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Dystrophic calcinosis, which is the accumulation of insoluble calcified crystalline materials within tissues with normal circulating calcium and phosphorus levels, is a frequent finding in systemic sclerosis (SSc) and represents a major burden for patients. In SSc, calcinosis poses significant challenges in management due to the associated risk of severe complications such as infection, ulceration, pain, reduction in functional capacity and quality of life, and lack of standardized treatment choices. The exact pathogenesis of calcinosis is still unknown. There are multifaceted factors contributing to calcinosis development, including osteogenic differentiation of cells, imbalance between promoter and inhibitors of mineralization, local disturbance in calcium and phosphate levels, and extracellular matrix as a template for mineralization. Several pathophysiological changes observed in SSc such as ischemia, exacerbated production of excessive reactive oxygen species, inflammation, production of inflammatory cytokines, acroosteolysis, and increased extracellular matrix production may promote the development of calcinosis in SSc. Furthermore, mitochondrial dynamics, particularly fission function through the activity of dynamin-related protein-1, may have an effect on the dystrophic calcinosis process. In-depth investigations of cellular mechanisms and microenvironmental influences can offer valuable insights into the complex pathogenesis of calcinosis in SSc, providing potential targeting pathways for calcinosis treatment. [ABSTRACT FROM AUTHOR]

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. The review by Melissaropoulos and Daoussis, focusing the attention on B-cell aberrations, provides a comprehensive overview on B-cell depletion as a therapeutic approach in systemic sclerosis (SSc) [[1]]. J Clin Lab Immunol. 1989; 29; 2: 59-63. 1:STN:280:DyaK3c3hvV2rsw%3D%3D. 2632802 3 Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. [Extracted from the article]

• Pulmonary arterial hypertension may complicate the course of systemic sclerosis and negatively impact on its prognosis. • Given the low prevalence and incidence, screening for pulmonary hypertension is indicated in high risk population. • Echocardiography represents the most frequently used screening tool, both alone or combined with other tests. • Multi-parameters combined screening algorithms increase the power to detect patients with positive right heart catheterization. • Repeated screening is useful to detect incident cases during longitudinal observation. Pulmonary arterial hypertension (PAH) carries a high morbidity and mortality burden in Systemic Sclerosis (SSc). Therefore, PAH screening and early detection are pivotal. A systematic literature review (SLR) to search for all screening tools and modalities for SSc-PAH was performed in reference to right heart catheterization as diagnostic gold standard. Papers from 2 previously published SLRs and derived from a systematic search on Pubmed, EMBASE, Web of Science for papers published from 03/10/2017 to 31/12/2018 were manually included. A total of 199 papers were reviewed and 32 were extracted, with a low bias risk according to QUADAS2. Echocardiography, pulmonary function tests, clinical features and serum biomarkers were the most frequently tools used for screening, with different parameters combined in a variable fashion, as single item or as part of composite algorithms. Among the composite algorithms, the DETECT score, ESC/ERS 2009 or 2015 guidelines, ASIG and ITINER-air algorithms were the most commonly used in a wide range of patients. In different cohorts, DETECT and ASIG showed higher sensitivity and negative predictive value than ESC/ERS 2009. In conclusion, the literature shows echocardiography as the leading screening tool for SSc-PAH. In particular, systolic pulmonary arterial pressure (sPAP) and tricuspid regurgitation velocity (TRV), both as single items or part of composite algorithms, including also serum biomarkers, clinical and functional items, are the most frequent parameters evaluated. [ABSTRACT FROM AUTHOR]

• Virus-negative myocarditis(VNM) is an inflammatory disease with diverse etiologies. • A shared immune-mediated pathogenic process leads to inflammation and tissue damage. • Therapies effectively curbing myocardial inflammation can improve patient's outcome. • We reviewed current immune-modulatory opportunities to treat VNM. • Promising therapies could pave the way to future strategies for VNM. Virus-negative or autoimmune myocarditis(VNM) is an inflammatory disease affecting the myocardium that may occur as a distinct disease with exclusive cardiac involvement, or in the context of systemic autoimmune or inflammatory disorders. The pathogenesis of VNM involves both innate and acquired immunity and is not completely elucidated: an early immune-mediated pathogenic process lead to subacute and chronic stages and eventually results in tissue remodeling, fibrosis, contractile dysfunction, dilated cardiomyopathy and arrhythmic burden, accounting for a dismal prognosis. Treatment interventions effectively curbing the acute inflammatory process at an early stage can prevent late cardiac remodeling and improve patient's outcome. The mainstay of treatment of VNM remains symptomatic therapy of heart failure and arrhythmia, while the use of immunosuppressive treatments has long been considered controversial until recently, and strategies effectively targeting the inflammatory and immune-mediated substrate of the disease remain elusive. Only steroids and azathioprine have been tested in clinical trials, and nowadays represent the therapy of choice. A substantial proportion of patients are resistant to first line strategies, suggesting that some critical inflammatory mechanisms are not responsive to conventional immunosuppression with steroids and azathioprine, or experience drug-related adverse events. Thus, second-line targeted therapeutic strategies to treat VNM are eagerly awaited. Recent data on the pathogenic mechanisms underlying myocardial inflammation are paving the way to novel, promising treatment strategies for myocarditis, which could reformulate future treatment strategies for VNM. In this review, we summarize the current therapeutic opportunities, beyond corticosteroids, to treat VNM, including conventional and biologic immunosuppressive drugs and cytokine blocking agents. [ABSTRACT FROM AUTHOR]

