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Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.

Background Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant–based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer–associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.

Background: The counterfactual definition of confounding is often explained in the context of exchangeability between the exposed and unexposed groups. One recent approach is to examine whether the measures of association (eg, associational risk difference) are exchangeable when exposure status is flipped in the population of interest. We discuss the meaning and utility of this approach, showing their relationships with the concept of confounding in the counterfactual framework. Methods: Three hypothetical cohort studies are used, in which the target population is the total population. After providing an overview of the notions of confounding in distribution and in measure, we discuss the approach from the perspective of exchangeability of measures of association (eg, factual associational risk difference vs counterfactual associational risk difference). Results: In general, if the measures of association are non-exchangeable when exposure status is flipped, confounding in distribution is always present, although confounding in measure may or may not be present. Even if the measures of association are exchangeable when exposure status is flipped, there could be confounding both in distribution and in measure. When we use risk difference or risk ratio as a measure of interest and the exposure prevalence in the population is 0.5, testing the exchangeability of measures of association is equivalent to testing the absence of confounding in the corresponding measures. Conclusion: The approach based on exchangeability of measures of association essentially does not provide a definition of confounding in the counterfactual framework. Subtly differing notions of confounding should be distinguished carefully.

Objective: The effects of semi-solid enteral formula were investigated in tube feeding patients with aspiration pneumonia and/or diarrhea caused by liquid enteral formula. Methods: In 25 cases of aspiration pneumonia and 10 cases of diarrhea (5 cases had both aspiration pneumonia and diarrhea) caused by liquid enteral formula, the rate of improvement by changing the liquid enteral formula to semi-solid enteral formula was studied. The semi-solid enteral formula (PG Soft® EJ) was infused via the nasogastric tube (16Fr) or percutaneous endoscopic gastrostomy (PEG) tube (20Fr). Results: The semi-solid enteral formula was effective in 72% of aspiration pneumonia cases and in 80% of diarrhea cases. Constipation was observed in one case but was controlled with magnesium oxide. Conclusion: In cases of aspiration pneumonia and/or diarrhea, changing liquid enteral formula to semi-solid enteral formula frequently shows improvement.

Purpose This study aimed to analyze whether the presence of refractile bodies (RFs) negatively affects fertilization, embryo development, and/or implantation rates following intracytoplasmic sperm injection (ICSI). Methods This retrospective embryo cohort study involved a total of 272 patients undergoing ICSI treatment of blastocyst cryopreservation. Results In the study, no significant differences were found regarding 2PN formation rates between RF(+) (76.5%) and RF(−) oocytes (77.2%). However, the blastocyst formation rate on Day 5 in RF(+) oocytes was 45.8%, which was significantly lower than that of 52.2% in RF(−) oocytes (aOR 0.74, 95% CI 0.59‐0.93, P = .011). Implantation rates were also significantly lower in RF(+) oocytes (24.2%) as compared to RF(−) oocytes (42.2%) (aOR 0.46, 95% CI 0.26‐0.78, P = .005). Furthermore, the implantation rate of RF(+) oocytes (28.6%), when high‐quality blastocysts were transferred, was significantly lower than that of RF(−) oocytes (46.1%) (aOR 0.50, 95% CI 0.25‐0.96, P = .043). Conclusion Our results suggest that oocytes with the presence of RFs have a lower potential for blastocyst development. Even when they develop into high‐quality blastocysts, the chances of implantation are reduced., Oocytes with the presence of RFs have a lower potential to develop into blastocysts, and even when they develop into high‐quality blastocysts, the chances of implantation are reduced.

