Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

Impact of radiologic variables on item responses of ODI, SRS22 and SF-36. in adult spinal deformity patients: differential item functioning (DIF) analysis results from a multi-center database.

PURPOSE: To determine if responses given to each question of the Scoliosis Research Society-22 (SRS22), Oswestry disability index (ODI) and Short Form-36 (SF-36) questionnaires are influenced by the radiological parameters. METHODS: Patients enrolled in a multi-centre prospectively collected adult spinal deformity database who had complete SRS22, ODI and SF-36 data at baseline and at one-year follow-up were analysed. The presence of a differential item function of each question within each score in relation to radiological parameters was analysed using a mixed Rasch model with the radiological threshold value(s) determined. RESULTS: Of those patients analysed (n = 1745; 1406 female, average age 51.0 ± 19.8 years), 944 were surgically and 801 were non-surgically treated. For the SRS22, questions (Q) 3, 5 and 18 were sensitive to almost all radiological parameters and the overall score was found sensitive to the Cobb angle. For the ODI, Q3, 6, 9 and 10 were not sensitive to any radiologic parameters whereas Q4 and 5 were sensitive to most. In contrast, only 3 of the SF-36 items were sensitive to radiological parameters. CONCLUSIONS: 78% of the SRS-22, 60% of the ODI and 8% of the questions in the SF-36 are sensitive to radiological parameters. Sagittal imbalance is independently associated with a poor overall outcome, but affects mental status and function more than pain and self-image. The assembly of questions responsive to radiological parameters may be useful in establishing a connection between changes in radiologic parameters and HRQL.

The Impact of Corrective Surgery on Health-Related Quality of Life Subclasses in Adult Scoliosis: Will Degree of Correction Prognosticate Degree of Improvement?

PURPOSE: Objectives in scoliosis corrective surgery include restoration of normal sagittal and coronal parameters to achieve patient satisfaction. HRQLs improvements remain limited after corrective surgery. The aim of this study was to evaluate the HRQL subclass variability specific to the sagittal and coronal correction in adult scoliosis surgery. METHODS: This multi-centre prospective analysis of consecutive adult spinal deformity (ASD) patients, from five European centres, only included multilevel instrumentation for scoliosis. d-(delta) values for each parameter represented pre to post-operative changes. Parameters included demographics, baseline, 1- and 2-year. HRQL outcomes (Oswestry disability index (ODI), Scoliosis Research Society (SRS)-22 and Short Form (SF36)), sagittal correction including relative spinopelvic alignment (dRSA) and coronal correction including major Cobb (dCobb) angles. RESULTS: A total of 353 patients reached 1-year and 2-year follow up. All HRQL total scores significantly improved postoperatively, including ODI, SRS-22 and SF36. HRQL subclasses which displayed persistent improvements correlated to dRSA included sex-life, self-image, fatigue, vitality, social functioning. The only HRQL subclass improvement that correlated with dCobb was self-image. CONCLUSION: Adult scoliosis surgery improves overall HRQL, having a minimal effect on each variable. Importantly, greater coronal deformity correction affects only greater self-image scores, whereas with greater sagittal correction there are many greater HRQL sub-class impacts. Correction and restoration of coronal balance is one of the surgical goals in adult scoliosis but the degree to which Cobb angle is corrected, apart from self-image, does not correlate with gains in sub-classes of HRQL. These results need to be taken into account when planning surgery.

Do aspermic (parthenogenetic) Fasciola forms have the ability to reproduce their progeny via parthenogenesis?

Across Far East Asia, aspermic Fasciola forms are found endemically. They have abnormal spermatogenesis and oogenesis, and it is presumed that their progeny are produced parthenogenetically and clonally. Because of this, they are also termed parthenogenic Fasciola forms. Currently, there is no evidence that they do indeed reproduce parthenogenetically and clonally. In this study, the multilocus genetic type (MLG) in 12 microsatellite markers of adult flukes and their subsequent progeny larvae were analysed using two laboratory aspermic Fasciola triploid strains. The MLGs of adults and their larvae were identical for all markers evaluated, suggesting that these strains reproduce their progeny clonally. The deviation between theoretical and actual frequency within the larvae genotype of the Fh_6 locus resulted in the inability for self-fertilization within individual adult flukes. These findings strongly suggested that aspermic Fasciola forms reproduce their progeny by means of parthenogenesis, possibly gynogenesis.