Abstract Objectives The aim of our study was to define the role of high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP in identifying Systemic Sclerosis (SSc) patients with cardiac involvement and at higher risk of cardiac death. Methods Plasma hs-cTnT and NT-proBNP concentrations were measured in 245 SSc-patients. Results hs-cTnT and NT-proBNP levels were higher in SSc-patients than in healthy controls. Hs-cTnT levels were higher than 0.014 ng/ml in 32.3% SSc-patients, while NT-proBNP was above 125 pg/ml in 31.8% of them, irrespective of classical cardiovascular risk factor and of pulmonary arterial hypertension. Elevated hs-cTnT and NT-proBNP were associated with diffuse skin involvement and directly correlated with the skin score. Patients with increased cardiac markers presented a lower left-ventricular ejection fraction (LVEF) and a higher rate of right bundle branch block (RBBB) on electrocardiogram (ECG) compared to patients with normal cardiac enzymes. During the follow-up, 12 SSc-patients experience a disease-related death; 9 of these were directly related to cardiac involvement (sudden cardiac death or heart failure) and the majority of them occurred among patients with increase of at least one cardiac biomarker. Long-term survival was worse in patients with increase of both cardiac biomarkers. Conclusions Evaluation of hs-cTnT and NT-proBNP levels may provide a tool to screen non-invasively SSc-patients for heart involvement. A higher incidence of impaired systolic function, ECG abnormalities and a poor outcome in SSc-patients with elevated cardiac enzymes suggests that they may be valuable screening biomarkers to detect a cardiac damage at early stages and to improve risk stratification. Highlights • Subclinical heart involvement is common in Systemic Sclerosis. • Primary heart involvement portend a dismal prognosis. • hs-cTnT and NT-proBNP are biomarkers of early cardiac damage. • hs-cTnT and NT-proBNP are predictors of poor outcome. • hs-cTnT and NT-proBNP should be measured in all patients with Systemic Sclerosis. [ABSTRACT FROM AUTHOR]

We propose a model where weak rulers have incentives to let ethnically divided countries plunge in civil war. Allowing inter-group fighting reduces production–and hence the tax base–but enables the ruler to devote more resources to increasing the tax rate. This mechanism is increasingly salient with larger amounts of natural resources, especially if these are unequally distributed across ethnic groups. We validate the theoretical predictions using cross-country data, and show that our empirical results are robust to controlling for the usual determinants of civil war incidence, and to using various proxies for the ruler's relative weakness and for the presence of natural resources. [ABSTRACT FROM AUTHOR]

In this paper we argue that natural resource conservation is jeopardised by the ability of users to resort to violence to appropriate resources when they become scarce. We provide evidence from a lab experiment that participants interacting in a dynamic game of common pool resource extraction reduce their cooperation on efficient levels of resource extraction when given the possibility to appropriate the resource at some cost, i.e. through conflict. Theoretically, cooperation is achievable via the threat of punishment strategies, which stop being subgame perfect in the presence of conflict. Accordingly we argue that the observed reduction of cooperation in the game's early stages in the lab is a consequence of participants (correctly) anticipating the use of appropriation when resources become scarce. [ABSTRACT FROM AUTHOR]

Background: Arrhythmias are frequent in Systemic Sclerosis (SSc) and portend a bad prognosis, accounting alone for 6% of total deaths. Many of these patients die suddenly, thus prevention and intensified risk-stratification represent unmet medical needs. The major goal of this study was the definition of ECG indexes of poor prognosis. Methods: We performed a prospective cohort study to define the role of 24h-ECG-Holter as an additional risk-stratification technique in the identification of SSc-patients at high risk of life-threatening arrhythmias and sudden cardiac death (SCD). One-hundred SSc-patients with symptoms and/or signs suggestive of cardiac involvement underwent 24h-ECG-Holter. The primary end-point was a composite of SCD or need for implantable cardioverter defibrillator (ICD). Results: Fifty-six patients (56%) had 24h-ECG-Holter abnormalities and 24(24%) presented frequent ventricular ectopic beats (VEBs). The number of VEBs correlated with high-sensitive cardiac troponin T (hs-cTnT) levels and inversely correlated with left-ventricular ejection fraction (LV-EF) on echocardiography. During a mean follow-up of 23.1±16.0 months, 5 patients died suddenly and two required ICD-implantation. The 7 patients who met the composite end-point had a higher number of VEBs, higher levels of hs-cTnT and NT-proBNP and lower LV-EF (p = 0.001 for all correlations). All these 7 patients had frequent VEBs, while LV-EF was not reduced in all and its range was wide. At ROC curve, VEBs>1190/24h showed 100% of sensitivity and 83% of specificity to predict the primary end-point (AUROC = 0.92,p<0.0001). Patients with VEBS>1190/24h had lower LV-EF and higher hs-cTnT levels and, at multivariate analysis, the presence of increased hs-cTnT and of right bundle branch block on ECG emerged as independent predictors of VEBs>1190/24h. None of demographic or disease-related characteristics emerged as predictors of poor outcome. Conclusions: VEBS>1190/24h identify patients at high risk of life-threatening arrhythmic complications. Thus, 24h-ECG-Holter should be considered a useful additional risk-stratification test to select SSc-patients at high-risk of SCD, in whom an ICD-implantation could represent a potential life-saving intervention. [ABSTRACT FROM AUTHOR]

B This article refers to 'Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis' by N. Rubio-Infante I et al i ., published in this issue on pages 1739-1747. b Immune checkpoint inhibitors (ICIs) have represented a major breakthrough in the field of oncology as their introduction has had a significant impact on oncologic patients' survival.1 Thanks to their unquestionable efficacy in different malignancies, ICI use has recently been expanded and nowadays many oncologic patients can benefit from this new treatment option.2 Unfortunately, nothing in life is free and everything comes with a cost. A deeper characterization of cardiac irAEs and an international multi-disciplinary effort specifically for cardiac irAEs is more than ever needed in the rapidly changing oncology world considering also the expansion of clinical indications for ICI treatment. It is now time to step forward in the field of cardiac irAEs and to establish clear follow-up diagnostic work-ups and potentially patient-tailored approaches that might include different treatment strategies,14 such as the use of anti-cytokine agents,15 in order to maintain ICI treatment for as long as possible. [Extracted from the article]

