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Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV‐1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV‐1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure–response (E–R) from five studies in treatment‐experienced and integrase‐resistant (INI‐r) patients infected with HIV‐1. Importantly, model‐based simulations of the E–R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub‐population with Q148‐driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation‐containing products) factors expected to influence the DTG E–R relationship. Model‐based post hoc exposure metrics (Cmin and Cavg) were incorporated into a mechanistic population viral dynamic model describing the short‐term effect of DTG on log10 HIV‐1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24‐week HIV RNA response was also assessed using logistic regression. There was good concordance between model‐based predictions and observed virologic response on day 10 and week 24. The E–R model‐based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor‐resistant (INI‐r) population. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G (IgG) subclass deficiencies and isolated lgA, IgM, IgE deficiencies have all been described in the literature with variable prevalence. Methods: These isotype deficiencies have a variable presentation front asymptomatic to recurrent infections resistant to prophylactic antibiotics. Results: Atopic disorders and autoimmime diseases are common coniorbidities. lgE deficiency has been associated with impaired vaccille response and an increased risk of nialignancy, particillarly in patients with no allergic comorbidities and those with non-common variable immunodeficiency (CVID) liumoral immunodeficiency, ISM deficiency, IgGZ deficiency, aild CL)4 li/iiip//openia. Conclusion: Close monitoring for malignancy sliould be strongly considered for the patients who are nt risk. Treatment is variable and may include alitimicrobial therapies for illnesses and prophylactic antibiotics iii select patients, and immunoglobulin replacement can be considered for patients with refractory, recurrent infections. [ABSTRACT FROM AUTHOR]

BackgroundThe receptor activator of NF-κB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD.MethodsSprague-Dawley, 12-week-old, male rats were used in this study. Anulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous endplate (CEP) cells isolated from dissected thoracolumbar discs were monolayer-cultured. RANK/RANKL/OPG expression in rat IVDs was examined using real-time polymerase chain reaction (PCR) and immunohistochemical analysis (cultured cells and IVD tissues). To examine the effect of interleukin-1β (IL-1β) stimulation on the mRNA levels of RANK, RANKL and OPG, the cells were cultured with or without recombinant human IL-1β (rhIL-1β). To evaluate the effect of RANKL on the mRNA expression of catabolic factors (IL-1β, matrix metalloproteinase-3 (MMP-3) and MMP-13), the cells were cultured with RANKL in the presence or absence of rhIL-1β. The immunohistochemical expression of this system was also evaluated using human IVD tissues with different grades of degeneration.ResultsmRNA expression levels of RANK, RANKL, and OPG were clearly identified in AF, NP and CEP cells. Immunoreactivity to RANK, RANKL and OPG was distributed in the cell membranes and/or cytoplasm of the three types of cells. The mRNA level of RANKL was significantly upregulated by treatment with rhIL-1β of the three types of cells. Treatment with RANKL without rhIL-1β did not induce significant effects on the mRNA expression of catabolic factors by AF, NP and CEP cells. However, the expression was significantly upregulated by stimulation with RANKL in the presence of rhIL-1β. There was a general trend for more RANK/RANKL/OPG-positive cells in human IVD tissues in an advanced stage of degeneration compared to an early stage.ConclusionsOur study showed the possibility that the RANK/RANKL/OPG system may play a part in the process of intervertebral disc degeneration.

Background: Inner-city asthma is associated with high morbidity and systemic steroid use. Chronic steroid use impacts immune function; however, there is a lack of data with regard to the extent of immunosuppression in patients with asthma and who are receiving frequent systemic steroids. Objective: To ident* the impact Off-equent systemic steroid bursts on the immune function of children with asthina who live in the inner city. Methods: Children ages 3-18 years with asthma were divided into study (22 systemic steroid bursts/year) find control groups (0-1 systemic steroid bursts/year). Lymphocyte subsets; mitogen prol*ration assay; total immunoglobulin G (IgG) value, and pneumococcal and diplitheria/tetanus IgG values were evaluated. Results: Ninety-one participants were enrolled (study group [n = 42] and control group Ill = 49 ]). There was no difference in adequate pneumococcal IgG value, diphtheria/tetanus IgG value, mitogen proliferation assays, lymphocyte subsets, and IgG values between the two groups. Children who received 22 steroid bursts/year had a signficantly lower median pneumococcal IgG serotype 7F value. Most of the immune laboratory results were normal except for the pneumococcal lgG vallie. Most of the participants (n/N = 72/91 [79°/o]) had an inadequate pneuinococcal IgG level (<7/14 serotypes 21.3 lig/mL). The participants with inadequate pneumococcal IgG level and who received a pneumococcal polysaccharide vaccine 23 (PPSV23) boost had a robust response. There was no significant difference in infection, steroid exposure, asthma severity, or morbidities between those with adequate versus inadequate pneumococcal IgG values. Conclusion: Children with asthma who live in the inner city and receive 22 steroid bursts/year do not have a significantly difFerent immune projile from those who receive 51 steroid bursts/year do not have a significantly different immune profile from those who do not. Although appropriately vaccinated, most participants had an inadequate pneumococcal IgG level, regardless of steroid exposure and asthma severity. These children may benefit from PPSV23. [ABSTRACT FROM AUTHOR]

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses.