Attenuated intracellular survival of Mycobacterium tuberculosis (Mtb) secretory gene mutants exemplifies their role as virulence factors. Mtb peptidyl prolyl isomerase A (PPiA) assists in protein folding through cis/trans isomerization of prolyl bonds. Here, we show that PPiA abets Mtb survival and aids in the disease progression by exploiting host-associated factors. While the deletion of PPiA has no discernable effect on the bacillary survival in a murine infection model, it compromises the formation of granuloma-like lesions and promotes host cell death through ferroptosis. Overexpression of PPiA enhances the bacillary load and exacerbates pathology in mice lungs. Importantly, PPiA interacts with the integrin α5β1 receptor through a conserved surface-exposed RGD motif. The secretion of PPiA as well as interaction with integrin contributes to the disease progression by upregulating multiple host matrix metalloproteinases. Collectively, we identified a novel non-chaperone role of PPiA that is critical in facilitating host-pathogen interaction ensuing disease progression.

Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification.

Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome wide methylation arrays for chromosomal and clinical variables predictive of survival.

Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%) and 16q loss (15.3%). The 5-year progression free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95%CI 45-55%) for balanced tumors, compared with 32% (95%CI 24-44%) for 1q gain only, 7.3% (95%CI 2.0-27%) for 6q loss only and 0 for both 1q gain and 6q loss (p=1.65×10 -13 ). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA-sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group.

We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.

We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. selleck inhibitor A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.

People living with HIV (PLWH) treated with antiretrovirals have lifespans similar to their HIV-negative peers. Yet, they experience elevated inflammation-related multi-morbidity. Drawing on biopsychosocial determinants of health may inform interventions, but these links are understudied in older PLWH. We investigated cross-sectional relationships between psychosocial factors (mood, loneliness, and stigma), inflammatory markers, and age-related health outcomes among 143 PLWH ages 54 to 78 years.

Participants provided blood samples for serum cytokines and C-reactive protein (CRP), completed surveys assessing psychosocial factors and health, and completed frailty assessments. Regression models tested relationships between key psychosocial, inflammation, and age-related health variables, adjusting for relevant sociodemographic and clinical factors.

Participants with more depressive symptoms had higher composite cytokine levels than those with fewer depressive symptoms (ß=0.22, t(126)=2.71, p=0.008). Those wght several factors (e.g., depressive symptoms, poorer physical function) that may share bidirectional relationships with chronic inflammation, a key factor driving morbidity. These links may be leveraged to modify factors that drive excessive health risk among older PLWH.

In order to expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes.

Data from three clinical trials were combined in this study, where Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during and up to six months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at six months.

The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within six months of follow-up at a cut-off of 20 parasites/mL (AUC 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ= 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a >80% power to detect a difference in cure rate between treatment regimens if this difference was high (>50%) and when minimally 30 patients were included per regimen.

Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.

Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.

Implementation of the Accelerate Pheno TM Gram-negative platform (RDT) paired with antimicrobial stewardship program (ASP) intervention projects to improve time to institutional-preferred antimicrobial therapy (IPT) for Gram-negative bacilli (GNB) bloodstream infections (BSI). However, few data describe the impact of discrepant RDT results from standard of care (SOC) methods on antimicrobial prescribing.

A single-center, pre-/post-intervention study of consecutive, non-duplicate blood cultures for adult inpatients with GNB BSI following combined RDT + ASP intervention was performed. The primary outcome was time to IPT. An a priori definition of IPT was utilized to limit bias and allow for an assessment of the impact of discrepant RDT results with the SOC reference standard.

Five hundred fourteen patients (PRE 264; POST 250) were included. Median time to antimicrobial susceptibility testing (AST) results decreased 29.4 hours (p < 0.001) post-intervention, and median time to IPT was reduced by 21.2 hours (p <0.