Rethinking the artificial urinary sphincter : from current knowledge to the development of a new smart device

Background: Urinary incontinence (UI) plagues millions of women and men worldwide, leading to social stigma, low self-esteem, poor quality of life, and affects their loved ones. In women, frequent causes include childbirth, and in men prostate surgery for benign or malignant disease. In both genders congenital anomalies, neurological diseases, pelvic surgery, and radiation therapy are incriminating factors. Many patients struggle daily with pads and/or diapers, often unaware of the existence of a surgical cure. Since the seventies, the AMS 800Ô (Boston Scientific - Marlborough, Massachusetts, USA) artificial urinary sphincter (AUS) has been the reference to treat severe male stress UI (SUI) secondary to intrinsic sphincter deficiency (ISD). In women, it constitutes a second-line option, the mid-urethral sling (MUS) being recommended as first-line surgical therapy in moderate to severe cases. However, although efficient, it has several drawbacks, namely poor ergonomics, untailored status to patients’ physical activities, high revision and explantation rates. Aims: To solve the above issues, a novel electronic AUS was incepted in France in 2007. This thesis tells the modern developmental journey of this device for severe SUI treatment. The objective is three- fold: to conduct a review of the current AMSÔ in both genders to identify potential literature gaps to identify and analyze data resulting from bench tests and clinical studies, and to conduct pre-clinical feasibility, performance and safety studies on human cadavers and animals prior to FIM studies. The 6 constituent papers present the results of the process rethinking the current AMS 800Ô known today, from State of the Art (papers I-III) to the design stages (paper IV) and subsequent pre-clinical implantation phases (papers V and VI) prior to the First in Man study, which eventually leads to the obtention of CE marking. Material, Methods, and Results: In Paper I, a systematic literature review of AMS 800Ô implantation in women with non-neurogenic severe SUI, non-extant to date, was performed. The 12 articles included showed a very low level of evidence, result heterogeneity in performance and safety outcomes and highlighted the need for post- market studies. Paper II addressed the absence of standardized continence outcome measurement tool, essential to homogenize functional reported outcomes data, but also crucial for defining the primary outcomes of the FIM study. We retrospectively assessed the 24- hour pad weight test in 180 men treated with primary AUS for PPUI. Secondarily, its correlation to quality-of-life was analyzed. Thirdly (Paper III), we retrospectively evaluated long-term continence and safety results of transscrotal versus transperineal (TP) primary AUS implantation in 183 men with PPUI in a single center. No statistical difference in performance outcomes was seen; however, the TP technique appeared to present worse long-term safety results. In Paper IV, we dimensioned the novel AUS by prospectively measuring the exact in vivo volume taken by the AMS 800Ô occlusive cuff after its pressurization at implantation. We found that the larger the cuff, the greater the accommodated volume, which did not surpass 1 cc. Therefore, the final prototype could be designed, an essential developmental milestone. In paper V the usability and performance of the novel AUS was established, in accordance with current FDA and European regulations on AIMDs in development. The device’s usability and performance were shown in 8 anatomical subjects, using randomly obtained urodynamic maximum urethral closure pressure ranges, equivalent to those of the AMS 800Ô. In Paper VI, we ascertained the novel device’s feasibility of implantation and histopathological safety in an animal pilot study using two wether models. The study showed the suitability of the models, the device’s ease of implantation and the absence of peri-or postoperative, and histopathological adverse events. We could therefore safely consider a Pivot study. Conclusion: Developing a novel AUS is a lengthy, expensive, and regulatory challenging process. In the ‘State of the Art’, essential to assess the ‘Gold standard’, we identified three literature gaps relevant for the risk analysis and evaluated similar competing devices. We showed a fine example of the application of ‘in vivo’ clinical study to the design of the smart AUS device. These initiated the required pre- clinical studies prior to FIM trials, demonstrating device feasibility, performance, and safety. the importance of post-market studies was also highlighted, and we strive to soon deliver a safe and efficient electronic device, tailored to the patient’s needs, whilst abiding to current regulations

Prevalence, risk factors, and impact on outcome of cytomegalovirus replication in serum of Cambodian HIV-infected patients (2004-2007)