Damage accrual related to pregnancies before and after diagnosis of systemic lupus erythematosus: a cross-sectional and nested case-control analysis from a lupus registry.

OBJECTIVE: The objective of this study was to evaluate the chronic damage associated with pregnancies before and after the diagnosis of systemic lupus erythematosus (SLE). METHODS: Using childbearing-aged female SLE patient data registered at the Okayama and Showa University Hospitals, a nested case-control analysis was performed to investigate the relationship between pregnancy and chronic damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: Pregnancy occurred in 22 patients before and 13 patients after the diagnosis of SLE in 104 eligible patients. Live births occurred in 82% (33/40) and 50% (9/18) of the pregnancies before and after the diagnosis of SLE, respectively. After matching age and disease duration, 33 case patients with chronic damage (SDI ≥ 1) and 33 control patients without chronic damage (SDI = 0) were selected. Hypertension was more frequent in cases than in controls (48% vs. 24%, p = 0.041). Pregnancies before and after the diagnosis of SLE were comparable between cases and controls (before the diagnosis: nine case patients and eight control patients; after the diagnosis: three case patients and five control patients; p = 1.00). Even after adjusting for hypertension using multivariate analysis, the pregnancies before and after the diagnosis were not significant predictors for chronic damage (odds ratio = 1.48 (95% confidence interval 0.33-6.65)), p = 0.60 of the pregnancy before the diagnosis; odds ratio = 0.78 (95% confidence interval 0.13-4.74), p = 0.78 of the pregnancy after the diagnosis). CONCLUSION: Pregnancies, either before or after the diagnosis of SLE, did not show any differences in chronic damage. Our results help alleviate fears regarding childbearing in female patients with SLE and their families.

Usefulness of real-time elastography for diagnosing lymph node metastasis of skin cancer: does elastography potentially eliminate the need for sentinel lymph node biopsy in squamous cell carcinoma?

BACKGROUND: The metastatic involvement of regional lymph nodes is the most important prognostic factor for overall survival of skin cancer patients. The sonographic technique of freehand real-time tissue elastography (RTE), which displays tissue rigidity as a colour overlay of the tissue image, was developed. OBJECTIVE: Our purpose was to evaluate the benefit of RTE for detecting lymph node metastases of skin cancer non-invasively before operation. METHODS: We first selected lymph nodes of skin cancer patients which had already been diagnosed by biopsy as being reactive or metastatic, and then retrospectively collected images of RTE and B-mode and colour Doppler ultrasound on those lymph nodes performed preoperatively. Twenty-one lymph nodes from 12 patients with squamous cell carcinoma (SCC), 23 lymph nodes from 14 patients with malignant melanoma (MM) and 14 lymph nodes from six patients with extramammary Paget disease (Paget) were investigated. Elastographic images were assessed on a scale of one to four according to the percentage of high elasticity (hard) area (HEA) in the lymph node. RESULTS: In all three skin cancers, lymph nodes evaluated as grade 3 or 4 by RTE were metastatic. All lymph nodes evaluated as grade 1 or 2 by RTE were reactive in SCC, whereas some lymph nodes evaluated as grade 1 or 2 were metastatic in MM and Paget. CONCLUSION: Real-time tissue elastography may aid in distinguishing reactive lymph nodes from metastatic ones especially in SCC.

Tissue-dependent DNA methylation of carp uncoupling protein 1 promoter.

DNA methylation of enhancers and promoters generally inhibits gene transcription. DNA methylation occurs predominantly at the dinucleotide CpG, a methyl group that is covalently bonded to cytosine. We have previously demonstrated tissue-restricted expression of the uncoupling protein 1 (Ucp1) in common carp. Here, we characterized the methylation status of the upstream region of the transcriptional initiation site of the carp Ucp1 gene in the liver, brain, kidney, skeletal muscle, and scales. In addition, we explored the direct role of methylation on Ucp1 transcription. Ucp1 expression was higher in the liver than that in other tissues including the kidney, skeletal muscle, and scales. The extent of methylation at nt -2178 and nt -2103 was lower in the liver and kidney than that in the brain, skeletal muscle, and scales. In addition, methylation at the upstream proximal-region of the Ucp1 gene was generally less frequent in the liver compared with that in the other organs. The transcriptional activation assay using the CpG-free luciferase-based reporter suggested that the methylation of the distal and proximal regions of the carp Ucp1 gene did not affect Ucp1 transcription. Unexpectedly, mutation of cytidylic acid to guanylic acid at nt -108 decreased Ucp1 promoter activity. The present results reveal that the status of DNA methylation of the upstream region of the carp Ucp1 gene is different among different tissues, but suggest that the DNA methylation do not directly repress the transcription of Ucp1.

Drug use and phylogenetic clustering of hepatitis C virus infection among people who use drugs in Vancouver, Canada: A latent class analysis approach.

This study estimated latent classes (ie, unobserved subgroups in a population) of people who use drugs in Vancouver, Canada, and examined how these classes relate to phylogenetic clustering of hepatitis C virus (HCV) infection. HCV antibody-positive people who use drugs from two cohorts in Vancouver, Canada (1996-2012), with a Core-E2 sequence were included. Time-stamped phylogenetic trees were inferred, and phylogenetic clustering was determined by time to most common recent ancestor. Latent classes were estimated, and the association with the phylogenetic clustering outcome was assessed using an inclusive classify/analyse approach. Among 699 HCV RNA-positive participants (26% female, 24% HIV+), recent drug use included injecting cocaine (80%), injecting heroin (70%), injecting cocaine/heroin (ie, speedball, 38%) and crack cocaine smoking (28%). Latent class analysis identified four distinct subgroups of drug use typologies: (i) cocaine injecting, (ii) opioid and cocaine injecting, (iii) crack cocaine smoking and (iv) heroin injecting and currently receiving opioid substitution therapy. After adjusting for age and HIV infection, compared to the group defined by heroin injecting and currently receiving opioid substitution therapy, the odds of phylogenetic cluster membership was greater in the cocaine injecting group (adjusted OR [aOR]: 3.06; 95% CI: 1.73, 5.42) and lower in the crack cocaine smoking group (aOR: 0.06; 95% CI: 0.01, 0.48). Combining latent class and phylogenetic clustering analyses provides novel insights into the complex dynamics of HCV transmission. Incorporating differing risk profiles associated with drug use may provide opportunities to further optimize and target HCV treatment and prevention strategies.

Refractory neuromyelitis optica spectrum disorder in systemic lupus erythematosus successfully treated with rituximab.

We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD.

Progressive reduction of serum complement levels: a risk factor for relapse in patients with hypocomplementemia in systemic lupus erythematosus.

OBJECTIVE: Serologically active clinically quiescent (SACQ)-SLE is a subtype of systemic lupus erythematosus (SLE); most SACQ-SLE patients relapse. Although complement and/or anti-dsDNA level fluctuations during SACQ status are reportedly not useful for predicting relapse, they might be useful in specific clinical settings. We aimed to assess the correlation between future relapse and progressive reductions in serum complement levels following remission in patients with hypocomplementemia . METHODS: We retrospectively reviewed patients aged ≥15 years who were treated with ≥20 mg/day of prednisolone for remission induction. After achieving remission, the patients treated with prednisolone tapered to ≤15 mg/day without relapse and followed by hypocomplementemia (first hypocomplementemia point) were analyzed. The primary outcome was the relapse during the first 24 months. RESULTS: Seventy-six patients were enrolled; 31 (40.8%) relapsed. A ≥10% reduction after the first hypocomplementemia point in serum C3, C4, and CH50 levels was found in 10, 21, and 16 patients, respectively. Hazard ratios (95% confidence intervals) for relapse were 2.32 (0.92-5.12) for serum C3 levels and 2.46 (1.18-5.01) for serum C4 levels. Progressive reductions in serum C3 and C4 levels had relatively high specificity (93.3% and 82.2%) but limited sensitivity (22.6% and 41.9%) for predicting relapse. However, simultaneous progressive reduction in C3 levels and increase in anti-dsDNA antibody levels had the highest specificity (97.8%), and simultaneous progressive reduction in C4 levels or increase in anti-dsDNA antibody levels had the highest sensitivity (71.0%). CONCLUSION: Simultaneous progressive reductions in complement levels and increases in anti-dsDNA antibody levels may indicate future relapse SACQ-SLE patients.

Laparoscopic ventral rectopexy in patients with fecal incontinence associated with rectoanal intussusception: prospective evaluation of clinical, physiological and morphological changes.

