‘Rapid Learning health care in oncology’ – An approach towards decision support systems enabling customised radiotherapy’

Purpose

An overview of the Rapid Learning methodology, its results, and the potential impact on radiotherapy.

Material and results

Rapid Learning methodology is divided into four phases. In the data phase, diverse data are collected about past patients, treatments used, and outcomes. Innovative information technologies that support semantic interoperability enable distributed learning and data sharing without additional burden on health care professionals and without the need for data to leave the hospital. In the knowledge phase, prediction models are developed for new data and treatment outcomes by applying machine learning methods to data. In the application phase, this knowledge is applied in clinical practice via novel decision support systems or via extensions of existing models such as Tumour Control Probability models. In the evaluation phase, the predictability of treatment outcomes allows the new knowledge to be evaluated by comparing predicted and actual outcomes.

Conclusion

Personalised or tailored cancer therapy ensures not only that patients receive an optimal treatment, but also that the right resources are being used for the right patients. Rapid Learning approaches combined with evidence based medicine are expected to improve the predictability of outcome and radiotherapy is the ideal field to study the value of Rapid Learning. The next step will be to include patient preferences in the decision making.     

Exercise training, genetics and type 2 diabetes-related phenotypes

Type 2 diabetes mellitus (T2DM) is at virtually pandemic levels world‐wide. Diabetes has been referred to as ‘a geneticist's nightmare’. However, dramatic advances in our understanding of the genetics of T2DM have occurred in the past 5 years. While endurance exercise training and increased habitual physical activity levels have consistently been shown to improve or be associated with improved T2DM‐related phenotypes, there is substantial interindividual variation in these responses. There is some evidence that T2DM‐related phenotype responses to exercise training are heritable, indicating that they might have a genetic basis. Genome‐wide linkage studies have not identified specific chromosomal loci that could account for these differences, and no genome‐wide association studies have been performed relative to T2DM‐related phenotype responses to exercise training. From candidate gene studies, there are relatively strong and replicated data supporting a role for the PPARγ Pro12Ala variant in the interindividual differences in T2DM‐related phenotype responses to training. This is a potentially important candidate locus because it affects T2DM susceptibility, has high biological plausibility and is the target for the primary pharmaceutical method for treating T2DM. Is it time to conduct a hypothesis‐driven large‐scale exercise training intervention trial based on PPARγ Pro12Ala genotype with T2DM‐related phenotypes as the primary outcome measures, while also assessing potential mechanistic changes in skeletal muscle and adipose tissue? Or would it be more appropriate to propose a smaller trial to address the specific skeletal muscle and adipose tissue mechanisms affected by the interaction between the PPARγ Pro12Ala genotype and exercise training?     

Quantitative 3-D colocalization analysis as a tool to study the intracellular trafficking and dissociation of pDNA-chitosan polyplexes

Multichannel microscopy is frequently used to study intermolecular interactions and spatial relationships between biomolecules and organelles or vesicles in cells. Based on multichannel images, quantitative colocalization analysis can provide valuable information about cellular internalization, vesicular transport, and the intracellular kinetics and location of biomolecules. However, such analyses should be performed carefully, because quantitative colocalization parameters have different interpretations and can be highly affected by image quality. We use quantitative three-dimensional colocalization analysis of deconvolved and chromatic-registered confocal images to study the dissociation of double-labeled pDNA-chitosan polyplexes in HeLa cells and their colocalization with early endosomes. Two chitosans that form polyplexes with highly different transfection efficacies are compared. Pearson's correlation coefficient, Manders' colocalization coefficients, and the intensity correlation quotient are estimated to determine the intracellular localization of polyplexes, free pDNA, and free chitosans. Differences are observed in the amount of uptake, and in the intracellular pathways and rates of dissociation for the two chitosans. The results support previous findings that polyplexes formed by self-branched, glycosylated chitosan oligomers are more favorable for cellular uptake and intracellular trafficking to the nucleus compared with polyplexes formed by linear chitosans.     

