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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

BackgroundPolymerase 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.MethodsVarying amounts of viable or non-viable uropathogenic E. coli (UTI89) or buffer control were titrated with mouse urine. The samples were centrifuged to collect urine sediment or not centrifuged. Urine samples were incubated with PMA and DNA cross-linked using blue LED light. DNA was isolated and uidA gene-specific PCR was performed. For in vivo studies, mice were inoculated with UTI89, followed by ciprofloxacin treatment or no treatment. After the completion of ciprofloxacin treatment, an aliquot of urine was plated on non-selective LB agar and another aliquot was treated with PMA and subjected to uidA-specific PCR.ResultsPMA’s efficiency in excluding DNA signal from non-viable bacteria was significantly higher in bacterial samples in phosphate-buffered saline (PBS, dCT=13.69) versus bacterial samples in unspun urine (dCT=1.58). This discrepancy was diminished by spinning down urine-based bacterial samples to collect sediment and resuspending it in PBS prior to PMA treatment. In 3 of 5 replicate groups of UTI89-infected mice, no bacteria grew in culture; however, there was PCR amplification of E. coli after PMA treatment in 2 of those 3 groups.ConclusionWe 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 E. coli can be present following treatment of UTI, and may explain why some patients have persistent symptoms but negative urine cultures following UTI treatment.

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.

Autonomous robotic suturing has the potential to improve surgery outcomes by leveraging accuracy, repeatability, and consistency compared to manual operations. However, achieving full autonomy in complex surgical environments is not practical and human supervision is required to guarantee safety. In this paper, we develop a confidence-based supervised autonomous suturing method to perform robotic suturing tasks via both Smart Tissue Autonomous Robot (STAR) and surgeon collaboratively with the highest possible degree of autonomy. Via the proposed method, STAR performs autonomous suturing when highly confident and otherwise asks the operator for possible assistance in suture positioning adjustments. We evaluate the accuracy of our proposed control method via robotic suturing tests on synthetic vaginal cuff tissues and compare them to the results of vaginal cuff closures performed by an experienced surgeon. Our test results indicate that by using the proposed confidence-based method, STAR can predict the success of pure autonomous suture placement with an accuracy of 94.74%. Moreover, via an additional 25% human intervention, STAR can achieve a 98.1% suture placement accuracy compared to an 85.4% accuracy of completely autonomous robotic suturing. Finally, our experiment results indicate that STAR using the proposed method achieves 1.6 times better consistency in suture spacing and 1.8 times better consistency in suture bite sizes than the manual results.

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.

Compared to open surgical techniques, laparoscopic surgical methods aim to reduce the collateral tissue damage and hence decrease the patient recovery time. However, constraints imposed by the laparoscopic surgery, i.e. the operation of surgical tools in limited spaces, turn simple surgical tasks such as suturing into time-consuming and inconsistent tasks for surgeons. In this paper, we develop an autonomous laparoscopic robotic suturing system. More specific, we expand our smart tissue anastomosis robot (STAR) by developing i) a new 3D imaging endoscope, ii) a novel actuated laparoscopic suturing tool, and iii) a suture planning strategy for the autonomous suturing. We experimentally test the accuracy and consistency of our developed system and compare it to sutures performed manually by surgeons. Our test results on suture pads indicate that STAR can reach 2.9 times better consistency in suture spacing compared to manual method and also eliminate suture repositioning and adjustments. Moreover, the consistency of suture bite sizes obtained by STAR matches with those obtained by manual suturing.

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.

Background Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods Mice were intravenously administered a single 25 μg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial CFU were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide and pattern recognition receptor expression. Results Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure. Conclusions Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enhancing vulnerability to this co-infection. Graphical Abstract

Morbidity associated with hepatic and urogenital schistosomiasis stems primarily from the host immune response directed against schistosome eggs. When eggs become entrapped in host tissues, the development of fibrotic plaques drives downstream pathology. These events occur due to the antigenic nature of egg excretory/secretory products (ESPs). Both Schistosoma mansoni and S. japonicum ESPs have been shown to interact with several cell populations in the host liver including hepatocytes, macrophages, and hepatic stellate cells, with both immunomodulatory and pathological consequences. Several protein components of the ESPs of S. mansoni and S. japonicum eggs have been characterised; however, studies into the collective contents of schistosome egg ESPs are lacking. Utilising shotgun mass spectrometry and an array of in silico analyses, we identified 266, 90 and 50 proteins within the S. mansoni, S. japonicum and S. haematobium egg secretomes respectively. We identified numerous proteins with already established immunomodulatory activities, vaccine candidates and vesicle markers. Relatively few common orthologues within the ESPs were identified by BLAST, indicating that the three egg secretomes differ in content significantly. Having a clearer understanding of these components may lead to the identification of new proteins with uncharacterised immunomodulatory potential or pathological relevance. This will enhance our understanding of host-parasite interactions, particularly those occurring during chronic schistosomiasis, and pave the way towards novel therapeutics and vaccines.

