A Pragmatic Pilot Trial Comparing Patient-Triggered Adaptive Pressure Control to Patient-Triggered Volume Control Ventilation in Critically Ill Adults.

BACKGROUND: Patient-triggered adaptive pressure control (APC) continuous mandatory ventilation (CMV) (APC-CMV) has been widely adopted as an alternative ventilator mode to patient-triggered volume control (VC) CMV (VC-CMV). However, the comparative effectiveness of the 2 ventilator modes remains uncertain. We sought to explore clinical and implementation factors pertinent to a future definitive randomized controlled trial assessing APC-CMV versus VC-CMV as an initial ventilator mode strategy. The research objectives in our pilot trial tested clinician adherence and explored clinical outcomes. METHODS: In a single-center pragmatic sequential cluster crossover pilot trial, we enrolled all eligible adults with acute respiratory failure requiring mechanical ventilation admitted during a 9-week period to the medical ICU. Two-week time epochs were assigned a priori in which subjects received either APC-CMV or VC-CMV The primary outcome of the trial was feasibility, defined as 80% of subjects receiving the assigned mode within 1 h of initiation of ICU ventilation. The secondary outcome was proportion of the first 24 h on the assigned mode. Finally, we surveyed clinician stakeholders to understand potential facilitators and barriers to conducting a definitive randomized trial. RESULTS: We enrolled 137 subjects who received 152 discreet episodes of mechanical ventilation during time epochs assigned to APC-CMV (n = 61) and VC-CMV (n = 91). One hundred and thirty-one episodes were included in the prespecified primary outcome. One hundred and twenty-six (96%) received the assigned mode within the first hour of ICU admission (60 of 61 subjects assigned APC-CMV and 66 of 70 assigned VC-CMV). VC-CMV subjects spent a lower proportion of first 24 h (84% [95% CI 78-89]) on the assigned mode than APC-CMV recipients (95% [95% CI 91-100]). Mixed-methods analyses identified preconceived perceptions of subject comfort by clinicians and need for real-time education to address this concern. CONCLUSIONS: In this pilot pragmatic, sequential crossover trial, unit-wide allocation to a ventilator mode was feasible and acceptable to clinicians.

Mechanism of endogenous regulation of the type I interferon response by suppressor of IκB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1).

TANK-binding kinase 1 (TBK1) serves as a key convergence point in multiple innate immune signaling pathways. In response to receptor-mediated pathogen detection, TBK1 phosphorylation promotes production of pro-inflammatory cytokines and type I interferons. Increasingly, TBK1 dysregulation has been linked to autoimmune disorders and cancers, heightening the need to understand the regulatory controls of TBK1 activity. Here, we describe the mechanism by which suppressor of IKKε (SIKE) inhibits TBK1-mediated phosphorylation of interferon regulatory factor 3 (IRF3), which is essential to type I interferon production. Kinetic analyses showed that SIKE not only inhibits IRF3 phosphorylation but is also a high affinity TBK1 substrate. With respect to IRF3 phosphorylation, SIKE functioned as a mixed-type inhibitor (K(i, app) = 350 nM) rather than, given its status as a TBK1 substrate, as a competitive inhibitor. TBK1 phosphorylation of IRF3 and SIKE displayed negative cooperativity. Both substrates shared a similar Km value at low substrate concentrations (∼50 nM) but deviated >8-fold at higher substrate concentrations (IRF3 = 3.5 µM; SIKE = 0.4 µM). TBK1-SIKE interactions were modulated by SIKE phosphorylation, clustered in the C-terminal portion of SIKE (Ser-133, -185, -187, -188, -190, and -198). These sites exhibited striking homology to the phosphorylation motif of IRF3. Mutagenic probing revealed that phosphorylation of Ser-185 controlled TBK1-SIKE interactions. Taken together, our studies demonstrate for the first time that SIKE functions as a TBK1 substrate and inhibits TBK1-mediated IRF3 phosphorylation by forming a high affinity TBK1-SIKE complex. These findings provide key insights into the endogenous control of a critical catalytic hub that is achieved not by direct repression of activity but by redirection of catalysis through substrate affinity.

Identification of an antiparallel coiled-coil/loop domain required for ligand binding by the Borrelia hermsii FhbA protein: additional evidence for the role of FhbA in the host-pathogen interaction.

Borrelia hermsii, an etiological agent of tick-borne relapsing fever in North America, binds host-derived serum proteins including factor H (FH), plasminogen, and an unidentified 60-kDa protein via its FhbA protein. Two distinct phylogenetic types of FhbA have been delineated (FhbA1 and FhbA2). These orthologs share a conserved C-terminal domain that contains two alpha helices with a high predictive probability of coiled-coil formation that are separated by a 14-amino-acid loop domain. Through site-directed mutagenesis, we have identified residues within these domains that influence the binding of both mouse and human FH, plasminogen, and/or the 60-kDa protein. To further investigate the involvement of FhbA in the host-pathogen interaction, strains that are either FhbA(+) (isolate YOR) or FhbA(-) (isolate REN) were tested for serum sensitivity. Significant differences were observed, with YOR and REN being serum resistant and serum sensitive (intermediate), respectively. To test the abilities of these strains to infect and persist in mice, mice were needle inoculated, and infectivity and persistence were then assessed. While both strains REN and YOR infected mice, only the FhbA(+) YOR strain persisted beyond day 4. Survival of the YOR isolate in blood correlated with the upregulation of the fhbA gene, as demonstrated by real-time reverse transcriptase PCR. These data advance our understanding of the unique interactions of FhbA with individual serum proteins and provide support for the hypothesis that FhbA is an important contributor to the pathogenesis of the relapsing fever spirochete B. hermsii.