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Respiratory viral infections are important cause of morbidity and mortality in early life. The relative influence of host and viral factors possibly contribute to the disease pathogenesis. Predisposing conditions like prematurity, Low birth weight and congenital heart diseases etc. have been incriminated in the disease progression. The development of cough, wheezing, and tachypnea, usually peaking on days 4 to 5, go parallel with host cytokine responses and viral load. Various host cytokines, chemokines and molecules involved in the immune response against RSV infection might be responsible for the outcome of the disease process. Nasopharyngeal aspirates (NPAs) from children (n = 349) between 2013-2017 were subjected for IL-17A, IFN-gamma, TNF-alpha, IL-10, IL-6 levels by CBA and MMP-9 and TIMP-1 levels by ELISA. The viral load in RSV positive samples and cytokine levels were correlated with the WHO criteria for acute lower respiratory tract illness (ALRTI). RSV viral load, Pro-inflammatory cytokine (TNF-alpha) levels in severe ALRTI patients were significantly higher than the ALRTI patients [p<0.001]. Whereas Th17 cytokine (IL-17) was found to be significantly higher (p<0.05) in ALRTI patients than severe patients. MMP-9 is secreted in higher levels in severe ALRTI patients (n = 77) in comparison to Acute LRTI patients (n = 35) with an increase of thirty seven fold (p<0.001). Thus, the study highlights the role of TNF -alpha, IL-17 and Th2 cytokine biasness in the pathogenesis of RSV disease with the possible contribution of higher MMP-9/TIMP-1 ratio as a bad prognostic marker towards disease severity. To study the gene expression of autophagy and mTOR signalling pathways in RSV infected children with ALRTI. Nasopharyngeal aspirate (NPA) samples (n = 145) from children suffering from ALRTI were subjected for detection of RSV (Oct 2019 to March 2020). Semi-quantitative gene expression analysis for 5 representative genes each of mTOR signalling and autophagy pathway were performed in respiratory tract epithelial cells using 25 RSV positive cases and 10 healthy controls subjects. Autophagy gene expression analysis revealed significant upregulation in NPC1 and ATG3 autophagy genes. mTOR, AKT1 and TSC1 genes of mTOR pathway were significantly down-regulated in RSV positive patients except RICTOR gene which was significantly upregulated. Thus, survival of RSV within autophagosome might have been facilitated by upregulation of autophagy and downregulation of mTOR signalling genes. To assess the impact of SARS-CoV2 pandemic on RSV, samples were collected from children with ALRTIs admitted to emergency, PICU and indoor admissions during pre-pandemic period (October 2019 to February 2020;n = 166) and during COVID-19 Pandemic (July 2021 to July 2022;n = 189, SARS-CoV2 negative). These NP swabs were analyzed for pdm InfA H1N1, InfA H3N2, Inf B, RSV, hMPV, hBoV, hRV, PIV-2 and PIV-3 by PCR. Higher proportion of children with ALRTIs have had virus/es isolated during pre-pandemic period than during pandemic period (p<0.001). During pre-pandemic period, significantly higher proportion of children had RSV positivity (p<0.001);and significantly lower positivity for hRV (p<0.05), hMPV (p<0.05), and hBoV (p <= 0.005). The occurrence of COVID-19 pandemic has significantly impacted the frequency and pattern of detection of RSV among hospitalized children with LRTIs. RSV Fusion protein plays a critical role in the entry of the virus into the host cell by initiating the fusion of host and viral membranes. It happens to be a target of neutralizing antibodies paving the way as a vaccine candidate. Hence effort was made to introduce point mutation in hRSV fusion protein which can confer stability in its prefusion form. In-silico a stable structure of RSV fusion protein was generated making it a potential vaccine candidate. The timely diagnosis of RSV infection in this population is important for initiating therapy and instituting appropriate infection prevention measures. Serological testing is not widely used for the diagnosis of RSV. C ll Cultures including shell vial culture were used for RSV diagnosis. However, culture approaches lack sensitivity, often quite significantly, compared to nucleic acid amplification assays for the diagnosis of RSV infections. Molecular multiplex assays now offer increased sensitivity for a more accurate diagnosis. However issues with the use of these types of commercial panel assays include the requirement for substantial training, quality systems, and infrastructure to maintain and run these assays and many a times identification of viruses where the true pathogenic potential of those multiple viruses are debatable. Studies are available with laboratory- developed nucleic acid amplification test systems for the detection of RSVA and RSVB in clinical specimens either by PCRbased technologies or RT-LAMP. Gene targets of laboratory-developed molecular assays point towards M gene and the N gene in RSVA and -B with the benefits of flexibility to modify assays when targets are under evolutionary pressure to change, as well as a perceived initial low cost to carry out testing.
