Stratifying patients at the risk of heart failure hospitalization using existing device diagnostic thresholds

AbstractBackgroundHeart failure hospitalizations (HFHs) cost the US health care system ∼$20 billion annually. Identifying patients at risk of HFH to enable timely intervention and prevent expensive hospitalization remains a challenge. Implantable cardioverter defibrillators (ICDs) and cardiac resynchronization devices with defibrillation capability (CRT-Ds) collect a host of diagnostic parameters that change with HF status and collectively have the potential to signal an increasing risk of HFH. These device-collected diagnostic parameters include activity, day and night heart rate, atrial tachycardia/atrial fibrillation (AT/AF) burden, mean rate during AT/AF, percent CRT pacing, number of shocks, and intrathoracic impedance. There are thresholds for these parameters that when crossed trigger a notification, referred to as device observation, which gets noted on the device report. We investigated if these existing device observations can stratify patients at varying risk of HFH.MethodsWe analyzed data from 775 patients (age: 69 ± 11 year, 68% male) with CRT-D devices followed for 13 ± 5 months with adjudicated HFHs. HFH rate was computed for increasing number of device observations. Data were analyzed by both excluding and including intrathoracic impedance. HFH risk was assessed at the time of a device interrogation session, and all the data between previous and current follow-up sessions were used to determine the HFH risk for the next 30 days.Results2276 follow-up sessions in 775 patients were evaluated with 42 HFHs in 37 patients. Percentage of evaluations that were followed by an HFH within the next 30 days increased with increasing number of device observations. Patients with 3 or more device observations were at 42× HFH risk compared to patients with no device observation. Even after excluding intrathoracic impedance, the remaining device parameters effectively stratified patients at HFH risk.ConclusionAvailable device observations could provide an effective method to stratify patients at varying risk of heart failure hospitalization

Genosenor Technology Development

Contains table of contents for Part IV, table of contents for Section 1, and reports on two research projects.Genometrix, Inc. Contract GMX-GH00776-04Defense Advanced Research Projects AgencyU.S. Air Force - Office of Scientific Researc

Workshop report on the evaluation of the updated and expanded carcinogen database to support derivation of threshold of toxicological concern values for DNA reactive carcinogens

Threshold of toxicological concern (TTC) values are frequently used for compounds occurring at low concentrations in feed and food or as impurities in drugs. This workshop report addresses the emerging alternatives for deriving TTC values for DNA reactive carcinogens and evaluating the acceptability of the Cramer Class TTC values to be adequately protective for non-DNA reactive carcinogens

Gigahertz (GHz) hard x-ray imaging using fast scintillators

Gigahertz (GHz) imaging technology will be needed at high-luminosity X-ray and charged particle sources. It is plausible to combine fast scintillators with the latest picosecond detectors and GHz electronics for multi-frame hard Xray imaging and achieve an inter-frame time of less than 10 ns. The time responses and light yield of LYSO, LaBr_3, BaF_2 and ZnO are measured using an MCP-PMT detector. Zinc Oxide (ZnO) is an attractive material for fast hard X-ray imaging based on GEANT4 simulations and previous studies, but the measured light yield from the samples is much lower than expected

Lower Rates of Heart Failure and All-Cause Hospitalizations During Pulmonary Artery Pressure-Guided Therapy for Ambulatory Heart Failure: One-Year Outcomes From the CardioMEMS Post-Approval Study.

BACKGROUND: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. METHODS: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. RESULTS: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39-0.47], CONCLUSIONS: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02279888

Secreted Bacterial Effectors and Host-Produced Eiger/TNF Drive Death in a Salmonella-Infected Fruit Fly

Death by infection is often as much due to the host's reaction as it is to the direct result of microbial action. Here we identify genes in both the host and microbe that are involved in the pathogenesis of infection and disease in Drosophila melanogaster challenged with Salmonella enterica serovartyphimurium (S. typhimurium). We demonstrate that wild-type S. typhimurium causes a lethal systemic infection when injected into the hemocoel of D. melanogaster. Deletion of the gene encoding the secreted bacterial effector Salmonella leucine-rich (PslrP) changes an acute and lethal infection to one that is persistent and less deadly. We propose a model in which Salmonella secreted effectors stimulate the fly and thus cause an immune response that is damaging both to the bacteria and, subsequently, to the host. In support of this model, we show that mutations in the fly gene eiger, a TNF homolog, delay the lethality of Salmonella infection. These results suggest that S. typhimurium-infected flies die from a condition that resembles TNF-induced metabolic collapse in vertebrates. This idea provides us with a new model to study shock-like biology in a genetically manipulable host. In addition, it allows us to study the difference in pathways followed by a microbe when producing an acute or persistent infection

Sensing and Adaptation to Low pH Mediated by Inducible Amino Acid Decarboxylases in Salmonella

During the course of infection, Salmonella enterica serovar Typhimurium must successively survive the harsh acid stress of the stomach and multiply into a mild acidic compartment within macrophages. Inducible amino acid decarboxylases are known to promote adaptation to acidic environments. Three low pH inducible amino acid decarboxylases were annotated in the genome of S. Typhimurium, AdiA, CadA and SpeF, which are specific for arginine, lysine and ornithine, respectively. In this study, we characterized and compared the contributions of those enzymes in response to acidic challenges. Individual mutants as well as a strain deleted for the three genes were tested for their ability (i) to survive an extreme acid shock, (ii) to grow at mild acidic pH and (iii) to infect the mouse animal model. We showed that the lysine decarboxylase CadA had the broadest range of activity since it both had the capacity to promote survival at pH 2.3 and growth at pH 4.5. The arginine decarboxylase AdiA was the most performant in protecting S. Typhimurium from a shock at pH 2.3 and the ornithine decarboxylase SpeF conferred the best growth advantage under anaerobiosis conditions at pH 4.5. We developed a GFP-based gene reporter to monitor the pH of the environment as perceived by S. Typhimurium. Results showed that activities of the lysine and ornithine decarboxylases at mild acidic pH did modify the local surrounding of S. Typhimurium both in culture medium and in macrophages. Finally, we tested the contribution of decarboxylases to virulence and found that these enzymes were dispensable for S. Typhimurium virulence during systemic infection. In the light of this result, we examined the genomes of Salmonella spp. normally responsible of systemic infection and observed that the genes encoding these enzymes were not well conserved, supporting the idea that these enzymes may be not required during systemic infection

Gigahertz (GHz) hard x-ray imaging using fast scintillators

Gigahertz (GHz) imaging technology will be needed at high-luminosity X-ray and charged particle sources. It is plausible to combine fast scintillators with the latest picosecond detectors and GHz electronics for multi-frame hard Xray imaging and achieve an inter-frame time of less than 10 ns. The time responses and light yield of LYSO, LaBr_3, BaF_2 and ZnO are measured using an MCP-PMT detector. Zinc Oxide (ZnO) is an attractive material for fast hard X-ray imaging based on GEANT4 simulations and previous studies, but the measured light yield from the samples is much lower than expected