Polyandry may mitigate the negative impact of reproductive interference among bumblebees in Japan.

In social hymenopterans, monandry of the queen is an ancestral trait, and polyandry is a derived trait. Polyandry of the queen is the norm in a limited number of lineages, such as honeybees, leaf-cutting ants, Pogonomyrmex ants, and Vespula wasps, which presumably provide fitness advantages for the whole colony. The queen of the introduced bumblebee, Bombus terrestris, is polyandrous in Japan, whereas it is monandrous in native regions. We hypothesize that polyandry can evolve in a process that avoids the negative impacts of reproductive interference caused by interspecific mating and conducted genetic studies of the invasive species B. terrestris and two native subspecies, Bombus hypocrita sapporoensis and Bombus hypocrita hypocrita, in Japan. Our results revealed that although the native queens of B. hypocrita hypocrita allopatric with B. terrestris were strictly monandrous, the native queens of B. hypocrita sapporoensis sympatric with B. terrestris were polyandrous. These results suggested that the queens of native B. hypocrita sapporoensis do not experience negative impacts on interspecific mating from the invasive B. terrestris. We discuss the possibility that reproductive interference is a driving force in selection for multiple mating through an arms race between sympatric species.

Clinical impact of atrial fibrillation progression in patients with heart failure with preserved ejection fraction: A report from the CHART-2 Study.

AIMS: Atrial fibrillation (AF) frequently coexists with heart failure with preserved ejection fraction (HFpEF), and clinical outcomes of patients with AF vary depending on its subtype. While AF progression characterized by the transition from paroxysmal AF to persistent AF is sometimes observed, the incidence and clinical impact of AF progression in patients with HFpEF remain to be explored. METHODS AND RESULTS: We enrolled patients with HFpEF and paroxysmal AF from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. AF progression was defined as the transition from paroxysmal AF to persistent AF. A total of 718 patients (median age: 72 years, 36% were female) were enrolled. For a median follow-up of 6.0 years (interquartile range: 3.0-10.2 years), AF progression occurred in 105 patients (14.6%), with a cumulative incidence of 16.7% at 10 years. In the multivariable Cox proportional hazards model, previous hospitalization for heart failure [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.16-2.60; P = 0.007] and left atrial diameter (per 5-mm increase) (HR 1.37, 95% CI 1.20-1.55; P < 0.001) were significantly associated with AF progression. Furthermore, AF progression was significantly linked to worsening heart failure (adjusted HR 1.68, 95% CI 1.18-2.40; P = 0.004). Notably, 27 cases (26%) of worsening heart failure occurred within 1 year following AF progression. CONCLUSION: In patients with HFpEF, AF progression is significantly associated with adverse outcomes, particularly worsening heart failure. An increased risk is observed in the early phases following progression to persistent AF. REGISTRATION: Clinical Trials.gov Identifier: NCT00418041.

Impact of Sex Differences on Clinical Outcomes in Patients Following Primary Revascularization for Acute Myocardial Infarction　- Insights From the Japanese Nationwide Registry.

BACKGROUND: Women with acute myocardial infarction (AMI) often present a worse risk profile and experience a higher rate of in-hospital mortality than men. However, sex differences in post-discharge prognoses remain inadequately investigated. We examined the impact of sex on 1-year post-discharge outcomes in patients with AMI undergoing percutaneous coronary intervention. METHODS AND RESULTS: We extracted patient-level data for the period January 2017-December 2018 from the J-PCI OUTCOME Registry, endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics. One-year all-cause and cardiovascular mortality and major adverse cardiovascular events were compared between men and women. In all, 29,856 AMI patients were studied, with 6,996 (23.4%) being women. Women were significantly older and had a higher prevalence of comorbidities than men. Crude all-cause mortality was significantly higher among women than men (7.5% vs. 5.4% [P<0.001] for ST-elevation myocardial infarction [STEMI]; 7.0% vs. 5.2% [P=0.006] for non-STEMI). These sex-related differences in post-discharge outcomes were attenuated after stratification by age. Multivariate analysis demonstrated an increase in all-cause mortality in both sexes with increasing age and advanced-stage chronic kidney disease (CKD). CONCLUSIONS: Within this nationwide cohort, women had worse clinical outcomes following AMI than men. However, these sex-related differences in outcomes diminished after adjusting for age. In addition, CKD was significantly associated with all-cause mortality in both sexes.

