Summary
Plague caused by the Gram‐negative bacterium, Yersinia pestis, is still endemic in parts of the world today. Protection against pneumonic plague is essential to prevent the development and ...spread of epidemics. Despite this, there are currently no licensed plague vaccines in the western world. Here we describe the means of delivering biologically active plague vaccine antigens directly to mucosal sites of plague infection using highly stable microvesicles (outer membrane vesicles; OMVs) that are naturally produced by the abundant and harmless human commensal gut bacterium Bacteroides thetaiotaomicron (Bt). Bt was engineered to express major plague protective antigens in its OMVs, specifically Fraction 1 (F1) in the outer membrane and LcrV (V antigen) in the lumen, for targeted delivery to the gastrointestinal (GI) and respiratory tracts in a non‐human primate (NHP) host. Our key findings were that Bt OMVs stably expresses F1 and V plague antigens, particularly the V antigen, in the correct, immunogenic form. When delivered intranasally V‐OMVs elicited substantive and specific immune and antibody responses, both in the serum immunoglobulin (Ig)G and in the upper and lower respiratory tract (IgA); this included the generation of serum antibodies able to kill plague bacteria. Our results also showed that Bt OMV‐based vaccines had many desirable characteristics, including: biosafety and an absence of any adverse effects, pathology or gross alteration of resident microbial communities (microbiotas); high stability and thermo‐tolerance; needle‐free delivery; intrinsic adjuvanticity; the ability to stimulate both humoral and cell‐mediated immune responses; and targeting of primary sites of plague infection.
Outer membrane vesicles from the commensal bacteria Bacteroides thetaiotaomicron expressing Fraction 1 (F1) and LcrV (V antigen) from Y. pestis were tested as mucosal plague vaccine delivery vehicles. When delivered intranasally V‐OMVs elicited substantive and specific immune and neutralizing antibody responses, both in the serum (IgG) and in the upper and lower respiratory tract (IgA).
Context:
Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear.
...Objective:
To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW.
Design, Settings and Patients:
Two-hundred ninety-three subjects (placebo PLAC, n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped.
Results:
Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0–120/G0–120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC.
Conclusions:
1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.
The protective effect of pioglitazone on the incidence of diabetes attenuates after discontinuation of therapy but the cumulative diabetes incidence remained significantly lower (56%) than placebo after followup of 11.4 months.
In acute myeloid leukemia (AML), the assessment of post‐treatment minimal residual disease (MRD) may inform a more effective management approach. We investigated the prognostic utility of ...next‐generation sequencing (NGS)‐based MRD detection undertaken before hematopoietic stem cell transplantation (HSCT). Forty‐two AML subjects underwent serial disease monitoring both by standard methods, and a targeted 42‐gene NGS assay, able to detect leukemia‐specific mutant alleles (with >0.5% VAF) (mean 5.1 samples per subject). The prognostic relevance of any persisting diagnostic mutation before transplant (≤27 days) was assessed during 22.1 months (median) of post‐transplant follow‐up. The sensitivity of the NGS assay (27 MRD‐positive subjects) exceeded that of the non‐molecular methods (morphology, FISH, and flow cytometry) (11 positive subjects). Only one of the 13 subjects who relapsed after HSCT was NGS MRD‐negative (92% assay sensitivity). The cumulative incidence of post‐transplant leukemic relapse was significantly higher in the pre‐transplant NGS MRD‐positive (vs MRD‐negative) subjects (P = .014). After adjusting for TP53 mutation and transplant conditioning regimen, NGS MRD‐positivity retained independent prognostic significance for leukemic relapse (subdistribution hazard ratio = 7.3; P = .05). The pre‐transplant NGS MRD‐positive subjects also had significantly shortened progression‐free survival (P = .038), and marginally shortened overall survival (P = .068). In patients with AML undergoing HSCT, the pre‐transplant persistence of NGS‐defined MRD imparts a significant, sensitive, strong, and independent increased risk for subsequent leukemic relapse and death. Given that NGS can simultaneously detect multiple leukemia‐associated mutations, it can be used in the majority of AML patients to monitor disease burdens and inform treatment decisions.
