Presenteeism and sleep duration on workdays and days off.

BACKGROUND: Presenteeism refers to being present at work but experiencing reduced productivity due to health problems, and has been known to be related to sleep loss. Workers commonly sleep longer on days off than on workdays, and presenteeism may be reduced with extended sleep on days off. AIMS: This study aimed to determine the association between sleep duration both on workdays and days off and presenteeism. METHODS: The participants were 1967 workers who engaged in work for 5 days and rested for 2 days weekly. Sleep duration was classified into less than 6 hours (short; S), 6-8 hours (medium; M), and 9 hours or longer (long; L), for workdays and days off, respectively. Presenteeism was assessed using the World Health Organization Health and Work Performance Questionnaire. RESULTS: On both workdays and days off, compared to medium sleep duration, short sleep duration was significantly associated with increased odds of presenteeism. The odds of presenteeism were significantly increased for S-S (odds ratio [OR] 2.17, 95% confidence interval [CI]1.40-3.37), S-M (OR 1.59, 95% CI 1.14-2.22), S-L (OR 2.71, 95% CI 1.05-7.00), and M-S (OR 6.82, 95% CI 2.71-17.17) combined sleep duration for workdays and days off, respectively, compared to an M-M (reference). CONCLUSIONS: Sleep loss on workdays cannot be compensated for with longer sleep on days off. This study suggests that sufficient sleep duration on both workdays and days off is important for reducing presenteeism.

Effect of influenza vaccine subsidies for older adults on vaccination coverage and mortality before and during the COVID-19 pandemic: an ecological study in Japan.

OBJECTIVE: We aimed to determine how municipal subsidies for seasonal influenza vaccines for the elderly affected vaccination coverage and health outcomes and how responses to vaccine prices changed during the COVID-19 pandemic. STUDY DESIGN AND METHODS: This ecological study includes 1245 municipalities in Japan between 2019 and 2020. Fixed-effects regression analysis was performed to evaluate the effect of influenza vaccine cost subsidy for people aged 65 years or older on vaccination coverage, all-cause mortality, and influenza-related mortality. RESULTS: The vaccination rate increased when patients' copayments decreased, and reducing the copayment by 1000 Japanese Yen (JPY) was estimated to increase the vaccination rate by 6.3% (95% confidence interval [CI] 4.5-8.2%) in the adjusted model. When examining the additional effect of a zero price compared to a nearly zero price, we found that a zero price increased the immunization rate by 6.4% (95% CI 1.4-11.5%). The effect of copayment on the increase in vaccination coverage was significantly lower during the pandemic than in the pre-pandemic period. The municipal and prefectural analyses found no association between influenza vaccine copayments and all-cause, influenza, or pneumonia mortality. CONCLUSION: Cost subsidies and the zero-price effect were shown to increase vaccination coverage but were not associated with relevant mortality measures. Although the impact was attenuated under pandemic conditions, cost subsidy effectively increases the vaccination rate.

Shape Changes in the Mirror Nuclei

We studied the proton-rich T_{z}=-1 nucleus ^{70}Kr through inelastic scattering at intermediate energies in order to extract the reduced transition probability, B(E2;0^{+}→2^{+}). Comparison with the other members of the A=70 isospin triplet, ^{70}Br and ^{70}Se, studied in the same experiment, shows a 3σ deviation from the expected linearity of the electromagnetic matrix elements as a function of T_{z}. At present, no established nuclear structure theory can describe this observed deviation quantitatively. This is the first violation of isospin symmetry at this level observed in the transition matrix elements. A heuristic approach may explain the anomaly by a shape change between the mirror nuclei ^{70}Kr and ^{70}Se contrary to the model predictions.

Sequential Nature of (p,3p) Two-Proton Knockout from Neutron-Rich Nuclei.

Twenty-one two-proton knockout (p,3p) cross sections were measured from neutron-rich nuclei at ∼250 MeV/nucleon in inverse kinematics. The angular distribution of the three emitted protons was determined for the first time, demonstrating that the (p,3p) kinematics are consistent with two sequential proton-proton collisions within the projectile nucleus. Ratios of (p,3p) over (p,2p) inclusive cross sections follow the trend of other many-nucleon removal reactions, further reinforcing the sequential nature of (p,3p) in neutron-rich nuclei.

Metastable States of

Here we present new information on the shape evolution of the very neutron-rich ^{92,94}Se nuclei from an isomer-decay spectroscopy experiment at the Radioactive Isotope Beam Factory at RIKEN. High-resolution germanium detectors were used to identify delayed γ rays emitted following the decay of their isomers. New transitions are reported extending the previously known level schemes. The isomeric levels are interpreted as originating from high-K quasineutron states with an oblate deformation of ß∼0.25, with the high-K state in ^{94}Se being metastable and K hindered. Following this, ^{94}Se is the lowest-mass neutron-rich nucleus known to date with such a substantial K hindrance. Furthermore, it is the first observation of an oblate K isomer in a deformed nucleus. This opens up the possibility for a new region of K isomers at low Z and at oblate deformation, involving the same neutron orbitals as the prolate orbitals within the classic Z∼72 deformed hafnium region. From an interpretation of the level scheme guided by theoretical calculations, an oblate deformation is also suggested for the ^{94}Se_{60} ground-state band.

Virtual monochromatic image at lower energy level for assessing pancreatic ductal adenocarcinoma in fast kV-switching dual-energy CT.

AIM: To evaluate the value of virtual monochromatic images (VMIs) at lower energy levels in fast-voltage-switching dual-energy computed tomography (DECT) for assessing pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The institutional review board approved this prospective study. Written informed consent was obtained from all patients. Seventy-four consecutive patients with PDAC underwent dynamic contrast-enhanced DECT. Two radiologists reviewed eight energy levels (40, 45, 50, 55, 60, 65, 70, and 75 keV) of the pancreatic parenchymal phase VMIs. CT attenuation of the PDAC and pancreatic parenchyma, background noise, signal-to-noise ratio (SNR) of the pancreas, tumour-to-pancreas contrast-to-noise ratio (CNR), major and minor axes of PDAC, and qualitative tumour conspicuity were compared among the VMIs at eight energy levels. RESULTS: CT attenuation of PDAC and pancreatic parenchyma, background noise, SNR, and CNR peaked on VMIs at 40 keV with statistically significant difference (p<0.0001) and gradually decreased with increasing energy levels. The reproducibility in measuring tumour size was better on VMIs at 40 keV (28.8 and 29.2 mm of major axis in readers 1 and 2, respectively) and tended to be overestimated at higher energy levels (29.8 and 30.9 mm of major axis at 75 keV in readers 1 and 2, respectively). Qualitative tumour conspicuity was also significantly superior on VMIs at 40 keV than at all other energy levels (p<0.0001). CONCLUSION: VMIs at 40 keV demonstrated significantly increased SNR of the pancreas, CNR, and tumour conspicuity and high reproducibility in measuring tumour size for assessing PDAC.

Mortality after transcatheter versus surgical aortic valve replacement: an updated meta-analysis of randomised trials.

BACKGROUND: To determine whether transcatheter aortic valve implantation (TAVI) improves early (30-day) and midterm (1-year) mortality compared with surgical aortic valve replacement (SAVR), we performed an updated meta-analysis of all the currently available randomised controlled trials (RCTs). METHODS: To identify all RCTs providing both 30-day and 1­year mortality after TAVI versus SAVR, PubMed and ClinicalTrials.gov were searched up to and including July 2019. A risk difference (RD) and its 95% confidence interval were generated using data of prespecified outcomes in both the TAVI and SAVR groups. Study-specific estimates were pooled using inverse variance-weighted averages of RDs in the random-effects model. RESULTS: We identified seven eligible high-quality RCTs including a total of 7631 as-treated patients. Pooled analyses demonstrated significantly lower 30-day (RD -0.60%; p = 0.046) and 1­year all-cause mortality (RD -1.12%; p = 0.03) after TAVI than after SAVR. No funnel plot asymmetry was detected for 30-day and 1­year mortality. Meta-regression analyses indicated that RDs of 30-day and 1­year mortality between TAVI and SAVR were not modulated by mean Society of Thoracic Surgeons Predicted Risk of Mortality score. Bleeding complications at 30 days and 1 year and stage 2/3 acute kidney injury at 30 days were significantly less frequent after TAVI than after SAVR, whereas major vascular complications and new permanent pacemaker implantation at 30 days and 1 year were significantly more frequent after TAVI than after SAVR. CONCLUSION: The best evidence from the present meta-analysis of all the currently available RCTs suggests that TAVI may reduce 30-day and 1­year all-cause mortality compared with SAVR.

REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients.