Bacterial and parasitic urinary tract infections(UTI) affect many, but our understanding of associated immunity remains poor. Prior work indicates interleukin-22(IL-22) is a key cytokine during infection of other epithelia. We hypothesized IL-22 is crucial during UTI.IL-22-null(KO) and wild-type(wt) mice underwent bladder wall injection with S. haematobium eggs or transurethral infection with uropathogenic E. coli UTI89.IL-22 and its soluble binding protein, IL-22BP, were increased in the bladder after S. haematobium egg injection. Genes typically induced by IL-22(CXCL2, REG3G[antimicrobial defense protein]], S100A8, S100A9, and Areg) were expressed at higher levels following S. haematobium egg injection. IL-22 stimulation of bladder tissue induced REG3B expression. IL-22 receptor alpha-1 expression was detectable in the urothelium by immunofluorescence and qPCR.Injection of S. haematobium eggs into IL-22-KO vs wt mice triggered differential expression of genes related to transferase activity(transferring alkyl or aryl groups) and epithelial cell development. Numerous uroplakin genes were downregulated in egg-injected, IL-22-KO mice versus their wt counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL-22 is important for replenishing the epithelium during infection-related injury.Following transurethral infection with UTI89, IL-22-KO mice had lower bacterial counts in their urine, bladder, and kidneys. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to higher kidney bacterial counts and increased morbidity.Our data suggest that IL-22 is indeed important in urinary tract immunity, and may interfere with clearance of bacteria from the urinary tract, potentially through its role in maintenance of mature urothelium.

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.

The male mouse is underrepresented in research of the urinary tract due to the difficulty of transurethral catheterization. As a result, there is a lack of analysis of sex differences in urinary tract research. Here, we present a novel catheter design and technique that enables urethral catheterization of male mice for bladder inoculation. Our catheterization technique uses the resistance met at the level of the external urinary sphincter and prostate to guide the retraction, positioning, and advancement of the catheter into the urinary bladder. We have shown that this method can be used to reproducibly catheterize 12 male mice with minimal urogenital trauma but cannot be used as a cystometric technique. This method will facilitate the expansion of research into sex differences in various genitourinary conditions that require transurethral catheterization of mice.

INTRODUCTION AND OBJECTIVE:The inconsistency and difficulty of suturing in minimally invasive surgeries stem from the limitations in tool motion and visualization. In pelvic surgery, difficulty is ...

INTRODUCTION AND OBJECTIVE:We have demonstrated that H-IPSE, the Schistosoma haematobium ortholog of the IL-4 Inducing Principle from Schistosoma mansoni Eggs, is therapeutic in ifosfamide-induced ...

Point clouds have been widely used due to their information being richer than images. Fringe projection profilometry (FPP) is one of the camera-based point cloud acquisition techniques that is being developed as a vision system for robotic surgery. For semi-autonomous robotic suturing, fluorescent fiducials were previously used on a target tissue as suture landmarks. This not only increases system complexity but also imposes safety concerns. To address these problems, we propose a numerical landmark localization algorithm based on a convolutional neural network (CNN) and a conditional random field (CRF). A CNN is applied to regress landmark heatmaps from the four-channel image data generated by the FPP. A CRF leveraging both local and global shape constraints is developed to better tune the landmark coordinates, reject extra landmarks, and recover missing landmarks. The robustness of the proposed method is demonstrated through ex vivo porcine intestine landmark localization experiments.

Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an "infiltrin," translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti-IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.-Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis.

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.

IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection withSchistosoma haematobiumworms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra−/−) and wild type mice withS. haematobiumeggs. Readouts included bladder histology andex vivoassessments of urothelial proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferationin vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall injectedS. haematobiumeggs inIl4ra−/−versus wild type mice.S. haematobiumegg injection triggered significant urothelial proliferation, including evidence of urothelial hyperdiploidy and cell cycle skewing in wild type but notIl4ra−/−mice. Urothelial exposure to IL-4in vitroled to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

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