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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.

Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, developmental delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs. To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.

Identifying the determinate factors of genetic disease has been quite successful for Mendelian inheritance of large-effect pathogenic variants. In these cases, two non- or low-functioning genes contribute to disease. However, Mendelian effects of lesser strength have generally been ignored when looking at genomic consequences in human health. Bastarache et al. used electronic records to identify the phenotypic effects of previously unidentified Mendelian variations. Their analysis suggests that individuals with undiagnosed Mendelian diseases may be more prevalent in the general population than assumed. Because of this, genetic analysis may be able to assist clinicians in arriving at a diagnosis. Science , this issue p. 1233 Electronic health records coupled with exome sequencing identify disease phenotypes linked to Mendelian inheritance. Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.

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.

Introduction and hypothesisVesicovaginal fistulae (VVF) repair success rates for simple surgical fistulae are high, but constitute a significantly greater challenge when occurring in a radiotherapy field. We aim to evaluate the causes, assessment, closure rates and functional outcomes of VVF surgery in patients with previous radiotherapy.MethodsData on all VVF repairs were collected prospectively. A retrospective review of outcomes in those with VVF performed between 2009 and 2018 was carried out. Details including time from radiotherapy, pre-operative assessments, approach to surgery and functional outcome were analysed.ResultsTwenty women with VVFs were identified. The mean age was 59 (range 25–88) years. Primary malignancy was cervical in 16 women, with the remaining 4 women having ovarian, urethral, endometrial and rectal cancer respectively. All women had external beam radiotherapy with 6 (30%) undergoing boosted brachytherapy. Mean interval between radiotherapy and fistula repair was 19 (range 0–40) years. Fistulae arose spontaneously in 14 patients, whereas 6 occurred following a further surgical intervention.Closure was attempted vaginally in 7 women and abdominally in 1, whereas 12 had a primary diversion owing to significant bladder contracture and ureteric involvement. The closure rate in those attempted was 62.5%, 40% in those with spontaneous fistulae compared with 100% for post-surgical fistulae, but only 20% for the total cohort.ConclusionsClosure of VVF is a significant challenge, with an initial success rate of 20% and an overall success rate of only 25%. Seventy percent required primary or secondary urinary diversion. Vaginal surgery was utilised in the majority to try to avoid a hostile pelvis, but the surgical approach should be tailored to individual circumstances.

Introduction and hypothesisThe objective was to assess the comparative provider costs of vaginal and open abdominal repair of vesicovaginal fistula (VVF) and to determine the most cost-effective means of managing VVF.MethodsA prospectively acquired database of all women undergoing VVF repair by a single surgeon between 2007 and 2015 was retrospectively reviewed to determine operating time, perioperative complications, inpatient stay and 30-day readmissions. The success and cost of the VVF repair were identified. Statistical analysis was by unpaired t test, Chi-squared test and Mann–Whitney U test.ResultsForty-seven consecutive women of mean age 51 years (range 21–88) undergoing a first attempt at VVF repair at our institution were included; 32(68%) had vaginal repair with Martius fat pad interposition and 15 (32%) had open abdominal repair with omental interposition. There were no perioperative complications or 30-day readmissions in either group. Mean operative time was longer for open abdominal (223.4 min) than vaginal repair (196.9 min). Median inpatient stay was longer for an open abdominal (8 days) than for a vaginal approach (4 days). Successful anatomical closure was achieved in 91% of vaginal and 86% of open abdominal repairs at first attempt, and in 100% after second repair, where required. Mean/median costs for an abdominal repair were significantly higher, at £4,608.69/£4,169.20 than for vaginal repair at £3,381.50/£3,009.24 (P<0.05).ConclusionsVesicovaginal fistulae were successfully repaired in 89% of cases at first attempt. The success rate did not differ between approaches. Vaginal repair is significantly more cost-effective than abdominal repair owing to the shorter operative time and length of stay.

Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up. To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data. We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106). Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included. Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.

To 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). Seven 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. Dorsal Genital Nerve Stimulation increased bladder capacity by 153 ± 146 ml ( = 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 ( = 0.016, = 0.031, = 0.016), respectively. SS results showed small reduction of 33 ± 26 ml ( = 0.063) from baseline bladder capacity in five participants. Maximum Detrusor Pressure before leakage was increased during TNS, by 10 ± 13 cmH O ( = 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 cmH O 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. In 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.

Introduction and hypothesisIn randomized clinical trials onabotulinumtoxinA was demonstrated to be an effective and well-tolerated treatment for overactive bladder (OAB) with urinary incontinence (UI). However, data reporting onabotulinumtoxinA use in everyday clinical practice are limited. Here, we present the results from a large, first-of-its-kind real-world study in patients with OAB.MethodsThis was a prospective, observational, multinational study (GRACE; ClinicalTrials.gov, NCT02161159) performed in four European countries. Patients (N = 504) aged ≥ 18 years with OAB inadequately managed with ≥ 1 anticholinergic received onabotulinumtoxinA per their physician’s normal clinical practice.ResultsPhysicians primarily used rigid cystoscopes for onabotulinumtoxinA injection; anesthesia/analgesia was utilized during most treatment procedures. Significant reductions in UI episodes/day from baseline to weeks 1 and 12 were observed as well as in micturition, urgency, and nocturia episodes/day. These improvements in urinary symptoms corresponded to higher scores on the treatment benefit scale at week 12. The use of other OAB medications dropped from baseline to weeks 1 and 12 and was sustained to week 52, which paralleled a reduction in the number of incontinence products used during that time frame. Adverse reactions were reported in 2.6% of patients throughout the study.ConclusionsIn this real-world study, significant improvements in urinary symptoms were seen following onabotulinumtoxinA treatment as early as week 1 and sustained to at least week 12. This was accompanied by a reduced reliance upon incontinence products and reduction in concomitant OAB medication use. OnabotulinumtoxinA was well tolerated with no new safety signals.

PurposeWith advances in treatment modalities and medical knowledge, girls with congenital urologic disorders are living well into adulthood. Although, sexual and reproductive function in this population is still poorly understood. The aim is to review existing literature about fertility and sexuality in women with congenital genitourinary disorders, including spina bifida (SB), bladder exstrophy–epispadias complex (BEEC) and congenital adrenal hyperplasia (CAH).MethodsThis review represents the joint SIU-ICUD (Société Internationale d’Urologie—International Consultation on Urological Disease) consultation on congenital lifelong urology. The results of this analysis were first presented at a joint consultation of the SIU and ICUD at the 2018 SIU annual conference in Seoul, South Korea. Appropriate experts were asked to write specific sections regarding sexuality and reproductive function in female patients with these complex congenital urogenital disorders. Each expert performed their own literature review which was reviewed by GDW, AFS, Hadley M. Wood and Dan Wood. Expert opinion was obtained where data are non-existent.ResultsOnly about half of the individuals with SB express a satisfactory sex life. In women with BEEC, cosmetic concerns surrounding genital appearance and function may increase psychological distress, including severe depression, suicide and sexual dysfunction. Professional health care is key for improving self-esteem and to interact in the biopsychosocial model of the quality of life. Patients with SB and BEEC should be informed about all the potential risks and difficulties before, during and after pregnancy. Screening for pelvic organ prolapse is important as it can exacerbate their already existing sexual dysfunction, difficulties achieving pregnancy and challenges with clean intermittent catheterization.ConclusionsLifelong multidisciplinary follow-up and management are complex but necessary. As these patients grow into their adolescence, they may have the desire to become involved in personal relationships and have sexual interactions. Their healthcare team needs to be increasingly sensitive to these aspects.