Search

Visual Abstract, Highlights • AAV9 vectors can upregulate Rxfp1 mRNA in murine heart after intravenous injection. • RXFP1 upregulation sensitizes the left ventricle to relaxin-induced inotropy. • RXFP1 overexpression protects heart from ischemia-reperfusion injury., Summary 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.

Background Coronavirus disease 2019 (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus that is affecting the entire world population. The objective of this study was to analyze the repercussion of the disease in a group of patients at risk such as heart transplant recipients. Methods From February 2020 to February 2021, heart transplant recipients diagnosed with COVID-19 were consecutively included. The total number of transplant recipients in outpatient follow-up at that time was 381. Three levels of infection were determined: group A: asymptomatic patients or with trivial symptoms without the need for hospital admission (6 patients); group B: patients admitted to the hospital for respiratory symptoms (12 patients); and group C: patients with severe symptoms and need for admission to the critical care unit (2 patients). At each risk level, medical performance was different: group A: close control, no therapeutic modification; group B: reduction of calcineurin inhibitor and substitution of mycophenolate mofetil for everolimus; group C: reduction of calcineurin inhibitor and withdrawal of mycophenolate mofetil. Results The prevalence of infection in the series was 5.2%. Most patients admitted had a pathologic chest x-ray with fever, cough, dyspnea, or vomiting. The change in immunosuppression performed in patients in group 2 was well tolerated and there was no graft rejection. Antiviral treatment was little used. However, boluses of steroids and some antibiotics were used frequently. The need for supplemental oxygen was 50% in group 2 and 100% in group 3. Conclusions A significant number of transplant recipients will be affected by COVID-19 (5.3%). Management of the infection will depend on the severity of the infection and must be based on a balance between reduction and adjustment of immunosuppression, strict control of the cardiologic situation, and treatment of the infection.

Background: Over the last two decades, humanity has observed the extraordinary anomaly caused by novel, weird coronavirus strains, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). As the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has made its entry into the world, it has dramatically affected life in every domain by continuously producing new variants. The vaccine development is an ongoing process, although some vaccines got marketed. The big challenge is now whether the vaccine candidates can provide long-lasting protection or prevention against mutant variants. Methods: The information was gathered from various journals, electronic searches via Internet-based information such as PubMed, Google Scholar, Science Direct, online electronic journals, WHO landscape, world meters, WHO website, and News. Results: This review will present and discuss some coronavirus disease 19 (COVID-19) related aspects including: the pathophysiology, epidemiology, mutant variants vaccine candidates, vaccine efficacy, and management strategies. Due to the high death rate, continuous spread, an inadequate workforce, lack of required therapeutics, and incomplete understanding of the viral strain, it becomes crucial to build the knowledge of its biological characteristics and make available the rapid diagnostic and vital therapeutic machinery for the combat and management of an infection. Conclusion: The data summarizes current research on the COVID 19 infection and therapeutic interventions, which will direct future decision-making on the effort-worthy phases of the COVID 19 and the development of critical therapeutics. The only possible solution is the vaccine development targeting against all variant strains to halt its progress; the identified theoretical and practical knowledge can eliminate the gaps to improve a better understanding of the novel coronavirus structure and its design of a vaccine. In addition, to that the long-lasting protection is another challenging objective that need to be looked into.