Objective. To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. Methods. Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. Results. At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P< 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. Conclusion. TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow-up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs. [ABSTRACT FROM AUTHOR]

We investigate how the employment relationship may lead employers to control the voting behavior and to induce the electoral registration of their workers. Forced registration and the control of votes become feasible when voting behavior is observable, as in open ballot elections. Workers whose vote is controlled are more likely to be registered as compared to other eligible voters, increasing their impact on electoral outcomes. Increasing the secrecy of the vote (for instance with the adoption of a secret ballot) significantly reduces the control of votes. Electoral registration, however, remains biased as long as the probability of voting behavior disclosure induces less ideologically motivated voters to comply with the political preference of the employer. We provide empirical support for the predictions of the model examining the effects of the introduction of the secret ballot in Chile in 1958. [Copyright &y& Elsevier]

I Background: i Histiocytoses are rare disorders characterized by tissue infiltration by macrophages, dendritic cells, or monocyte-derived cells ([1]). Langerhans-related histiocytoses comprise Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), both inflammatory myeloid neoplasms characterized by clonal activating mutations along the mitogen-activated protein kinase or related pathways, most commonly I BRAF V600E i ([1], [2]). I Discussion: i Clinical and pathologic features supported inclusion of this condition in the spectrum of Langerhans-related histiocytoses because it shared similarities with both LCH and ECD ([1]). [Extracted from the article]

Abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive extracellular matrix (ECM) deposition in the skin and other visceral organs and it is associated with immune activation characterized by autoantibody production, release of various cytokines and T-lymphocyte activation. Several recent lines of evidence in animal models and in SSc patients indicate a potential role for B cells in the SSc. B cells have arisen as a possible player in tissue fibrosis in some experimental models and, since IL-6 produced by B cells, along with TGF-β, may induce matrix synthesis and less collagen degradation, targeting B cells could be one way to reduce ECM deposition and reduce the inflammatory background. Both SSc patients and tight-skin mice, a genetic model of SSc, have intrinsic B-cell abnormalities characterized by chronic B-cell activation. SSc patients present an increased number of naïve B cells and an activation of memory B cells, despite a reduction in their number. B cells from SSc patients exhibit increased expression of CD19. Remarkably, CD19 loss or B-cell depletion using antimouse CD20 antibody suppresses the development of skin hyperplasia and autoimmunity in tight-skin mice. Additionally, recent studies revealed a possible beneficial effect of anti-human CD20 antibody (Rituximab) therapy on skin fibrosis and lung involvement in SSc patients. These studies reported also the safety of Rituximab in SSc patients. All these findings suggest a possible role of antiCD20 treatment in SSc patients. [Copyright &y& Elsevier]

Intravenous immunoglobulins (IVIG) are a new therapeutic approach in systemic sclerosis SSc. An immunomodulatory and antifibrotic activity has been postulated. IVIG are generally well tolerated and have only rare side effects. Our retrospective study focused its attention on SSc, an autoimmune connective tissue disease, characterized by several complications which has a significant impact on patient's quality of life. The pathophysiology comprises fibrotic, vascular and immunological aspects. The aim of this study was to verify the effectiveness of IVIG on SSc skin involvement. Moreover, a systematic review of the literature (SLR) of the results obtained to date on the use of Intravenous immunoglobulin (IVIG) in SSc has been also performed. The data of 24 patients (21 women, 3 male) with refractory diffuse SSc skin involvement were evaluated (mean age was 52.13 years). IVIG infusion at a dosage of 2 g/Kg body weight for 4 consecutive days/month, was started between 2002 and 2019. Skin involvement was evaluated with the modified Rodnan Skin Score (mRSS) before therapy and then again after 6 and 12 months. To perform the SLR, the PubMed, Medline, Embase, and Web of Science database were searched from 1990 to 2020 (keywords: IVIG, systemic sclerosis). Three assessors (E.A., C.B. & M.M.C) identified the criteria to scan all papers. From the total SLR (106 results), 17 papers were identified after the separation of the clinical cases from the studies (total number of treated patients 183). The studies were classified according to the organ involvement considered in each study, as well as the prescribed dose (high or low doses), and the therapeutic regimens. In the selected papers, the organs mainly involved were the skin, the gastrointestinal, the joint and the cardiovascular systems. Only in one case, plasmapheresis was associated to IVIG. All papers reported significant reduction of the skin involvement, although generally the strength of the works was limited the lack of control cases or by the low number of patients involved. From the real life experience, a statistically significant reduction of mRSS was obtained at 6 months follow-up (average value of −6.61 ± 5.2, p < 0.001), and it was further maintained with a significant stabilization after 12-months (−11.45 ± 9.63, p < 0.002). This SLR and the data of the retrospective study suggest that IVIG may improve skin involvement reducing mRSS in particular in those patients that were refractory to other standard of care therapies and represents a therapeutic option in patients with concomitant myositis. The literature review revealed encouraging perspectives on the use of this therapy, given the effectiveness found in the selected works. [ABSTRACT FROM AUTHOR]