New Directions for Advanced Targeting Strategies of EGFR Signaling in Cancer.

Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling studies paved the way for a basic understanding of growth factor and oncogene signaling pathways and the development of tyrosine kinase inhibitors (TKIs). Due to resistance mutations and the activation of alternative pathways when cancer cells escape TKIs, highly diverse cell populations form in recurrent tumors through mechanisms that have not yet been fully elucidated. In this review, we summarize recent advances in EGFR basic research on signaling networks and intracellular trafficking that may clarify the novel mechanisms of inhibitor resistance, discuss recent clinical developments in EGFR-targeted cancer therapy, and offer novel strategies for cancer drug development.

Impact of osteosclerosis on cervical pedicle screw insertion using preoperative CT-based navigation.

PURPOSE: Preoperative computed tomography (CT)-based navigation is used for cervical pedicle screw (CPS) insertion to mitigate the risk of spinal cord and vertebral artery injury. In vertebrae with osteosclerosis due to degeneration or other factors, however, probing may not proceed easily, with difficulty creating the CPS insertion hole. This study investigated the impact of osteosclerosis on the accuracy of CPS insertion. METHODS: A total of 138 patients with CPS inserted at the C3-C7 level using preoperative CT navigation were retrospectively analyzed. Pre- and postoperative CT was employed to investigate screw position and Hounsfield unit (HU) values at the lateral mass to evaluate the degree of osteosclerosis in the CPS insertion pathway. RESULTS: Among 561 CPS insertions, the Grade 3 perforation rate was 1.8%, and the Grade 2 or higher perforation rate was 8.0%. When comparing insertions with and without CPS perforation, HU values were significantly higher in the perforation group (578 ± 191 vs. 318 ± 191, p < 0.01). The frequency of CPS insertion into the mid-cervical spine was also significantly greater in the perforation group (68.9% vs. 62.5%, p < 0.01). Logistic regression analysis revealed that a high HU value at the lateral mass (odds ratio 1.09, 95% confidence interval: 1.07-1.11, p < 0.01) was a significant independent factor associated with CPS deviation. CONCLUSIONS: The screw perforation rate of Grade 2 or higher in CPS insertion using preoperative CT-based navigation was 8.0%. Since osteosclerosis was an independent factor related to CPS deviation, additional care may be required during insertion into affected vertebrae.

Excessive posterior placement of upper instrumented vertebra relative to lower instrumented vertebra as a predictor of proximal junction kyphosis after selective spinal fusion for adolescent idiopathic scoliosis Lenke type 5C curves.

PURPOSE: We defined sagittal S-line tilt (SSLT) as the tilt of the line connecting the upper instrumented vertebra and the lower instrumented vertebra. This study aimed to: (1) examine the correlation between SSLT and proximal junctional angle (PJA) change values, and (2) determine the cut-off value of SSLT with respect to proximal junctional kyphosis (PJK) occurrence. METHODS: Eighty-six consecutive patients (81 female and 5 male; mean age: 15.8 years) with Lenke 5C AIS who underwent posterior selective spinal fusion. Pearson's correlation coefficients were used to examine the relationship between preoperative SSLT and changes in PJA from preoperative to 2 years postoperative. The impact of SSLT on PJK at 2 years after surgery was assessed using a receiver operating characteristic (ROC) curve. RESULTS: We observed a moderate positive correlation between preoperative SSLT and change in PJA (R = 0.541, P < 0.001). We identified 18 patients (21%) with PJK at 2 years postoperative. Mean preoperative SSLT in the PJK group and the non-PJK group differed significantly at 23.3 ± 4.1° and 16.1 ± 5.0°, respectively (P < 0.001). The cut-off value of preoperative SSLT for PJK at 2 years postoperative was 18° in ROC curve analysis, with a sensitivity of 94%, specificity of 68%, and area under the ROC curve of 0.868. CONCLUSION: In selective lumbar fusion for AIS Lenke type 5C curves, preoperative SSLT was significantly correlated with PJA change from preoperative to 2 years postoperative. SSLT was a predictor of PJK occurrence, with a cut-off value of 18°.

