Poster 345 Cubitus Valgus ‐ An Uncommon Etiology for Ulnar Neuropathy: A Case Report

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146993/1/pmr2s204.pd

How Does Cross-Reactive Stimulation Affect the Longevity of CD8+ T Cell Memory?

Immunological memory—the ability to “remember” previously encountered pathogens and respond faster upon re-exposure is a central feature of the immune response in vertebrates. The cross-reactive stimulation hypothesis for the maintenance of memory proposes that memory cells specific for a given pathogen are maintained by cross-reactive stimulation following infections with other (unrelated) pathogens. We use mathematical models to examine the cross-reactive stimulation hypothesis. We find that: (i) the direct boosting of cross-reactive lineages only provides a very small increase in the average longevity of immunological memory; (ii) the expansion of cross-reactive lineages can indirectly increase the longevity of memory by reducing the magnitude of expansion of new naive lineages which occupy space in the memory compartment and are responsible for the decline in memory; (iii) cross-reactive stimulation results in variation in the rates of decline of different lineages of memory cells and enrichment of memory cell population for cells that are cross-reactive for the pathogens to which the individual has been exposed

When does humoral memory enhance infection?

Antibodies and humoral memory are key components of the adaptive immune system. We consider and computationally model mechanisms by which humoral memory present at baseline might instead increase infection load; we refer to this effect as EI-HM (enhancement of infection by humoral memory). We first consider antibody dependent enhancement (ADE) in which antibody enhances the growth of the pathogen, typically a virus, and typically at intermediate "Goldilocks" levels of antibody. Our ADE model reproduces ADE in vitro and enhancement of infection in vivo from passive antibody transfer. But notably the simplest implementation of our ADE model never results in EI-HM. Adding complexity, by making the cross-reactive antibody much less neutralizing than the de novo generated antibody or by including a sufficiently strong non-antibody immune response, allows for ADE-mediated EI-HM. We next consider the possibility that cross-reactive memory causes EI-HM by crowding out a possibly superior de novo immune response. We show that, even without ADE, EI-HM can occur when the cross-reactive response is both less potent and "directly" (i.e. independently of infection load) suppressive with regard to the de novo response. In this case adding a non-antibody immune response to our computational model greatly reduces or completely eliminates EI-HM, which suggests that "crowding out" is unlikely to cause substantial EI-HM. Hence, our results provide examples in which simple models give qualitatively opposite results compared to models with plausible complexity. Our results may be helpful in interpreting and reconciling disparate experimental findings, especially from dengue, and for vaccination

Interleukin 15 Is Required for Proliferative Renewal of Virus-specific Memory CD8 T Cells

The generation and efficient maintenance of antigen-specific memory T cells is essential for long-lasting immunological protection. In this study, we examined the role of interleukin (IL)-15 in the generation and maintenance of virus-specific memory CD8 T cells using mice deficient in either IL-15 or the IL-15 receptor α chain. Both cytokine- and receptor-deficient mice made potent primary CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV), effectively cleared the virus and generated a pool of antigen-specific memory CD8 T cells that were phenotypically and functionally similar to memory CD8 T cells present in IL-15+/+ mice. However, longitudinal analysis revealed a slow attrition of virus-specific memory CD8 T cells in the absence of IL-15 signals.This loss of CD8 T cells was due to a severe defect in the proliferative renewal of antigen-specific memory CD8 T cells in IL-15−/− mice. Taken together, these results show that IL-15 is not essential for the generation of memory CD8 T cells, but is required for homeostatic proliferation to maintain populations of memory cells over long periods of time

Estimating the Precursor Frequency of Naive Antigen-specific CD8 T Cells

The constraint of fitting a diverse repertoire of antigen specificities in a limited total population of lymphocytes results in the frequency of naive cells specific for any given antigen (defined as the precursor frequency) being below the limit of detection by direct measurement. We have estimated this precursor frequency by titrating a known quantity of antigen-specific cells into naive recipients. Adoptive transfer of naive antigen-specific T cell receptor transgenic cells into syngeneic nontransgenic recipients, followed by stimulation with specific antigen, results in activation and expansion of both donor and endogenous antigen-specific cells in a dose-dependent manner. The precursor frequency is equal to the number of transferred cells when the transgenic and endogenous responses are of equal magnitude. Using this method we have estimated the precursor frequency of naive CD8 T cells specific for the H-2Db–restricted GP33–41 epitope of LCMV to be 1 in 2 × 105. Thus, in an uninfected mouse containing ∼2-4 × 107 naive CD8 T cells we estimate there to be 100–200 epitope-specific cells. After LCMV infection these 100–200 GP33-specific naive CD8 T cells divide >14 times in 1 wk to reach a total of ∼107 cells. Approximately 5% of these activated GP33-specific effector CD8 T cells survive to generate a memory pool consisting of ∼5 × 105 cells. Thus, an acute LCMV infection results in a >1,000-fold increase in precursor frequency of DbGP33-specific CD8 T cells from 2 × 102 naive cells in uninfected mice to 5 × 105 memory cells in immunized mice

