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Introduction: Hypospadias surgery has progressed steadily over recent years. There remains considerable variation in the operative management of boys with hypospadias in the UK, and it is therefore difficult to identify acceptable standards with regards to reoperation rates., Objective: To determine the frequency of reoperations and complications from all centres performing hypospadias surgery in England and to identify variables that influence outcome., Methods: All children undergoing NHS hypospadias surgery in England between 1999 and 2009 were identified using the Hospital Episode Statistics database. Patient demographics, centre type, and associated diagnostic (ICD-10) and treatment codes (OPCS4.6) were collected for both primary repairs and postoperative complications. Centres were classed as high volume if they performed an average of 20 or more operations a year. Operative complications were split into revisions (repeat repairs), repairs of urethral fistulae, repairs of meatal stenosis, or urethral stricture repairs. Statistical analysis included logistic regression, Spearman's correlation, and Mann-Whitney U for non-parametric data, with p < 0.05 taken as significant. Data are presented as median (interquartile range) unless otherwise stated., Results: children underwent a total of 23,962 operations at 75 centres in England during the study period. The median age at primary repair was 21 (15-38) months. The overall complication rate was 18.1%. The median complication rate for individual centres was 20.0% (13.9-27.4%) overall; 10.8% (4.7-15.9%) for revision procedures, 8.1% (5.5-11.7%) for urethral fistulae, 2.3% (1.1-3.7%) for meatal stenosis repairs, and 1.8% (0-2.8%) for urethral strictures. High volume centres had significantly lower complication rates than low volume centres (17.5% vs. 25%, p = 0.01) (Figure), and this was proven to be an independent predictor of outcomes (p = 0.01). Staged repairs were associated with more complications (p < 0.001); however, patient age and centre type were not. Median time to repair of complication was 13 (8-22) months., Discussion: This national population-based study used hospital episode statistics data. While accuracy is high and it has been validated for use in research, it has intrinsic limitations which affect our study. We are unable to fully account for the severity of hypospadias or the number of operating surgeons within institutions., Conclusions: This study has found a clear relationship between caseload volume and complications following hypospadias surgery. Furthermore, there is significant variability between centres in terms of their surgical outcomes. Taken together these results suggest that surgeons, particularly those in centres with small caseloads should assess their results against such benchmarks when evaluating the service they provide., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA., Methods: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies., Results: The addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage., Conclusion: Matriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA., (© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

The importance of aldehyde oxidase (AOX) is becoming increasingly recognized in the prediction of human pharmacokinetic parameters from animal data. The objectives of these studies were to ascertain whether an in vitro-in vivo correlation existed in the clearance and metabolic pathways of AOX substrates and to establish whether the minipig represented an appropriate non-rodent model for man in the pre-clinical development of drugs metabolized by AOX. Using the AOX substrates carbazeran, 6-deoxypenciclovir and zaleplon, clearance was estimated from in vitro depletion experiments with minipig and human liver cytosol and microsomes and scaled before comparison with data generated in parallel in vivo studies in minipigs. In vitro and in vivo metabolic pathways were characterized by LC-MS/MS. Scaling of in vitro metabolism data to predict in vivo clearance underestimated in vivo values, although the rank order of clearance for the three compounds was preserved. Prediction of human in vivo clearance from scaled minipig in vivo data produced results which correlated well with published clinical values. Overall, this study is the first to compare minipig in vitro metabolism data with in vivo pharmacokinetic data for compounds metabolized by AOX and provides a scientific rationale for the selection of this species as a model for humans in the development of drugs which are substrates of AOX.

AZD5122, N-(2-(2,3-difluorobenzylthio)-6-((2R,3R)-3,4-dihydroxybutan-2-ylamino)pyrimidin-4-yl)azetidine-1-sulfonamide was under investigation as a potential chemokine receptor CXCR2 antagonist for the treatment for inflammatory diseases. To gain a better understanding of the human pharmacokinetic profile, an exploratory phase I IV microtracer study was conducted using carbon-14 radiolabelled AZD5122. [(14) C]AZD5122 was carbon-14 labelled in the pyrimidine ring in five steps in an overall radiochemical yield of 19% from [(14) C]thiourea. The absolute oral bioavailability of AZD5122 was assessed in healthy subjects by an oral administration of AZD5122, followed by a concomitant intravenous [(14) C]AZD5122 microdose., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aim: To compare complication rates after distal hypospadias surgery using the tubularized incised plate (TIP) and Mathieu techniques., Methods: For this meta-analysis, the Medline (1990-2009), Embase (1990-2009) and Cochrane databases were searched using the keyword 'hypospadias'. Inclusion criteria were: i) primary repairs; ii) distal hypospadias; iii) paediatric case series; iv) standard Mathieu and TIP techniques; v) complication data obtainable from the paper. Cases were only included in the denominator for each complication if explicitly identified in the paper. Fisher's exact was used for statistical analysis, with P < 0.05 considered significant., Main Results: 129 papers were selected for full analysis; 23 papers met the inclusion criteria comprising 1872 TIP repairs and 1496 Mathieu repairs. We identified an increased incidence of urethral fistulae with the Mathieu technique (3.8% vs 5.3%, P = 0.028); however, this is lost on subgroup analysis. An increased incidence of meatal stenosis was identified in the TIP group (3.1% vs 0.7%, P < 0.001)., Conclusions: There is no clear consensus on the ideal method of repair for distal hypospadias. Both the Mathieu and TIP techniques have been shown to have low rates of postoperative complications. Comparison between series is difficult because of a lack of consistency in reporting complications and follow up. We advocate uniform standards for reporting outcomes of hypospadias., (Copyright © 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)