No Difference in Graft Signal Intensity on Magnetic Resonance Imaging or Clinical Outcome Between Anterior Cruciate Ligament Reconstruction With and Without Suture Augmentation.

PURPOSE: To evaluate the safety of anterior cruciate ligament reconstruction (ACLR) with suture augmentation (SA) through clinical evaluations, monitoring of complications, and evaluation of early graft remodeling using magnetic resonance imaging (MRI). METHODS: Data of participants who underwent anatomic double-bundle ACLR using hamstring tendon autografts, with a minimum 2-year follow-up, were retrospectively reviewed. Participants undergoing ACLR with SA were propensity-matched with those without SA. Postoperative clinical evaluations were recorded, including Lysholm Knee Scoring Scale, Tegner activity score, International Knee Documentation Committee (IKDC) evaluation scores, KT-1000 side-to-side difference for knee stability at a 2-year follow-up, and complications. The minimal clinically important difference (MCID) was calculated for IKDC scores. The anteromedial bundle graft was categorized into distal, middle, and proximal regions on the 6-month and 1-year postoperative MRIs. The signal-to-noise quotient (SNQ) of each region of interest was calculated to evaluate the graft signal intensity, which was compared between the 2 groups using Welch's t test. RESULTS: Fifty-three participants were included in each group. No significant differences were observed between the non-SA and SA groups in the Lysholm scores (96.6 ± 6.2 and 95.3 ± 5.8, respectively; P = .25), Tegner activity scores (4.8 ± 1.4 and 5.0 ± 1.3, respectively; P = .49), IKDC scores (90.4 ± 10.8 and 87.1 ± 12.9, respectively; P = .15), percentage of patients meeting the MCID (94.3% and 83.0%, respectively; P = .12), or postoperative KT-1000 side-to-side difference (0.9 ± 1.2 and 0.7 ± 1.8 mm, respectively; P = .56). One (1.8%) and 2 (3.7%) cases of retears occurred in the non-SA and SA groups, respectively; no other complications occurred. The postoperative SNQ measurements revealed no significant differences in signal changes in all regions of the grafts between the 2 groups. CONCLUSIONS: This study confirmed no difference in graft signal intensity on MRI or clinical outcome between ACLR with and without SA at the 2-year follow-up. LEVEL OF EVIDENCE: Level III, retrospective, comparative study.

Postoperative patient-reported outcome measures after medial open-wedge high tibial osteotomy was improved by decreased joint line convergence angle.

PURPOSE: To evaluate the relationship between pre- and postoperative joint line convergence angle (JLCA) changes and patient-reported outcome measures related to medial open-wedge high tibial osteotomy (MOWHTO). METHODS: Sixty-one patients (71 knees) who underwent MOWHTO were examined. Preoperative and 2-year postoperative radiographic parameters (hip-knee-ankle angle, weight-bearing line ratio, medial proximal tibial angle and JLCA) were measured, and knee injury and osteoarthritis outcome scores (KOOS) were assessed. Patients were divided into two groups: group D (decreased JLCA compared with preoperative status) included 44 knees with a ΔJLCA < 0° and group I (increased JLCA and no-change JLCA compared with preoperative status) included 27 knees with a ΔJLCA ≥ 0°. KOOS sub-scores and the proportion of patients whose improvement exceeded the minimum clinically important difference (MCID) were compared between both groups using Student's t tests, Mann-Whitney U tests and chi-square tests. Multiple regression analysis was performed to determine the factor that had an influential effect on the postoperative KOOS total. RESULTS: Significant differences in 2-year postoperative KOOS were observed between the two groups, including total, symptom, pain and activities of daily living scores. Group D had significantly more patients who achieved MCID for both KOOS symptoms and pain scores than group I did. Multivariate analysis indicated that JLCA change and body mass index were significantly associated with the postoperative KOOS total. CONCLUSION: Patients with decreased JLCA had better 2-year post-MOWHTO KOOS and better symptom and pain improvements. Therefore, strategies that reduce JLCA are crucial to improving clinical outcomes, and efforts should be made to improve JLCA in surgical techniques. LEVEL OF EVIDENCE: Level Ⅳ, Case series.

