Citations

Primary care patients frequently present with anxiety with prevalence ratios up to 30%. Brief cognitive–behavioural therapy (CBT) has been shown in meta-analytic studies to have a strong effect size in the treatment of anxiety. However, in surveys of anxious primary care patients, nearly 80% indicated that they had not received CBT. In 2010, a model of CBT (Coordinated Anxiety Learning and Management (CALM)) adapted to primary care for adult anxiety was published based on results of a randomised controlled trial. This project aimed to integrate an adaptation of CALM into one primary care practice, using results from the published research as a benchmark with the secondary intent to spread a successful model to other practices. A quality improvement approach was used to translate the CALM model of CBT for anxiety into one primary care clinic. Plan-Do-Study-Act steps are highlighted as important steps towards our goal of comparing our outcomes with benchmarks from original research. Patients with anxiety as measured by a score of 10 or higher on the Generalized Anxiety Disorder 7 item scale (GAD-7) were offered CBT as delivered by licensed social workers with support by a PhD psychologist. Outcomes were tracked and entered into an electronic registry, which became a critical tool upon which to adapt and improve our delivery of psychotherapy to our patient population. Challenges and adaptations to the model are discussed. Our 6-month response rates on the GAD-7 were 51%, which was comparable with that of the original research (57%). Quality improvement methods were critical in discovering which adaptations were needed before spread. Among these, embedding a process of measurement and data entry and ongoing feedback to patients and therapists using this data are critical step towards sustaining and improving the delivery of CBT in primary care.

ABSTRACT We describe results from a multicenter study evaluating the Accelerate Pheno system, a first of its kind diagnostic system that rapidly identifies common bloodstream pathogens from positive blood cultures within 90 min and determines bacterial phenotypic antimicrobial susceptibility testing (AST) results within ∼7 h. A combination of fresh clinical and seeded blood cultures were tested, and results from the Accelerate Pheno system were compared to Vitek 2 results for identification (ID) and broth microdilution or disk diffusion for AST. The Accelerate Pheno system accurately identified 14 common bacterial pathogens and two Candida spp. with sensitivities ranging from 94.6 to 100%. Of fresh positive blood cultures, 89% received a monomicrobial call with a positive predictive value of 97.3%. Six common Gram-positive cocci were evaluated for ID. Five were tested against eight antibiotics, two resistance phenotypes (methicillin-resistant Staphylococcus aureus and Staphylococcus spp. [MRSA/MRS]), and inducible clindamycin resistance (MLSb). From the 4,142 AST results, the overall essential agreement (EA) and categorical agreement (CA) were 97.6% and 97.9%, respectively. Overall very major error (VME), major error (ME), and minor error (mE) rates were 1.0%, 0.7%, and 1.3%, respectively. Eight species of Gram-negative rods were evaluated against 15 antibiotics. From the 6,331 AST results, overall EA and CA were 95.4% and 94.3%, respectively. Overall VME, ME, and mE rates were 0.5%, 0.9%, and 4.8%, respectively. The Accelerate Pheno system has the unique ability to identify and provide phenotypic MIC and categorical AST results in a few hours directly from positive blood culture bottles and support accurate antimicrobial adjustment.

Summary A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP ‐1/ CCL 2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 ( MCP ‐1) levels increased in an age‐dependent manner in wild‐type ( WT ) mice. That age‐dependent increase was accelerated in Ercc1 −/Δ and Bubr1 H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1 −/Δ and WT mice lowered serum MCP ‐1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP ‐1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP ‐1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.

Fredberg, J. J., K. A. Jones, M. Nathan, S. Raboudi, Y. S. Prakash, S. A. Shore, J. P. Butler, and G. C. Sieck. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J. Appl. Physiol. 81(6): 2703–2712, 1996.—In muscle, active force and stiffness reflect numbers of actin-myosin interactions and shortening velocity reflects their turnover rates, but the molecular basis of mechanical friction is somewhat less clear. To better characterize molecular mechanisms that govern mechanical friction, we measured the rate of mechanical energy dissipation and the rate of actomyosin ATP utilization simultaneously in activated canine airway smooth muscle subjected to small periodic stretches as occur in breathing. The amplitude of the frictional stress is proportional to ηE, where E is the tissue stiffness defined by the slope of the resulting force vs. displacement loop and η is the hysteresivity defined by the fatness of that loop. From contractile stimulus onset, the time course of frictional stress amplitude followed a biphasic pattern that tracked that of the rate of actomyosin ATP consumption. The time course of hysteresivity, however, followed a different biphasic pattern that tracked that of shortening velocity. Taken together with an analysis of mechanical energy storage and dissipation in the cross-bridge cycle, these results indicate, first, that like shortening velocity and the rate of actomyosin ATP utilization, mechanical friction in airway smooth muscle is also governed by the rate of cross-bridge cycling; second, that changes in cycling rate associated with conversion of rapidly cycling cross bridges to slowly cycling latch bridges can be assessed from changes of hysteresivity of the force vs. displacement loop; and third, that steady-state force maintenance (latch) is a low-friction contractile state. This last finding may account for the unique inability of asthmatic patients to reverse spontaneous airways obstruction with a deep inspiration.

