54,916 research outputs found

    PD-l preserves the stem-like properties of memorylike CD8+ T cells during chronic viral infection

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    Plusieurs virus rĂ©sistent Ă  la rĂ©ponse immunitaire et causent une infection chronique, comme les virus des hĂ©patites B (VHB) et C (VHC), le virus de l’immunodĂ©ficience humaine (VIH) chez l’homme ou le virus de la choriomĂ©ningite lymphocytaire (CMLV) chez les souris. C’est-Ă -dire que les cellules CD8+ spĂ©cifiques de l’antigĂšne (TEX) de l’infection sont moins efficaces qu’elles le seraient lors d’une infection aiguĂ«. Ces cellules TEX expriment des rĂ©cepteurs sur leur surface, ce qui diminue leur efficacitĂ© et les Ă©puise (rĂ©cepteurs inhibiteurs). Cette population est maintenue par des cellules ancĂȘtres (TML) qui possĂšdent non seulement des caractĂ©ristiques d’épuisement, comme l’expression des rĂ©cepteurs inhibiteurs, mais aussi des caractĂ©ristiques de cellules souches, comme la capacitĂ© de s’auto-renouveler et de produire des cellules plus spĂ©cifiques. Le plus important rĂ©cepteur inhibiteur est le rĂ©cepteur « programmed cell death protein 1 » (PD-1). Ce dernier interagit avec son ligant PD-L1. Le rĂ©sultat est l’inhibition de l’activitĂ© des cellules CD8+. Lorsque l’on empĂȘche l’interaction de maniĂšre momentanĂ©e ou permanente entre PD-1 et PD-L1, la quantitĂ© de TML augmente et elles produisent plus de TEX : les cellules sont plus efficaces. Il existe dĂ©jĂ  des Ă©tudes sur l’effet de PD-1 sur les TEX, mais pas sur les TML. C’est donc la question que nous avons abordĂ©e. Pour rĂ©pondre Ă  cette question, nous nous sommes penchĂ©s sur le comportement des cellules CD8+ spĂ©cifiques de la CMLV dĂ©ficientes en PD-1 (PD-1 ko) ou des cellules CD8+ correspondantes de type sauvage (WT) soumises au blocage de PD-1 Ă  l’aide d’anticorps dans un modĂšle d’infection chronique par la CMLV. Les TML PD-1 ko ou traitĂ©es par anti-PD-L1 Ă©taient, phĂ©notypiquement et au niveau de l’expression des gĂšnes, similaires aux TML WT. Cependant, les TML PD-1 ko prĂ©sentes durant la phase chronique de l’infection avaient une capacitĂ© rĂ©duite Ă  rĂ©pondre Ă  une re-stimulation, c’est-Ă -dire que leur « caractĂšre souche » Ă©tait rĂ©duit par rapport aux TML WT. Cette diminution, chez les TML PD-1 ko, n’a pas Ă©tĂ© observĂ©e lors la phase aiguĂ« de l’infection, suggĂ©rant que le dĂ©faut a Ă©tĂ© acquis lors de l’infection chronique. Le « caractĂšre souche » des TML Ă©tait Ă©galement rĂ©duit lorsqu’elles Ă©taient soumises Ă  une interruption du signal PD-1 durant la phase chronique. L’analyse de l’expression de gĂšnes a rĂ©vĂ©lĂ© que les principales voies de signalisation en aval du rĂ©cepteur des cellules T (TCR) avaient une activitĂ© rĂ©duite chez les TML PD-1 ko et aussi en partie chez les TML soumises au blocage de PD-1 par rapport aux TML WT. De plus, ces TML PD-1 ko prĂ©sentaient une expression rĂ©duite des gĂšnes liĂ©s au « caractĂšre souche » des cellules CD8+ Myb et Klf4, identifiĂ©s prĂ©cĂ©demment. En effet, la diminution de l’expression de Myb et Klf4 dans les cellules WT CD8+ spĂ©cifiques au virus a diminuĂ© la capacitĂ© d’auto-renouvelement et la production de cellules plus spĂ©cialisĂ©es, reproduisant dans une large mesure le phĂ©notype des TML PD-1 ko. Nos donnĂ©es montrent que l’expression de PD-1 protĂšge le « caractĂšre souche » des TML, et assure ainsi le maintien Ă  long terme d’une rĂ©ponse immunitaire nĂ©cessaire pour contenir l’infection. Nous suggĂ©rons que PD-1 servirait de mĂ©canisme de rĂ©troaction nĂ©gative physiologique pour empĂȘcher la surstimulation des TML durant la phase chronique de l’infection. Lorsqu’une surstimulation se produit sur une pĂ©riode prolongĂ©e, en raison de l’absence de PD-1, les cellules CD8+ s'adaptent en rĂ©duisant la transduction des signaux via le TCR. Cela pourrait se traduire par une rĂ©duction du « caractĂšre souche » de ces cellules. Ces rĂ©sultats ont des implications pour l’immunothĂ©rapie du cancer mĂ©diĂ©e par le blocage de PD-1. Il pourrait donc ĂȘtre bĂ©nĂ©fique de limiter le nombre de cycles de blocage du PD-1 pour prĂ©server la fonction des TML et ainsi maintenir une activitĂ© antitumorale Ă  long terme. -- La rĂ©ponse immunitaire des lymphocytes T (LT) CD8+ est normalement capable d'Ă©liminer les cellules infectĂ©es par un virus. Cependant, plusieurs virus, tels que le virus de l'hĂ©patite B (VHB), le virus de l'hĂ©patite C (VHC), le virus de l'immunodĂ©ficience humaine (VIH) ou certaines souches du virus de la choriomĂ©ningite lymphocytaire (CMLV) peuvent Ă©tablir une infection chronique chez des individus/souris immunocompĂ©tents en dĂ©pit d'une rĂ©ponse des lymphocytes T (LT) CD8+. Contrairement Ă  une rĂ©ponse protectrice, les LT CD8+ chroniquement activĂ©s perdent progressivement leurs capacitĂ©s prolifĂ©ratives et effectrices, subissent une diffĂ©renciation terminale et augmentent l'expression de rĂ©cepteurs inhibiteurs tels que « programmed cell death protein 1 » (PD-1). C'est ce qu'on appelle l'Ă©puisement des LT. RĂ©cemment, il a Ă©tĂ© dĂ©montrĂ© que les LT CD8+ dits "de type mĂ©moire" (TML) soutenaient la rĂ©ponse immunitaire Ă  une infection virale chronique. Les TML prĂ©sentent des propriĂ©tĂ©s semblables Ă  celles des cellules souches : ils conservent une capacitĂ© prolifĂ©rative, s'auto- renouvellent et produisent des cellules diffĂ©renciĂ©es (cellules Ă©puisĂ©es ou TEX) qui ont un potentiel lytique mais ont perdu leur potentiel prolifĂ©ratif. Alors que le rĂŽle de PD-1 dans l'Ă©puisement des LT a Ă©tĂ© largement Ă©tudiĂ©, l'impact de son expression sur la fonction des TML n'a pas encore Ă©tĂ© abordĂ©. Pour rĂ©pondre Ă  cette question, nous avons Ă©tudiĂ© le comportement des LT CD8+ spĂ©cifiques au CMLV dĂ©ficients en PD-1 (PD-1 ko) ou des LT CD8+ correspondants de type sauvage (WT) soumis au blocage de PD-1 Ă  l'aide d'anticorps dans un modĂšle d'infection chronique par le CMLV. Les TML PD-1 ko ou traitĂ©es par anti-PD-L1 Ă©taient, phĂ©notypiquement et transcriptionnellement, similaires aux TML WT. Cependant, les TML PD-1 ko prĂ©sentes durant la phase chronique de l'infection avaient une capacitĂ© rĂ©duite Ă  rĂ©pondre Ă  une re-stimulation, c'est-Ă -dire que leur "caractĂšre souche" Ă©tait rĂ©duit par rapport aux TML WT. Cette rĂ©duction, chez les TML PD-1 ko, n'a pas Ă©tĂ© observĂ©e lors de la phase aiguĂ« de l'infection, suggĂ©rant que le dĂ©faut a Ă©tĂ© acquis pendant de l'infection chronique. Leur "caractĂšre souche" Ă©tait Ă©galement rĂ©duit lorsque les TML Ă©taient soumis Ă  un blocage de PD- 1 durant la phase chronique. L'analyse du transcriptome a rĂ©vĂ©lĂ© que les principales voies de signalisation en aval du rĂ©cepteur des cellules T (TCR), y compris les voies NFAT, AP-1 et NF- B, avaient une activitĂ© rĂ©duite dans les TML PD-1 ko par rapport aux TML WT. L'activitĂ© de la voie NF-B Ă©tait Ă©galement rĂ©duite lorsque les TML Ă©taient soumis au blocage de PD-1. De plus, ces TML PD-1 ko prĂ©sentaient une expression rĂ©duite des gĂšnes liĂ©s au "caractĂšre souche" des LT CD8+ Myb et Klf4, identifiĂ©s prĂ©cĂ©demment. En effet, le knock down de Myb et Klf4 dans les LT CD8+ spĂ©cifiques du virus a rĂ©capitulĂ© dans une large mesure le phĂ©notype des TML PD-1 ko. Nos donnĂ©es montrent que l'expression de PD-1 protĂšge le "caractĂšre souche" des TML, et assure ainsi le maintien Ă  long terme d'une rĂ©ponse immunitaire nĂ©cessaire pour contenir l'infection. Nous proposons que PD-1 servirait de mĂ©canisme de rĂ©troaction nĂ©gative physiologique pour empĂȘcher la surstimulation des TML durant la phase chronique de l'infection. Lorsqu'une surstimulation se produit sur une pĂ©riode prolongĂ©e, en raison de l'absence de PD-1, les LT CD8+ s'adaptent en rĂ©duisant la transduction des signaux via le TCR. Cela pourrait ĂȘtre responsable de la