Collaborative Cross mice have diverse phenotypic responses to infection with Methicillin-resistant Staphylococcus aureus USA300.

Staphylococcus aureus (S. aureus) is an opportunistic pathogen causing diseases ranging from mild skin infections to life threatening conditions, including endocarditis, pneumonia, and sepsis. To identify host genes modulating this host-pathogen interaction, we infected 25 Collaborative Cross (CC) mouse strains with methicillin-resistant S. aureus (MRSA) and monitored disease progression for seven days using a surgically implanted telemetry system. CC strains varied widely in their response to intravenous MRSA infection. We identified eight 'susceptible' CC strains with high bacterial load, tissue damage, and reduced survival. Among the surviving strains, six with minimal colonization were classified as 'resistant', while the remaining six tolerated higher organ colonization ('tolerant'). The kidney was the most heavily colonized organ, but liver, spleen and lung colonization were better correlated with reduced survival. Resistant strains had higher pre-infection circulating neutrophils and lower post-infection tissue damage compared to susceptible and tolerant strains. We identified four CC strains with sexual dimorphism: all females survived the study period while all males met our euthanasia criteria earlier. In these CC strains, males had more baseline circulating monocytes and red blood cells. We identified several CC strains that may be useful as new models for endocarditis, myocarditis, pneumonia, and resistance to MRSA infection. Quantitative Trait Locus (QTL) analysis identified two significant loci, on Chromosomes 18 and 3, involved in early susceptibility and late survival after infection. We prioritized Npc1 and Ifi44l genes as the strongest candidates influencing survival using variant analysis and mRNA expression data from kidneys within these intervals.

Genetic background influences survival of infections with Salmonella enterica serovar Typhimurium in the Collaborative Cross.

Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection.

Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity.

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.

Module representatives for refining gene co-expression modules.

This paper concerns the identification of gene co-expression modules in transcriptomics data, i.e. collections of genes which are highly co-expressed and potentially linked to a biological mechanism. Weighted gene co-expression network analysis (WGCNA) is a widely used method for module detection based on the computation of eigengenes, the weights of the first principal component for the module gene expression matrix. This eigengene has been used as a centroid in ak-means algorithm to improve module memberships. In this paper, we present four new module representatives: the eigengene subspace, flag mean, flag median and module expression vector. The eigengene subspace, flag mean and flag median are subspace module representatives which capture more variance of the gene expression within a module. The module expression vector is a weighted centroid of the module which leverages the structure of the module gene co-expression network. We use these module representatives in Linde-Buzo-Gray clustering algorithms to refine WGCNA module membership. We evaluate these methodologies on two transcriptomics data sets. We find that most of our module refinement techniques improve upon the WGCNA modules by two statistics: (1) module classification between phenotype and (2) module biological significance according to Gene Ontology terms.

Modeling of adaptive immunity uncovers disease tolerance mechanisms.

When an organism is challenged with a pathogen a cascade of events unfolds. The innate immune system rapidly mounts a preliminary nonspecific defense, while the acquired immune system slowly develops microbe-killing specialists. These responses cause inflammation, and along with the pathogen cause direct and indirect tissue damage, which anti-inflammatory mediators seek to temper. This interplay of systems is credited for maintaining homeostasis but may produce unexpected results such as disease tolerance. Tolerance is characterized by the persistence of pathogen and damage mitigation, where the relevant mechanisms are poorly understood. In this work we develop an ordinary differential equations model of the immune response to infection in order to identify key components in tolerance. Bifurcation analysis uncovers health, immune- and pathogen-mediated death clinical outcomes dependent on pathogen growth rate. We demonstrate that decreasing the inflammatory response to damage and increasing the strength of the immune system gives rise to a region in which limit cycles, or periodic solutions, are the only biological trajectories. We then describe areas of parameter space corresponding to disease tolerance by varying immune cell decay, pathogen removal, and lymphocyte proliferation rates.

Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel.

BACKGROUND: Patients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships. AIM: We convened an international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients' and partners' sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship. METHODS: The guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995-2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR). OUTCOMES: Guidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel. RESULTS: The guidelines account for patients' cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship. CLINICAL IMPLICATIONS: The guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer. STRENGTHS & LIMITATIONS: The strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries. CONCLUSION: The guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research. Wittmann D, Mehta A, McCaughan E, et al. Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel. J Sex Med 2022;19:1655-1669.

