Lifestyle behaviour patterns in the prevention of type 2 diabetes mellitus: the Fukushima Health Database 2015-2020.

OBJECTIVES: Lifestyle behaviours associated with the incidence of type 2 diabetes mellitus (T2DM) need further clarification using health insurance data. STUDY DESIGN: This is a cohort study. METHODS: In 2015, 193,246 participants aged 40-74 years attended the specific health checkups and were observed up to 2020 in Fukushima, Japan. Using the principal component analysis, we identified two patterns from ten lifestyle behaviour questions, namely, the "diet-smoking" pattern (including smoking, alcohol drinking, skipping breakfast, eating fast, late dinner, and snacking) and the "physical activity-sleep" pattern (including physical exercise, walking equivalent activity, walking fast, and sufficient sleep). Then, individual pattern scores were calculated; the higher the scores, the healthier the behaviours. RESULTS: The accumulative incidence rate of T2DM was 630.5 in men and 391.9 in women per 100,000 person-years in an average of 4 years of follow-up. Adjusted for the demographic and cardiometabolic factors at the baseline, the hazard ratio (95% confidence interval) of the highest versus lowest quartile scores of the "diet-smoking" pattern for T2DM risk was 0.82 (0.72, 0.92; P for trend = 0.002) in men and 0.87 (0.76, 1·00; P for trend = 0.034) in women; that of the "physical activity-sleep" pattern was 0.92 (0.82, 1·04; P for trend = 0.0996) in men and 0.92 (0.80, 1·06; P for trend = 0.372) in women. The "physical activity-sleep" pattern showed a significant inverse association in non-overweight men. CONCLUSIONS: Lifestyle behaviour associated with a healthy diet and lack of smoking may significantly lower the risk of T2DM in middle-aged Japanese adults.

Time-resolved Coulomb collision of single electrons.

A series of recent experiments have shown that collision of ballistic electrons in semiconductors can be used to probe the indistinguishability of single-electron wavepackets. Perhaps surprisingly, their Coulomb interaction has not been seen due to screening. Here we show Coulomb-dominated collision of high-energy single electrons in counter-propagating ballistic edge states, probed by measuring partition statistics while adjusting the collision timing. Although some experimental data suggest antibunching behaviour, we show that this is not due to quantum statistics but to strong repulsive Coulomb interactions. This prevents the wavepacket overlap needed for fermionic exchange statistics but suggests new ways to utilize Coulomb interactions: microscopically isolated and time-resolved interactions between ballistic electrons can enable the use of the Coulomb interaction for high-speed sensing or gate operations on flying electron qubits.

Prevalence trends of metabolic syndrome in residents of postdisaster Fukushima: a longitudinal analysis of Fukushima Health Database 2012-2019.

OBJECTIVES: The study aimed to evaluate the long-term metabolic risk profiles of Fukushima residents after the Great East Japan Earthquake of March 2011. STUDY DESIGN: This was a cross-sectional and a longitudinal design. METHODS: The Fukushima Health Database (FDB) contains 2,331,319 annual health checkup records of participants aged 40-74 years between 2012 and 2019. We checked the validity of the FDB by comparing the prevalence of metabolic factors with the National Database of Health Insurance Claims and Specific Health Checkups (NDB). We applied a regression analysis to determine the changes and project the trends of metabolic factors over the years. RESULTS: Compared to the NDB, the prevalence of metabolic factors in Fukushima was higher than the country average from 2013 to 2018, and they showed the same trends as those from the FDB. The prevalence of metabolic syndrome (MetS) increased from 18.9% in 2012 to 21.4% in 2019 (an annual increase of 2.74%) in men and from 6.8 to 7.4% (an annual increase of 1.80%) in women in Fukushima. The standardized prevalence of MetS, being overweight, and diabetes is projected to continue increasing, with disparities among subareas being higher in evacuees than in non-evacuees. An annual decrease of 0.38-1.97% in hypertension was mainly observed in women. CONCLUSIONS: The prevalence of metabolic risk is higher in Fukushima as compared to the country average. The increasing metabolic risk in subareas, including the evacuation zone, highlights the need to control MetS in Fukushima residents.

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11).

BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

Continuous-variable tomography of solitary electrons.

A method for characterising the wave-function of freely-propagating particles would provide a useful tool for developing quantum-information technologies with single electronic excitations. Previous continuous-variable quantum tomography techniques developed to analyse electronic excitations in the energy-time domain have been limited to energies close to the Fermi level. We show that a wide-band tomography of single-particle distributions is possible using energy-time filtering and that the Wigner representation of the mixed-state density matrix can be reconstructed for solitary electrons emitted by an on-demand single-electron source. These are highly localised distributions, isolated from the Fermi sea. While we cannot resolve the pure state Wigner function of our excitations due to classical fluctuations, we can partially resolve the chirp and squeezing of the Wigner function imposed by emission conditions and quantify the quantumness of the source. This tomography scheme, when implemented with sufficient experimental resolution, will enable quantum-limited measurements, providing information on electron coherence and entanglement at the individual particle level.