rĂ©duction du "caractĂšre souche" de ces cellules. Ces rĂ©sultats ont des implications pour l'immunothĂ©rapie du cancer mĂ©diĂ©e par le blocage de PD-1. Un excĂšs de cycles de traitement par blocage du PD-1 peut finir par dĂ©grader l'efficacitĂ© des TML spĂ©cifiques Ă  la tumeur. Il pourrait donc ĂȘtre important de limiter le nombre de cycles de traitement afin de prĂ©server la fonction des TML et de maintenir une activitĂ© anti-tumorale Ă  long terme. -- An immune response by CD8+ T cells is normally able to clear virus infected cells. However, several viruses, such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or certain lymphocytic choriomeningitis virus (LCMV) strains can establish chronic infection in immunocompetent individual/mouse strains despite the induction of a CD8+ T cell response. Compared to a protective response, chronically activated CD8+ T cells progressively lose their proliferative and effector capacities, undergo terminal differentiation and upregulate the expression of inhibitory receptors such as, programmed death protein 1 (PD-1). This is referred to as T cell exhaustion. Recently, so called memory-like (TML) CD8+ T cells were found to sustain the immune response to chronic viral infection. TML cells have stem cell-like properties i.e. they retain proliferative capacity and self-renew or yield differentiated cells (exhausted or TEX cells) that have lytic potential but have lost proliferative potential. While the role of PD-1 for T cell exhaustion has been extensively studied, how PD-1 expression impacts the function of TML cells has not been addressed before. To address this question, we investigated the behavior of LCMV-specific CD8+ T cells deficient of PD-1 (PD-1 ko) or of corresponding wild type (WT) CD8+ T cells subjected to PD-1 blockade using antibodies in a model of chronic LCMV infection. PD-1 ko and anti-PD-L1 treated TML cells were phenotypically and transcriptomically remarkably similar to WT TML cells. However, PD-1 ko TML present during the chronic phase of the infection had reduced capacity to respond to recall stimulation i.e. the stemness of these cells was reduced compared to WT TML cells. Reduced stemness of PD-1 ko TML cells was not observed at the acute phase of the infection suggesting that the defect was acquired during chronic infection. The stemness was also reduced when TML cells were subjected to PD-1 blockade during the chronic phase. Transcriptome analysis revealed that key downstream T cell receptor (TCR) signalling pathways, including the NFAT, AP-1 and NF-B pathways, had reduced activity in PD-1 ko compared to WT TML cells. The activity of the NF-B pathway was also reduced when TML cells were subjected to PD-1 blockade. Moreover, PD-1 ko TML had reduced expression of the previously identified CD8+ T cell stemness genes Myb and Klf4. Indeed, knock down of Myb and Klf4 in virus-specific CD8+ T cells recapitulated to a significant extent the phenotype of PD-1 ko TML cells. Our data show that PD-1 expression protects the stemness of TML cells, and thus ensures the long-term maintenance of an immune response that is needed to contain the infection, although not sufficient to clear the infection. We propose that PD-1 serves as a physiological negative feedback mechanism to prevent overstimulation of TML cells during the chronic phase of the infection. When overstimulation occurs over a prolonged period of time, due to the absence of PD-1, CD8+ T cells adapt by reducing the transduction of signals via the TCR. This may be responsible for the reduced stemness of these cells. These findings have implications for PD-1 blockade-mediated cancer immunotherapy. An excess of PD-1 blockade treatment cycles may eventually degrade the effectiveness of tumor-specific TML cells. It may thus be important to limit the number of treatment cycles to preserve T L function in order to maintain anti-tumor activity long-term