The management of sexual dysfunction resulting from radiotherapy and androgen deprivation therapy to treat prostate cancer: A comparison of uro-oncology practice according to disease stage.

OBJECTIVES: To establish current uro-oncology practice in the management of sexual dysfunction (SD) following radiotherapy (RT) and/or androgen deprivation therapy (ADT) to treat prostate cancer. To identify differences in approach to the management of SD according to disease stage. SUBJECTS AND METHODS: A 14-question mixed methods survey was designed to assess the current UK practice. Closed- and open-ended questions were used to quantify results while allowing participants to expand on answers. The survey was distributed to members of the British Uro-Oncology Group at the 2019 annual meeting. RESULTS: Surveys were completed by 63 uro-oncologists attending the annual meeting of the British Uro-Oncology Group (response rate 66%). The major issue highlighted was a difference in approach to managing SD according to disease stage. More than half of the participants (56%) said 'advanced stage of disease' was a barrier to discussing SD. Clinicians were less likely to discuss SD, take baseline assessments, refer to a specialist clinic or offer rehabilitation when dealing with patients with advanced disease. Only a minority said that the management of SD was primarily their responsibility (11%). Nearly all clinicians (92%) had access to SD clinics; however, the majority of clinicians did not routinely refer patients. CONCLUSIONS: This study shows that men with advanced prostate cancer need better support in managing SD. Patients receiving long-term ADT are less likely to be offered any kind of help or intervention. Specific guidance on managing SD in this cohort may result in improvements in sexual function, emotional well-being, quality of life, mental health and confidence.

Efficacy, Use, and Acceptability of a Web-Based Self-management Intervention Designed to Maximize Sexual Well-being in Men Living With Prostate Cancer: Single-Arm Experimental Study.

BACKGROUND: Sexual dysfunction is a frequent side effect associated with different prostate cancer treatment approaches. It can have a substantial impact on men and their partners and is associated with increased psychological morbidity. Despite this, sexual concerns are often not adequately addressed in routine practice. Evidence-based web-based interventions have the potential to provide ongoing information and sexual well-being support throughout all stages of care. OBJECTIVE: The aim of this study is to examine the efficacy of a web-based self-management intervention designed to maximize sexual well-being in men living with prostate cancer and explore user perspectives on usability and acceptability. METHODS: We used a single-arm study design, and participants were provided with access to the 5-step intervention for a period of 3 months. The intervention content was tailored based on responses to brief screening questions on treatment type, relationship status, and sexual orientation. Efficacy was assessed by using two-tailed, paired sample t tests for comparing the mean differences between pre- and postintervention measurements for exploring the participants' self-reported knowledge and understanding, sexual satisfaction, and comfort in discussing sexual issues. Usability and acceptability were determined based on the program use data and a postintervention survey for exploring perceived usefulness. RESULTS: A total of 109 participants were recruited for this study. Significant postintervention improvements at follow-up were observed in the total scores (out of 20) from the survey (mean 12.23/20 points, SD 2.46 vs mean 13.62/20, SD 2.31; t88=9.570; P=.001) as well as in individual item scores on the extent to which the participants agreed that they had sufficient information to manage the impact that prostate cancer had on their sex life (mean 2.31/4 points, SD 0.86 vs mean 2.57/4, SD 0.85; t88=3.660; P=.001) and had the potential to have a satisfying sex life following treatment (mean 2.38/4 points, SD 0.79 vs mean 3.17/4, SD 0.78; t88=7.643; P=.001). The median number of intervention sessions was 3 (range 1-11), and intervention sessions had a median duration of 22 minutes (range 8-77). Acceptable usability scores were reported, with the highest result observed for the question on the extent to which the intervention provided relevant information. CONCLUSIONS: This study provides evidence on the efficacy of a tailored web-based intervention for maximizing sexual well-being in men living with prostate cancer. The results indicate that the intervention may improve one's self-perceived knowledge and understanding of how to manage sexual issues and increase self-efficacy or the belief that a satisfactory sex life could be achieved following treatment. The findings will be used to refine the intervention content before testing as part of a larger longitudinal study for examining its effectiveness.

Anti-Cancer Effects of Cyclic Peptide ALOS4 in a Human Melanoma Mouse Model.