Objective COVID-19 patients may develop coagulopathy which is associated with poor prognosis and high risk of thrombosis. The objective of this work was to evaluate the prevalence of deep venous thrombosis of lower limbs (DVT) through ultrasonography in patients infected with COVID-19 admitted to hospital in conventional units with 5 days monitoring. The secondary objective was to determine if D-dimer levels body mass index (BMI) and C-reactive ; protein (CRP) were associated with DVT. Materials and Methods 72 patients with a mean age of 65±12.3 years infected with COVID-19 were admitted to three conventional units at our institution ,28 patients were women. A COVID-19 diagnosis was made by transcriptase polymerase chain reaction by means of nasopharyngeal swab or by chest computer tomography (CT) without iodine contrast media. Demographics ,co-morbidities characteristics and laboratory parameters were collected . A preventive anticoagulation treatment was established on admission with low molecular weight heparin (LMWH) . A complete venous duplex ultrasound (DU) test of lower limbs was performed on Day (D) 0 and D5 .A pulmonary CT angiograms with iodine contrast media (CTPA) was required when was ; suspected pulmonary embolism (PE). Results On D0 the DU showed acute DVT in seven patients (9.75%).A CTPA was performed in 12 patients (16.65%) ,3 of whom with an acute PE (25 %). On D0 acute DVT was not significantly associated with CRP (mean 101±98.6 in the group without DVT versus 67.6±58.4 mg/l p=0.43) or BMI ( 27.7 ±5.04 versus 28.1 ± 2.65 Kg/m2 p=0.54 ).However we found a significant association between acute DVT and D-dimer levels (1536±2347 versus 9652 ±10205 ng/ml p, In 72 patients admitted to standard hospital wards with COVID-19 pneumonia screening duplex ultrasound (DU) found 9.7% had DVT on admission and 15.6% without DVT on admission had and examined with DU on day 5 had developed DVT despite preventative anticoagulation justifying DU screening in non-ICU hospitalized patients with COVID-19 pneumonia.

Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies., Highlights • Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. • Immune evasion is a fundamental feature of CSCs. • Immune evasion mechanisms must be precisely clarified to improve tumor immunotherapy. • CSCs are promising targets for tumor immunotherapy.

A 56-year-old man underwent cardiac transplantation in April 2018. His post-operative course was uncomplicated and he had normal allograft function. On December 2019 he was admitted for fever and diarrhea and was found to have cytomegalovirus infection. A few weeks later, he presented with Guillain-Barré Syndrome. (Level of Difficulty: Advanced.), Graphical abstract

The novel betacoronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread across the globe at an unprecedented rate since its first emergence in Wuhan City, China in December 2019. Scientific communities around the world have been rigorously working to develop a potent vaccine to combat COVID-19 (coronavirus disease 2019), employing conventional and novel vaccine strategies. Gene-based vaccine platforms based on viral vectors, DNA, and RNA, have shown promising results encompassing both humoral and cell-mediated immune responses in previous studies, supporting their implementation for COVID-19 vaccine development. In fact, the U.S. Food and Drug Administration (FDA) recently authorized the emergency use of two RNA-based COVID-19 vaccines. We review current gene-based vaccine candidates proceeding through clinical trials, including their antigenic targets, delivery vehicles, and route of administration. Important features of previous gene-based vaccine developments against other infectious diseases are discussed in guiding the design and development of effective vaccines against COVID-19 and future derivatives., Graphical abstract Unlabelled Image

We report the case of a 10-year-old boy with acute-onset diplopia and ptosis in the right eye. CR was positive for SARS-CoV-2. The patient was managed successfully with corticosteroids. We highlight the need for heightened suspicion of occult COVID-19 infection among children presenting with unusual III nerve palsy.

We report a case of giant cell myocarditis in a 76-year-old patient managed with combined immunosuppression and biventricular intravascular microaxial blood pumps. This case highlights a feasible approach for managing such patients who are not candidates for transplantation or durable ventricular assist devices. (Level of Difficulty: Intermediate.), Graphical abstract, We report a case of giant cell myocarditis in a 76-year-old patient managed with combined immunosuppression and biventricular intravascular m…

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:39 issue:11 pages:1171-1190 ispartof: location:United States status: published

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome. ispartof: TRANSPLANT INTERNATIONAL vol:35 ispartof: location:Switzerland status: published

We present the case of an acute onset ANCA positive vasculitis in an asymptomatic COVID-19 infected teenager, resulting in significant colonic damage. The patient was initially diagnosed with Henoch-Schönlein purpura and presented with worsening symptoms with significant necrosis of her perineum and rectum requiring surgical debridement and diverting colostomy. As a part of her work-up, she tested positive for COVID-19 total IgG/IgM antibodies and ANCA antibodies. This case complements previously reported cases of COVID-19 induced autoimmune disease in children but is novel in describing extensive intestinal disease as a result of an autoimmune vasculitis in a child.

