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

Threshold of Toxicological Concern - an update for non-genotoxic carcinogens

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with known chemical structure to derive a threshold for exposure below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumour incidence were compared with no observed effect levels (NOEL) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the CPDB as either non- or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a data set of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well known repositories including RepDose, ToxRef and COSMOS DB. Further, an effective tumour dose (ETD10) was calculated and compared to the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in region of the 5th percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher, but comparable 5th percentile chronic NOEL and BMDL10 values, while the 5th percentile EDT10 value was slightly higher, but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non genotoxic compounds, including non_genotoxic carcinogens

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

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

The Impact of HIV Infection and CD4 Cell Count on the Performance of an Interferon Gamma Release Assay in Patients with Pulmonary Tuberculosis

BACKGROUND:The performance of the tuberculosis specific Interferon Gamma Release Assays (IGRAs) has not been sufficiently documented in tuberculosis- and HIV-endemic settings. This study evaluated the sensitivity of the QuantiFERON TB-Gold In-Tube (QFT-IT) in patients with culture confirmed pulmonary tuberculosis (PTB) in a TB- and HIV-endemic population and the effect of HIV-infection and CD4 cell count on test performance. METHODOLOGY/PRINCIPAL FINDINGS:161 patients with sputum culture confirmed PTB were subjected to HIV- and QFT-IT testing and measurement of CD4 cell count. The QFT-IT was positive in 74% (119/161; 95% CI: 67-81%). Sensitivity was higher in HIV-negative (75/93) than in HIV-positive (44/68) patients (81% vs. 65%, p = 0.02) and increased with CD4 cell count in HIV-positive patients (test for trend p = 0.03). 23 patients (14%) had an indeterminate result and this proportion decreased with increasing CD4 cell count in HIV-positive patients (test for trend p = 0.03). Low CD4 cell count (<300 cells/microl) did not account for all QFT-IT indeterminate nor all negative results. Sensitivity when excluding indeterminate results was 86% (95% CI: 81-92%) and did not differ between HIV-negative and HIV-positive patients (88 vs. 83%, p = 0.39). CONCLUSIONS/SIGNIFICANCE:Sensitivity of the QFT-IT for diagnosing active PTB infection was reasonable when excluding indeterminate results and in HIV-negative patients. However, since the test missed more than 10% of patients, its potential as a rule-out test for active TB disease is limited. Furthermore, test performance is impaired by low CD4 cell count in HIV-positive patients and possibly by other factors as well in both HIV-positive and HIV-negative patients. This might limit the potential of the test in populations where HIV-infection is prevalent

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

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

Tuberculosis associated with Mycobacterium tuberculosis Beijing and non-Beijing genotypes: a clinical and immunological comparison

BACKGROUND: The Mycobacterium tuberculosis Beijing genotype is biologically different from other genotypes. We aimed to clinically and immunologically compare human tuberculosis caused by Beijing and non-Beijing strains. METHODS: Pulmonary tuberculosis patients were prospectively enrolled and grouped by their M. tuberculosis genotypes. The clinical features, plasma cytokine levels, and cytokine gene expression levels in peripheral blood mononuclear cells (PBMC) were compared between the patients in Beijing and non-Beijing groups. RESULTS: Patients in the Beijing group were characterized by significantly lower frequency of fever (odds ratio, 0.12, p = 0.008) and pulmonary cavitation (odds ratio, 0.2, p = 0.049). Night sweats were also significantly less frequent by univariate analysis, and the duration of cough prior to diagnosis was longer in Beijing compared to non-Beijing groups (medians, 60 versus 30 days, p = 0.048). The plasma and gene expression levels of interferon (IFN) γ and interleukin (IL)-18 were similar in the two groups. However, patients in the non-Beijing group had significantly increased IL-4 gene expression (p = 0.018) and lower IFN-γ : IL-4 cDNA copy number ratios (p = 0.01). CONCLUSION: Patients with tuberculosis caused by Beijing strains appear to be less symptomatic than those who have disease caused by other strains. Th1 immune responses are similar in patients infected with Beijing and non-Beijing strains, but non-Beijing strains activate more Th2 immune responses compared with Beijing strains, as evidenced by increased IL-4 expression