Impact of the Comprehensive Awareness Modification of Mouth, Chewing and Meal (CAMCAM) Program on the Attitude and Behavior Towards Oral Health and Eating Habits as Well as the Condition of Oral Frailty: A Pilot Study.

OBJECTIVES: Preserving sufficient oral function and maintaining aadequate nutrition are essential for preventing physical frailty and the following long-term care. We recently developed the 6-month Comprehensive Awareness Modification of Mouth, Chewing And Meal (CAMCAM) program, in which participants gather monthly to learn about oral health and nutrition while eating a textured lunch together. This study examined whether the CAMCAM program could improve attitude and behavior towards oral health, mastication, and diet as well as ameliorate oral frailty in community-dwelling older adults. DESIGN: Single-arm pre-post comparison study. SETTING AND PARTICIPANTS: A total of 271 community-dwelling adults (72.3 ± 5.7 years of age; 159 women [58.7%]) in 4 Japanese municipalities were recruited, of which 249 participants (92%) were assessed at the final evaluation. INTERVENTION: Participants gathered once a month at community centers to learn about oral health and nutrition while eating a "munchy" textured lunch containing proper nutrition. MEASUREMENTS: Oral frailty, frailty, and eating behavior were evaluated with the Oral Frailty Index-8 (OFI-8), Kihon checklist (KCL), and CAMCAM checklist, respectively. Participants were divided into Oral frailty (OF) and Robust groups according to OFI-8 scores. The differences in KCL and CAMCAM checklist results between the OF and Robust groups were statistically tested along with changes in scores after the program. RESULTS: KCL and CAMCAM checklist scores were significantly lower in the OF group at the initial assessment. OFI-8 and KCL findings were significantly improved in the OF group after completing the program (all P <0.05). Regarding the CAMCAM checklist, awareness of chewing improved significantly in the Robust group (P=0.009), with a similar tendency in the OF group (P=0.080). CONCLUSION: The findings of this pilot study suggest that the CAMCAM program may improve both oral and systemic frailty in addition to attitudes towards chewing, oral health, and meals, especially in individuals with oral frailty. The CAMCAM program merits expansion as a community-based frailty prevention program.

Absence of the Anterior Communicating Artery on Selective MRA is Associated with New Ischemic Lesions on MRI after Carotid Revascularization.

BACKGROUND AND PURPOSE: ICA-selective MRA using a pencil beam presaturation pulse can accurately visualize anterior communicating artery flow. We evaluated the impact of anterior communicating artery flow on the perioperative hemodynamic status and new ischemic lesions after carotid revascularization. MATERIALS AND METHODS: Eighty-three patients with carotid artery stenosis were included. We assessed anterior communicating artery flow using ICA-selective MRA. The preoperative hemodynamic status was measured using SPECT. We also measured the change in regional cerebral oxygen saturation after temporary ICA occlusion. New ischemic lesions were evaluated by DWI on the day after treatment. RESULTS: Anterior communicating artery flow was detected in 61 patients, but it was not detected in 22 patients. Preoperative cerebrovascular reactivity was significantly higher in patients with (versus without) anterior communicating artery flow with a mean peak systolic velocity of ≥200 cm/s (39.6% [SD, 23.8%] versus 25.2% [SD, 16.4%]; P = .030). The decrease in mean regional cerebral oxygen saturation was significantly greater in patients without (versus with) anterior communicating artery flow (8.5% [SD, 5.6%] versus 3.7% [SD, 3.8%]; P = .002). New ischemic lesions after the procedure were observed in 23 patients. The multivariate logistic regression analysis revealed that anterior communicating artery flow (OR, 0.07; 95% CI, 0.012-0.45; P = .005) was associated with new ischemic lesions. CONCLUSIONS: The absence of anterior communicating artery flow influenced the perioperative hemodynamic status in patients with carotid stenosis and was associated with an increased incidence of new ischemic lesions after carotid revascularization.

Hospital surgical volume-outcome relationship in caesarean hysterectomy for placenta accreta spectrum.

