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Myasthenia gravis (MG) is an autoimmune disease characterised by muscular degeneration and autoantibodies to components of the neuromuscular junction. Development of MG is thought to occur from a combination of genetic and environmental factors, and viral infections have been suggested to be involved in the onset of MG through molecular mimicry and/or chronic inflammation. In this work, we analysed sera from MG patients for antibodies to members of the human herpes virus family and other selected pathogens to determine the virus antibody status in the sera of these patients. Enzyme-linked immunosorbent assay, western blotting and line blotting analyses using MG serum pools showed an association between elevated IgG antibody titers to cytomegalovirus (CMV) and MG. These results were replicated using individual serum samples, and showed significant differences in CMV antibody titer between MG patients and healthy controls. Other viruses did not show the same tendency.

While outcomes after liver transplantation have increased over the last two decades, this is primarily as a consequence of a reduction in early deaths and survival of those who survive the first 6 months has not significantly changed. Causes of premature death and graft loss include cardiovascular disease, renal impairment, malignancy and some infections. As the number of transplant recipients increase, care is being given by primary and secondary care clinicians. Management of the well patient is crucially dependent on careful assessment and where appropriate intervention, especially of cardiovascular risk - such as advice about avoidance of weight gain; management of hypertension, hyperlipidaemia and diabetes; and provision of appropriate lifestyle advice. Other interventions include surveillance for de novo malignancies, active management of immunosuppressive regimen with the need to tailor immunosuppression to the individual. Prompt investigation of abnormalities of liver function is essential. Immune-mediated graft damage still occurs but is less common as a cause for graft loss. Adherence is sometimes an issue, especially in teenagers and young adults, and should be considered and support given where needed. Immunisations (avoiding live and attenuated vaccines) should be encouraged. Recurrence of disease remains an issue, and some interventions (such as appropriate use of antiviral therapy for those grafted with viral hepatitis, use of ursodeoxycholic acid for those grafted for primary biliary cholangitis or long-term steroids for those grafted for autoimmune disease) may improve and maintain graft function. Close collaboration between recipient and the attending clinicians in primary, secondary and tertiary care and close attention to modifiable conditions will lead to improved outcomes., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9-transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied., Competing Interests: This study was supported by research funds from the National Institutes of Health (R01HL147968, R01 HL155344), the Veterans Administration (AN # 4345132), and the Wilkinson Foundation to Dr Mann. Dr Diwan was supported by grants from the National Institutes of Health (HL107594, HL143431, and NS094692) and the Department of Veterans Affairs (I01BX004235). Dr Finck was supported by grants from the National Institutes of Health (R01 HL119225, P30 DK05634). Dr Kovacs was supported by grants from the National Institutes of Health (S10 OD028597). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition., Competing Interests: None., (© 2022 The Authors.)

