Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

A consensus process to identify research priorities in paediatric urology in the United Kingdom.

INTRODUCTION: Paediatric urologists manage a spectrum of conditions, much of the evidence for relevant treatment pathways is of low quality. For many conditions treatment varies according to location and surgeon; children with the same condition might have surgery in one unit but watchful waiting in another. Underlying this variation are differences in opinion, and insufficient high-level evidence with few prospective randomized studies. Such studies may be challenging to design, fund and recruit into, and are more likely to succeed if there is a collaborative approach. Research prioritization is a tool to identify the research of most value. Delphi methodology is an interpretive technique aiming to gain the consensus view of interested parties. The British Association of Paediatric Urologists (BAPU) set out to ascertain consensus on what paediatric urologists, working in the UK, consider to be areas of priority for research. This paper describes the process used, and the resulting list of research questions. METHODS: A scoping survey of paediatric urologists in the UK was undertaken to identify an initial set of research questions. These were refined by the BAPU research committee (BAPU RC), then prioritized using a modified Delphi process. During Stage 1a multiple new research questions were submitted leading to Stage 1b, an interim process. All UK paediatric urologists were invited to take part in Stage 2 of the prioritization process. RESULTS: Sixty-five questions were submitted to the scoping survey by 24 paediatric urologists. The BAPU RC refined these to 60 questions, which were submitted to Stage 1a of the modified Delphi process. Sixty-seven people completed Stage 1a, at the same time submitting 224 additional research questions. The BAPU RC revised the entire question set, ensuring the key subject of the original question was not altered and novel questions were retained. The BAPU RC undertook interim scoring of the resultant 79 questions, the top scoring 25 questions plus 5 lower scoring 'wild card' questions (to ensure the breadth of the specialty was represented) were put forward to Stage 2. A total of 65 people completed Stage 2, including a lay representative. A list of 30 priority research questions was generated; the top 10 includes management of neuropathic bladder, posterior urethral valves, antibiotic prophylaxis, DSD & CAH, continence, male external genitalia, VUR and transition care (Table). CONCLUSION: This process has provided BAPU, paediatric urologists in the UK, and funders with areas of research considered a priority in the specialty.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

The emerging landscape of eukaryotic polyphosphatases.

Polyphosphate (polyP) is a conserved polymer of inorganic phosphate residues that can reach thousands of moieties in length. PolyP has been implicated in cellular functions ranging from energy and phosphate homeostasis to cell signalling in eukaryotes from yeast to humans. Despite the interest in the role of polyP as a signalling molecule, the spatiotemporal regulation of polyP itself remains poorly understood. This knowledge gap limits our ability to understand how polyP impacts the physiology of normal and diseased cells and how this might be exploited in a therapeutic context. Polyphosphatases, enzymes that degrade polyP to generate shorter chains and free inorganic phosphate are ideally positioned to mediate polyP dynamics. However, little is known about how the activities of these enzymes are linked to specific cellular functions and how they might be regulated. Here, we provide an in-depth overview of polyphosphatase enzymes in budding yeast, which has served as a workhorse for polyP research, and in mammalian cells where the enzymes that make and degrade polyP have remained elusive. We identify critical open questions in both systems and propose strategies to guide future work.

Ddp1 Cooperates with Ppx1 to Counter a Stress Response Initiated by Nonvacuolar Polyphosphate.