OBJECTIVE: To examine the association between hospital surgical volume of caesarean hysterectomy and surgical morbidity in women with placenta accreta spectrum (PAS). DESIGN: Population-based retrospective cohort study. SETTING: National Inpatient Sample, January 2016 to December 2018. POPULATION: Six thousand and ten women with PAS who underwent caesarean hysterectomy in 738 centres. METHODS: (1) Comprehensive modelling for relative hospital surgical volume cut-point selection, (2) multinomial regression analysis for characterising hospital surgical volume, and (3) binary logistic regression analysis to examine the volume-outcome relationship. MAIN OUTCOME MEASURES: Surgical morbidity (haemorrhage, coagulopathy, shock, urinary tract injury, and death). RESULTS: The majority of centres had five surgeries over the 3-year period (468 centres, 63.4%) and were grouped as the low-volume group. Surgical morbidity decreased after a relative hospital surgical volume of 25 cases (24 centres, 3.3%) was reached, grouped as the high-volume group. The remaining centres were grouped as the mid-volume group (246 centres, 33.3%). In multivariable analysis, women in the high-volume group were more likely to be Black, have lower median household income, medical comorbidity, previous caesarean delivery, placenta praevia or placenta percreta, and to have undergone surgeries at large urban teaching hospitals compared with those in the low-volume group (all, P < 0.05). After controlling for patient demographics, hospital characteristics and pregnancy factors, performance of caesarean hysterectomy at high-volume centres was associated with a 22% decreased risk of surgical complications compared with surgery at the low-volume centres (adjusted odds ratio 0.78, 95% CI 0.64-0.94). CONCLUSION: Caesarean hysterectomy for PAS is a rare surgical procedure. Higher hospital surgical volume may be associated with improved surgical outcome in PAS. TWEETABLE ABSTRACT: Higher hospital caesarean hysterectomy volume may be associated with improved surgical outcome in PAS.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

Fast electron transport dynamics and energy deposition in magnetized, imploded cylindrical plasma.

Inertial confinement fusion approaches involve the creation of high-energy-density states through compression. High gain scenarios may be enabled by the beneficial heating from fast electrons produced with an intense laser and by energy containment with a high-strength magnetic field. Here, we report experimental measurements from a configuration integrating a magnetized, imploded cylindrical plasma and intense laser-driven electrons as well as multi-stage simulations that show fast electrons transport pathways at different times during the implosion and quantify their energy deposition contribution. The experiment consisted of a CH foam cylinder, inside an external coaxial magnetic field of 5 T, that was imploded using 36 OMEGA laser beams. Two-dimensional (2D) hydrodynamic modelling predicts the CH density reaches [Formula: see text], the temperature reaches 920 eV and the external B-field is amplified at maximum compression to 580 T. At pre-determined times during the compression, the intense OMEGA EP laser irradiated one end of the cylinder to accelerate relativistic electrons into the dense imploded plasma providing additional heating. The relativistic electron beam generation was simulated using a 2D particle-in-cell (PIC) code. Finally, three-dimensional hybrid-PIC simulations calculated the electron propagation and energy deposition inside the target and revealed the roles the compressed and self-generated B-fields play in transport. During a time window before the maximum compression time, the self-generated B-field on the compression front confines the injected electrons inside the target, increasing the temperature through Joule heating. For a stronger B-field seed of 20 T, the electrons are predicted to be guided into the compressed target and provide additional collisional heating. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Relativistic magnetic reconnection in laser laboratory for testing an emission mechanism of hard-state black hole system.

Magnetic reconnection in a relativistic electron magnetization regime was observed in a laboratory plasma produced by a high-intensity, large energy, picoseconds laser pulse. Magnetic reconnection conditions realized with a laser-driven several kilotesla magnetic field is comparable to that in the accretion disk corona of black hole systems, i.e., Cygnus X-1. We observed particle energy distributions of reconnection outflow jets, which possess a power-law component in a high-energy range. The hardness of the observed spectra could explain the hard-state x-ray emission from accreting black hole systems.

Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter?

OBJECTIVE: The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes. METHODS: This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11). CONCLUSIONS: Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

Conservative surgery for ovarian torsion in young women: perioperative complications and national trends.

OBJECTIVE: To analyse populational trends and perioperative complications following conservative surgery versus oophorectomy in women <50 years of age with ovarian torsion. DESIGN: Population-based retrospective observational study. SETTING: Nationwide Inpatient Sample in the USA (2001-2015). POPULATION: In all, 89 177 ovarian torsions including 20 597 (23.1%) conservative surgeries and 68 580 (76.9%) oophorectomies. METHODS: (1) Trend analysis to assess utilisation of conservative surgery over time, (2) multivariable binary logistic regression to identify independent factors associated with conservative surgery and (3) inverse probability of treatment weighting with a generalised estimating equation to analyze perioperative complications. MAIN OUTCOME MEASURES: Trends, characteristics and complications related to conservative surgery. RESULTS: Performance of conservative surgery increased from 18.9 to 25.1% between 2001 and 2015 (32.8% relative increase, P = 0.001) but decreased steadily after age 15, and sharply declined after age 35 (P < 0.001). On multivariable analysis, younger age exhibited the largest effect size for conservative surgery among the independent factors (adjusted odds ratios 3.39-7.96, P < 0.001). In the weighted model, conservative surgery was associated with an approximately 30% decreased risk of perioperative complications overall (10.0% versus 13.6%, odds ratio 0.73, 95% confidence interval 0.62-0.85, P < 0.001) and was not associated with venous thromboembolism (0.2 versus 0.3%, P = 0.457) or sepsis (0.4 versus 0.3%, P = 0.638). CONCLUSION: There has been an increasing utilisation of conservative surgery for ovarian torsion in the USA in recent years. Our study suggests that conservative surgery for ovarian torsion may not be associated with increased perioperative complications. TWEETABLE ABSTRACT: Conservative surgery for ovarian torsion may not be associated with increased perioperative complications.

Positive Effects of "Textured Lunches" Gatherings and Oral Exercises Combined with Physical Exercises on Oral and Physical Function in Older Individuals: A Cluster Randomized Controlled Trial.

OBJECTIVES: Proper nutrition and physical exercises are essential to prevent frailty in older adults. Proper masticatory performance and oral function may influence on physical activities as well since the mouth is the entrance of nutrition and digestion. Thus, the present study aimed to test the combined program of specially devised lunch gatherings containing textured foods with oral and physical exercises on the improvement of oral and physical function in community-dwelling older adults. DESIGN: A Cluster randomized controlled trial; Setting and Participants: Eighty-six community-dwelling older adults in Daito city, Japan, were randomly assigned into control (n = 43) or intervention (n = 43) groups. INTERVENTION: The control group performed the physical exercise regimen only. The intervention group participated in a 12-week physical and oral exercise program and ate a so-called "munchy lunch" that introduced textured foods with proper nutrients together after performing the physical exercise twice a week following brief dietary instruction at the intervention onset. Physical training and lunch gatherings were held at local public centers. MEASUREMENTS: The differences in measured variables for physical and oral function between baseline and 12 weeks of intervention were statistically tested. RESULTS: Oral function as measured by tongue pressure increased significantly in the intervention group (p=0.031), but not in the control group. Physical properties and activities, including body fat percentage and results of the timed up and go test, decreased more significantly in the intervention group than in controls (p<0.05). CONCLUSIONS: Our findings suggest that a combined program of textured lunch gatherings with oral and physical exercises may improve physical and oral function as a preventative approach for frailty in community-dwelling older adults.

Enhancing laser beam performance by interfering intense laser beamlets.

Increasing the laser energy absorption into energetic particle beams represents a longstanding quest in intense laser-plasma physics. During the interaction with matter, part of the laser energy is converted into relativistic electron beams, which are the origin of secondary sources of energetic ions, γ-rays and neutrons. Here we experimentally demonstrate that using multiple coherent laser beamlets spatially and temporally overlapped, thus producing an interference pattern in the laser focus, significantly improves the laser energy conversion efficiency into hot electrons, compared to one beam with the same energy and nominal intensity as the four beamlets combined. Two-dimensional particle-in-cell simulations support the experimental results, suggesting that beamlet interference pattern induces a periodical shaping of the critical density, ultimately playing a key-role in enhancing the laser-to-electron energy conversion efficiency. This method is rather insensitive to laser pulse contrast and duration, making this approach robust and suitable to many existing facilities.

Assessment of Oral Function and Proper Diet Level for Frail Elderly Individuals in Nursing Homes Using Chewing Training Food.

OBJECTIVES: We aimed to investigate the relationship between the ability to press Process Lead (PL) in the oral cavity and the tongue pressure and recommended diet form for elderly individuals in nursing homes, using PL normalized physical properties. DESIGN: Cross-sectional observation study. SETTING: Geriatric facilities. PARTICIPANTS: A 100 elderly individuals aged between 67-96 years. MEASUREMENTS: PL was pressed between the tongue and palate to evaluate its deformation. The thickness was set at 6, 9, and 18 mm. The tongue pressure was measured with a JMS tongue pressure manometer. The number of chewing cycles until an 18-mm thick PL was first swallowed was measured (PL chewing test). The diet was set to level 4, and the recommended form was evaluated by video endoscopic evaluation of swallowing (VE). The results of the PL pressing test and correlations between PL chewing test, tongue pressure, and diet level were statistically examined. RESULTS: The tongue pressure was significantly decreased in groups that could not press the PL. The PL pressing test and recommended diet form showed a significant correlation, and the elderly with difficulty in pressing the PL had a lower diet level. In addition, the diet level decreased with decreased PL chewing test performance in those without molar occlusion. CONCLUSIONS: The PL pressing and chewing tests may aid in ascertaining the appropriate diet level. In the future, we would like to verify the usefulness of these tests in determining the diet level of elderly people requiring long-term care at the time of entering the facility.

Proposal for a new classification for perihilar cholangiocarcinoma based on tumour depth.

BACKGROUND: The T system for distal cholangiocarcinoma has been revised from a layer-based to a depth-based approach in the current American Joint Committee on Cancer (AJCC) classification. In perihilar cholangiocarcinoma, tumour depth in the staging scheme has not yet been addressed. The aim of this study was to propose a new T system using measured tumour depth in perihilar cholangiocarcinoma. METHODS: Patients who underwent hepatectomy for perihilar cholangiocarcinoma between 2001 and 2014 were reviewed retrospectively. The vertical distance between the top of the tumour and deepest invasive cells was measured as invasive tumour thickness (ITT) by two independent pathologists. Log rank statistics were used to determine cut-off points, and the concordance (C) index was used to assess survival discrimination of each T system. RESULTS: ITT was measurable in all 440 patients, with a median value of 6·0 (range 0-45) mm. The median difference in ITT between observers was 0·6 (range 0-20) mm. Cut-off points for prognosis were 1, 5 and 8 mm. Five-year survival decreased with increasing ITT (P < 0·001): 67 per cent for ITT less than 1 mm (25 patients), 54·9 per cent for ITT 1 mm and over to less than 5 mm (138 patients), 43·4 per cent for ITT 5 mm and over to less than 8 mm (118 patients), and 32·2 per cent for ITT 8 mm and over (159 patients). The C-index of this classification was comparable to that of the current AJCC T classification (0·598 versus 0·589). CONCLUSION: ITT is a reliable approach for making a depth assessment in perihilar cholangiocarcinoma. A four-tier ITT classification with cut-off points of 1, 5 and 8 mm is an adequate alternative to the current layer-based T classification.

A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

Cigarette smoking and cervical cancer risk: an evaluation based on a systematic review and meta-analysis among Japanese women.

BACKGROUND: There is a body of evidence to suggest that cigarette smoking increases the risk of cervical cancer in women, but no study has examined the magnitude of the association in Japanese women. Here, we evaluated the association between cigarette smoking and the risk of cervical cancer in Japanese women based on a systematic review of epidemiological evidence. METHODS: Original data were obtained from a MEDLINE search using PubMed or from a search of the 'Ichushi' database, as well as by a manual search. Evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as evaluated previously by the International Agency for Research on Cancer. Meta-analysis of associations was also conducted to obtain a summarized overview of the data. RESULTS: We identified two cohort studies and three case-control studies. All five studies had indicated strong positive associations between cigarette smoking and the risk of cervical cancer. Our summary estimate indicated that the relative risk (RR) for individuals who had ever-smoked relative to never-smokers was 2.03 (95% confidence interval: 1.49-2.57). Four studies had also demonstrated dose-response relationships between cigarette smoking and the risk of cervical cancer. CONCLUSION: We conclude that there is convincing evidence that cigarette smoking increases the risk of cervical cancer among Japanese women.

