Small molecule and peptide inhibitors of the pro-survival protein Mcl-1

The ability of protein–protein interactions to regulate cellular processes in both beneficial and detrimental ways has made them obvious drug targets. The Bcl-2 family of proteins undergo a series of protein–protein interactions which regulate the intrinsic cell-death pathway. The pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-xL, and Mcl-1, are commonly overexpressed in a number of human cancers. Effective modulators of members of the Bcl-2 family have been developed and are undergoing clinical trials, but the efficient modulation of Mcl-1 is still not represented in the clinic. In addition, Mcl-1 is a major cause of resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. Subsequently, the inhibition of Mcl-1 has become of significant interest to the scientific community. This review covers the progress made to date in modulating the activity of Mcl-1, by both stapled peptides and small molecules. The development of peptides as drug candidates, and the advancement of experimental and computational techniques used to discover small molecules are also highlighted

A public health perspective of the higher education experiences of women studying nursing: A hermeneutic inquiry into commencement and progression

While student retention is a central goal across higher education, the projected shortage in the Australian health workforce has intensified its importance to undergraduate nursing. Nursing degrees attract a higher proportion of mature-age women students than ever before. More are therefore beginning university at life stage characterised by marriage (or co-habitation) and traditional family structures. Nursing retention strategies require an understanding of the unique university experiences of these women, however, this is missing in the nursing literature. This study is the first to explore the experiences of these women students, doing so from the perspective of Bachelor of Science (Nursing) undergraduates in Western Australia. The study was qualitative, guided by Gadamer’s hermeneutic philosophy and informed by feminist research principles. A public health approach considered the interdependent influences of structure and agency on the student experience, through the lens of social justice, equity and empowerment. Twenty-nine women participated in in-depth interviews during the second and third year of their degree. This two phase approach, unusual in the nursing literature, created understanding of the student experience across the degree journey. An analysis of the participants’ sociodemographic data revealed all were non-traditional students. The majority were first generation, a group known to face disadvantage at university. Interpreting their university experiences through the lens of student capital revealed a complex picture of influences on the student experience. Limited reserves of cultural and social capital in the form traditionally recognised as crucial to student success (Bourdieu, 1986) created significant barriers to commencement and progression. The differences in women’s expectations of the degree, compared to the reality they encountered, presented further challenges. Although the university offered extracurricular centralised support services, the traditional ideas of gender within the intimate relationship reduced participants’ capacity to engage with them. Participants described how their multiple responsibilities outside the university left them struggling to meet the demands of the degree. Their partners’ consistent unwillingness to offer help, combined with the rigid organisation of the curriculum, led many to compromise their achievement expectations to remain at university. Partners with no experience of university were described as emotionally unsupportive and resentful of the degree’s time demands. Tension within these relationships was often high; eight women experienced separation. The university’s inflexible response during these intensely difficult periods presented a further challenge. The women’s capacity to continue can be partly attributed to dimensions of student capital previously unrecognised in the nursing literature. Importantly, the availability of these dimensions fluctuated throughout the degree. The ongoing issues of inequity described in this study suggest that social justice, a central goal of higher education, was not fully available to these participants. To counter this, the university must have an understanding of a woman’s lived reality outside the university, and its influence on her experiences within. An understanding of gender as a determinant of educational opportunity is particularly important. The multiple situations of dissonance women may encounter at university and at home, also requires consideration. A strengths-based approach is also important, which recognises and nurtures the diverse student attributes that support nurse student progression. Nurse education may achieve this change through the conscious adoption of a social justice approach. A personalised and responsive model is proposed to translate this into practice in the university and healthcare settings

Frequency-dependent and correlational selection pressures have conflicting consequences for assortative mating in a color-polymorphic lizard, Uta stansburiana

Acknowledgments We would like to thank the numerous undergraduate researchers involved with this project for their invaluable assistance in lizard rearing and data collection. We also thank D. Haisten, A. Runemark, Y. Takahashi, and M. Verzijden for insightful comments on the manuscript. This project was funded by National Science Foundation DEBOS-15973 to A.G.M. and B.R.S.Peer reviewedPublisher PD

Do patients who die from an alcohol-related condition ‘drift’ into areas of greater deprivation? Alcohol-related mortality and health selection theory in Scotland

Background: Health selection has been proposed to explain the patterning of alcohol-related mortality by area deprivation. This study investigated whether persons who die from alcohol-related conditions are more likely to experience social drift than those who die from other causes. Methods: Deaths recorded in Scotland (2013, >21 years) were coded as ‘alcohol-related’ or ‘other’ and by deprivation decile of residence at death. Acute hospital admissions data from 1996 to 2012 were used to provide premortality deprivation data. χ² tests estimated the difference between observed and expected alcohol-related deaths by first Scottish Index of Multiple Deprivation (SIMD) decile and type of death. Logistic regression models were fitted using type of death as the outcome of interest and change in SIMD decile as the exposure of interest. Results: Of 47 012 deaths, 1458 were alcohol-related. Upward and downward mobility was observed for both types of death. An estimated 31 more deaths than expected were classified ‘alcohol-related’ among cases whose deprivation score decreased, while 204 more deaths than expected were classified ‘alcohol-related’ among cases whose initial deprivation ranking was in the four most deprived deciles. Becoming more deprived and first deprivation category were both associated with increased odds of type of death being alcohol-related after adjusting for confounders. Conclusion: This study suggests that health selection appears to contribute less to the deprivation gradient in alcohol-related mortality in Scotland than an individual’s initial area deprivation category

Repositioning Manhattan office buildings

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 1989.Includes bibliographical references (leaves 129-131).by Lesley D. Cummin and Andrew H. Popik.M.S