Comparison of 2-octyl cyanoacrylate with polyester mesh with standard suture and staples in total knee and hip arthroplasty.

OBJECTIVE: The use of 2-octyl cyanoacrylate with polyester mesh (OCA-M) has become common in total hip and knee arthroplasty (THA, TKA). We aimed to compare the safety and cosmetic outcomes between OCA-M and standard suture techniques and staples, and determine whether OCA-M can safely be used for TKA. METHOD: Inclusion criteria were patients who underwent THA or TKA from January 2010 to October 2011 (Suture group), November 2011 to August 2013 (Staple group), March 2017 to September 2018 (OCA-M group). Exclusion criteria was loss of imaging data. Complications during hospitalisation (early complication) and after discharge (late complication) were compared in groups. Plastic and orthopaedic surgeons performed cosmetic evaluations with the modified Vancouver Scar Scale (VSS) and Likert scale at three and six months postoperatively and compared in groups. RESULTS: A total of 249 arthroplasties (suture group=88 patients; staple group=94 patients; OCA-M group=67 patients) were included in the study. The OCA-M group had a significantly lower early complication rate than the suture group (p=0.015). For THA, the OCA-M group had a significantly lower total complication rate than the suture group (p=0.048). For TKA, there was no significant difference among the three groups. The complication rate in the OCA-M group showed no significant difference between THA/TKA. With regards to the VSS, the OCA-M group was significantly better for cosmetic qualities than the suture group (p=<0.001, p=0.021 at three and six months, respectively). For the Likert scale, the OCA-M group was also significantly better for cosmetic qualities than the suture group and staple group (suture-OCA-M, p=0.003 (three months), p=<0.001 (six months); staple-OCA-M, p=0.027 (three months)). CONCLUSION: In this study, the OCA-M complication rate was low compared to suturing and similar to stapling. Moreover, better cosmetic outcomes were achieved compared to suturing and stapling.

Association between restricted outings and geriatric locomotive function scale score in the general elderly population during the COVID-19 pandemic.

BACKGROUND: Restrictions in daily activities due to coronavirus infection countermeasures reduced opportunities for physical activity and social participation in people of all ages. This study investigated the associations of restricted outings on locomotive function during the COVID-19 pandemic using a cohort of middle-aged and elderly community-dwelling residents. METHODS: Registered citizens of 50-89 years old were targeted for this investigation. We established 8 groups based on age (50's, 60's, 70's, and 80's) and gender (male and female) after random sampling from the basic resident registry of Obuse town in 2014. All participants were surveyed by a 25-question geriatric locomotive function scale (GLFS-25) at the time of checkup before the COVID-19 pandemic. Then, in 2021 and 2022 after government restrictions on outings were lifted for COVID-19 pandemic, all participants were mailed questionnaires including the GLFS-25. A total of 296 (143 male and 153 female) participants who responded at least once were included. We evaluated the changes in opportunities to go out between pre- and post-pandemic time points and the impact on GLFS-25 scores. RESULTS: In total, 128 (43.2%) respondents had fewer opportunities to go out than the previous year. Pre- and post-pandemic GLFS-25 scores in the decreased outing (+) group were significantly worse than in the decreased outing (-) group (both p < 0.01). The final multivariate model revealed GLFS-25 score worsening beta coefficient of 0.27 for age (+10 years), 3.97 for male, 4.54 for decreased outings, and 4.46 for spinal canal stenosis. CONCLUSIONS: In this randomly sampled Japanese cohort based on a resident registry, restricted outings during the COVID-19 pandemic was a significant independent factor associated with lower locomotive function.

Does early administration of denosumab delay bone healing after intertrochanteric femoral fractures?

