CD8
T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8
T cell ...dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (T
) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8
T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8
T cells in the liver without substantially altering T
or NK cell counts. These expanded CD8
T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen-positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8
T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8
T cells without affecting NK or T
cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.
Understanding health disparities Stevenson, David K; Wong, Ronald J; Aghaeepour, Nima ...
Journal of perinatology,
03/2019, Letnik:
39, Številka:
3
Journal Article
Recenzirano
Based upon our recent insights into the determinants of preterm birth, which is the leading cause of death in children under five years of age worldwide, we describe potential analytic frameworks ...that provides both a common understanding and, ultimately the basis for effective, ameliorative action. Our research on preterm birth serves as an example that the framing of any human health condition is a result of complex interactions between the genome and the exposome. New discoveries of the basic biology of pregnancy, such as the complex immunological and signaling processes that dictate the health and length of gestation, have revealed a complexity in the interactions (current and ancestral) between genetic and environmental forces. Understanding of these relationships may help reduce disparities in preterm birth and guide productive research endeavors and ultimately, effective clinical and public health interventions.
Highlights ► We see immune interference with same-day administration of two similar inactivated vaccines. ► ACIP dogma regarding same-day administration of inactivated vaccines is disproven. ► Gender ...differences were seen in vaccine response rates. ► Immunological mechanisms of induction of inactivated viral vaccine protection need further study.
The evolution of steep waves in the open ocean is nonlinear. In narrow-banded but directionally spread seas, this nonlinearity does not produce significant extra elevation but does lead to a large ...change in the shape of the wave group, causing, relative to linear evolution, contraction in the mean wave direction and lateral expansion. We use the nonlinear Schrödinger equation (NLSE) to derive an approximate analytical relationship for these changes in group shape. This shows excellent agreement with the numerical results both for the NLSE and for the full water wave equations. We also consider the application of scaling laws from the NLSE in terms of wave steepness and bandwidth to solutions of the full water wave equations. We investigate these numerically. While some aspects of water wave evolution do not scale, the major changes that a wave group undergoes as it evolves scale very well.
Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo- ...controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval CI, 82%–99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%–94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.
Results of a clinical study using intravenous (IV) ribavirin for treating Department of Defense personnel with hemorrhagic fever with renal syndrome (HFRS) acquired in Korea from 1987 to 2005 were ...reviewed to determine the clinical course of HFRS treated with IV ribavirin. A total of 38 individuals enrolled in the study had subsequent serological confirmation of HFRS. Four of the 38 individuals received three or fewer doses of ribavirin and were excluded from treatment analysis. Of the remaining 34 individuals, oliguria was present in one individual at treatment initiation; none of the remaining 33 subjects developed oliguria or required dialysis. The mean peak serum creatinine was 3.46
mg/dl and occurred on day 2 of ribavirin therapy. Both the peak serum creatinine and the onset of polyuria occurred on mean day 6.8 of illness. Reversible hemolytic anemia was the main adverse event of ribavirin, with a ≥25% decrease in hematocrit observed in 26/34 (76.5%) individuals. While inability to adjust for all baseline variables prevents comparison to historical cohorts in Korea where oliguria has been reported in 39–69% cases and dialysis required in approximately 40% HFRS cases caused by Hantaan virus, the occurrence of 3% oliguria and 0% dialysis requirement in the treatment cohort is supportive of a previous placebo-controlled HFRS trial in China where IV ribavirin given early resulted in decreased occurrence of oliguria and decreased severity of renal insufficiency.
This article provides an overview of service development processes used to design a therapeutic approach that promotes desistance amongst men who have committed acts of Intimate Partner Violence ...(IPV) against their male partner or ex-partner. The article aims to explore how inclusive therapeutic service provision can be developed using the best available evidence, stakeholder consultation, co-production and technology. It does so by presenting a two-part study that draws upon a review of inclusive IPV theory alongside responses to a consultation designed to canvas stakeholder opinions (n = 14) of a proposed IPV service. It also provides a case study (n = 1) of the co-production of digital media with someone from the target group for that service. Implications for future service design for marginalised groups in the Criminal Justice System and provisions for people who have committed IPV are discussed. This article represents the views of the authors’ and not those of Her Majesty’s Prison and Probation Service (HMPPS).
Abstract We compared the effect of order of administration of investigational alphavirus vaccines on neutralizing antibody response. Volunteers who received the inactivated eastern and western equine ...encephalitis (EEE and WEE) vaccines before live attenuated Venezuelan (VEE) vaccine had significantly lower rates of antibody response than those receiving VEE vaccine before EEE and WEE vaccines (66.7% vs. 80.6%; p = 0.026). The odds of having a VEE antibody non-response among those initially receiving EEE and WEE vaccines, adjusted for gender, were significant (odds ratio OR = 2.20; 95% CI = 1.2–4.1 p = 0.0145) as were the odds of non-response among females adjusted for group (OR = 1.81; 95% CI = 1.2–2.7 p = 0.0037). Antibody interference and gender effect have major implications for vaccine strategy among those receiving multiple alphavirus vaccines and those developing next generation vaccines for these threats.
Bacillus anthracis is the major terrorist and biological warfare agent of concern to civilian and military medical planners. The licensed anthrax vaccine, adsorbed (AVA) is believed to be an ...effective prophylactic medical countermeasure against this threat. Our objective in this report was to expand the safety database for this vaccine by assessing data on self-reported, short-term safety of AVA during more than 25 years of use, measured by local and systemic adverse events temporally associated with the administration of AVA. A minority of AVA recipients reported systemic and injection site reactions. Females reported a higher incidence of injection site and systemic adverse events than males. Data show a difference in incidence of local reactions between lots. A prospective, randomized, placebo-controlled study to actively examine reactogenicity is needed to more completely define the extent and nature of reactions associated with receipt of AVA in humans as well as to confirm the gender lot differences in local reaction rates.
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