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Probiotics have received significant attention within both the scientific and lay communities for their potential health-promoting properties, including the treatment or prevention of various conditions in children. In this article, we review the published data on use of specific probiotic strains for three common pediatric conditions: the prevention of urinary tract infections and antibiotic-associated diarrhea and the treatment of atopic dermatitis. Research into the utility of specific probiotic strains is of varying quality, and data are often derived from small studies and case series. We discuss the scientific merit of these studies, their overall findings regarding the utility of probiotics for these indications, issues in reporting of methods, and results from these clinical trials, as well as future areas of investigation., Impact: Review of data for commonly encountered diagnoses in the general pediatric population.Highlights gaps in the evidence and provides insight into new avenues of research.

Polymerase chain reaction (PCR) is an important means by which to study the urine microbiome and is emerging as possible alternative to urine cultures to identify pathogens that cause urinary tract infection (UTI). However, PCR is limited by its inability to differentiate DNA originating from viable, metabolically active versus non-viable, inactive bacteria. This drawback has led to concerns that urobiome studies and PCR-based diagnosis of UTI are confounded by the presence of relic DNA from non-viable bacteria in urine. Propidium monoazide (PMA) dye can penetrate cells with compromised cell membranes and covalently bind to DNA, rendering it inaccessible to amplification by PCR. Although PMA has been shown to differentiate between non-viable and viable bacteria in various settings, its effectiveness in urine has not been previously studied. We sought to investigate the ability of PMA to differentiate between viable and non-viable bacteria in urine.Varying amounts of viable or non-viable uropathogenicPMA's efficiency in excluding DNA signal from non-viable bacteria was significantly higher in bacterial samples in phosphate-buffered saline (PBS, dCWe have successfully developed PMA-based PCR methods for amplifying DNA from live bacteria in urine. Our results suggest that non-PMA bound DNA from live bacteria can be present in urine, even after antibiotic treatment. This indicates that viable but non-culturable

Study question Is it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities? Summary answer Centralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice. What is known already Several centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring. Study design, size, duration Testicular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded. Participants/materials, setting, methods Human testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient's tissue was donated to research and 75% was stored for patient's future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1. Main results and the role of chance The average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg-6880.2 mg. Malignancies (n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders (n = 45) and other conditions (n = 26). Thirty nine percent (n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132. Limitations, reasons for caution This is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size. Wider implications of the findings Patients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of those spermatogonia was not tested. Study funding/competing interest(s) Support for the research was from the Eunice Kennedy Shriver National Institute for Child Health and Human Development grants HD061289 and HD092084, the Scaife Foundation, the Richard King Mellon Foundation, the Departments of Ob/Gyn & Reproductive Sciences and Urology of the University of Pittsburgh Medical Center, United States-Israel Binational Science Foundation (BSF), and the Kahn Foundation. The authors declare that they do not have competing financial interests.

Urogenital schistosomiasis remains a major global challenge. Optimal management of this infection depends upon imaging-based assessment of sequelae. Although established imaging modalities such as ultrasonography, plain radiography, magnetic resonance imaging (MRI), narrow band imaging, and computerized tomography (CT) have been used to determine tissue involvement by urogenital schistosomiasis, newer refinements in associated technologies may lead to improvements in patient care. Moreover, application of investigational imaging methods such as confocal laser endomicroscopy and two-photon microscopy in animal models of urogenital schistosomiasis are likely to contribute to our understanding of this infection's pathogenesis. This review discusses prior use of imaging in patients with urogenital schistosomiasis and experimentally infected animals, the advantages and limitations of these modalities, the latest radiologic developments relevant to this infection, and a proposed future diagnostic standard of care for management of afflicted patients.

Purpose: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. Methods: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. Results: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. Conclusion: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Summary Background Torsion of the spermatic cord and the resulting testicular ischemia leads to the production of inflammatory cytokines and cell death due to impaired aerobic metabolism. Following reperfusion of the testis, a robust innate inflammatory response furthers tissue injury due to the production of reactive oxygen species and disruption of normal capillary function. Blunting the innate immune response with antioxidants, anti-inflammatory medications and targeted genetic interventions reduces long term testicular injury in animal models of torsion, however these approaches have limited clinical applicability. Mediated via α7 nACh receptors, the cholinergic anti-inflammatory pathway limits NFKB signaling and prevents renal fibrosis following warm renal ischemia. We identified varenicline as an FDA approved α7 nAChR agonist and hypothesized that varenicline administration would decrease long-term testicular atrophy and fibrosis in a murine model of testicular torsion. Methods Using an established model, unilateral testicular torsion was induced in mature male CD1 mice by rotating the right testicle 720° for 2 h. In the treatment group, 4 doses of varenicline (1mg/grm) were administered via intraperitoneal injection every 12 h, with the first dose given 1 h after the creation of testicular torsion. The acute inflammatory response was evaluated 48 h following reperfusion of the testis. Long term outcomes were evaluated 30 days following testicular perfusion. Results 48 h following reperfusion, the testis of animals treated with varenicline demonstrated a significant reduction in the inflammatory response as measured by the acute immune cell infiltrate, myeloperoxidase activity, concentration of reduced glutathione and expression of downstream NF-KB targets. 30 days following reperfusion, animals treated with varenicline, demonstrated decreased testicular atrophy (Summary Figure), fibrosis and expression of pro-fibrotic genes. Conclusion Activation of a central immunosuppressive cascade with varenicline after the onset of testicular torsion reduces ischemia reperfusion injury and prevents long term testicular atrophy and fibrosis. Further studies are needed to define the optimum dose and varenicline administration regimen. Our results suggest that varenicline offers a novel, FDA approved, adjunct to the current management of testicular torsion. Download : Download high-res image (102KB) Download : Download full-size image Summary Figure . Varenicline prevents long term testicular atrophy following testicular torsion. 30 days following reperfusion, untreated animals demonstrated a significant decrease in the weight of the torsed testis when compared to the contralateral control. Animals treated with the α7 nAChR agonist Cytisine or Varenicline demonstrated preservation of testicular weight and a significant decreased in testicular atrophy.

The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle ofSchistosoma mansonieggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE’s analgesic effect. In contrast, IPSE’s analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes.In vitrotesting of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE’s nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

We sought to examine the literature reporting the effect of urinary tract infection (UTI) on non-schistosomiasis-related UBC (UBCNS) through a systematic review and meta-analysis. A predefined study protocol was developed according to PRISMA. Medline and Scopus were searched for all studies investigating exposure to UTI with UBCNS as the primary outcome. Potential studies were screened against eligibility criteria. Clinical heterogeneity was assessed and groups with more than two studies were evaluated by random effect meta-analysis. Study-level bias was assessed with the Newcastle–Ottawa Scale (NOS). In cases of substantial between study heterogeneity (I2 > 50%), predefined sensitivity and subgroup analyses were performed. Of 16 eligible studies, eight case–control studies spanning four decades and five countries were suitable for quantitative analysis. Main analysis favored exposure to UTI increasing risk of subsequent UBCNS (RR 1.33 [95% CI 1.14–1.55]). This effect was no longer statistically significant after excluding studies published prior to year 2000 and at high risk of bias. Between study heterogeneity was considerable for nearly all analyses and not reduced by predefined sensitivity or subgroup analyses. Exposure to UTI favors increased risk for UBCNS, particularly in men, but these effects were statistically insignificant when pooling data from the most recent and highest quality studies. These data do not support findings of previously published studies, that report on heterogenous populations with poor definitions of UTI and minimal control for important confounders. Results from previous studies should be viewed as hypothesis generating. This review highlights the need for higher quality investigation.