INTRODUCTION: Hip fractures are commonly associated with osteoporosis and pose a risk for secondary fractures. Although the administration of anti-osteoporotic drugs is recommended after fractures to mitigate this risk, the potential effect of strong anti-resorptive drugs (e.g., denosumab) on fracture healing processes have not been extensively studied. This prospective study aimed to evaluate the feasibility of early denosumab administration after femoral intertrochanteric fracture surgery and to compare its effect on fracture healing to that of bisphosphonate-treated patients. MATERIALS AND METHODS: Patients who underwent surgery for intertrochanteric femoral fragility fractures between November 2018 and November 2020 were prospectively examined. Patients were randomized into two groups (denosumab [DSM] and ibandronate [IBN] groups) using a simple randomization procedure. Physical findings, plain radiographs, and computed tomography (CT) were used to evaluate fracture healing at 3 months postoperatively. RESULTS: Physical findings showed no significant differences between the two groups in pain on loading, tenderness at fracture site, or walking ability. There were inter-rater differences in radiological fracture healing rate: plain radiographs, 57.5%-81.8% in the DSM group and 51.5%-90.9% in the IBN group; CT, 51.5%-72.7% in the DSM group and 45.4%-81.8% in the IBN group. Although there were variations, there were no significant differences in the fracture healing rate between groups on plain radiographs or CT among all three raters. CONCLUSIONS: Early administration of denosumab after intertrochanteric femoral fracture surgery did not delay radiological or clinical fracture healing times when compared with ibandronate administration.

Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study: PCA involvement in unilateral moyamoya.

OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.

[Presurgical Simulation for Brain Arteriovenous Malformation].

Surgical extirpation of brain arteriovenous malformations(AVMs)requires precise pre-surgical simulation. Utilizing image software, widely used with picture archiving and communication systems(PACS), surgeons can generate simulation images that precisely illustrate the proper feeders, passing arteries, and drainers. The crucial steps for creating informative simulation images include: (1)the free rotation of reconstructed 3D digital subtraction angiography(DSA)images; (2)removal of irrelevant arteries(the most important procedure); and(3)construction of stereo imagery of the "core images." This article presents a detailed description of these procedures.

Five-Year Stroke Risk and Its Predictors in Asymptomatic Moyamoya Disease: Asymptomatic Moyamoya Registry (AMORE).

BACKGROUND: Long-term outcomes are unknown in patients with asymptomatic moyamoya disease. In this report, we aimed to clarify their 5-year risk of stroke and its predictors. METHODS: We are conducting a multicenter, prospective cohort study (Asymptomatic Moyamoya Registry) in Japan. Participants were eligible if they were 20 to 70 years, had bilateral or unilateral moyamoya disease, experienced no episodes suggestive of TIA and stroke; and were functionally independent (modified Rankin Scale score 0-1). Demographic and radiological information was collected at enrollment. In this study, they are still followed up for 10 years. In this interim analysis, we defined the primary end point as a stroke occurring during a 5-year follow-up period. Independent predictors for stroke were also determined, using a stratification analysis method. RESULTS: Between 2012 and 2015, we enrolled 109 patients, of whom 103 patients with 182 involved hemispheres completed the 5-year follow-up. According to the findings on DSA and MRA, 143 hemispheres were judged as moyamoya disease and 39 hemispheres as questionable manifestations (isolated middle cerebral artery stenosis). The patients with questionable hemispheres were significantly older, more often male, and more frequently had hypertension than those with moyamoya hemisphere. Moyamoya hemispheres developed 7 strokes, including 6 hemorrhagic and 1 ischemic stroke, during the first 5 years. The annual risk of stroke was 1.4% per person, 0.8% per hemisphere, and 1.0% per moyamoya hemisphere. Independent predictor for stroke was Grade-2 choroidal anastomosis (hazard ratio, 5.05 [95% CI, 1.24-20.6]; P=0.023). Furthermore, microbleeds (hazard ratio, 4.89 [95% CI, 1.13-21.3]; P=0.0342) and Grade-2 choroidal anastomosis (hazard ratio, 7.05 [95% CI, 1.62-30.7]; P=0.0093) significantly predicted hemorrhagic stroke. No questionable hemispheres developed any stroke. CONCLUSIONS: The hemispheres with asymptomatic moyamoya disease may carry a 1.0% annual risk of stroke during the first 5 years, the majority of which are hemorrhagic stroke. Grade-2 choroidal anastomosis may predict stroke, and the microbleeds and Grade-2 choroidal anastomosis may carry the risk for hemorrhagic stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: UMIN000006640.

