Gap in the prognostic impact of short physical performance battery among phenotypes of heart failure.

BACKGROUND: The Short Physical Performance Battery (SPPB) has been reported to predict clinical outcomes in patients with heart failure (HF). However, whether the discriminative capacity of SPPB score for adverse outcomes varies according to the phenotypes of HF, such as HF with reduced, mid-range, and preserved left-ventricular ejection fraction (HFrEF, HFmrEF, and HFpEF) remains unclear. The aim of this study was to investigate the difference in discriminative capacity of SPPB score for predicting 2-year mortality among phenotypes of HF. METHODS: We consecutively enrolled 542 adult patients admitted for HF (HFrEF, n = 187; HFmrEF, n = 94; HFpEF, n = 261). The patients underwent SPPB score when discharged from hospital. The primary endpoint was all-cause mortality during the 2 years after hospital discharge. We assessed the discriminative capacity of SPPB score for predicting mortality by using receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 95 events (17.5%) occurred during the follow-up period. The area under the curve of ROC (95% confidence interval) was 0.80 (0.71-0.88) in HFrEF, 0.61 (0.46-0.76) in HFmrEF, and 0.70 (0.61-0.79) in HFpEF group. After adjustment for potential confounders, the hazard ratios (95% confidence interval) of the lower SPPB score were 5.38 (2.34-14.6) in HFrEF group, 1.12 (0.36-3.29) in HFmrEF group, and 3.19 (1.68-6.22) in HFpEF group. CONCLUSIONS: Prognostic value of SPPB score varies according to the HF phenotype. SPPB score predicts mortality in patients with HFrEF and HFpEF, but not in patients with HFmrEF. These findings lead to more precise risk prediction by SPPB score in patients with HF.

Real-World Evidence of Diagnostic Testing for Driver Oncogene Mutations in Lung Cancer in Japan.

INTRODUCTION: Diagnostic testing is important in determining appropriate treatment for individuals with lung cancer. In 2018, testing of five biomarkers (EGFR, ALK, ROS1, BRAF, programmed cell death-ligand 1 [PD-L1]) was approved in Japan. Information is lacking regarding real-world testing patterns. METHODS: This descriptive, retrospective observational study used the Japan Medical Data Vision Co., Ltd. (MDV), database (June 2017-November 2018) and covered data for EGFR, ALK, ROS1, and PD-L1; records on BRAF testing were not yet available. Adults diagnosed with having lung cancer (International Classification of Diseases-10 C34) with record of any biomarker test ordered were included. RESULTS: Of 8323 patients with any biomarker test, 83.2% were tested for EGFR, 55.3% for ALK, 32.2% ROS1, and 77.2% PD-L1. Combinations of EGFR with other biomarkers accounted for approximately 80% of the testing patterns; 1427 patients (17.1%) had combination testing ordered for EGFR/ALK/ROS1/PD-L1, but some biomarker combinations were tested in less than 1% of the cases. Median time from first testing order to treatment order was 22 (range: 2-525) days overall and increased with number of testing instances: 21 (2-509) days for patients with one, 28 (3-525) days for patients with two, and 30 (9-502) days for patients with three. A 7-day pattern of peaks was observed in the test order date and time to treatment. CONCLUSIONS: This real-world evidence revealed variations in diagnostic testing patterns, which could affect time to treatment in Japan. Variations are likely influenced by individual biomarker prioritization considering limited tissue samples in clinical practice.

Indirect analysis of first-line therapy for advanced non-small-cell lung cancer with activating mutations in a Japanese population.

Background: Five EGFR-tyrosine kinase inhibitors (EGFR TKIs) are currently available in the first-line setting for non-small-cell lung cancer (NSCLC) in Japan. The aim here was to compare the relative efficacy of EGFR TKIs in the Japanese population. Materials & methods: A systematic review identified randomized controlled trials examining the efficacy of first-line EGFR TKIs. A Bayesian network meta-analysis was used to assess these EGFR TKI comparisons for progression-free survival (PFS). Results: A total of seven randomized controlled trials were identified and considered for network meta-analysis. Dacomitinib showed a trend toward improved PFS versus all comparators. Conclusion: Dacomitinib demonstrated a trend toward improved PFS and therefore, should be considered one of the standard first-line therapies for Japanese patients diagnosed with EGFR+ non-small-cell lung cancer.

Clinical Characteristics and Social Frailty of Super-Elderly Patients With Heart Failure　- The Kitakawachi Clinical Background and Outcome of Heart Failure Registry.