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Background: To search for molecular biomarkers of pulmonary pathologies using non-invasive samples, such as urine, is of high clinical relevance. However, there are almost no proteomic studies using urine applied to respiratory diseases. Aim(s): To develop a biomarker discovery strategy using non-targeted proteomics in urine with applicability to different pulmonary diseases. Method(s): Urine samples were centrifuged and DTT treated to decrease uromodulin (THP). Low-THP samples were concentrated (ultrafiltration), ultracentrifugated, and exosome free urine was analysed using LC-MS/MS. GO terms/Pathway analyses were performed using STRING database. Result(s): Urine proteome (765 proteins) was enriched (FDR < 0.05) in proteins from different tissues, including respiratory system (N = 124), lung (N = 107), and immune system (N = 88). We detected an enrichment of relevant pathways for respiratory diseases, including several innate (e.g., TLR and NFkB pathways, complement system), and adaptive (e.g., interleukin signalling) immune system pathways. Some of these proteins have been previously studied in respiratory system disease (e.g., MPO, NAPSA, CHL1, FREM2, PLG), lower respiratory tract disease (e.g., NCAM1, MTOR, SERPINA1), viral infectious disease (e.g., ITIH4, CD209, CLEC4M, CD55), or specific pathologies such as coronavirus infection (e.g., ACE2, TMPRSS2), bronchiectasis (e.g., SAA1, SAA2, ELANE) or asthma (e.g., IGFALS, IGFBP7, HSPG2, DPP4, CD44, IL6R, MASP1). Conclusion(s): We have developed a protocol for the detection of proteomic biomarkers in urine. This proteome is enriched in proteins from the immune and respiratory systems, with a potential clinical and translational relevance.
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We describe the case of a 12-year-old boy who presented via teledermatology with a 5-6-year history of multiple lesions on the right side of his face. They were unchanged since their initial appearance at 6 years of age but were slowly increasing in number across his right cheek and extending onto the chin. Although the lesions were asymptomatic, growing older had made him feel increasingly self-conscious. He was otherwise fit and well, and attended mainstream school, with no past medical history or family history of note. Perinatal and birth history were also uneventful. On examination, he had multiple, 1-2-mm, erythematous papules confined to the right cheek and right chin. Dermoscopy showed an unusual pattern of vessels with nonspecific globules in between. The rest of the skin, hair and nails were entirely normal in appearance. There were no systemic symptoms and a detailed general and systemic examination, as well as radiological imaging, did not reveal any abnormality. An excisional biopsy was taken of one of the lesions, with histological examination demonstrating focal superficial telangiectasia with associated bland round-tospindle cell proliferation, appearances most in keeping with an angiofibroma. This correlated well clinically, apart from unilateral facial angiofibromas being the solitary finding in our patient. Facial angiofibromas - also called adenoma sebaceum - are well described as part of the cutaneous manifestations of tuberous sclerosis (TSC). Classically, these appear as a facial rash in the form of small pink or red spots across the cheeks and nose in a butterfly distribution, at between 3 and 10 years of age, increasing in size and number until adolescence. TSC is an autosomal dominant disorder with defective mammalian target of rapamycin (mTOR) signalling, characterized by hamartomas in many organs, particularly the skin, central nervous system, renal and cardiovascular systems. The clinical presentation is variable, with other well known and frequently reported cutaneous findings such as shagreen patches, ash-leaf macules and periungual fibromas. Unilateral multiple facial angiofibromas in the absence of other cutaneous or systemic manifestations of TSC - as in our patient - are rare, with only 13 reported cases. These may form part of the clinical spectrum of TSC as a probable consequence of cutaneous mosaicism in which a postzygotic genetic mutation has occurred. Our patient was referred for genetic testing, but this has been delayed as a result of the COVID-19 pandemic. Topical sirolimus 1% - an mTOR inhibitor - has been used with good effect for facial angiofibromas, and our patient also responded well to this.