Aqueous Povidone-Iodine Versus Normal Saline For Intraoperative Wound Irrigation on The Incidence of Surgical Site Infection in Clean-Contaminated Wounds After Gastroenterological Surgery: A Single-Institute, Prospective, Blinded-Endpoint, Randomized Controlled Trial.

OBJECTIVE: This trial evaluated the superiority of intraoperative wound irrigation (IOWI) with aqueous povidone-iodine (PVP-I) compared with that with saline for reducing the incidence of surgical site infection (SSI). BACKGROUND: IOWI with aqueous PVP-I is recommended for the prevention of SSI by the World Health Organization and the Centers for Disease Control and Prevention, although the evidence level is low. METHODS: This single institute in Japan, prospective, randomized, blinded-endpoint trial was conducted to assess the superiority of IOWI with aqueous PVP-I in comparison with IOWI with saline for reducing the incidence of SSI in clean-contaminated wounds after gastroenterological surgery. Patients 20 years or older were assessed for eligibility, and the eligible participants were randomized at a 1:1 ratio using a computer-generated block randomization. In the study group, IOWI was performed for 1 minute with 40 mL of aqueous 10% PVP-I before skin closure. In the control group, the procedure was performed with 100 mL of saline. Participants, assessors, and analysts were masked to the treatment allocation. The primary outcome was the incidence of incisional SSI in the intention-to-treat set. RESULTS: Between June 2019 and March 2022, 941 patients were randomized to the study group (473 patients) or the control group (468 patients). The incidence of incisional SSI was 7.6% in the study group and 5.1% in the control group (risk difference 0.025, 95% CI -0.006 to 0.056; risk ratio 1.484, 95% CI 0.9 to 2.448; P =0.154). CONCLUSION: The current recommendation of IOWI with aqueous PVP-I should be reconsidered.

Optimization of physical microenvironment to maintain the quiescence of human induced pluripotent stem cell-derived hepatic stellate cells.

Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis by producing excessive extracellular matrix (ECM) following chronic inflammation. However, studying HSC function has been challenging due to the limited availability of primary human quiescent HSCs (qHSCs) in vitro, and the fact that primary qHSCs quickly activate when cultured on plastic plates. Advances in stem cell technology have allowed for the generation of qHSCs from human induced pluripotent stem cells (hiPSCs) with the potential to provide an unlimited source of cells. However, differentiated quiescent-like HSCs (iqHSCs) also activate spontaneously on conventional plastic plates. In this study, we generated iqHSCs from hiPSCs and developed a culture method to maintain such iqHSCs in a lowly activated state for up to 5 days by optimizing their physical culture microenvironment. We observed that three-dimensional (3D) culture of iqHSCs in soft type 1 collagen hydrogels significantly inhibited their spontaneous activation in vitro while maintaining their ability to convert to activated state. Activation of iqHSC was successfully modeled by stimulating them with the fibrotic cytokine TGFß1. Hence, our culture method can be used to generate HSCs with functions comparable to those in a healthy liver, facilitating the development of accurate in vitro liver models for identifying novel therapeutic agents.

Distinct dietary risk factors for incident osteoporotic fractures in early and late postmenopausal phase women.

INTRODUCTION: Available evidence on favorable nutritional factors for preventing osteoporosis remains controversial. Considering the recent increases in life expectancy, we investigated the relationship between incident osteoporotic fractures and dietary habits in early and late postmenopausal phase women. MATERIALS AND METHODS: Subjects were Japanese postmenopausal outpatients recruited at a primary care institution in Nagano Prefecture (Nagano Cohort Study). Patients with critical or acute illness or secondary osteoporosis were not included in this study. In total, 1,071 participants were prospectively followed for a mean of 5.8 years. The cohort was divided into early (≤ 70 years) and late (> 70 years) postmenopausal phases based on median age. Dietary nutrient intake was estimated by the food frequency questionnaire method. According to baseline nutrient intake characteristics, we focused on protein/energy and Ca/NaCl intake ratios, which were also divided by the median values. RESULTS: Kaplan-Meier plots revealed a significantly higher occurrence of fractures for the high protein/energy intake group in early postmenopausal subjects (P = 0.009), whereas the low Ca/NaCl intake group in late postmenopausal subjects exhibited a significantly earlier occurrence of fractures (P = 0.002). Multivariate Cox regression uncovered significant independent risks of higher protein/energy (HR 1.35; 95% CI 1.04-1.74) and lower Ca/NaCl (HR 0.79; 95% CI 0.63-0.99) intake ratios for incident osteoporotic fractures in the early and late postmenopausal cohorts, respectively. CONCLUSION: Distinct dietary risk factors for osteoporotic fractures were identified in early and late postmenopausal phase women. Appropriate nutritional guidance according to patient age will be important for maintaining bone health and quality of life.