The introduction of Cystic Fibrosis Trans Regulatory modulator (CFTRm) drugs has seen a transformation in Cystic Fibrosis (CF) treatment. This has led to a significant improvement in lung function and quality of life with the potential for a real impact on life expectancy. Transient mild to moderate hepatic transaminitis is a well-known side effect of CFTRm drugs, which often improves on cessation and may not recur following the re-institution of the drug. We describe a case of transaminitis developing nine months after the initiation of Kaftrio, which progressed to liver necrosis despite stopping Kaftrio and took many months to resolve. The patient had experienced significant improvement in lung function and overall health while on Kaftrio and deteriorated when it was stopped. He was keen to restart; however, Kaftrio was not reinstated due to the potential risk of acute liver failure.

Graphical abstract, Background The SARS-CoV-2 coronavirus epidemic is hastening the discovery of the most efficient vaccines. The development of cost-effective vaccines seems to be the only solution to terminate this Pandemic. However, the vaccines’ effectiveness has been questioned due to recurrent mutations in the SARS-CoV-2 genome. Most of the mutations are associated with the spike protein, a vital target for several marketed vaccines. Many Countries were highly affected by the 2nd wave of the SARS-CoV-2, like the UK, India, Brazil, France. Experts are also alarming the further COVID-19 wave with the emergence of Omicron, which is highly affecting the South African populations. This review encompasses the detailed description of all vaccine candidates and COVID-19 mutants that will add value to design further studies to combat the COVID-19 Pandemic. Methods The information was generated using various search engines like google scholar, PubMed, clinicaltrial.gov.in, WHO database, ScienceDirect, and news portals by using keywords SARS-CoV-2 Mutants, COVID-19 Vaccines, Efficacy of SARS-CoV-2 Vaccines, COVID-19 waves. Results This review has highlighted the evolution of SARS-CoV2 variants and the vaccine efficacy. Currently, various vaccine candidates are also undergoing several phases of development. Their efficacy still needs to check for newly emerged variants. We have focused on the evolution, multiple mutants, waves of the SARS-CoV-2, and different marketed vaccines undergoing various clinical trials and the design of the trials to determine vaccine efficacy. Conclusion Various mutants of SARS-CoV-2 arrived, mainly concerned with the spike protein, a key component to design the vaccine candidates. Various vaccines are undergoing clinical trial and show impressive results, but their efficacy still needs to be checked in different SARS-CoV-2 mutants. We discussed all mutants of SARS-CoV-2 and the vaccine's efficacy against them. The safety concern of these vaccines is also discussed. It is important to understand how coronavirus gets mutated to design better new vaccines, providing long-term protection and neutralizing broad mutant variants. A proper study approach also needs to be considered while designing the vaccine efficacy trials, which further improved the study outcomes. Taking preventive measures to protect from the virus is also equally important, like vaccine development.

The coronavirus disease 2019 (COVID-19) has swept the world, posing a serious threat to people's lives and health. Several cases of COVID-19 infection in renal transplant recipients (RTRs) have been reported, but the treatment and prognosis have not been fully elucidated. We followed-up with RTRs infected with SARS-CoV2 in our center and classified them as five clinical types-asymptomatic, mild, moderate, severe, and critical. The immunosuppressive agents were not adjusted in asymptomatic carriers and mild patients, the former was mainly treated by isolation, and the latter was treated by low-dose intravenous immunoglobulin (IVIG) to enhance immunity. For moderate or severe patients, the immunosuppressive agents were largely reduced or even interrupted, low-dose IVIG was adopted, and low-dose methylprednisolone (MP) was used to inhibit inflammation and rejection. Immunosuppressants were discontinued early in critical patients; IVIG, high-dose MP, and antibiotics were used. Meanwhile, all patients received at least one antiviral drugs. After aggressive treatment, three patients developed acute kidney injury, and two showed reversal, while the remaining one lost the allograft kidney; one patient died, while other patients were discharged. For different clinical types of RTRs infected with COVID-19, personalized therapies were essential, Meanwhile, patients with COVID-19 infection may have different outcomes due to their different clinical manifestations.

GGGGCC (G4C2) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat-associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G4C2 repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G4C2 repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G4C2 repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G4C2 repeat RNA. Urea-resistant interaction between G4C2 repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G4C2 repeat translation elongation.