Control strategies to reduce human schistosomiasis have evolved from 'snail picking' campaigns, a century ago, to modern wide-scale human treatment campaigns, or preventive chemotherapy. Unfortunately, despite the rise in preventive chemotherapy campaigns, just as many people suffer from schistosomiasis today as they did 50 years ago. Snail control can complement preventive chemotherapy by reducing the risk of transmission from snails to humans. Here, we present ideas for modernizing and scaling up snail control, including spatiotemporal targeting, environmental diagnostics, better molluscicides, new technologies (e.g., gene drive), and 'outside the box' strategies such as natural enemies, traps, and repellants. We conclude that, to achieve the World Health Assembly's stated goal to eliminate schistosomiasis, it is time to give snail control another look.

Many patients suffer from chronic, irritative lower urinary tract symptoms (LUTS). The evaluation and management of these patients have proven difficult with the use of standard diagnostic tools, including urinalysis and urine culture. The growing body of literature on the urinary microbiome has looked at the possible implications of the bladder microbiome and dysbiosis, or perturbations in the microbiome, in conditions associated with chronic LUTS. Disorders such as recurrent urinary tract infections (UTIs) and interstitial cystitis have been studied utilizing 16S rRNA rapid next-generation gene sequencing (NGS) and expanded quantitative urine culture (EQUC). In this article, we first present a brief review of the literature describing the current understanding of the urinary microbiome and the features and applications of NGS and EQUC. Next, we discuss the conditions most commonly associated with chronic, persistent LUTS and present the limitations of current diagnostic practices utilized in this patient population. We then review the limited data available surrounding treatment efficacy and clinical outcomes in patients who have been managed based on results provided by these two recently established diagnostic tools (DNA NGS and/or EQUC). Finally, we propose a variety of clinical scenarios in which the use of these two techniques may affect patients' clinical outcomes.

Context/objective: Manipulation of the microbiome is an emerging approach to promote health. We conducted a Phase Ia safety study of a single bladder instillation of probiotics in asymptomatic patients with neuropathic bladder to determine the tolerability and safety of a single Lactobacillus instillation. Design: Phase Ia safety study. Setting: Outpatient rehabilitation clinic at a rehabilitation hospital (adults) and urology clinic at a free-standing children’s hospital (children). Participants: Ten patients with neuropathic bladder were included: five children with spina bifida and five adults with spinal cord injury. Interventions: A single Lactobacillus rhamnosus GG (Culturelle, 20 billion live organisms) instillation. Outcome measures: After the instillation, participants self-monitored symptoms using the Urinary Symptoms Questionnaire for People with Neuropathic Bladder using Intermittent Catheterization daily for one week. Repeat urinalysis, urine culture, and 16S bacterial rRNA-based microbiome analyses were performed 7–10 days after instillation. Results: Probiotic instillation was well-tolerated. One child had upper respiratory tract symptoms during the trial, and two had transient cloudy urine. No adults reported any symptoms following instillation. Lactobacillus did not grow on culture post-instillation. There were differences in beta diversity of the urine microbiome in children vs. adults with neuropathic bladder (P

We used the PathoScope platform to perform species level analyses of publicly available, 16S rRNA pyrosequenced, asymptomatic urine data to determine relationships between microbiomes, and clinical and functional phenotypes.We reanalyzed previously reported, cross-sectionally acquired urine samples from 47 asymptomatic subjects, including 23 controls and 24 subjects with neuropathic bladder. Urine was originally collected by the usual method of bladder drainage and analyzed by urinalysis, culture and pyrosequencing. Urinalysis and culture values were stratified as leukocyte esterase (0, or 1 or greater), nitrite (positive or negative), pyuria (fewer than 5, or 5 or greater white blood cells per high power field), cloudy urine (positive or negative) and urine culture bacterial growth (less than 50,000, or 50,000 or greater cfu/ml). PathoScope was used for next generation sequencing alignment, bacterial classification and microbial diversity characterization.Subjects with neuropathic bladder were significantly more likely to have positive leukocyte esterase and pyuria, cloudy urine and bacterial growth. Of 47 samples 23 showed bacterial growth on culture and in all samples bacteria were identified by pyrosequencing. Nonneuropathic bladder urine microbiomes included greater proportions of Lactobacillus crispatus in females and Staphylococcus haemolyticus in males. The Lactobacillus community differed significantly among females depending on bladder function. Irrespective of gender the subjects with neuropathic bladder had greater proportions of Enterococcus faecalis, Proteus mirabilis and Klebsiella pneumonia. In 4 subjects with neuropathic bladder Actinobaculum sp. was detected by sequencing and by PathoScope but not by cultivation and in all cases it was associated with pyuria.Using PathoScope plus 16S pyrosequencing we were able to identify unique, phenotype dependent, species level microbes. Novel findings included absent L. crispatus in the urine of females with neuropathic bladder and the presence of Actinobaculum only in subjects with neuropathic bladder.

When was the last time you read medical literature on your smartphone while standing in line for coffee, riding on a train, or lying in bed? In a 2014 Doximity survey, more than two-thirds of physicians reported using their mobile device or laptop to read medical news [1]. This figure is probably outdated given the growth of smartphone technology and mobile websites in the last 2 yr. The increased portability of information has revolutionized the way[2_TD$DIFF] physicians digest medical literature. Of course, the ability to readmedical literature onmobile devices depends on portable access. In this realm, themerits of open access (OA) publishing are well documented. In general, scientific articles published in OA formats attract more press coverage and are more frequently cited than non-OA articles (Fig. 1) [2]. In addition, there is evidence [3_TD$DIFF] articles originally published behind paywalls benefit from post-embargo citation bumps when they are later made OA [3]. While there are no good data to prove why this is the case, an intuitive explanation sits squarely on exposure and ease of access: OA articles can be read anywhere, at any time, and by anyone with access to the Internet. Consequently, OA journals have been able to keep pace with the scientific impact generated by subscription journals [4]. OA publishing has increased its relative share of all scholarly journal articles published by approximately 1% annually [5]. In the urologic literature, the concept of OA often exists as a ‘‘gold’’ option whereby publishers offset OA costs via author-levied article processing charges (APCs). Journals offering traditional subscription-based publication with options to publish OA through APCs are often referred to as ‘‘hybrid’’ journals. It is easy to imagine how OA increases an article’s influence. Think back to the last time you tapped an article link on your smartphone only to be taken to a journal website paywall. You probably read the abstract, but even if you have subscription permissions at a medical library, it is

