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Cystine-knot miniproteins are a class of 30-50 amino acid long peptides widespread in eukaryotic organisms. Due to their very peculiar three-dimensional structure, they exhibit high resistance to heat and peptidase attack. The cystine-knot peptides are well represented in several plant species including medicinal herbs and crops. The pharmacological interest in plant cystine-knot peptides derives from their broad biological activities, mainly cytotoxic, antimicrobial and peptidase inhibitory and in the possibility to engineer them to incorporate pharmacophoric information for oral delivery or disease biomonitoring. The mechanisms of action of plant cystine-knot peptides are still largely unknown, although the capacity to interfere with plasma membranes seems a feature common to several cystine-knot peptides. In some cases, such as potato carboxypetidase inhibitor (PCI) and tomato cystine-knot miniproteins (TCMPs), the cystine-knot peptides target human growth factor receptors either by acting as growth factor antagonist or by altering their signal transduction pathway. The possibility to identify specific molecular targets of plant cystine-knot peptides in human cells opens novel possibilities for the pharmacological use of these peptides besides their use as scaffold to develop stable disease molecular markers and therapeutic agents. [ABSTRACT FROM AUTHOR]

Hypothesis/introduction: The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy.Materials and Methods: In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively.Results: After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (-11.37% and -8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (-10.67% and -9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (-67.62% and -49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001).Conclusions: The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril. [ABSTRACT FROM AUTHOR]

Key Clinical Message Cutaneous malar rash and kidney involvement has not previously been reported as presenting symptoms of an angioimmunoblastic T-cell lymphoma (AITL). We report a case of a woman with erythematous rash. A PET- CT revealed a lymphadenopathy and splenomegaly. An inguinal lymph node biopsy showed an AITL. There was clinical improvement after prednisone. [ABSTRACT FROM AUTHOR]

Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1–T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1–T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population. [ABSTRACT FROM AUTHOR]

Purpose: Identify the factors related to failure ablation after percutaneous ultrasound guided single electrode radiofrequency ablation (RFA) for hepatocarcinoma (HCC) and propose a score for improving patient selection and treatment allocation.Methods: From 2010 to 2020 585 HCC nodules treated with RFA were prospectively collected. Ablation Difficulty Score (ADS) was built-up according to clinical and radiological factors related to failure ablation identified by Cox-logistic regression analysis. The study population was stratified in low risk (ADS 0), intermediate risk (ADS 1), and high risk (ADS ≥ 2) of failure ablation.Results: Overall ablation success rate was 85.5%. Morbidity and mortality rates were 3.5% and 0.0%. According to per nodule analysis the following factors resulted related to failure ablation: size > 20 mm (p = 0.002), sub-capsular location (p = 0.008), perivascular location (p = 0.024), isoechoic appearance (p = 0.008), and non-cirrhotic liver (p = 0.009). The ablation success rate was 93.5% in ADS 0, 85.8% in ADS 1 and 71.3% in ADS ≥ 2 (p < 0.001). The 1-year local tumor progression (LTP) free survival was 90.2% in ADS 0, 80.6% in ADS 1, and 72.3% in ADS ≥ 2 (p = 0.009). Nodule's size > 20 mm (p = 0.014), isoechoic appearance (p = 0.012), perivascular location (p = 0.012) resulted related to lower LTP free survival.Conclusion: Ablation Difficulty Score could be a simple and useful tool for guiding the treatment decision making of HCC. RFA in high risk nodules (ADS ≥ 2) should be carefully evaluated and reserved for patients not suitable for surgery or liver transplantation. [ABSTRACT FROM AUTHOR]