In diverse cells from bacterial to mammalian species, inorganic phosphate is stored in long chains called polyphosphate (polyP). These nearly universal polymers, ranging from three to thousands of phosphate moieties in length, are associated with molecular functions, including energy homeostasis, protein folding, and cell signaling. In many cell types, polyphosphate is concentrated in subcellular compartments or organelles. In the budding yeast Saccharomyces cerevisiae, polyP synthesis by the membrane-bound vacuolar transporter chaperone (VTC) complex is coupled to its translocation into the lumen of the vacuole, a lysosome-like organelle, where it is stored at high concentrations. In contrast, the ectopic expression of the bacterial polyphosphate kinase (PPK) results in the toxic accumulation of polyP outside the vacuole. In this study, we used label-free mass spectrometry to investigate the mechanisms underlying this toxicity. We find that PPK expression results in the activation of a stress response mediated in part by the Hog1 and Yak1 kinases and the Msn2/Msn4 transcription factors as well as by changes in protein kinase A (PKA) activity. This response is countered by the combined action of the Ddp1 and Ppx1 polyphosphatases that function together to counter polyP accumulation and downstream toxicity. In contrast, the ectopic expression of previously proposed mammalian polyphosphatases did not impact PPK-mediated toxicity in this model, suggesting either that these enzymes do not function directly as polyphosphatases in vivo or that they require cofactors unique to higher eukaryotes. Our work provides insight into why polyP accumulation outside lysosome-like organelles is toxic. Furthermore, it serves as a resource for exploring how polyP may impact conserved biological processes at a molecular level. IMPORTANCE Cells from bacteria to humans have a molecule called polyphosphate (polyP) that functions in diverse processes. In many microbes, polyP is sequestered in granules or lysosome-related organelles such as vacuoles. In this study, we use an ectopic expression system to force budding yeast to accumulate polyP outside the vacuole. We use proteomics to demonstrate that this nonvacuolar polyP initiates a stress response mediated by a signaling cascade involving the Yak1 and Hog1 kinases and the Msn2 and Msn4 transcription factors. This response is countered by a pair of polyphosphatases with different enzymatic activities that function in concert to degrade polyP. Our results provide new insights into why polyP is confined to specific cell locations in many microbial cells.

Controlled aspiration of large paediatric ovarian cystic tumours.

AIM: Cystic ovarian masses in children may be physiological or neoplastic. It is mandatory that suspected neoplastic lesions are resected without tumour spillage. However, a large midline incision is cosmetically unappealing incision to young women. Here we describe our experience of using controlled drainage without spillage that allows a cosmetic pfannenstiel approach without compromising oncological principles. METHOD: All girls treated with large ovarian cystic masses since 2008 in our centre were identified and data was collected prospectively. A small pfannenstiel incision was performed followed by peritoneal washings; tissue glue was used to stick an Opsite™ dressing to the cyst surface and fluid drained so there was no leakage back into the patient. Once aspirated the cyst was delivered and an ovarian preserving cystectomy was performed where possible. RESULTS: Twenty-three girls (median age 14.5 years (8.1 to 16.5 years) were included. Pre-operative MRI scan showed a complex lesions with median volume of 1169 ml (range 252-7077 ml). At surgery 22/23 cysts were intact and removed without spillage. HISTOLOGY: mature teratoma (11), serous cyst (3), mucinous cyst adenocarcinoma (2), mucinous cystadenoma (5), Sertoli-Leydig tumour, sclerosing stromal tumour. One girl with pre-operative rupture of a mucinous adenocarcinoma subsequently died. Ovarian sparing cystectomy was performed in 17/23 girls. All other patients are well without evidence of recurrence. CONCLUSION: This is the largest series in children and adolescents using controlled drainage of cystic ovarian tumours. Though there were a range of diagnoses we have shown that these can be removed safely with a cosmetic pfannenstiel approach while following oncological principles.

Complete Genome Sequence of Microbacterium Bacteriophage Erla.

We characterized the complete genome sequence of Siphoviridae bacteriophage Erla, an obligatory lytic subcluster EA1 bacteriophage infecting Microbacterium foliorum NRRL B-24224, with a capsid width of 65 nm and a tail length of 112 nm. The 41.5-kb genome, encompassing 62 predicted protein-coding genes, is highly similar (99.52% identity) to that of bacteriophage Calix.

Recommendations of patients and families of girls with 46XX congenital adrenal hyperplasia in the United Kingdom regarding the timing of surgery.