LO-Phonon Emission Rate of Hot Electrons from an On-Demand Single-Electron Source in a GaAs/AlGaAs Heterostructure.

Using a recent time-of-flight measurement technique with 1 ps time resolution and electron-energy spectroscopy, we develop a method to measure the longitudinal-optical-phonon emission rate of hot electrons traveling along a depleted edge of a quantum Hall bar. Comparison to a single-particle model implies the scattering mechanism involves a two-step process via an intra-Landau-level transition. We show that this can be suppressed by control of the edge potential profile, and a scattering length >1 mm can be achieved, allowing the use of this system for scalable single-electron device applications.

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701).

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.

Label-free photoacoustic imaging of human palmar vessels: a structural morphological analysis.

We analysed the vascular morphology of the palm using a photoacoustic tomography (PAT) instrument with a hemispherical detector array. The three-dimensional (3D) morphology of blood vessels was determined noninvasively. Overall, 12 females and 11 males were recruited as healthy volunteers. Their ages were distributed almost evenly from 22 to 59 years. In all cases, many vascular networks were observed just beneath the skin and were determined to be veins anatomically. To analyse the major arteries, the layer containing the subcutaneous venous network was removed from the image. The analysis focused on the common and proper palmar digital arteries. We used the curvature of these arteries as a parameter to analyse their morphologies. There was no significant difference in the curvature between genders when comparing the subjects as a whole. The blood vessel curvature increased with age. Good agreement was found between the 3D numerical analysis results and the subjective evaluation of the two-dimensional (2D) projection image. The PAT system enabled visualization of the 3D features of blood vessels in the palm and noninvasive analysis of arterial tortuousness.

Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.

Pulmonary arterial hypertension (PAH) is a rare but serious disease with a grave prognosis. Bone morphogenetic protein type 2 receptor (BMPR2) gene is a strong pathogenic factor for PAH. As a collaborative team from Kyorin University and Keio University in Japan, we have analyzed the BMPR2 gene in 356 probands and more than 50 family members, including secondary patients. Importantly, the study population is a racially, ethnically, and socially homogeneous population. In PAH patients, there is a high incidence of unique mutations in BMPR2, and several mutations are frequently observed in the Japanese population, suggesting that these common and recurring mutations may be highly pathogenic or have high penetrance, explaining why they are found frequently throughout the world. We have also mapped each breakpoint of exonic deletions/duplications and found that most break and rejoining points are in the Alu elements. Reviewing the distribution of the reported mutations on each exon of BMPR2 revealed that the number and frequency of mutations are imbalanced among exons. The penetrance of BMPR2 gene mutations was 3-fold higher in females than males. Full elucidation of BMPR2-mediated pathogenic mechanisms in PAH requires persistent efforts to achieve precision or individualized medicine as a therapeutic strategy for PAH.

Characterization of porcine sapelovirus isolated from Japanese swine with PLC/PRF/5 cells.

Porcine sapelovirus (PSV) is a causative agent of neurological disorders, fertility disorders and dermal lesions of swine. In this study, we isolated two PSV strains, Jpsv477 and Jpsv1315, from swine faecal specimens using a PLC/PRF/5 cell culture system. The PSV infection of PLC/PRF/5 cells induced a cytopathic effect (CPE). Two types of virus particles with identical diameter (~35 nm) but different densities (1.300 and 1.285 g/cm3 ) were observed in the cell culture supernatants. Analysis of the entire genome sequence of Jpsv477 and Jpsv1315 revealed that both strains possess 7,558 nucleotides and the poly (A) tail and have a typical PSV genome organization consisting of a 5' terminal untranslated region (5'UTR), a large open reading frame (ORF), and a 3' terminal untranslated region (3'UTR). The ORF encodes a single polyprotein that is subsequently processed into a leader protein (L), four structural proteins (VP1, VP2, VP3 and VP4) and seven functional proteins (2A, 2B, 2C, 3A, 3B, 3C and 3D). The structural proteins VP1, VP2, VP3 and VP4 have molecular masses of ~35, ~26, ~25 and ~6 kDa. The N-terminal amino acid sequence analysis of VP1, VP2, VP3 and VP4 confirmed that the cleavage sites between VP4 and VP2, VP2 and VP3, and VP3 and VP1 are K/A, Q/G and Q/G, respectively. We further confirmed that HepG2/C3A, Vero E6 and primary green monkey kidney cells (PGMKC) were also susceptible to PSV infection. The stability assay demonstrated that PSV was inactivated by heating at 60°C for 10 min or 65°C for 5 min. The virus also lost infectivity by incubation with 62.5 ppm of NaClO for 30 min.