Background and Aims: Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients., Approach and Results: From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients' OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1-19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75-37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85-16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69-2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28-2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98-5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34-0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25-0.93)., Conclusions: Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus disease 2019 (COVID-19), characterized by pulmonary infection ranging from asymptomatic forms to respiratory insufficiency and death. Evidence of cardiac involvement in COVID-19 is increasing, and systemic inflammation or direct heart damage by SARS-CoV-2 can prolong the corrected QT interval (QTc)., Methods: In this observational study, a total of 333 consecutive patients admitted to the Covid Center of Verona University Hospital from November 2020 to April 2021 were included. Patients with bundle branch block, pacemaker-controlled heart rhythm and heart rate >120 beats/min were excluded. A complete electrocardiogram (ECG) was performed at admission, and QTc values of ≥440 ms for males and ≥460 ms for females were considered prolonged., Results: Overall, 153 patients had prolonged QTc (45.5%). In multivariate logistic regression analysis, male sex (odds ratio (OR)=6.612, p=0.046), troponin (OR=1.04, p=0.015) and lymphocyte count (OR=3.047, p=0.019) were independently associated with QTc prolongation. Multivariate logistic regression showed that QTc was independently associated with mortality (OR=4.598, p=0.036). Age, sex, the ratio between the partial pressure of oxygen (PaO2) and the fraction of inspired oxygen (FiO2) (P/F), and fibrosis-4 index for liver fibrosis (FIB-4) were also independently associated with mortality., Conclusion: QTc interval prolongation appears to be a frequent finding in patients with COVID-19. Moreover, prolonged QTc may be predictive of more severe forms of COVID-19 and worse outcome., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Since the SARS-CoV-2 pandemic emerged, antimicrobial stewardship (AS) activities need to be diverted into COVID-19 management., Methods: In order to assess the impact of COVID-19 on AS activities, we analyzed changes in antibiotic consumption in moderate-to-severe COVID-19 patients admitted to four units in a tertiary-care hospital across three COVID-19 waves. The AS program was introduced at the hospital in 2018. During the first wave, COVID-19 forced the complete withdrawal of hospital AS activities. In the second wave, antibiotic guidance calibration for COVID-19 patients was implemented in all units, with enhanced stewardship activities in Units 1, 2, and 3 (intervention units). In a controlled before and after study, antimicrobial usage during the three waves of the COVID-19 pandemic was compared to the 12-month prepandemic unit (Unit 4 acted as the control). Antibiotic consumption data were analyzed as the overall consumption, stratified by the World Health Organization AWaRe classification, and expressed as defined-daily-dose (DDD) and days-of-therapy (DOT) per 1000 patient-day (PD)., Results: In the first wave, the overall normalized DOT in units 2-4 significantly exceeded the 2019 level (2019: 587 DOT/1000 PD ± 42.6; Unit 2: 836 ± 77.1; Unit 3: 684 ± 122.3; Unit 4: 872, ± 162.6; p < 0.05). After the introduction of AS activities, consumption decreased in the intervention units to a significantly lower level when compared to 2019 (Unit 1: 498 DOT/1000 PD ± 49; Unit 2: 232 ± 95.7; Unit 3: 382 ± 96.9; p < 0.05). Antimicrobial stewardship activities resulted in a decreased amount of total antibiotic consumption over time and positively affected the watch class and piperacillin-tazobactam use in the involved units., Conclusions: During a pandemic, the implementation of calibrated AS activities represents a sound investment in avoiding inappropriate antibiotic therapy.

Background: Aortic stiffness index (AoSI) has to be considered a proxy outcome measure in patients with rheumatoid arthritis (RA). The aim of this study was to comparatively describe AoSI progression in two groups of RA patients on long-term treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with or without tumour necrosis factor inhibitors (TNFi)., Methods: AoSI was evaluated by Doppler echocardiography at the level of the aortic root, using a two-dimensional guided M-mode evaluation. Eligible participants were assessed at baseline and after 12 months. Changes in serum lipids, glucose and arterial blood pressure were assessed. All patients who did not change DMARD treatment during follow-up were consecutively selected for this study., Results: We included 107 (64 TNFi and 43 csDMARDs) RA patients. Most patients (74%) were in remission or low disease activity and had some CVD risk factors (45.8% hypertension, 59.8% dyslipidaemia, 45.3% smoking). The two groups did not differ significantly for baseline AoSI (5.95±3.73% vs 6.08±4.20%, p=0.867). Follow-up AoSI was significantly increased from baseline in the csDMARDs group (+1.00%; p<0.0001) but not in the TNFi group (+0.15%, p=0.477). Patients on TNFi had significantly lower follow-up AoSI from baseline than the csDMARDs group (-1.02%, p<0.001; ANCOVA corrected for baseline AoSI, age and systolic blood pressure). Furthermore, follow-up AoSI was significantly lower in TNFi than in csDMARDs users with an increasing number of CVD risk factors., Conclusion: Long-term treatment with TNFi was associated with reduced aortic stiffness progression in patients with established RA and several CVD risk factors.