Visual Abstract, Highlights • rAAV vectors increase cardiac-specific expression of RNR and elevate cardiomyocyte 2-dATP levels. • Elevated myocardial RNR and subsequent increase in 2-dATP rescues the performance of failing myocardium, an effect that persists long term. • We show the ability to increase both cardiac baseline function and high workload contractile performance in aged (22- to 24-month old) mdx4cv mice, by high-level muscle-specific expression of either microdystrophin or RNR. • Five months post-treatment, mice systemically injected with rAAV6 vector carrying a striated muscle-specific regulatory cassette driving expression of microdystrophin in both skeletal and cardiac muscle, exhibited the greatest effect on systolic function. In comparison, mice treated with rAAV6 vector carrying RNR that expresses exclusively in cardiac muscle not only exhibited greatly improved baseline systolic function but also improved diastolic function. • Importantly, vector-directed overexpression of RNR did not impair cardiac reserve during increased physiological demand in aged mdx4cv hearts., Summary Mutations in the gene encoding for dystrophin leads to structural and functional deterioration of cardiomyocytes and is a hallmark of cardiomyopathy in Duchenne muscular dystrophy (DMD) patients. Administration of recombinant adeno-associated viral vectors delivering microdystrophin or ribonucleotide reductase (RNR), under muscle-specific regulatory control, rescues both baseline and high workload-challenged hearts in an aged, DMD mouse model. However, only RNR treatments improved both systolic and diastolic function under those conditions. Cardiac-specific recombinant adeno-associated viral treatment of RNR holds therapeutic promise for improvement of cardiomyopathy in DMD patients.

Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16–91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement. Keywords: Adrenoleukodystrophy, Allogeneic stem cell transplantation, Loes score, Very long chain fatty acid

Highlights • In the patients with DPD deficiency, advert events appear more rapidly than usual and can be lethal. • Cytomegalovirus enterocolitis is likely to occur in the state of immunosuppression and lethal because of massive bleeding or perforation. • Screening for DPD deficiency should be done, and genetic study can be effective screening for DPD deficiency., Introduction 5-Fluorouracil (5-FU) is widely used for cancer treatment. The reduced activity of dihydropyrimidine dehydrogenase (DPD), the key enzyme in 5-FU inactivation, increases a patient’s risk of developing severe 5-FU related toxicity. However, screening for DPD deficiency is rarely performed before 5-FU administration. Presentation of case Our patient was a 69-year-old man with rectal cancer (T2N1bM0 stage IIIA) who underwent laparoscopic low anterior resection. He developed severe neutropenia and diarrhea 15 days after the administration of capecitabine for adjuvant chemotherapy, and was admitted to our hospital. Four days after admission, he was transferred to the intensive care unit for sepsis. DPD protein screening revealed DPD deficiency. On day 27, massive melena suddenly appeared. He died of continual bleeding 41 days after admission. Pathological autopsy revealed cytomegalovirus enterocolitis. Discussion The administration of 5-FU to patients with DPD deficiency is lethal. Genotypic and phenotypic assessments are reliable tests for DPD deficiency. A genetic study can effectively screen for DPD deficiency; however, its use has not been established in the national insurance system. Patients with DPD deficiency tend to develop severe neutropenia, so clinicians should pay attention to opportunistic infections such as cytomegalovirus enterocolitis. Conclusion Screening for DPD deficiency is necessary prior to 5-FU administration.

Background & Aims Hepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein–protein interaction was considered as a new molecular target of HBV treatment. Methods To identify candidate compounds that target the HBx–DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes. Results We show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx–DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV. Conclusions These results indicate that NTZ, which targets an HBV-related viral–host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure., Graphical abstract

Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at significantly lower concentrations than the plasma trough levels achieved by the dosage adopted for influenza treatment and exhibits efficacy against coronavirus disease 2019 (COVID-19) pneumonia. Although high doses of favipiravir are required due to the molecule being a purine analog, its conversion into the active form in infected cells with active viral RNA synthesis enhances the antiviral specificity and selectivity as a chain terminator with lethal mutagenesis. Another characteristic feature is the lack of generation of favipiravir-resistant virus. COVID-19 pneumonia is caused by strong cell-mediated immunity against virus-infected cells, and the inflammatory response induced by adaptive immunity continues to peak for 3 to 5 days despite antiviral treatment. This has also been observed in herpes zoster (HZ) and cytomegalovirus (CMV) pneumonia. Inflammation due to an immune response may mask the effectiveness of favipiravir against COVID-19 pneumonia. Favipiravir significantly shortened the recovery time in patients with mild COVID-19 pneumonia by 3 days with the start of treatment by the 5th day of symptom onset. Since both CMV and COVID-19 pneumonia are caused by adaptive immunity and prevention of cytomegalovirus pneumonia is the standard treatment due to difficulties in treating refractory CMV pneumonia, COVID-19 pneumonia should be prevented with early treatment as well. In the present study, we have comprehensively reviewed the optimal antiviral therapy for COVID-19 based on clinical trials of favipiravir for the treatment of COVID-19 pneumonia and the concurrently established therapies for other viral infections, particularly HZ and CMV pneumonia. Optimally, antivirals should be administered immediately after COVID-19 diagnosis, similar to that after influenza diagnosis, to prevent COVID-19 pneumonia and complications resulting from microangiopathy.

By the end of year 2019, the new virus SARS-CoV-2 appeared, causing the Coronavirus Disease 2019 (COVID-19), and spread very fast globally. A continuing need for diagnostic tools is a must to contain its spread. Till now, the gold standard method, the reverse transcription polymerase chain reaction (RT-PCR), is the precise procedure to detect the virus. However, SARS-CoV-2 may escape RT-PCR detection for several reasons. The development of well-designed, specific and sensitive serological test like enzyme immunoassay (EIA) is needed. This EIA can stand alone or work side by side with RT-PCR. In this study, we developed several EIAs including plates that are coated with either specially designed SARS-CoV-2 nucleocapsid or surface recombinant proteins. Each protein type can separately detect anti-SARS-CoV-2 IgM or IgG antibodies. For each EIAs, the cut-off value, specificity and sensitivity were determined utilizing RT-PCR confirmed Covid-19 and pre-pandemic healthy and other viruses-infected sera. Also, the receiver operator characteristic (ROC) analysis was performed to define the specificities and sensitivities of the optimized assay. The in-house EIAs were validated by comparing against commercial EIA kits. All in-house EIAs showed high specificity (98–99%) and sensitivity (97.8–98.9%) for the detection of IgG/IgM against RBD and N proteins of SARS-CoV-2. From these results, the developed Anti-RBD and anti-N IgG and IgM antibodies EIAs can be used as a specific and sensitive tool to detect SARS-CoV-2 infection, calculate the burden of disease and case fatality rates.

COVID-19 infection can cause inflammatory reactions that could involve several organs. In the pediatric population, Multi-System Inflammatory Syndrome in Children (MIS-C) has been reported as one of the consequences of COVID-19. We report a unique pediatric COVID-19 patient with MIS-C, associated with paralysis of the extremities. MRI showed abnormal signal in the cervical spinal cord compatible with transverse myelitis. Methylprednisolone and IVIG were administered, without significant symptom improvement. As a next step, Infliximab was tried for her, and she responded remarkably well to this treatment. Infliximab may be considered as a treatment option in COVID-19 patients with transverse myelitis.

The outbreak of coronavirus disease 2019 (COVID-19) has disproportionately affected patients with comorbidities, including recipients of solid organ and hematopoietic stem cell transplants (SCT). Upon recovery from COVID-19, the degree of the immunological protection from reinfection remains unclear. Here we describe a 33-year-old patient with erythropoietic protoporphyria (EPP) who had undergone liver transplantation with splenectomy followed by allogeneic SCT in 2013 after an initial failed liver and umbilical cord transplant. The patient developed mild upper respiratory symptoms in the spring of 2020 and was found to have anti-SARS-CoV2 antibodies suggesting past infection. A comprehensive analysis of T cell functionality in peripheral blood from this patient revealed robust in vitro responses against SARS CoV2 antigens Spike (S) 1 and 2, membrane (M) and nucleoprotein (NP), comparable to the reactivity against common antigens from CMV, EBV, Ad and BK viruses, while only low reactivity was seen in healthy donors without documented history of COVID-19. Moreover, the patient displayed a marked recognition of counterpart antigens from related human coronaviruses (hCoVs) 229E, OC43, NL63 and HKU1. Thus, despite lifelong immunosuppression, this survivor of COVID-19 retained a remarkable degree of immunocompetence and showed broad-spectrum T cell memory specific for SARS-CoV2 and related hCoVs including less studied hCoV M and NP antigens. The study highlights the role of cellular immunity after natural COVID-19 infection, suggesting broader use of T cell assays as a tool for risk stratification, measurement of immunocompetence and/or post-infection or post-vaccination protection, and possible T cell-based adoptive immunotherapy strategies in high-risk patients.