BACKGROUND: The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins. RESULTS: One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib. CONCLUSIONS: The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.

Prominence of Pairing in Inclusive (p,2p) and (p,pn) Cross Sections from Neutron-Rich Nuclei.

Fifty-five inclusive single nucleon-removal cross sections from medium mass neutron-rich nuclei impinging on a hydrogen target at ∼250 MeV/nucleon are measured at the RIKEN Radioactive Isotope Beam Factory. Systematically higher cross sections are found for proton removal from nuclei with an even number of protons as compared to odd-proton number projectiles for a given neutron separation energy. Neutron removal cross sections display no even-odd splitting, contrary to nuclear cascade model predictions. Both effects are understood through simple considerations of neutron separation energies and bound state level densities originating in pairing correlations in the daughter nuclei. These conclusions are supported by comparison with semimicroscopic model predictions, highlighting the enhanced role of low-lying level densities in nucleon-removal cross sections from loosely bound nuclei.

Induction of humoral and cellular immune response to hepatitis B virus (HBV) vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand.

A persistent hepatitis B virus (HBV) infection is characterized by a lack of or a weak immune response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific immune response leads to the clearance of HBV in patients with a chronic HBV infection. CpG oligodeoxynucleotides (ODN) has a powerful adjuvant effect in HBV vaccination. A recent report demonstrated that the immunization by B/K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand, schizophyllan (SPG), namely K3-SPG, was more effective in the induction of antigen-specific immune response than that by K3. In this study, we examined the efficacy of K3-SPG as a HBV vaccine adjuvant. Wild-type (WT) mice and HBV transgenic (HBV-Tg) mice were subcutaneously immunized with hepatitis B surface antigen (HBsAg) alone, HBsAg and K3, or HBsAg and K3-SPG. The vaccination with HBsAg and K3-SPG significantly enhanced humoral and cellular immune response to HBV antigen compared to the other vaccinations in WT and HBV-Tg mice. K3-SPG induced the accumulation of dendritic cells (DCs) into draining lymph node and the activation of DCs. The expression of cytokines and chemokines related to Th1 and Th2 responses was upregulated after the vaccination including with K3-SPG. In conclusion, these results indicated that the vaccination using K3-SPG may overcome tolerance even in patients with chronic HBV infection.

Gamma Decay of Unbound Neutron-Hole States in

Excited states in the nucleus ^{133}Sn, with one neutron outside the double magic ^{132}Sn core, were populated following one-neutron knockout from a ^{134}Sn beam on a carbon target at relativistic energies at the Radioactive Isotope Beam Factory at RIKEN. Besides the γ rays emitted in the decay of the known neutron single-particle states in ^{133}Sn additional γ strength in the energy range 3.5-5.5 MeV was observed for the first time. Since the neutron-separation energy of ^{133}Sn is low, S_{n}=2.402(4) MeV, this observation provides direct evidence for the radiative decay of neutron-unbound states in this nucleus. The ability of electromagnetic decay to compete successfully with neutron emission at energies as high as 3 MeV above threshold is attributed to a mismatch between the wave functions of the initial and final states in the latter case. These findings suggest that in the region southeast of ^{132}Sn nuclear structure effects may play a significant role in the neutron versus γ competition in the decay of unbound states. As a consequence, the common neglect of such effects in the evaluation of the neutron-emission probabilities in calculations of global ß-decay properties for astrophysical simulations may have to be reconsidered.

Are There Signatures of Harmonic Oscillator Shells Far from Stability? First Spectroscopy of

The first measurement of the low-lying states of the neutron-rich ^{110}Zr and ^{112}Mo was performed via in-beam γ-ray spectroscopy after one proton removal on hydrogen at ∼200 MeV/nucleon. The 2_{1}^{+} excitation energies were found at 185(11) keV in ^{110}Zr, and 235(7) keV in ^{112}Mo, while the R_{42}=E(4_{1}^{+})/E(2_{1}^{+}) ratios are 3.1(2), close to the rigid rotor value, and 2.7(1), respectively. These results are compared to modern energy density functional based configuration mixing models using Gogny and Skyrme effective interactions. We conclude that first levels of ^{110}Zr exhibit a rotational behavior, in agreement with previous observations of lighter zirconium isotopes as well as with the most advanced Monte Carlo shell model predictions. The data, therefore, do not support a harmonic oscillator shell stabilization scenario at Z=40 and N=70. The present data also invalidate predictions for a tetrahedral ground state symmetry in ^{110}Zr.