Background: Heart involvement (HInv) in systemic sclerosis (SSc) may relate to myocarditis and is associated with poor prognosis. Serum anti-heart (AHA) and anti-intercalated disk autoantibodies (AIDA) are organ and disease-specific markers of isolated autoimmune myocarditis. We assessed frequencies, clinical correlates, and prognostic impacts of AHA and AIDA in SSc. Methods: The study included consecutive SSc patients (n = 116, aged 53 ± 13 years, 83.6% females, median disease duration 7 years) with clinically suspected heart involvement (symptoms, abnormal ECG, abnormal troponin I or natriuretic peptides, and abnormal echocardiography). All SSc patients underwent CMR. Serum AHA and AIDA were measured by indirect immunofluorescence in SSc and in control groups of non-inflammatory cardiac disease (NICD) (n = 160), ischemic heart failure (IHF) (n = 141), and normal blood donors (NBD) (n = 270). AHA and AIDA status in SSc was correlated with baseline clinical, diagnostic features, and outcome. Results: The frequency of AHA was higher in SSc (57/116, 49%, p < 0.00001) than in NICD (2/160, 1%), IHF (2/141, 1%), or NBD (7/270, 2.5%). The frequency of AIDA was higher (65/116, 56%, p < 0.00001) in SSc than in NICD (6/160, 3.75%), IHF (3/141, 2%), or NBD (1/270, 0.37%). AHAs were associated with interstitial lung disease (p = 0.04), history of chest pain (p = 0.026), abnormal troponin (p = 0.006), AIDA (p = 0.000), and current immunosuppression (p = 0.01). AHAs were associated with death (p = 0.02) and overall cardiac events during follow-up (p = 0.017). Conclusions: The high frequencies of AHA and AIDA suggest a high burden of underdiagnosed autoimmune HInv in SSc. In keeping with the negative prognostic impact of HInv in SSc, AHAs were associated with dismal prognosis. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 57-year-old man with a two-year history of dilated cardiomyopathy. The patient was hospitalized for chronic fatigue and dyspnea secondary to New York Heart Association class III heart failure. It discusses the results of his transthoracic echocardiography, blood tests and magnetic resonance imaging. It also outlines the results of treatment which focused on dampening the inflammation mediated by interleukin-1.

Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P =.027) and micro-thrombosis (P <.016), sludge flow (P =.001), and pericapillary edema (P <.001), while recovered patients showed a higher prevalence of enlarged capillaries (P <.001), loss of capillaries (P =.002), meandering capillaries (P <.001), and empty dermal papillae (P =.006). COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19. • We assessed and accurately described peripheral microvasculature in COVID-19 patients through nailfold videocapillaroscopy. • Capillary alterations at the nailfold bed suggest a broad COVID-related microvascular involvement. • Different alterations in acutely-ill and recovered patients resemble a transition from acute to post-acute injury. [ABSTRACT FROM AUTHOR]

virus-negative lymphocytic myocarditis (VNLM) is a severe inflammatory heart disease with elusive therapies. We aimed to assess the efficacy of mycophenolate-mofetil (MMF) in patients with VNLM. Methods: patients were enrolled in this prospective cohort study and were treated with MMF, as the initial treatment in case of concomitant systemic immune diseases (SIDs), or as rescue therapy in isolated myocarditis intolerant/resistant to azathioprine. All were initially evaluated for endomyocardial biopsy; ECG, 24-h Holter, echocardiography, troponin T and NT-proBNP were obtained in all patients at baseline and after 6 months. The primary end-point was the change in left-ventricular ejection-fraction (LVEF) on echocardiogram after 6 months. Secondary outcomes: decrease in serum NT-proBNP and troponin-T levels, reduction of LV end-diastolic-volume (LVEDV), amelioration of regional wall motion abnormalities (RWMA), and modification of clinical status. 20 patients (10 females, median age at diagnosis 32 [41–59] years) were enrolled. Baseline echocardiography revealed a reduced LVEF (<55%) in 11 patients (55%) and a median LV-EF of 53.5 [44–60.5]%. Baseline median troponin T and NT-proBNP were 50.5 (14.4–288.5)ng/L and 257.0 (90.5–912.0)pg/ml, respectively. After 6 months, the median LVEF significantly improved (57 [50–61]%,p = 0.016), irrespective of concomitant steroid dose. Consistently, after 6 months LVEDV decreased from 135 ± 50 ml to 114 ± 38 ml (p < 0.001), and only 6 patients had RWMA, compared to 14 at baseline (p = 0.016). The amelioration of cardiac function was paralleled by a reduction of median troponin T (12.0 [10.0–24.0],p = 0.02) and NT-proBNP(79.5 [74.5-223-2],p = 0.007) and by a reduction in the number of patients with dyspnea NYHA class II-III(p = 0.02). None of the patients required drug discontinuation. MMF migh be a safe and effective therapeutic option in VNLM, both as first-line agent and as a rescue therapy. • Virus-negative myocarditis is a severe heart disease with elusive therapies. • Mycophenolate improves left ventricular function and reduces cardiac biomarkers. • Mycophenolate might be safe and effective in treating virus-negative myocarditis. • Mycophenolate is effective both as first-line agent and as rescue therapy. • Mycophenolate could be part of the portfolio of treatments for virus-negative myocarditis. [ABSTRACT FROM AUTHOR]

• Neuropsychological deficits may be present in dystrophinopathies. • Neurocognitive profile has been less explored in patients with Becker Muscular Dystrophy. • Longitudinal study to explore the neuropsychological evolution in paediatric BMD. • Results showed stable neurocognitive profile but deflection in executive functions. • We recommend careful monitoring to intercept learning disabilities. It has long been reported that neuropsychological deficits may be present in dystrophinopathies, specifically non-progressive cognitive impairment and a global deficit in executive functions; this neurocognitive profile has been less explored in patients with Becker than Duchenne muscular dystrophy (BMD/DMD). We conducted a longitudinal study to explore the evolution of neuropsychological and behavioural profile in a cohort of paediatric BMD. Seventeen patients with BMD without intellectual disability were assessed using a full battery of tests, including intellectual, adaptive and executive functioning, language and behavioral features. Tests were performed at baseline and after 12 months. The results showed adequate cognitive and adaptive profile with falls in Working Memory, as well as lower scores in executive functions. An improvement was observed in Processing Speed. Behavioral questionnaires confirmed a negative trend, while in normal ranges. We found a statistically significant difference between T0 and T1 in some items exploring executive functions. No statistically significant difference was observed stratifying patients by mutation site or IQ level. In conclusion, our study suggests that BMD patients have a stable neurocognitive profile, while a deflection in the executive functions may be observed. We recommend a careful monitoring to intercept learning disabilities and promptly start a multimodal rehabilitation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a study by B. M. Everett and colleagues which reported increased level of high-sensitivity cardiac troponin T in patients with both type 2 diabetes and ischemic heart disease.

• Performance of upper limb 2.0 measures DMD patients' changes. • Ambulant patients demonstrate reduced loss, particularly in shoulder function. • Transitioning subgroup witnesses significant shoulder decline. • Non-ambulant patients experience notable loss in elbow and distal functions. Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by muscle weakness. The Performance of upper limb (PUL) test is designed to evaluate upper limb function in DMD patients across three domains. The aim of this study is to identify frequently lost or gained PUL 2.0 abilities at distinct functional stages in DMD patients. This retrospective study analyzed prospectively collected data on 24-month PUL 2.0 changes related to ambulatory function. Ambulant patients were categorized based on initial 6MWT distance, non-ambulant patients by time since ambulation loss. Each PUL 2.0 item was classified as shift up, no change, or shift down. The study's cohort incuded 274 patients, with 626 paired evaluations at the 24-month mark. Among these, 55.1 % had activity loss, while 29.1 % had gains. Ambulant patients showed the lowest loss rates, mainly in the shoulder domain. The highest loss rate was in the shoulder domain in the transitioning subgroup and in elbow and distal domains in the non-ambulant patients. Younger ambulant patients demonstrated multiple gains, whereas in the other functional subgroups there were fewer gains, mostly tied to singular activities. Our findings highlight divergent upper limb domain progression, partly linked to functional status and baseline function. [ABSTRACT FROM AUTHOR]

Background: Cardiac involvement in systemic sclerosis (SSc) affects the prognosis of the disease. Echocardiography is the first line imaging tool to detect cardiac involvement, but it is not able to routinely detect myocardial fibrosis. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is the gold standard for replacement myocardial fibrosis assessment, but its availability is currently limited. Aim: We aimed to assess the clinical and instrumental parameters that would be useful for predicting the presence of LGE-CMR, to achieve a better selection of patients with SSc that could benefit from third-level CMR imaging. Methods: 344 SSc patients underwent a comprehensive echocardiogram and LGE-CMR on the same day; for 189 patients, a 24 h ECG Holter monitoring was available. Results: CMR showed non-junctional replacement myocardial fibrosis via LGE in 25.1% patients. A history of digital ulcers (OR 2.188; 95% C.I. 1.069–4.481) and ventricular arrhythmias at ECG Holter monitoring (OR 3.086; 95% C.I. 1.191–7.998) were independent predictors of replacement myocardial fibrosis. Conclusions: CMR can detect patterns of clinical and subclinical cardiac involvement, which are frequent in SSc. A history of digital ulcers and evidence of ventricular arrhythmias at ECG Holter monitoring are red flags for the presence of replacement myocardial fibrosis in CMR. The association between digital ulcers and myocardial fibrosis suggests that a similar pathological substrate of abnormal vascular function may underlie peripheral vascular and cardiac complications. [ABSTRACT FROM AUTHOR]

Abstract Introduction Myocarditis has been described in association with many systemic immune-mediated diseases (SIDs). However, the role of SIDs in influencing clinical presentation and outcome of patients with a new diagnosis of biopsy-proved myocarditis, has never been investigated so far. Methods We enrolled 25 consecutive cases with biopsy-proved myocarditis in the context of SIDs, and controls with isolated myocarditis, matched 1:1 by age, gender, ethnicity and clinical presentation. All of the patients presented with acute symptoms, normal coronary arteries, and no previous history of myocarditis. Detailed diagnostic workup, including blood exams, echocardiogram, arrhythmia monitoring and cardiac magnetic resonance (CMR) were obtained at baseline and at defined time points, up to 12-month follow-up (FU). Results At presentation, patients with SIDs had more commonly inflammatory biomarkers elevation, signs of associated pericarditis, and replacement fibrosis at histology, as compared to controls (18 vs. 6, 20 vs. 12, and 21 vs. 11, respectively; all p < 0.05). The Lake Louise criteria at CMR were negative in 19 vs. 10 patients with and without underlying SIDs, respectively (p = 0.021). Baseline ECG, in-hospital arrhythmia telemonitoring and echocardiographic findings were not significantly different between groups (all p = n.s.). At 12-month FU, the composite major endpoint of cardiac death, end-stage heart failure or malignant ventricular arrhythmias was significantly more common in cases than in controls (7 vs. 1, respectively, p = 0.049). Conclusion In patients with a new diagnosis of myocarditis, the presence of underlying SIDs is associated with distinct baseline clinical features and a significantly worse 1-year outcome. Highlights • Heart involvement in systemic immune-mediated diseases (SIDs) is a relevant but often neglected clinical issue. • In particular, little is known about baseline manifestations and prognosis of inflammatory heart disease in the context of SIDs. • We present here a prospective study on 25 patients with biopsy-proved myocarditis in the context of SIDs, compared to matched controls with isolated myocarditis. • Interestingly, patients with SIDs had distinct clinical features at onset, and grater occurrence of major and minor events in follow-up. [ABSTRACT FROM AUTHOR]

No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria. [ABSTRACT FROM AUTHOR]

Background: No studies investigated the prevalence of arrhythmias among clinically‐stable patients affected by COVID‐19 infection. Methods: We assessed prevalence, type, and burden of arrhythmias, by a single‐day snapshot in seven non‐intensive COVID Units at a third‐level center. Results: We enrolled 132 inhospital patients (mean age 65±14y; 66% males) newly diagnosed with COVID‐19 infection. Arrhythmic episodes were detected in 12 patients (9%). In detail, 8 had atrial fibrillation, and 4 self‐limiting supraventricular tachyarrhythmias. There were no cases of ventricular arrhythmias or new‐onset atrioventricular blocks. In addition, we report no patients with QTc interval >450 ms. Conclusions: Our single‐day snapshot survey suggests that the prevalence of arrhythmias among clinically stable COVID‐19 patients is low. In particular, no life‐threatening arrhythmic events occurred. [ABSTRACT FROM AUTHOR]