Systemic chronic inflammation may favor the onset of metabolic syndrome (MetS) which represents a risk factor for CV events. Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders with high prevalence of MetS. We assessed the factors associated with MetS and its prognostic role in non-selected RA/AS/PsA patients. Between March 2014 and April 2016, 458 patients (228 RA, 134 PsA, 96 AS) selected for a primary prevention program for cardiovascular diseases were analyzed. Primary and co-primary end points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively. MetS was diagnosed according to the IDF Task Force on Epidemiology and Prevention. Patients were divided into MetS + (73 = 16%) and MetS - (385 = 84%). At multivariate logistic analysis, cancer, moderate/high disease activity, higher LV mass (LVM) and degree of LV diastolic dysfunction were independently associated with MetS. At 36-month follow-up, the event rate for primary/co-primary end point was 52/15% in MetS + vs 23/7% in MetS - (both p < 0.001). At multivariate Cox regression analysis, MetS was related to primary end point (HR 1.52 [CI 1.01-2.47], p = 0.04) together with higher LVM, disease duration and higher prevalence of biologic DMARDs refractoriness, and to co-primary end point (HR 2.05 [CI 1.16-3.60], p = 0.01) together with older age and higher LVM. The RA/AS/PsA phenotype MetS + is a subject with moderate/high disease activity, LV structural and functional abnormalities at increased risk for cancer. MetS + identifies RA/AS/PsA patients at higher risk for CV and non-CV events, independently of traditional CV risk factors analyzed individually and traditional indexes of inflammation.

Background: Several studies on community populations found that metabolic syndrome (MetS) is associated with higher risk for total incident cancer with a predisposition for specific types of cancer. These findings have never been analyzed in patients with chronic inflammatory rheumatic and musculoskeletal diseases (RMD). We assessed prevalence/incidence and factors related to the development of cancer in a large cohort of these patients and evaluate whether MetS and its components were associated with cancer independent of traditional markers of inflammation., Methods: Between March 2014 and April 2016, 474 patients with RMD involved in a cardiovascular primary prevention program were consecutively recruited into this ambispective (combination of retrospective/prospective) study. They underwent clinical, laboratory, and echocardiographic evaluations. MetS was diagnosed according to the ATPIII criteria., Results: Duration of follow-up was 42 [18-60] months. Patients with a diagnosis of cancer (made before recruitment or during follow-up) were 46 (9.7%). Cancer was diagnosed in 22/76 patients (29%) with MetS and in 24/398 patients (6%, p < 0.001) without MetS; nearly two thirds of malignancies belonged to those traditionally related to MetS. MetS was the strongest cancer risk factor. Cancer was positively associated with the number of MetS components identified in each patient. Beyond MetS, cancer was associated to older age and increased inflammatory disease activity; this information allowed to build a simple performance indicator highly sensitive for cancer development., Conclusion: In light of our results, an increasingly accurate assessment of MetS would be required in patients with RMD as potential measure of clinical outcomes including the risk of cancer.

Background: To assess the overall prevalence of clinical signs, symptoms, and radiological findings in children and/or adolescents with COVID-19., Methods: We systematically researched in PubMed, Scopus and Web of Science databases observational studies describing COVID-19 in children and/or adolescents until April 11, 2020. Data regarding clinical and radiological features were extracted from eligible studies and meta-analysis was performed using random-effects modeling., Results: We examined 19 eligible studies for a total of 2855 children and/or adolescents with COVID-19. Approximately 47% of subjects had fever (95% confidence interval [CI] 22-72%; I 2  = 98.6%), 37% cough (95%CI 15-63%; I 2  = 98.6%), 4% diarrhea (95%CI 0-12%; I 2  = 92.2%), 2% nasal congestion (95%CI 0-7%; I 2  = 87.7%), 1% dyspnea (95%CI 0-7%; I 2  = 91.5%) and 0% abdominal pain (95%CI 0-1%; I 2  = 76.3%). Subjects presented mild symptoms in 79% (95%CI 65-91%; I 2  = 93.5%) of cases, whereas only 4% (95%CI 1-9%; I 2  = 76.4%) were critical. Among those with pneumonia on computed tomography, 26.4% (95%CI 13-41%; I 2  = 80.8%) presented a unilateral involvement, 16% (95%CI 5-29%, I 2  = 81.2%) had bilateral involvement and 9% (95%CI 0-24%; I 2  = 88.7%) had interstitial pneumonia., Conclusions: Children and/or adolescents tend to have a mild COVID-19 course with a good prognosis., Impact: Compared to adults, children and/or adolescents tend to have a mild COVID-19 course with a good prognosis. This study provides new and consistence information on the clinical and radiological characteristics of COVID-19 in pediatrics. This study may help to fight COVID-19 in pediatric population.