    Pharmacist Intervention to Address Drug Related Problems in Patients with Decompensated Liver Cirrhosis

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    Background: Patients with decompensated cirrhosis are often given therapeutic and prophylactic drugs. Polypharmacy raises both the likelihood of prescription errors and the complications associated with drugs. Clinical pharmacists are excellent at recognizing, addressing, and preventing clinically significant drug-related problems. Objectives: Identification types of pharmacist interventions to address drug-related problems in patients with decompensated cirrhosis and assess the acceptance/implementation of these recommendations. And identify patient factors associated with accepting pharmacist recommendations. Subjects and Methods: Prospective, interventional, clinical study for 80 hospitalized decompensated cirrhosis patients was conducted at Baghdad Teaching Hospital and lasted for four months, from the first of December 2021 until the last of March 2022. The study involved two phases, the first one was observational to identify drug-related problems and classify them according to the Pharmaceutical Care Network Europe classification version 9.1,   and the second phase was interventional to increase the awareness of patients and health care providers about those problems and to propose a proper solution for each one. Results: The most frequent pharmacist intervention was proposed to the prescriber (54.7%), followed by speaking to the caregiver (37.7%). Acceptance and full implementation were highly observed in 71.1% of the intervention. There is a significant  association between occurring ascites and bleeding in patients and accepting/implementing pharmacist recommendations Conclusions: Patients with decompensated liver cirrhosis have a significant prevalence of drug-related problems. Clinical pharmacists are excellent at recognizing drug-related problems and reducing their incidence, and their interventions were well accepted.      

    Hepatitis C prevalence and elimination planning in Pakistan, a bottom-up approach accounting for provincial variation

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    In Pakistan, substantial changes to hepatitis C virus (HCV) programming and treatment have occurred since the 2008 nationwide serosurvey estimated a 4.8% anti-HCV prevalence. In the absence of an updated national study, this analysis uses provincial data to estimate a national prevalence and the interventions needed to achieve elimination. Using a Delphi process, epidemiologic HCV data for the four provinces of Pakistan (accounting for 97% of the population) were reviewed with 21 subject-matter experts in Pakistan. Province-level estimates were inputted into a mathematical model to estimate the national HCV disease burden in the absence of intervention (Base), and if the World Health Organization (WHO) elimination targets are achieved by 2030 (80% reduction in new infections, 90% diagnosis coverage, 80% treatment coverage, and 65% reduction in mortality: WHO Elimination). An estimated 9,746,000 (7,573,000-10,006,000) Pakistanis were living with viraemic HCV as of January 1, 2021; a viraemic prevalence of 4.3% (3.3-4.4). WHO Elimination would require an annual average of 18.8 million screens, 1.1 million treatments, and 46,700 new infections prevented anually between 2022 and 2030. Elimination would reduce total infections by 7,045,000, save 152,000 lives and prevent 104,000 incident cases of hepatocellular carcinoma from 2015 to 2030. Blood surveys, programmatic data, and expert panel input uncovered more HCV infections and lower treatment numbers in the provinces than estimated using national extrapolations, demonstrating the benefits of a bottom-up approach. Screening and treatment must increase 20 times and 5 times, respectively, to curb the HCV epidemic in Pakistan and achieve elimination by 203

    Reverse inflammaging: Long-term effects of HCV cure on biological age.

