Search

Abstract Background The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs. Methods We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods. Results These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS. Conclusion The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.

Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous STT3A variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity.

OBJECTIVES/GOALS: Congenital anomalies (CAs) affect 3% of live births, yet the cause of 80% of CAs is unknown and for the 20% with an identified cause, variability in penetrance suggests additional risk drivers exist. Our method for identifying and categorizing CAs in electronic health record (EHR) linked biobank databases can expand and improve CA etiologic research. METHODS/STUDY POPULATION: We identified individuals with CAs in three groups: 1. Those with at least one CA 2. Those with multiple CAs (MCA), those with two or more ‘major’ CAs, and 3. Those with CAs in a specific organ system. We also created a novel quantitative approach, using phenome-wide association studies (pheWAS), for determining CA-associated genetic disease billing codes in order to separate individuals that have a known genetic cause for their CAs from those with idiopathic CAs. We updated CA phecodes, aggregates of clinical billing codes, which we used to identify CA cases in Vanderbilt’s EHR-linked biobank database, BioVU. We create a new phecode, ‘All CAs’, for researchers to quickly identify all individuals with at least one CA. We evaluate the definition of MCA using pheWAS analyses to compare ‘minor’ vs ‘major’ CA. RESULTS/ANTICIPATED RESULTS: The new CA phecode nomenclature includes 5.8 times more codes for CAs compared with the previous version (365 vs 56), improving granularity. 85 (19.7%) CA-associated genetic disease billing codes were identified through literature review. PheWAS analyses revealed an additional 16 (3.7%) genetic disease billing codes with one or more significant (p< 2.75 x10-5) association with CA-related phecodes. Identifying CA-associated genetic disease billing codes allows researchers to differentiate between idiopathic CAs and those that have a known genetic cause. PheWAS analyses of individuals with previously considered “minor” CAs showed many associated severe health problems, revealing that the differentiation between “minor” vs “major” CAs when identifying individuals with MCA in the EHR is arbitrary. DISCUSSION/SIGNIFICANCE: Our CA identification method is scalable for the growing number of EHR-linked biobanks. Differentiating between idiopathic CAs from those with known causes will increase power in studies discovering additional genetic drivers of CAs. Our novel method allows for expansion and acceleration of CA epidemiological research in EHR-linked biobank data.

Mucocele of Maxillary sinus is a rare entity comprising 2-10% of all mucoceles and develops due to obstruction of drainage ostium. Here, we present a case of maxillary sinus mucocele in a 20-year-old male who presented with diffuse swelling on the left side of his face. Provisional diagnosis of mucocele was made on a computed tomography scan, which was later confirmed on histopathology. The lesion was managed surgically with uneventful healing at 2 weeks and 3 months follow-up. Mucoceles are often misdiagnosed as cysts or tumours of odontogenic origin on the conventional radiograph. Delay in diagnosis can result in complications due to the expansion of mucocele towards adjacent structures such as the nose and orbit. Therefore, it becomes crucial to diagnose it appropriately with the help of higher imaging modalities so that it can be managed well in time.

Abstract Due to the widespread usage of Android smartphones in the present era, Android malware has become a grave security concern. The research community relies on publicly available datasets to keep pace with evolving malware. However, a plethora of apps in those datasets are mere clones of previously identified malware. The reason is that instead of creating novel versions, malware authors generally repack existing malicious applications to create malware clones with minimal effort and expense. This paper investigates three benchmark Android malware datasets to quantify repacked malware using package names-based similarity. We consider 5560 apps from the Drebin dataset, 24,533 apps from the AMD and 695,470 apps from the AndroZoo dataset for analysis. Our analysis reveals that 52.3% apps in Drebin, 29.8% apps in the AMD and 42.3% apps in the AndroZoo dataset are repacked malware. Furthermore, we present AndroMalPack, an Android malware detector trained on clones-free datasets and optimized using Nature-inspired algorithms. Although trained on a reduced version of datasets, AndroMalPack classifies novel and repacked malware with a remarkable detection accuracy of up to 98.2% and meagre false-positive rates. Finally, we publish a dataset of cloned apps in Drebin, AMD, and AndrooZoo to foster research in the repacked malware analysis domain.

This is the second manuscript from the Neuro-urology Promotion Committee of the International Continence Society (ICS) discussing uncommon neuro-urological conditions that are not well described in urological literature. Readers are referred to the first document for a more detailed understanding of how neurological disease might affect lower urinary tract function ( https://doi.org/10.1016/j.cont.2022.100022).Eleven conditions are covered. This includes five genetic conditions — Duchene muscular dystrophy, mitochondrial encephalopathy, Down’s syndrome, adrenoleukodystrophy and Ochoa’s syndrome. Three infection-associated conditions are covered including central nervous system tuberculosis, schistosomal myeloradiculopathy and post-polio syndrome. Three other conditions covered are myasthenia gravis, syringomyelia and the vegetative state. Key aspects and specific recommendations related to clinical practice are summarized in tables.Knowledge of unusual neurological conditions that can affect the lower urinary tract is important for ensuring a timely and precise diagnosis. This document from the ICS, along with Part I published earlier, can serve as a reference for clinicians presented with unusual forms of neurogenic lower urinary tract dysfunction.

Objective:: To survey members of the International Continence Society (ICS) for exploring global differences in practices with regard to intermittent catheterization (IC) and reuse of catheters in the neuro-urological patient. A project of the Neuro-Urology Promotion Committee (NUPC) of the ICS. Methods:: Cross-sectional survey of ICS members using the SurveyMonkey platform. Initial survey preparation, revisions, pilot, and finalization were performed within the NUPC. Opt-in survey emailed to all members by the ICS office. Foundation questions ascertained type of clinical practice, health care system, and country of residence which was stratified by World Bank criteria as ‘high-income group, HIG’ or ‘not high-income group, non-HIG’ for analysis. Several questions addressed the reuse of catheters and related practices. Survey results were analyzed using R (version 3.1.3) statistical analysis (p-value 90 times, and till visible deterioration in 25.0%, 25.8%, 15.8%, 7.5%, 5.0%, 5.0%, and 15.8%, respectively. Conclusion:: Reuse of catheters by patients on IC was not restricted to less affluent countries. There were wide variations in every aspect of the IC protocol. These issues are critical to patients, communities, and the environment and urgently require research.

Objectives: Whilst ambulatory urodynamics (aUDS) may be used as a second-stage test for patients with refractory lower urinary tract symptoms (LUTS) having non-diagnostic conventional urodynamics (UDS), the evidence for their use is limited. We have assessed the diagnostic utility and consequent symptomatic outcome of aUDS in patients with refractory LUTS. Methods: A retrospective review of a prospectively acquired urodynamics database was made of 84 consecutive patients (23 male) with a median age 50.5 years (range 18 to 79) having aUDS following non-diagnostic or contradictory baseline UDS over a 12-month period. Patient demographics and urodynamic and clinical diagnosis before and after aUDS were recorded. Forty-six patients (55%) had formal urinary symptom assessment recorded before and a minimum of 6 months following aUDS-related change in management. Results: Eighty-two patients (98%) had a urodynamic diagnosis made following aUDS, 57(68%) of whom had detrusor overactivity (DO); the final 2 patients had no abnormalities detected on aUDS. Change in primary UDS diagnosis occurred in 66 patients (79%). Of these 66 patients, 59 (89%) also had their clinical diagnosis changed, and 55 (83%) had their management pathway changed. There was a significant improvement in urinary symptoms 6 months following aUDS. Conclusion: Change in primary diagnosis following aUDS led to a significant change in treatment care pathway and resulted in significant improvement in urinary symptoms

Summary: Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a “personalized structural biology” (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a de novo VUS in KCNC2 (p.V469L), the Kv3.2 voltage-gated potassium channel. A nearby KCNC2 variant (p.V471L) was recently suggested to cause DEE-like phenotypes. Computational structural modeling suggests that both affect protein function. However, despite their proximity, the p.V469L variant is likely to sterically block the channel pore, while the p.V471L variant is likely to stabilize the open state. Biochemical and electrophysiological analyses demonstrate heterogeneous loss-of-function and gain-of-function effects, as well as differential response to 4-aminopyridine treatment. Molecular dynamics simulations illustrate that the pore of the p.V469L variant is more constricted, increasing the energetic barrier for K+ permeation, whereas the p.V471L variant stabilizes the open conformation. Our results implicate variants in KCNC2 as causative for DEE and guide the interpretation of a UDN individual. They further delineate the molecular basis for the heterogeneous clinical phenotypes resulting from two proximal pathogenic variants. This demonstrates how the PSB approach can provide an analytical framework for individualized hypothesis-driven interpretation of protein-coding VUS.

