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Background: Menopause, a dramatical estrogen-deficient condition, is considered the most significant milestone in women’s health. Purpose: To investigate the metabolite changes attributed to estrogen deficiency using random forest (RF)-based machine learning (ML) modeling strategy in ovariectomized (OVX) mice as well as determine the clinical relevance of selected metabolites in older women. Methods and results: Untargeted and targeted metabolomic analyses revealed that metabolites related to TCA cycle, sphingolipids, phospholipids, fatty acids, and amino acids, were significantly changed in the plasma and/or muscle of OVX mice. Subsequent ML classifiers based on RF algorithm selected alpha-ketoglutarate (AKG), arginine, carnosine, ceramide C24, phosphatidylcholine (PC) aa C36:6, and PC ae C42:3 in plasma as well as PC aa 34:1, PC aa C34:3, PC aa C36:5, PC aa C32:1, PC aa C36:2, and sphingosine in muscle as top featured metabolites that differentiate the OVX mice from the sham-operated group. When circulating levels of AKG, arginine, and carnosine, which showed the most significant changes in OVX mice blood, were measured in postmenopausal women, higher plasma AKG levels were associated with lower bone mass, weak grip strength, poor physical performance, and increased frailty risk. Conclusions: Metabolomics- and ML-based methods identified the key metabolites of blood and muscle that were significantly changed after ovariectomy in mice, and the clinical implication of several metabolites was investigated by looking at their correlation with body composition and frailty-related parameters in postmenopausal women. These findings provide crucial context for understanding the diverse physiological alterations caused by estrogen deficiency in women.

AbstractThe eBlock37 is a subscale electrically heated and heat-pipe-cooled prototype of a fast spectrum microreactor that is under development at Los Alamos National Laboratory. The prototype consists of an electrically heated core and gas-cooled heat exchanger. These subassemblies, both built from 316 L stainless steel, are thermally linked by an array of 37 sodium heat pipes that transfer a nominal 100 kW from the core at 700°C. An overarching objective of this effort is to overcome challenges associated with core block and heat exchanger manufacture and integration of high-temperature heat pipes into the assembly. Components that would be safety critical in an actual reactor, such as the heat pipe wicks, are being built under a Nuclear Quality Assurance 1 quality program. The completed assembly is intended for non-nuclear electrically heated testing, which will be conducted at a demonstration facility at Idaho National Laboratory. This paper provides a top-level summary of the efforts to date.

Metastatic breast cancer is an extremely complex disease with limited treatment options due to the lack of information about the major characteristics of metastatic disease. There is an urgent need, therefore, to understand the changes in cellular complexity and dynamics that occur during metastatic progression. In the current study, we analyzed the cellular and molecular differences between primary tumors and paired lung metastases using a syngeneic p53-null mammary tumor model of basal-like breast cancer. Distinct subpopulations driven by the Wnt- and/or STAT3 signaling pathways were detected in vivo using a lentiviral Wnt- and STAT3 signaling reporter system. A significant increase in the overlapping populations driven by both the Wnt- and STAT3 signaling pathways was observed in the lung metastases as compared to the primary tumors. Furthermore, the overlapping populations showed a higher metastatic potential relative to the other populations and pharmacological inhibition of both signaling pathways was shown to markedly reduce the metastatic lesions in established lung metastases. An analysis of the unique molecular features of the lung metastases revealed a significant association with immune response signatures. Specifically, Foxp3 gene expression was markedly increased and elevated levels of Foxp3?+?Treg cells were detected in close proximity to lung metastases. Collectively, these studies illustrate the importance of analyzing intratumoral heterogeneity, changes in population dynamics, and the immune microenvironment during metastatic progression.

Background and Aims: This study was designed to analyze the feasibility of laparoscopic right posterior sectionectomy compared to laparoscopic right hemihepatectomy in patients with hepatocellular carcinoma located in the posterior segments.Material and Methods: The study included patients who underwent either laparoscopic right posterior sectionectomy or laparoscopic right hemihepatectomy for hepatocellular carcinoma located in segment 6 or 7 from January 2009 to December 2016 at Samsung Medical Center. After 1:1 propensity score matching, patient baseline characteristics and operative and postoperative outcomes were compared between the two groups. Disease-free survival and overall survival were compared using Kaplan–Meier log-rank test.Results: Among 61 patients with laparoscopic right posterior sectionectomy and 37 patients with laparoscopic right hemihepatectomy, 30 patients from each group were analyzed after propensity score matching. After matching, baseline characteristics of the two groups were similar including tumor size (3.4 ± 1.2 cm in laparoscopic right posterior sectionectomy vs 3.7 ± 2.1 cm in laparoscopic right hemihepatectomy, P = 0.483); differences were significant before matching (3.1 ± 1.3 cm in laparoscopic right posterior sectionectomy vs 4.3 ± 2.7 cm in laparoscopic right hemihepatectomy, P = 0.035). No significant differences were observed in operative and postoperative data except for free margin size (1.04 ± 0.71 cm in laparoscopic right posterior sectionectomy vs 2.95 ± 1.75 cm in laparoscopic right hemihepatectomy, P < 0.001). Disease-free survival (5-year survival: 38.0% in laparoscopic right posterior sectionectomy vs 47.0% in laparoscopic right hemihepatectomy, P = 0.510) and overall survival (5-year survival: 92.7% in laparoscopic right posterior sectionectomy vs 89.6% in laparoscopic right hemihepatectomy, P = 0.593) did not differ between the groups based on Kaplan–Meier log-rank test.Conclusion: For hepatocellular carcinoma in the posterior segments, laparoscopic right posterior sectionectomy was feasible compared to laparoscopic right hemihepatectomy when performed by experienced laparoscopic surgeons.

