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We develop a new distance-based test of localized knowledge spillovers that embeds the concept of control patents. Using microgeographic data, we identify localization distance for each technology class while allowing for spillovers across geographic units. We revisit the debate between Thompson and Fox-Kean (2005a, 2005b) and Henderson, Jaffe, and Trajtenberg (2005) on the existence of localized knowledge spillovers and find solid evidence supporting localization even when using finely grained controls. Unless biases induced by imperfect matching between citing and control patents due to unobserved heterogeneity are extremely large, our distance-based test detects localization for the majority of technology classes.

Background Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC. Methods In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. Results Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension ( n  = 10 [38.5%]), proteinuria ( n  = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. Conclusions Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. Trial registration ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.

In flowering plants, pollen germinates on the stigma and pollen tubes grow through the style to fertilize the ovules. Enzymatic production of reactive oxygen species (ROS) has been suggested to be involved in pollen tube tip growth. Here, we characterized the function and regulation of the NADPH oxidases RbohH and RbohJ (Respiratory burst oxidase homolog H and J) in pollen tubes in Arabidopsis thaliana. In the rbohH and rbohJ single mutants, pollen tube tip growth was comparable to that of the wild type; however, tip growth was severely impaired in the double mutant. In vivo imaging showed that ROS accumulation in the pollen tube was impaired in the double mutant. Both RbohH and RbohJ, which contain Ca²⁺ binding EF-hand motifs, possessed Ca²⁺-induced ROS-producing activity and localized at the plasma membrane of the pollen tube tip. Point mutations in the EF-hand motifs impaired Ca²⁺-induced ROS production and complementation of the double mutant phenotype. We also showed that a protein phosphatase inhibitor enhanced the Ca²⁺-induced ROS-producing activity of RbohH and RbohJ, suggesting their synergistic activation by protein phosphorylation and Ca²⁺. Our results suggest that ROS production by RbohH and RbohJ is essential for proper pollen tube tip growth, and furthermore, that Ca²⁺-induced ROS positive feedback regulation is conserved in the polarized cell growth to shape the long tubular cell.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablatedmice, but not in orexin receptor-deficient mice. Peripherally administered YNT- 185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

ObjectiveTo clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease.DesignRetrospective cohort study.SettingMulticentre.ParticipantsThis study included 735 patients with Kawasaki disease aged ≤10 years and hospitalised between 4 and 10 days of illness in eight Japanese hospitals from January 2016 to December 2020.ExposuresHigh-dose (HD) ASA was administered with initial IVIG to 333 patients in 6 hospitals (HD group). ASA was not administered routinely to 402 patients in the other two hospitals, and low-dose ASA was only administered when patients developed coronary artery lesions or pericardial effusion (non-HD group).Primary and secondary outcome measuresThe primary outcome was the presence of coronary artery lesions, defined as a coronary artery diameter >+2.5 SD of body surface area within 1 month of onset. The secondary outcome was responsiveness to the initial IVIG therapy. Adjusted risk ratios for the outcomes were calculated using modified Poisson regression models. Bayesian analysis was conducted to estimate the posterior probability of the treatment effect of HD ASA under several prior distributions.ResultsThe incidence of coronary artery lesions was not significantly higher in the HD group than in the non-HD group (12/333 (3.6%) vs 15/402 (4.0%)). The proportion of non-responders to initial IVIG was similar between the two groups (HD group: 78/333 (23%); non-HD group: 83/402 (22%)). In the Bayesian analysis, considering a difference of ≤2% to be of no clinical importance, there was only a 9.3% chance of reduced risk of coronary artery lesions in the HD group compared with the non-HD group even with a strongly enthusiastic prior for HD treatment.ConclusionsCompared with HD ASA treatment, treatment without ASA in the acute phase of Kawasaki disease was not associated with increased complications from Kawasaki disease.

The deuteron is a loosely bound system that can easily break up into its constituent proton and neutron whilst in the presence of Coulomb and nuclear fields. Previous experimental studies have shown that this breakup process has a significant impact on residual-nucleus production from deuteron bombardment in the high-energy range of 50–210 MeV/nucleon. However, there remains a lack of cross-section data at energies below 50 MeV/nucleon. The current study determined 93Zr + d reaction cross sections under inverse kinematics at approximately 28 MeV/nucleon using the BigRIPS separator, OEDO beamline, and SHARAQ spectrometer. Cross sections from this research were compared with previous measurements and theoretical calculations. The experimental results show a large enhancement of the production cross sections of residual nuclei, especially those produced from a small number of particle emissions, compared to the proton-induced reaction data at similar bombarding energy. The DEURACS calculation, which quantitatively takes deuteron-breakup effects into account, reproduces the data well. As a long-lived fission product, 93Zr remains a challenge for nuclear-waste disposal and treatment. This study’s low-energy data may assist future consideration of nuclear-waste treatment facilities, where 93Zr + d may feasibly transmute the waste into short-lived/stable nuclei.

