Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

Background Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. Results Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. Conclusions Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

Current pre-hospital traumatic brain injury management in China

BACKGROUND Traumatic brain injury (TBI) is associated with mo st trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre- hospital service can signifi cantly reduce case-fata lity rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China. DATA SOURCES A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain hern iation was extracted from the identifi ed articles. RESULTS Of the 471 articles identified, 65 met the selecti on criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions. CONCLUSION Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China.

When coroners care too much: Therapeutic jurisprudence and suicide findings

In common law countries such as England and Australia, violent and otherwise unnatural deaths are investigated by coroners who make findings as to the “manner of death”. This includes determining whether the deceased person intentionally caused their own death. Previous research (Tait and Carpenter 2013a, 2013b, 2014) has suggested that coroners are reluctant to reach such determinations, citing the stigma of suicide and a need for sensitivity to grieving and traumatized families. Based on interviews with both English and Australian coroners, this paper explores whether an ‘ethic of care’ evident in English and Australian coronial suicide determinations, can be understood as an application of the ‘practices and techniques’ of therapeutic jurisprudence. Based on the ways in which coroners position the law as a potential therapeutic agent, we investigate how they understand their role and position as legal actors, and the effects of their decision making in the context of suspected suicides.

Estimating the burden of disease attributable to childhood and maternal undernutrition in South Africa in 2000

OBJECTIVES To estimate the disease burden attributable to being underweight as an indicator of undernutrition in children under 5 years of age and in pregnant women for the year 2000. DESIGN World Health Organization comparative risk assessment (CRA) methodology was followed. The 1999 National Food Consumption Survey prevalence of underweight classified in three low weight-for-age categories was compared with standard growth charts to estimate population-attributable fractions for mortality and morbidity outcomes, based on increased risk for each category and applied to revised burden of disease estimates for South Africa in 2000. Maternal underweight, leading to an increased risk of intra-uterine growth retardation and further risk of low birth weight (LBW), was also assessed using the approach adopted by the global assessment. Monte Carlo simulation-modeling techniques were used for the uncertainty analysis. SETTING South Africa. SUBJECTS Children under 5 years of age and pregnant women. OUTCOME MEASURES Mortality and disability-adjusted life years (DALYs) from protein- energy malnutrition and a fraction of those from diarrhoeal disease, pneumonia, malaria, other non- HIV/AIDS infectious and parasitic conditions in children aged 0 - 4 years, and LBW. RESULTS Among children under 5 years, 11.8% were underweight. In the same age group, 11,808 deaths (95% uncertainty interval 11,100 - 12,642) or 12.3% (95% uncertainty interval 11.5 - 13.1%) were attributable to being underweight. Protein-energy malnutrition contributed 44.7% and diarrhoeal disease 29.6% of the total attributable burden. Childhood and maternal underweight accounted for 2.7% (95% uncertainty interval 2.6 - 2.9%) of all DALYs in South Africa in 2000 and 10.8% (95% uncertainty interval 10.2 - 11.5%) of DALYs in children under 5. CONCLUSIONS The study shows that reduction of the occurrence of underweight would have a substantial impact on child mortality, and also highlights the need to monitor this important indicator of child health.

Estimating the burden of disease attributable to diabetes in South Africa in 2000

OBJECTIVES To estimate the burden of disease attributable to diabetes by sex and age group in South Africa in 2000. DESIGN The framework adopted for the most recent World Health Organization comparative risk assessment (CRA) methodology was followed. Small community studies used to derive the prevalence of diabetes by population group were weighted proportionately for a national estimate. Population-attributable fractions were calculated and applied to revised burden of disease estimates. Monte Carlo simulation-modelling techniques were used for uncertainty analysis. SETTING South Africa. SUBJECTS Adults 30 years and older. OUTCOME MEASURES Mortality and disability-adjusted life years (DALYs) for ischaemic heart disease (IHD), stroke, hypertensive disease and renal failure. RESULTS Of South Africans aged >or= 30 years, 5.5% had diabetes which increased with age. Overall, about 14% of IHD, 10% of stroke, 12% of hypertensive disease and 12% of renal disease burden in adult males and females (30+ years) were attributable to diabetes. Diabetes was estimated to have caused 22,412 (95% uncertainty interval 20,755 - 24,872) or 4.3% (95% uncertainty interval 4.0 - 4.8%) of all deaths in South Africa in 2000. Since most of these occurred in middle or old age, the loss of healthy life years comprises a smaller proportion of the total 258,028 DALYs (95% uncertainty interval 236,856 - 290,849) in South Africa in 2000, accounting for 1.6% (95% uncertainty interval 1.5 - 1.8%) of the total burden. CONCLUSIONS Diabetes is an important direct and indirect cause of burden in South Africa. Primary prevention of the disease through multi-level interventions and improved management at primary health care level are needed.