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In recent years, new data have been obtained on the significant prevalence of vitamin D (VD) deficiency in the population, and knowledge about the role of vitamin D in the regulation of many physiological processes in the body, including the functioning of the immune system, has increased. The SARS-CoV-2 pandemic has further highlighted the issue of an adequate immune response in vitamin D deficiency. Objective of the review. To present and summarize the evidence on the role of VD in different parts of the immune response in COVID-19, to analyze available studies of the VD status effect on the course and outcome of COVID-19 in patients from different population groups. Material and methods. A search of domestic and foreign literature on the role of VD in the immune response in respiratory viral infections and SARS-CoV-2, as well as practical measures of VD-status correction in COVID-19, was performed. We used Scopus, Web of Science, PubMed, Google Scholar, eLibrary, and Cyberleninka databases. Results. Numerous clinical and observational studies have found an association between 25-hydroxyvitamin D levels, COVID-19 severity, and mortality. This association can be explained by the multifaceted role of vitamin D in the physiology of the human immune and endocrine systems. On the immunological side, the active form of VD promotes the secretion of antimicrobial peptides responsible for inhibiting viral replication and stimulates autophagy by increasing the level of Beclin1 protein and decreasing the level of mTOR protein regulating cellular homeostasis. It leads to the presentation of antigens followed by activation of the antiviral pathway of type I interferons. VD also stabilizes intercellular junctions, including those in the airway epithelium, reducing their permeability to pathogens, stimulates the activity of angiotensin-converting enzyme-2, whose receptors are a conduit for SARS-CoV-2 into cells, and several pathophysiological responses associated with the disease symptoms and acute lung injury. Adequate vitamin D status can provide significant benefits during the pandemic. Conclusion. To date, ideas about the role of vitamin D in regulating the immune response in respiratory infections have significantly expanded. However, its use in the complex preventive measures and adjuvant therapy of viral infections, including COVID-19, should be the subject of further scientific research.Copyright © 2023, Media Sphera Publishing Group. All rights reserved.
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An outburst of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a grave threat to global health and the economy. As of May 13, 2020, a total of 42,81,838 cases have been confirmed, with over 2,92,376 deaths worldwide. In India, 75,048 cases have been reported to date with 2,440 deaths. Management of this new coronavirus (COVID19) has mainly focused on infection prevention, case detection, monitoring, and supportive care. As there is no vaccine or specific antiviral treatment for human SARS-CoV-2, therefore identifying the drug treatment options as soon as possible is critical for the response to the COVID19 outbreak. Pro-inflammatory cascade and cytokine storm play a key role in the pathogenesis of new coronavirus. A large number of therapeutic interventions such as antiviral, antimalarial, convalescent plasma therapy, BCG vaccine, mTOR inhibi-tors, Tissue Plasminogen Activator, Human monoclonal antibodies, Anti-parasitic agents, Immunoen-hancers, Nutritional interventions, JAK-STAT signaling inhibitors, ACE2 receptor modulators, and An-giotensin II receptor blockers have been either tried or suggested for effective treatment of patients with SARS-CoV-2 disease. Hence, we recommend that all the above potential interventions must be imple-mented in terms of their safety and efficacy through proper clinical experiments to control the emerging SARS-CoV-2 disease.Copyright © 2021 Bentham Science Publishers.
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In recent years, new data have been obtained on the significant prevalence of vitamin D (VD) deficiency in the population, and knowledge about the role of vitamin D in the regulation of many physiological processes in the body, including the functioning of the immune system, has increased. The SARS-CoV-2 pandemic has further highlighted the issue of an adequate immune response in vitamin D deficiency. Objective of the review. To present and summarize the evidence on the role of VD in different parts of the immune response in COVID-19, to analyze available studies of the VD status effect on the course and outcome of COVID-19 in patients from different population groups. Material and methods. A search of domestic and foreign literature on the role of VD in the immune response in respiratory viral infections and SARS-CoV-2, as well as practical measures of VD-status correction in COVID-19, was performed. We used Scopus, Web of Science, PubMed, Google Scholar, eLibrary, and Cyberleninka databases. Results. Numerous clinical and observational studies have found an association between 25-hydroxyvitamin D levels, COVID-19 severity, and mortality. This association can be explained by the multifaceted role of vitamin D in the physiology of the human immune and endocrine systems. On the immunological side, the active form of VD promotes the secretion of antimicrobial peptides responsible for inhibiting viral replication and stimulates autophagy by increasing the level of Beclin1 protein and decreasing the level of mTOR protein regulating cellular homeostasis. It leads to the presentation of antigens followed by activation of the antiviral pathway of type I interferons. VD also stabilizes intercellular junctions, including those in the airway epithelium, reducing their permeability to pathogens, stimulates the activity of angiotensin-converting enzyme-2, whose receptors are a conduit for SARS-CoV-2 into cells, and several pathophysiological responses associated with the disease symptoms and acute lung injury. Adequate vitamin D status can provide significant benefits during the pandemic. Conclusion. To date, ideas about the role of vitamin D in regulating the immune response in respiratory infections have significantly expanded. However, its use in the complex preventive measures and adjuvant therapy of viral infections, including COVID-19, should be the subject of further scientific research.