Streptomyces incarnatus NRRL8089 produces the antiviral, antifungal, antiprotozoal nucleoside antibiotic sinefungin. To enhance sinefungin production, multiple mutations were introduced to the rpoB gene encoding RNA polymerase (RNAP) β-subunit at the target residues, D447, S453, H457, and R460. Sparse regression analysis using elastic-net lasso-ridge penalties on previously reported H457X mutations identified a numeric parameter set, which suggested that H457R/Y/F may cause production enhancement. H457R/R460C mutation successfully enhanced the sinefungin production by 3-fold, while other groups of mutations, such as D447G/R460C or D447G/H457Y, made moderate or even negative effects. To identify why the rif cluster residues have diverse effects on sinefungin production, an RNAP/DNA/mRNA complex model was constructed by homology modeling and molecular dynamics simulation. The 4 residues were located near the mRNA strand. Density functional theory–based calculation suggested that D447, H457, and R460 are in direct contact with ribonucleotide, and partially positive charges are induced by negatively charged chain of mRNA.

Background:Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area.

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.

Factor analysis is a popular statistical model for analyzing correlation structures among observed variables. It is well known that this model has a rotational indeterminacy. Traditionally, the model parameters are estimated by the maximum likelihood method; then, factor rotation methods are applied to obtain an interpretable factor loading matrix. Recently, several sparse estimation procedures via penalization have been developed. Sparse estimation via penalization is an alternative to the factor rotation; it leads to an interpretable and sufficiently sparse solution. In this paper, we give an overview of several sparse factor analysis models, followed by a discussion of a relation between ordinary factor rotation and penalized maximum likelihood approaches. Then, we introduce a novel analyzing tool wherein a user can select a model that is easy to interpret and also possesses desirable values of goodness-of-fit indices based on the graphical representation of solution path.

To confirm the effectiveness of sivelestat, a clinical trial was conducted comparing sivelestat with conventional treatment in an open, nonrandomized, multicenter study of patients with systemic inflammatory response syndrome (SIRS)-associated acute lung injury. The primary endpoint was ventilator-free days (VFD).This study adopted a "cluster entry" method to control for patient selection bias arising from the unblinded and nonrandomized clinical trial. Thus, all patients in the same hospital during the same entry period entered the same treatment arm, and entry periods did not overlap. In the primary analysis of VFD, adjusted mean VFD values were compared between groups using the inverse probability of treatment weighted (IPTW) method, based on propensity score, for control of confounding factors.There were 374 patients in the sivelestat group and 168 in the conventional therapy group. The primary analysis confirmed that sivelestat was effective (between-group difference of adjusted mean was 3.5 [2-sided 95% confidence interval, 1.3-5.8]; P = .0022).In general, a study where all patients in the same cluster enter the same treatment arm has within-cluster correlations, which need to be considered in the study analysis. However, in analysis using the IPTW method, it is usual to use a robust variance estimator, the sandwich variance estimator, which is consistent regardless of whether the specification of within-cluster correlation structure is correct. Thus, in the analysis using the IPTW method, it was found that it was not necessary to adopt any other adjustment method for within-cluster correlation.

To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment.This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone).The linear regression model identified age (P=0.001), pretreatment hearing level (P0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery.The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment.

Background The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients. Methods The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD-L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC). Results We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-γ production. Conclusion Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy.

Background The findings of COMPASS, a randomized phase II study, suggested that the regimens and courses of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) did not affect the pathological response. However, pathological complete response was achieved in 10% patients who received four courses of either S-1/cisplatin or paclitaxel/cisplatin. We hypothesized that if relevant biomarkers could be used to predict the suitable NAC regimen before treatment initiation, further improvements could be ensured in the outcomes of locally advanced GC. Materials and methods mRNA extraction, real-time polymerase chain reaction, and immunohistochemical analyses were performed using endoscopic biopsy specimens of primary tumors, collected prior to NAC, to determine the clinically relevant biomarkers. Results TIMP1, DSG2, RRM1, MUC2, EGFR, ZDHHC14, and CLDN18.2 were identified as biomarker candidates, since their expression was significantly associated with the pathological responses to each NAC regimen. Furthermore, TIMP1 and DSG2 were identified as predictive biomarkers of the pathological response to each NAC regimen. Conclusions The effective prediction of the pathological response to NAC regimens in locally advanced GC using biomarkers identified from endoscopic biopsy specimens indicates the possibility of personalizing NAC based on biomarker analysis.