We examined the effects of ALOS4, a cyclic peptide discovered previously by phage library selection against integrin αvß3, on a human melanoma (A375) xenograft model to determine its abilities as a potential anti-cancer agent. We found that ALOS4 promoted healthy weight gain in A375-engrafted nude mice and reduced melanoma tumor mass and volume. Despite these positive changes, examination of the tumor tissue did not indicate any significant effects on proliferation, mitotic index, tissue vascularization, or reduction of αSMA or Ki-67 tumor markers. Modulation in overall expression of critical downstream αvß3 integrin factors, such as FAK and Src, as well as reductions in gene expression of c-Fos and c-Jun transcription factors, indirectly confirmed our suspicions that ALOS4 is likely acting through an integrin-mediated pathway. Further, we found no overt formulation issues with ALOS4 regarding interaction with standard inert laboratory materials (polypropylene, borosilicate glass) or with pH and temperature stability under prolonged storage. Collectively, ALOS4 appears to be safe, chemically stable, and produces anti-cancer effects in a human xenograft model of melanoma. We believe these results suggest a role for ALOS4 in an integrin-mediated pathway in exerting its anti-cancer effects possibly through immune response modulation.

Biological Sex and IgE Sensitization Influence Severity of Depression and Cortisol Levels in Atopic Dermatitis.

BACKGROUND: Depression is a common comorbid condition with atopic dermatitis (AD), particularly during the active disease cycle. Controversial results regarding the contribution of biological sex, immunoglobulin E (IgE) sensitization, and cortisol on AD severity and comorbid depression justify further investigation. OBJECTIVE AND METHODS: To explore the influence of sex and IgE sensitization on biochemical and psychological parameters, and severity of AD, a case-control study of 105 volunteers (56 AD, 49 healthy controls (HC); 50 males, 55 females) was conducted over 10 weeks, starting at dermatological symptom onset. Disease severity, serum IgE, cortisol and testosterone levels, and depression scores were assessed at study baseline and after 10 weeks of conventional treatment. RESULTS: Dermatological severity differed among AD males by IgE sensitization and was elevated in males with extrinsic atopic dermatitis (EAD). Hamilton Depression Rating Scale (HAMD) scores were elevated in all patients at study baseline and improved with symptom reduction to HC levels, except female EAD. Severity of depression and dermatitis were correlated in EAD males at baseline and at week 10. Serum cortisol was elevated in male EAD at baseline, in contrast to males with intrinsic atopic dermatitis (IAD) at week 10. In addition, cortisol levels were found negatively correlated with SCORAD and HAMD scores in EAD males at week 10. CONCLUSION: Pathophysiological features of AD and depression are likely related to different inflammation-based effects and appear to be biological sex-dependent. Cortisol levels depend on biological sex and IgE sensitization in AD and increase in males with EAD at exacerbation and IAD males at resolution. Biological sex-related disease triggers, IgE sensitization, and cortisol levels are important for the understanding of the mechanisms underlying AD and comorbid depression.

Prescription switching: Rationales and risks.

BACKGROUND: Therapeutic drug switching is commonplace across a broad range of indications and, within a drug class, is often facilitated by the availability of multiple drugs considered equivalent. Such treatment changes are often considered to improve outcomes via better efficacy or fewer side effects, or to be more cost-effective. Drug switching can be both appropriate and beneficial for several reasons; however, switching can also be associated with negative consequences. AIM: To consider the impact of switching in two situations: the use of statins as a well-studied example of within-class drug switching, and gonadotropin-releasing hormone (GnRH)-targeting drug switching as an example of cross-class switching. RESULTS: With the example of statins, within-class switching may be justified to reduce side effects, although the decision to switch is often also driven by the lower cost of generic formulations. With the example of GnRH agonists/antagonists, switching often occurs without the realisation that these drugs belong to different classes, with potential clinical implications. CONCLUSION: Lessons emerging from these examples will help inform healthcare practitioners who may be considering switching drug prescriptions.

New tools for the visualization of biological pathways.

This paper presents several geometrically motivated techniques for the visualization of high-dimensional biological data sets. The Grassmann manifold provides a robust framework for measuring data similarity in a subspace context. Sparse radial basis function classification as a visualization technique leverages recent advances in radial basis function learning via convex optimization. In the spirit of deep belief networks, supervised centroid-encoding is proposed as a way to exploit class label information. These methods are compared to linear and nonlinear principal component analysis (autoencoders) in the context of data visualization; these approaches may perform poorly for visualization when the variance of the data is spread across more than three dimensions. In contrast, the proposed methods are shown to capture significant data structure in two or three dimensions, even when the information in the data lives in higher dimensional subspaces. To illustrate these ideas, the visualization techniques are applied to gene expression data sets that capture the host immune system's response to infection by the Ebola virus in non-human primate and collaborative cross mouse.