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Purpose: Compared to azathioprine (AZA), mycophenolate (MPA) is implicated in an increased risk of several viral infections. Contrariwise, mTOR inhibitors (mTORi) are protective. Therefore, the study proposal is to evaluate the Covid-19 outcomes among kidney transplants (KT) patients under different maintenance immunosuppressive regimens. Method(s): We analyzed 90-day outcomes after Covid-19 infection using nationalwide Brazilian cohort data. RT-PCR positive patients tested between Mar/20 and Apr/21 (before immunization) were included. Patients using calcineurin-inhibitors (CNI)-free regimens were excluded. Result(s): 1,833 patients from 44 centers were analyzed, divided into three groups: CNI-AZA (n=389), CNI-MPA (n=1,258), and CNI-mTORi (n=186). Except for donor source, time after KT, and diabetes, demographics were similar among groups (Table1). The main outcomes are shown in Table 1. Considering CNI-AZA as the reference group, center-adjusted multivariable Cox regression showed that the CNIMPA group was associated with higher 30-day fatality (HR 1.65, 95% CI 1.17-2.33, p=0.004), effected also demonstrated in 90-day fatality (HR 1.43, 95%CI 1.06-1.93, p=0.020). CNI-mTORi was neutral for the 30-day fatality (HR 0.75, 95%CI 0.43- 1.29, p=0.296), but protective for the 90-day (HR 0.56, 95%CI 0.34-0.94, p=0.027). Conclusion(s): This data suggests that maintenance immunosuppressive drugs impact Covid-19 outcomes in kidney transplant patients. While MPA is associated with poor prognosis, mTORi seems to be protective. (Figure Presented).
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Purpose: To characterize demographics, treatment patterns, and outcomes among 3,998 transplant patients hospitalized for COVID-19 over 16 months of the pandemic (May '20-Aug '21). Method(s): Adult patients in a transplant cohort (TC) and non-transplant cohort (NTC) hospitalized with COVID-19 (ICD-10: U07.1) were compared in the Premier Healthcare Database from May '20-Aug '21. Baseline measures in first two days, demographics, comorbidity, COVID-19 treatments and immunosuppressants were analyzed. Outcomes included mortality (discharge status expired or hospice) and hospital and ICU LOS. Result(s): 3,998 TC patients were hospitalized for COVID-19 in 587 US hospitals. Compared to NTC, TC were younger (61 vs 64 yrs;p<.0001), less likely to be white (59% vs 67%;p<.0001), obese (24% vs 33%;p<.0001) or have COPD (17% vs 24%;p<.0001). TC had higher rates hypertension (84% vs 69%;p<.0001), renal disease (80% vs 22%, p<.0001), diabetes (48% vs 29%;p<.0001) and chronic heart failure (23% vs 18%;p<.0001). During hospitalization, a lower proportion of TC needed any oxygen therapy compared to NTC (p<.05). Compared to NTC, fewer TC received remdesivir (RDV) (44% vs 48%;p<.0001), but more received corticosteroids (87% vs 78%;p<.0001), anticoagulants (44% vs 29%;p<.0001) and convalescent plasma (18% vs 16%;p=0.007). In TC, 44% received MMF, 73% calcineurin inhibitors and 5% mTOR. Use of MMF did not change over time (43% May-Jul 2020;43% Aug- Dec 2020;45% 2021). TC had higher ICU admission rates (31% vs 28%;p.001), but similar hospital LOS and ICU LOS compared to NTC. All-cause mortality in NTC (15% overall;16% May-Jul 2020;16% Aug-Dec 2020;14% 2021) was not significantly different than TC over time (16% overall;13% May-Jul 2020;16% Aug-Dec 2020;16% 2021). Conclusion(s): Very few large studies have assessed COVID-19 management in transplant patients over time. All-cause mortality was comparable in both cohorts despite TC immunosuppression. RDV use was lower in TC. Uncertainty around MMF use in COVID-19 patients did not impact reported use of MMF. Further analyses are needed to evaluate confounding factors (medication sequence, time since transplant, disease severity) and impact of external factors such as earlier testing and treatment for COVID-19, vaccination, and new variants. (Table Presented).
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Purpose: Mycophenolate mofetil (MMF) use is associated with decreased antibody response to the SARS-CoV-2 mRNA vaccine series in heart and lung transplant recipients (HLTRs). Higher MMF doses have been associated with poor immunogenicity in kidney transplant recipients, but limited data exist on HLTRs. We evaluated the relationship between daily MMF dose and vaccine-induced antibody response in HLTRs. Method(s): HLTRs (n= 212) from an observational cohort were categorized by daily MMF doses (None, Low: <1000mg, Moderate: 1000-2000mg, High: >=2000mg). Semi-quantitative antibody testing was performed at 1, 3, and 6-months post-dose 2 (D2) using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (EIA), testing for antibodies to SARSCoV2 spike protein receptor binding domain, and the EUROIMMUN EIA, testing for S1 domain of SARS-CoV-2 spike protein. Multivariable Poisson regression was used to estimate the risk of a negative antibody response with increasing MMF dose. Result(s): At the time of vaccination, 94 (44.3%) HLTRs reported receiving no MMF, 33 (15.6%) reported a low dose, 54 (25.7%) reported a moderate dose, and 31 (14.8%) reported a high dose regimen. There were statistically significant differences in the number of participants on mTOR inhibitors and Triple immunosuppression among the groups but the participants in all 4 dose categories were otherwise comparable (Table 1) The risk ratio of a negative post-D2 titer with low, moderate and high dose regimens compared to no MMF was 0.65 1.15 2.05 (p=0.63), 1.34 2.043.10 (p=0.001) and 1.83 2.77 4.21 (p<0.001) after adjusting for age, sex, vaccine type, time since transplant, and corticosteroid use. Conclusion(s): HLTRs taking MMF >1000mg/day are at higher risk of remaining seronegative after mRNA vaccination, with evidence of a dose-nonresponse effect. The findings support the exploration of whether targeted MMF reduction strategies in HLTRs increase SARS-CoV-2 vaccine immunogenicity. (Table Presented).