Machine learning (ML) based botnet detectors are no exception to traditional ML models when it comes to adversarial evasion attacks. The datasets used to train these models have also scarcity and imbalance issues. We propose a new technique named Botshot, based on generative adversarial networks (GANs) for addressing these issues and proactively making botnet detectors aware of adversarial evasions. Botshot is cost-effective as compared to the network emulation for botnet traffic data generation rendering the dedicated hardware resources unnecessary. First, we use the extended set of network flow and time-based features for three publicly available botnet datasets. Second, we utilize two GANs (vanilla, conditional) for generating realistic botnet traffic. We evaluate the generator performance using classifier two-sample test (C2ST) with 10-fold 70-30 train-test split and propose the use of ’recall’ in contrast to ’accuracy’ for proactively learning adversarial evasions. We then augment the train set with the generated data and test using the unchanged test set. Last, we compare our results with benchmark oversampling methods with augmentation of additional botnet traffic data in terms of average accuracy, precision, recall and F1 score over six different ML classifiers. The empirical results demonstrate the effectiveness of the GAN-based oversampling for learning in advance the adversarial evasion attacks on botnet detectors.

Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.

The management of patients with neurogenic lower urinary tract dysfunction has been well-described, however this is most frequently discussed for common conditions such as spinal cord injury or multiple sclerosis. Our objective was to review uncommon neurologic disorders and summarize both the underlying disease process, and the relevant disease-specific research on the impact of the neurologic condition on the lower urinary tract. Among the degenerative and traumatic brain disorders, we have included frontotemporal dementia, amyotrophic lateral sclerosis, Huntington’s Disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and traumatic brain injury. Among the autoimmune disorders, we reviewed transverse myelitis, neuromyelitis optica spectrum disorders, Myelin oligodendrocyte glycoprotein antibody-associated disease, glial fibrillary acidic protein astrocytopathy, and meningitis-retention syndrome (a form of aseptic meningitis that presents with urinary retention). Hereditary spastic paraplegia, VACTERL association, and several peripheral neuropathies (Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, autoimmune autonomic gangliopathy, Wolfram syndrome spectrum disorder (a progressive peripheral neuropathy disorder with early onset diabetes, optic atrophy and megacystis in the early stage), Charcot Marie Tooth disease, and amyloid neuropathy are included. Practice points specific to the disorders are included where appropriate.

We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient’s ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient’s nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.

Neurogenic lower urinary tract dysfunction (NLUTD), the abnormal function of the lower urinary tract in the context of neurological pathology, has been the subject of multiple efforts worldwide for the development of clinical practice guidelines. These guidelines are based on the same body of evidence, and are therefore subject to the same gaps. For example, sexual and bowel dysfunction in the context of NLUTD, optimal renal function assessment in those who are non-ambulatory or with low muscle mass, optimal upper tract surveillance timing, and modification of diagnostic and treatment modalities for low-resource nations and communities are inadequately addressed. In addition, many aspects of the conclusions and final recommendations of the guidelines are similar. This duplicative work represents a large expenditure of time and effort, which we believe could be focused instead on evidence gaps. Here, we call for a global unified approach to create a single, resource-independent, comprehensive guidance on NLUTD, neurogenic sexual, and neurogenic bowel dysfunction. Targeted research addressing the evidence gaps should be called for and pursued. This will allow for focus to shift to filling the gaps in the evidence for future guidelines.