Summary Background Distinguishing a urinary tract infection (UTI) from asymptomatic bacteriuria (ASB) in children with neuropathic bladders is difficult. Currently used markers of infection, such as the routine urinalysis, lack specificity for UTI in this population. The urinary microbiome may help differentiate these states. Objective The objective of this work was to describe the baseline microbiome in children with neuropathic bladders, and to determine if differences exist among the urine microbiomes of children with neuropathic bladders who have negative urine cultures, ASB, or UTI. Study design This is a cross-sectional study of children with neuropathic bladders who use clean intermittent catheterization for bladder management who had a urine culture sent as part of clinical management. Residual urine, initially collected via catheter for urine culture, was obtained for use in this work. Microbial DNA was isolated, and the V4 region of the 16SrRNA gene sequenced. The relative abundance of each bacteria was measured in each group. Alpha diversity, measured by Chao1 and the Shannon Diversity Index, was also measured in each group. PERMANOVA was used to compare the microbiota between groups. Results 36 children with neuropathic bladders were included in this study (UTI = 11, ASB = 19, negative cultures = 4). The most abundant bacteria were unspecified Enterobacteriaceae, Klebsiella, Staphylococcus, Streptococcus, and Enterococcus. Children who catheterize their urethra have a higher proportion of Staphylococcus, while the urine microbiome of those who catheterize through a Mitrofanoff consists predominantly of members of the family Enterobacteriaceae. Given the low numbers of patients with Mitrofanoffs and augmented bladders, we did not statistically compare the urine microbiomes between these patients. There was no difference in either alpha diversity or the overall microbiota between children with neuropathic bladders with UTI, ASB, and negative cultures. Discussion In this pilot cohort of children with neuropathic bladders, bacteria that are members of the family Enterobacteriaceae are the most predominant bacteria in the urine microbiomes. There was no difference in the urine microbiome between those with UTI, ASB, and negative cultures. Route of catheterization may affect the composition of the urine microbiome, although due to limited sample size, this was not confirmed statistically. Conclusion There was no difference in the urine microbiome between patients with negative urine cultures, ASB, and UTI. Further work is needed to determine if the urine microbiome varies based on either the route of catheterization or the presence of augmented bladder. Download : Download high-res image (113KB) Download : Download full-size image Summary Figure . Principal coordinate analysis chart demonstrating a lack of clustering between patients with no growth, asymptomatic bacteriuria (ASB), and urinary tract infection (UTI).

Robot-assisted minimally invasive surgical systems enable procedures with reduced pain, recovery time, and scarring compared to traditional surgery. While these improvements benefit a large number of patients, safe access to diseased sites is not always possible for specialized patient groups, including pediatric patients, due to their anatomical differences. We propose a patient-specific design paradigm that leverages the surgeon's expertise to design and fabricate robots based on preoperative medical images. The components of the patient-specific robot design process are a virtual reality design interface enabling the surgeon to design patient-specific tools, 3-D printing of these tools with a biodegradable polyester, and an actuation and control system for deployment. The designed robot is a concentric tube robot, a type of continuum robot constructed from precurved, elastic, nesting tubes. We demonstrate the overall patient-specific design workflow, from preoperative images to physical implementation, for an example clinical scenario: nonlinear renal access to a pediatric kidney. We also measure the system's behavior as it is deployed through real and artificial tissue. System integration and successful benchtop experiments in ex vivo liver and in a phantom patient model demonstrate the feasibility of using a patient-specific design workflow to plan, fabricate, and deploy personalized, flexible continuum robots.

In spite of the extensive contribution of intestinal pathology to the pathophysiology of schistosomiasis, little is known of the impact of schistosome infection on the composition of the gut microbiota of its mammalian host. Here, we characterised the fluctuations in the composition of the gut microbial flora of the small and large intestine, as well as the changes in abundance of individual microbial species, of mice experimentally infected with Schistosoma mansoni with the goal of identifying microbial taxa with potential roles in the pathophysiology of infection and disease. Bioinformatic analyses of bacterial 16S rRNA gene data revealed an overall reduction in gut microbial alpha diversity, alongside a significant increase in microbial beta diversity characterised by expanded populations of Akkermansia muciniphila (phylum Verrucomicrobia) and lactobacilli, in the gut microbiota of S. mansoni-infected mice when compared to uninfected control animals. These data support a role of the mammalian gut microbiota in the pathogenesis of hepato-intestinal schistosomiasis and serves as a foundation for the design of mechanistic studies to unravel the complex relationships amongst parasitic helminths, gut microbiota, pathophysiology of infection and host immunity.

In this review, we highlight the effects of the microbiome on urologic diseases that affect the pediatric patient. Perturbations in the urinary microbiome have been shown to be associated with a number of urologic diseases affecting children, namely urinary tract infection, overactive bladder/urge urinary incontinence, and urolithiasis. Recently, improved cultivation and sequencing technologies have allowed for the discovery of a significant and diverse microbiome in the bladder, previously assumed to be sterile. Early studies aimed to identify the resident bacterial species and demonstrate the efficacy of sequencing and enhanced quantitative urine culture. More recently, research has sought to elucidate the association between the microbiome and urologic disease, as well as to demonstrate effects of manipulation of the microbiome on various urologic pathologies. With an improved appreciation for the impact of the urinary microbiome on urologic disease, researchers have begun to explore the impact of these resident bacteria in pediatric urology.

Chronic urogenital schistosomiasis can lead to squamous cell carcinoma of the bladder. The International Agency for Research on Cancer classifies the infection with S. haematobium as a group 1 carcinogen, a definitive cause of cancer. By contrast, hepatointestinal schistosomiasis due to the chronic infection with S. mansoni or S. japonicum associated with liver periportal fibrosis, does not apparently lead to malignancy. The effects of culturing human epithelial cells, HCV29, established from normal urothelium, and H69, established from cholangiocytes, in the presence of S. haematobium or S. mansoni eggs were investigated. Cell growth of cells co-cultured with schistosome eggs was monitored in real time, and gene expression analysis of oncogenesis, epithelial to mesenchymal transition and apoptosis pathways was undertaken. Schistosome eggs promoted proliferation of the urothelial cells but inhibited growth of cholangiocytes. In addition, the tumor suppressor P53 pathway was significantly downregulated when exposed to schistosome eggs, and downregulation of estrogen receptor was predicted in urothelial cells exposed only to S. haematobium eggs. Overall, cell proliferative responses were influenced by both the tissue origin of the epithelial cells and the schistosome species.

Urogenital schistosomiasis, caused by the parasitic trematode Schistosoma haematobium , affects over 112 million people worldwide. As with Schistosoma mansoni infections, the pathology of urogenital schistosomiasis is related mainly to the egg stage, which induces granulomatous inflammation of affected tissues. Schistosoma eggs and their secretions have been studied extensively for the related organism S. mansoni , which is more amenable to laboratory studies. Indeed, we have shown that IPSE/alpha-1 (here M-IPSE), a major protein secreted from S. mansoni eggs, can infiltrate host cells. Although the function of M-IPSE is unknown, its ability to translocate to the nuclei of host cells and bind DNA suggests a possible role in immune modulation of host cell tissues. Whether IPSE homologs are expressed in other schistosome species has not been investigated. Here, we describe the cloning of two paralog genes, H03-IPSE and H06-IPSE, which are orthologs of M-IPSE, from egg cDNA of S. haematobium . Using PCR and immunodetection, we confirmed that the expression of these genes is restricted to the egg stage and female adult worms, while the H-IPSE protein is detectable only in mature eggs and not adults. We show that both H03-IPSE and H06-IPSE proteins can infiltrate HTB-9 bladder cells when added exogenously to culture medium. Monopartite C-terminal nuclear localization sequence (NLS) motifs conserved in H03-IPSE, SKRRRKY, and H06-IPSE SKRGRKY, are responsible for targeting the proteins to the nucleus of HTB-9 cells, as demonstrated by site-directed mutagenesis and green fluorescent protein (GFP) tagging. Thus, S. haematobium eggs express IPSE homologs that appear to perform similar functions in infiltrating host cells.

Urogenital schistosomiasis (infection with Schistosoma haematobium) is a major cause of bladder carcinogenesis. However, the exact mechanisms of the sequelae leading up to the development of bladder cancer are poorly understood, mainly because of a dearth of tractable mouse models. We developed a mouse model of urogenital schistosomiasis through intramural injection of parasite eggs into the bladder wall to mimic the trapping of parasite eggs in the bladder. This approach recapitulates many of the sequelae observed in infected humans. Here, we describe procedures for utilizing this surgical technique in combination with well-established transgenic mouse strains to dissect the role of cancer-related genes in the initiation and establishment of bladder carcinogenesis. The described method utilizes CRE-mediated flox activity to render mice p53 haploinsufficient before challenging them with bladder wall egg injection. These techniques are potentially amenable to studying the role of other pro-carcinogenic and cancer suppressor gene(s) in urogenital schistosomiasis-associated urothelial carcinogenesis.

Percutaneous techniques and robot-assisted surgical systems have enabled minimally invasive procedures that offer reduced scarring, recovery time, and complications compared to traditional open surgeries. Despite these improvements, access to diseased sites using the standard, straight needle-based percutaneous techniques is still limited for certain procedures due to intervening tissues. These limitations can be further exacerbated in specific patient groups, particularly pediatric patients, whose anatomy does not fit the traditional tools and systems. We therefore propose a patient-specific paradigm to design and fabricate dexterous, robotic tools based on the patient's preoperative images. In this paper, we present the main steps of our proposed paradigm - image-based path planning, robot design, and fabrication - along with an example case that focuses on a class of dexterous, snake-like tools called concentric tube robots. We demonstrate planning a safe path using a patient's preoperative ultrasound images. We then determine the concentric tube robot parameters needed to achieve this path, and finally, we use 3-D printing to fabricate the patient-specific robot.

Over the last five decades, healthcare advances have yielded quantum improvements in life expectancy for individuals with congenital genitourinary conditions (CGCs), leading to a crisis of care. Many individuals with CGC enter adulthood unprepared to manage their condition. Pediatric CGC specialists lack training to manage adulthood-related healthcare issues, while adult genitourinary specialists lack training within the context of CGCs. To address these challenges, the National Institutes of Diabetes and Digestive and Kidney Diseases convened individuals with CGCs and experts from a variety of fields to identify research needs to improve transitional urology care. This manuscript outlines identified research needs.

Urogenital schistosomiasis is one of the greatest single infectious sources of human morbidity and mortality known. Through a complex cycle of infection, migration and eventual maturation and mating, S. haematobium (the aetiological agent of urogenital schistosomiasis) deposits highly immunogenic eggs within the bladder and other pelvic organs, activating a wide range of immune programs that determine both infection outcome as well as downstream immunopathology. In this review, we discuss the experimental and observational bases for our current understanding of these immune programs, focusing specifically on how the balance of type 1 and type 2 responses governs subsequent immunopathology and clinical outcome.

Urogenital schistosomiasis, infection with Schistosoma haematobium, is linked to increased risk for the development of bladder cancer, but the importance of various mechanisms responsible for this association remains unclear, in part, owing to lack of sufficient and appropriate animal models. New advances in the study of this parasite, bladder regenerative processes, and human schistosomal bladder cancers may shed new light on the complex biological processes that connect S. haematobium infection to bladder carcinogenesis.

Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium. These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma in situ. Shh-expressing basal cells within this precursor lesion become tumour-initiating cells, although Shh expression is lost in subsequent carcinomas. We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.

BACKGROUND: Robot-assisted surgery is widely adopted for many procedures but has not realized its full potential to date. Based on human motor control theories, the authors hypothesized that the dynamics of the master manipulators impose challenges on the motor system of the user and may impair performance and slow down learning. Although studies have shown that robotic outcomes are correlated with the case experience of the surgeon, the relative contribution of cognitive versus motor skill is unknown. This study quantified the effects of da Vinci Si master manipulator dynamics on movements of novice users and experienced surgeons and suggests possible implications for training and robot design. METHODS: In the reported study, six experienced robotic surgeons and ten novice nonmedical users performed movements under two conditions: teleoperation of a da Vinci Si Surgical system and freehand. A linear mixed model was applied to nine kinematic metrics (including endpoint error, movement time, peak speed, initial jerk, and deviation from a straight line) to assess the effects of teleoperation and expertise. To assess learning effects, t tests between the first and last movements of each type were used. RESULTS: All the users moved slower during teleoperation than during freehand movements (F(1,9343) = 345; p < 0.001). The experienced surgeons had smaller errors than the novices (F(1,14) = 36.8; p < 0.001). The straightness of movements depended on their direction (F(7,9343) = 117; p < 0.001). Learning effects were observed in all conditions. Novice users first learned the task and then the dynamics of the manipulator. CONCLUSIONS: The findings showed differences between the novices and the experienced surgeons for extremely simple point-to-point movements. The study demonstrated that manipulator dynamics affect user movements, suggesting that these dynamics could be improved in future robot designs. The authors showed the partial adaptation of novice users to the dynamics. Future studies are needed to evaluate whether it will be beneficial to include early training sessions dedicated to learning the dynamics of the manipulator.