Objective: To assess the variables associated with the status of low myocardial mechano-energetic efficiency (MEE) [the ratio between myocardial left ventricular (LV) work and magnitude of myocardial oxygen consumption] and whether low-MEE is a prognosticator of adverse cardiovascular outcome in patients with chronic inflammatory arthritis., Methods: A total of 432 outpatients with established chronic inflammatory arthritis without overt cardiac disease were recruited from March 2014-March 2016; 216 participants were used as comparison group. Low-MEE status was a priori identified by standard echocardiography at rest as less than 0.32 ml/s per g (5th percentile of MEE calculated in 145 healthy individuals). The pre-specified primary end-point of the study was a composite of cardiovascular death/hospitalization. Follow-up ended September 2019., Results: MEE was significantly lower in chronic inflammatory arthritis patients than controls (0.35 ± 0.11 vs. 0.45 ± 0.10 ml/s per g; P < 0.001). Low-MEE was detected in 164 patients (38%). Independent predictors of low-MEE were older age, higher SBP, diabetes mellitus, LV concentric geometry and lower LV systolic function. During a follow-up of 36 (21-48) months, a primary end-point occurred in 37 patients (8.6%): 22/164 patients with low-MEE (13.4%) and 15/268 (5.6%) without low-MEE (P = 0.004). Low-MEE predicted primary end-points in multivariate Cox regression analysis [heart rate 2.23 (confidence interval 1.13-4.38), P = 0.02] together with older age, lower renal function and higher LV mass., Conclusion: Low-MEE is detectable in more than one-third of patients with chronic inflammatory arthritis and is associated with traditional cardiovascular risk factors and abnormalities in LV geometry and systolic function. In these patients low-MEE is a powerful prognosticator of adverse cardiovascular events.

Patients with rheumatoid arthritis (RA) have an increased incidence of cardiovascular events. Ultrasound examination of the carotid arteries can show the presence of plaques and detect the atherosclerotic subclinical process through the evaluation of intima-media thickness (cIMT) and carotid segmental distensibility (cCD). The aim of the present study was to identify which factors could independently influence the evolution of atherosclerosis (plaques, cIMT, and cCD) after 1 year of follow-up in a sample of patients with RA. A total of 137 patients with RA without previous cardiovascular (CV) events were enrolled at baseline, and 105 (M/F: 21/84, age 59.34 ± 11.65 years) were reassessed after one year using ultrasound of carotid arteries to detect atheromatous plaques and to measure cIMT and cCD. After one year, all the indices of subclinical atherosclerosis worsened with respect to baseline (Δ-cIMT = 0.030 ± 0.10 mm, p = 0.005; Δ-cCD = -1.64 ± 4.83, 10-3/KPa, p = 0.005; Δ-plaques = 8.6%, p = 0.035). Traditional CV risk factors (age, mean arterial pressure, and diabetes) and corticosteroid therapy were independently associated with the worsening of subclinical atherosclerosis. Interestingly, when considering RA patients divided according to the degree of disease activity score 28 with C-reactive protein (DAS28 [CRP] ≥2.6), the worsening of subclinical atherosclerosis indices was detectable exclusively in the group of patients with active disease. Our longitudinal study supports the hypothesis of a key role of both traditional CV risk factors and the inflammatory activity of arthritic disease in the progression of subclinical atherosclerosis in RA patients. In addition, corticosteroids might have a deleterious effect.

Objectives: Patients with rheumatoid arthritis (RA) are exposed to impairment in left ventricular (LV) function, which is a prognosticator of poorer clinical outcomes. In this study we assessed prevalence and factors associated with adverse outcomes in patients with RA and asymptomatic LV systolic dysfunction (LVSD)., Methods: We prospectively analysed 102 RA patients with asymptomatic LVSD consecutively selected by a pool of 418 RA patients referred to the Division of Rheumatology, University of Verona, between March 2014 and March 2015. LVSD was defined as impaired global longitudinal strain (GLS) measured by echocardiography. The pre-specified study end-points were all-cause death/hospitalisation, and death/hospitalisation for cardiovascular cause., Results: During a follow-up of 35 [13-54] months, all-cause death/hospitalisation occurred in 40 patients (39%). No patient died during the follow-up, 18 patients (18% of the study population) had a cardiovascular event which required hospitalisation, while 22 (22% of patients) required hospitalisation, but this was unrelated to CV. Multiple Cox regression analysis identified worse renal function, more frequent use and a higher number of biologic DMARDs used before enrolment as independent predictors of all-causes hospitalisation. The same variables together with higher LV mass predicted CV hospitalisation. Prognostic cut-off points were 90 ml/min/1.73 m2 for glomerular filtration rate and 49 g/m2.7 for LV mass., Conclusions: RA patients with asymptomatic LVSD have a very high rate of all-cause and cardiovascular hospitalisation at mid-term follow-up, predicted by worse renal function, higher LV mass, more frequent use and higher number of biologic DMARDs used before enrolment, suggesting that biologic DMARDs refractory is a proxy of adverse events.