A 73-year-old woman who visited our hospital complaining of dry cough for three months was refractory to antimicrobial therapy. Chest computed tomography revealed subpleural consolidation. Specimens obtained from surgical lung biopsy revealed subpleural perilobular airspace organization and fibrosis. After the biopsy, mechanic's hand and Gottron's papules appeared, and anti-melanoma differentiation-associated gene 5 (MDA5) antibody was found to be positive. Subsequently, anti-MDA5 antibody measured in cryopreserved serum from her first admission proved to be positive. It is difficult to suspect the presence of anti-MDA-5 antibody in patients with interstitial lung disease without typical dermatomyositis symptoms or slow disease progression.

Ubiquitination is a posttranslational protein modification that has been shown to have a range of effects, including regulation of protein function, interaction, localization, and degradation. We have previously shown that the muscle-specific ubiquitin E3 ligase, ASB2β, is downregulated in models of muscle growth and that overexpression ASB2β is sufficient to induce muscle atrophy. To gain insight into the effects of increased ASB2β expression on skeletal muscle mass and function, we used liquid chromatography coupled to tandem mass spectrometry to investigate ASB2β-mediated changes to the skeletal muscle proteome and ubiquitinome, via a parallel analysis of remnant diGly-modified peptides. The results show that viral vector-mediated ASB2β overexpression in murine muscles causes progressive muscle atrophy and impairment of force-producing capacity, while ASB2β knockdown induces mild muscle hypertrophy. ASB2β-induced muscle atrophy and dysfunction were associated with the early downregulation of mitochondrial and contractile protein abundance and the upregulation of proteins involved in proteasome-mediated protein degradation (including other E3 ligases), protein synthesis, and the cytoskeleton/sarcomere. The overexpression ASB2β also resulted in marked changes in protein ubiquitination; however, there was no simple relationship between changes in ubiquitination status and protein abundance. To investigate proteins that interact with ASB2β and, therefore, potential ASB2β targets, Flag-tagged wild-type ASB2β, and a mutant ASB2β lacking the C-terminal SOCS box domain (dSOCS) were immunoprecipitated from C2C12 myotubes and subjected to label-free proteomic analysis to determine the ASB2β interactome. ASB2β was found to interact with a range of cytoskeletal and nuclear proteins. When combined with the in vivo ubiquitinomic data, our studies have identified novel putative ASB2β target substrates that warrant further investigation. These findings provide novel insight into the complexity of proteome and ubiquitinome changes that occur during E3 ligase-mediated skeletal muscle atrophy and dysfunction., Graphical abstract, Highlights • Proteomic and ubiquitinomic analysis of increased ASB2β in skeletal muscle • ASB2β increased the abundance of proteome and cytoskeletal proteins • ASB2β reduced the abundance of mitochondrial and contractile proteins • No simple relationship between changes in protein abundance and ubiquitination, In Brief The E3 ubiquitin ligase ASB2β has been identified as a regulator of skeletal muscle mass. To gain insights into potential mechanisms of action, mouse muscles expressing a Flag-tagged ASB2β were investigated using quantitative proteomic methods. The results identified ASB2β-induced changes in the abundance and ubiquitination of proteins associated with mitochondria, the sarcomere, and the cytoskeleton. Additional in vitro studies identified novel putative ASB2β target substrates. The results highlight the complex relationship between protein abundance and ubiquitination in ASB2β-mediated muscle adaptation.