Background. Exercise stress test (EST) has been scarcely investigated in patients with arrhythmic myocarditis. Objectives. To report the results of EST late after myocarditis with arrhythmic vs. nonarrhythmic presentation. Methods. We enrolled consecutive adult patients with EST performed at least six months after acute myocarditis was diagnosed using gold-standard techniques. Patients with ventricular arrhythmia (VA) at presentation were compared with the nonarrhythmic group. Adverse events occurring during follow-up after EST included cardiac death, disease-related rehospitalization, malignant VA, and proven active myocarditis. Results. The study cohort was composed of 128 patients (age 41 ± 9 y, 70% males) undergoing EST after myocarditis. Of them, 64 (50%) had arrhythmic presentation. EST was performed after 15 ± 4 months from initial diagnosis, and was conducted on betablockers in 75 cases (59%). During EST, VA were more common in the arrhythmic group (43 vs. 4, p < 0.001), whereas signs and symptoms of ischemia were more prevalent in the nonarrhythmic one (6 vs. 1, p = 0.115). By 58-month mean follow-up, 52 patients (41%) experienced adverse events, with a greater prevalence among arrhythmic patients (39 vs. 13, p < 0.001). As documented both in the arrhythmic and nonarrhythmic subgroups, patients had greater prevalence of adverse events following a positive EST (40/54 vs. 12/74 with negative EST, p < 0.001). Electrocardiographic features of VA during EST correlated with the subsequent inflammatory restaging of myocarditis. Nonarrhythmic patients with uneventful EST both on- and off-treatment were free from subsequent adverse events. Conclusions. Late after the arrhythmic presentation of myocarditis, EST was frequently associated with recurrent VA. In both arrhythmic and nonarrhythmic myocarditis, EST abnormalities correlated with subsequent adverse outcomes. [ABSTRACT FROM AUTHOR]

• Rheumatic immune-related adverse events (irAEs) may encompass severe and steroid-refractory clinical manifestations. • Baseline autoantibody positivity predicts the requirement of add-on immunosuppressants to effectively control irAEs. • An early start of immunosuppressants in patients with irAEs and autoantibody positivity may be beneficial. Immune-related adverse events (irAEs) due to immune checkpoint inhibitors are responsible for a considerable burden of morbidity and mortality. Predictors of severity of rheumatic irAEs have not been identified yet. The objective of this study was to test the hypothesis whether the presence of autoantibodies could be associated with a more severe and difficult-to-treat clinical phenotype of rheumatic irAEs. Patients referred to our centre due to the onset of rheumatic irAEs were prospectively recruited between June 2018 and December 2020. A pre-specified panel of autoantibodies was tested in each patient at baseline visit. All patients were started on glucocorticoids and then followed-up. Conventional or biologic immunosuppressants were started in case of steroid-refractory or relapsing disease. Logistic regression analysis was performed to evaluate the association between the baseline positivity of at least one autoantibody and the necessity of an add-on therapy. Fourty-three patients with rheumatic irAEs were enrolled. Twenty-five (58%) patients had positivity of at least one of the tested autoantibodies. Twenty-two (51%) patients required the start of an additional immunosuppressant during follow-up. The only factor associated with the necessity of an add-on therapy was autoantibody positivity (OR=9.65, 95% CI:2.09–44.56; p-value 0.004). The presence of autoantibodies in patients with cancer who develop rheumatic irAEs could predict their progression to difficult-to-treat clinical manifestations. This finding might prompt a future therapeutic approach based on a tailored and earlier immunosuppressive treatment in selected cases. [ABSTRACT FROM AUTHOR]

Mean time from vaccine administration to clinical manifestations onset was 9 days (range 1-28); most patients 16 (53.3%) received the BNT162b2 vaccine. Interestingly, amongst systemic AEs, arthralgia is one of the most common [[2]] and only isolated cases [[6]-[9]] of inflammatory rheumatic diseases developed after COVID-19 vaccine administration have been described to date. [Extracted from the article]

Objectives: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Methods: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Results: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Conclusion: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Clinical relevance statement: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Key Points: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Graphical Abstract: Chronic myocardial inflammation is the substrate for arrhythmias and dilated cardiomyopathy onset, causing morbidity and mortality. Cardiovascular magnetic resonance (CMR) is the noninvasive gold standard for myocardial inflammation detection, due to the high sensitivity of the parametric mapping techniques. However, the potential prognostic capabilities of CMR mapping have not been studied in the setting of chronic myocarditis.This is a retrospective study on consecutive patients undergoing CMR with suspicion of chronic myocarditis from September 2017 to November 2021. CMR was acquired according to 2018 Lake Louise Criteria recommendations. The outcome (chronic heart failure, recurrent chronic myocarditic chest pain, ICD/PM implantation, arrhythmias [Lown class ≥ 2]) was collected at follow-up. The extent and degree of native T1, T2, and extracellular volume fraction alterations were used to create multivariate binary logistic regression models for outcome prediction, with or without left ventricle ejection fraction; their AUCs were compared with DeLong test. Differences between other parameters were assessed using Chi-square test, Fisher’s exact test, or Mann-Whitney U-test.The population included 88 patients (age 43 [32–52] yo), mostly male (53/88, 60%). After a median follow-up of 21 (17–34) months, 31/88 (35%) patients experienced the outcome. The model based on the extension of mapping alterations and LV dysfunction reached a good predictability (AUC 0.71). The model based on the intensity of mapping alterations and LV dysfunction had a very good performance (AUC 0.80).The quantitative analysis of CMR mapping parameters indicative of myocardial damage severity may improve risk stratification in patients with chronic myocarditis.The intensity of myocardial damage, assessed as the degree of native T1, T2, and ECV alteration, together with left ventricle dysfunction, improved patient risk stratification. Further prospective studies will be necessary for validation before clinical application.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms.Risk stratification of patients affected by chronic myocarditis is an unmet clinical need.Cardiovascular MRI (CMR) can role in risk stratification thanks to its multiparametric capabilities of tissue characterization.A model based on CMR parametric mapping and left ventricle ejection fraction can predict arrhythmia, heart failure, and recurrent symptoms. [ABSTRACT FROM AUTHOR]