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKIand CKDand examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKIwas assessed in the first year posttransplant. Among 303 children, perioperative AKI(within the first week) occurred in 67% of children, and AKIafter the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty‐three children (8%) developed CKDafter a median follow‐up of 3.4 years. Less than 5 children developed end‐stage renal disease, all within 65 days posttransplant. Those with 1 AKIepisode by 3 months posttransplant had significantly greater risk for developing CKDafter adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13‐6.80, Ptrend = .008). AKIis common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney‐sparing strategies to decrease risk for progression to CKD. In an observational cohort study of 303 children after heart, lung, liver, or multiorgan transplantation, acute kidney injury occurs in approximately one‐third of children in the first year posttransplant and is associated with significantly greater risk of developing chronic kidney disease.

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKIImice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Population‐based cancer screening recommendations are also suggested for solid organ transplant recipients (SOTR); however, recommendation adherence is unknown. In a population‐based cohort of SOTRin Ontario between 1997 and 2010, we determined the uptake of breast, cervical, and colorectal cancer screening tests and identified factors associated with up‐to‐date screening using recurrent event analysis. We identified 4436 SOTReligible for colorectal, 2252 for cervical, and 1551 for breast cancer screening. Of those, 3437 (77.5%), 1572 (69.8%), and 1417 (91.4%), respectively, were not up‐to‐date for cancer screening tests during the observation period. However, these rates are likely an overestimate due to the inability to differentiate between tests done for screening or for diagnosis. SOTRwith fewer comorbidities had higher rates of becoming screen up‐to‐date. Assessment by a primary care provider (PCP) was associated with becoming up‐to‐date with cancer screening (breast relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.12–1.76, cervical RR= 1.29, 95% CI: 1.06–1.57, colorectal RR= 1.30, 95% CI: 1.15–1.48). Similar results were observed for continuity of care by transplant specialist at a transplant center. In conclusion, cancer screening for most SOTRdoes not adhere to standard recommendations. Involvement of PCPs in posttransplant care and continuity of care at a transplant center may improve the uptake of screening. This population‐based study finds that cancer screening for most solid organ transplant recipients does not adhere to standard recommendations.

In the United States, kidney transplant rates vary significantly across end‐stage renal disease (ESRD) networks. We conducted a population‐based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1‐, 5‐, and 10‐year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRDnetworks). We also assessed the cumulative incidence of kidney transplant for “healthy” dialysis patients (aged 18–50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow‐up of 11 years). Among 23 022 chronic dialysis patients, the 10‐year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8–10.7%) to 31.4% (95% CI16.5–47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI0.2–0.5) to 1.5 (95% CI1.4–1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system. A population‐based cohort study finds significant variation in kidney transplant rates across Ontario, Canada, renal programs despite patients having access to the same publicly funded healthcare system.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0–10) and donor’s intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30–39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

Hydrogen permeation of two kinds of ferritic steel with different level of 2nd phase particles are compared utilising electrochemical permeation technique evaluated under various loads. This study indicates that tensile stress in plastic domain induces expansion of the interface between the 2nd phase particles and steel matrix, and formation of blister crack. Such microstructural-discontinuity provides additional hydrogen traps, resulting in slower diffusion and lower steady-state permeation flux. These phenomena appear predominantly in steel containing coarse-sized inclusion and precipitate having sharp extremities. The numerical analysis also supports that the steel containing coarse-sized 2nd phase particles with sharp extremities exhibits higher parameters of hydrogen capture rate per irreversible traps and blister crack formation rate than the steel containing fine-sized ones with spherical shape.

Solid organ transplant recipients (SOTRs) are at increased risk of developing and dying from cancer. However, controversies exist around cancer screening in this population owing to reduced life expectancy and competing causes of death. This systematic review assesses the availability, quality and consistency of cancer screening recommendations in clinical practice guidelines (CPGs). We systematically searched bibliographic databases and gray literature to identify CPGs and assessed their quality using AGREE II. Recommendations were extracted along with their supporting evidence. Thirteen guidelines were included in the review. CPGs for kidney recipients were the most frequent source of screening recommendations, and recommendations for skin cancer screening were most frequently presented. Some screening recommendations differed from those for the general population, based on literature demonstrating higher cancer incidence among SOTRs versus direct evidence of screening effectiveness. Relevant stakeholders such as oncology specialists, primary care providers and public health experts were not involved in the formulation of the screening recommendations. In conclusion, although several guidelines make recommendations for cancer screening in SOTRs, the availability of cancer screening recommendations varied considerably by transplanted organ. More studies are required to inform cancer screening recommendations in SOTRs, and guideline development should involve transplant patients, oncologists and cancer screening specialists. This systematic review assesses cancer screening recommendations in posttransplant care clinical practice guidelines and finds that although 13 guidelines make recommendations for cancer screening in transplant recipients, the availability of recommendations varies considerably by transplanted organ and that relevant stakeholders were not involved in the formulation of screening recommendations. See Blosser's editorial on page 9.

AimsThe aim of the study was to develop a quantitative scoring system to predict whether a large-to-massive rotator cuff tear was arthroscopically reparable prior to surgery.Patients and MethodsWe conducted a retrospective review of the pre-operative MR imaging and surgical records of 87 patients (87 shoulders) who underwent arthroscopic repair of a large-to-massive rotator cuff tear. Patients were divided into two groups, based on the surgical outcome of the repair. Of the 87 patients, 53 underwent complete repair (Group I) and 34 an incomplete repair (Group II). Pre-operative MR images were reviewed to quantify several variables. Between-group differences were evaluated and multiple logistic regression analysis was used to calculate the predictive value of significant variables. The reparability index (RI) was constructed using the odds ratios of significant variables and a receiver operating characteristic curve analysis performed to identify the optimal RI cutoff to differentiate between the two groups.ResultsThe following variables were identified as independent predictors of arthroscopic reparability: the size of the defect with medial-lateral diameter (cutoff, 4.2 cm) and anterior-posterior diameter (cutoff, 3.7cm); Patte’s grade of muscle atrophy (cutoff, grade 3) and Goutallier grade of fatty degeneration (cutoff, grade 3). An RI cutoff value of 2.5 provided the highest differentiation between groups I and II, with an area under the curve of 0.964, and a sensitivity of 73.5% and specificity of 96.2%.ConclusionThe RI developed in our study may prove to be an efficient clinical scoring system to predict whether a large-to-massive rotator cuff tear is arthroscopically reparable.Cite this article: Bone Joint J2016;98-B:1656–61.

Objectives:: The aim of this study was to explore the phenotypic differences underpinning obesity susceptibility or resistance based on the metabolic and transcriptional profiling of C57BL/6J mice fed a high-fat diet (HFD). Methods:: The mice were fed either a normal diet or HFD for 12 weeks. After 6 weeks, the mice on HFD were classified as either obesity-prone (OP) or obesity-resistant (OR) depending on the body weight gain. Results:: Lipid profiles from plasma and liver significantly improved in OR mice relative to the OP group. Energy expenditure was greater in OR mice than in OP mice, with a simultaneous decrease in body fat mass. Epididymal white adipose tissue (eWAT) and liver were enlarged in OP mice (with visible immune-cell infiltration), but these effects were attenuated in OR mice compared with OP mice. Overall glucose metabolism was enhanced in OR mice compared with OP mice, including homeostasis model assessment for insulin resistance, plasma glucose and insulin concentrations, glucokinase activity and hepatic glycogen. Plasma adipokines and proinflammatory cytokines were upregulated in OP mice, and these changes were attenuated in OR mice. Transcriptomic profiles of eWAT and liver revealed common and divergent patterns of transcriptional changes in OP and OR mice, and pointed to differential metabolic phenotypes of OP and OR mice. There were substantial differences between OP and OR mice in molecular pathways, including atherosclerosis signaling, sperm motility, cAMP-mediated signaling in eWAT; and fibrosis, agranulocyte adhesion and diapedesis, and atherosclerosis signaling in liver. Conclusions:: Taken altogether, the results provide robust evidence of major divergence in the transcriptomes, phenotypes and metabolic processes between obesity susceptibility and obesity resistance in the HFD-fed C57BL/6J mice.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long‐term mortality. In a typical analysis of time‐to‐event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of “independent censoring,” which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause‐specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation. The authors review the principles of competing risk analysis, provide a summary of the transplant literature where competing risk methods have been applied, and use data from the Scientific Registry of Transplant Recipients to compare the risk of mortality in sensitized waitlisted kidney transplant candidates using standard survival analysis models versus subdistribution hazards models.

As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia–reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRIin relation with autophagy. The effects of everolimus were investigated in both in vitroand in vivohepatic IRImodels. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI‐induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule‐associated protein 1 light chain 3 and p62) and decreased pro‐apoptotic proteins (cleaved caspase 3 and cleaved poly‐ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si‐autophagy‐related protein 5, abrogated these anti‐apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI‐induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro‐apoptotic proteins, (2) inhibiting the release of pro‐inflammatory cytokines (IL‐6 and tumor necrosis factor‐α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRIby way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI. This experimental study suggests that everolimus protects the liver against hepatic ischemia–reperfusion injury by way of activating autophagy, and thus could be a potential therapeutic agent.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) for extranodal natural killer/T-cell lymphoma (ENKTL) is a reasonable option for a subset of patients. The impact of response status, according to positron emission tomography/computed tomography (PET/CT) results and/or presence of circulating EBV DNA prior to ASCT, has not yet been established. We analyzed 27 ENKTL patients with pre-ASCT circulating EBV DNA who had undergone pre-ASCT PET/CT between 2009 and 2014. We classified patients into two groups based on the result of pretransplantation assessment: a favorable risk group (pretransplant five-point Deauville score (DS) of 1–2 based on PET/CT and no detectable EBV DNA) and an unfavorable risk group (DS 1–2 with detectable EBV DNA, DS 3–5 with or without detectable EBV DNA). After a median follow-up of 37 months, overall survival and PFS were significantly different between the two groups (median OS: not reached for favorable risk group vs 7.0 months for unfavorable risk group, P=0.017; median PFS: 16.0 vs 5.0 months, P=0.019). Multivariate analysis revealed that pre-ASCT DS and EBV DNA was the only independent prognostic factor considering stage, IPI and NKPI. Precise assessment of the status of disease before transplantation may provide more benefit from ASCT to ENKTL patients.

The Korea Atomic Energy Research Institute (KAERI) has been developing the 150 MWe Prototype Generation-IV Sodium-cooled Fast Reactor (PGSFR). The design concept is highly based on passive safety mechanisms, minimizing the need for engineered safety systems. Presently, it is of primary importance to assure the reactor dynamics and stability against small reactivity disturbances under power operating conditions. KAERI has therefore developed the NuSTAB code for stability analysis of the PGSFR. In NuSTAB, the neutron-kinetic and thermal-hydraulic coupling equations are linearized to form the characteristic equation, which is solved as a generalized eigenvalue problem for determining the decay ratio, an indicator of the system stability. In this paper, the stability of the PGSFR was analyzed by applying the point kinetic and spatial kinetic options in the NuSTAB code. System responses to temperature feedbacks including the Doppler effect, thermal expansion, coolant density change, and overall feedback were studied. The results indicate that the initial U and final TRU cores of the PGSFR are both inherently stable thanks to the temperature feedbacks.

Background:: It is well known that high-fat diet (HFD) can cause immune system-related pathological alterations after a significant body weight gain. The mechanisms of the delayed pathological alterations during the development of diet-induced obesity (DIO) are not fully understood. Methods:: To elucidate the mechanisms underlying DIO development, we analyzed time-course microarray data obtained from a previous study. First, differentially expressed genes (DEGs) were identified at each time point by comparing the hepatic transcriptome of mice fed HFD with that of mice fed normal diet. Next, we clustered the union of DEGs and identified annotations related to each cluster. Finally, we constructed an ‘integrated obesity-associated gene regulatory network (GRN) in murine liver’. We analyzed the epididymal white adipose tissue (eWAT) transcriptome usig the same procedure. Results:: Based on time-course microarray data, we found that the genes associated with immune responses were upregulated with an oscillating expression pattern between weeks 2 and 8, relatively downregulated between weeks 12 and 16, and eventually upregulated after week 20 in the liver of the mice fed HFD. The genes associated with immune responses were also upregulated at late stage, in the eWAT of the mice fed HFD. These results suggested that a critical transition occurred in the immune system-related transcriptomes of the liver and eWAT around week 16 of the DIO development, and this may be associated with the delayed pathological alterations. The GRN analysis suggested that Maff may be a key transcription factor for the immune system-related critical transition thatoccurred at week 16. We found that transcription factors associated with immune responses were centrally located in the integrated obesity-associated GRN in the liver. Conclusions:: In this study, systems analysis identified regulatory network modules underlying the delayed immune system-related pathological changes during the development of DIO and could suggest possible therapeutic targets.

Recipients of pancreas transplant alone (PTA) may be at increased risk for developing end‐stage renal disease (ESRD). The survival experience of PTA recipients developing ESRD has not been described. Furthermore, the relative survival of these patients as compared to diabetics on chronic dialysis is unknown. We studied all adult PTA recipients from January 1, 1990 to September 1, 2008 using the Scientific Registry of Transplant Recipients. Each PTA recipient developing ESRD was matched to 10 diabetics on chronic dialysis from the United States Renal Data System. Cox proportional hazards models were fitted to determine the relation between ESRD and mortality among PTA recipients, and the relation between PTA and mortality among diabetics on chronic dialysis. There were 1597 PTA recipients in the study, of which 207 developed ESRD. Those with ESRD had a threefold increase in mortality versus those without (adjusted hazard ratio 3.28 [95% confidence interval: 2.27, 4.76]). There was no significant difference in the risk of death among PTA recipients with ESRD versus diabetics on dialysis. PTA recipients developing ESRD are three times more likely to die than PTA recipients without ESRD; however, the risk of death in these patients was similar to diabetics on chronic dialysis without PTA.

Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.

Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase‐1 (HO‐1) or soluble tumor necrosis factor‐α receptor type I with human IgG1Fc (sTNF‐αR‐Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO‐1, sTNF‐αR‐Fc, sTNF‐αR‐Fc/HO‐1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood–derived CD34+stem cells into NOD‐scid‐IL‐2Rγnullmice. Both HO‐1 and sTNF‐αR‐Fc reduced islet apoptosis under in vitrohypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig‐to‐humanized mice transplantation. The sTNF‐αR‐Fc/HO‐1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor‐α and IL‐6 in treatment groups; however, frequency of pig‐specific interferon‐γ–producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO‐1 or sTNF‐αR‐Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO‐1 or sTNF‐αR‐Fc transgenic pigs have potential for islet xenotransplantation. In an adult pig islet to humanized mouse transplantation model, overexpression of human HO–1 or sTNF–α–Fc in porcine islets improves islet xenograft survival by suppressing both early apoptosis of islet cells and inflammation.

We compared the ceiling effects of two patient-rating scores, the Disability of the Arm, Shoulder and Hand (DASH) and Patient-Rated Wrist Evaluation (PRWE), and a physician-rating score, the Modified Mayo Wrist Score (MMWS) in assessing the outcome of surgical treatment of an unstable distal radial fracture. A total of 77 women with a mean age of 64.2 years (50 to 88) who underwent fixation using a volar locking plate for an unstable distal radial fracture between 2011 and 2013 were enrolled in this study. All completed the DASH and PRWE questionnaires one year post-operatively and were assessed using the MMWS by the senior author. The ceiling effects in the outcome data assessed for each score were estimated.The data assessed with both patient-rating scores, the DASH and PRWE, showed substantial ceiling effects, whereas the data assessed with MMWS showed no ceiling effect.Researchers should be aware of a possible ceiling effect in the assessment of the outcome of the surgical treatment of distal radial fractures using patient-rating scores. It could also increase the likelihood of a type II error.Cite this article: Bone Joint J2015;97-B:1651–6.

Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig‐to‐nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen‐free (DPF) miniature pigs and infused intraportally into streptozotocin‐induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti‐thymocyte globulin (ATG) induction and maintenance with anti‐CD154 monoclonal antibody and low‐dose sirolimus. Ex vivoexpanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90–110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow‐up period showed excellent glucose disposal capacity and porcine C‐peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy. The authors report control of diabetes for longer than six months in four consecutive nonhuman primates by the transplantation of adult pig islets using a modest immunosuppressive regimen with an acceptable adverse effect profile.

The authors describe their experience of one heart recipient and two kidney recipients with fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly drowned victim of a suicide attempt.

This single‐center, retrospective cohort study of 1,170 incident kidney transplant recipients shows that the association of serum uric acid level and graft failure is dependent on the analytical method used to account for time‐varying levels of both uric acid and graft function.

TiO2photocatalyst beads were synthesised using the circulating fluidised bed–chemical vapour deposition (CFB-CVD) method. Their photocatalytic activity was compared with the TiO2photocatalyst balls synthesised using the conventional CVD (C-CVD) method. The TiO2film synthesized by CFB-CVD showed (110) oriented anatase crystal structure. Compared to the film synthesised by C-CVD, the CFB-CVD synthesised film had much less dense crystal structure owing to TiO2powders precipitated during the film growth. When the CFB-CVD synthesised TiO2beads were used in the photocatalytic decomposition of RhB in a fluidised bed reactor, the decomposition rate increased with increasing UV intensity and circulating flowrate and with decreasing initial RhB concentration. One important shortcoming of the TiO2photocatalyst beads synthesised by CFB-CVD turned out to be that the photocatalytic activity was decreased significantly by repeated reuse, calling for further investigation to improve the durability.

To cope with increasing spent fuel disposals and limited domestic spent fuel storages in Korea, the Korea Atomic Energy Research Institute has developed an advanced sodium-cooled fast reactor for TRU transmutation with an electricity output of 600?MWe (called the KALIMER-600 TRU burner). The design philosophy of the KALIMER-600 TRU burner concept is highly focused on inherent safety mechanisms, i.e., passive responses to abnormal and emergency conditions, and thereby minimizes the need for engineered safety systems. Accordingly, the main concern is on the sodium coolant void reactivity, a very important safety parameter of the KALIMER-600 TRU burner. This study was therefore performed to analyze the sodium void reactivity of the KALIMER-600 TRU burner to the finest resolution possible, e.g., contributions from any isotope in each core region. Such detailed analysis could be valuable and applicable to further optimization of the core passive safety characteristics against severe coolant voiding accident conditions.