BACKGROUND: In developing countries, the study of cytomegalovirus (CMV) coinfection in HIV-infected patients remains neglected. Quantitative CMV polymerase chain reaction (PCR) is the gold standard diagnostic tool for analyzing serum CMV replication and for predicting CMV disease. We estimated the prevalence of replicating CMV in sera of newly diagnosed HIV-infected Cambodian patients and examined its impact on mortality. METHODS: This cohort study was based on 2 highly active antiretroviral therapy treatment programs in Cambodia between 2004 and 2007. Quantitative CMV PCR was performed on baseline serum samples of 377 HIV-infected patients. RESULTS: The prevalence of serum CMV DNA was 55.2% (150 of 272) in patients with CD4 count <100/mm. In multivariate analysis, hemoglobin <9 g/dL, CD4 count <100/mm, and Karnofsky index <50 were independently associated with positive serum CMV DNA at baseline. During a 3-year follow-up period, CMV viral load >or=3.1 log10 copies per milliliter was significantly associated with death independently of CD4 count, other opportunistic infections, and highly active antiretroviral therapy. CONCLUSIONS: As in industrialized countries, serum CMV replication is highly prevalent among HIV-infected Cambodian patients and is associated with increased mortality. This underscores the importance of diagnostic CMV infection by PCR in sera of HIV-infected patients with CD4 count <100/mm and treating this opportunistic infection to reduce its associated mortality

Stretching the IR theoretical spectrum on Irish neutrality: a critical social constructivist framework

In a 2006 International Political Science Review article, entitled "Choosing to Go It Alone: Irish Neutrality in Theoretical and Comparative Perspective," Neal G. Jesse argues that Irish neutrality is best understood through a neoliberal rather than a neorealist international relations theory framework. This article posits an alternative "critical social constructivist" framework for understanding Irish neutrality. The first part of the article considers the differences between neoliberalism and social constructivism and argues why critical social constructivism's emphasis on beliefs, identity, and the agency of the public in foreign policy are key factors explaining Irish neutrality today. Using public opinion data, the second part of the article tests whether national identity, independence, ethnocentrism, attitudes to Northern Ireland, and efficacy are factors driving public support for Irish neutrality. The results show that public attitudes to Irish neutrality are structured along the dimensions of independence and identity, indicating empirical support for a critical social constructivist framework of understanding of Irish neutrality

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder

The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and other quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. In the eQTL analysis, we utilize a recently proposed hierarchical multiple testing strategy which controls error rates regarding the discovery of functional variants. Our results elucidate the heritability and regulation of gene expression in this unique Latin American study population and identify a set of regulatory SNPs which may be relevant in future investigations of complex disease in this population. Since our subjects belong to extended families, we are able to compare traditional kinship-based estimates with those from more recent methods that depend only on genotype information.National Institutes for Health/[R01 HG006695]/NIH/Estados UnidosNational Institutes for Health/[R01 MH101782]/NIH/Estados UnidosNational Institutes for Health/[R01 MH075007]/NIH/Estados UnidosIsrael Science Foundation/[1112/14]/ISF/IsraelUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

Intergroup bridging dynamics affecting organizational knowledge sharing over time

This paper investigates the social structure between online groups within an Enterprise Social Network (ESN). We analyze the nature and composition of bridges between groups over time and how they affect the intergroup network. We perform regression analyses of data generated by an ESN within a Dutch youth-care organization. We find that the intergroup network develops small world characteristics and suggest that this will foster organizational knowledge sharing. We follow development of bridges and their composition week after week over a period of five years. We show the relative importance of so-called flexible bridging members who recurrently bridge the same groups over time. The importance of relatively more flexible compared to stable bridging members changes over time, so that flexible bridging members are more important in earlier stages of the ESN adoption lifecycle, and stable bridging members at later stages. Further, we show that there is a difference in how early adopters versus late adopters are active on the bridges and how this bridging behavior develops over time. Our findings are enhanced by interview data with bridging members. This study contributes to the understanding of brokerage dynamics by zooming in on how the intergroup network changes over time due to stable and flexible bridges, and we suggest that this affects organizational knowledge sharing over time