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Purpose: Kidney transplant recipients (KTR) are at increased risk of mortality from COVID-19. We conducted a cohort study among KTR from the French Solid Organ Transplant COVID-19 (SOT COVID) registry to investigate the association between maintenance immunosuppressive drugs and 60-day mortality in KTR with COVID-19. Method(s): Data from all KTR with COVID-19 included in SOT COVID 02/28/2020 and 12/30/2020 were retrieved. Among them, 116 were excluded because of missing data on immunosuppressive therapy. We evaluated associations between immunosuppressive drugs and death <=60 days of 1st symptoms using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. Benjamini-Hochberg correction was used for controlling false positive rate;40 multiple imputations were performed. Adjusted p-value <0.05 was considered statistically significant. Result(s): There were 1,451 KTR included. Median age was 58 years, 963 (66.4%) were men. Most frequent comorbidities were hypertension (n=1188, 81.9%), diabetes (501, 34.5%), cardiovascular disease (428, 29.5%). Median time since transplant was 71 months. Maintenance immunosuppression regimen included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), Mammalian Target of Rapamycin inhibitors (144, 9.9%) and belatacept (58, 4.0%). Among 1,451 KTR, 201 (13.9%) died <=60 days. Older age and baseline creatininemia were associated with mortality (OR: 1.09 [1.07-1.11];1.01 [1.005- 1.009], p<0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (OR: 0.48 [0.31;0.76], p=0.011). All other variables yielded non-significant adjusted p-values. Conclusion(s): Corticosteroid-free regimens were associated with a lower risk of death in KTR with COVID-19. While a short course of high-dose corticosteroids is beneficial in severely ill COVID-19 patients, prolonged maintenance corticosteroids expose to chronic immune disorders that may predispose KTR to severe forms of COVID-19.
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Purpose: The diverse factors affecting the vaccine induced neutralizing antibody response in solid organ transplant recipients and their immunity against CoV2 variants are needed to be well characterize to understand how we improve the vaccine efficacy. Method(s): Anti-CoV2 receptor binding domain (RBD) plasma antibody response and their neutralization potency in 29 kidney and 22 heart transplant patients was determined with recombinant RBD protein binding ELISA and by calculating the 50% virus neutralization titer of the plasma antibody with ACE2-Hu-HeLa cell based pseudo virus neutralization assay against CoV2 wild type and delta variant. Result(s): We detected strong binding and protective neutralizing plasma antibody response in SOTR who were infected with CoV-2 either prior to or after the first dose of vaccine (n=8), who showed high median IC50 value > 10,000 against both the CoV2 wild type strain and the more transmissible delta variant. In contrast to this, the CoV2 uninfected and vaccinated SOTR ( naive vaccinees, n=43) had considerably lower anti-RBD plasma antibody binding titers, and only 19% of this population possessed minimally protective neutralizing antibody titer (IC50 >50) against the wild type CoV2 strain, which further decreased to 10% against the delta variant. While IgG and IgA were dominant isotypes of anti-RBD antibody induced by the CoV2 vaccines and correlated significantly (r=0.84, p=<0.001) with the CoV2 neutralization. The COV2 uninfected SOTR vaccinees who were within 1.5 years from transplantation or African American ethnicity were less likely to have detectable vaccine induced neutralizing antibody responses than the other populations. In the naive vaccinees, administration of corticosteroids in combination with calcineurin or mTOR inhibitors and antimetabolites also negatively affected the CoV2 antibody responses, while female and younger organ transplant recipients tended towards higher IgM and IgA titers. Kidney transplant recipients showed better IgG responses vs heart transplant recipients and elevated serum creatinine levels correlated with poorer antibody response to the vaccines in both kidney and heart transplant groups. Conclusion(s): These results suggest that in the absence of immunity due to CoV2 infection, vaccination in SOTRs induces much lower protective antibody levels than in healthy controls and identifies African-American ethnicity, less than 1.5 years post transplantation as additional risk factors that further exacerbate these effects. Poor kidney function negatively affected the vaccine induced antibody response.