Economic evaluation of a group-based exercise program for falls prevention among the older community-dwelling population

BACKGROUND: Falls among older people are of growing concern globally. Implementing cost-effective strategies for their prevention is of utmost importance given the ageing population and associated potential for increased costs of fall-related injury over the next decades. The purpose of this study was to undertake a cost-utility analysis and secondary cost-effectiveness analysis from a healthcare system perspective, of a group-based exercise program compared to routine care for falls prevention in an older community-dwelling population. METHODS: A decision analysis using a decision tree model was based on the results of a previously published randomised controlled trial with a community-dwelling population aged over 70. Measures of falls, fall-related injuries and resource use were directly obtained from trial data and supplemented by literature-based utility measures. A sub-group analysis was performed of women only. Cost estimates are reported in 2010 British Pound Sterling (GBP). RESULTS: The ICER of GBP£51,483 per QALY for the base case analysis was well above the accepted cost-effectiveness threshold of GBP£20,000 to £30,000 per QALY, but in a sensitivity analysis with minimised program implementation the incremental cost reached GBP£25,678 per QALY. The ICER value at 95% confidence in the base case analysis was GBP£99,664 per QALY and GBP£50,549 per QALY in the lower cost analysis. Males had a 44% lower injury rate if they fell, compared to females resulting in a more favourable ICER for the women only analysis. For women only the ICER was GBP£22,986 per QALY in the base case and was below the cost-effectiveness threshold for all other variations of program implementation. The ICER value at 95% confidence was GBP£48,212 in the women only base case analysis and GBP£23,645 in the lower cost analysis. The base case incremental cost per fall averted was GBP£652 (GBP£616 for women only). A threshold analysis indicates that this exercise program cannot realistically break even. CONCLUSIONS: The results suggest that this exercise program is cost-effective for women only. There is no evidence to support its cost-effectiveness in a group of mixed gender unless the costs of program implementation are minimal. Conservative assumptions may have underestimated the true cost-effectiveness of the program

A peer-observation initiative to enhance student engagement in the synchronous virtual classroom: A case study of a COVID-19 mandated move to online learning

The global COVID-19 pandemic has necessitated a rapid shift to online delivery in higher education. This learning and teaching environment is associated with reduced student engagement, a crucial prerequisite of student satisfaction, retention and success. This paper presents a case study that explored student engagement in the synchronous virtual learning environment, during the mandatory move to exclusive online learning in Australian higher education in April to June 2020. Three university instructors used the Teaching and Learning Circles Model to observe a series of their peers\u27 synchronous virtual classrooms, from which they reflected on ways to enhance their own practice. The findings demonstrate how student engagement in these classrooms can be strengthened across the four constructs of Kahu and Nelson’s (2018) engagement conceptual framework: belonging; emotional response; wellbeing and self-efficacy. The case study also reveals limitations of the synchronous virtual environment as a means of supporting student engagement in the online learning and teaching environment, and proposes ways to address them. Against emerging reports of increased mental health issues among isolated university students during the current pandemic, the case study\u27s recommendations to improve student wellbeing and belonging are particularly salient. This article also highlights the usefulness of the Teaching and Learning Circles Model of peer observation as a way to guide its participants\u27 reflections on their own practice, support their collegiality with academic peers and build their confidence and competence in the synchronous virtual learning environment

Production Equations for Tower Yarding in Coastal British Columbia

Cable yarding is an important means for primary extraction of timber on steep slopes and/or sensitive soils throughout the world. Comprehensive planning for cable yarding requires detailed production and cost estimates which can be made using production equations. Such equations can come from the literature or independent time studies. Both options depend on previously published studies either for direct use or to improve study design. An elemental time study was designed and used in an investigation of tower yarding in coastal British Columbia. A comprehensive statistical analysis was applied to the data including stratification, fitting regression equations, and hypothesis testing. The findings include a library of production equations applicable over a wide range of operating conditions

The knowledge, attitudes and beliefs of midwives on the vaccination coverage rates in Perth’s Aboriginal children

Background: Midwives are well placed to promote vaccination awareness throughout a women’s pregnancy and strengthen childhood vaccination demand following hospital discharge. In Perth, Western Australia, Aboriginal children experience some of the lowest vaccination coverage rates across the nation. To identify factors preventing greater vaccination uptake amongst the target population, a theory-based study was conducted with midwives across two Perth maternity hospitals to explore behavioural attributes, knowledge, attitudes and beliefs surrounding vaccination provision and the vaccines administered to Aboriginal children. Methods: A purpose-designed questionnaire was distributed to midwives working in two Perth public maternity hospitals. The proximal constructs of The Theory of Planned Behavior were used to frame the questionnaire to enable the barriers to greater vaccination coverage to be identified and behaviourally situated. Descriptive statistics described the demographics of the study sample. Chi-square and the Fisher’s exact test were used to identify associations between midwife characteristics and awareness of the coverage rates. Significance was set at α = 0.05. Results: Of the 58 midwives who completed the study questionnaire, 77.2% were unaware of the sub-optimal vaccination coverage in Perth’s Aboriginal children. Level of education (p = 0.53) and years worked as a practising midwife (p = 0.47) were not found to be associated with an awareness of the coverage rates. Approximately, 50% of midwives reported some concern over the efficacy of childhood vaccines, 44.4% did not feel confident with their knowledge of vaccines, while 33.3% do not routinely discuss childhood vaccinations with parents prior to hospital discharge. Conclusions: Key findings in the study identified that a range of educational, leadership and system-based issues are affecting midwives’ capacity to play a more substantial role in influencing vaccination coverage in Perth’s Aboriginal children