Background: Inflammatory arthritis including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders at increased risk of morbidity and mortality for which a validated prognostic tool for facilitating clinical management is needed. CHA 2 DS 2 -VASc (congestive heart failure/hypertension/age diabetes/stroke/vascular disease/age/sex category) score was initially conceived and used to estimate thromboembolic risk in non-valvular atrial fibrillation, and then successfully applied in community populations with sinus rhythm. We tested CHA 2 DS 2 -VASc-score as a prognosticator of adverse outcomes in patients in sinus rhythm with RA/AS/PsA., Methods: Between March 2014 and March 2015, 414 patients (214 RA, 75 AS, 125 PsA) in sinus rhythm without cardiac disease were consecutively analyzed and prospectively followed-up. Primary and co-primary end-points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively., Results: Patients were divided into LOWscore and HIGHscore groups if CHA 2 DS 2 -VASc was = 0/1 point or greater than 1 point, respectively. The HIGHscore group comprised 190 patients who were older with higher prevalence of CV risk factors and arthritis disease activity than 224 LOWscore patients. During a follow up of 36 months, the event rate for primary and co-primary end-point was 37% and 12% in the HIGHscore vs 22% and 4% in LOWscore group (P = .001 and .002 respectively). At multivariate Cox regression analysis CHA 2 DS 2 -VASc-score was related to primary end-point (hazards ratio [HR] 1.30 [1.07-1.59], P = .009) and co-primary end-point (HR 1.35 [1.01-1.79], P = .04) independently of traditional CV risk factors analyzed individually and indexes of inflammation or disease duration., Conclusion: CHA 2 DS 2 -VASc-score accurately identifies in the mid-term patients in sinus rhythm with RA/AS/PsA at different risks for CV and non-CV mortality and hospitalization., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Purpose: Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children., Methods: We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (r S ) were calculated to evaluate associations between FA and features of the MetS., Results: Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (r S  = - 0.352), triglycerides (r S  = - 0.379), fasting insulin (r S  = - 0.337) and 24-h SBP (r S  = - 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (r S  = 0.354), triglycerides (r S  = 0.400) and fasting insulin (r S  = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (r S  = 0.515) and inversely to AA (r S  = - 0.472)., Conclusions: Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.

Data on the progression of atherosclerosis in spondyloarthritis (SpA) are scarce, despite a high burden of cardiovascular diseases (CVD). The aim of this study was to identify the predictors of an accelerated subclinical atherosclerosis in patients with SpA. Study participants were 66 patients free of CVD classified according to ASAS criteria. The patients were evaluated at baseline and after 13.5 ± 3.6 months. Ultrasound measurements of carotid intima-media thickness (cIMT) and distensibility coefficient (cDC) were used to assess the extent of subclinical atherosclerosis. cIMT progression rate was calculated dividing the cIMT change by the time between the scans. Accelerated atherosclerosis was defined as the top cIMT progression rate quartile. At baseline, the mean Framingham Risk Score was 14 ± 11%. At follow-up, cIMT increased in 39 patients (59%; mean difference 0.01 ± 0.10; p = 0.334). Mean cIMT progression rate was 0.01 mm/year (95% CI - 0.02 to 0.03). cDC was unchanged at follow-up. Patients with accelerated atherosclerosis (n = 16) had significantly higher serum creatinine and lower glomerular filtration rate (eGFR) at baseline. In multiple logistic regression, only eGFR and the presence of syndesmophytes were associated with an accelerated atherosclerosis, independent of traditional cardiovascular risk factors. In patients with SpA without overt CV disease, a decrease in renal function and radiographic damage are conditions associated with the development of subclinical accelerated atherosclerosis. Longitudinal assessment of cIMT could be useful to better evaluate the individual CV risk of these patients improving their prognostic stratification.