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Objective To explore the application pattern and mechanism of medicine and food homologous traditional Chinese medicine (TCM) against modern viral diseases. Methods The method of literature mining was applied based on the characteristics of modern viral diseases, combining with ancient books and modern prescriptions for the prevention and treatment of viral diseases to build a relevant prescription database. Then SPSS and R language were used to analyze the high-frequency medicine and food homologous TCM and high confidence medicine and food homologous prescriptions in these prescriptions, and cluster analysis was carried out. The antiviral characteristic active ingredients of high-frequency medicinal and food homologous TCN were identified and analyzed, and the action mechanism of active ingredients against modern viral diseases was evaluate by network pharmacology. Results In the prevention and treatment of modern viral diseases, Gancao (Glycyrrhizae Radix et Rhizoma)-Chenpi (Citri Reticulatae Pericarpium)-Fuling (Poria) had the highest confidence, Glycyrrhizae Radix et Rhizoma-Jiegeng (Platycodonis Radix) had the highest support. At the same time, the prescriptions were clustered and analyzed to obtain Jinyinhua (Lonicerae Japonicae Flos)-Huangqi (Astragali Radix)-Huoxiang (Agastache rugosa), Glycyrrhizae Radix et Rhizoma-Xingren (Armeniacae Semen Amarum)-Poria-Platycodonis Radix-Citri Reticulatae Pericarpium, Ganjiang (Zingiberis Rhizoma)-Renshen (Ginseng Radix et Rhizoma), Zisu (Perilla frutescens)-Gegen (Puerariae Lobatae Radix), Lugen (Phragmitis Rhizoma)-Sangye (Mori Folium), Shengjiang (Zingiberis Rhizoma Recens)-Dazao (Jujubae Fructus) clustering new prescription. The core action targets of EGFR, CASP3, VEGFA, STAT3, MMP9, HSP90AA1, mTOR, PTGS2, MMP2, TLR4, MAPK14, etc were identified. The action mechanism involved human cytomegalovirus infection, coronavirus disease-coronavirus disease 2019 (COVID-19), etc. The core action pathway were phosphatidylinositol-3/kinase protein kinase B (PI3K/Akt) signal pathway, mitogen activated protein kinase (MAPK) signal pathway, interleukin-17 (IL-17) signal pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal pathway, etc. Conclusion Through data mining, six new prescriptions for preventing and controlling modern viral diseases were obtained, and the mechanism of action was preliminarily discussed, which provided some reference for the research and development of medicine and food homologous TCM prescriptions for the prevention and treatment of viral epidemics and related health products.
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We present familial tuberous sclerosis (TS) case complicated by COVID-19. COVID-19 aggravates the course of TS and may lead to a fatal outcome. We review the role of mTORC1 (mechanistic/mammalian Target of Rapamycin Complex 1) in the development and functions of the nervous system and the pathogenesis of TS and COVID-19 with emphasis on the involvement of the brain and lungs. We observed that COVID-19 worsens the course of epilepsy in patients with TS. In TS patients, lymphangioleiomyomatosis may predispose to SARS-CoV-2 invasion into the respiratory system because of the increased expression of ACE2 and TMPRSS2 in type II pneumocytes and thus may worsen the prognosis. We also review the current data on the continuation/termination of everolimus administration in patients with TS associated with COVID-19.
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BACKGROUND AND AIMS: COVID-19 infection in solid organ transplant recipients (SOT) is associated with increased morbidity and mortality due to comorbidities and immunosuppression state (Chaudhry ZS et al, 2020). Although vaccines represent the greatest hope to control COVID-19 pandemic, several studies showed the low immunogenicity of a two-dose mRNA COVID-19 vaccine regimen in SOT as compared with general population (Boyarsky BJ et al, 2021). Based on this evidence, on September 2021, the Italian Medicine Agency (AIFA) authorized a third vaccine administration as additional primary dose to immunocompromised patients. The aim of this study is to evaluate the seroconversion rate after the third dose of BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 mRNA vaccine in kidney transplant recipients (KTRs) and to investigate the baseline factors associated with the absence of the antibody response. METHOD: we performed a prospective and observational study on a monocentric cohort of 329 consecutive Caucasian KTRs given three doses of the BNT162b2 COVID-19 vaccine. Key exclusion criteria were a previous history of COVID-19 infection and transplantation or having underwent chemotherapy treatment within the last year. Antibody response against the spike protein was tested on blood sample collected before the administration of vaccine (T0), at 15 and 90 days after the second dose (T2 and T3, respectively) and one month after the third dose (T5). The level of antibodies was assessed using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (positive cut-off ≥ 0.8 U/mL). A total of 22 