Correlation between extent of osteolytic damage and metastatic burden of human breast cancer metastasis in nude mice: Real-time PCR quantitation

Orthotopic or intracardiac injection of human breast cancer cell lines into immunocompromised mice allows study of the molecular basis of breast cancer metastasis. We have established a quantitative real-time PCR approach to analyze metastatic spread of human breast cancer cells inoculated into nude mice via these routes. We employed MDA-MB-231 human breast cancer cells genetically tagged with a bacterial β-galactosidase (Lac-Z) retroviral vector, enabling their detection by TaqMan® real-time PCR. PCR detection was linear, specific, more sensitive than conventional PCR, and could be used to directly quantitate metastatic burden in bone and soft organs. Attesting to the sensitivity and specificity of the PCR detection strategy, as few as several hundred metastatic MDA-MB-231 cells were detectable in 100 μm segments of paraffin-embedded lung tissue, and only in samples adjacent to sections that scored positive by histological detection. Moreover, the measured real-time PCR metastatic burden in the bone environment (mouse hind-limbs, n=48) displayed a high correlation to the degree of osteolytic damage observed by high resolution X-ray analysis (r 2=0.972). Such a direct linear relationship to tumor burden and bone damage substantiates the so-called `vicious cycle' hypothesis in which metastatic tumor cells promote the release of factors from the bone which continue to stimulate the tumor cells. The technique provides a useful tool for molecular and cellular analysis of human breast cancer metastasis to bone and soft organs, can easily be extended to other cell/marker/organ systems, and should also find application in preclinical assessment of anti-metastatic modalities.

Attributable risk analysis reveals potential healthcare savings from increased consumption of dairy products.

With rising burdens of obesity and chronic disease, the role of diet as a modifiable risk factor is of increasing public health interest. There is a growing body of evidence that low consumption of dairy products is associated with elevated risk of chronic metabolic and cardiovascular disorders. Surveys also suggest that dairy product consumption falls well below recommended targets for much of the population in many countries, including the USA, UK, and Australia. We reviewed the scientific literature on the health effects of dairy product consumption (both positive and negative) and used the best available evidence to estimate the direct healthcare expenditure and burden of disease [disability-adjusted life years (DALY)] attributable to low consumption of dairy products in Australia. We implemented a novel technique for estimating population attributable risk developed for application in nutrition and other areas in which exposure to risk is a continuous variable. We found that in the 2010-2011 financial year, AUD$2.0 billion (USD$2.1 billion, €1.6 billion, or ∼1.7% of direct healthcare expenditure) and the loss of 75,012 DALY were attributable to low dairy product consumption. In sensitivity analyses, varying core assumptions yielded corresponding estimates of AUD$1.1-3.8 billion (0.9-3.3%) and 38,299-151,061 DALY lost. The estimated healthcare cost attributable to low dairy product consumption is comparable with total spending on public health in Australia (AUD$2.0 billion in 2009-2010). These findings justify the development and evaluation of cost-effective interventions that use dairy products as a vector for reducing the costs of diet-related disease.

Web search activity data accurately predict population chronic disease risk in the USA

BACKGROUND: The WHO framework for non-communicable disease (NCD) describes risks and outcomes comprising the majority of the global burden of disease. These factors are complex and interact at biological, behavioural, environmental and policy levels presenting challenges for population monitoring and intervention evaluation. This paper explores the utility of machine learning methods applied to population-level web search activity behaviour as a proxy for chronic disease risk factors. METHODS: Web activity output for each element of the WHO's Causes of NCD framework was used as a basis for identifying relevant web search activity from 2004 to 2013 for the USA. Multiple linear regression models with regularisation were used to generate predictive algorithms, mapping web search activity to Centers for Disease Control and Prevention (CDC) measured risk factor/disease prevalence. Predictions for subsequent target years not included in the model derivation were tested against CDC data from population surveys using Pearson correlation and Spearman's r. RESULTS: For 2011 and 2012, predicted prevalence was very strongly correlated with measured risk data ranging from fruits and vegetables consumed (r=0.81; 95% CI 0.68 to 0.89) to alcohol consumption (r=0.96; 95% CI 0.93 to 0.98). Mean difference between predicted and measured differences by State ranged from 0.03 to 2.16. Spearman's r for state-wise predicted versus measured prevalence varied from 0.82 to 0.93. CONCLUSIONS: The high predictive validity of web search activity for NCD risk has potential to provide real-time information on population risk during policy implementation and other population-level NCD prevention efforts.

The burden of severe obesity and the efficiency and equity of treatment

 Severe obesity rates have doubled during the last twenty years, particularly in disadvantaged Australians. Paradoxically, disadvantaged Australians are the least likely group to receive treatment using bariatric surgery. Health care costs for individuals with severe obesity are double the population average. These costs are decreased after bariatric surgery, particularly in individuals with diabetes.

Measuring the economic consequences of racial discrimination in Australia

 Racial discrimination results in economic inefficiency. This thesis has investigated its impact and estimated, for the first time, the health-related costs attributable to racial discrimination. The study found that the Australian economy incurs substantial loss due to the burden of disease associated with the exposure of minorities to racial discrimination.