BACKGROUND: Physiological changes after laparoscopic ventral rectopexy (LVR) in patients with rectoanal intussusception (RAI) remain unclear. This study was undertaken to evaluate physiological and morphological changes after LVR for RAI, and to study clinical outcomes following LVR with special reference to fecal incontinence (FI). METHODS: The study was conducted on patients who had LVR for RAI between February 2012 and December 2016 at our institution Patients with RAI and FI were included in the study. Patients with RAI and obstructed defecation and those with RAI and neurologic FI were not included. The patients had anorectal manometry preoperatively, and 3, 6, and 12 months postoperatively. Defecography was performed before and 6 months after the procedure. FI was evaluated using the Fecal Incontinence Severity Index (FISI). RESULTS: There were 34 patients (median age 77 years (range 60-93) years). Thirty-two patients (94%) were female and the median number of vaginal deliveries was 2 (range 0-5). Neither maximum resting pressure nor maximum squeeze pressure increased postoperatively. There was an overall increase in both defecatory desire volume (median preoperative 75 ml vs. 90 ml at 12 months; p = 0.002) and maximum tolerated volume (median preoperative 145 ml vs.175 ml at 12 months; p = 0.002). Postoperatively, RAI was eliminated in all patients but one, although 13 had residual rectorectal intussusception found at defecography. There was an overall reduction in both rectocele size (median preop 29 mm vs. postop 10 mm; p = 0.008) and pelvic floor descent (median preop 26 mm vs. postop 20 mm; p = 0.005). Twelve months after surgery, a reduction of at least 50% was observed in the FISI score for 31 incontinent patients (91%). CONCLUSIONS: LVR for RAI produced adequate improvement of FI, and successful anatomical correction of RAI was confirmed by postoperative proctography. Postoperative increase in the rectal volume may have a positive effect on continence.

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.

BACKGROUND: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. PATIENTS AND METHODS: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). RESULTS: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. CONCLUSION: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

CYFRA 21-1 as a tumor marker for squamous cell carcinoma of the esophagus.

This study assessed the clinical value of CYFRA 21-1 in comparison with squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) in patients with esophageal squamous cell carcinoma. In 112 primary cancer patients, the diagnostic sensitivity of CYFRA 21-1 (33.9%) was superior to SCC-Ag (28.6%), CEA (12.5%), and CA19-9 (6.3%). Levels of CYFRA 21-1 were closely correlated with TNM stage and were below the cutoff value in all 21 patients with stage I disease. All 38 patients with a CYFRA 21-1 level over the cutoff value among the 80 patients who underwent esophagectomy had lymph node metastases (pNl). A correlation was found between CYFRA 21-1 levels and clinical response in serial measurements of 21 patients who received chemotherapy or chemo radiotherapy. Our findings suggest that CYFRA 21-1 is not useful for diagnosis, but that it is valuable for monitoring the efficacy of therapy.

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study.

The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 ± 0.5 and 1.0 ± 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of ΔDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r = -0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.

Healthcare avoidance by people who inject drugs in Bangkok, Thailand.

BACKGROUND: Although people who inject drugs (IDU) often contend with various health-related harms, timely access to health care among this population remains low. We sought to identify specific individual, social and structural factors constraining healthcare access among IDU in Bangkok, Thailand. METHODS: Data were derived from a community-recruited sample of IDU participating in the Mitsampan Community Research Project between July and October 2011. We assessed the prevalence and correlates of healthcare avoidance due to one's drug use using multivariate logistic regression. RESULTS: Among 437 participants, 112 (25.6%) reported avoiding health care because they were IDU. In multivariate analyses, factors independently associated with avoiding health care included having ever been drug tested by police [adjusted odds ratio (AOR) = 1.80], experienced verbal abuse (AOR = 3.15), been discouraged from engaging in usual family activities (AOR = 3.27), been refused medical care (AOR = 10.90), experienced any barriers to health care (AOR = 4.87) and received healthcare information and support at a drop-in centre (AOR = 1.92) (all P < 0.05). CONCLUSIONS: These findings highlight the need to address the broader policy environment, which perpetuates the criminalization and stigmatization of IDU, and to expand peer-based interventions to facilitate access to health care for IDU in this setting.

Determination of HLA-A, -C, -B, -DRB1 allele and haplotype frequency in Japanese population based on family study.

The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies.

Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients.

STUDY QUESTION: What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome? SUMMARY ANSWER: Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation. WHAT IS KNOWN ALREADY: Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias. STUDY DESIGN, SIZE, DURATION: Systematic mutation screening and genome-wide copy-number analysis of 62 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization. MAIN RESULTS AND THE ROLE OF CHANCE: Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome. LIMITATIONS, REASONS FOR CAUTION: The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Variations in survival and perioperative complications between hospitals based on data from two phase III clinical trials for oesophageal cancer.