Estimating the burden of disease attributable to iron deficiency anaemia in South Africa in 2000

OBJECTIVES To estimate the extent of iron deficiency anaemia (IDA) among children aged 0 - 4 years and pregnant women aged 15 - 49 years, and the burden of disease attributed to IDA in South Africa in 2000. DESIGN The comparative risk assessment (CRA) methodology of the World Health Organization (WHO) was followed using local prevalence and burden estimates. IDA prevalence came from re-analysis of the South African Vitamin A Consultative Group study in the case of the children, and from a pooled estimate from several studies in the case of the pregnant women (haemoglobin level < 11 g/dl and ferritin level < 12 microg/l). Monte Carlo simulation-modelling was used for the uncertainty analysis. SETTING South Africa. SUBJECTS Children under 5 years and pregnant women 15 - 49 years. OUTCOME MEASURES Direct sequelae of IDA, maternal and perinatal deaths and disability-adjusted life years (DALYs) from mild mental disability related to IDA. Results. It is estimated that 5.1% of children and 9 - 12% of pregnant women had IDA and that about 7.3% of perinatal deaths and 4.9% of maternal deaths were attributed to IDA in 2000. Overall, about 174,976 (95% uncertainty interval 150,344 - 203,961) healthy years of life lost (YLLs), or between 0.9% and 1.3% of all DALYs in South Africa in 2000, were attributable to IDA. CONCLUSIONS This first study in South Africa to quantify the burden from IDA suggests that it is a less serious public health problem in South Africa than in many other developing countries. Nevertheless, this burden is preventable, and the study highlights the need to disseminate the food-based dietary guidelines formulated by the National Department of Health to people who need them and to monitor the impact of the food fortification programme.

Empirical reference points for Bernstein’s model of pedagogic rights: Recontextualising the reconciliation agenda to Australian schooling

In this chapter we use Bernstein’s (2000) model of pedagogic rights to examine the learning experiences for non-Indigenous teachers in two reconciliation projects. In the context within which we write, reconciliation is the process of establishing a culture of mutual respect between Aboriginal and Torres Strait Islander peoples and non-Indigenous Australians. In 1991, the Royal Commission into Aboriginal Deaths in Custody linked the continuation of racism in Australian society to the weak coverage of Aboriginal and Torres Strait Islander content in the school curriculum (Reconciliation Australia 2010). Nearly two decades later, the Melbourne Declaration on Educational Goals for Young Australians issued by the council of Federal, State and Territory Ministers of Education proclaimed that curriculum should enable all students to ‘understand and acknowledge the value of Indigenous cultures and possess the knowledge, skills and understanding to contribute to, and benefit from reconciliation between Indigenous and non-Indigenous Australians’ (MCEETYA 2008, 9). Education holds out promise not only of better life chances for Indigenous young people, but also of replacing myths with understanding and tackling prejudice and racism within the non-Indigenous population. Bernstein’s (2000) model of pedagogic rights promises some purchase on this pedagogic work by providing concepts for looking systematically at the participation of non-Indigenous teachers in education. As observed by Frandji and Vitale (Chapter 2, this volume), the model is not sufficient to achieve a democratic reality, ‘but simply provides a basis for problematizing reality and considering possibilities’.

Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Pull-through failure tests of thin steel roof battens under wind uplift load

Thin profiled steel roof sheeting and battens are increasingly used in the construction of roofing systems of residential, commercial, industrial and farm buildings in Australia. The critical load combination of external wind suction and internal wind pressures that occur during high wind events such as thunderstorms and tropical cylcones often dislocate the roofing systems partially or even completely due to premature roof connection failures. Past wind damage investigations have shown that roof sheeting failures occured at their screw connections to battens. In most of these cases, the screw fastener head pulled through the thin roof sheeting whilst the screw fasteners also pulled out from the battens. Research studis undertaken on the roof sheeting to batten connection failures have improved this situation. However, the batten to rafter or truss connections have not been investigated adequately. Failure of these connections can cause the failure of the entire roof structure as observed during the recent high wind events. Therefore a detailed experimental study consisting of both small scale and full scale tests has been undertaken to investigate the steel roof batten pull-through failures in relation to many critical parameters such as steel batten geometry, thickness and grade, screw fastener head sizes and screw tightening. This paper presents the details of this experimental study and the pull-through failure load results obtained from them. Finally it discusses the development of suitable design rules that can be used to determine the pull-through connection capacities of thin steel roof battens under wind uplift loads.

Numerical modeling of thin steel roof battens under wind uplift loads

Extreme wind events such as tropical cyclones, tornadoes and storms are more likely to impact the Australian coastal regions due to possible climate changes. Such events can be extremely destructive to building structures, in particular, low-rise buildings with lightweight roofing systems that are commonly made of thin steel roofing sheets and battens. Large wind uplift loads that act on the roofs during high wind events often cause premature roof connection failures. Recent wind damage investigations have shown that roof failures have mostly occurred at the batten to rafter or truss screw connections. In most of these cases, the screw fastener heads pulled through the bottom flanges of thin steel roof battens. This roof connection failure is very critical as both roofing sheets and battens will be lost during the high wind events. Hence, a research study was conducted to investigate this critical pull-through failure using both experimental and numerical methods. This paper presents the details of numerical modeling and the results.