BACKGROUND: Social background is important in preventing admission/readmission of heart failure (HF) patients. However, few clinical studies have been conducted to assess the social background of these patients, especially elderly patients.Methods and Results:The Kitakawachi Clinical Background and Outcome of Heart Failure (KICKOFF) Registry is a prospective multicenter community-based cohort of HF patients, established in April 2015. We compared the clinical characteristics and social background of the super-elderly group (≥85 years old) and the non-super-elderly group (<85 years old). This study included 647 patients; 11.8% of the super-elderly patients were living alone, 15.6% were living with only a partner, and of these, only 66.7% had the support of other family members. The super-elderly group had less control over their diet and drug therapies than the non-super-elderly group. Most patients in the super-elderly group were registered for long-term care insurance (77.4%); 73.5% of the super-elderly patients could walk independently before admission, but only 55.5% could walk independently at discharge, whereas 94% of the non-super-elderly patients could walk independently before admission and 89.4% could walk independently at discharge. CONCLUSIONS: The KICKOFF Registry provides unique detailed social background information of Japanese patients with HF. Super-elderly patients are at serious risk of social frailty; they need the support of other people and their ability to perform activities of daily living decline when hospitalized.

Comparing thoracic and intra-nasal pressure transients to monitor active odor sampling during odor-guided decision making in the mouse.

BACKGROUND: Recording of physiological parameters in behaving mice has seen an immense increase over recent years driven by, for example, increased miniaturization of recording devices. One parameter particularly important for odorant-driven behaviors is the breathing frequency, since the latter dictates the rate of odorant delivery to the nasal cavity and the olfactory receptor neurons located therein. NEW METHOD: Typically, breathing patterns are monitored by either measuring the breathing-induced temperature or pressure changes in the nasal cavity. Both require the implantation of a nasal cannula and tethering of the mouse to either a cable or tubing. To avoid these limitations we used an implanted pressure sensor which reads the thoracic pressure and transmits the data telemetrically, thus making it suitable for experiments which require a freely moving animal. RESULTS: Mice performed a Go/NoGo odorant-driven behavioral task with the implanted pressure sensor, which proved to work reliably to allow recording of breathing signals over several weeks from a given animal. COMPARISON TO EXISTING METHOD(S): We simultaneously recorded the thoracic and nasal pressure changes and found that measuring the thoracic pressure change yielded similar results compared to measurements of nasal pressure changes. CONCLUSION: Telemetrically recorded breathing signals are a feasible method to monitor odorant-guided behavioral changes in breathing rates. Its advantages are most significant when recording from a freely moving animal over several weeks. The advantages and disadvantages of different methods to record breathing patterns are discussed.

Urinary volatile compounds as biomarkers for lung cancer.

Lung cancer is a leading cause of deaths in cancer. Hence, developing early-stage diagnostic tests that are non-invasive, highly sensitive, and specific is crucial. In this study, we investigated to determine whether biomarkers derived from urinary volatile organic compounds (VOCs) can be used to discriminate between lung cancer patients and normal control patients. The VOCs were extracted from the headspace by solid-phase microextraction and were analyzed by gas chromatography time-of-flight mass spectrometry. Nine putative volatile biomarkers were identified as elevated in the lung cancer group. Receiver operating characteristic curve analysis was also performed, and the markers were found to be highly sensitive and specific. Next we used principal component analysis (PCA) modeling to make comparisons compare within the lung cancer group, and found that 2-pentanone may have utility in differentiating between adenocarcinoma and squamous cell carcinomas.

Furan fatty acid as an anti-inflammatory component from the green-lipped mussel Perna canaliculus.

A lipid extract of Perna canaliculus (New Zealand green-lipped mussel) has reportedly displayed anti-inflammatory effects in animal models and in human controlled studies. However, the anti-inflammatory lipid components have not been investigated in detail due to the instability of the lipid extract, which has made the identification of the distinct active components a formidable task. Considering the instability of the active component, we carefully fractionated a lipid extract of Perna canaliculus (Lyprinol) and detected furan fatty acids (F-acids). These naturally but rarely detected fatty acids show potent radical-scavenging ability and are essential constituents of plants and algae. Based on these data, it has been proposed that F-acids could be potential antioxidants, which may contribute to the protective properties of fish and fish oil diets against chronic inflammatory diseases. However, to date, in vivo data to support the hypothesis have not been obtained, presumably due to the limited availability of F-acids. To confirm the in vivo anti-inflammatory effect of F-acids in comparison with that of eicosapentaenoic acid (EPA), we developed a semisynthetic preparation and examined its anti-inflammatory activity in a rat model of adjuvant-induced arthritis. Indeed, the F-acid ethyl ester exhibited more potent anti-inflammatory activity than that of the EPA ethyl ester. We report on the in vivo activity of F-acids, confirming that the lipid extract of the green-lipped mussel includes an unstable fatty acid that is more effective than EPA.

Urinary volatile compounds as biomarkers for lung cancer: a proof of principle study using odor signatures in mouse models of lung cancer.