Pour comprendre la supraconductivité à haute température critique, et tester les modèles théoriques proposés, l'effet tunnel et le couplage Josephson sont des outils très importants. En mesurant la densité d'états au niveau de Fermi d'une part, et les propriétés intrinsèques du paramètre d'ordre supraconducteur d'autre part, ces expériences apportent un éclairage indispensable sur la physique de ces composés. Cependant, ces techniques sont tributaires de la qualité de surface des matériaux, ainsi que de leur microstructure (joints de grains, macles, défauts étendus...). Dans un premier temps, nous présentons une vue générale de la supraconductivité à haute Tc aujourd'hui et des questions fondamentales qui restent en suspend. Ensuite, nous analysons les principaux résultats d'effet tunnel et Josepshon. Enfin, nous discutons l'influence des imperfections cristallines sur ces mesures, et sur les conclusions qui peuvent en être tirées.

The surface relief is one of the main factors defining the trybological properties of friction pairs, especially in the case of diamond and diamond like carbon (DLC) coatings. Even such thin as 10 - 100 nm coating can considerably increase the wear resistance and drastically reduce the friction coefficient of friction pairs. The most convenient techniques for investigation microrelief effect on trybologyc properties of thin films seems to be the scanning tunneling microscopy (STM). The microrelief was changed by surface bombardment with 1 keV ions of O, Ar and N. The fiction coefficients was found to depend upon ion bombardment time and the minimal value could be achieved. The STM studies showed that namely at this time the surface relief was the most smooth. For the coatings in the initial state the surface relief was about 15 - 20 nm and in the state with minimal friction coefficient - about 1.5 - 3 nm.

This cohort study finds no significant difference in the rates of kidney stones with surgical intervention or hospital encounters for kidney stones when comparing 2019 living kidney donors to 20 190 healthy nondonors.

This study highlights that the conversion of twice‐daily tacrolimus to once‐daily tacrolimus formulation results in highly variable changes in pharmacokinetic parameters of tacrolimus in stable pediatric kidney transplant patients.

The timing of total hip replacement (THR) in patients with active tuberculosis (TB) of the hip is controversial, because of the potential risk of reactivation of infection. There is little information about the outcome of THR in these patients. We conducted a systematic review of published studies that evaluated the outcome of THR in patients with active TB of the hip. A review of multiple databases referenced articles published between 1950 and 2012. A total of six articles were identified, comprising 65 patients. TB was confirmed histologically in all patients. The mean follow-up was 53.2 months (24 to 108). Antituberculosis treatment continued post-operatively for between six and 15 months, after debridement and THR. One non-compliant patient had reactivation of infection. At the final follow-up the mean Harris hip score was 91.7 (56 to 98). We conclude that THR in patients with active TB of the hip is a safe procedure, providing symptomatic relief and functional improvement if undertaken in association with extensive debridement and appropriate antituberculosis treatment.Cite this article: Bone Joint J2013;95-B:578–82.

The outcomes of kidney transplants that simultaneously exhibit donation after cardiac death (DCD) and expanded criteria donor (ECD) characteristics have not been well studied. We examined the outcomes of DCD versus non‐DCD kidney transplants as a function of ECD status and the kidney donor risk index (KDRI). A cohort study of 67 816 deceased donor kidney transplant recipients (KTR), including 562 ECD/DCD KTR, from January 1, 2000 to December 31, 2009 was conducted using the Scientific Registry of Transplant Recipients. In a multivariable Cox proportional hazards model, the modestly increased risk of total graft failure in DCD versus non‐DCD KTR was not significantly modified by ECD status (hazard ratio1.07 [95% CI: 1.01, 1.15] for non‐ECD vs. 1.21 [95% CI: 1.04, 1.40] for ECD, p for interaction = 0.14).Moreover, the hazard ratios did not significantly vary by KDRI quintiles (p = 0.40). Similar trends were seen for death‐censored graft failure and death with graft function. In conclusion, ECD status or higher KDRI score did not appreciably increase the relative hazard of adverse graft and patient outcomes in DCD KTR. These findings suggest that the judicious use of ECD/DCD donor kidneys may be an appropriate strategy to expand the donor pool.