Background: Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early‐onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited. Methods: To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment‐naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25‐hydroxyvitamin D, and liver enzyme levels. Results: Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58‐102.70) μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest–positive patients than in those negative (64.37 [IQR: 57.45‐121.82] vs 45.35 [IQR: 24.53‐74.61] μg/g of Hb, respectively; P =.04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5‐84] μg/dL vs 109 [IQR: 63.25‐154] μg/dL, respectively; P =.01862) and transferrin saturation values (15.005 [IQR: 7.0775‐18.41] % vs 29.645 [IQR: 17.8225‐34.3575] %; P =.0109) than those negative. Conclusions: Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP. [ABSTRACT FROM AUTHOR]

• TCZ is an effective treatment option for irAEs secondary to ICI. • TCZ seems to be associated with a favorable profile in terms of oncologic outcome. • The combination of TCZ and ICI might guarantee the control of both cancer and irAEs. Research is moving towards a more personalized management of immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI). Our objective was to evaluate the efficacy and safety of tocilizumab in the treatment of these clinical manifestations. A systematic literature review was performed to retrieve data about the use of tocilizumab in the treatment of irAEs. Additionally, data from cancer patients referred to our Immune-related Adverse Event Clinic and treated with tocilizumab were collected. Our literature review identified 20 articles and 11 meeting abstracts. Data about 91 cancer patients who received tocilizumab for the treatment of irAEs were collected. In 85% of cases, this therapy was associated with clinical benefit and no case of disease progression was reported. ICI therapy was continued following irAE onset and biologic therapy initiation in only three patients. Five patients developed irAEs upon ICI initiation and were subsequently treated with tocilizumab at our Centre. At a median follow-up of eight months, tocilizumab was safely continued along with ICI in three out of five patients, and an adequate control of irAE was obtained in all cases. No significant adverse reactions to tocilizumab were reported. Only one patient experienced a disease progression 18 months after ICI discontinuation. Both our systematic literature review and case series highlight the efficacy and safety of tocilizumab in the treatment of irAEs. Furthermore, they both support the possibility of a combined approach with tocilizumab and ICI, to guarantee an effective irAEs management without losing the oncologic response. [ABSTRACT FROM AUTHOR]

The aim of our study was to describe the incidence and predictive factors of secondary infections in patients with coronavirus disease 2019 (COVID-19). This was a cohort study of patients hospitalized with COVID-19 at IRCCS San Raffaele Hospital between 25th February and 6th April 2020 (NCT04318366). We considered secondary bloodstream infections (BSIs) or possible lower respiratory tract infections (pLRTIs) occurring 48 hours after hospital admission until death or discharge. We calculated multivariable Fine–Gray models to assess factors associated with risk of secondary infections. Among 731 patients, a secondary infection was diagnosed in 68 patients (9.3%); 58/731 patients (7.9%) had at least one BSI and 22/731 patients (3.0%) at least one pLRTI. The overall 28-day cumulative incidence was 16.4% (95%CI 12.4–21.0%). Most of the BSIs were due to Gram-positive pathogens (76/106 isolates, 71.7%), specifically coagulase-negative staphylococci (53/76, 69.7%), while among Gram-negatives (23/106, 21.7%) Acinetobacter baumanii (7/23, 30.4%) and Escherichia coli (5/23, 21.7%) predominated. pLRTIs were caused mainly by Gram-negative pathogens (14/26, 53.8%). Eleven patients were diagnosed with putative invasive aspergillosis. At multivariable analysis, factors associated with secondary infections were low baseline lymphocyte count (≤0.7 versus >0.7 per 109/L, subdistribution hazard ratios (sdHRs) 1.93, 95%CI 1.11–3.35), baseline PaO 2 /FiO 2 (per 100 points lower: sdHRs 1.56, 95%CI 1.21–2.04), and intensive-care unit (ICU) admission in the first 48 hours (sdHR 2.51, 95%CI 1.04–6.05). Patients hospitalized with COVID-19 had a high incidence of secondary infections. At multivariable analysis, early need for ICU, respiratory failure, and severe lymphopenia were identified as risk factors for secondary infections. [ABSTRACT FROM AUTHOR]

Background: Little is known about the risk stratification of patients with myocarditis undergoing ventricular tachycardia (VT) ablation.Objectives: This study sought to describe VT ablation results and identify factors associated with arrhythmia recurrences in a cohort of patients with myocarditis.Methods: The authors enrolled 125 consecutive patients with myocarditis, undergoing VT ablation. Before ablation, disease stage was evaluated, to identify active (AM) versus previous myocarditis (PM). The primary study endpoint was assessment of VT recurrences by 12-month follow-up. Predictors of VT recurrences were retrospectively identified.Results: All patients (age 51 ± 14 years, 91% men, left ventricular ejection fraction 52% ± 9%) had history of myocarditis diagnosed by endomyocardial biopsy (59%) and/or cardiac magnetic resonance (90%). Furthermore, all had multiple episodes of drug-refractory VTs. Multimodal pre-procedural staging identified 47 patients with AM (38%) and 78 patients with PM (62%). All patients showed low-voltage areas (LVA) at electroanatomical map (97% epicardial or endoepicardial); of them, 25 (20%) had wide borderzone (WBZ, constituting >50% of the whole LVA). VT recurrences were documented in 25 patients (20%) by 12 months, and in 43 (34%) by last follow-up (median 63 months; interquartile range: 39 to 87). At multivariable analysis, AM stage was the only predictor of VT recurrences by 12 months (hazard ratio: 9.5; 95% confidence interval: 2.6 to 35.3; p < 0.001), whereas both AM stage and WBZ were associated with arrhythmia recurrences anytime during follow-up. No VT episodes were found after redo ablation was performed in 23 patients during PM stage.Conclusion: Our findings suggest that VT ablation should be avoided during AM, but is often of benefit for recurrent VT after the acute phase of myocarditis. [ABSTRACT FROM AUTHOR]