Urogenital schistosomiasis, caused by Schistosoma haematobium, is the most prevalent form of schistosomiasis affecting humans, and can result in severe bladder, kidney, ureteral, and genital pathologies. Chronic infection with S. haematobium has been linked with bladder cancer and increased risk for HIV infection. As mass drug administration with praziquantel increases in an attempt to transition from control to elimination of schistosomiasis, the need for updated, more sensitive diagnostic tools becomes more apparent, especially for use in areas of low infection intensity and for individuals with light infections. Here, we review established and investigational diagnostic tests utilized for urogenital schistosomiasis, highlighting new insights and recent advances.

Cyclophosphamide and ifosfamide are widely used drugs for malignancies and rheumatologic conditions. One of the most significant adverse reactions to these drugs is hemorrhagic cystitis. Mesna is the most widely used uroprotective agent that acts to neutralize the caustic metabolite, acrolein, responsible for induction of hemorrhagic cystitis. However, mesna is not a perfect alternative, and studies since its discovery have investigated the use of alternative drugs and adjuncts to increase mesna's efficacy. This review details some of the recent work into novel uroprotective agents for drug-induced hemorrhagic cystitis.

Schistosomiasis is a parasitic disease affecting over 200 million people worldwide. This study reports the design and development of a microfiltration device for isolating schistosome eggs in urine for rapid diagnostics of urogenital schistosomiasis. The design of the device comprises a linear array of microfluidic traps to immobilize and separate schistosome eggs. Sequential loading of individual eggs is achieved autonomously by flow resistance, which facilitates observation and enumeration of samples with low-abundance targets. Computational fluid dynamics modeling and experimental characterization are performed to optimize the trapping performance. By optimizing the capture strategy, the trapping efficiency could be achieved at 100% with 300 μl/min and 83% with 3000 μl/min, and the filtration procedure could be finished within 10 min. The trapped eggs can be either recovered for downstream analysis or preserved in situ for whole-mount staining. On-chip phenotyping using confocal laser fluorescence microscopy identifies the microstructure of the trapped schistosome eggs. The device provides a novel microfluidic approach for trapping, counting and on-chip fluorescence characterization of urinal Schistosoma haematobium eggs for clinical and investigative application.

Scientists and clinicians studying a particular disease have an ideal goal that, if achieved, would be paradoxical: finding the disease cure and thereby putting themselves out of work. 2015 marks the 35th year since the cure for smallpox eradicated this human scourge. Before a vaccine was developed, infection with smallpox virus occurred in over 10 million people per year around the world, with a death rate greater than 30% [1]. The World Health Organization’s (WHO’s) intensive eradication program against smallpox began in 1967 and was maintained for over ten years. The last known case of smallpox was recorded in Somalia in 1977, and WHO declared the global eradication of smallpox a success in 1980. Vaccinia virus (VACV), like smallpox a member of the Poxviridae family, was used to produce the vaccine that led to smallpox eradication. Today, VACV remains a critical research tool and serves as the laboratory model for poxvirus. VACV is currently used for the production of 2nd- and 3rd-generation smallpox vaccines as well as for the exploration of immuno-oncolytic therapies against melanoma and other cancers [2,3]. VACV and its derivatives, including modified vaccinia virus (MVA) and New York attenuated vaccinia virus (NYVAC), are used as vectors by which to induce immunity to pathogens including HIV, Plasmodium falciparum, and Mycobacterium tuberculosis [4,5]. VACV also continues to be an important tool for examining fundamental viral mechanisms of immune evasion, including viral immunomodulation and inhibition of cell apoptosis, and has aided investigators in characterizing the innate and adaptive host immune response to viral infection [6]. Therefore, despite the eradication of human disease caused by smallpox virus, basic and applied research using the model vaccinia virus continues to guide our understanding of host immune responses, antigen immunogenicity, viral manipulation of host defenses, and vaccine efficacy. A second infectious pathogen that is targeted for eradication is Dracunculus medinensis, or guinea worm, the nematode parasite that causes drancunculiasis. D. medinensis is contracted by drinking larvae-contaminated water. The parasite matures to an adult worm in the host gut and emerges painfully months later through the skin of the lower extremities. Through efforts of the World Health Assembly (as part of WHO), the Carter Center, and other organizations, dracunculiasis is nearing worldwide eradication. In the 1980s, 20 endemic countries accounted for 3.5 million cases of dracunculiasis; by 2014, only 126 cases were reported in four countires: Chad, Ethiopia, Mali, and South Sudan [7,8]. Despite being close to eradicating D. medinensis, we continue to use this parasite to understand endosymbiotic relationships in organisms. Wolbachia, a bacterial symbiont found in many filarial nematodes and necessary for worm survival, are absent in D. medinensis [9]. Understanding why most filarial nematodes require Wolbachia, through comparative laboratory-based studies of Drancunculus, may inform endosymbiont-targeted efforts to eradicate other filarial parasites. Thus, we contend that there is an important scientific role for maintenance of selected pathogens that have otherwise been eradicated, or nearly eradicated, outside the laboratory setting. Like dracunculiasis, schistosomiasis is a tropical disease caused by a parasitic worm. This snail-borne disease is deeply tied to modifiable environmental conditions (i.e., bodies of water conducive to snail survival), a feature which has, in large part, led to calls to set an agenda for schistosomiasis elimination [10]. Schistosomes are spread by freshwater snails when the larval form of schistosomes, the cercariae, emerges from infected snails and penetrates the skin of its human host, taking up residence in blood vessels following maturation to adult worms. The adult worms produce hundreds of eggs per day, some exiting the host in the urine and/or feces, contributing to the pernicious cycle of environmental contamination and reinfection in people. However, many of the eggs become trapped in host tissues including the liver, intestine, and bladder. The damage caused by chronic parasite egg deposition is significant and contributes to the high morbidity and mortality observed in schistosomiasis. Schistosome infection presents unique challenges to worldwide eradication goals and has even proven difficult to eliminate from a targeted endemic region. If eradication of schistosomiasis were achieved, however, the benefits of schistosomiasis research would remain. In fact, the study of schistosomes, schistosomiasis pathogenesis, and immunological characterizations of the host response to parasite egg antigen are currently large areas of study that have been driven by use of schistosomes as a model organism to study stem cell biology, acute and chronic inflammation, liver and gut fibrosis, and T helper 2-type responses, among many others. These and other research objectives will remain a focus of study for many scientists and clinicians, independently of a “cure” for schistosomiasis. For example, it has long been observed that schistosomes persist for years to decades in the blood vessels of humans. This successful parasitism underscores Schistosoma species’ aptitude for host immune evasion and longevity. In recognition of this interesting property of Schistosoma worms, planaria scientists have begun adapting their versatile toolbox to schistosomes, also a flatworm of the phylum Platyhelminthes. Collins et al. [11] have characterized a proliferating somatic cell (PSC) population in adult worms that may contribute to the ability of schistosomes to repair injury and resist senescence. Studying the stem cell biology of long-lived metazoans may reveal pathways relevant to human aging. Schistosomes have also proven to be powerful tools by which some of the earliest delineation of the TH1 versus TH2 immunity paradigm was shaped [12], with implications for immunological pathway discovery across many diseases. Infection with pathogens that induce TH1 CD4+ lymphocytes and secrete interferon gamma (IFNg) and interleukin-2 (IL-2) can be compared to induction of the TH2 response following schistosome infection or exposure to parasite eggs or egg antigen resulting in the production of IL-4, IL-5, and IL-13. In addition, the mouse model of Schistosoma mansoni infection has helped characterize the role of IL-10 as an anti-inflammatory cytokine required to control liver pathology following egg deposition and, more broadly, has helped define IL-10 immunoregulation in other diseases in which inflammation drives pathology, including ulcerative colitis, Crohn’s disease, and, in the lung, allergy and asthma. In addition to schistosomiasis, IL-10 helps control the immunopathogenesis observed following infection with Plasmodium spp., Mycobacterium spp., and Trypanosoma cruzi. Several investigators have taken advantage of the strong immunogenic properties and ease of use of S. mansoni parasite eggs and soluble egg antigens (SEA). Graham et al. [13] have modeled pulmonary hypertension following intravenous injection of Schistosoma eggs and showed that vascular endothelial growth factor (VEGF) contributes to the TH2 environment that supports airway remodeling and vascular inflammation. SEA has also been utilized as an adjuvant to boost a cytotoxic lymphocyte population following vaccination with an HIV-1 Gag construct [14]. Last, and not least, we introduce Schistosoma haematobium to dissect the link between inflammation and cancer. The International Agency for Research in Cancer (IARC) of WHO has declared S. haematobium to be a class I carcinogen for the bladder, "definitely carcinogenic for humans" [15]. Despite the strong link between S. haematobium, the causative agent of urogenital schistosomiasis, and bladder carcinogenesis, we understand very little regarding how this helminth causes cancer. Most hypotheses suggest that S. haematobium-induced chronic inflammation is critical in the oncogenic process. Interestingly, S. haematobium is linked to higher rates of squamous cell carcinoma of the bladder, a form of bladder cancer that is unusual in non-S. haematobium-infected patients. Our inadequate knowledge of schistosomal bladder carcinogenesis underscores the importance of tractable animal models of urogenital schistosomiasis [16–23]. These models have identified potential mediators of fibrosis, immunomodulation, and carcinogenesis that may be common to multiple neoplasms. Given the evidence that urogenital schistosomiasis-induced bladder cancer is an inflammatory process, studying schistosomiasis, even if eradicated, may reveal new links between inflammation and carcinogenesis that are suitable as therapeutic targets in non-schistosomal cancers. Thus, prudent laboratory maintenance and study of particular pathogens that have been globally eliminated or eradicated may yield unique scientific discoveries of broad significance.