Background & Aims: Biliary complications (BC) following liver transplantation (LT) are responsible for significant morbidity. No technical procedure during reconstruction has been associated with a risk reduction of BC. The placement of an intraductal removable stent (IRS) during reconstruction followed by its endoscopic removal showed feasibility and safety in a preliminary study. This multicentric randomised controlled trial aimed at evaluating the impact of an IRS on BC following LT., Methods: This multicentric randomised controlled trial was conducted in 7 centres from April 2015 to February 2019. Randomisation was done during LT when a duct-to-duct anastomosis was confirmed with at least 1 of the stump diameters ≤7 mm. In the IRS group, a custom-made segment of a T-tube was placed into the bile duct to act as a stake during healing and was removed endoscopically 4 to 6 months post LT. The primary endpoint was the incidence of BC (fistulae and strictures) within 6 months post LT. The secondary criteria were complications related to the IRS placement or extraction, including endoscopic retrograde cholangio-pancreatography (ERCP)-related complications., Results: In total, 235 patients were randomised: 117 in the IRS group and 118 in the control group. BC occurred in 31 patients (26.5%) in the IRS group vs . 24 (20.3%) in the control group ( p  = 0.27), including 16 (13.8%) and 15 (12.8%) strictures, respectively. IRS migration occurred in 24 patients (20.5%), cholangitis in 1 (0.9%), acute pancreatitis in 2 (1.8%), and difficulty during endoscopic extraction in 19 (19.4%). No predictive factor for BC was identified., Conclusions: IRS does not prevent BC after LT and may require specific endoscopic expertise for removal., Trial Registration Number Clinicaltrialsgov: NCT02356939 (https://clinicaltrials.gov/ct2/show/NCT02356939?term=NCT02356939&draw=2&rank=1)., Lay Summary: Liver transplantation is a life-saving treatment for many patients with end-stage liver disease. However, it can be associated with complications involving the bile duct reconstruction. Herein, the placement of a specific stent called an intraductal removable stent was trialled as a way of reducing bile duct complications in patients undergoing liver transplantation. Unfortunately, it did not help preventing such complications., Competing Interests: The authors have declared no conflicts of interest in relation to this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Background: Cardiovascular magnetic resonance (CMR) is the test of choice for diagnosis and risk stratification of myocardial inflammation in acute viral myocarditis. The objective of this study was to assess patterns of CMR inflammation in a cohort of acute myocarditis patients from Northern Africa, Asia, and the Middle East using unsupervised machine learning., Methods: A total of 169 racially and ethnically diverse adults ( ≥ 18 years of age) with CMR confirmed acute myocarditis were studied. The primary outcome was a combined clinical endpoint of cardiac death, arrhythmia, and dilated cardiomyopathy. Machine learning was used for exploratory analysis to identify patterns of CMR inflammation., Results: Our cohort was diverse with 25% from Northern Africa, 33% from Southern Asia, and 28% from Western Asia/the Middle East. Twelve patients met the combined clinical endpoint - 3 had arrythmia, 8 had dilated cardiomyopathy, and 1 died. Patients who met the combined endpoint had increased anterior (p = 0.034) and septal (p = 0.042) late gadolinium enhancement (LGE). Multivariable logistic regression, adjusted for age, gender, and BMI, found that patients from Southern Asia (p = 0.041) and the Middle East (p = 0.043) were independently associated with lateral LGE. Unsupervised machine learning and factor analysis identified two distinct CMR patterns of inflammation, one with increased LGE and the other with increased myocardial T1/T2., Conclusions: We found that anteroseptal inflammation is associated with worsened outcomes. Using machine learning, we identified two patterns of myocardial inflammation in acute myocarditis from CMR in a racially and ethnically diverse group of patients from Southern Asia, Northern Africa, and the Middle East., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Competing Interests: The authors have none to declare.

The coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously affected public health around the world. In-depth studies on the pathogenic mechanisms of SARS-CoV-2 is urgently necessary for pandemic prevention. However, most laboratory studies on SARS-CoV-2 have to be carried out in bio-safety level 3 (BSL-3) laboratories, greatly restricting the progress of relevant experiments. In this study, we used a bacterial artificial chromosome (BAC) method to assemble a SARS-CoV-2 replication and transcription system in Vero E6 cells without virion envelope formation, thus avoiding the risk of coronavirus exposure. Furthermore, an improved real-time quantitative reverse transcription PCR (RT-qPCR) approach was used to distinguish the replication of full-length replicon RNAs and transcription of subgenomic RNAs (sgRNAs). Using the SARS-CoV-2 replicon, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 facilitates the transcription of sgRNAs in the discontinuous synthesis process. Moreover, two high-frequency mutants of N protein, R203K and S194L, can obviously enhance the transcription level of the replicon, hinting that these mutations likely allow SARS-CoV-2 to spread and reproduce more quickly. In addition, remdesivir and chloroquine, two well-known drugs demonstrated to be effective against coronavirus in previous studies, also inhibited the transcription of our replicon, indicating the potential applications of this system in antiviral drug discovery. Overall, we developed a bio-safe and valuable replicon system of SARS-CoV-2 that is useful to study the mechanisms of viral RNA synthesis and has potential in novel antiviral drug screening., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction., Competing Interests: This study was supported by the American Heart Association (grant 18PRE33990001 to Mr Devarakonda), the Wright Center for Clinical and Translational Research Center (Wright Scholarship to Mr Devarakonda), and the National Institutes of Health (grants R01HL142281, R21AG053654, R01HL133167, and R35HL155651 to Dr Salloum). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)