Anytime RRTs Ferguson, D.; Stentz, A.
2006 IEEE/RSJ International Conference on Intelligent Robots and Systems,
2006-Oct.
Conference Proceeding
We present an anytime algorithm for planning paths through high-dimensional, non-uniform cost search spaces. Our approach works by generating a series of rapidly-exploring random trees (RRTs), where ...each tree reuses information from previous trees to improve its growth and the quality of its resulting path. We also present a number of modifications to the RRT algorithm that we use to bias the search in favor of less costly solutions. The resulting approach is able to produce an initial solution very quickly, then improve the quality of this solution while deliberation time allows. It is also able to guarantee that subsequent solutions will be better than all previous ones by a user-defined improvement bound. We demonstrate the effectiveness of the algorithm on both single robot and multirobot planning domains
The properties and fiber dependence of distributed Raman pre-amplifiers and, in particular, the effects of Rayleigh backscattering, which limits the sensitivity improvements that can be realized, is ...discussed. Bit-error-rate (BER) measurements show improvements In the effective receiver sensitivity of 6.2 and 7.0 dB for dispersion shifted fiber (DSF) and silica-core fiber (SCF), respectively. Theoretical predictions of the effective noise figure based on measured fiber parameters indicate improvements of 6.6 dB for DSF and 7.4 dB for SCF in good agreement with the measured optical SNR. The optimum receiver sensitivity is obtained in DSF with less than 600 mW of pump power, whereas the 0.8-dB superior performance of the SCF requires approximately 1 W.
High-grade B cell lymphoma with MYC and BCL2 rearrangements (double hit) has a poor prognosis with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We report here ...a treatment algorithm of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) followed by BEAM (carmustine, etoposide, cytarabine, melphalan) autologous transplant in 36 cases of previously untreated double hit lymphoma (DHL) from 2010 to 2015. A high risk International Prognostic Index (IPI) was present in 42% of cases. At median follow-up of 38 months, the 2-year progression free survival (PFS) and overall survival (OS) were 69% (95% CI 54-84%) and 71% (95% CI 56-86%). Eight cases were refractory to induction with 1-year OS 20%, and no factors were predictive for primary refractory disease. Of 28 responders, 17 proceeded to transplant while 11 were observed, primarily due to age and co-morbidities. By 24-week landmark analysis after diagnosis, the 2-year PFS and OS were both 94% (95% CI 83-100%) vs 79% (95% CI 52-100%) for transplant vs observation (p = .59 for both PFS and OS). There was no significant benefit to consolidative transplant in our series, and primary refractory DHL needs novel approaches.
Acute lung injury (ALI) is associated with high mortality. Low tidal volume (Vt) ventilation has been shown to reduce mortality in ALI patients in the intensive care unit. Anesthesiologists do not ...routinely provide lung-protective ventilation strategies to patients with ALI in the operating room. The authors hypothesized that an alert, recommending lung-protective ventilation regarding patients with potential ALI, would result in lower Vt administration.
The authors conducted a randomized controlled trial on anesthesia providers caring for patients with potential ALI. Patients with an average or last collected ratio of partial pressure of arterial oxygen to inspired fraction of oxygen less than 300 were randomized to providers being sent an alert with a recommended Vt of 6 cc/kg predicted body weight or conventional care. Primary outcomes were Vt/kg predicted body weight administered to patients. Secondary outcomes included ventilator parameters, length of postoperative ventilation, and death.
The primary outcome was a clinically significant reduction in mean Vt from 508-458 cc (P = 0.033), with a reduction in Vt when measured in cc/kg predicted body weight from 8 to 7.2 cc/kg predicted body weight (P = 0.040). There were no statistically significant changes in other outcomes or adverse events associated with either arm.
Automated alerts generated for patients at risk of having ALI resulted in a statistically significant reduction in Vt administered when compared with a control group. Further research is required to determine whether a reduction in Vt results in decreased mortality and/or postoperative duration of mechanical ventilation.
PDF
