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Sitagliptin has been suggested as a treatment option for older adults with type 2 diabetes (T2D). However, no randomized controlled trial has been performed to evaluate the efficacy and safety of sitagliptin treatment in older Japanese patients with T2D. The STREAM study was a multicenter, open-label, randomized controlled trial. T2D outpatients aged 65–80 years with moderately controlled glycemic levels (HbA1c 7.4–10.4%) under lifestyle interventions without or with oral anti-diabetic drugs excluding DPP4 inhibitors or GLP-1 receptor agonists were recruited (n = 176). The participants were randomized into sitagliptin group (n = 88) who received sitagliptin as an initial or an additive anti-diabetic drug and control group (n = 88) who did not. The treatment goal was HbA1c level < 7.4%. Efficacy and safety during 12-month treatment period were investigated. The mean (± SD) ages were 70.6 ± 3.9 and 71.9 ± 4.4 years old in sitagliptin and control groups, respectively. According to a mixed-effects model analysis, average changes from baseline over the treatment period in fasting plasma glucose (FPG), HbA1c, and glycated albumin (GA) were − 27.2 mg/dL, − 0.61%, and − 2.39%, respectively, in sitagliptin group, and 0.50 mg/dL, − 0.29%, and − 0.93%, respectively, in control group. The reductions in FPG, HbA1c, and GA were significantly greater in sitagliptin group (P < 0.0001, P < 0.01, and P < 0.0001, respectively). There were no differences in the incidence of adverse effects, except for cystatin C elevation and platelet count reduction in sitagliptin group. Sitagliptin treatment effectively improved the glycemic profile without any serious adverse effects in older T2D patients. Trial registration number: UMIN000010376.

Background:The association between gastro-oesophageal reflux disease (GORD) and chronic obstructive pulmonary disease (COPD) exacerbation has so far remained unclear.Objective:To prospectively establish the clinical significance of GORD symptoms on exacerbation.Methods:82 patients with COPD and 40 age matched controls were enrolled in this study. Symptoms were evaluated by a questionnaire using the Frequency Scale for the Symptoms of GORD (FSSG). Patients with COPD were prospectively surveyed for 6 months, and episodes of exacerbation were identified using a diary based on modified Anthonisen’s criteria. Exhaled breath condensate (EBC) pH was measured in both groups, and induced sputum was evaluated in patients with COPD.Results:Positive GORD symptoms were reported in 22 (26.8%) patients with COPD and in five (12.5%) controls (p = 0.10). The frequency of exacerbations was significantly associated with the FSSG score (p = 0.03, r = 0.24, 95% CI 0.02 to 0.43). Multiple regression analysis revealed that GORD symptoms were significantly associated with the occurrence of exacerbations (p<0.01; relative risk 6.55, 95% CI 1.86 to 23.11). EBC pH was inversely correlated with FSSG score in both groups (p = 0.01, r = –0.37, 95% CI –0.55 to −0.14 in patients with COPD, and p<0.01, r = –0.45, 95% CI –0.67 to −0.16 in control subjects).Conclusions:GORD symptoms were identified as an important factor associated with COPD exacerbation.

Microbial life inhabits deeply buried marine sediments, but the extent of this vast ecosystem remains poorly constrained. Here we provide evidence for the existence of microbial communities in ∼40° to 60°C sediment associated with lignite coal beds at ∼1.5 to 2.5 km below the seafloor in the Pacific Ocean off Japan. Microbial methanogenesis was indicated by the isotopic compositions of methane and carbon dioxide, biomarkers, cultivation data, and gas compositions. Concentrations of indigenous microbial cells below 1.5 km ranged from <10 to ∼104 cells cm–3. Peak concentrations occurred in lignite layers, where communities differed markedly from shallower subseafloor communities and instead resembled organotrophic communities in forest soils. This suggests that terrigenous sediments retain indigenous community members tens of millions of years after burial in the seabed.

The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo , supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

Flow structures formed in a rectangular fluid layer with an aspect ratio of four driven by a horizontal temperature gradient along the top boundary, so-called horizontal convection in both developing and equilibrium cases, were investigated via flow visualization using thermochromic liquid crystal microcapsules. Four separated heating panels on the top of the vessel allowed the influence of the heating plate arrangement on the determination of the flow structure to be examined. The velocity vector fields averaged in local space and time showed that the flow structures in the developing cases with an initial stable temperature stratification consisted of shallow circulation beneath the top boundary, with the time development of the structures being independent of the plate arrangement. The number of circulations along the top boundary is associated with locations having horizontal temperature gradients. In the equilibrium state, however, the flow structures are more complex because of the influence of the unstable temperature stratification, which is modified by the circulation. Graphical abstract

Most factor-based forecasting models for the term structure of interest rates depend on a fixed number of factor loading functions that have to be specified in advance. In this study, we relax this assumption by building a yield curve forecasting model that learns new factor decompositions directly from data for an arbitrary number of factors, combining a Gaussian linear state-space model with a neural network that generates smooth yield curve factor loadings. In order to control the model complexity, we define prior distributions with a shrinkage effect over the model parameters, and we present how to obtain computationally efficient maximum a posteriori numerical estimates using the Kalman filter and automatic differentiation. An evaluation of the model’s performance on 14 years of historical data of the Brazilian yield curve shows that the proposed technique was able to obtain better overall out-of-sample forecasts than traditional approaches, such as the dynamic Nelson and Siegel model and its extensions.

Purpose The purpose of this study was to assess the effects of recent surgical rib fixation and establish its indications not only for flail chest but also for multiple rib fractures. Methods Between 2007 and 2015, 187 patients were diagnosed as having multiple rib fractures in our institution. After the propensity score matching was performed, ten patients who had performed surgical rib fixation and ten patients who had treated with non-operative management were included. Categorical variables were analyzed with Fischer’s exact test and non-parametric numerical data were compared using the Mann–Whitney U test. Wilcoxon signed-rank test was performed for comparison of pre- and postoperative variables. All statistical data are presented as median (25–75 % interquartile range [IQR]) or number. Results The surgically treated patients extubated significantly earlier than non-operative management patients (5.5 [1–8] vs 9 [7–12] days: p  = 0.019). The duration of continuous intravenous narcotic agents infusion days (4.5 [3–6] vs 12 [9–14] days: p  = 0.002) and the duration of intensive care unit stay (6.5 [3–9] vs 12 [8–14] days: p  = 0.008) were also significantly shorter in surgically treated patients. Under the same ventilating conditions, the postoperative values of tidal volume and respiratory rate improved significantly compared to those values measured just before the surgery. The incidence of pneumonia as a complication was significantly higher in non-operative management group ( p  = 0.05). Conclusions From the viewpoints of early respiratory stabilization and intensive care unit disposition without any complications, surgical rib fixation is a sufficiently acceptable procedure not only for flail chest but also for repair of severe multiple rib fractures.

For the purpose of realising the battery-less smart shoes, we have developed piezoelectric vibration energy harvesters (PVEHs), and PVEH-driven sports shoes. The smart shoes are equipped with acceleration sensors in the sole and Bluetooth LE (BLE) modules, which were driven by PVEHs composed of piezoelectric bimorph cantilevers. We have confirmed the capability of the PVEHs to frequently transmit the sensing data from the beacons of BLE when the subjects practically run while wearing shoes.

This study evaluated the relationship between radiation and Eustachian tube dysfunction, and examined the radiation dose required to induce otitis media with effusion. The function of 36 Eustachian tubes in 18 patients with head and neck cancer were examined sonotubometrically before, during, and 1, 2 and 3 months after, intensity-modulated radiotherapy. Patients with an increase of 5 dB or less in sound pressure level (dB) during swallowing were categorised as being in the dysfunction group. Additionally, radiation dose distributions were assessed in all Eustachian tubes using three dose-volume histogram parameters. Twenty-two of 25 normally functioning Eustachian tubes before radiotherapy (88.0 per cent) shifted to the dysfunction group after therapy. All ears that developed otitis media with effusion belonged to the dysfunction group. The radiation dose threshold evaluation revealed that ears with otitis media with effusion received significantly higher doses to the Eustachian tubes. The results indicate a relationship between radiation dose and Eustachian tube dysfunction and otitis media with effusion.