The purpose of this study was to measure the radiological parameters of femoral component alignment of the Oxford Phase 3 unicompartmental knee replacement (UKR), and evaluate their effect on clinical outcome. Multiple regression analysis was used to examine the relative contributions of the radiological assessment of femoral component alignment in 189 consecutive UKRs performed by a single surgeon. The American Knee Society scores were compared between groups, defined as being within or outside recommended tolerances of the position of the femoral component. For the flexion/extension position 21 UKRs (11.1%) lay outside the recommended limits, and for posterior overhang of the femoral component nine (4.8%) lay outside the range. The pre-operative hip/knee/ankle (HKA) angle, narrowest canal distance from the distal femoral entry point of the alignment jig and coronal entry-point position had significant effects on the flexion/extension position. Pre-operative HKA angle had a significant influence on posterior overhang of the femoral component. However, there was no significant difference in American Knee Society scores relative to the position of the femoral component.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hocanalysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all‐cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49±18 mL/min/1.73 m2. In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m2higher eGFR at levels below 45 mL/min/1.73 m2was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m2. In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

Medium-term survivorship of the Oxford phase 3 unicompartmental knee replacement (UKR) has not yet been established in an Asian population. We prospectively evaluated the outcome of 400 phase 3 Oxford UKRs in 320 Korean patients with a mean age at the time of operation of 69 years (48 to 82). The mean follow-up was 5.2 years (1 to 10). Clinical and radiological assessment was carried out pre- and post-operatively. At five years, the mean Knee Society knee and functional scores had increased significantly from 56.2 (30 to 91) pre-operatively to 87.2 (59 to 98) (p = 0.034) and from 59.2 (30 to 93) to 88.3 (50 to 100) (p = 0.021), respectively. The Oxford knee score increased from a mean of 25.8 (12 to 39) pre-operatively to 39.8 (25 to 58) at five years (p = 0.038). The ten-year survival rate was 94% (95% confidence interval 90.1 to 98.0). A total of 14 UKRs (3.5%) required revision. The most common reason for revision was dislocation of the bearing in 12 (3%). Conversion to a total knee replacement was required in two patients who developed osteoarthritis of the lateral compartment.This is the largest published series of UKR in Korean patients. It shows that the mid-term results after a minimally invasive Oxford phase 3 UKR can yield satisfactory clinical and functional results in this group of patients.

The possibility that a technical error may occur during nerve conduction studies due to ulnar nerve dislocation when the elbow is flexed has recently been suggested. We investigated normal volunteers using ultrasonography to observe the effects of ulnar nerve dislocation during elbow flexion on short-segment nerve conduction studies. We found significant conduction block in all of the subjects with ulnar nerve dislocation, and the finding was defined as a technical error caused by volume conduction. The results of the present study suggest that caution should be exercised when interpreting the results of short-segment nerve conduction studies at the across-elbow segment due to the possibility of technical error induced by ulnar nerve dislocation.

Lengthening of the humerus is now an established technique. We compared the complications of humeral lengthening with those of femoral lengthening and investigated whether or not the callus formation in the humerus proceeds at a higher rate than that in the femur. A total of 24 humeral and 24 femoral lengthenings were performed on 12 patients with achondroplasia. We measured the pixel value ratio (PVR) of the lengthened area on radiographs and each radiograph was analysed for the shape, type and density of the callus. The quality of life (QOL) of the patients after humeral lengthening was compared with that prior to surgery. The complication rate per segment of humerus and femur was 0.87% and 1.37%, respectively. In the humerus the PVR was significantly higher than that of the femur. Lower limbs were associated with an increased incidence of concave, lateral and central callus shapes. Humeral lengthening had a lower complication rate than lower-limb lengthening, and QOL increased significantly after humeral lengthening. Callus formation in the humerus during the distraction period proceeded at a significantly higher rate than that in the femur. These findings indicate that humeral lengthening has an important role in the management of patients with achondroplasia.

The growth of graphene on copper foil has attracted attention in the last two years due to its feasibility for a controllable growth process. One of the key issues remaining for practical application of graphene in solid-state devices is growth with a large grain size. Because the C–C bond in graphene is strong enough to prevent the evaporation–condensation process, Smoluchowski ripening is expected to be the dominant process for coalescence. In this article, we present the initial growth process of graphene on a Cu foil via the chemical vapor deposition method by using secondary electron microscopy and Raman microscopy. In contrast to the other transition-metal substrates, such as Ir and Rh, the center of graphene islands binds to the substrate more rigidly than the edge. For the growth with a large grain size, the graphene should be grown on a substrate with a low diffusion barrier for the carbon clusters (or islands) with low flux; this is the controlling parameter for the grain size. In addition, high-temperature growth (or annealing) generally becomes a dominant condition for the completion of graphene growth with large grains after the coalescence.

Published data on the new carbon nanomaterial, graphene, are described systematically from the chemist's standpoint. The attention is focused on the chemical methods of the synthesis of graphene-like materials from various precursors: natural and expanded graphite, graphite oxide, graphite intercalation compounds, etc. Approaches to the chemical modification of the graphene plane by various reagents and routes for the preparation of colloidal dispersions of graphene are considered. The bibliography includes 220 references.