A potential strategy for diagnosing lung cancer, the leading cause of cancer-related death, is to identify metabolic signatures (biomarkers) of the disease. Although data supports the hypothesis that volatile compounds can be detected in the breath of lung cancer patients by the sense of smell or through bioanalytical techniques, analysis of breath samples is cumbersome and technically challenging, thus limiting its applicability. The hypothesis explored here is that variations in small molecular weight volatile organic compounds ("odorants") in urine could be used as biomarkers for lung cancer. To demonstrate the presence and chemical structures of volatile biomarkers, we studied mouse olfactory-guided behavior and metabolomics of volatile constituents of urine. Sensor mice could be trained to discriminate between odors of mice with and without experimental tumors demonstrating that volatile odorants are sufficient to identify tumor-bearing mice. Consistent with this result, chemical analyses of urinary volatiles demonstrated that the amounts of several compounds were dramatically different between tumor and control mice. Using principal component analysis and supervised machine-learning, we accurately discriminated between tumor and control groups, a result that was cross validated with novel test groups. Although there were shared differences between experimental and control animals in the two tumor models, we also found chemical differences between these models, demonstrating tumor-based specificity. The success of these studies provides a novel proof-of-principle demonstration of lung tumor diagnosis through urinary volatile odorants. This work should provide an impetus for similar searches for volatile diagnostic biomarkers in the urine of human lung cancer patients.

Major histocompatibility complex-regulated odortypes: peptide-free urinary volatile signals.

Major histocompatibility complex (MHC) genes influence urinary odors (odortypes) of mice. That volatile odorants are involved is supported by the observation that odortype identity can be detected from a distance. Furthermore, chemical analyses of urines have revealed numerous volatile odorants that differ in relative abundance between mice that differ only in MHC genotypes. In addition, urines from MHC-different mice evoke distinct odor-induced activity maps in the main olfactory bulbs. However, recent studies report that non-volatile MHC class I peptides may directly act as MHC-associated signals and may thereby be seen to call into question the evidence for a volatile MHC signal. To evaluate this question, we designed a procedure to collect peptide-free urinary volatiles and tested these volatiles for their ability to mediate chemosensory discrimination of MHC-congenic mice differing in their MHC genotype. The headspace volatiles from urines of C57BL/6 congenic mice (haplotypes H2(b) and H2(k)) were collected by solid phase microextraction (SPME). These volatiles were then desorbed into a gas chromatograph (GC) and the entire chromatographic eluate was collected into a buffer solution. Our results conclusively demonstrate that mice trained to discriminate between unadulterated urinary signals of the congenic mice generalize the discrimination, without reward or training, to the buffer solution containing the peptide-free urinary volatiles (p<0.001, binomial test). Thus volatile signals, perhaps along with non-volatile ones, are capable of mediating behavioral discriminations of mice of different MHC genotypes.

Genetically-based olfactory signatures persist despite dietary variation.

Individual mice have a unique odor, or odortype, that facilitates individual recognition. Odortypes, like other phenotypes, can be influenced by genetic and environmental variation. The genetic influence derives in part from genes of the major histocompatibility complex (MHC). A major environmental influence is diet, which could obscure the genetic contribution to odortype. Because odortype stability is a prerequisite for individual recognition under normal behavioral conditions, we investigated whether MHC-determined urinary odortypes of inbred mice can be identified in the face of large diet-induced variation. Mice trained to discriminate urines from panels of mice that differed both in diet and MHC type found the diet odor more salient in generalization trials. Nevertheless, when mice were trained to discriminate mice with only MHC differences (but on the same diet), they recognized the MHC difference when tested with urines from mice on a different diet. This indicates that MHC odor profiles remain despite large dietary variation. Chemical analyses of urinary volatile organic compounds (VOCs) extracted by solid phase microextraction (SPME) and analyzed by gas chromatography/mass spectrometry (GC/MS) are consistent with this inference. Although diet influenced VOC variation more than MHC, with algorithmic training (supervised classification) MHC types could be accurately discriminated across different diets. Thus, although there are clear diet effects on urinary volatile profiles, they do not obscure MHC effects.

Phosphatidylcholine profile-mediated group recognition in catfish.

Animal groups are integrated by emission of discrete signals from members, so-called social signals, which have evolved for each species. Among communication signals, chemical signals play an important role for recognition of group membership. The catfish Plotosus lineatus forms a dense school immediately after hatching, and school recognition is under the control of chemical signals emitted by the school members. The key substance(s) governing this recognition are deduced to be a mixture of phosphatidylcholines (PC). To substantiate this hypothesis that a mixture of PC molecular species functions as recognition of school-specific odor, we examined the ability of P. lineatus to discriminate between familiar and unfamiliar PCs. P. lineatus responded only to PCs from a familiar school, and not to those from unfamiliar schools. PC molecular species were then analyzed by quantitative high performance liquid chromatography, which resulted in not only a complex mixture of PC molecular species, but also school-specific PC profiles. Furthermore, multivariate analysis of the quantified PC peaks revealed the presence of various PC profiles. Finally, we showed that the modification of PC profiles disrupts the recognition of school odor in P. lineatus. Therefore, we conclude that the recognition of school odor in P. lineatus is governed by school-specific PC profiles.