Asymptotic distributions of normal-theory-based ML/MI estimators are studied in a simple regression model under general distributions with MAR missing data. The asymptotic variance of the ML/MI estimator of residuals’ variance is explicitly derived, from which it follows that the kurtosis of the error distribution primarily affects the asymptotic variance. Results of numerical simulations conducted to study finite sample properties of the estimators, conformed largely to the asymptotic results, and they also indicated interesting findings particularly for small samples, which do not follow from the asymptotic property. It is concluded that the ML estimators perform best in the situation studied here.

Objective Postoperative early oral or enteral intake is a crucial element of the Enhanced Recovery After Surgery (ERAS) protocol. However, normal food intake or enteral feeding cannot be started early in the presence of coexisting bowel dysfunction in patients undergoing liver transplantation (LT). The aim of this multicenter, randomized, double-blinded, placebo-controlled trial was to determine the enhancement effects of the Japanese herbal medicine Daikenchuto (DKT) on oral/enteral caloric intake in patients undergoing LT. Methods A total of 112 adult patients undergoing LT at 14 Japanese centers were enrolled. The patients were randomly assigned to receive either DKT or placebo from postoperative day (POD) 1 to 14. The primary endpoints were total oral/enteral caloric intake, abdominal distension, and pain on POD 7. The secondary endpoints included sequential changes in total oral/enteral caloric intake after LT, and portal venous flow volume and velocity in the graft. Results A total of 104 patients (DKT, n = 55; placebo, n = 49) were included in the analyses. There were no significant differences between the two groups in terms of primary endpoints. However, postoperative total oral/enteral caloric intake was significantly accelerated in the DKT group compared with the placebo group (P = 0.023). Moreover, portal venous flow volume (POD 10, 14) and velocity (POD 14) were significantly higher in the DKT group than in the placebo group (P = 0.047, P = 0.025, P = 0.014, respectively). Conclusions Postoperative administration of DKT may enhance total oral/enteral caloric intake and portal venous flow volume and velocity after LT and favorably contribute to the performance of the ERAS protocol.

OBJECTIVEThe clinical outcomes of a direct aspiration first-pass technique (ADAPT) and stent retriever (SR) have been reported to be similar in several observational studies. In this study, procedural and clinical outcomes with ADAPT and SR for the treatment of acute ischemic stroke with large artery occlusion were compared in different time periods.METHODSIn each specific time period, SR and ADAPT were used as the first-line treatment approach for acute ischemic stroke patients with large artery occlusion at the authors’ institution. Baseline characteristics, procedural variables, and functional outcome at 90 days were compared between patients treated with SR and those treated with ADAPT. These 2 groups were divided into 3 sequential subgroups to assess the learning curve effects of the endovascular team and individual operators on the procedural variables of each treatment strategy.RESULTSOverall, 89 patients were treated. In the SR group, the recanalization rate was higher (84% vs 65%; p = 0.01) and the procedure time was shorter than in the ADAPT group (median 42 minutes vs 76 minutes, p = 0.04). On the subgroup analysis of the learning curve, the SR group showed more rapid improvement in procedure time than the ADAPT group (p = 0.01 for the team; p < 0.01 for individual operators).CONCLUSIONSIn this initial experience, a higher recanalization rate and shorter procedure time were achieved with SR than with ADAPT. A high recanalization rate with SR was possible with relatively less clinical experience, whereas procedure time dramatically decreased with experience. These observed effects on the learning curve might be useful when choosing the method for initial endovascular treatment of acute ischemic stroke at relatively small stroke centers.