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    BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection can be cured with direct-acting antivirals (DAAs). However, not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). Recently, chronic viral infections have been shown to be associated with biological age acceleration defined by the epigenetic clock. The aim of this study was to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR. METHODS: We included 54 well-characterized individuals with chronic hepatitis C who achieved SVR after DAA therapy at three time points: DAA treatment initiation, end of treatment, and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA methylation status was determined in peripheral blood mononuclear cells (PBMCs) and used to calculate epigenetic age acceleration (EAA) using Horvath's clock. RESULTS: Individuals with HCV had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age- and sex-matched reference group (p <0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased to 1.37 years at long-term follow-up. The decrease in EAA was significant only between the end of treatment and follow-up (p = 0.01). Interestingly, eight individuals who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR. CONCLUSIONS: Our data contribute to the understanding of the biological impact of HCV elimination after DAA therapy and demonstrate that HCV elimination can lead to "reverse inflammaging". In addition, our data support the potential use of biological age as a biomarker for HCV sequelae after SVR. IMPACT AND IMPLICATIONS: Chronic hepatitis C virus infection is now curable with direct-acting antivirals, but it remains unclear whether hepatitis C sequelae are fully reversible after viral elimination. Our results suggest that epigenetic changes or acceleration of biological age are reversible in principle, but this requires time, while a lack of reversibility appears to be associated with the development of hepatocellular carcinoma. While most clinical risk scores now take chronological age into account, it may be worthwhile to explore how biological age might improve these scores in the future. Biological age may be a cornerstone for the individualized clinical assessment of patients in the future, as it better reflects patients' lifestyle and environmental exposures over decades

    Prevalence of Chronic Kidney Disease with Hepatitis B and/or Hepatitis C Comorbid in Hemodialysis Installation at the University of Muhammadiyah Malang General Hospital

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    Chronic Kidney Disease (CKD) is a clinical condition in which kidney function and/or structure is characterized by irreversible and slow, progressive evolution. CKD cases in Indonesia in 2018 amounted to 3.8% of the total population (713,783 cases). Prevalence of CKD patients with Hepatitis B and/or Hepatitis C at UMM General Hospital has never been reported before. Data were taken from the medical records of UMM General Hospital. Characteristics of the patients were age, gender, aetiology, vascular access and duration of hemodialysis. The results of the laboratory examinations analyzed were HBsAg and Anti-HCV on CKD patients who underwent hemodialysis every 6 months, starting from January 2020. Data were analyzed with descriptive analysis using SPSS v25. The demographic proportion of CKD patients undergoing hemodialysis was highest in the 50-59 year age group (33.8%). Males were more than females (85 patients, 53.1%). The most common aetiology of CKD at UMM General Hospital was caused by hypertension (92 patients, 57.5%). Vascular access mostly used was AV shunt (107 patients, 66.9%). 107 (66.9%) patients had undergone hemodialysis for 1-5 years. In January-June 2022, there were 2 (1.25%) Hepatitis B patients with CKD and 8 (5%) CKD patients with Hepatitis C. The majority of CKD patients at UMM General Hospital were male patients aged 50-59 years, having had hemodialysis for 1-5 years, using AV Shunt, with the most common cause being hypertension. In January-June 2022, there were 1.25% CKD patients with Hepatitis B and 5% CKD patients with Hepatitis C. Keywords: CKD, hemodialysis, Hepatitis B, Hepatitis

    Annual SHOT Report 2018

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    SHOT is affiliated to the Royal College of PathologistsAll NHS organisations must move away from a blame culture towards a just and learning culture. All clinical and laboratory staff should be encouraged to become familiar with human factors and ergonomics concepts. All transfusion decisions must be made after carefully assessing the risks and benefits of transfusion therapy. Collaboration and co-ordination among staff is vital

    Artificial neural network scheme to solve the hepatitis B virus model

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    This article aims to describe the simulation studies of the hepatitis B virus non-linear system using supervised neural networks procedures supported by Levenberg-Marquardt back propagation methodology. The proposed strategy has five distinct quantities: susceptible X(t), symptomatic infections Y(t), chronic infections W(t), recovered population R(t), and a population that has received vaccinations Z(t). The reference data set for all three distinct cases has been obtained utilizing the ND-Solver and Adams method in Mathematica software. The outcomes have been validated with performance plots for all cases. To check the accuracy and effectiveness of proposed methodology mean square error has are presented. State transition, and regression plots are illustrated to elaborated the testing, training, and validation methodology. Additionally, absolute errors for different components of hepatitis B virus model are demonstrated to depict the error occurring during distinct cases. Whereas the data assigned to training is 81%, and 9% for each testing and validation. The mean square error for all three cases is 10−12 this show the accuracy and correctness of proposed methodology

    Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses

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    Type I interferons (IFNs-α/ÎČ) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines
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