Evaluation of the safety of ramucirumab in Japanese patients with advanced gastric cancer.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Evidence-based cancer prevention recommendations for Japanese.

A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: 'Cancer Prevention Recommendation for Japanese'. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination.

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

Development of an oesophageal stimulation method to elicit swallowing reflex in humans.

Swallowing reflex is known to be evoked by gastroesophageal regurgitation or oesophageal stimulation in animal studies. However, details regarding the stimulating material, bolus size and stimulation area remain unclear for the stimulation-induced type of swallowing reflex in humans. Here, we evaluated the effects of different kinds of stimulation via water and air injection of the oesophagus on the initiation of the swallowing reflex. Nine healthy individuals participated in this study. A fibre-optic endoscope was passed transnasally, and a thin catheter for injection was passed through the other side. The tip of the catheter was placed at the upper, upper middle, lower middle or lower region of the oesophagus, and the rate of injection was controlled at 0.2 mL/s. Swallowing reflex latency was calculated as the time from injection via air or thin/thick fluid until the onset of white-out in endoscopic images. Reflex latency was significantly shorter when injection occurred at the upper region of the oesophagus than at the lower region, for both thin and thick fluids (P < .01). At the upper region of the oesophagus, the latency was significantly shorter after injection of thin fluid than with thick fluid (P < .05). Injection of air did not induce the swallowing reflex at all sites. These findings suggest that while the swallowing reflex is evoked by stimulation via fluid injection of the oesophagus in humans, sensitivity is greatest in the upper region of the oesophagus compared with the lower region and can vary depending on the injecting material.

Randomized clinical trial of duct-to-mucosa versus invagination pancreaticojejunostomy after pancreatoduodenectomy.

BACKGROUND: The postoperative pancreatic fistula (POPF) rate for duct-to-mucosa and invagination anastomosis after pancreatoduodenectomy is still debated. The aim of this RCT was to investigate the POPF rate for duct-to-mucosa versus invagination pancreaticojejunostomy. METHODS: Patients were stratified by pancreatic texture and diameter of the main pancreatic duct and randomized to the duct-to-mucosa or invagination group. The primary endpoint was the rate of clinically relevant POPF (defined as grade B or C). Secondary endpoints were suture material cost for pancreaticojejunostomy, drain insertion duration and duration of postoperative hospital stay. RESULTS: Some 120 patients undergoing pancreatoduodenectomy were included following consent. Clinically relevant POPF developed in six of 59 patients (10 per cent) in the invagination group and in 14 of 61 patients (23 per cent) in the duct-to-mucosa group (P = 0·077). Duration of drain insertion (6 versus 7 days respectively; P = 0·027) and postoperative hospital stay (19 versus 24 days; P = 0·015) were shorter in the invagination group. Subgroup analysis for 61 patients with a soft pancreas revealed a lower rate of clinically relevant POPF in the invagination group (10 per cent versus 42 per cent in the duct-to-mucosa group; P = 0·010). Among 20 patients with a clinically relevant POPF, the six patients in the invagination group had a shorter duration of drain insertion (38·5 days versus 49 days for 14 patients in the duct-to-mucosa group; P = 0·028) and postoperative hospital stay (42 versus 54·5 days respectively; P = 0·028). CONCLUSION: This study did not demonstrate a superiority of invagination over duct-to-mucosa pancreaticojejunostomy in the risk of POPF. However, in high-risk patients with a soft pancreas, invagination may reduce the risk of clinically relevant POPF compared with duct-to-mucosa. Registration number: UMIN000005890 (http://www.umin.ac.jp).