Background: Speckle-tracking echocardiography allows early detection of subclinical left ventricular systolic dysfunction (LVSD) in patients with rheumatoid arthritis (RA). In this prospective study, we assessed the prevalence and the prognostic role of subclinical LVSD detected by speckle-tracking echocardiography in RA patients., Methods: Two-dimensional global longitudinal strain (GLS) and global circumferential strain (GCS) were measured in 209 RA patients without overt cardiac disease. LVSD was defined as low GLS (> -16.0%), low GCS (> -17.8%), or both. The primary end point was all-causes hospitalization; the coprimary end point was hospitalization for cardiovascular causes., Results: The study population had a mean age of 58 ± 11 years; 67% were female, 52% had hypertension, and the RA duration was 14 ± 10 years. Low GLS was detected in 51 patients (24%), low GCS in 42 patients (20%), and combined low GLS and GCS in 18 patients (9%). During a median follow-up time of 16 months (range, 10-21 months), a primary end point occurred in 50 patients (24%), and 25 patients were hospitalized for a cardiovascular event. Multiple Cox regression analyses revealed that combined low GLS and GCS was independently associated with the end point defined as all-causes hospitalization together with higher aortic stiffness. Examined individually, neither low GCS nor low GLS showed an independent association with this typology of clinical outcome. Conversely, both low GCS and low GLS (examined individually or as combined low GLS and GCS) emerged as strong independent prognosticators of cardiovascular events., Conclusions: Subclinical LVSD defined as low GLS, GCS, or both is common in RA patients without overt cardiac disease and provides additional prognostic information in these individuals., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&L LVSD in patients with rheumatoid arthritis., Methods: One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S'). Combined C&L LVSD was defined if sc-MS was <86.5% and S' was <9.0 cm/sec (the 10th percentiles of sc-MS and S' derived in 132 healthy subjects)., Results: Combined C&L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01-1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07-7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&L LVSD (odds ratio, 2.57; 95% CI, 1.06-6.25). The relationship between sc-MS and S' was statistically significant in the subgroup of 142 patients without combined C&L LVSD (r = 0.40, F < 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S'; r(2) = 0.19, P < .0001), absent in patients with combined C&L LVSD., Conclusions: Combined C&L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients., Notice of Clarification: The aim of this "notice of clarification" is to analyze in brief the similarities and to underline the differences between the current article (defined as "paper J") and a separate article entitled "Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis" (defined as "paper E"), which was written several months before paper J, and recently accepted for publication by the journal "Echocardiography" (Cioffi et al. http://dx.doi.org/10.1111/echo.13186). We wish to explain more clearly how the manuscript described in "paper J" relates to the "paper E" and the context in which it ought to be considered. Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers. In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis. Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S') as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E. The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E. It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered. Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer's comment. That is why we did not put both findings in the same paper. We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers' right to understand how the work described in the paper J relates to other work by our research group. Giovanni Cioffi On behalf of all co-authors Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Patients with rheumatoid arthritis (RA) have a high risk for cardiovascular disease due to a chronic inflammatory state, accelerated atherosclerosis, and changes in left ventricular (LV) geometry. These conditions predispose patients to LV systolic dysfunction (LVSD). In this study we assessed whether RA is a condition associated with LVSD, and analyzed the prevalence and factors associated with LVSD in patients with RA., Patients and Methods: Echocardiographic and clinical data from 198 patients with RA without presence or history of symptoms of cardiac disease were compared with 198 non-RA controls matched for cardiovascular risk factors. LVSD was identified with tissue Doppler echocardiography (TDE) when mitral annular peak systolic velocity (S') was < 9.0 cm/s., Results: Patients with RA were 61 ± 12 years old and 71 % were female (disease duration 14 ± 10 years). LVSD was found in 89 patients with RA (45 %). By multiple regression analysis including both RA patients and controls, RA emerged as an independent condition associated with LVSD (exp β 3.89; CI: 1.87-8.08) together with higher E/E' ratio (index of LV diastolic function) and diabetes mellitus. For the 198 patients with RA, the variables associated with LVSD were higher E/E' ratio and systolic blood pressure., Conclusions: Almost half of asymptomatic RA patients without history of cardiac disease have subclinical LVSD easily detectable with TDE. RA is closely related to LVSD. A higher degree of LV diastolic dysfunction and systolic blood pressure are associated with LVSD in these patients, whose risk for cardiovascular events could be better defined using such information in the asymptomatic stage of cardiac disease.

Introduction: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature., Aim: To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage)., Methods: HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona)., Results and Conclusion: The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.