• This is the first study comparing tocilizumab to standard of care in severe COVID-19 • Tocilizumab in severe COVID-19 patients did influence 28-day clinical outcomes • Tocilizumab safety was satisfactory except for ICU-admitted patients Tocilizumab (TCZ), a humanized monoclonal antibody targeting the interleukin-6 (IL-6) receptor, has been proposed for the treatment of COVID-19 patients; however, limited data are available on the safety and efficacy. We performed a retrospective study on severe COVID-19 patients with hyper-inflammatory features admitted outside intensive care units (ICUs). Patients treated with intravenous TCZ in addition to standard of care were compared to patients treated with standard of care alone. Safety and efficacy were assessed over a 28-day follow-up. 65 patients were included. Among them, 32 were treated with TCZ. At baseline, all patients were on high-flow supplemental oxygen and most (78% of TCZ patients and 61% of standard treatment patients) were on non-invasive ventilation. During the 28-day follow-up, 69% of TCZ patients experienced a clinical improvement compared to 61% of standard treatment patients (p = 0.61). Mortality was 15% in the tocilizumab group and 33% in standard treatment group (p = 0.15). In TCZ group, at multivariate analysis, older age was a predictor of death, whereas higher baseline PaO2:FiO2 was a predictor of clinical improvement at day 28. The rate of infection and pulmonary thrombosis was similar between the two groups. At day 28, clinical improvement and mortality were not statistically different between tocilizumab and standard treatment patients in our cohort. Bacterial or fungal infections were recorded in 13% of tocilizumab patients and in 12% of standard treatment patients. Confirmation of efficacy and safety will require ongoing controlled trials. [ABSTRACT FROM AUTHOR]

Background: Ventricular arrhythmias (VAs) have never been systematically investigated in patients with myocarditis at different stages.Objectives: The purpose of this study was to compare baseline and follow-up characteristics of VAs in patients with active myocarditis (AM) versus previous myocarditis (PM).Methods: A total of 185 consecutive patients (69% males, age 44 ± 15 years, left ventricular ejection fraction 49 ± 14%) with myocarditis and VA at index hospitalization, including ventricular fibrillation, ventricular tachycardia (VT), nonsustained ventricular tachycardia (NSVT), and Lown's grade ≥2 premature ventricular complexes, were enrolled. AM and PM groups were defined based on endomyocardial biopsy and cardiac magnetic resonance findings. A subset of patients (n = 46, 25%) also underwent electroanatomic mapping and VA transcatheter ablation.Results: At presentation, AM patients (n = 123, 66%) more commonly had ventricular fibrillation (8 cases vs. 0 cases; p = 0.053), and both irregular (61% vs. 11%; p < 0.001) and polymorphic VA (NSVT and VT: 19% vs. 2%; p = 0.002; premature ventricular complexes: 63% vs. 16%; p < 0.001). Only in PM patients with NSVT or VT, the dominant morphology (right-bundle branch block with superior axis) was 100% predictive of abnormal LV inferoposterior substrate at both cardiac magnetic resonance and electroanatomic mapping. At 27 ± 7 months prospective follow-up, 55 patients (30%) experienced malignant VA (AM vs. PM, p = 0.385). Although a prevalence of polymorphic and irregular VA was confirmed in AM patients with persistent inflammation in follow-up (58%), a predominance of monomorphic and regular VA was found in AM patients after myocarditis healing (42%), as well as in PM patients (all p < 0.001).Conclusions: In myocarditis patients, polymorphic and irregular VA are more common during the active inflammatory phase, whereas monomorphic and regular VA are associated with healed myocarditis. [ABSTRACT FROM AUTHOR]

Highlights • Leucocytoclastic vasculitis is associated with immune-checkpoint inhibitors therapy. • Thrombocytopenic purpura is the main differential diagnosis. • Steroids and hydroxychloroquine are an effective and safe therapy. [ABSTRACT FROM AUTHOR]

Background: Leukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL.Methods: We reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD.Results: There were seven males and three females; mean age at clinical onset was 49.6 years (range 38–59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up.Conclusions: Symptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease. [ABSTRACT FROM AUTHOR]

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases. [ABSTRACT FROM AUTHOR]

Background. Myocarditis lacks systematic characterization in COVID-19 patients. Methods. We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. Results. Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. Conclusions. Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by xanthogranulomatous tissue infiltration by foamy histiocytes. Fibrosis, a histologic hallmark of ECD, is responsible for lesion growth and clinical manifestations. Unraveling molecular fibrotic pathway in ECD would allow the identification of new pharmacologic targets. In this study, we evaluated serum and tissue samples from a large cohort of ECD patients focusing on two major pro-fibrotic mediators, TGF-β1 and chemokine ligand 18 (CCL18). We found a marked increase in CCL18 but not TGF-β1 levels in serum and lesions of ECD patients (p < 0.001), independently of treatment status and consistently over time. Using a linear mathematical model, we also found that elevated CCL18 serum levels correlate with both number and severity of disease localizations. These findings suggest the involvement of CCL18-induced fibrosis in ECD pathogenesis, providing a rationale for exploring CCL18 inhibition as a treatment for progressive fibrosis in ECD. [ABSTRACT FROM AUTHOR]