Fatal consequences: An analysis of the failed employee voice system at the Bundaberg Hospital

In this paper we discuss the failure of the employee voice system at the Bundaberg Base Hospital (BBH) in Australia. Surgeon Jayant Patel was arrested over the deaths of patients on whom he operated when he was the director of surgery at the hospital. Our interest is in the reasons the established employee voice mechanisms failed when employees attempted to bring serious issues to the attention of managers. Our data is based on an analysis of the sworn testimonies of participants who participated in two inquiries concerning these events. An analysis of the events with a particular focus on the failings of the voice system is presented. We ask the following: how and why did the voice systems in the case of the BBH fail?

DNA repair pathways and their therapeutic potential in lung cancer

Lung cancer is the leading cause of cancer-related mortality. According to WHO, 1.37 million deaths occur globally each year as a result of this disease. More than 70% of these cases are associated with prior tobacco consumption and/or cigarette smoking, suggesting a direct causal relationship. The development and progression of lung cancer and other malignancies involves the loss of genetic stability, resulting in acquisition of cumulative genetic changes; this affords the cell increased malignant potential. As such, an understanding of the mechanisms through which these events may occur will potentially allow for development of new anticancer therapies. This review will address the association between lung cancer and genetic instability, with a central focus on genetic mutations in the DNA damage repair pathways. In addition, we will discuss the potential clinical exploitation of these pathways, both in terms of biomarker staging, as well as through direct therapeutic targeting.

Eco-crime and freshwater

The unsustainable and exploitative use of one of the most important but scarce resources on the planet - freshwater - continues to create conflict and human dislocation on a grand scale. Instead of witnessing nation-states adopting more equitable and efficient conservation strategies, powerful corporations are permitted to privatise and monopolise diminishing water reservoirs based on flawed neo-liberal assumptions and market models of the ‘global good’. The commodification of water has enabled corporate monopolies and corrupt states to exploit a fundamental human right, and in the process have created new forms of criminality. In recent years, affluent industrialised nations have experienced violent rioting as protestors express opposition to government ‘freshwater taxes’ and to corporate investors seeking to privatise drinking water. These water conflicts have included unprecedented clashes with police and deaths of innocent civilians in South Africa (BBC News, 2014a); the United Nations intervention in Detroit USA after weeks of public protest (Burns, 2014); and the hundreds of thousands of people protesting in Ireland (BBC News, 2014,b; Irish Times 2015). Subsequently, the commodification of freshwater has become a criminological issue for water-abundant rich states, as well as for the highly indebted water-scarce nations.

Is comfort important for optimal use of child restraints?

Suboptimal restraint use, particularly the incorrect use of restraints, is a significant and widespread problem among child vehicle occupants, and increases the risk of injury. Previous research has identified comfort as a potential factor influencing suboptimal restraint use. Both the real comfort experienced by the child and the parent’s perception of the child’s comfort are reported to influence the optimal use of restraints. Problems with real comfort may lead the child to misuse the restraint in their attempt to achieve better comfort whilst parent-perceived discomfort has been reported as a driver for premature graduation and inappropriate restraint choice. However, this work has largely been qualitative. There has been no research that objectively studies either the association between real and parental perceived comfort, or any association between comfort and suboptimal restraint use. One barrier to such studies is the absence of validated tools for quantifying real comfort in children. We aimed to develop methods to examine both real and parent-perceived comfort and examine their effects on suboptimal restraint use. We conducted online parent surveys (n=470) to explore what drives parental perceptions of their child’s comfort in restraint systems (study 1) and used data from field observation studies (n=497) to examine parent-perceived comfort and its relationship with observed restraint use (study 2). We developed methods to measure comfort in children in a laboratory setting (n=14) using video analysis to estimate a Discomfort Avoidance Behaviour (DAB) score, pressure mapping and adapted survey tools to differentiate between comfortable and induced discomfort conditions (study 3). Preliminary analysis of our recent online survey of Australian parents (study 1) indicates that 23% of parents report comfort as a consideration when making a decision to change restraints. Logistic regression modelling of data collected during the field observation study (study 2) revealed that parent-perceived discomfort was not significantly associated with premature graduation. Contrary to expectation, children of parents who reported that their child was comfortable were almost twice as likely to have been incorrectly restrained (p<0.01, 95% CI 1.24 - 2.77). In the laboratory study (study 3) we found our adapted survey tools did not provide a reliable measurement of real comfort among children. However our DAB score was able to differentiate between comfortable and induced discomfort conditions and correlated well with pressure mapping. Our results suggest that while some parents report concern about their child’s comfort, parent-reported comfort levels were not associated with restraint choice. If comfort is important for optimal restraint use, it is likely to be the real comfort of the child rather than that reported by the parent. The method we have developed for studying real comfort can be used in naturalistic studies involving child occupants to further understand this relationship. This work will be of interest to vehicle and child restraint manufacturers interested in improving restraint design for young occupants as well as researchers and other stakeholders interested in reducing the incidence of restraint misuse among children.