Context: While much has been published on vesicovaginal fistula (VVF), little is known about the urinary, bowel, and sexual functional outcomes following successful anatomical closure. Aims: We assessed the medium- to long-term urological, sexual, and bowel function outcomes following the successful anatomical closure of VVF. Patients and Methods: We conducted interviews with 36 women (median age – 47.5 years) who had successful anatomical closure of their VVF (28 vaginally and 8 abdominally) with a median of 40.5 months earlier. All completed validated questionnaires on urinary (Urogenital Distress Inventory-6 [UDI-6] and Incontinence Impact Questionnaire-7 [IIQ-7]), bowel (low anterior resection syndrome [LARS] score), and overall function (EQ5D). Sexually active patients completed the pelvic organ prolapse/ urinary incontinence sexual questionnaire (PISQ-12). All women also completed these questionnaires retrospectively for their status immediately before VVF repair. Functional outcomes were compared with preoperative function, and outcomes of those women having vaginal repair were compared with those having abdominal repair. Statistical analysis was by Student's t-test and Mann–Whitney U-test. Results: Median UDI-6 and IIQ-7 scores (low score is better) reduced significantly (P ≤ 0.01) from 16.5 and 25.5 preoperatively to 4 and 2.5 postclosure. Median LARS score was not significantly altered. Sexual function was restored in 67.6% while overall function postclosure was good (PISQ12 – low score better). Both EQ5D (low score better) and health thermometer (high score better) medians were significantly improved (P < 0.01) from 9 and 25 to 6 and 75 postclosure, respectively. There was no significant difference in the medium- to long-term outcomes of women who had had vaginal repair of their VVF and those who had had abdominal repair. Conclusions: Successful repair of VVF results in medium- to long-term significant improvement in urinary symptoms and distress, general well-being, and quality of life with no long-term adverse effects on bowel function regardless of route of repair. Sexual function is restored in 67.6%.

Introduction: About 40% of women suffer pelvic organ prolapse (POP) in a lifetime. The current standard intervention for vault prolapse is a mesh sacrocolpopexy or sacrohysteropexy. However, patients and surgeons are increasingly hesitant to use mesh given recent the UK and Food and Drug Administration warnings and litigation. A possible alternative is to use autologous tissue to support the vault, as a mesh-free solution. We report the outcomes from an initial series of autologous rectus fascia sheath (RFS) sacrocolpopexy and sacrohysteropexy in patients with complex pelvic floor dysfunction. Patients and Methods: All patients had previous, multiple urological/gynecological surgery and declined standard mesh repairs. All had preoperative videourodynamics and defecating magnetic resonance imaging evaluation. The autologous POP repair was performed using 10–18 cm of rectus sheath with a similar technique to that employing mesh to support the anterior-posterior vaginal walls or encircle the cervix and secured to the sacral promontory. Results: Seven patients with a mean age of 52 (33–64) years underwent autologous RFS POP repair between 2014 and 2017. Mean follow-up is 16 (range 2–33) months. All patients have durable result at last follow-up. No significant complications are reported. Conclusions: This is the first report of patients with complex pelvic floor dysfunction and apical POP being managed with autologous RFS sacrocolpopexy/sacrohysteropexy, and only the second report of a free graft being utilized with success. Autologous RFS sacrocolpopexy/sacrohysteropexy avoids the 10%–15% risks of mesh-related complications. Further studies of long-term durability are needed.

Angiokeratomas consist of ectasias of dermal capillaries associated with an acanthotic and hyperkeratotic overlying epidermis. These dark red-to-purple, papular vascular anomalies can vary considerably in size, depth, and location. It is a skin disorder that rarely involves oral cavity. It can occur in localized or generalized form and is often associated with underlying metabolic disorder such as Fabry's disease and fucosidosis. It has many clinical variants with the same underlying histopathology. Mucosal involvement, including the oral cavity, is occasionally found either as a component of the systemic variety, called angiokeratoma corporis diffusum, or associated with cutaneous lesions in more locations. Isolated oral involvement seems to be rather infrequent, and only eighteen cases have been described in the world literature thus far. Isolated multiple angiokeratomas of tongue without plaque formation have been reported only four times before this. Here, we report a fifth case of isolated multiple angiokeratomas of tongue in a 16-year-old female which was confirmed by immunohistochemical pattern in consonance with a blood vessel origin, with expression of CD31, CD34, and von Willebrand factor. The lesion did not express D2-40 and CD45. No other malformation or metabolic disorder was found in the patient.

Abstract Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD. Methods To identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene. Results We identified SOX17 as a novel candidate risk gene (p = 5.5e−7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases. Conclusions These data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.

Urinary incontinence remains one of the most significant complications of radical prostatectomy, known as post-prostatectomy incontinence (PPI), can have profound effects on quality of life. The correct diagnosis is critical, and the urodynamic cause of incontinence established as either stress urinary incontinence or detrusor overactivity. Patient evaluation should also include the use of quality of life questionnaires to assess severity of symptoms and a quantitative pad weight or pad usage assessment. Treatment regimes should incorporate conservative measures pelvic floor exercises, and then failing this, a discussion of the more invasive therapies, including bulking injections, the artificial urinary sphincter or the male suburethral sling. All of these options should be discussed carefully with the patient, including success rates of outcomes and potential adverse effects of treatment. Key words: Radical prostatectomy, urinary incontinence, post-prostatectomy incontinence, assessment, stress urinary incontinence, detrusor overactivity, management

Objectives: The objective of this study is to present the outcomes of men undergoing implantation of artificial urinary sphincter, after treatment for prostate cancer and also to determine the effect of radiotherapy on continence outcomes after artificial urinary sphincter (AUS) implantation. Material and Methods: A prospectively acquired database of all 184 patients having AUS insertion between 2002 and 2012 was reviewed, and demographic data, mode of prostate cancer treatment(s) before implantation, and outcome in terms of complete continence (pad free, leak free) were assessed. Statistical analysis was performed by Chi-squared and Fisher's exact tests. Results: A total of 58 (32%) men had bulbar AUS for urodynamically proven stress urinary incontinence consequent to treatment for prostate cancer in this period. Median follow-up post-AUS activation was 19 months (1–119). Forty-eight (83%) men had primary AUS insertion. Twenty-one (36%) men had radiotherapy as part of or as their sole treatment. Success rates were significantly higher in nonirradiated men having primary sphincter (89%) than in irradiated men (56%). Success rates were worse for men having revision AUS (40%), especially in irradiated men (33%). Conclusion: Radiotherapy as a treatment for prostate cancer was associated with significantly lower complete continence rates following AUS implantation.

Introduction: There is a multiplicity of treatments currently available for patients with symptomatic refractory urodynamic idiopathic detrusor overactivity (SRU IDO). We have assessed patient treatment preferences and their outcomes over a 12-month period from January 1 2009 to December 31 2009. Patients and Methods: A retrospective database of all patients with SRU IDO was reviewed for patient demographics, treatment preference, and outcome. All patients attending for treatment in the time period were offered: no further treatment, repeat bladder training ± antimuscarinic (BT ± AM), acupuncture, intravesical botulinum toxin injection, sacral neuromodulation (SNM), clam cystoplasty ± Mitrofanoff channel formation, and ileal conduit. Statistical Analysis Used: Statistical analysis of outcomes was done by Chi–square test, and statistical significance was determined as P< 0.05. Results: A total of 217 patients with SRU IDO underwent primary treatment in this time period, with a median age of 56 years and follow-up for a minimum of 12 months' posttreatment to determine outcome. No patients opted for any further treatment or an ileal conduit. The majority of patients opted for intravesical botulinum toxin injections and SNM with similar success rates (approximately 70%). A small number of patients decided to have nonsurgical interventions (BT ± AM or acupuncture) and had a broadly similar success rate (50%). A minority opted for clam cystoplasty ± Mitrofanoff channel formation – this group reported the highest success rate at 86%. Conclusions: Treatment options in SRU IDO are diverse, with the majority of patients opting for minimally invasive surgery. Clinicians should be familiar with all treatment options for management of SRU IDO.

ObjectivesTo assess and compare the effect of transcutaneous Dorsal Genital Nerve Stimulation (DGNS), Tibial Nerve Stimulation (TNS), Sacral Nerve Stimulation (SNS), and Spinal Stimulation (SS) on Neurogenic Detrusor Overactivity (NDO) and bladder capacity in people with Spinal Cord Injuries (SCI).Materials and MethodsSeven male participants with supra-sacral SCI were tested. Standard cystometry (CMG) was performed to assess bladder activity at baseline and with stimulation applied at each site. This was conducted over four separate sessions. All stimulation was monophasic, 15 Hz, 200 μS pulses and applied at maximum tolerable amplitude. Results were analysed against individual control results from within the same session.ResultsDorsal Genital Nerve Stimulation increased bladder capacity by 153 ± 146 ml (p = 0.016) or 117 ± 201%. DGNS, TNS and SNS all increased the volume held following the first reflex contraction, by 161 ± 175, 46 ± 62, and 34 ± 33 ml (p = 0.016, p = 0.031, p = 0.016), respectively. SS results showed small reduction of 33 ± 26 ml (p = 0.063) from baseline bladder capacity in five participants. Maximum Detrusor Pressure before leakage was increased during TNS, by 10 ± 13 cmH2O (p = 0.031) but was unchanged during stimulation of other sites. DGNS only was able to suppress at least one detrusor contraction in five participants and reduced first peak detrusor pressure below 40 cmH2O in these 5. Continuous TNS, SNS, and SS produced non-significant changes in bladder capacity from baseline, comparable to conditional stimulation. Increase in bladder capacity correlated with stimulation amplitude for DGNS but not TNS, SNS or SS.ConclusionIn this pilot study DGNS acutely suppressed detrusor contractions and increased bladder capacity whereas TNS, SNS, and SS did not. This is the first within individual comparison of surface stimulation sites for management of NDO in SCI individuals.

