it.Saline load and physical exercise can be viewed as the most suitable provocative tests seeking to help for the differential diagnosis in this specific patient population. Although normative values for the hemodynamic response to these maneuvers have been proposed, supporting evidence is still preliminary or equivocal. In this paper, we will review the pathophysiological background for the application of provocative tests in the cath lab, as well as methodological and interpretative aspects to discriminate between HFpEF and PAH, highlighting strengths and weaknesses of fluid load and physical exercise.

Since the pandemic began, an association among COVID-19 and venous thromboembolism has been reported, in particular for inpatients [...]

Background Histamine fish poisoning, known as scombroid syndrome, is a foodborne disease caused by histamine toxicity that results from eating specific types of spoiled fish. In some cases it can lead to the development of life–threatening anaphylactic reactions. In literature is widely recognized and accepted the possibility of correlated coronary involvements, cases described are rare, but even more rare if combined with the novel human coronavirus disease Covid–19 infection, the fifth documented pandemic since the 1918 flu pandemic. In this report, we describe a case of acute coronary syndrome in infected patient with Covid–19, for the first time. The occurrence of acute coronary events with allergic or hypersensitivity reactions has been described as the Kounis syndrome, but in few cases it has been associated with scombroid syndrome. Case Report A young woman came to our Emergency Department with erythematous lesions, mild itching, nausea, diaphoresis and weakness, after a meal with canned tuna. Her clinical situation worsened and she developed acute coronary syndrome due to vasospasm. After first negative result for rapid oropharyngeal swab test of SARS–CoV–2 RNA, waiting for molecular oropharyngeal swab during her hospitalization, a few days later she tested positive for SARS–CoV2 infection. Acute coronary syndrome in patients with scombroid syndrome is rare to find and more rare if associated with Covid–19–infection. This case demonstrated a linkage of Histamine fish poisoning with Kounis syndrome and SARS–CoV–2 infection, allowing us to foster the treatment decision–making process. Why should an emergency physician be aware of this? This syndrome can represent a life threatening, if not promptly and early known. An emergency physician must have this knowledge, to evaluate accurately the anamnesis of affected patients. Only a circumspect anamnesis can lead us to correct diagnosis and change our decision–making process for treatment.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective and safe lipid-lowering treatments (LLT). The primary endpoint of the study was to assess the prevalence of patients eligible for treatment with PCSK9 inhibitors in a real-life clinical setting in Italy before and after the recent enlargement of reimbursement criteria. For this study, we consecutively considered the clinical record forms of 6231 outpatients consecutively admitted at the Lipid Clinic of the University Hospital of Bologna (Italy). Patients were stratified according to whether they were allowed or not allowed to access to treatment with PCSK9 inhibitors based on national prescription criteria and reimbursement rules issued by the Italian Medicines Agency (AIFA). According to the indications of the European Medicines Agency (EMA), 986 patients were candidates to treatment with PCSK9 inhibitors. However, following the prescription criteria issued by AIFA, only 180 patients were allowed to access to PCSK9 inhibitors before reimbursement criteria enlargement while 322 (+14.4%) with the current ones. Based on our observations, low-cost tailored therapeutic interventions for individual patients can significantly reduce the number of patients potentially needing treatment with PCSK9 inhibitors among those who are not allowed to access to the treatment. The application of enlarged reimbursement criteria for PCSK9 inhibitors could mildly improve possibility to adequately manage high-risk hypercholesterolemic subjects in the setting of an outpatient lipid clinic.

The RIETE Investigators., [Background] The optimal therapy of patients with acute subsegmental pulmonary embolism (PE) is controversial., [Methods] We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of symptomatic PE recurrences during anticoagulation in patients with subsegmental, segmental, or more central PEs. [Results] Among 15 963 patients with a first episode of symptomatic PE, 834 (5.2%) had subsegmental PE, 3797 (24%) segmental, and 11 332 (71%) more central PE. Most patients in all subgroups received initial therapy with low‐molecular‐weight heparin, and then most switched to vitamin K antagonists. Median duration of therapy was 179, 185, and 204 days, respectively. During anticoagulation, 183 patients developed PE recurrences, 131 developed deep vein thrombosis (DVT), 543 bled, and 1718 died (fatal PE, 135). The rate of PE recurrences was twofold higher in patients with subsegmental PE than in those with segmental (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.16‐3.85) or more central PE (HR, 1.89; 95% CI, 1.12‐3.13). On multivariable analysis, patients with subsegmental PE had a higher risk for PE recurrences than those with central PE (adjusted HR, 1.75; 95% CI, 1.02‐3.03). After stratifying patients with subsegmental PE according to ultrasound imaging in the lower limbs, the rate of PE recurrences was similar in patients with DVT, in patients without DVT, and in those with no ultrasound imaging. [Conclusions] Our study reveals that the risk for PE recurrences in patients with segmental PE is not lower than in those with more central PE, thus suggesting that the risk of PE recurrences is not influenced by the anatomic location of PE.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Objective Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and COVID-19. This study aims at evaluating the prevalence of neurological comorbidities, and their association with COVID-19 severity. Methods We evaluated all consecutive patients admitted to the Emergency Room (ER) of our hospital between the 3rd March and the 14th April 2020, and diagnosed with COVID-19. Data on neurological and non-neurological diseases were extracted, as well as data on demographic characteristics and on severity degree of COVID-19. The prevalence of neurological comorbidities was calculated, and multivariate binary logistic regression analyses were used to estimate the association between neurological diseases and COVID-19 severity. Results We included 344 patients. Neurological comorbidities accounted for 22.4% of cases, with cerebrovascular diseases and cognitive impairment being the most frequent. Neurological comorbidity resulted independently associated with severe COVID-19 (OR 2.305; p = 0.012), as well as male gender (p = 0.001), older age (p = 0.001), neoplastic diseases (p = 0.039), and arterial hypertension (p = 0.045). When neurological comorbidity was associated with non-neurological comorbidities, the OR for severe COVID-19 rose to 7.394 (p = 0.005). Neurological patients, in particular cerebrovascular and cognitively impaired ones, received more respiratory support indication. Conclusion Neurological comorbidities represent a significant determinant of COVID-19 severity, deserving a thorough evaluation since the earliest phases of infection. The vulnerability of patients affected by neurological diseases should suggest a greater attention in targeting this population for proactive viral screening.

Gait and posture parameters of ten advanced Parkinson's disease (PD) patients were assessed before and after starting levodopa-carbidopa intestinal gel (LCIG) treatment by means of both objective video analysis and clinical assessment. After 3 years of treatment, gait and posture remained stable. A slower gait velocity at baseline significantly correlates with a higher axial and motor severity at follow-up. This pilot study suggests that validated video analysis software may support the clinical assessment of axial signs in PD patients who are candidates for device-aided therapies.

BackgroundHeart failure with reduced ejection fraction (HFrEF) is a clinical condition frequently diagnosed in clinical practice. In patients affected by HFrEF, sleep apnea (SA) can be detected among the most frequent comorbidities. Sacubitril–valsartan (sac/val) association has been proven to be effective in reducing disease progression and all-cause mortality in HFrEF patients. Sac/val treatment can potentially attenuate SA development via several pathophysiologic mechanisms, including improvement of global hemodynamics, reduction of extracellular fluid overload, and decrease of sympathetic neural activity.MethodsWe recruited 132 patients affected by HFrEF and SA, already under treatment with continuous positive airway pressure (CPAP), which was discontinued 24 h before the scheduled study timepoints. Physical examination, echocardiography, nocturnal cardio-respiratory monitoring, and laboratory tests were performed in each patient at baseline and after a 6-month treatment with sac/val.ResultsAfter 6 months, sac/val induced statistically significant changes in clinical, hemodynamic, biohumoral (NT-proBNP, serum electrolytes, creatinine, and uric acid), and echocardiographic parameters. In particular, cardiac index (CI), both atrial and ventricular volumes and global longitudinal strain (GLS) improved. Moreover, polysomnography, carried out during a temporary CPAP interruption, revealed a significant reduction in global apnea-hypopnea index (AHI) value (p < 0.0001), central AHI (p < 0.0001), obstructive AHI (p < 0.0001), oxygen desaturation index (ODI) (p < 0.0001), and percentage time of saturation below 90% (TC90) (p < 0.0001). The changes of CI, estimated glomerular filtration rate (eGFR), NT-proBNP, and tricuspid annular plane excursion (TAPSE) contributed to 23.6, 7.6, 7.3, and 4.8% of AHI variability, respectively, and the whole model accounted for a 43.3% of AHI variation.ConclusionsOur results suggest that treatment with sac/val is able to significantly improve the cardiorespiratory performance of patients with HFrEF and SA, integrating the positive impact of CPAP. Thus, both CPAP and sac/val therapy may synergistically contribute to lower the risks of both cardiac and pulmonary complications in HFrEF patients with SA.