Making lifestyle changes is an essential element of abdominal obesity (AO) reduction. To support lifestyle modification and self-management, we developed an information and communication technology-based self-management system-DialBeticsLite-with a fully automated dietary evaluation function for the treatment of AO. The objective of this study was to evaluate the preliminary efficacy and feasibility of DialBeticsLite among Japanese office workers with AO. A 2- to 3-month prospective single-arm pilot intervention study was designed to assess the effects of the intervention using DialBeticsLite. The information and communication technology system was composed of 4 modules: data transmission (body weight, blood pressure, blood glucose, and pedometer count); data evaluation; exercise input; and food recording and dietary evaluation. Eligible participants were workers who were aged ≥20 years and with AO (waist circumference ≥85 cm for men and ≥90 cm for women). Physical parameters, blood tests, nutritional intake, and self-care behavior were compared at baseline and after the intervention. A total of 48 participants provided completed data for analysis, which yielded a study retention rate of 100%. The average age was 46.8 (SD 6.8) years, and 92% (44/48) of participants were male. The overall average measurement rate of DialBeticsLite, calculated by dividing the number of days with at least one measurement by the number of days of the intervention, was 98.6% (SD 3.4%). In total, 85% (41/48) of the participants reported that their participation in the study helped them to improve their lifestyle. BMI, waist circumference, and visceral fat area decreased significantly after the intervention (P<.001). In addition, the daily calorie intake reduced significantly (P=.02). There was a significant improvement in self-care behavior in terms of exercise and diet (P=.001). Using DialBeticsLite was shown to be a feasible and potentially effective method for reducing AO by providing users with a motivational framework to evaluate their lifestyle behaviors.

This paper examines the role of peer effects in teenagers' smoking behaviour in the U.S.A. I present a random utility model that incorporates complementarity between individual and peer smoking. A Markov process model of smoking interactions between individuals is presented. I estimate the structural parameters of the model using a steady-state distribution that is determined by the Markov process. The empirical results strongly support the presence of positive peer effects. Interestingly, peer interactions are found to be stronger within the same gender than across genders. The same result is found for race. Moreover, a multiplier effect is found.

A microwave irradiation probe was newly developed for downsizing microwave applicators and the overall microwave heating apparatus. The key component of the proposed probe is a tapered section composed of polytetrafluoroethylene (PTFE) and alumina. Insertion of the tapered section between the input port and the applicator vessel realizes impedance matching to the microwave power source and reduces the reflected power from the applicator. The proposed microwave probe for a cylindrical applicator was designed using 3D electromagnetic simulations. The permittivity data of two liquid samples—ultrapure water and 2 M NaOH solution—were measured and taken into simulations. The conductivity of the NaOH solution was estimated from the measurement results. The measured reflection ratio of the fabricated applicator was in good accordance with the simulated one. The frequency ranges in which the measured reflection ratio was less than 10% were from 1.45 GHz to 2.7 GHz when using water and from 1.6 GHz to 2.7 GHz when using the NaOH solution as the sample. The heating rate of the applicator was roughly estimated as 63 to 69 K for a 5 min interval during the 2.45 GHz microwave irradiation at the input power of 100 W.

To achieve both high-efficiency power generation and high detoxification performance, advanced-type waste power generation plants such as pyrolysis and gas reforming plants are suggested. Further surveys on actual operational data of these plants are required in terms of reliability of the system when it is introduced to waste disposal sites. To verify the technical effectiveness of advanced-type waste power generation using the pyrolysis and gas reforming method, we evaluated 10 tons/day of municipal solid wastes (MSW) treated in a demonstration plant. A demonstration test was conducted over 100 days including 35 consecutive days of operation treating MSWs. The test results show high recycling performance and harmless nature of the plant which proves it to be an excellent waste recycling system. Major test results are as follows: (1) stabilization of waste treatment is possible with the wastes of various qualities, (2) clean gas is produced from the waste whose energy recovery ratio is approximately 40 %. (3) 99.3 % weight % of dried waste are recovered as valuable materials such as clean gas, char and metal, (4) total amount of dioxin emission to the outside of the plant is very small, down to 0.0051–0.018 μg TEQ per ton waste.