All that we view of the world begins with an ultrafast cis to trans photoisomerization of the retinylidene chromophore associated with the visual pigments of rod and cone photoreceptors. The continual responsiveness of these photoreceptors is then sustained by regeneration processes that convert the trans-retinoid back to an 11-cis configuration. Recent biochemical and electrophysiological analyses of the retinal G-protein-coupled receptor (RGR) suggest that it could sustain the responsiveness of photoreceptor cells, particularly cones, even under bright light conditions. Thus, two mechanisms have evolved to accomplish the reisomerization: one involving the well-studied retinoid isomerase (RPE65) and a second photoisomerase reaction mediated by the RGR. Impairments to the pathways that transform all-trans-retinal back to 11-cis-retinal are associated with mild to severe forms of retinal dystrophy. Moreover, with age there also is a decline in the rate of chromophore regeneration. Both pharmacological and genetic approaches are being used to bypass visual cycle defects and consequently mitigate blinding diseases. Rapid progress in the use of genome editing also is paving the way for the treatment of disparate retinal diseases. In this review, we provide an update on visual cycle biochemistry and then discuss visual-cycle-related diseases and emerging therapeutics for these disorders. There is hope that these advances will be helpful in treating more complex diseases of the eye, including age-related macular degeneration (AMD).

Neonates and prematures are among the most transfused categories of patients. Adverse reactions due to transfusions, such as transfusion-transmitted infections, can affect the rest of their lives. In this systematic review, we revised the literature concerning transfusion-transmitted infection in neonates. We reported case-reports and case-series previously published and we integrated these data with our experience at local neonatal intensive care unit. Moreover, we illustrated strategies for mitigating transfusion-transmitted infections, including donor selection and testing, pathogen inactivation technologies and combined approaches, as for Cytomegalovirus infection, integrating leukoreduction and identification of seronegative donors.

Disseminated histoplasmosis is a rare opportunistic infection in non-endemic areas, where the disease is often diagnosed late. The spectrum of clinical manifestations is broad and life-threatening complications occur. We present a detailed case of a kidney liver transplant patient with disseminated histoplasmosis in a non-endemic area. Our case highlights the wide range of pathogens to consider in the immunocompromised patient, the delayed diagnosis of Histoplasmosis Capsulatum in non-endemic areas and the possibility of severe gastrointestinal disease. We also briefly review diagnostic tests and treatment options. ispartof: IDCASES vol:22 ispartof: location:Netherlands status: published

Receptor Interacting Protein Kinases (RIPKs) are cellular signaling molecules that are critical for homeostatic signaling in both communicable and non-communicable disease processes. In particular, RIPK1, RIPK2, RIPK3 and RIPK7 have emerged as key mediators of intracellular signal transduction including inflammation, autophagy and programmed cell death, and are thus essential for the early control of many diverse pathogenic organisms. In this review, we discuss the role of each RIPK in host responses to bacterial and viral pathogens, with a focus on studies that have used pathogen infection models rather than artificial stimulation with purified pathogen associated molecular patterns. We also discuss the intricate mechanisms of host evasion by pathogens that specifically target RIPKs for inactivation, and finally, we will touch on the controversial issue of drug development for kinase inhibitors to treat chronic inflammatory and neurological disorders, and the implications this may have on the outcome of pathogen infections.

Background Community-acquired pneumonia (CAP) guidelines have improved the management and outcomes of patients with CAP, primarily by standardization of initial empiric therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no concensus regarding the initial management of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the management of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiological work-up, general principles of empiric therapy, and empiric therapy for specific pathogens. Interpretation This document offer general suggestions for the initial management of the immunocompromised patient who arrives at the hospital with pneumonia.

Purpose Takayasu arteritis (TA) is a systemic granulomatous large vessel vasculitis that involves mainly the aorta and its primary branches, and occurs most commonly in young females. Ocular manifestations of TA include small vessels dilation, microaneurysm, arteriovenous anastomosis, retinal ischemia and retinopathy. However, no specific and effective treatments for Takayasu retinopathy is applied. This case aimed to demonstrate the role of anti-VEGF (vascular endothelial growth factor) therapy in treating Takayasu retinopathy. Observations We herein reported an 18-year-old Asian woman who presented with typical wreath-like arteriovenous anastomosis around the disc in the right eye and vitreous hemorrhage in the left eye. The stenosis and occlusion of bilateral subclavian arteries, carotid arteries and other proximal arteries on angiography confirmed the diagnosis of TA. Meanwhile, elevated ESR and CRP revealed that TA was in the active stage. We applied anti-VEGF therapy in treating Takayasu retinopathy specially to inhibit neovascularization. Additionally, vitreous extraction was conducted in the left eye after the treatment of anti-VEGF therapy. Conclusions and importance This is the first report of effective application of anti-VEGF therapy in inhibiting wreath-like arteriovenous anastomosis and improving vitrectomy in TA.