HIV and HCV Epidemics: Lessons for Lawyers and Policymakers.

This article arises from a summary offered by the author to an international conference held at Wilton Park, England, on policy and action necessary to respond effectively to the epidemics caused by the Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). The article begins with 10 lessons derived by the author from his involvement with the HIV epidemic since 1989. These lessons compare and contrast the features of the HIV/AIDS epidemic and those of the HCV epidemic. Although there is overlap between the persons exposed to the respective viruses, HCV is different in two important respects. First, unlike HIV, Hepatitis C can be cured with available but usually expensive therapy. No cure or vaccine has yet been developed for HIV. Second, HIV resulted in a major international response stimulated by engagement with people living with that virus. HCV attracts event greater stigma. Because of national and international treaty law and national criminal law, stigma is even greater in the case of HCV. The article identifies 10 lessons to be learned, including the need for reform of national and international drug control law. It concludes with a list of urgent initiatives that are needed globally to combat the growing but treatable HCV epidemic.

Erectile dysfunction and testosterone deficiency as cardiovascular risk factors?

Graham Jackson introduced the concept that erectile dysfunction was a marker for undiagnosed cardiovascular disease and future events. Unfortunately this had had modest impact on CVD management as ED is not incorporated into current risk calculators. In this paper, we examine recent evidence as to whether ED should be upgraded to a risk factor, especially with the high predictive value in younger men. In the Princeton 3 guidelines, he recognised the important impact of testosterone deficiency (TD) on all-cause and cardiovascular mortality. Recent evidence suggests that testosterone therapy to target levels and for sufficient duration, reduces cardiovascular events. In this paper, we also produce a case for testosterone deficiency to be considered as an independent risk factor. The evidence for inclusion of both ED and TD may now be stronger than accepted risk factors and have the advantages of being easily assessed, being quantitative, symptomatic and clinically relevant, especially in younger men.

British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice.

BACKGROUND: Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. AIM: To review the available literature on TD and provide evidence-based statements for UK clinical practice. METHODS: Evidence was derived from Medline, EMBASE, and Cochrane searches on hypogonadism, testosterone (T) therapy, and cardiovascular safety from May 2005 to May 2015. Further searches continued until May 2017. OUTCOMES: To provide a guideline on diagnosing and managing TD, with levels of evidence and grades of recommendation, based on a critical review of the literature and consensus of the British Society of Sexual Medicine panel. RESULTS: 25 statements are provided, relating to 5 key areas: screening, diagnosis, initiating T therapy, benefits and risks of T therapy, and follow-up. 7 statements are supported by level 1, 8 by level 2, 5 by level 3, and 5 by level 4 evidence. CLINICAL IMPLICATIONS: To help guide UK practitioners on effectively diagnosing and managing primary and age-related TD. STRENGTHS AND LIMITATIONS: A large amount of literature was carefully sourced and reviewed, presenting the best evidence available at the time. However, some statements provided are based on poor-quality evidence. This is a rapidly evolving area of research and recommendations are subject to change. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions and take personal values and preferences and individual circumstances into account. Many issues remain controversial, but in the meantime, clinicians need to manage patient needs and clinical expectations armed with the best clinical evidence and the multidisciplinary expert opinion available. CONCLUSION: Improving the diagnosis and management of TD in adult men should provide somatic, sexual, and psychological benefits and subsequent improvements in quality of life. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. J Sex Med 2017;14:1504-1523.

UK policy statements on testosterone deficiency.

To address widespread media and scientific concerns over the appropriate treatment of TDS with Testosterone Therapy (T Therapy), the Executive Committee of the British Society for Sexual Medicine developed eight consensus statements, based on current scientific evidence to address these controversial issues. These statements were in no-way designed to replace the published evidence-based guidelines on the subject developed by various professional organisations, but to provide specific answers to several current controversial issues. This review examined evidence from Medline, EMBASE and Cochrane searches on HG, T Therapy and cardiovascular safety from May 2005 to May 2015, which revealed 1714 articles, with 52 clinical trials and 32 placebo-controlled randomised controlled trials. The task force developed the following eight key statements.

Oestrogens and overactive bladder.

Estrogens are known to have a major role in the function of the lower urinary tract although the role of exogenous estrogen replacement therapy in the management of women with lower urinary tract dysfunction remains controversial. Whilst for many years systemic and vaginal estrogen therapy was felt to be beneficial in the treatment of lower urinary and genital tract symptoms this evidence has recently been challenged by large epidemiological studies investigating the use of systemic hormone replacement therapy. Consequently the role of estrogen in the management of postmenopausal women with Overactive Bladder (OAB) remains uncertain. In addition the evidence base regarding the use of exogenous estrogen therapy has changed significantly over the last decade and has led to a major changes in current clinical practice. The aim of this article is to review the evidence for the role of estrogen therapy in the management of OAB focusing on current knowledge with regard to both systemic and local estrogen therapy as well as investigating the emerging role of combination therapy with antimuscarinic agents.

Simvastatin improves the sexual health-related quality of life in men aged 40 years and over with erectile dysfunction: additional data from the erectile dysfunction and statin trial.

BACKGROUND: Erectile dysfunction is prevalent in men over 40 years, affecting their quality of life and that of their partners. The aims of this study were:a) To evaluate the internal reliability of the male erectile dysfunction specific quality of life (MED-QoL) scale and explore its factor structure.b) To evaluate the effect of simvastatin on subscales of the MED-QoL in men over forty years with erectile dysfunction. METHODS: This is a double blind randomised controlled trial of 40 mg simvastatin or placebo given once daily for six months to men over forty years with untreated erectile dysfunction, who were not at high cardiovascular risk and were not on anti-hypertensive or lipid-lowering medication. 173 eligible men were recruited from 10 general practices in East of England. Data were collected at two points over 30 weeks.We report on the factor structure of MED-QoL, the internal reliability of the scale and the derived subscales, and the effect of simvastatin on MED-QoL subscales. RESULTS: An initial analysis of the MED-QoL items suggested that a number of items should be removed (MED-QoL-R). Exploratory factor analysis identified three subscales within the MED-QoL-R which accounted for 96% of the variance, related to feelings of Control, initiating Intimacy, and Emotional response to erectile dysfunction. The alpha value for the revised scale (MED-Qol-R) was >0.95 and exceeded .82 for each subscale. Regression analysis showed that patients in the placebo group experienced a significantly reduced feeling of Control over erectile dysfunction than those in the statin group. Those in the placebo group had significantly lower Emotional response than those in the statin group at the close of trial, but there was no significant treatment effect on Intimacy. CONCLUSIONS: Our revised MED-QoL-R identified three subscales. Secondary analysis showed a significant improvement in sexual health related quality of life, specifically in relation to perception of control and emotional health in men with untreated erectile dysfunction given 40 mg simvastatin for six months. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66772971.

Iterative feature removal yields highly discriminative pathways.

BACKGROUND: We introduce Iterative Feature Removal (IFR) as an unbiased approach for selecting features with diagnostic capacity from large data sets. The algorithm is based on recently developed tools in machine learning that are driven by sparse feature selection goals. When applied to genomic data, our method is designed to identify genes that can provide deeper insight into complex interactions while remaining directly connected to diagnostic utility. We contrast this approach with the search for a minimal best set of discriminative genes, which can provide only an incomplete picture of the biological complexity. RESULTS: Microarray data sets typically contain far more features (genes) than samples. For this type of data, we demonstrate that there are many equivalently-predictive subsets of genes. We iteratively train a classifier using features identified via a sparse support vector machine. At each iteration, we remove all the features that were previously selected. We found that we could iterate many times before a sustained drop in accuracy occurs, with each iteration removing approximately 30 genes from consideration. The classification accuracy on test data remains essentially flat even as hundreds of top-genes are removed.Our method identifies sets of genes that are highly predictive, even when comprised of genes that individually are not. Through automated and manual analysis of the selected genes, we demonstrate that the selected features expose relevant pathways that other approaches would have missed. CONCLUSIONS: Our results challenge the paradigm of using feature selection techniques to design parsimonious classifiers from microarray and similar high-dimensional, small-sample-size data sets. The fact that there are many subsets of genes that work equally well to classify the data provides a strong counter-result to the notion that there is a small number of "top genes" that should be used to build classifiers. In our results, the best classifiers were formed using genes with limited univariate power, thus illustrating that deeper mining of features using multivariate techniques is important.