PURPOSE: The timing of surgery for congenital adrenal hyperplasia (CAH) is contentious. We aimed to survey expert families and patients for their recommendations regarding timing of surgery for a family with a newly diagnosed CAH child. METHODS: A Survey Monkey questionnaire was performed at the 2017 meeting of the CAH support group, "Living with CAH", and also sent to the members of the CAH support group. The surgical-timing responses were a Likert score from 1 (strongly disagree) to 5 (strongly agree). Data were analysed by Kruskal-Wallis test. p < 0.05 taken as significant. RESULTS: Of the 61 respondents, 12 were CAH patients, 43 were CAH parents, 3 were physicians, 1 surgeon and 2 others. For all respondents, the Likert score was 3 for infant, toddler and adult timing of surgery (neutral), not statistically significant (ns). For parents and/or children who had surgery (n = 26), the score was 4 (3-5) for infant vs. 4 (3-4) for toddler-years vs. 2 (1-3) for adulthood. This was statistically significant (p = 0.0002). When only patients who had CAH surgery were included, there were only 8 respondents and their scores were: infancy 3 (2-4) vs. toddler-years 4 (2-4) vs. adulthood 1 (1-4), ns. CONCLUSION: Expert families and patients in the United Kingdom who have had CAH surgery, recommend surgery in the first few years of life vs. adulthood. There is a selection bias, however this may support MDTs in continuing to discuss surgery as an option in childhood.

A Broad Response to Intracellular Long-Chain Polyphosphate in Human Cells.

Polyphosphates (polyPs) are long chains of inorganic phosphates linked by phosphoanhydride bonds. They are found in all kingdoms of life, playing roles in cell growth, infection, and blood coagulation. Unlike in bacteria and lower eukaryotes, the mammalian enzymes responsible for polyP metabolism are largely unexplored. We use RNA sequencing (RNA-seq) and mass spectrometry to define a broad impact of polyP produced inside of mammalian cells via ectopic expression of the E. coli polyP synthetase PPK. We find that multiple cellular compartments can support accumulation of polyP to high levels. Overproduction of polyP is associated with reprogramming of both the transcriptome and proteome, including activation of the ERK1/2-EGR1 signaling axis. Finally, fractionation analysis shows that polyP accumulation results in relocalization of nuclear/cytoskeleton proteins, including targets of non-enzymatic lysine polyphosphorylation. Our work demonstrates that internally produced polyP can activate diverse signaling pathways in human cells.

Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast.

Polyphosphates (polyP) are long chains of inorganic phosphates that can be attached to lysine residues of target proteins as a nonenzymatic post-translational modification. This modification, termed polyphosphorylation, may be particularly prevalent in bacterial and fungal species that synthesize large quantities of polyP. In this study, we evaluated the polyphosphorylation status of over 200 candidate targets in Saccharomyces cerevisiae. We report eight new polyphosphorylated proteins that interact genetically and physically with previous targets implicated in ribosome biogenesis. The expanded target network includes vacuolar proteins Prb1 and Apl5, whose modification with polyP suggests a model for feedback regulation of polyP synthesis, while raising questions regarding the location of polyphosphorylation in vivo.

The postnatal management of boys in a national cohort of bladder outlet obstruction.

AIM: The most common cause of congenital bladder outlet obstruction (BOO) is posterior urethral valves (PUV). Initial treatment requires decompression, but transurethral incision (TUI) or primary diversion is all described. There is no randomized control trial to guide management. This study aims to describe management, circumcision, and UTI rate in a national cohort of PUV boys. METHODS: Boys diagnosed with BOO were recruited (via BAPS CASS) over 1 year with ethics committee approval (ref: 12/SC/0416). Data were collected via questionnaire, presented as number (%), analyzed by Mann-Whitney/chi-square/Fisher Exact tests, and p < 0.05 was taken as significant. RESULTS: BOO presented in 121 boys during 2014-2015, and 113 were PUV. Catheter placement in 87/121(72%) was more likely to happen in antenatal vs. postnatal vs. late(>1 y) presentations, p < 0.0001. Polyuria occurred in 23/45(51%), 12/48(25%), 0/28(0%), respectively, p < 0.0001. Initial surgical treatment was TUI in 108/121(89%) and vesicostomy in 2. Two ureterostomies were secondary procedures. Circumcision was performed in 52/121(43%) in antenatal presentation vs. postnatal vs. late 27/45(60%), 20/48(42%), 2/28(7%), respectively, p = 0.01. 69 UTIs occurred in 49 patients. Circumcision was associated with an 86% reduced risk of UTI, p < 0.0001. There was a 66% reduction in UTI risk associated with TUI alone, p < 0.01. There was 1 death due to pulmonary hypoplasia and renal failure, and 2 experienced end-stage renal failure (ESRF). CONCLUSION: Standard treatment for BOO and PUV in the current UK cohort is urethral catheterization followed by TUI. Supravesical diversion is a rescue therapy. UTIs are common and reduced by circumcision, with 43% being circumcised. Initial mortality rate was 1%, and 1.6% present in ESRF. LEVEL OF EVIDENCE: Prognostic study - Level I - Prospective National Cohort Study.