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naive, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB immune deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.

Summary Individual patients with life-threatening or severely debilitating diseases can petition the U.S. Food and Drug Administration (FDA) through their physicians to have expanded access (EA) to drugs that are in clinical trials but have not reached full FDA approval (the “single-patient” investigational new drug [IND] application). Additionally, recent state and federal laws—so-called “right to try legislation”—allow patients to approach drug companies directly for access prior to FDA approval. While these pathways provide potential access for individual patients to investigational drugs, different EA pathways permit entire groups of certain patients to access investigational drugs prior to FDA approval. This review focuses on special categories of EA INDs intended for multiple patients—the intermediate-group IND and the widespread-treatment IND—as well as emergency authorization for use of investigational drugs and biological products (e.g., vaccines) in public health emergencies.

The central importance of cell polarity control is emphasized by the frequency with which it is targeted by many diverse viruses. It is clear that in targeting key polarity control proteins, viruses affect not only host cell polarity, but also influence many cellular processes, including transcription, replication, and innate and acquired immunity. Examination of the interactions of different virus proteins with the cell and its polarity controls during the virus life cycles, and in virally‐induced cell transformation shows ever more clearly how intimately all cellular processes are linked to the control of cell polarity., Graphical Abstract Unlabelled Image, Highlights • Multiple viruses target cell polarity. • Viral targeting of polarity frequently occurs through PDZ recognition. • Biological effects include immune-avoidance, cell proliferation and apoptosis inhibition.

Background The impact of viral infections on acute exacerbations in idiopathic pulmonary fibrosis (IPF) and/or non-IPF interstitial lung disease (ILDs) has been scarcely described. Objectives To elucidate the frequency of virus infections in patients with IPF or non-IPF ILDs including idiopathic interstitial pneumonia (IIP) or connective tissue disease (CTD)-associated pneumonia, and its influence on their short-term mortality. Methods We prospectively enrolled adult patients with acute exacerbation of IPF and non-IPF ILDs who were admitted to the hospital during the last 3 years, and examined the respiratory samples obtained from nasopharyngeal, sputum, and bronchoalveolar lavage fluid. Results A total of 78 patients were identified, consisting of 27 patients with acute exacerbation of IPF and 51 patients with non-IPF ILDs (IIP: n = 27, CTD-associated IP: n = 24). Of all patients, 15 (19.2%) had viruses detected in their respiratory samples including the human herpesvirus 7 (HHV7; n = 4) and cytomegalovirus (CMV) plus HHV7 (n = 3). The proportion of virus infections in the IPF and non-IPF ILDs groups was comparable. The Kaplan-Meier survival curves over 60 days revealed a lower survival probability in the virus positive group (n = 15, 60%) than in the virus negative group (n = 60, 83.3%, p

PURPOSE: To examine the performance of radiologists in differentiating COVID-19 from non-COVID-19 atypical pneumonia and to perform an analysis of CT patterns in a study cohort including viral, fungal and atypical bacterial pathogens. METHODS: Patients with positive RT-PCR tests for COVID-19 pneumonia (n = 90) and non-COVID-19 atypical pneumonia (n = 294) were retrospectively included. Five radiologists, blinded to the pathogen test results, assessed the CT scans and classified them as COVID-19 or non-COVID-19 pneumonia. For both groups specific CT features were recorded and a multivariate logistic regression model was used to calculate their ability to predict COVID-19 pneumonia. RESULTS: The radiologists differentiated between COVID-19 and non-COVID-19 pneumonia with an overall accuracy, sensitivity, and specificity of 88% ± 4 (SD), 79% ± 6 (SD), and 90% ± 6 (SD), respectively. The percentage of correct ratings was lower in the early and late stage of COVID-19 pneumonia compared to the progressive and peak stage (68 and 71% vs 85 and 89%). The variables associated with the most increased risk of COVID-19 pneumonia were band like subpleural opacities (OR 5.55, p