The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure.

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure.

Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.

In this study, we aimed to investigate whether short-term and low-dose treatment with hydroxychloroquine (HCQ), an antimalarial drug, can modulate heart function in a preclinical model of dilated cardiomyopathy (DCM) expressing the D94A mutation in cardiac myosin regulatory light chain (RLC) compared with healthy non-transgenic (NTg) littermates. Increased interest in HCQ came with the COVID-19 pandemic, but the risk of cardiotoxic side effects of HCQ raised concerns, especially in patients with an underlying heart condition, e.g., cardiomyopathy. Effects of HCQ treatment vs. placebo (H2O), administered in Tg-D94A vs. NTg mice over one month, were studied by echocardiography and muscle contractile mechanics. Global longitudinal strain analysis showed the HCQ-mediated improvement in heart performance in DCM mice. At the molecular level, HCQ promoted the switch from myosin's super-relaxed (SRX) to disordered relaxed (DRX) state in DCM-D94A hearts. This result indicated more myosin cross-bridges exiting a hypocontractile SRX-OFF state and assuming the DRX-ON state, thus potentially enhancing myosin motor function in DCM mice. This bottom-up investigation of the pharmacological use of HCQ at the level of myosin molecules, muscle fibers, and whole hearts provides novel insights into mechanisms by which HCQ therapy mitigates some abnormal phenotypes in DCM-D94A mice and causes no harm in healthy NTg hearts.

Dilated Cardiomyopathy With Multiple Left Ventricular Thrombi and Embolic Stroke After Mild COVID-19.

COVID-19 is a novel disease with multisystem involvement, but most patients have pulmonary and cardiovascular involvement in the acute stages. The cardiovascular impact of acute COVID-19 is well recognized and ranges from myocarditis, arrhythmias, and thrombotic occlusion of coronary arteries to spontaneous coronary artery dissection and microthrombi in small coronary vessels on autopsy. We report a case of a 37-year-old man who recovered from mild COVID-19 only to present a few weeks later with devastating cardiovascular involvement that included severe left ventricular impairment resulting from nonischemic cardiomyopathy, multiple left ventricular thrombi, and embolic stroke.

Transcriptome analysis uncovers the autophagy-mediated regulatory patterns of the immune microenvironment in dilated cardiomyopathy.

The relationship between autophagy and immunity has been well studied. However, little is known about the role of autophagy in the immune microenvironment during the progression of dilated cardiomyopathy (DCM). Therefore, this study aims to uncover the effect of autophagy on the immune microenvironment in the context of DCM. By investigating the autophagy gene expression differences between healthy donors and DCM samples, 23 dysregulated autophagy genes were identified. Using a series of bioinformatics methods, 13 DCM-related autophagy genes were screened and used to construct a risk prediction model, which can well distinguish DCM and healthy samples. Then, the connections between autophagy and immune responses including infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes were systematically evaluated. In addition, two autophagy-mediated expression patterns in DCM were determined via the unsupervised consensus clustering analysis, and the immune characteristics of different patterns were revealed. In conclusion, our study revealed the strong effect of autophagy on the DCM immune microenvironment and provided new insights to understand the pathogenesis and treatment of DCM.

Consistency in Change: Architecture for Optimistic Living

Beacons of inspiration for generations of architects, Peter Cook’s drawings often have similar but differently expressed architectural preoccupations. Concerned with transparency, time and change, they choreograph ‘growies’ or ‘veggies’ and a wealth of typologies and topologies. Bartlett School of Architecture and Architectural Association design tutor Ricardo de Ostos takes us through some of his recent work. Copyright © 2022 John Wiley & Sons, Ltd.

A rare case of atrial and biventricular thrombi with dilated cardiomyopathy as a delayed presentation in a patient with COVID-19.

Introduction: Coronavirus 2019 (COVID-19) can cause cardiovascular manifestations including myocardial injury and thromboembolic events. Case presentation: Here, we report a case of a 27-year-old female with dilated cardiomyopathy, right atrial and biventricular thrombi infected with COVID-19. Discussion: There are several complex coagulation abnormalities in COVID-19 patients that have been suggested to create a hypercoagulable state. Evidence have shown that endothelial injury potentially leading to thromboembolic events is caused by direct invasion of endothelial cell by SARS-CoV-2 and complement activation contributed by the virus spike protein. Conclusion: DCM can be complicated by atrial and biventricular thrombi due to coagulation abnormalities that are likely to persist after recovery from COVID-19. Thus, long-term careful monitoring of cardiac function is necessary after recovery of COVID-19.

Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments.

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.

Modeling Early Phases of COVID-19 Pandemic in Northern Italy and Its Implication for Outbreak Diffusion.

The COVID-19 pandemic has sparked an intense debate about the hidden factors underlying the dynamics of the outbreak. Several computational models have been proposed to inform effective social and healthcare strategies. Crucially, the predictive validity of these models often depends upon incorporating behavioral and social responses to infection. Among these tools, the analytic framework known as "dynamic causal modeling" (DCM) has been applied to the COVID-19 pandemic, shedding new light on the factors underlying the dynamics of the outbreak. We have applied DCM to data from northern Italian regions, the first areas in Europe to contend with the outbreak, and analyzed the predictive validity of the model and also its suitability in highlighting the hidden factors governing the pandemic diffusion. By taking into account data from the beginning of the pandemic, the model could faithfully predict the dynamics of outbreak diffusion varying from region to region. The DCM appears to be a reliable tool to investigate the mechanisms governing the spread of the SARS-CoV-2 to identify the containment and control strategies that could efficiently be used to counteract further waves of infection.

The SARS-CoV-2 pandemic course in Saudi Arabia: A dynamic epidemiological model.

OBJECTIVE: Saudi Arabia ranks second in the number of coronavirus disease 2019 (COVID-19) cases in the Eastern Mediterranean region. It houses the two most sacred religious places for Muslims: Mecca and Medina. It is important to know what the trend in case numbers will be in the next 4-6 months, especially during the Hajj pilgrimage season. METHODS: Epidemiological data on COVID-19 were obtained from the Saudi Arabian Ministry of Health. A susceptible-exposed-infectious-recovered (SEIR) prediction model was constructed to predict the trend in COVID-19 in Saudi Arabia in the next 6 months. FINDINGS: The model predicts that the number of active cases will peak by 22 May 2020. The cumulative infected cases are predicted to reach 70,321 at that time. The total number of infected individuals is estimated reach to 114,580 by the end of the pandemic. CONCLUSION: Our estimates show that by the time the Hajj season commences in Saudi Arabia, the pandemic will be in the midst of its deceleration phase (phase 3). This information will likely be useful to policymakers in their management of the outbreak.