Current epidemiology and antenatal presentation of posterior urethral valves: Outcome of BAPS CASS National Audit.

AIM: Posterior urethral valves (PUVs) are the most common cause of congenital bladder outlet obstruction (BOO) in boys and end-stage renal failure (ESRF) in childhood. In the 1980s, 1 in 4000 boys had PUV. Presentation was 1/3 antenatal/neonatally, 1/3 postnatal, 1/3 late (>1 year). This study aimed to describe the current proportions in a contemporary cohort. METHODS: A national audit (BAPS CASS) of referrals in the UK and Ireland of boys diagnosed with suspected or confirmed PUV in a year was conducted. National registration data provided the male birth-rate. Data were presented as number (%), analysed by Mann-Whitney U-test and Chi-square test, with P < 0.05 taken as significant. The study was approved by a national ethics committee (NRES Committee South Central Oxford A (12/SC/0416)). RESULTS: Data were collected from 1st October 2014 to 30th September 2015 from 25/26 centres on 121 cases of suspected bladder outlet obstruction (BOO), of which 113 (93%) were because of PUV. The male birth rate during the period was 432,806/year. The calculated incidence of BOO was 1/3580 and for PUV was 1/3800 per-annum. The proportion of PUV presenting according to age was: antenatally (n = 40, 35%), infancy (n = 47, 42%), and late (n = 26, 23%). Plasma creatinine was higher in antenatally-diagnosed BOO vs. postnatal, 54 (39.5-109.5) µmol/l vs. 34(21-47) µmol/l, P = 0.0005. Hydronephrosis and ureteric dilatation were significantly greater in antenatally diagnosed BOO vs. postnatal vs. late. Renal dysplasia (cortical thinning, poor corticomedullary differentiation, or renal cysts) was significantly more likely in antenatally diagnosed BOO. CONCLUSION: Neither the incidence (~1/4000) nor the proportion antenatally diagnosed (~1/3) of boys with PUV appears to have changed in the past 30 years. Those boys who were antenatally diagnosed have significantly higher postnatal plasma creatinine, more hydroureteronephrosis, and renal dysplasia than those diagnosed in infancy or later. It may be hypothesized that this is the reason they are detected antenatally. LEVEL OF EVIDENCE: Prognosis study - Level I - prospective national cohort study.

Using sound pulses to solve the crystal-harvesting bottleneck.

Crystal harvesting has proven to be difficult to automate and remains the rate-limiting step for many structure-determination and high-throughput screening projects. This has resulted in crystals being prepared more rapidly than they can be harvested for X-ray data collection. Fourth-generation synchrotrons will support extraordinarily rapid rates of data acquisition, putting further pressure on the crystal-harvesting bottleneck. Here, a simple solution is reported in which crystals can be acoustically harvested from slightly modified MiTeGen In Situ-1 crystallization plates. This technique uses an acoustic pulse to eject each crystal out of its crystallization well, through a short air column and onto a micro-mesh (improving on previous work, which required separately grown crystals to be transferred before harvesting). Crystals can be individually harvested or can be serially combined with a chemical library such as a fragment library.

Bladder dysfunction in Wolfram syndrome is highly prevalent and progresses to megacystis.