Disparity of Performance Measure by Door-to-Balloon Time Between a Rural and Urban Area for Management of Patients With ST-Segment Elevation Myocardial Infarction　- Insights From the Nationwide Japan Acute Myocardial Infarction Registry.

BACKGROUND: Although a door-to-balloon (D2B) time ≤90 min is recognized as a key indicator of timely reperfusion for patients with ST-segment elevation myocardial infarction (STEMI), it is unclear whether regional disparities in the prognostic value of D2B remain in contemporary Japan.Methods and Results: We retrospectively analyzed 17,167 STEMI patients (mean [±SD] age 68±13 years, 77.6% male) undergoing primary percutaneous coronary intervention. With reference to the Japanese median population density of 1,147 people/km2, patients were divided into 2 groups: rural (n=6,908) and urban (n=10,259). Compared with the urban group, median D2B time was longer (70 vs. 62 min; P<0.001) and the rate of achieving a D2B time ≤90 min was lower (70.7% vs. 75.4%; P<0.001) in the rural group. In-hospital mortality was lower for patients with a D2B time ≤90 min than >90 min, regardless of residential area, whereas multivariable analysis identified prolonged D2B time as a predictor of in-hospital death only in the rural group (adjusted odds ratio 1.57; 95% confidence interval 1.18-2.09; P=0.002). Importantly, the rural-urban disparity in in-hospital mortality emerged most distinctively among patients with Killip Class IV and a D2B time >90 min. CONCLUSIONS: These data suggest that there is a substantial rural-urban gap in the prognostic significance of D2B time among STEMI patients, especially those with cardiogenic shock and a prolonged D2B time.

Prevalence and Impact of Polyvascular Disease in Patients With Acute Myocardial Infarction in the Contemporary Era of Percutaneous Coronary Intervention　- Insights From the Japan Acute Myocardial Infarction Registry (JAMIR).

BACKGROUND: This post hoc subanalysis aimed to investigate the impact of polyvascular disease (PolyVD) in patients with acute myocardial infarction (AMI) in the contemporary era of percutaneous coronary intervention (PCI).Methods and Results: The Japan Acute Myocardial Infarction Registry (JAMIR), a multicenter prospective registry, enrolled 3,411 patients with AMI between December 2015 and May 2017. Patients were classified according to complications of a prior stroke and/or peripheral artery disease into an AMI-only group (involvement of 1 vascular bed [1-bed group]; n=2,980), PolyVD with one of the complications (2-bed group; n=383), and PolyVD with both complications (3-bed group; n=48). The primary endpoint was all-cause death. Secondary endpoints were major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and major bleeding. In the 1-, 2-, and 3-bed groups, the cumulative incidence of all-cause death was 6.8%, 17.5%, and 23.7%, respectively (P<0.001); that of MACE was 7.4%, 16.4%, and 33.8% (P<0.001), respectively; and that of major bleeding was 4.8%, 10.0%, and 13.9% (P<0.001), respectively. PolyVD was independently associated with all-cause death (hazard ratio [HR] 2.21; 95% confidence interval [CI], 1.48-3.29), MACE (HR 2.07; 95% CI 1.40-3.07), and major bleeding (HR 1.68; 95% CI 1.04-2.71). CONCLUSIONS: PolyVD was significantly associated with worse outcomes, including thrombotic and bleeding events, in the contemporary era of PCI in AMI patients.

Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model.

Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.