Abdominal sacrocolpopexy is considered a standard of care operation for apical vaginal vault prolapse repair. Using outcomes at our center we evaluated whether the robotic approach to sacrocolpopexy is as cost-effective as the open approach.After obtaining institutional review board approval we performed cost-minimization analysis in a retrospective cohort of patients who underwent sacrocolpopexy at our institution between 2006 and 2010. Threshold values, that is model variable values at which the most cost effective approach crosses over to an alternative approach, were determined by testing model variables over realistic ranges using sensitivity analysis. Hospital billing data were also evaluated to confirm our findings.Operative time was similar for robotic and open surgery (226 vs 221 minutes) but postoperative length of stay differed significantly (1.0 vs 3.3 days, p0.001). Base case analysis revealed an overall 10% cost savings for robot-assisted vs open sacrocolpopexy ($10,178 vs $11,307). Tornado analysis suggested that the number of institutional robotic cases done annually, length of stay and cost per hospitalization day in the postoperative period were the largest drivers of cost. Analysis of our hospital billing data showed a similar trend with robotic surgery costing 4.2% less than open surgery.A robot-assisted approach to sacrocolpopexy can be equally or less costly than an open approach. This depends on a sufficient institutional robotic case volume and a shorter postoperative stay for patients who undergo the robot-assisted procedure.

Purpose We hypothesized that there are practice variations in the use of surgical antibiotics by pediatric urologists in the United States. Materials and methods A 31-question online survey was distributed to members of the Society of Pediatric Urology. The questionnaire examined physician preferences for surgical antibiotic use, including indications, antibiotic selection, timing of administration, and duration. Results 189 pediatric urologists responded to the survey. >85% of responders give antibiotics before open pyeloplasty, after hypospadias repair (when a urethral catheter is left in place), or perioperative or postoperative antibiotics for open neoureterocystostomy or bladder reconstructive surgery. >90% of responders do not give postoperative antibiotics to children who have undergone circumcisions, simple chordee repairs, herniorrhapies, or hydrocelectomies. For all other open, laparoscopic, and endoscopic operations, use of antibiotics varied significantly. Diverse opinions exist regarding antibiotic use, including the importance of costs, potential adverse reactions, reduction in infection risk, and antibiotic resistance. There are major differences in gentamicin dosing and timing of administration of perioperative antibiotics. Conclusions Perioperative and postoperative antibiotics are widely used by pediatric urologists. However, there is significant practice variation in surgical antibiotic administration with regards to most areas of pediatric urology, in particular laparoscopic, endoscopic and hypospadias surgery.

Objectives Endoscopic injection of non–animal-stabilized hyaluronic acid/dextranomer gel is an increasingly recognized treatment option for vesicoureteral reflux. The procedure is minor compared with open surgery and, when successful, avoids the need for long-term antibiotic prophylaxis. We present data from 3 years of using non–animal-stabilized hyaluronic acid/dextranomer gel to treat children with vesicoureteral reflux. Methods Pediatric patients aged 16 years with uncomplicated primary vesicoureteral reflux were recruited for endoscopic treatment with non–animal-stabilized hyaluronic acid/dextranomer gel. A follow-up voiding cystourethrogram was scheduled at 2 weeks after treatment, and vesicoureteral reflux resolution was defined as grade 0. Repeat non–animal-stabilized hyaluronic acid/dextranomer gel treatment was offered to patients with persistent vesicoureteral reflux. Results Of 178 patients treated, 12 were lost to follow-up or yet to undergo post-treatment voiding cystourethrogram. The 166 remaining patients (efficacy population) had a mean age of 4.21 years (range: 0-16), and the median reflux grade was 3 (range: 1-5). Vesicoureteral reflux was resolved in 81.9% of patients and 86.4% of ureters after initial endoscopic treatment with non–animal-stabilized hyaluronic acid/dextranomer gel. The overall reflux resolution rate for patients increased to 89.6% after a second treatment in 19 patients, and 90.2% after a third treatment in 1 patient. No adverse events were reported. Five patients underwent open ureteral reimplantation after failed endoscopic injections. Conclusions Endoscopic treatment with non–animal-stabilized hyaluronic acid/dextranomer gel is effective in a high proportion of children with vesicoureteral reflux and, in our opinion, should be considered as a first-line treatment option.

