Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren’s Disease

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease

Mammary stem cells have myoepithelial cell properties.

Contractile myoepithelial cells dominate the basal layer of the mammary epithelium and are considered to be differentiated cells. However, we observe that up to 54% of single basal cells can form colonies when seeded into adherent culture in the presence of agents that disrupt actin-myosin interactions, and on average, 65% of the single-cell-derived basal colonies can repopulate a mammary gland when transplanted in vivo. This indicates that a high proportion of basal myoepithelial cells can give rise to a mammary repopulating unit (MRU). We demonstrate that myoepithelial cells, flow-sorted using two independent myoepithelial-specific reporter strategies, have MRU capacity. Using an inducible lineage-tracing approach we follow the progeny of myoepithelial cells that express α-smooth muscle actin and show that they function as long-lived lineage-restricted stem cells in the virgin state and during pregnancy.This work was funded by Cancer Research UK, Breast Cancer Campaign, the University of Cambridge, Hutchison Whampoa Limited, La Ligue Nationale Contre le Cancer (Equipe Labelisée 2013) and a grant from Agence Nationale de la Recherche ANR- 08-BLAN-0078-01 to M.A.G.This is the author accepted manuscript. The final version is available from Nature at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3025.html

Phenotypic Complexity, Measurement Bias, and Poor Phenotypic Resolution Contribute to the Missing Heritability Problem in Genetic Association Studies

Background The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this ‘missing heritability’ have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms. Methodology We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants. Conclusion We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20-99

Reliability and validity of the ESRD Symptom Checklist – Transplantation Module in Norwegian kidney transplant recipients

BACKGROUND: The aim of the study was to validate the Norwegian version of a self-administered 43-item questionnaire designed to assess quality of life in kidney transplant recipients, the End-Stage Renal Disease Symptom Checklist – Transplantation Module (ESRD-SCL). METHODS: In total, 53 kidney transplant recipients from one university-affiliated hospital responded to a questionnaire including the ESRD-SCL and the Short Form 36 (SF-36). We assessed internal consistency reliability and test-retest reliability with 2 weeks between assessments. Construct validity was assessed by correlations of the ESRD-SCL subscales with related and unrelated SF-36 scales, demographic, and clinical characteristics. RESULTS: Subscales of the ESRD-SCL showed good internal consistency reliability (Cronbach's = 0.72–0.81) and for the aggregate total scale α was 0.94. Test-retest reliability median 14 days apart was excellent with intraclass coefficients ranging from 0.87 to 0.95. The pattern of correlations of the ESRD-SCL scales with related and unrelated scales SF-36 scales and demographic and clinical characteristics gave support to the construct validity of the ESRD-SCL. CONCLUSION: The Norwegian translation of the ESRD-SCL showed satisfactory internal consistency reliability, test-retest reliability and construct validity, at the level of the original German version

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820)

Encouraging female entrepreneurship in Jordan: environmental factors, obstacles and challenges

The number of female entrepreneurs and their contribution to the economy is steadily rising. Yet research suggests that female entrepreneurs face more challenges and barriers than their male counterparts. This is expected to be even more prevalent in Islamic contexts, which are characterised by conservative and patriarchal societies. In this research, 254 female business students from a private and a public university responded to a questionnaire that gauges their perceptions about potential barriers to entrepreneurship in Jordan and whether the business education they are receiving helps to prepare them for future entrepreneurial activity. Our results help to form a basis on which a deeper understanding of the phenomena can be achieved through more in depth future research. Among the main environmental factors that worry potential female entrepreneurs are the weakness of Jordanian economy, lack of finance, fear of risk, gender inequality and inability to maintain a work and private life balance. Our results also show that students are really not aware of the opportunities available to them and are unable to make a proper assessment. We call on both universities and the Jordanian government to put more emphasis on practical entrepreneurial education and encouraging women to play a much more active role within the workforce

Locally advanced and recurrent cancer

A successful treatment of locally advanced and recurrent rectal cancer is based on the responsibility of the surgeon to perform a radical resection. Planning of treatment starts with imaging with a pelvic MRI and a CT scan of chest and the abdomen. Neoadjuvant chemoradiation is given to achieve downstaging and downsizing. After a waiting period of at least 6 weeks, a total mesorectal excision is performed with often an extra-anatomical extension based on the initial imaging. Reconstruction using several types of pedicled flaps is often necessary to close the defect of the pelvic floor.</p

The temporal reliability of serum estrogens, progesterone, gonadotropins, SHBG and urinary estrogen and progesterone metabolites in premenopausal women

BACKGROUND: There is little existing research to guide researchers in estimating the minimum number of measurement occasions required to obtain reliable estimates of serum estrogens, progesterone, gonadotropins, sex hormone-binding globulin (SHBG), and urinary estrogen and progesterone metabolites in premenopausal women. METHODS: Using data from a longitudinal study of 34 women with a mean age of 42.3 years (SD = 2.6), we calculated the minimum number of measurement occasions required to obtain reliable estimates of 12 analytes (8 in blood, 4 in urine). Five samples were obtained over 1 year: at baseline, and after 1, 3, 6, and 12 months. We also calculated the percent of true variance accounted for by a single measurement and intraclass correlation coefficients (ICC) between measurement occasions. RESULTS: Only 2 of the 12 analytes we examined, SHBG and estrone sulfate (E(1)S), could be adequately estimated by a single measurement using a minimum reliability standard of having the potential to account for 64% of true variance. Other analytes required from 2 to 12 occasions to account for 81% of the true variance, and 2 to 5 occasions to account for 64% of true variance. ICCs ranged from 0.33 for estradiol (E(2)) to 0.88 for SHBG. Percent of true variance accounted for by single measurements ranged from 29% for luteinizing hormone (LH) to 92% for SHBG. CONCLUSIONS: Experimental designs that take the natural variability of these analytes into account by obtaining measurements on a sufficient number of occasions will be rewarded with increased power and accuracy

Dominance, reproductive behaviours and female mate choice in sterilised versus non-sterilised invasive male crayfish

© 2020, The Author(s). Many methods of controlling invasive crayfishes have limited success because they fail to target all life stages of the population, notably by capturing only large adults that can result in increased juvenile recruitment by removing intraspecific predation. An alternative approach uses the sterile male release technique that involves the mass release of sterile males into the environment, which then mate with fertile females, resulting in unfertilised eggs and, ultimately, reduced juvenile recruitment. This does, however, rely on the sterilised males exhibiting behaviours similar to non-sterilised (entire) males and remaining attractive to females during mate choice. Post-copulatory male guarding behaviour and female promiscuity might also be affected by male sterilisation. To test for the presence of normal reproductive behaviours in sterilised male American signal crayfish Pacifastacus leniusculus, a two-stage experiment examined how sterilisation affects female mate choice and promiscuity, male hierarchical status (relative dominance) and post-copulation guarding. Sterilised males showed similar reproductive behaviours to entire males and remained as attractive to females, with no differences in relative dominance. Post-copulation, guarding behaviours were also unaffected. Females did not display promiscuous behaviour and this was unaffected by whether males were entire or sterilised. The results demonstrated that sterilised males were equally as capable as entire males of achieving dominance and winning mates. In combination, these findings suggest that male sterilisation could be an effective control technique to help reduce juvenile recruitment in wild P. leniusculus populations by reducing reproductive success