Shape Evolution in Neutron-Rich Krypton Isotopes Beyond N=60: First Spectroscopy of

We report on the first γ-ray spectroscopy of low-lying states in neutron-rich ^{98,100}Kr isotopes obtained from ^{99,101}Rb(p,2p) reactions at ∼220 MeV/nucleon. A reduction of the 2_{1}^{+} state energies beyond N=60 demonstrates a significant increase of deformation, shifted in neutron number compared to the sharper transition observed in strontium and zirconium isotopes. State-of-the-art beyond-mean-field calculations using the Gogny D1S interaction predict level energies in good agreement with experimental results. The identification of a low-lying (0_{2}^{+}, 2_{2}^{+}) state in ^{98}Kr provides the first experimental evidence of a competing configuration at low energy in neutron-rich krypton isotopes consistent with the oblate-prolate shape coexistence picture suggested by theory.

DISC1 causes associative memory and neurodevelopmental defects in fruit flies.

Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.

Fine mapping of a major quantitative trait locus, qLG-9, that controls seed longevity in rice (Oryza sativa L.).

KEY MESSAGE: We fine-mapped a quantitative trait locus, qLG - 9, for seed longevity detected between Japonica-type and Indica-type cultivars. qLG - 9 was mapped in a 30-kb interval of the Nipponbare genome sequence. A quantitative trait locus, qLG-9, for seed longevity in rice has previously been detected on chromosome 9 by using backcross inbred lines derived from a cross between Japonica-type (Nipponbare) and Indica-type (Kasalath) cultivars. In the present study, the chromosomal location of qLG-9 was precisely determined by fine-scale mapping. Firstly, allelic difference in qLG-9 was verified by QTL analysis of an F2 population derived from a cross between Nipponbare and NKSL-1, in which a segment of Kasalath chromosome 9 was substituted in Nipponbare genetic background. Then, we selected F2 plants in which recombination had occurred near qLG-9 and performed F3 progeny testing on these plants to determine the genotype classes of qLG-9. Eventually, qLG-9 was mapped in a 30-kb interval (defined by two markers, CAPSb and CHPa12) of the Nipponbare genome sequence. This allowed us to nominate positional candidate genes of qLG-9. Additionally, we developed near-isogenic lines (NIL) for qLG-9 by marker-assisted selection. qLG-9 NIL showed significantly higher seed longevity than isogenic control of Nipponbare. These results will facilitate cloning of the gene(s) underlying qLG-9 as well as marker-assisted transfer of desirable genes for seed longevity improvement in rice.

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Prevention of orofacial injury via the use of mouthguards among young male rugby players.

The purpose of this study was to examine factors hindering the use of mouthguards and the incidence of orofacial injury among young male rugby players. 69 high school rugby players (Group 1) and 431 medical student rugby players (Group 2) participated in this study. Participants in Group 1 used custom-made mouthguards fabricated according to a standardized method, whereas participants in Group 2 used custom-made or over-the-counter mouthguards of their choice. The factors associated with orofacial injury were assessed by logistic regression analysis, while factors hindering mouthguard use were assessed by multinomial logistic regression analysis. All data were obtained from a questionnaire developed by the Japanese Academy of Sports Dentistry. We found that breathing problems were the main factor contributing to the reduced frequency of mouthguard use. In both groups, a significant negative association was observed between the frequency of mouthguard use and the risk of orofacial injury. The group using standardized custom-made mouthguards reported fewer complaints about breathing problems and a higher frequency of mouthguard use. The results of this study suggest that increasing the frequency of mouthguard use would reduce the risk of orofacial injury among young male rugby players. We also conclude that users of custom-made mouthguards complain less frequently of breathing difficulties.

Systemic lupus erythematosus complicated with liver cirrhosis in a patient with Papillon-Lefèvre syndrome.

We report the first case of a girl who presented with Papillon-Lefèvre syndrome (PLS) and subsequently developed systemic lupus erythematosus and liver cirrhosis. This indicates that autoimmune diseases can be a complication in patients with PLS. Cathepsin C gene mutations were not found in our patient or her mother. Thus, other genetic factors may have been involved in this patient.

Multiple drug combination of anti-diabetic agents as a predictor for poor clinical response to liraglutide.

AIM: Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues. METHODS: We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups. RESULTS: Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide. CONCLUSION: Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.