OEIS complex (Omphalocele, Exstrophy of the cloaca, Imperforate anus, and Spine abnormalities) is a rare defect with estimated incidence of 1 in 200,000 live births. Most cases are sporadic, with no obvious cause. However, it has been rarely reported in patients with family members having similar malformations or with chromosomal anomalies. In addition, OEIS complex has been observed in association with environmental exposures, twinning, and in vitro fertilization. Monosomy 1p36 is the most common terminal deletion syndrome, with a prevalence of 1 in 5,000 newborns. It is characterized by specific facial features, developmental delay, and heart, skeletal, genitourinary, and neurological defects. We describe an infant with OEIS complex and 1p36 deletion who had features of both disorders, including omphalocele, cloacal exstrophy, imperforate anus, sacral multiple segmentation, renal malposition and malrotation, genital anomalies, diastasis of the symphysis pubis, microbrachycephaly, large anterior fontanel, cardiac septal defects, rib fusion, a limb deformity, developmental delay, and typical facial features. Chromosomal microarray analysis detected a 2.4 Mb terminal deletion of chromosome 1p. This is the first reported case with OEIS complex in association with a chromosome 1p36 deletion.

Laparoscopic orchiopexy is a safe operation. However, the bladder can be injured during creation of the transperitoneal tunnel for the cryptorchid testis. We reviewed our experience with this complication.We searched the operative notes of patients who had undergone laparoscopic orchiopexy between August 15, 2002 and October 1, 2008, and identified bladder injuries and their treatment.A total of 93 patients underwent laparoscopic orchiopexies for 101 undescended testes during the study interval, with 3 procedures resulting in bladder injuries. The 3 operations varied with regard to whether the injury was recognized intraoperatively or postoperatively, and repaired in an open or laparoscopic fashion.Bladder injury during laparoscopic orchiopexy is a rare but serious complication that can be managed by an open or laparoscopic approach. We recommend placement of a urethral catheter and syringe assisted drainage of all urine from the bladder at the beginning of the operation, careful perivesical dissection particularly in children with prior inguinal surgery, filling and emptying of the bladder during the procedure, and maintaining a high index of suspicion especially when hematuria is observed.

To determine the prevalence of urologic disease among infants hospitalized for urinary tract infections (UTIs) at our institution. The prevalence of urologic anomalies among infants (400 days old) hospitalized for UTIs has not been previously reported.We retrospectively examined the records of all infants hospitalized for UTI at our institution, a free-standing children's hospital in the United States, for a 10-year period. Race, sex, and subsequent urologic diagnosis (using codes from the 9(th) edition of the International Classification of Diseases [ICD-9] were tabulated. Individual charts were reviewed to confirm documentation and workup of UTI.We identified 914 infants hospitalized at our institution from January 1996 to December 2007, with an ICD-9-coded diagnosis of UTI. Of these 914 infants, 258 were subsequently given a urologic diagnosis. However, only 130 of these patients had well-documented UTI (14.2% of 914 children). Of this cohort, 55.4% were boys. The most common diagnoses were hydronephrosis (37.7%), vesicoureteral reflux (69.2%), and obstructive uropathy (23.1%).Our data have indicated thator =14% of all infants hospitalized for UTI have urologic anomalies. Vesicoureteral reflux, obstructive uropathy, and hydronephrosis are common diagnoses. We therefore conclude that infants admitted with a diagnosis of UTI should undergo screening for anatomic abnormalities.

Objectives To use decision analysis to determine the economic benefits of early vs late orchiopexy, specifically with respect to testicular cancer development and management. Studies have suggested that prepubertal orchiopexy might confer additional protection from the development of testicular cancer compared with postpubertal orchiopexy. Infant surgery is often performed by pediatric subspecialists and hence might be more costly. Although rare, testicular cancer can require significant medical expenditures. Methods We examined the resource index (RI) (physician charges and hospital costs) from the medical establishment's perspective. Economic modeling was performed to determine whether early or late orchiopexy minimized the RI. The stage- and histologic-specific costs of subsequent testicular cancer were incorporated into our models. The variables were tested over realistic ranges in the sensitivity analysis to determine the threshold values. Results In the base case analysis, the RI for infant and postpubertal orchiopexy was $7500 and $10 928 per patient, respectively. The sensitivity analysis demonstrated that the costs for operating room time, physicians' fees, operative times, and baseline cancer risk were important parameters. However, only the surgeons' fees demonstrated threshold values. The RI for treating cancer and the cancer risk reduction after early orchiopexy did not significantly affect our models. Conclusions Our models of orchiopexy for prevention of testicular cancer showed that infant orchiopexy is less costly than later surgery, provided that the surgeons' fees are not excessive. It appears that early surgery might significantly reduce the treatment costs of testicular cancer for cryptorchid boys and supports the current standard of care in the United States.

Given that the prevalence of childhood obesity is increasing in the United States, we tested the timely hypothesis that obesity hinders physical examination based localization of the cryptorchid testis.Body mass index and percentiles of weight for height and body mass index for age were calculated for boys undergoing surgery for cryptorchidism at the University of California San Francisco Children's Hospital and Children's Hospital of Oakland. Two definitions of obesity were examined, ie greater than 85% or greater than 95% for either percentile. Patients were examined in the office and under general anesthesia before the skin incision. Intraoperative testicular location was recorded for each patient. The numbers of correct and incorrect preoperative determinations of testicular location were stratified by weight classification. Results were analyzed using contingency tables and Fisher's exact test.A total of 161 boys were recruited, accounting for 171 testes. The predictive value of palpating a suspected testis preoperatively with patients under anesthesia was greater than 95% for all weight classifications (p0.0001). The predictive value of not palpating a testis preoperatively under anesthesia was greater than 56% for obese boys and greater than 42% for nonobese boys (p0.0001). The concordance rates between examinations in the office and those performed under anesthesia were 90.9% and 82.7% for obese and nonobese boys, respectively (p = 0.51). The predictive value of not palpating a suspected cryptorchid testis in the office was higher in nonobese boys than in obese boys (81% vs 22%, p0.0001).In our series childhood obesity did not make preoperative testicular examinations under anesthesia less accurate. However, office examinations may be more accurate in nonobese boys.

The “human super-organism” refers to the human body and the massive numbers of microbes which dwell within us and on the skin surface. Despite the large numbers of microbes co-existing within the human body, humans including infants and children achieve a physiologic state of equilibrium known as health in the context of this microbial world. These key concepts suggest that many individual members of the human microbiome, including bacterial and fungal species, confer different benefits on the human host. Probiotics, or beneficial microbes, may modulate immune responses, provide key nutrients, or suppress the proliferation and virulence of infectious agents. The human microbiome is in fact dynamic and often in flux, which may be indicative of the continuous interplay among commensal microbes, pathogens, and the human host. In this article we review the state-of-the-art regarding probiotics applications to prevent or treat diseases of the pediatric gastrointestinal and genitourinary systems. Additionally, probiotics may regulate local and systemic immunity, thereby reducing allergic disease severity and susceptibilities of infants and children to allergies and atopic diseases. In summary, beneficial microbes offer promising alternatives for new strategies in therapeutic microbiology with implications for different subspecialties within pediatrics. Instead of simply trying to counteract microbes with vaccines and antibiotics, a new field of medical microbiology is emerging that strives to translate human microbiome research into new probiotics strategies for promotion of health and prevention of disease in children.