patients were excluded from the analysis because categorized as SARS-CoV-2-pre-immunized according to the antibodies' baseline status (T0) above the positivity cut-off. The Local Ethics Committees approved the study protocol and written informed consent was obtained before enrolment. RESULTS: The study population of 307 KTRs was 57.10 ± 13.10 years, with a predominance of male sex (64.2%). Median time from transplantation to vaccine was 10 [IQR 5-17] years. Blood analysis at baseline revealed mean eGFR assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to be 56.95 ± 23.04 mL/min/1.73 m2. The standard immunosuppressive regimen consisted of glucocorticoids in all patients, calcineurin inhibitors (88.6% of patients), antimetabolites (73.3% of patients) and mTOR inhibitors (in 15.6% of patients). The first two doses were administered 21 days apart, and the third dose was administrated 172 ± 4 days after the second dose. In our cohort, 43.3% patients (133/307) responded to the vaccine at T2. The proportion of responders increased to 68.4% (186/272) at T3 (median antibody level: 5.2 [0.40-74.07]). One month after the third dose, a positive antibody titer was detected in 251 of 307 patients (81.8%) (median antibody titre: 1137.50 [9.32- 4189.75]). The response curve starting at T2 and increasing at T3 makes apparent that there is a distinctive kinetic of humoral response in immunocompromised patients compared to immunocompetent individuals (Walsh EE et al., 2020). A multivariate analysis showed that the negative response to the third primary dose was associated with antimetabolite immunosuppressants (P = .001), lower estimated glomerular filtration rate (P < .001) and female sex (P = .04) (Figure 1). No serious adverse events were reported. Neither De novo DSAs nor change in proteinuria were reported after vaccination. The limitation of this study is the absence of assays for cellular immune response. CONCLUSION: Although the exact threshold of antibody titer for protection against SARS-CoV-2 infection remains unclear, the ability of the additional mRNA COVID- 19 vaccine dose to increase both immune response (Figure 2A) and the prevalence of seroconversion rate (Figure 2B) associated with the acceptable safety profile supports its use after an initial 2-dose mRNA COVID-19 primary vaccine series in immunocompromised patients. (Table Presented).
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Introduction: Nivolumab is a PD-1 checkpoint inhibitor that restores the pre-existing antitumor immune response by selectively blocking the interaction between PD-1 receptors on T-cells and PD-1 ligands, PD-L1 and PD-L2, on tumor cells and antigen presenting cells. Nivolumab prolongs survival in patients with metastatic kidney cancer with a good safety profile as demonstrated in the CheckMate 025 clinical trial. Material And Methods: This retrospective data involved prospectively monitored patients (named patient programm) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from 2016 to 2018 and the treatment continued to be funded by the Croatian Health Insurance. Patients with metastatic kidney cancer (mRCC) received tyrosine kinase inhibitors (TKI), (29/30), one patient received mTOR inhibitor as first line therapy, and subsequently they initially received nivolumab 3 mg kg NPP every 2 weeks. Later we applied a monthly dose 480 mg. Nivolumab treatment was continued in patients who did not have disease progression or grade 3 and 4 toxicity. Patients were monitored every three momths with CT of the chest, abdomen and pelvis and laboratory tests (hemathology, biochemistry, T4, TSH). We also respected patients' preference in regard to cycle dynamic by stopping nivolumab therapy or introducing SBRT during nivolumab therapy. Results: We treated a total of 30 patients (22 men and 8 women) with mRCC, who initially received TKI or mTOR therapy with median age 60.2 ± 9.79 years at diagnosis of kidney cancer. Most patients belonged to intermediate-risk groups. Majority of patients (23/30) were treated with sunitinib as the first line treatment after nephrectomy. Six patients had CR (20%) but two of them died in 2021, one of COVID- 19 and one of haed and neck cancer. Currently, 6 (20%) are alive, ECOG=0, 4 (13.3%) have CR without therapy, expressed in months-23, 33, 35 and 53 (treatment-free survival). Median OS first line with TKI therapy was 34 months while median OS second line with nivolumab was 17 months. Patients with sarcomatoid component in pathohistology report have longer survival. Patients with bone metastases have shorter survival to patients with other metastases. Conclusion: Nivolumab demonstrated clinical efficacy in the CheckMate 025 clinical trial and in clinical practice as second line treatment after patients had previously received TKI. Our results show that six years after first cycle of nivolumab as second line therapy 6 out of 30 patient (20%) are alive, ECOG=0. Further research should show which sequence therapy would be the best for each patient. Research about potential immunotherapy biomarkers which would indicate who responds to the therapy and who does not is ongoing.