We compared the complications and outcome of tibial lengthening using the Ilizarov method with and without the use of a supplementary intramedullary nail. In a retrospective case-matched series assembled from 176 patients with tibial lengthening, we matched 52 patients (26 pairs, group A with nail and group B without) according to the following criteria in order of importance: 1) difference in amount of lengthening (± 2 cm); 2) percentage difference in lengthening (± 5%); 3) difference in patient’s age (± seven years); 4) aetiology of the shortening, and 5) level of difficulty in obtaining the correction. The outcome was evaluated using the external fixator index, the healing index and an outcome score according to the criteria of Paley. It was found that some complications were specific to group A or B respectively, but others were common to both groups.The outcome was generally better in lengthenings with a nail, although there was a higher incidence of rectifiable equinus deformity in these patients.

Older living kidney donors are regularly accepted. Better knowledge of recipient outcomes is needed to inform this practice. This retrospective cohort study observed kidney allograft recipients from Ontario, Canada between January 2000 and March 2008. Donors to these recipients were older living (≥60 years), younger living, or standard criteria deceased (SCD). Review of medical records and electronic healthcare data were used to perform survival analysis. Recipients received 73 older living, 1187 younger living and 1400 SCD kidneys. Recipients of older living kidneys were older than recipients of younger living kidneys. Baseline glomerular filtration rate (eGFR) of older kidneys was 13 mL/min per 1.73 m2lower than younger kidneys. Median follow‐up time was 4 years. The primary outcome of total graft loss was not significantly different between older and younger living kidney recipients [adjusted hazard ratio, HR (95%CI): 1.56 (0.98–2.49)]. This hazard ratio was not proportional and increased with time. Associations were not modified by recipient age or donor eGFR. There was no significant difference in total graft loss comparing older living to SCD kidney recipients [HR: 1.29 (0.80–2.08)]. In light of an observed trend towards potential differences beyond 4 years, uncertainty remains, and extended follow‐up of this and other cohorts is warranted.

We aimed to document the pre-operative expectations in Korean patients undergoing total knee replacement using an established survey form and to determine whether expectations were influenced by sociodemographic factors or pre-operative functional status. Expectations regarding 17 items in the Knee Replacement Expectation Survey form were investigated in 454 patients scheduled for total knee replacement. The levels and distribution patterns of summated expectation and of five expectation categories (relief from pain, baseline activity, high flexion activity, social activity and psychological well-being) constructed from the 17 items were assessed. Univariate analyses and multivariate logistic regression were performed to examine the associations of expectations with the sociodemographic factors and the functional status.The top three expectations were relief from pain, restoration of walking ability, and psychological well-being. Of the five expectation categories, relief from pain was ranked the highest, followed by psychological well-being, restoration of baseline activity, ability to perform high flexion activities and ability to participate in social activities. An age of < 65 years, being employed, a high Western Ontario and McMaster Universities osteoarthritis index function score and a low Short-form 36 social score were found to be significantly associated with higher overall expectations.

This study was performed to test if hearing a recorded maternal voice reduces anxiety, emergence agitation and anaesthetic requirements in children. With written informed consent, children scheduled for cardiac catheterisation under intravenous ketamine anaesthesia and their mothers (n=46) were randomly assigned to either the mother-voice (MV) or control group. While the MV group (n=23) listened via headphones to a recording of their mothers’ voices during the perioperative period, the control group (n=23) wore headphones with no auditory stimulation. Ketamine requirements and haemodynamics were recorded. Anxiety of the patients and the parents were measured before and after the procedure with the modified Yale preoperative anxiety scale and Spielberger's State-Trait Anxiety Inventory, respectively. Emergence agitation was graded. The demographic and haemodynamic data were comparable, except for a longer procedure time in the MV group. Mothers’ State-Trait Anxiety Inventory was not different preoperatively between the groups. Mothers’ state and trait anxiety was lower after the procedure in the MV group compared with the preoperative values. In the control group only maternal state anxiety was diminished after the procedure. There was no significant group difference with respect to ketamine requirement (5.1±1.9 mg vs 4.9±1.6 mg, P=0.645). The anxiety score of children was lower in the MV group before the procedure (modified Yale preoperative anxiety scale score 35±12 vs 28±9, P=0.038), but there was no significant difference postoperatively. Emergence agitation was attenuated in the MV group (P=0.005).

In the early development stage, the prediction of interior noise due to powertrain vibration is important for enhancement of the noise vibration harshness (NVH) performance. Traditional transfer path analysis (TPA) technology has been used to estimate interior noise on the basis of experiment by using real parts of the powertrain. When a structural modification of the powertrain is necessary to reduce interior noise, it is efficient to use a finite element (FE) model of the powertrain components to identify the effect of that modification. In this paper, hybrid TPA is employed. Until now, no paper has been presented on predicting the interior noise caused by a powertrain on the basis of hybrid TPA with a real vehicle. The hybrid TPA uses a simulated excitation force as the input force, which excites the flexible body of a car at the mount point, whereas the traditional TPA uses the measured force. This simulated force is obtained by numerical analysis for the FE model of a powertrain. The interior noise is predicted by multiplying the simulated force by the vibroacoustic transfer function (VATF) of the vehicle. The trend of the predicted interior noise based on the hybrid TPA corresponds very well to the measured interior noise.