OBJECTIVES The optimal timing of pyeloplasty for children diagnosed with ureteropelvic junction obstruction (UPJO) after workup for antenatal hydronephrosis is disputed. We sought to examine the potential costs and clinical outcomes of treatment protocols featuring different indications for pediatric pyeloplasty using Markov models. METHODS Cost and outcomes analysis using Markov modeling was performed for three treatment algorithms: medical management, immediate pyeloplasty (during the first year of life), and pyeloplasty after no improvement on imaging. The costs were determined from the perspective of the medical institution. The variables tracked during Markov model simulation included age at resolution of UPJO, the proportion of patients with worsened hydronephrosis, the number of pyeloplasties, the number of pyelonephritis episodes, and costs. Sensitivity analyses were performed to determine which elements affected the model and to determine threshold values. RESULTS Immediate pyeloplasty and pyeloplasty after no improvement on imaging resulted in rapid resolution of UPJO (mean age at resolution younger than 2 years) with lower rates of worsened hydronephrosis and pyelonephritis compared with observation alone. For the surgical protocols, the costs per resolved case of UPJO were greater than those for medical management alone at the probability values tested in the Markov models. The sensitivity analysis of all variables over realistic ranges demonstrated that the costs of surgery, annual antibiotics and imaging, and the rate of pyelonephritis were critical in determining the costs. CONCLUSIONS Pediatric urologists should include practice-specific features such as the costs of surgery, annual antibiotics and imaging, and pyelonephritis rates when considering efficacious, yet less costly, treatment protocols for UPJO.

To apply Markov models to assess the cost effectiveness of the relative impact of obstructive interval and female partner age on fertility using either assisted reproductive technology (ART) or vasectomy reversal, and elucidate the impact of these variables on fertility.Markov models based on review of published literature and available ART outcome data.University-based clinical practice.Simulation runs of 50,000 patients for each analysis.Varying vasectomy obstructive interval and maternal age.Cost effectiveness, willingness to pay (WTP), and net health benefit.Base case analysis showed ART yields a higher pregnancy rate and higher cost than vasectomy reversal. Sensitivity analysis showed female age has a greater effect on cost effectiveness than obstructive interval. At a WTP$65,000, vasectomy reversal is more cost effective than ART. With increasing WTP, ART is more cost effective over wider windows of female age.Markov modeling of fertility after vasectomy suggests female age has more impact than vasectomy obstructive interval on cost effectiveness.

Background Despite control efforts, human schistosomiasis remains prevalent throughout Africa, Asia, and South America. The global schistosomiasis burden has changed little since the new anthelmintic drug, praziquantel, promised widespread control. Methodology We evaluated large-scale schistosomiasis control attempts over the past century and across the globe by identifying factors that predict control program success: snail control (e.g., molluscicides or biological control), mass drug administrations (MDA) with praziquantel, or a combined strategy using both. For data, we compiled historical information on control tactics and their quantitative outcomes for all 83 countries and territories in which: (i) schistosomiasis was allegedly endemic during the 20th century, and (ii) schistosomiasis remains endemic, or (iii) schistosomiasis has been "eliminated," or is "no longer endemic," or transmission has been interrupted. Principal Findings Widespread snail control reduced prevalence by 92 ± 5% (N = 19) vs. 37 ± 7% (N = 29) for programs using little or no snail control. In addition, ecological, economic, and political factors contributed to schistosomiasis elimination. For instance, snail control was most common and widespread in wealthier countries and when control began earlier in the 20th century. Conclusions/Significance Snail control has been the most effective way to reduce schistosomiasis prevalence. Despite evidence that snail control leads to long-term disease reduction and elimination, most current schistosomiasis control efforts emphasize MDA using praziquantel over snail control. Combining drug-based control programs with affordable snail control seems the best strategy for eliminating schistosomiasis., Author Summary Schistosomiasis is a parasitic disease infecting more than 250 million people worldwide, with almost 800 million at risk. Over the past century, nations undertook schistosomiasis control programs, with outcomes varying from little effect to elimination. The biggest hope for elimination began about 40 years ago with the discovery of the antischistosomal drug praziquantel, after which snail control was seen as old fashioned. Here, we review control program outcomes over the past 100 years across all major schistosomiasis endemic zones, including Africa, Asia, and the Americas. We screened for differences in long-term schistosomiasis reductions among countries and found the most successful programs focused on transmission control (most often snail control, with or without engineering interventions), sometimes in tandem with praziquantel. Although praziquantel has important human-health benefits, our results suggest old-fashioned snail control has been the key to schistosomiasis elimination.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum β lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Object. Tethering of the spinal cord is a pathological fixation of the cord in the vertebral column that can result in neurogenic bladder dysfunction and other neurological problems. It occurs in patients with closed spinal dysraphisms and those in whom postoperative scarring develops following spina bifida closure procedures. The authors of this study sought to determine the effects of detethering on the urodynamic profile of children with a tethered cord. Methods. The authors retrospectively reviewed the records of children who underwent surgical release of a tethered cord at a single institution between 2001 and 2003. They identified 17 children (nine girls and eight boys) who had undergone both preoperative and postoperative urodynamic evaluation. Preoperatively, 10 (59%) of the children with a tethered cord had abnormal urodynamic study (UDS) results. Only two (20%) of these patients had urological symptoms. All seven patients with normal preoperative UDS results had normal UDS results after detethering. In addition, in five (50%) of the 10 children with abnormal preoperative UDS results, the postoperative UDS demonstrated improved or normal urodynamics. Conclusions. Because more than half of the children who underwent detethering were found to have abnormal preoperative UDS results, preoperative urodynamic evaluation should be performed in all cases in which detethering is considered. With regard to voiding function, detethering is relatively safe for children with normal preoperative UDS results. In children with abnormal preoperative UDS results, detethering may lead to improvement or even normalization of voiding, especially if the procedure is performed prior to 1 year of age. Finally, children with anorectal anomalies and a tethered cord may represent a subset of patients who are particularly likely to experience urodynamic improvement after detethering.

Scrotal swelling in young boys is a common problem. The differential diagnosis includes testicular torsion, epididymoorchitis, and idiopathic scrotal edema. We report the unusual case of a 17-year-old boy who presented with recurrent episodes of penile and scrotal edema as extraintestinal manifestations of Crohn's disease. Genitourinary complications of Crohn's disease are not uncommon; however, they more typically present in the form of nephrolithiasis, obstructive uropathy, and enterovesical fistulization. Few reports have described Crohn's disease presenting with isolated genital edema in the absence of associated intestinal or systemic symptoms.