Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Retrospective study: The diagnostic accuracy of conventional forceps biopsy of gastric epithelial compared to endoscopic submucosal dissection (STROBE compliant).

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

RUNNING TITLE: Bone marrow and pancreatic islet

Erdheim-Chester disease (ECD) is a rare multisystem histiocytosis, whose cardiovascular involvement has not been systematically characterized so far. We aimed to systematically (qualitatively and quantitatively) describe the features of cardiovascular involvement in a large cohort of ECD patients and to evaluate its impact on myocardial fibrosis extension and cardiac function.Among 54 patients with biopsy-proven ECD, 29 patients (59 ± 12 years, 79% males) underwent 1.5-T CMR using a standardized protocol for qualitative and quantitative assessment of disease localization, evaluation of atrial and ventricular function, and assessment of non-dense and dense myocardial fibrosis.The right atrioventricular (AV) groove was the most commonly affected cardiac site (76%) followed by the right atrial walls (63%), thoracic aorta (59%), and superior vena cava (38%). Right AV groove involvement, encasing the right ventricular artery, was associated with non-dense myocardial fibrosis in the infero-septal (20/26 patients) and the inferior (14/26 patients) mid-basal left ventricular (LV) wall. In two patients with right AV groove localization, LGE revealed myocardial infarction in the same myocardial segments. Three out of five patients with left AV groove involvement had non-dense LGE on the lateral LV mid-basal wall. Bulky right atrial pseudomass was associated with atrial dysfunction and superior and inferior vena cava stenosis.In ECD patients, AV groove localization is associated with LV wall fibrosis in the downstream coronary territories, suggesting hemodynamic alterations due to coronary encasement. Conversely, atrial pseudomass ECD localizations impact on atrial contractility causing atrial dysfunction and are associated with atrio-caval junction stenosis. 

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Cardiovascular involvement in Erdheim–Chester diseases is associated with myocardial fibrosis and atrial dysfunction

Le miocarditi, definite come “infiammazioni del miocardio”, sono secondarie piu frequentemente a infezioni virali o a processi autoimmunitari. Recenti studi postmortem hanno identificato la miocardite come causa di morte improvvisa nel 12% dei giovani adulti ed un loro ruolo eziologico in circa il 9% delle cardiomiopatie dilatative [1]. La presentazione clinica delle miocarditi e estremamente variabile, dall’astenia all’insufficienza cardiaca congestizia fulminante fino alla morte improvvisa. Quando associate a coinvolgimento del pericardio, la sintomatologia dolorosa acuta retrosternale frequentemente simula una sindrome coronarica acuta, da cui le miocarditi devono essere differenziate. L’attuale gold standard diagnostico e la biopsia endomiocardica; tuttavia tale procedura e invasiva, con rischi non irrilevanti, e possiede elevata sensibilita, ma bassa specificita [1]: e pertanto auspicabile disporre di una tecnica non invasiva che possa guidare alla diagnosi ed essere utile nel follow-up di questa patologia estremamente frequente.

Malattie infiammatorie del miocardio

Transcatheter Pulmonary Valve Replacement With 32-mm Balloon-Expandable Prosthesis: Another Strategy in Mildly Dilated RVOT.


 The liver hosts an immune suppressive environment favouring metastatic seeding and proliferation of cancer cells. Pharmacological treatments, including immunotherapies, fail in the presence of liver metastases (LMS). Therefore, identifying new interventional tools and key targetable players involved in the immunosuppressive environment is of pivotal importance. We developed a lentiviral vector (LV)-based platform for selective genetic engineering of resident and tumour-associated macrophages enabling locally-sourced delivery of therapeutic molecules to LMS. Selective transgene expression is driven by a macrophage specific promoter and fine-tuned by microRNA target sequences. Upon systemic delivery of the LV, we observed enhanced transgene expression in macrophages located in areas surrounding LMS. We then equipped the LV with an IFNα-coding sequence, a cytokine with pleiotropic immune effects. Long term analysis in mice showed LV dose-dependent, sustained and well-tolerated IFNα expression. To investigate the therapeutic efficacy, we employed a colorectal cancer (CRC) organoid-based syngeneic mouse model of LMS containing molecular and histopathological hallmarks of the human disease. IFNα LV treatment significantly delayed LMS growth reaching a complete response in up to 50%. Single cell omics of LMS from IFNα LV-treated mice showed upregulation of IFNα-responsive genes, macrophage skewing to an antigen presenting (M1-like) polarization state, and expansion as well as reduced exhaustion of LMS-associated antigen specific CD8 T cells. Employing spatial transcriptomics, we found that the interface between LMS and liver parenchymal tissue was the major site of IFNα action, which was associated with enhanced immune activation and antigen presentation. Furthermore, we observed decreased angiogenesis and hypoxia in IFNα LV-treated LMS. When comparing LMS of treatment responsive to resistant mice, we found accumulation of activated CD8 T-cells in responsive whereas a high number of immunosuppressive T regulatory type 1 (TR1)-like cells in resistant mice. Molecular analyses suggest that TR1-like cell infiltration was associated with increased IL10 signaling in resistant mice. Furthermore, we found a positive correlation between IFNα and TR1-like cell signatures in human LMS and primary CRC thus supporting the link between IFNα activation and expansion of TR1-like cells in cancer. In summary, we developed an innovative gene-based platform that upon a single well-tolerated intravenous LV infusion rapidly promotes a protective therapeutic response against LMS through enabling immune activation. However, we also found that TR1-like cells might promote tumor immune evasion in presence of IFNα signaling in this setting, suggesting targeting of TR1-like cells when facing resistance to cancer immunotherapies that trigger IFNα signaling.
 Citation Format: Thomas Kerzel, Stefano Beretta, Eloise Scamardella, Chiara Balestrieri, Tamara Canu, Federica Pedica, Rossana Norata, Lucia Sergi Sergi, Marco Genua, Ostuni Renato, Anna Kajaste-Rudnitski, Antonio Esposito, Masanobu Oshima, Giovanni Tonon, Francesca Sanvito, Mario Leonardo Squadrito, Luigi Naldini. IFNalpha by in vivo-engineered macrophages abates liver metastases and triggers counter regulatory responses limiting efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3297.

Antonio Esposito

Papers

RUNNING TITLE: Bone marrow and pancreatic islet

Cardiovascular involvement in Erdheim–Chester diseases is associated with myocardial fibrosis and atrial dysfunction

Malattie infiammatorie del miocardio

Transcatheter Pulmonary Valve Replacement With 32-mm Balloon-Expandable Prosthesis: Another Strategy in Mildly Dilated RVOT.

Abstract 3297: IFNalpha by in vivo-engineered macrophages abates liver metastases and triggers counter regulatory responses limiting efficacy