ABSTRACT
Background: SARS-CoV-2 infection in immunocompromised individuals has been associated with prolonged virus shedding and the development of novel viral variants. Rapamycin and rapamycin analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer and autoimmunity, but a common side effect of these drugs is immunosuppression and increased susceptibility to infection. Immune impairment caused by rapalog use is traditionally attributed to their impacts on T cell signaling and cytokine production. Methods: We used replication-competent SARS-CoV-2 and HIV pseudotyped with betacoronavirus Spike proteins to assess how rapalog pretreatment of cells ex vivo and rodent animals in vivo impacts susceptibility to Spike-mediated infection. Results: We show that exposure to rapalogs increases cellular susceptibility to SARS-CoV-2 infection by antagonizing components of the constitutive and interferon-induced cell-intrinsic immune response. Pre-treatment of cells (including human lung epithelial cells and primary human small airway epithelial cells) with rapalogs promoted the early stages of SARS-CoV-2 infection by facilitating Spike-mediated virus entry. Rapalogs also boosted infection mediated by Spike from SARS-CoV and MERS-CoV in addition to hemagglutinin of influenza A virus and glycoprotein from vesicular stomatitis virus, suggesting that rapalogs downmodulate antiviral defenses that pose a common barrier to these viral fusion proteins. By identifying one rapalog (ridaforolimus) that lacks this function, we demonstrate that the extent to which rapalogs promote virus entry is linked to their capacity to trigger the lysosomal degradation of IFITM2 and IFITM3, intrinsic inhibitors of virus-cell membrane fusion. Mechanistically, rapalogs that promote virus entry inhibit the mTOR-mediated phosphorylation of TFEB, a transcription factor controlling lysosome biogenesis and lysosomal degradation pathways such as autophagy. In contrast, TFEB phosphorylation by mTOR was not inhibited by ridaforolimus. In the hamster model of SARS-CoV-2 infection, injection of rapamycin four hours prior to virus exposure resulted in elevated virus titers in lungs, accelerated weight loss, and decreased survival. Conclusion: Our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating a lysosome-mediated suppression of intrinsic immunity.
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The proceedings contain 12 papers. The topics discussed include: prognostic implication of MYC/BCL2 expressions in patients with diffuse large B-cell NHL;clinical outcomes of pediatric-inspired chemotherapy protocol in adolescent and young adults (AYAs) acute lymphoblastic leukemia patients;effect of nutritional status on survival of Egyptian patients with gastrointestinal malignancies;characterization of COVID-19 disease in cancer patients, single institute experience, low income setting;malignant obstructive jaundice;review of 232 patients;determining resectability in pancreatic tumors;review of 70 cases;Inhibition of dynamins restricts the survival of vasopressin stimulated and PI3K/Akt/mTOR inhibited breast cancer cells;and complete mesocolic excision and central vascular ligation in colon cancer surgery, feasibility and outcome.
ABSTRACT
Background. Studies of solid organ transplant recipients (SOTr) hospitalized for Covid-19 have focused on short-term outcomes with approximately 30 days of follow-up time. Intermediate-term mortality and associated risk factors for intermediate-term death have not previously been reported. Methods. Using data from a multi-center registry, we assessed mortality by 90 days among SOTr hospitalized for Covid-19 between 3/1/2020 and 12/31/2020. Multivariable Cox-proportional hazard models were used to compare risk factors for mortality by 28 and 90 days. Covariates were selected a priori based on known predictors of death in SOTr hospitalized for Covid-19. All patients were followed for 90 days or were censored at the time of death or last clinical contact, if this occurred prior to day 90 after diagnosis. Results. Among SOTr hospitalized for Covid-19, 198/979 (20%) died within 90 days of diagnosis and 37/198 (19%) of deaths occurred between days 29 and 90. Risk factors for mortality by day 90 days included age >65 years (1.8, 95% CI 1.3-2.4, P< 0.001), lung transplant (compared to non-lung) (1.6, 95% CI 1.1-2.4, P=0.02), chronic lung disease (2.2, 95% CI 1.5-3.4, P=0.002) and heart failure (1.9, 95% CI 1.2-2.9), which were similar to risk factors reported for 28-day mortality (Table 1). Diagnosis during the second half of 2020 (6/20-12/31/20) was associated with lower mortality by 28 days (aHR 0.7, 95% CI 0.5-1.0, P=0.03) compared to diagnosis during the early half of 2020 (3/1-6/19/20);however, mortality by 90 days was similar in the late and early time periods (aHR 0.9, 95% CI 0.7-1.2, P=0.54). Obesity and mTOR inhibitor use were also associated with death by 28 but not 90 days. Kaplan-Meier survival curves by time period of diagnosis are shown in Figure 1. Vertical tick marks represent censored cases. Early 2020 refers to cases diagnosed between March 1 and June 19, 2020 and late 2020 refers to cases diagnosed between June 20 and December 31, 2020. Conclusion. Approximately 20% of deaths among SOTr hospitalized for Covid-19 occurred between days 29 and 90. Future investigations are required to discern the mechanism(s) for the improvement in early, but not late, mortality among SOTr with Covid-19 during the course of the pandemic.