Abstract Background Family screening of a 48‐year‐old male with recently diagnosed IgG4‐related disease (IgG4‐RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons. Methods We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4‐RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2. Results The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T‐lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical‐turn‐helix structure, unable to adopt a stable conformation. The proband and the two sons had 5–10‐fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4‐RD cohort, showing enrichment in idiopathic IgG4‐RD. Conclusions The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4‐RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4‐RD supports the likelihood of participation in disease.

Abstract Background Rare variants (RV) in immunoglobulin mu‐binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot‐Marie‐Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns. Methods and Results An 11‐year‐old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non‐coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT‐PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense‐mediated decay (NMD), resulting in halpoinsufficiency. Conclusion This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.

Context: Excision of urethral diverticulum in females has been reported to be associated with new onset urodynamic stress urinary incontinence (USUI) in up to 49%. Aims: We have assessed the incidence of new onset USUI in all patients having urethral diverticulum excision with Martius fat pad interposition under the care of a single surgeon between May 1, 2007, and December 1, 2011. The incidence of new onset USUI has been correlated with the preoperative magnetic resonance imaging (MRI) appearance of the urethral diverticulum. Patients and Methods: All 33 patients (mean age 42) having urethral diverticulum with Martius fat pad interposition had prospective data tabulated on demographics, preoperative MRI appearance, and pre- and post-operative videocystometrogram. Statistical Analysis Used: Statistical analysis was performed by Chi-squared and Fisher's exact. Results: Of the 33 patients, 10 (30%) had preoperative USUI and have been excluded from this study. Other preoperative urodynamic findings included idiopathic detrusor overactivity in ten (30%) and bladder outflow obstruction in five (16%). Two (10%) of the patients had a simple diverticulum, 16 (73%) had a horseshoe diverticulum, and 5 (17%) had a circumferential diverticulum. The rate of new onset USUI was 0% for simple, 6% for saddle, and 20% for circumferential. Conclusions: New onset USUI occurs in 9% of patients having excision of urethral diverticulum with Martius fat pad interposition. The incidence appears to increase with increasing complexity of urethral diverticulum on preoperative MRI – rising from 0% following simple urethral diverticulum excision to 20% following circumferential diverticulum excision.

OBJECTIVE: Women with drug refractory neurogenic mixed incontinence (NMI) have limited minimally invasive treatment options and require reconstructive surgery. We examined efficacy of a combination of day case intradetrusor (ID) botulinum toxin (BTX-A) bladder injections and transobturator (TOT) or tension free vaginal tape (TVT). MATERIALS AND METHODS: Eleven women who are pharmacotherapy intolerant or who have drug refractory NMI were treated. Two opted for open surgery and the remaining 9 received 1000 units of Dysport diluted in 30 mL saline cystoscopically at 30 ID sites followed by TOT in 6 or TVT in 3 as a day case combination treatment. Patient demographics, pre and post treatment videocystometrogram (VCMG), pad test and International Committee on Incontinence Questionnaire (ICIQ) scores were recorded. At 6 weeks (repeat ICIQ, pad test and patient satisfaction), at 3 and 12 months (VCMG) and 'current' (ICIQ and patient satisfaction) was recorded. RESULTS: The mean age was 56.7 years (range 41 to 78) with a mean follow up of 19.1 months (range 7 to 33). All women were continent at 3 and 12 months. Quality of life (ICIQ scores) improved at 6 weeks (p > 0.001) and remained stable up to the last follow up (p > 0.001). Eight women have stopped using pads. At 3 months, there was significant improvement in MDP (p > 0.014) and MCC (p = 0.002). Anticholinergics were discontinued in 7 with global high satisfaction with the treatment BTX-A injections were repeated in 4 (mean 13.5 months). CONCLUSION: Anticholinergic refractory women with NMI can be effectively treated as a day case with combination of ID BTX-A injections and TVT or TOT.

More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations.