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Satoshi Igawa,1 Noriko Nishinarita,1 Akira Takakura,1 Takahiro Ozawa,1 Shinya Harada,1 Seiichiro Kusuhara,1 Hideyuki Niwa,2 Shinji Hosotani,1 Hideyuki Sone,1 Yoshiro Nakahara,1,3 Tomoya Fukui,1 Hisashi Mitsufuji,4 Masanori Yokoba,5 Masaru Kubota,1 Masato Katagiri,5 Jiichiro Sasaki,6 Katsuhiko Naoki1 1Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara 252-0374, Kanagawa, Japan; 2Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Aichi, Japan; 3Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Kanagawa, Japan; 4Kitasato University School of Nursing, Sagamihara 252-0329, Kanagawa, Japan; 5School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan; 6Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara 252-0374, Kanagawa, Japan Background: The optimal chemotherapy regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remains unknown. Therefore, in this study, we investigated the real-world efficacy and safety of carboplatin (CBDCA) plus nab-paclitaxel (nab-PTX) as a first-line regimen for NSCLC patients with ILD. Patients and methods: We retrospectively reviewed advanced NSCLC patients with ILD who had received CBDCA plus nab-PTX as a first-line chemotherapy regimen between April 2013 and March 2018. Patients were diagnosed with ILD based on the findings of a pretreatment high-resolution computed tomography of the chest. Results: The 34 patients enrolled in this study were included in the efficacy and safety analysis. Collagen vascular disease or a history of exposure to dust or asbestos was not reported for any patients. The median age of patients was 71 years (range, 59–83 years), and 32 patients had a performance status of 0 or 1. The overall response rate was 38.2%. The median progression-free survival and overall survival were 5.8 months and 12.7 months, respectively. Chemotherapy-related acute exacerbation of ILD was observed in two patients (5.7%). Other toxicities were feasible, and no treatment-related deaths occurred. Conclusion: CBDCA plus nab-PTX, as a first-line chemotherapy regimen for NSCLC, showed favorable efficacy and safety in patients with preexisting ILD. Keywords: interstitial lung disease, non-small-cell lung cancer, carboplatin, nab-paclitaxel

To examine the association between treatment-achieved HbA 1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments. Associations of treatment-achieved HbA 1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox's regression analysis examined risks over a 5.1-year follow-up. A significant linear trend was associated with HbA 1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA 1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA 1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA 1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA 1c ≤ 7.0% and 7.1–8.0% in those treated with either SU alone, SU with glinides, or insulin. These findings suggest that the relationship between treatment-achieved HbA 1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Aims: To examine the effects of a sodium–glucose co‐transporter 2 (SGLT2) inhibitor, tofogliflozin, on resting heart rate by exploring baseline factors that independently influenced changes in the resting heart rate. Methods: Data on 419 participants in tofogliflozin phase 2/3 trials were analysed. Changes in resting heart rate from baseline to week 24 were analysed using an analysis of covariance (ANCOVA) model with groups (tofogliflozin/placebo) as a fixed effect and baseline values as covariates. The antilipolytic effect was evaluated as adipose tissue insulin resistance (Adipo‐IR) and was calculated as the product of fasting insulin and free fatty acid. Multivariate analysis evaluated independent factors for changes in resting heart rate from baseline to week 24. Results: Of the participants, 58% were men, and mean age, HbA1c, BMI and resting heart rate were 57.6 years, 65 mmol/mol (8.1%), 25.5 kg/m2 and 66 bpm, respectively. At week 24, adjusted mean difference vs. placebo in the change from baseline was −2.3 bpm [95% confidence interval (CI) −4.6, −0.1] with tofogliflozin. Changes in resting heart rate were positively correlated with changes in Adipo‐IR, whereas reductions in HbA1c, body weight and blood pressure were similar independent of changes in resting heart among quartiles of resting heart rate change. On multivariate analysis, higher baseline resting heart rates and Adipo‐IR values were significantly associated with greater reductions in resting heart rate. Conclusions: Tofogliflozin corrected resting heart rate levels in accordance with baseline levels. Correction of high resting heart rates may be attributed to improved adipose tissue insulin resistance, leading to correction of hyperinsulinaemia. What's new?: A high resting heart rate is related to increased cardiovascular and microvascular risks in persons with type 2 diabetes.Tofogliflozin significantly reduced resting heart rate compared with placebo, irrespective of reductions in HbA1c, body weight and blood pressure.Reduction in resting heart rate was associated with improvements in adipose tissue insulin resistance.Higher baseline adipose tissue insulin resistance levels were independently associated with a greater decline in resting heart rate.Correcting the resting heart rate via improved adipose tissue insulin resistance by tofogliflozin treatment might contribute to lowering the risks of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Tension cracks were generated by past megathrust earthquakes along the coastal forearc of Chile‐Peru. To explain why elastic rebound in an offshore earthquake can cause widespread permanent deformation onshore, we propose a model in which the near‐surface material exhibits viscoelastic behavior, analogous to laboratory‐observed behavior of petroleum reservoir rocks. Because of near‐surface relaxation, interseismic deformation builds up stress only in the deeper crust. Elastic rebound of the deeper crust during an earthquake induces near‐surface tension to generate cracks. We numerically demonstrate the proposed mechanism using hypothetical and real megathrust earthquakes. The location of the zone of peak tension, assumed to be responsible for the crack generation, is controlled by downdip rupture termination. A rupture farther downdip or terminating more gradually causes the zone of peak tension to be farther landward and broader. The tension cracks thus may contain important information on megathrust rupture dynamics. Plain Language Summary: Earthquakes are the operation of elastic rebound. Tension cracks induced by megathrust earthquakes observed in Chile‐Peru therefore require special explanation. In this work, we propose a testable model for these cracks. We propose that the cemented soil and the highly fractured shallow bedrock in this area exhibit a viscoelastic behavior analogous to petroleum reservoir rocks. When the megathrust is locked in preparation for the next earthquake, the deeper crust is elastically shortened like a spring, but the shallow material deforms in a viscous fashion and do not store energy. During the megathrust earthquake, elastic rebound of the deeper crust induces tension in the shallow material, causing it to crack. If we assume that the observed crack distribution is controlled by the peak tension during the earthquake, it can be used to constrain how the megathrust rupture terminates in the deep end, which helps to understand the physics of earthquakes. Key Points: Viscoelastic relaxation of near‐surface material allows permanent interseismic shortening contemporaneous with deeper elastic deformationElastic rebound of deeper crust in earthquakes induces tension in the relaxed shallow material, explaining cracks in Chile‐Peru forearcCrack distribution, assumed to be controlled by peak coseismic tension, contains important information on megathrust rupture termination [ABSTRACT FROM AUTHOR]

The production of hydrocarbons from unconventional reservoirs, like tight shale plays, increased tremendously over the past decade. Hydraulic fracturing is a commonly applied method to increase the productivity of a well drilled in these reservoirs. Unfortunately, the production rate decreases over time presumably due to fracture closure. The fracture closure rate induced by proppant crushing and embedment depends on mechanical properties of shales and proppants that are influenced by confining pressure (pc), temperature (T), and shale composition. We performed constant strain rate deformation tests at ambient and in situ conditions of a typical shale reservoir (pc ≤ 100 MPa, T ≤ 125 °C) using European shale samples exhibiting variable mineralogy, porosity and maturity. We focused on a comparison of Posidonia shale with Bowland shale, which is believed to be the most prospective shale formation in the United Kingdom. Compression tests were performed perpendicular to bedding orientation. Stress-strain curves show that Bowland shales are relatively strong and brittle compared to Posidonia shale which display semibrittle deformation behavior. Brittleness estimated from elastic properties is in good agreement with the recorded stress-strain behavior but shows no clear relation to composition. Compressive strengths (σUCS = uniaxial compressive strength, σTCS = triaxial compressive strength) and static Young’s moduli, E, reveal a strong confining pressure and mineralogy dependence, whereas temperature and strain rate only have a minor influence on σTCS and E. The coefficient of internal friction for both shales is  ≈ 0.42 ± 0.03. With increasing amount of weak minerals (e.g., clay, mica) σUCS, σTCS and E strongly decrease. This may be related to a shift from deformation supported by a load-bearing framework of hard minerals to deformation of interconnected weak minerals at about 25-30 vol% of weak phases. At the applied conditions, the triaxial compressive strength and Young’s moduli of most shales deformed normal to bedding are close to the Reuss bound. To our knowledge, this is the first study, which presents results of experimental investigations carried out to characterize the mechanical behavior of Bowland shale. The observed results are helpful to estimate the potential of the Bowland reservoir with respect to the economical extraction of hydrocarbons. [ABSTRACT FROM AUTHOR]

Summary: Background: Bariatric surgery leads to a higher remission rate for type 2 diabetes mellitus than non‐surgical treatment. However, it remains unsolved which surgical procedure is the most efficacious. This network meta‐analysis aimed to rank surgical procedures in terms of diabetes remission. Methods and findings: We electronically searched for randomized controlled trials in which at least one surgical treatment was included among multiple arms and the diabetes remission rate was included in study outcomes. A random‐effects network meta‐analysis was performed within a frequentist framework. The hierarchy of treatments was expressed as the surface under the cumulative ranking curve value. Results of the analysis of 25 eligible randomized controlled trials that covered non‐surgical treatments and eight surgical procedures (biliopancreatic diversion [BPD], BPD with duodenal switch, Roux‐en Y gastric bypass, mini gastric bypass [mini‐GBP], laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, greater curvature plication and duodenal‐jejunal bypass) showed that BPD and mini‐GBP had the highest surface under the cumulative ranking curve values among the eight surgical treatments. Conclusion: Current network meta‐analysis indicated that BPD or mini‐GBP achieved higher diabetes remission rates than the other procedures. However, the result needs to be interpreted with caution considering that these procedures were in the minority of bariatric surgeries. [ABSTRACT FROM AUTHOR]

Objective This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. Methods This population-based retrospective cohort study included 123,746 Japanese men aged 18–72 years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI ≥ 25 kg/m 2 . Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. Results The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32–2.95; prediabetes: 2.91, 95% CI: 1.85–4.55; diabetes: 1.90, 95% CI: 1.18–3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94–9.56) and 7.86 (95% CI: 5.21–11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. Conclusion A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status. [ABSTRACT FROM AUTHOR]