Effect of ultrasound parameters on the release of liposomal calcein

The ultrasound exposure parameters that maximize drug release from dierucoyl-phosphatidylcholine (DEPC)-based liposomes were studied using two transducers operating at 300 kHz and 1 MHz. Fluorescent calcein was used as a model drug, and the release from liposomes in solution was measured using a spectrophotometer. The release of calcein was more efficient at 300 kHz than at 1 MHz, with thresholds of peak negative pressures of 0.9 MPa and 1.9 MPa, respectively. Above this threshold, the release increased with increasing peak negative pressure, mechanical index (MI), and duty cycle. The amount of drug released followed first-order kinetics and increased with exposure time to a maximal release. To increase the release further, the MI had to be increased. The results demonstrate that the MI and the overall exposure time are the major parameters that determine the drug's release. The drug's release is probably due to mechanical (cavitation) rather than thermal effects, and that was also confirmed by the detection of hydroxide radicals.     

An unusual presentation of Huntington’s disease

We describe the case of a 59‐year‐old woman who exhibited psychotic symptoms, cognitive dysfunction, and restlessness. While the clinical picture and 18F‐FDG PET/CT suggested the presence of a tauopathy, especially frontotemporal dementia or progressive supranuclear palsy, genetic testing eventually revealed Huntington''s disease.     

Filaggrin in atopic dermatitis: flaky tail mice as a novel model for developing drug targets in atopic dermatitis

The barrier abnormality, a loss-of-function mutation in the gene encoding filaggrin (FLG), which is linked to the incidence of atopic dermatitis (AD), is a recently discovered but important factor in the pathogenesis of AD. To investigate this issue in greater detail, mice that have a genetic defect (FLG) in barrier function will provide a model of AD closer to the human disease. Flaky tail (Flg(ft)) mice, essentially deficient in filaggrin, recently have been introduced to investigate the role of filaggrin on AD. These mice showed eczematous skin lesion in the steady state in line with increased of total IgE and Th17 expression in the skin. There is also an altered skin barrier function as a key element of AD either outside-to-inside barrier function or vice versa in Flg(ft) mice. Moreover, like human AD, these mice showed enhanced percutaneous allergen priming or response to cutaneous stimulants. Application of mite allergen in Flg(ft) mice, even without prior barrier disruption, remarkably enhanced both the clinical manifestations and the laboratory findings that correspond to indicators of human AD. These features of Flg(ft) mice allow us to investigate further the role of filaggrin in AD, and the knowledge obtained using these mice will be quite useful to develop a new therapeutic target for AD.     

Sickness Presenteeism Among Swedish Police Officers

Introduction The aim was to describe the prevalence of sickness presenteeism (SP) and to explore possible associations with work characteristics among Swedish police officers. Methods Questionnaire data from 11,793 police officers were analysed. Relative risks (RR) and 95% confidence intervals (CI) for SP were calculated with modified Poisson regression. SP was defined as having gone to work on two or more occasions during the past 12 months despite judging that one’s health would have motivated sickness absence. Results Of the police officers, 47% reported SP. All studied work environment factors were significantly associated with SP. The strongest association was found for stress (RR = 1.46; 95% CI: 1.41–1.52). Low support from colleagues and low control had higher impact on the risk estimates for SP among older subjects. Adjustment for self-rated health lowered the RRs, however, estimates remained statistically significant. The results indicated that SP was most affected by work environment among subjects with good self-rated health. Conclusions SP was high among police officers. Work environment factors seem to be associated with SP, particularly among subjects with good general health.     

Monitoring pesticide use and associated health hazards in Central America

We established methods for monitoring pesticide use and associated health hazards in Central America. With import data from Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama for 2000-2004, we constructed quantitative indicators (kg active ingredient) for general pesticide use, associated health hazards, and compliance with international regulations. Central America imported 33 million kg active ingredient per year. Imports increased 33% during 2000-2004. Of 403 pesticides, 13 comprised 77% of the total pesticides imported. High volumes of hazardous pesticides are used; 22% highly/extremely acutely toxic, 33% moderately/severely irritant or sensitizing, and 30% had multiple chronic toxicities. Of the 41 pesticides included in the Stockholm Convention on Persistent Organic Pollutants (POPs), the Rotterdam Convention on Prior Informed Consent (PIC), the Montreal Protocol on Substances that Deplete the Ozone Layer, the Pesticide Action Network (PAN) Dirty Dozen, and the Central American Dirty Dozen, 16 (17% total volume) were imported, four being among the 13 most imported pesticides. Costa Rica is by far the biggest consumer. Pesticide import data are good indicators of use trends and an informative source to monitor hazards and, potentially, the effectiveness of interventions.     