AIM: Wolfram syndrome is a rare genetic defect in WFS1 or WSF2(CISD2). It includes diabetes mellitus and insipidis, sensorineural deafness, optic atrophy, but not bladder dysfunction. However, this has appeared a common finding in our national referral clinic, and we sought to quantify this problem. METHODS: Data were collected from a multidisciplinary team managing all Wolfram patients in the UK. The following was analyzed: age, date of non-invasive urodynamics (NIU), symptoms, bladder capacity, voided volume, post-void residual and uroflow pattern. Bladder capacity was given as percentage predicted bladder capacity (PBC). Bladders were divided into normal, overactive (OAB), and underactive (UAB). Symptoms, bladder behavior, and genotyping were correlated. Data were expressed as median (interquartile range). MAIN RESULTS: Forty patients with Wolfram syndrome were identified, and 38 underwent NIU. This showed normal bladder function (n=4), OAB (n=9), UAB (n=25). Symptoms were present in only 11 children. The different patterns of bladder behavior (OAB vs. normal vs. UAB) were significantly associated with different %PBC (36 (29-59)% vs. 105 (93-233)% vs. 100 (77.5-337)%; p<0.001), and percentage emptying (100 (80-100)% vs. 100 (87-100)% vs. 69 (48-93)%; p<0.05). There was no association of genotype, symptoms and bladder behavior. Patients with megacystis were older: [13.4 (9.7-16.1) vs. 15.4 (13.9-18.7) years; p<0.05). CONCLUSION: Bladder dysfunction is very common in Wolfram syndrome (~90%), but most children cope (symptoms ~30%). With time there is a significant progression to megacystis, which may represent an underlying neuropathic myogenic failure and is likely to require intervention in the future. LEVEL OF EVIDENCE: Level II (National cohort study of prognosis).

Prediction of need for intervention in posterior urethral valves: Use of urine osmolality.

AIM: Renal tubular dysfunction (RTD) causing obligate production of hypoosmolar urine in boys with posterior urethral valves (PUVs) has been described. It is not known how clinically significant this is. We hypothesize that a feedback loop is present in many PUV boys who suffer deterioration of their lower urinary tract (LUT). RTD results in hypoosmolar urine, obligate polyuria, and bladder stretch-injury. The increasing back-pressure worsens RTD, thus exacerbating the injury. Coexisting renal dysplasia and acquired renal scarring exacerbate this. We compared the concentrating ability (random clinic urine osmolality) of PUV boys who had no LUT deterioration to those who required intervention, examining the confounding effect of renal impairment with a subgroup analysis comparing those with plasma creatinine ≤80µmol/l. METHODS: A retrospective review of our PUV database was performed. Age, intervention, and highest recorded random clinic urine osmolality (>1year) with concurrent plasma creatinine were recorded (normal urine osmolality 500-850 mOsm/kg). Data are given as median values, analyzed by Mann-Whitney u-test, with P<0.05 deemed significant. MAIN RESULTS: Urine osmolality was available in 77 boys with PUV out of 125 in our series. Of these, 34 required subsequent intervention (e.g., Mitrofanoff procedure, bladder augmentation). Age at testing trended towards being higher in the intervention group [7.9 (4.3-10.9) years vs. nonintervention 6.3 (4-8.4); P=0.06]. Urine osmolality was significantly reduced in the intervention group [411(293-547) vs. 631 (441-805) mOsm/kg; P<0.001]. Subgroup analysis comparing only those with creatinine ≤80µmol/l was respectively 451 (322-567) mOsm/kg (n=22) vs. 645 (469-810) mOsm/kg (n=40), P<0.01. CONCLUSION: This study confirms that hypoosmolar urine is highly associated with progression of LUT dysfunction, requiring intervention. Even boys with normal creatinine values have a greater risk of LUT deterioration if they have a RTD and produce hypoosmolar urine. LEVEL OF EVIDENCE: IV (retrospective service development project).

Bladder augmentation in anuric/defunctioned microbladders and a novel antireflux mechanism for Mitrofanoff anastomosis to the ileal patch.

BACKGROUND/PURPOSE: Reconstruction of microbladders is a difficult surgical challenge: How can a neobladder be recreated when >90% of the new bladder is augmented patch, and how can a Mitrofanoff conduit be anastomosed when the native bladder is so tiny? This series describes microbladders secondary to anuria and/or diversion that required augmentation. This was done using a de-tubularized ileal segment, and because of the small size of the native bladder, Mitrofanoff anastomosis was performed to the bowel patch (using a novel "Keel Procedure"). METHODS: Our surgical experience in reconstruction of microbladders was reviewed: pre and post augmentation capacity, compliance and maximum detrusor pressure were compared. The success of the Mitrofanoff anti-reflux technique is described. Data are given as median (interquartile range) and compared by Wilcoxon paired rank test. RESULTS: 10 patients, median bladder capacity pre-op 10 (9-20) mls were reconstructed. The follow up time is 2.7years (2.2-4.2). Post-op bladder capacity increased 16-fold to 167 (114-281) mls, P<0.01. Compliance significantly improved from 1.7 (0.3-4.8) to 14.3 (4.1-66.3) mls/cmH2O, P<0.05. Maximum detrusor over-activity decreased from 27 (7-120) to 12.5 (8-26) cmH2O, (N.S. P=0.3). Videourodynamics confirmed a leak in 2 patients, leading to incorporation into the technique of a non-absorbable seromuscular suture to provide long-term robustness to the antireflux procedure. CONCLUSION: Bladder augmentation in microbladders is possible, and a functional Mitrofanoff procedure with a continent anti-reflux procedure can be created using the "Birmingham keel technique" implanting the Mitrofanoff into the augment patch, with 80% success (similar to published results for conventional anastomosis to native bladders). LEVEL OF EVIDENCE: Level IV.

Extended spectrum beta lactamase (ESBL) producing bacteria urinary tract infections and complex pediatric urology.

AIM OF THE STUDY: Extended spectrum beta lactamase (ESBL) producing bacteria are resistant to most beta-lactam antibiotics including third-generation cephalosporins, quinolones and aminoglycosides. This resistance is plasmid-borne and can spread between species. Management of ESBL is challenging in children with recurrent urinary tract infections (UTIs) and complex urological abnormalities. We aim to quantify the risk in children and specifically in urological patients. METHODS: Retrospective review of a microbiology database (April 2014 to November 2015). This identified urine isolates, pyuria, ESBL growth and patient demographics. Data analysis was by Chi square, Mann-Whitney U-test and ANOVA. A P value of <0.05 was taken as significant. MAIN RESULTS: Analysis of 9418 urine samples showed 2619 with pure isolates, of which 1577 had pyuria (>10×106 WC/L). 136 urine cultures (n=79 patients) grew purely ESBL. Overall, 5.2% of urine isolates were ESBL and 9.5% isolates with pyuria (>100×106 WC/L) had ESBL, whereas only 22/1032 (2.1%) with no pyuria, (P<0.0001). Urology patients had 86/136 (63%) ESBL positive cultures. These represented 86/315 (27%) of all positive cultures for urology patients vs. 50/2267 (2.2%) for all other specialties (P<0.0001). Potential ESBL transmission between organisms occurred in 3 (all on prophylactic antibiotics). Over the study period, there was no significant rise of the monthly incidence between 2014 and 2015 (ANOVA P=0.1). CONCLUSION: This study is the first to document the incidence of ESBL in children (5%), and estimate the frequency of possible plasmid transmission between bacterial species in children. This quantifies the risk of ESBL, especially to urology patients, and mandates better antibiotic stewardship. LEVEL OF EVIDENCE: Level IIc.

Combined creatinine velocity and nadir creatinine: A reliable predictor of renal outcome in neonatally diagnosed posterior urethral valves.

INTRODUCTION: Nadir creatinine (lowest creatinine during the first year following diagnosis) is a recognised indicator of future chronic renal impairment (CRI) in posterior urethral valve (PUV) patients. We recently described "creatinine velocity" (Cvel), the rate of change of creatinine following initial bladder drainage, as a new early predictor of CRI in neonatally diagnosed PUV. Rising Cvel (>3 µmol/L/day) is associated with increased risk of CRI. OBJECTIVE: We studied these two prognostic indicators in combination, as a test for future CRI in neonatally diagnosed PUV patients. STUDY DESIGN: Medical records for patients treated by endoscopic valve ablation at our institution between 1993 and 2004 were reviewed. Simple linear regression was used to calculate Cvel. Creatinine velocity and nadir creatinine were considered predictive of future CRI if they were greater than 3 µmol/L/day or greater than 75 µmol/L (0.85 mg/dL), respectively. Chronic renal insufficiency was defined as CKD2 or higher. Outcomes in test groups were analysed by Fisher exact test. Statistical significance was defined as p < 0.05. RESULTS: Sixty-two patients were treated within the first 30 days of life and had sufficient data to calculate both Cvel and nadir creatinine. Mean follow-up was 9.4 years. Patients were grouped as having both risk factors (Group A), one risk factor (Group B), or neither risk factor (Group C). All four (100%) patients from Group A developed CRI, compared with 11 of 17 (64.7%) patients from Group B and three of 41 (7.3%) patients from Group C (p ≤ 0.0005). As a diagnostic test for future CRI, "presence of at least one risk factor" had a specificity of 86.4%, sensitivity of 83.3%, positive predictive value of 71.4%, and negative predictive value of 92.7%. Additional prognostic information was obtained by assigning a score from 1 to 3 for each prognostic indicator (Table). The sum of these scores gave a PUV Risk Score. No patient with a PUV Risk Score of 2 developed CRI, while all patients with a Score of 6 developed CRI. Incidence of CRI in patients with PUV Risk Scores of 3, 4, and 5 was 8.3%, 50%, and 63.6%, respectively (p ≤ 0.0005). CONCLUSION: Considered together, these prognostic indicators provide a powerful test for future CRI. Presence of at least one of these risk factors should be considered "at risk for CRI". Patients with neither risk factor are unlikely to develop CRI. Calculation of the PUV Risk Score provides an even more accurate prognosis.

What is the efficacy of circumcision in boys with complex urinary tract abnormalities?

The risk of urinary tract infection (UTI) in normal boys is 1%. This risk is significantly increased in boys with congenital abnormalities of the urinary tract, which includes such abnormalities as vesico-ureteric reflux, obstructive megaureter (VUJO) and posterior urethral valves. UTI in these boys can lead to urosepsis, a potentially life-threatening complication, and in the longer term renal scarring complicating pyelonephritis can lead to chronic renal impairment or even end-stage renal disease. Circumcision has been shown in normal boys to reduce the risk of UTI by 90%, and potentially could be a simple intervention to reduce the risk of urosepsis and renal scarring. In order to make this decision a clinician really needs to have the answers to two questions: 1) What is the risk of UTI in this particular boy? 2) What is the evidence of efficacy of circumcision in this particular condition? This article reviews what evidence exists to make a calculation of the risk/benefit ratio for circumcision in boys with abnormalities of the urinary tract.

Introduction of sodium pentosan polysulfate and avoidance of urethral catheterisation: improved outcomes in children with haemorrhagic cystitis post stem cell transplant/chemotherapy.

PURPOSE: Haemorrhagic cystitis (HC) is an uncommon but potentially devastating complication of chemotherapy and bone marrow transplantation in children. We aimed to test the hypothesis that early recognition, sodium pentosan polysulfate (SPP), and avoidance of urethral catheterisation improve outcomes in children with HC. METHODS: A retrospective case note review was performed of all patients treated for HC in our hospital from 2002 to 2010. A protocol for the management of HC was introduced in 2007 advocating early detection, use of SPP, and avoidance of urethral catheterisation. Data collected on each patient included primary condition, medications at onset, blood transfusions, duration of symptoms, catheter usage, and outcome. Statistical analysis was performed using the Mann-Whitney U test, and Fisher's Exact test as appropriate, P < .05 being significant. RESULTS: Five patients were treated using protocol with 5 historical controls. There was no significant difference between the ages of the group, diagnosis, and treatment at onset of HC. In the historical group, 4 of 5 died with HC, but all recovered in the protocol group (P < .05). Blood transfusion requirements were also significantly reduced after protocol introduction (P < .05). CONCLUSION: Early identification, avoidance of urethral catheterisation, and use of SPP significantly reduces blood transfusion requirements and mortality from HC.