BACKGROUND: Variations in institutional practice may contribute to different outcomes of cancer treatment. The impact of interinstitutional heterogeneity on outcomes between hospitals after oesophagectomy has not been examined previously using data from surgical clinical trials. METHODS: The data from two phase III trials for oesophageal cancer were used. Japan Clinical Oncology Group (JCOG) 9204 involved oesophagectomy (92-OP) versus oesophagectomy plus postoperative chemotherapy (92-POST), with accrual from 1992 to 1997. JCOG9907 involved postoperative chemotherapy (99-POST) versus preoperative chemotherapy (99-PRE), with accrual from 2000 to 2006. Hospitals contributing fewer than three patients were excluded. The influence of time and preoperative chemotherapy on interinstitutional heterogeneity related to postoperative complications and 5-year overall survival were evaluated by comparisons within and between these trial groups. Heterogeneity was estimated by a mixed-effects model after adjusting for age, sex, performance status, location of the primary tumour and clinical stage. RESULTS: Twelve hospitals in 92-OP (114 patients), 13 in 92-POST (114), 19 in 99-POST (158) and 18 in 99-PRE (154) were eligible. There was considerable heterogeneity in predicted postoperative complications in both groups in JCOG9204 (median 31.3 (range 15.0-68.2) per cent), and in 99-PRE (35.2 (22.6-46.6) per cent) but not in 99-POST (27.7 (27.7-27.7) per cent) from JCOG9907. A similar pattern was seen for predicted overall survival (92-POST: 66.4 (range 64.1-68.9) per cent; 99-PRE: 55.9 (54.0-59.7) per cent; 99-POST: 44.4 (44.4-44.4) per cent). CONCLUSION: Interinstitutional heterogeneity regarding complications and survival after oesophagectomy is a problem that merits wider consideration.

Total serum IgE level influences oral food challenge tests for IgE-mediated food allergies.

Probability curves predicting oral food challenge test (OFC) results based on specific IgE levels are widely used to prevent serious allergic reactions. Although several confounding factors are known to affect probability curves, the main factors that affect OFC outcomes are currently unclear. We hypothesized that an increased total IgE level would reduce allergic reactivity. Medical records of 337 and 266 patients who underwent OFCs for 3.5 g boiled hen's egg white and 3.1 ml raw cow's milk, respectively, were examined retrospectively. We subdivided the patients into three groups based on total IgE levels and age by percentile (<25th, 25-75th, and >75th percentiles), and logistic regression analyses were performed on each group. Patients with higher total IgE levels were significantly less responsive. In addition, age did not significantly affect the OFC results. Therefore, total IgE levels should be taken into account when predicting OFC results based on food-specific IgE levels.

The Helioseismic and Magnetic Imager (HMI) Vector Magnetic Field Pipeline: Magnetohydrodynamics Simulation Module for the Global Solar Corona.

Time-dependent three-dimensional magnetohydrodynamics (MHD) simulation modules are implemented at the Joint Science Operation Center (JSOC) of the Solar Dynamics Observatory (SDO). The modules regularly produce three-dimensional data of the time-relaxed minimum-energy state of the solar corona using global solar-surface magnetic-field maps created from Helioseismic and Magnetic Imager (HMI) full-disk magnetogram data. With the assumption of a polytropic gas with specific-heat ratio of 1.05, three types of simulation products are currently generated: i) simulation data with medium spatial resolution using the definitive calibrated synoptic map of the magnetic field with a cadence of one Carrington rotation, ii) data with low spatial resolution using the definitive version of the synchronic frame format of the magnetic field, with a cadence of one day, and iii) low-resolution data using near-real-time (NRT) synchronic format of the magnetic field on a daily basis. The MHD data available in the JSOC database are three-dimensional, covering heliocentric distances from 1.025 to 4.975 solar radii, and contain all eight MHD variables: the plasma density, temperature, and three components of motion velocity, and three components of the magnetic field. This article describes details of the MHD simulations as well as the production of the input magnetic-field maps, and details of the products available at the JSOC database interface. To assess the merits and limits of the model, we show the simulated data in early 2011 and compare with the actual coronal features observed by the Atmospheric Imaging Assembly (AIA) and the near-Earth in-situ data.