Background Guidelines for rectal cancer treatment differ in Japan, Europe, and the United States. Neoadjuvant chemoradiotherapy (CRT) has been used to control lateral lymph nodes (LLNs) in the West. The usefulness of LLN dissection (LLND) has been discussed in Japan, and a randomized study stated the possible advantage of local control. However, it is still unclear whether adding LLND to CRT is beneficial. Methods To investigate the effectiveness of LLND on rectal cancer patients who underwent neoadjuvant CRT, we retrospectively collected magnetic resonance images (MRIs) in a cohort of 1500 patients with cStage II/III lower rectal cancer below the peritoneal reflection and centrally reviewed MRIs. We measured short-axis LLN sizes on pre- and post-CRT images and evaluated patients’ prognosis according to LLN size and whether LLND was performed. Results MRIs were collected from 752 patients, of whom 189 underwent neoadjuvant CRT. Both pre- and post-CRT MRIs were available in 155 patients, of whom 66 underwent LLND (LLND group) and 89 did not (non-LLND group). The LLND and non-LLND group showed the following differences: positive circumferential resection margin by MRI after CRT: 53.0% vs. 32.6%; positive extramural venous invasion: 36.4% vs. 24.7%; laparoscopic surgery: 39.4% vs. 88.8%; and mean pre-CRT LLN size: 5.2 mm vs. 3.6 mm. Five-year relapse-free survival (5y-RFS) was 73.8% and 66.1% in the LLND and non-LLND groups, respectively (p = 0.38). Two local recurrences occurred in the LLND group. In stratified analysis, 5y-RFS of 40 patients whose LLN size was ≥5 mm in pre-CRT images was 77.8% in the LLND group and 46.2% in the non-LLND group (p = 0.06). On the other hand, 115 patients whose LLN size was Conclusions Our data indicated that adding LLND to CRT may have survival benefits on those who had LLN size of ≥ 5 mm before CRT. Stratification by short-axis LLN size using pre-CRT MRIs may facilitate optimal multidisciplinary treatment strategies for low rectal cancer. Legal entity responsible for the study Department of Surgery, Kyoto University Graduate School of Medicine. Funding The Japanese Foundation for Research and Promotion of Endoscopy, The Japan Society of Clinical Oncology, and Kondou Kinen Medical Foundation. Disclosure All authors have declared no conflicts of interest.

3578 Background: The usefulness of lateral lymph node dissection (LLND) for lower rectal cancer has been discussed. Concerning relapse-free survival (RFS), in the JCOG0212 trial, the non-inferiority of avoiding LLND for rectal cancer without LLN enlargement of ≥10 mm was not shown; however, the superiority of LLND was also not demonstrated. Methods: To examine whether the difference in dissection effect could be demonstrated by the size of LLN, magnetic resonance imaging (MRI) for the central review of pre-registered patients with stages II/III lower rectal cancer below the peritoneal reflection was performed, and the prognosis of the patients were prospectively investigated as a cohort. The relationship between LLND and RFS was also evaluated. Results: MR images of 738 cases (mean distance from anal verge: 4.5 cm) were evaluated. Twenty patients with LLN enlargement of ≥10 mm were excluded from the analysis. Overall, of 718 patients, 310 did not undergo LLND (non-LLND group), whereas the other 408 underwent LLND (LLND group). The lymph node sizes of ≥5 mm were observed in 10.0% and 21.1% of patients in the non-LLND and LLND groups, respectively. Although there was some bias in the background characteristics of the two groups (non-LLND vs. LLND; median age 66 vs. 61 years; laparoscopic surgery 64.2% vs. 17.9%; preoperative treatment 39.4% vs. 27.9%; circumferential resection margin evaluated by MRI 37.3% vs. 49.9%; and postoperative complications 33.2% vs. 44.4%), almost no difference in the 5-year RFS was observed (63.4% vs. 67.5%).The LLND group had significantly more favorable with ≥5 mm LLN (non-LLND 51.6% vs. LLND 69.0% P = 0.023) than with < 5 mm LLN (non-LLND 64.7%; LLND 67.0%). Conclusions: Oncological benefit of LLND was suggested in patients with enlarged lateral nodes on MRI using a large cohort of clinical stage II/III lower rectal cancer.