Abstract TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

Abstract Summary Gap-filling is a necessary step to produce quality genome-scale metabolic reconstructions capable of flux-balance simulation. Most available gap-filling tools use an organism-agnostic approach, where reactions are selected from a database to fill gaps without consideration of the target organism. Conversely, our likelihood based gap-filling with probabilistic annotations selects candidate reactions based on a likelihood score derived specifically from the target organism’s genome. Here, we present two new implementations of probabilistic annotation and likelihood based gap-filling: a web service called ProbAnnoWeb, and a standalone python package called ProbAnnoPy. Availability and implementation Our tools are available as a web service with no installation needed (ProbAnnoWeb) at probannoweb.systemsbiology.net, and as a local python package implementation (ProbAnnoPy) at github.com/PriceLab/probannopy. Supplementary information Supplementary data are available at Bioinformatics online.

Purpose: Data regarding best practices for ventilator management strategies that improve outcomes in acute respiratory distress syndrome (ARDS) are readily available. However, little is known regarding processes to ensure compliance with these strategies. We developed a goal-directed mechanical ventilation order set that included physician-specified lung-protective ventilation and oxygenation goals to be implemented by respiratory therapists (RTs). We sought as a primary outcome to determine whether an RT-driven order set with predefined oxygenation and ventilation goals could be implemented and associated with improved adherence with best practice. Methods: We evaluated 1302 patients undergoing invasive mechanical ventilation (1693 separate episodes of invasive mechanical ventilation) prior to and after institution of a standardized, goal-directed mechanical ventilation order set using a controlled before-and-after study design. Patient-specific goals for oxygenation partial pressure of oxygen in arterial blood (Pao 2 ), ARDS Network [Net] positive end-expiratory pressure [PEEP]/fraction of inspired oxygen [Fio 2 ] table use) and ventilation (pH, partial pressure of carbon dioxide) were selected by prescribers and implemented by RTs. Results: Compliance with the new mechanical ventilation order set was high: 88.2% compliance versus 3.8% before implementation of the order set ( P < .001). Adherence to the PEEP/Fio 2 table after implementation of the order set was significantly greater (86.0% after vs 82.9% before, P = .02). There was no difference in duration of mechanical ventilation, intensive care unit (ICU) length of stay, and in-hospital or ICU mortality. Conclusions: A standardized best practice mechanical ventilation order set can be implemented by a multidisciplinary team and is associated with improved compliance to written orders and adherence to the ARDSNet PEEP/Fio 2 table.

AbstractBackgroundThe implications of early readmission on long‐term mortality after transient ischemic attack (TIA) are not known. We aimed at examining the effect of 180‐day readmission on subsequent long‐term mortality after index hospitalization for TIA.MethodsA retrospective study of patients hospitalized for first‐ever TIA at Mayo Clinic from 2000 through 2017. Patients readmitted within 180 days postdischarge were compared with those not readmitted in long‐term risk of death.ResultsOf 251 TIA patients aged 73 ± 15 years with 1509 person‐years of follow‐up, 65 (26%) were readmitted within 180 days of discharge and 125 died during a median follow‐up of 5.7 years. The mortality was 10 vs. 7 deaths per 100 person‐years in patients who were readmitted compared to those who were not readmitted with hazard ratio (HR) 1.73 (95% confidence interval [CI] 1.13–2.66). Other competing predictors of mortality were age ≥65 years (HR 5.70, 95% CI 2.72–11.96), cancer (HR 1.65, 95% CI 1.03–3.38), chronic obstructive pulmonary disease (HR 1.90, 95% CI 1.07–3.38), heart failure (HR 3.03, 95% CI 1.82–5.06), dementia (HR 5.87, 95% CI 3.27–10.52), creatinine ≥1.4 mg/dl (HR 1.89, 95% CI 1.17–3.06), and hemoglobin level <10 g/dl (HR 2.80, 95% CI 1.20–6.66).ConclusionsHospital readmission within 180 days of discharge from index TIA was associated with increased risk of death several years after initial readmission. Older age and several comorbidities identified during index hospitalization also confer increased risk for long‐term mortality.