Registration of fatal occupational injuries in Costa Rica, 2005-2006

Data on fatal occupational injuries (FOIs) for Latin America are controversial. Costa Rican national rates are inconsistent with estimates extrapolated from other countries. We reviewed the files for all possible FOIs in Costa Rica for 2005-2006 at the National Insurance Institute and at the Center of Forensic Sciences by formality/informality of work, sex, age, economic activity, occupation, and cause of death. The national mortality rate was estimated at 9.5/100,000 person-years (342 deaths). The informal/formal rate ratio was 1.06. Men's rates were over 10 times higher than women's and increased with age. The highest rates were found for transport, storage, and communication (32.1/100,000 person-years), and, by occupation, for messengers and delivery men (91.4). Leading causes of death were traffic injuries and gunshots. Recalculated rates are probably underestimates. Data limitations include the absence of systematic identification and registration among informal sector workers and other groups such as children and farm workers.     

Estimating and comparing incidence and prevalence of chronic diseases by combining GP registry data: the role of uncertainty

Background

As the promotion of alcohol and tobacco to young people through direct advertising has become increasingly restricted, there has been greater interest in whether images of certain behaviours in films are associated with uptake of those behaviours in young people. Associations have been reported between exposure to smoking images in films and smoking initiation, and between exposure to film alcohol images and initiation of alcohol consumption, in younger adolescents in the USA and Germany. To date no studies have reported on film images of recreational drug use and young people's own drug use.

Methods

Cross sectional multivariable logistic regression analysis of data collected at age 19 (2002-4) from a cohort of young people (502 boys, 500 girls) previously surveyed at ages 11 (in 1994-5), 13 and 15 in schools in the West of Scotland. Outcome measures at age 19 were: exceeding the 'sensible drinking' guidelines ('heavy drinkers') and binge drinking (based on alcohol consumption reported in last week), and ever use of cannabis and of 'hard' drugs. The principle predictor variables were an estimate of exposure to images of alcohol, and of drug use, in films, controlling for factors related to the uptake of substance use in young people.

Results

A third of these young adults (33%) were classed as 'heavy drinkers' and half (47%) as 'binge drinkers' on the basis of their previous week's consumption. Over half (56%) reported ever use of cannabis and 13% ever use of one or more of the 'hard' drugs listed. There were linear trends in the percentage of heavy drinkers (p = .018) and binge drinkers (p = 0.012) by film alcohol exposure quartiles, and for ever use of cannabis by film drug exposure (p = .000), and for ever use of 'hard' drugs (p = .033). The odds ratios for heavy drinking (1.56, 95% CI 1.06-2.29 comparing highest with lowest quartile of film alcohol exposure) and binge drinking (1.59, 95% CI 1.10-2.30) were attenuated by adjustment for gender, social class, family background (parental structure, parental care and parental control), attitudes to risk-taking and rule-breaking, and qualifications (OR heavy drinking 1.42, 95% CI 0.95-2.13 and binge drinking 1.49, 95% CI 1.01-2.19), and further so when adjusting for friends' drinking status (when the odds ratios were no longer significant). A similar pattern was seen for ever use of cannabis and 'hard' drugs (unadjusted OR 1.80, 95% CI 1.24-2.62 and 1.57, 95% CI 0.91-2.69 respectively, 'fully' adjusted OR 1.41 (0.90-2.22 and 1.28 (0.66-2.47) respectively).

Conclusions

Despite some limitations, which are discussed, these cross-sectional results add to a body of work which suggests that it is important to design good longitudinal studies which can determine whether exposure to images of potentially health-damaging behaviours lead to uptake of these behaviours during adolescence and early adulthood, and to examine factors that might mediate this relationship.