Laser Vaporization of Mouth Lesions, an Overview

Lasers are utilized in dentistry as a therapeutic tool or as an auxiliary tool. The major purpose of employing lasers in dentistry is to overcome the difficulties that are currently observed in traditional dental treatment treatments. The laser is used in hard tissue applications such as caries prevention, bleaching, restorative removal and curing, cavity preparation, dentinal hypersensitivity, growth modulation, and diagnostics, whereas soft tissue applications include wound healing, removal of hyperplastic tissue to uncover impacted or partially erupted teeth, photodynamic therapy for malignancies, and photo-stimulation of herpetic lesions. Lasers' capacity to perform minimally invasive operations with minimum patient discomfort has proven effective in the patient delivery system in dentistry practice. The availability of lasers with various wavelengths has produced a surgical panacea, and laser technology has replaced traditional surgical techniques in many oral surgical operations

Darunavir-cobicistat versus lopinavir-ritonavir in the treatment of COVID-19 infection (DOLCI): A multicenter observational study

Background Coronavirus Disease 2019 (COVID-19) is an evolving pandemic that urged the need to investigate various antiviral therapies. This study was conducted to compare efficacy and safety outcomes of darunavir-cobicistat versus lopinavir-ritonavir in treating patients with COVID-19 pneumonia. Methods and findings This retrospective, multicenter, observational study was conducted on adult patients hospitalized in one of the COVID-19 facilities in Qatar. Patients were included if they received darunavir-cobicistat or lopinavir-ritonavir for at least three days as part of their COVID-19 treatments. Data were collected from patients' electronic medical records. The primary outcome was a composite endpoint of time to clinical improvement and/or virological clearance. Descriptive and inferential statistics were used at alpha level of 0.05. A total of 400 patients was analyzed, of whom 100 received darunavir-cobicistat and 300 received lopinavir-ritonavir. Majority of patients were male (92.5%), with a mean (SD) time from symptoms onset to start of therapy of 7.57 days (4.89). Patients received lopinavir-ritonavir had significantly faster time to clinical improvement and/or virological clearance than patients received darunavir-cobicistat (4 days [IQR 3-7] vs. 6.5 days [IQR 4-12]; HR 1.345 [95%CI: 1.070-1.691], P = 0.011). Patients received lopinavir-ritonavir had significantly faster time to clinical improvement (5 days [IQR 3-8] vs. 8 days [IQR 4-13]; HR 1.520 (95%CI: 1.2-1.925), P = 0.000), and slower time to virological clearance than darunavir-cobicistat (25 days [IQR 15-33] vs. 21 days [IQR 12.8-30]; HR 0.772 (95%CI: 0.607-0.982), P = 0.035). No significant difference in the incidence or severity of adverse events between groups. The study was limited to its retrospective nature and the possibility of covariates, which was accounted for by multivariate analyses. Conclusion In patients with COVID-19 pneumonia, early treatment with lopinavir-ritonavir was associated with faster time to clinical improvement and/or virological clearance than darunavir-cobicistat. Future trials are warranted to confirm these findings.Scopu

Darunavir-Cobicistat versus Lopinavir-Ritonavir for COVID-19 Pneumonia: Qatar's Experience

Background: Coronavirus Disease 2019 (COVID-19) was first discovered in China and resulted in a pandemic crisis. 1,2 Many agents were investigated with inconclusive outcomes. 3 This study was conducted to compare the efficacy and safety outcomes of darunavir-cobicistat versus lopinavir-ritonavir in the treatment of patients with COVID-19. Methods: This retrospective, multicenter, observational study was conducted on adult patients hospitalized in COVID-19 facilities in Qatar. Patients were included if they had pneumonia and received darunavir-cobicistat or lopinavir-ritonavir for at least three days as part of their COVID-19 treatment. Data were collected from patients' electronic medical records. The primary outcome was a composite endpoint of time to clinical improvement and/or virological clearance. Data were analyzed descriptively and inferential statistics were applied at alpha level of 0.05. Results: A total of 400 patients' medical records were analyzed, of whom 100 received darunavir-cobicistat and 300 received lopinavir-ritonavir. The majority of patients were male (92.5%), with a mean (SD) time from symptoms onset to start of therapy of 7.57 days (SD 4.89). Patients who received lopinavir-ritonavir had a significantly faster time to the primary composite endpoint of clinical improvement and/or virological clearance than patients who received darunavir-cobicistat (4 days [IQR 3-7] vs. 6.5 days [IQR 4-12]; HR 1.345 [95%CI: 1.070-1.691], p = 0.011) [Figure 1]. Patients who received lopinavir-ritonavir had a significantly faster time to clinical improvement (5 days [IQR 3-8] vs. 8 days [IQR 4-13]; HR 1.520 (95%CI: 1.2-1.925), p = 0.000), and slower time to virological clearance than those who received darunavir-cobicistat (25 days [IQR 15-33] vs. 21 days [IQR 12.8-30]; HR 0.772 (95%CI: 0.607-0.982), p = 0.035) [Figure 2]. No significant difference in adverse events incidence or severity was observed. Conclusion: In patients with COVID-19, early treatment with lopinavir-ritonavir was associated with faster time to reach the primary composite endpoint of clinical improvement and/or virological clearance than treatment with darunavir-cobicistat. Future trials are warranted to confirm these findings.qscienc