Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Leadership as purpose: Exploring the role of purpose in leadership practice

This article initiates a long overdue discussion regarding purpose within leadership, an integral yet often taken-for-granted and subsumed function of leadership. Specifically, the article problematicizes the manifestation of purpose in everyday organizational leadership practices through the work of the moral philosopher Alasdair MacIntyre. The article argues that purpose requires greater attention if it is to become manifest in both the corporate and the societal orientations of leaders in organizations. In support of this argument we identify the implications of singularly focusing upon corporate purpose to the exclusion of societal purpose against the backdrop of the credit crunch aftermath. The article develops a theoretical argument that, when conceptualized as a process of sensemaking, leadership can provide an opportunity for notions of societal purpose to come to the fore in countervailing balance with corporate purposes. We conclude by suggesting a research agenda centred on further explicating and developing the idea of leadership as purpose

The financial losses from the migration of nurses from Malawi

<p>Abstract</p> <p>Background</p> <p>The migration of health professionals trained in Africa to developed nations has compromised health systems in the African region. The financial losses from the investment in training due to the migration from the developing nations are hardly known.</p> <p>Methods</p> <p>The cost of training a health professional was estimated by including fees for primary, secondary and tertiary education. Accepted derivation of formula as used in economic analysis was used to estimate the lost investment.</p> <p>Results</p> <p>The total cost of training an enrolled nurse-midwife from primary school through nurse-midwifery training in Malawi was estimated as US$9,329.53. For a degree nurse-midwife, the total cost was US$ 31,726.26. For each enrolled nurse-midwife that migrates out of Malawi, the country loses between US$71,081.76 and US$ 7.5 million at bank interest rates of 7% and 25% per annum for 30 years respectively. For a degree nurse-midwife, the lost investment ranges from US$241,508 to US$ 25.6 million at 7% and 25% interest rate per annum for 30 years respectively.</p> <p>Conclusion</p> <p>Developing countries are losing significant amounts of money through lost investment of health care professionals who emigrate. There is need to quantify the amount of remittances that developing nations get in return from those who migrate.</p

Understanding suicidal ideation in psychosis: findings from the Psychological Prevention of Relapse in Psychosis (PRP) Trial

Objective: To examine the clinically important phenomenon of suicidal ideation in psychosis in relation to affective processes and the multidimensional nature of hallucinations and delusions.Method: In a cross-sectional study of 290 individuals with psychosis, the associations between level of suicidal ideation, affective processes, positive symptoms, clinical and demographic variables were examined.Results: Forty-one per cent of participants expressed current suicidal ideation. Suicidal ideation was associated with depressed mood, anxiety, low self-esteem, negative illness perceptions, negative evaluative beliefs about the self and others and daily alcohol consumption. Frequency of auditory hallucinations and preoccupation with delusions were not associated with suicidal ideation; however, positive symptom distress did relate to suicidal thoughts.Conclusion: Affective dysfunction, including distress in response to hallucinations and delusions, was a key factor associated with suicidal ideation in individuals with psychotic relapse. Suicidal ideation in psychosis appears to be an understandable, mood-driven process, rather than being of irrational or 'psychotic' origin