We propose a novel approach to finding an optimal subspace of multi-dimensional variables for identifying a cluster structure of objects. When some variables are irrelevant to the cluster structure and are correlated between themselves, they are likely to have an adverse effect on clustering of objects. In such situations, the proposed method aims to obtain an optimal subspace for partitioning objects by eliminating the effects of these irrelevant variables. The proposed method can be considered an extension of reduced k-means analysis and factorial k-means analysis for the settings where irrelevant variables are correlated. The proposed method is applied for the analyses of artificial and real data to investigate how it performs as compared to the existing methods.

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8−/− mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL–dysregulated genes and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued BCR-ABL–expressing dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML. Cancer Res; 73(22); 6642–53. ©2013 AACR.

Monocytes regulate host defenses, inflammation, and tissue homeostasis. The transcription factor interferon regulatory factor-8 (IRF8) stimulates monocyte/macrophage differentiation, yet genome-wide understanding of the differentiation program initiated by IRF8 is lacking. By combining chromatin immunoprecipitation sequencing with gene expression profiling, we show that during IRF8-dependent monocyte differentiation, IRF8 binding occurs at both promoter-proximal and promotor-distal regions together with the transcription factor PU.1 and is associated with gene induction. Many of the promoter-distal IRF8 binding sites show an increase in histone H3 lysine 4 monomethylation, a signature for enhancers. However, about half the IRF8-induced genes were not bound by IRF8, suggesting the involvement of downstream transcription factors. Analysis of DNA motifs in cis-regulatory elements of these indirect IRF8 target genes predicted that Krüppel-like factor-4 (KLF4)-essential for Ly6C(+) monocyte development-is one such factor. Indeed, monocyte development in Irf8(-/-) mice is as defective as that in Klf4(-/-) chimeric mice. Moreover, Irf8(-/-) monocyte-dendritic cell progenitors do not express Klf4 messenger RNA. Introduction of KLF4 into an Irf8(-/-) myeloid progenitor cell line induced a subset of IRF8 target genes and caused partial monocyte differentiation. Taken together, our present results uncover genome-wide behavior of IRF8 and identify an IRF8-KLF4 axis that operates during monocyte differentiation.

Introduction This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). Methods and analysis The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. Ethics and dissemination The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. Trial registration number The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.

Functional principal component analysis (FPCA) and functional multiple-set canonical correlation analysis (FMCCA) are data reduction techniques for functional data that are collected in the form of smooth curves or functions over a continuum such as time or space. In FPCA, low-dimensional components are extracted from a single functional dataset such that they explain the most variance of the dataset, whereas in FMCCA, low-dimensional components are obtained from each of multiple functional datasets in such a way that the associations among the components are maximized across the different sets. In this paper, we propose a unified approach to FPCA and FMCCA. The proposed approach subsumes both techniques as special cases. Furthermore, it permits a compromise between the techniques, such that components are obtained from each set of functional data to maximize their associations across different datasets, while accounting for the variance of the data well. We propose a single optimization criterion for the proposed approach, and develop an alternating regularized least squares algorithm to minimize the criterion in combination with basis function approximations to functions. We conduct a simulation study to investigate the performance of the proposed approach based on synthetic data. We also apply the approach for the analysis of multiple-subject functional magnetic resonance imaging data to obtain low-dimensional components of blood-oxygen level-dependent signal changes of the brain over time, which are highly correlated across the subjects as well as representative of the data. The extracted components are used to identify networks of neural activity that are commonly activated across the subjects while carrying out a working memory task.