The extra resource burden of in-hospital falls: a cost of falls study

OBJECTIVE: To quantify the additional hospital length of stay (LOS) and costs associated with in-hospital falls and fall injuries in acute hospitals in Australia. DESIGN, SETTING AND PARTICIPANTS: A multisite prospective cohort study conducted during 2011-2013 in the control wards of a falls prevention trial (6-PACK). The trial included all admissions to 12 acute medical and surgical wards of six Australian hospitals. In-hospital falls data were collected from medical record reviews, daily verbal reports by ward nurse unit managers, and hospital incident reporting and administrative databases. Clinical costing data were linked for three of the six participating hospitals to calculate patient-level costs. OUTCOME MEASURES: Hospital LOS and costs associated with in-hospital falls and fall injuries for each patient admission. RESULTS: We found that 966 of a total of 27 026 hospital admissions (3.6%) involved at least one fall, and 313 (1.2%) at least one fall injury, a total of 1330 falls and 418 fall injuries. After adjustment for age, sex, cognitive impairment, admission type, comorbidity and clustering by hospital, patients who had an in-hospital fall had a mean increase in LOS of 8 days (95% CI, 5.8-10.4; P < 0.001) compared with non-fallers, and incurred mean additional hospital costs of $6669 (95% CI, $3888-$9450; P < 0.001). Patients with a fall-related injury had a mean increase in LOS of 4 days (95% CI, 1.8-6.6; P = 0.001) compared with those who fell without injury, and there was also a tendency to additional hospital costs (mean, $4727; 95% CI, -$568 to $10 022; P = 0.080). CONCLUSION: Patients who experience an in-hospital fall have significantly longer hospital stays and higher costs. Programs need to target the prevention of all falls, not just the reduction of fall-related injuries.

Brain substrates of social decision-making in dual diagnosis: cocaine dependence and personality disorders

Cocaine dependence frequently co-occurs with personality disorders, leading to increased interpersonal problems and greater burden of disease. Personality disorders are characterised by patterns of thinking and feeling that divert from social expectations. However, the comorbidity between cocaine dependence and personality disorders has not been substantiated by measures of brain activation during social decision-making. We applied functional magnetic resonance imaging to compare brain activations evoked by a social decision-making task-the Ultimatum Game-in 24 cocaine dependents with personality disorders (CDPD), 19 cocaine dependents without comorbidities and 19 healthy controls. In the Ultimatum Game participants had to accept or reject bids made by another player to split monetary stakes. Offers varied in fairness (in fair offers the proposer shares ~50 percent of the money; in unfair offers the proposer shares <30 percent of the money), and participants were told that if they accept both players get the money, and if they reject both players lose it. We contrasted brain activations during unfair versus fair offers and accept versus reject choices. During evaluation of unfair offers CDPD displayed lower activation in the insula and the anterior cingulate cortex and higher activation in the lateral orbitofrontal cortex and superior frontal and temporal gyri. Frontal activations negatively correlated with emotion recognition. During rejection of offers CDPD displayed lower activation in the anterior cingulate cortex, striatum and midbrain. Dual diagnosis is linked to hypo-activation of the insula and anterior cingulate cortex and hyper-activation of frontal-temporal regions during social decision-making, which associates with poorer emotion recognition.

The Counterweight Programme: prevalence of CVD risk factors by body mass index and impact of a 10% weight change

Objectives

To examine relationships between body mass index (BMI), prevalence of physician-recorded cardiovascular disease (CVD) risk factors in primary care, and changes in risk with 10% weight change.

Methods

The Counterweight Project conducted a baseline cross-sectional survey of medical records of 6150 obese (BMI ≥ 30 kg/m2), 1150 age- and sex-matched overweight (BMI 25 to <30 kg/m2), and 1150 age- and sex-matched normal weight (BMI 18.5 to <25 kg/m2) controls, in primary care. Data were collected for the previous 18 months to examine BMI and disease prevalence, and then modelled to show the potential effect of 10% weight loss or gain on risk.

Results

Obese patients develop more CVD risk factors than normal weight controls. BMI ≥ 40 kg/m2 exhibits increased prevalence of type 2 diabetes mellitus (DM), odds ratio (OR) men: 6.16 (p < 0.001); women: 7.82 (p < 0.001) and hypertension OR men: 5.51 (p < 0.001); women: 4.16 (p < 0.001). Dyslipidaemia peaked around BMI 35 to <37.5 kg/m2, OR men: 3.26 (p < 0.001); women 3.76 (p < 0.001) and CVD at BMI 37.5 to <40 kg/m2 in men, OR 4.48 (p < 0.001) and BMI ≥ 40 kg/m2 in women, OR 3.98 (p < 0.001).

A 10% weight loss from the sample mean of 32.5 kg/m2 reduced the OR for type 2 DM by 30% and CVD by 20%, while 10% weight gain increased type 2 DM risk by more than 35% and CVD by 20%.

Conclusion

Obesity plays a fundamental role in CVD risk, which is reduced with weight loss. Weight management intervention strategies should be a public health priority to reduce the burden of disease in the population.