Dodecylmaltoside Modulates Bicellular Tight Junction Contacts To Promote Enhanced Permeability.

Intestinal permeation enhancers are a crucial component of many oral formulations, without which many drugs would show an insufficient absorption in the gut. The present study sought to provide a better understanding of the molecular interaction of such absorption enhancers with the intestine, by investigating the effect of the surfactant-like permeation enhancer dodecylmaltoside (DDM) on Caco-2 cells. The extent to which the action of DDM is apportioned between the para- and transcellular routes was addressed by examining the transport of relevant marker compounds ([3H]-mannitol and [3H]-propranolol, respectively). In the case of [3H]-mannitol, a robust permeation enhancement was achieved with 0.5 mM DDM (∼6-fold), whereas little effect was seen on the permeation of [3H]-propranolol. Concomitantly measured TEER values revealed a rapid onset of action of DDM with a swift recovery and complete restitution (>90%) within 4 h after washout. To localize the site(s) of action of DDM at the absorptive surface of Caco-2 cells, sulfo-NHS-SS-biotin, a membrane-impermeable compound, was applied apically. In the presence of 0.5 mM DDM, translocated biotin was found to be accumulated toward bicellular contacts, whereas no biotin permeation was observed in untreated control cells. Western blot analysis of DDM-treated and untreated Caco-2 cells revealed an interaction of DDM with specific tight junction associated proteins, resulting in a reduction of claudin-3 and -4 and also occludin, as well as a depletion of claudin-2 from lipid rafts. Collectively, the results presented provide a more in depth understanding of the molecular mechanism(s) underlying the permeation-enhancing actions of DDM.

Visualization of tumor-related blood vessels in human breast by photoacoustic imaging system with a hemispherical detector array.

Noninvasive measurement of the distribution and oxygenation state of hemoglobin (Hb) inside the tissue is strongly required to analyze the tumor-associated vasculatures. We developed a photoacoustic imaging (PAI) system with a hemispherical-shaped detector array (HDA). Here, we show that PAI system with HDA revealed finer vasculature, more detailed blood-vessel branching structures, and more detailed morphological vessel characteristics compared with MRI by the use of breast shape deformation of MRI to PAI and their fused image. Morphologically abnormal peritumoral blood vessel features, including centripetal photoacoustic signals and disruption or narrowing of vessel signals, were observed and intratumoral signals were detected by PAI in breast cancer tissues as a result of the clinical study of 22 malignant cases. Interestingly, it was also possible to analyze anticancer treatment-driven changes in vascular morphological features and function, such as improvement of intratumoral blood perfusion and relevant changes in intravascular hemoglobin saturation of oxygen. This clinical study indicated that PAI appears to be a promising tool for noninvasive analysis of human blood vessels and may contribute to improve cancer diagnosis.

Ultrafast Emission and Detection of a Single-Electron Gaussian Wave Packet: A Theoretical Study.

Generating and detecting a prescribed single-electron state is an important step towards solid-state fermion optics. We propose how to generate an electron in a Gaussian state, using a quantum-dot pump with gigahertz operation and realistic parameters. With the help of a strong magnetic field, the electron occupies a coherent state in the pump, insensitive to the details of nonadiabatic evolution. The state changes during the emission from the pump, governed by competition between the Landauer-Buttiker traversal time and the passage time. When the former is much shorter than the latter, the emitted state is a Gaussian wave packet. The Gaussian packet can be identified by using a dynamical potential barrier, with a resolution reaching the Heisenberg minimal uncertainty ℏ/2.

Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations.

Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.

Time-of-Flight Measurements of Single-Electron Wave Packets in Quantum Hall Edge States.

We report time-of-flight measurements on electrons traveling in quantum Hall edge states. Hot-electron wave packets are emitted one per cycle into edge states formed along a depleted sample boundary. The electron arrival time is detected by driving a detector barrier with a square wave that acts as a shutter. By adding an extra path using a deflection barrier, we measure a delay in the arrival time, from which the edge-state velocity v is deduced. We find that v follows 1/B dependence, in good agreement with the E[over →]×B[over →] drift. The edge potential is estimated from the energy dependence of v using a harmonic approximation.

Local dynamics coupled to hydration water determines DNA-sequence-dependent deformability.

Molecular dynamics (MD) simulations and quasielastic neutron scattering (QENS) experiments were conducted on two hydrated DNA dodecamers with distinct deformability: 5'CGCG[under AATT]̲CGCG3' and 5'CGCG[under TTAA]̲CGCG3'. The former is known to be rigid and the latter to be flexible. The mean-square displacements of DNA dodecamers exhibit so-called dynamical transition around 200-240 K for both sequences. To investigate the DNA-sequence-dependent dynamics, the dynamics of DNA and hydration water above the transition temperature were examined using both MD simulations and QENS experiments. The fluctuation amplitude of the AATT central tetramer is smaller, and its relaxation time is longer, than that observed in TTAA, suggesting that the AT step is kinetically more stable than TA. The sequence-dependent local base pair step dynamics correlates with the kinetics of breaking the hydrogen bond between DNA and hydration water. The sequence-dependent DNA base pair step fluctuations appear above the dynamical transition temperature. Together with these results, we conclude that DNA deformability is related to the local dynamics of the base pair steps, themselves coupled to hydration water in the minor groove.

Clock-controlled emission of single-electron wave packets in a solid-state circuit.

We demonstrate the energy- and time-resolved detection of single-electron wave packets from a clock-controlled source transmitted through a high-energy quantum Hall edge channel. A quantum dot source is loaded with single electrons which are then emitted ~150 meV above the Fermi energy. The energy spectroscopy of emitted electrons indicates that at high magnetic field these electrons can be transported over several microns without inelastic electron-electron or electron-phonon scattering. Using a time-resolved spectroscopic technique, we deduce the wave packet size at picosecond resolution. We also show how this technique can be used to switch individual electrons into different electron waveguides (edge channels).

Gigahertz quantized charge pumping in graphene quantum dots.

Single-electron pumps are set to revolutionize electrical metrology by enabling the ampere to be redefined in terms of the elementary charge of an electron. Pumps based on lithographically fixed tunnel barriers in mesoscopic metallic systems and normal/superconducting hybrid turnstiles can reach very small error rates, but only at megahertz pumping speeds that correspond to small currents of the order of picoamperes. Tunable barrier pumps in semiconductor structures are operated at gigahertz frequencies, but the theoretical treatment of the error rate is more complex and only approximate predictions are available. Here, we present a monolithic, fixed-barrier single-electron pump made entirely from graphene that performs at frequencies up to several gigahertz. Combined with the record-high accuracy of the quantum Hall effect and proximity-induced Josephson junctions, quantized-current generation brings an all-graphene closure of the quantum metrological triangle within reach. Envisaged applications for graphene charge pumps outside quantum metrology include single-photon generation via electron-hole recombination in electrostatically doped bilayer graphene reservoirs, single Dirac fermion emission in relativistic electron quantum optics and read-out of spin-based graphene qubits in quantum information processing.

Glycaemic responses to glucose and rice in people of Chinese and European ethnicity.

AIMS: Diabetes rates are especially high in China. Risk of Type 2 diabetes increases with high intakes of white rice, a staple food of Chinese people. Ethnic differences in postprandial glycaemia have been reported. We compared glycaemic responses to glucose and five rice varieties in people of European and Chinese ethnicity and examined possible determinants of ethnic differences in postprandial glycaemia. METHODS: Self-identified Chinese (n = 32) and European (n = 31) healthy volunteers attended on eight occasions for studies following ingestion of glucose and jasmine, basmati, brown, Doongara(®) and parboiled rice. In addition to measuring glycaemic response, we investigated physical activity levels, extent of chewing of rice and salivary α-amylase activity to determine whether these measures explained any differences in postprandial glycaemia. RESULTS: Glycaemic response, measured by incremental area under the glucose curve, was over 60% greater for the five rice varieties (P < 0.001) and 39% greater for glucose (P < 0.004) amongst Chinese compared with Europeans. The calculated glycaemic index was approximately 20% greater for rice varieties other than basmati (P = 0.01 to 0.05). Ethnicity [adjusted risk ratio 1.4 (1.2-1.8) P < 0.001] and rice variety were the only important determinants of incremental area under the glucose curve. CONCLUSIONS: Glycaemic responses following ingestion of glucose and several rice varieties are appreciably greater in Chinese compared with Europeans, suggesting the need to review recommendations regarding dietary carbohydrate amongst rice-eating populations at high risk of diabetes.

Towards a quantum representation of the ampere using single electron pumps.

Electron pumps generate a macroscopic electric current by controlled manipulation of single electrons. Despite intensive research towards a quantum current standard over the last 25 years, making a fast and accurate quantized electron pump has proved extremely difficult. Here we demonstrate that the accuracy of a semiconductor quantum dot pump can be dramatically improved by using specially designed gate drive waveforms. Our pump can generate a current of up to 150 pA, corresponding to almost a billion electrons per second, with an experimentally demonstrated current accuracy better than 1.2 parts per million (p.p.m.) and strong evidence, based on fitting data to a model, that the true accuracy is approaching 0.01 p.p.m. This type of pump is a promising candidate for further development as a realization of the SI base unit ampere, following a redefinition of the ampere in terms of a fixed value of the elementary charge.