We aimed to construct a prognostic model to predict survival in patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy using readily available pretreatment factors.The model was constructed using data from 306 consecutive patients with APC who received palliative chemotherapy between January 2006 and March 2013. The predictive accuracy of the model was assessed using a concordance index (c-index) and calibration curves.Among the 12 potential prognostic factors investigated, multivariate analysis identified the following six independent negative prognostic factors-performance status (PS), the presence of distant metastatic disease, the status of initially unresectable disease, carcinoembryonic antigen (CEA) level, carbohydrate antigen 19-9 (CA19-9) level, and neutrophil-lymphocyte ratio (NLR). A prognostic index (PI) based on the coefficients of these factors was constructed as follows-PI = 2 (if PS 2-3) + 1 (if distant metastatic disease) + 1 (if initially unresectable disease) + 1 (if CEA level ≥5.0 ng/ml) + 1 (if CA 19-9 level ≥1,000 U/ml) + 2 (if NLR ≥5). The patients were classified into three prognostic groups-favorable (PI 0-1, n = 73), intermediate (PI 2-3, n = 145), and poor (PI 4-8, n = 88). The median overall survival times for each prognostic group were 16.5, 12.3, and 6.2 months, respectively (P0.001). Bootstrapping verified the good fitness of this model for predicting 1-year survival, and the c-index was 0.658.This simple prognostic model could help clinicians to estimate survival in patients with APC who receive palliative chemotherapy.

Myeloid progenitors lose their potential to generate neutrophils when they adopt the mononuclear phagocyte lineage. The mechanism underlying this lineage restriction remains unknown. We here report that the protein expression of IRF8, an essential transcription factor for the development of dendritic cells (DCs) and monocytes, sharply increases at the monocyte-DC progenitor (MDP) stage and remains high in common monocyte progenitors (cMoPs). Irf8(-/-) MDPs and cMoPs accumulate but fail to efficiently generate their downstream populations, instead giving rise to neutrophils in vivo. IRF8 physically interacts with the transcription factor C/EBPα and prevents its binding to chromatin in MDPs and cMoPs, blocking the ability of C/EBPα to stimulate transcription and neutrophil differentiation. A partial inhibition of C/EBP activity in Irf8(-/-) haematopoietic progenitors alleviates the neutrophil overproduction in vivo. Thus, IRF8 not only bestows monocyte and DC differentiation potential upon mononuclear phagocyte progenitors but also restrains these progenitors from differentiating into neutrophils.

http://dx.doi.org/10.1016/S0387-7604(01)00344-8, A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur. Author

ラリンゲルマスクのカフにエアーを注入したときの内頸静脈・総頸動脈の位置変化を超音波エコーにより観察し,内頸静脈の血流変化を超音波ドプラーと,内頸静脈の圧変化により検討した.カフにエアーを注入すると総頸動脈の外側偏位,内頸静脈壁の変形を認め,内頸静脈の血流に乱流を生じた.しかし,カフより頭側で測定した内頸静脈圧に変化は認めなかった.本研究の結果よりラリンゲルマスクの使用が内頸静脈や総頸動脈の狭窄や閉塞を起こす危険性は少ないと考えられた.ただし,血管の位置や形状の変化,血液の乱流を生じるため内頸静脈穿刺時や一部の血液疾患症例では注意が必要である.

眼科症例を対象に市販の球後針に改良を加え,20ゲージの球後針を通して眼窩底に小児用硬膜外カテーテルを留置する持続球後神経ブロックを考案した.全身麻酔に,このブロックを用いたところ,局所麻酔薬の追加が可能で,覚醒が早く,呼吸抑制は少なく,眼球心臓反射による徐脈,不整脈の発生頻度は全身麻酔単独例に比べ有意に少なかった.針やカテーテルの挿入に際しての合併症は認められなかった.この方法は網膜剥離や硝子体手術などの長時間の眼科手術に対して安全かっ有用な方法であると思われる.

Hepatocellular carcinoma (HCC) and inflammatory pseudotumor of the liver (IPL) are often difficult to differentiate before surgery. To date, colocalization of IPL and HCC has not been reported. We experienced a case of necrotic HCC surrounded by IPL-like tissue. The raised levels of alpha-fetoprotein and PIVKA-II declined to within the normal ranges after resection of the tumor. The IPL-like nodule most likely developed as a process of an inflammatory reaction such as abscess formation after the spontaneous destruction of the HCC. Our case is a warning that the presence of a 'pseudotumor' does not rule out the possible simultaneous presence of carcinoma.