Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis.

BACKGROUND: Neoadjuvant therapy is gaining acceptance as a valid treatment option for borderline resectable pancreatic cancer; however, its value for clearly resectable pancreatic cancer remains controversial. The aim of this study was to use a Markov decision analysis model, in the absence of adequately powered randomized trials, to compare the life expectancy (LE) and quality-adjusted life expectancy (QALE) of neoadjuvant therapy to conventional upfront surgical strategies in resectable pancreatic cancer patients. METHODS: A Markov decision model was created to compare two strategies: attempted pancreatic resection followed by adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy followed by restaging with, if appropriate, attempted pancreatic resection. Data obtained through a comprehensive systematic search in PUBMED of the literature from 2000 to 2015 were used to estimate the probabilities used in the model. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Of the 786 potentially eligible studies identified, 22 studies met the inclusion criteria and were used to extract the probabilities used in the model. Base case analyses of the model showed a higher LE (32.2 vs. 26.7 months) and QALE (25.5 vs. 20.8 quality-adjusted life months) for patients in the neoadjuvant therapy arm compared to upfront surgery. Probabilistic sensitivity analyses for LE and QALE revealed that neoadjuvant therapy is favorable in 59% and 60% of the cases respectively. CONCLUSION(S): Although conceptual, these data suggest that neoadjuvant therapy offers substantial benefit in LE and QALE for resectable pancreatic cancer patients. These findings highlight the value of further prospective randomized trials comparing neoadjuvant therapy to conventional upfront surgical strategies.

Variation in RBE for Survival of V79-4 Cells as a Function of Alpha-Particle (Helium Ion) Energy.

High linear energy transfer (LET) α particles are important with respect to the carcinogenic risk associated with human exposure to ionizing radiation, most notably to radon and its progeny. Additionally, the potential use of alpha-particle-emitting radionuclides in radiotherapy is increasingly being explored. Within the body the emitted alpha particles slow down, traversing a number of cells with a range of energies and therefore with varying efficiencies at inducing biological response. The LET of the particle typically rises from between ~70-90 keV µm(-1) at the start of the track (depending on initial energy) to a peak of ~237 keV µm(-1) towards the end of the track, before falling again at the very end of its range. To investigate the variation in biological response with incident energy, a plutonium-238 alpha-particle irradiator was calibrated to enable studies with incident energies ranging from 4.0 MeV down to 1.1 MeV. The variation in clonogenic survival of V79-4 cells was determined as a function of incident energy, along with the relative variation in the initial yields of DNA double-strand breaks (DSB) measured using the FAR assay. The clonogenic survival data also extends previously published data obtained at the Medical Research Council (MRC), Harwell using the same cells irradiated with helium ions, with energies ranging from 34.9 MeV to 5.85 MeV. These studies were performed in conjunction with cell morphology measurements on live cells enabling the determination of absorbed dose and calculation of the average LET in the cell. The results show an increase in relative biological effectiveness (RBE) for cell inactivation with decreasing helium ion energy (increasing LET), reaching a maximum for incident energies of ~3.2 MeV and corresponding average LET of 131 keV µm(-1), above which the RBE is observed to fall at lower energies (higher LETs). The effectiveness of single alpha-particle traversals (relevant to low-dose exposure) at inducing cell inactivation was observed to increase with decreasing energy to a peak of ~68% survival probability for incident energies of ~1.8 MeV (average LET of 190 keV µm(-1)) producing ~0.39 lethal lesions per track. However, the efficiency of a single traversal will also vary significantly with cell morphology and angle of incidence, as well as cell type.

Radon emanation in Saskatchewan soils.

Saskatchewan prairie soils in central Canada were studied from areas where many homes are known to exceed the Health Canada indoor radon guideline of 200 Bq m. This study sampled 32 soils from 11 sites, which varied in clay content and presence of bedrock materials. Soils were analyzed for (238)U, (226)Ra, (222)Rn in soil gas, bulk density, moisture, and particle size. Radon emanation from the soil samples varied from 10% to 43% and increased significantly with clay content with radon concentrations in soil gas of 18-38 kBq m(-3). Total uranium in soils was 2.1-4 ppm and 26-51 Bq kg(-1) dry weight for (238)U, (234)Th, and (226)Ra. Homes built on soils with high clay content may be at greater risk of high radon levels, particularly when the soils are dry and cracked, enhancing their permeability to gases such as radon. One sample of coal bedrock, originating from Tertiary marine shales, was particularly high for total uranium (53 ppm), (238)U, (234)Th, and (226)Ra activities (68-1,303 Bq kg(-1)) with radon emanation up to 1,363 kBq m(-3).

Would children be adequately protected by existing intervention levels during a radionuclear emergency?

The question arises as to whether radiation standards and guidelines set for adults are sufficiently protective of children. To answer this question, published literature values have been used to calculate radiation doses to children and adults from external and internal exposure to a suite of 30 radionuclides commonly found in the environment. It was found that older children and adults face about the same degree of risk from external radiation exposures, although doses may be ∼30 % elevated for infants due to their smaller body size. Inhalation risks in children are to a large degree offset by lower breathing rates and it is only in the case of iodine isotopes that children are more at risk. Ingestion of contaminated food products is more complex. Isotopes of iodine and the bone-seeking elements strontium and radium can give radiation doses up to an order of magnitude higher than for adults.

Radon control systems in existing and new construction: a review.

In support of the implementation of the new Canadian radon guideline, a comprehensive review of radon mitigation techniques used in countries around the world was undertaken, with particular emphasis on North America and Europe that have climates and construction techniques similar to Canada. The results of this review are presented here as an aid to administrators of radon control programmes, companies offering radon testing and mitigation services and other concerned parties, both in Canada and elsewhere, who are facing issues of implementing a radon control strategy. A wide variety of radon mitigation strategies have been employed worldwide and all have achieved some success in reducing radon concentrations. Generally, active mitigation techniques involving physical alterations to a house (e.g. sub-slab depressurisation) are more effective in achieving a sustained and substantial radon reduction than passive techniques (e.g. improved ventilation or sealing of cracks). To a large extent, the choice of an optimal mitigation strategy will depend on the building type, soil conditions and climate. Radon levels should be measured at periodic intervals after remediation, perhaps once every 5 y, to ensure that concentrations continue to remain at acceptable levels.

A preliminary radon map for Canada according to health region.

The recent publications of the combined analyses of residential radon studies in Europe and North America have shown that there is a significant risk of lung cancer at residential radon levels. In order to assess the population risk due to radon, the knowledge of the spatial distribution of indoor radon levels is essential. Here a preliminary radon map for Canada is presented, based on historical radon measurements collected in 6016 locations across Canada with the health region as the basic geographic units.

Determining the sample size required for a community radon survey.

Radon measurements in homes and other buildings have been included in various community health surveys often dealing with only a few hundred randomly sampled households. It would be interesting to know whether such a small sample size can adequately represent the radon distribution in a large community. An analysis of radon measurement data obtained from the Winnipeg case-control study with randomly sampled subsets of different sizes has showed that a sample size of one to several hundred can serve the survey purpose well.

Radiocesium in caribou and reindeer in northern Canada, Alaska and Greenland from 1958 to 2000.

This study summarizes the spatial and temporal trends of fallout (137)Cs concentrations in caribou and reindeer (Rangifer tarandus ssp.), reported in various programs in Canada, Alaska and Greenland, over a 40-y period. During the 1960s, the highest (137)Cs concentrations (2000-3000Bqkg(-1) wet weight in muscle) were found in the large caribou herds of central northern Canada, with levels about 50% lower in Alaska and Greenland. Concentrations varied by up to a factor of 6 between spring and fall. Concentrations in reindeer were comparable to those in caribou from the same regions. The highest (137)Cs concentrations (750Bqkg(-1)) in the late 1980s were found in the Caniapiscau herd of central Québec. The contribution from the Chernobyl accident in 1986 was estimated from (134)Cs measurements to be 10-40% of the total (137)Cs. Present concentrations have declined to 200-300Bqkg(-1). The effective half-life (T(eff)) of (137)Cs in Canadian caribou herds was estimated to be about 6 y. The potential impact on the health of northern residents is discussed.

Assessment and management of residential radon health risks: a report from the health Canada radon workshop.

Epidemiologic studies of uranium miners and other underground miners have consistently shown miners exposed to high levels of radon to be at increased risk of lung cancer. More recently, concern has arisen about lung cancer risks among people exposed to lower levels of radon in homes. The current Canadian guideline for residential radon exposure was set in 1988 at 800 Bq/m(3). Because of the accumulation of a considerable body of new scientific evidence on radon lung cancer risks since that time, Health Canada sponsored a workshop to review the current state-of-the-science on radon health risks. The specific objectives of the workshop were (1) to collect and assess scientific information relevant to setting national radon policy in Canada, and (2) to gather information on social, political, and operational considerations in setting national policy. The workshop, held on 3-4 March 2004, was attended by 38 invited scientists, regulators, and other stakeholders from Canada and the United States. The presentations on the first day dealt primarily with scientific issues. The combined analysis of North American residential radon and lung cancer studies was reviewed. The analysis confirmed a small but detectable increase in lung cancer risk at residential exposure levels. Current estimates suggest that radon in homes is responsible for approximately 10% of all lung cancer deaths in Canada, making radon the second leading cause of lung cancer after tobacco smoking. This was followed by a perspective from an UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) working group on radon. There were two presentations on occupational exposures to radon and two presentations considered the possibility of radon as a causative factor for cardiovascular disease and for cancer in other organs besides the lung. The possible contribution of environmental tobacco smoke to lung cancers in nonsmokers was also considered. Areas for future research were identified. The second day was devoted to policy and operational issues. The presentations began with a perspective from the U.S. Environmental Protection Agency, followed by a history of radon policy development in Canada. Subsequent presentations dealt with the cost-effectiveness of radon mitigation, Canadian building codes and radon, and a summary of radon standards from around the world. Provincial representatives and a private consultant were given opportunities to present their viewpoints. A number of strategies for reducing residential radon exposure in Canada were recognized, including testing and mitigation of existing homes (on either a widespread or targeted basis) and changing the building code to require that radon mitigation devices be installed at the time a new home is constructed. The various elements of a comprehensive national radon policy were set forth.

Model results of kidney burdens from uranium intakes.

Uranium is a naturally occurring element, which is both radiologically and chemically toxic. When dealing with intakes of uranium, whether natural or depleted, chemical toxicity to the kidney usually predominates over radiological toxicity. This is especially true for uranium compounds in soluble (inhalation Type F) and moderately soluble (inhalation Type M) forms. To assess chemical toxicity, information on kidney burden per unit intake is required. This study summarizes the kidney burdens per unit intake for common exposures from uranium ingestion and inhalation. ICRP models developed for radiation dosimetry purposes can equally well be used to estimate kidney burdens from uranium intakes. While dosimetric quantities and data are tabulated in ICRP publications, data on uranium burdens in kidney are not explicitly given in these tabulations. In this work, the most recent ICRP models were utilized to generate a compilation of kidney burdens from common intakes. Calculations were made for four age groups from infant to adult. For all age groups, long-term chronic uranium ingestion will result in a kidney burden of 6.6% of daily uranium intake. Comparisons of kidney burdens due to acute ingestion and acute inhalation show that inhaled uranium compounds of Type F and Type M will generally result in higher burdens to kidney compared to the same amount of uranium compounds ingested.

Interferon-gamma and skin test responses of schoolchildren in southeast England to purified protein derivatives from Mycobacterium tuberculosis and other species of mycobacteria.

The immune responses of schoolchildren in southeast England to Mycobacterium tuberculosis and other species of mycobacteria were studied prior to vaccination with bacille Calmette-Guérin (BCG). Data are presented for tuberculin (Heaf) skin test and interferon-gamma (IFN-gamma) responses to M. tuberculosis purified protein derivative (PPD), and IFN-gamma responses to PPDs from eight other environmental mycobacteria, measured in 424 schoolchildren (13-15 years of age). Responses to M. tuberculosis PPD were detected in 27% of schoolchildren by in vitro IFN-gamma response and in 20% by the Heaf test. IFN-gamma responses were more prevalent to PPDs from species of mycobacteria other than M. tuberculosis, predominantly those of the MAIS complex and M. marinum (45-60% responders). Heaf test and IFN-gamma responses were associated (P<0.001) for M. tuberculosis, MAIS and M. marinum. These findings have implications for appropriate implementation of vaccination against tuberculosis.

'Seeing old people with real problems like leaving the gas on': students' and tutors' reflections after piloting the second phase of a new, community based course for second-year medical students.

This short communication presents the results of an evaluation carried out with tutors and students at the end of the pilot phase of a new, community-based teaching course for second year students at St Bartholomew's and the Royal London School of Medicine and Dentistry. Students were placed with different community-based healthcare teams in East London. The aims of the course were to enable students to observe, and be part of, the work of the multidisciplinary team, and to experience the continuing care of patients with chronic illnesses within the community.

Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi.

Interferon (IFN)-gamma responsiveness to 12 purified protein derivative (PPD) and new tuberculin antigens from 9 species of mycobacteria was assessed, using a whole blood assay, in 616 young adults living in northern Malawi, where Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination provides no protection against pulmonary tuberculosis. The prevalence of IFN-gamma responsiveness was highest for PPDs of M. avium, M. intracellulare, and M. scrofulaceum (the MAIS complex). Correlations between responsiveness paralleled genetic relatedness of the mycobacterial species. A randomized, controlled trial was carried out, to assess the increase in IFN-gamma responsiveness to M. tuberculosis PPD that can be attributed to M. bovis BCG vaccination. The BCG-attributable increase in IFN-gamma response to M. tuberculosis PPD was greater for individuals with low initial responsiveness to MAIS antigens than for those with high initial responsiveness. Although not statistically significant, the trend is consistent with the hypothesis that prior exposure to environmental mycobacteria interferes with immune responses to BCG vaccination.

Relationship between IFN-gamma and skin test responsiveness to Mycobacterium tuberculosis PPD in healthy, non-BCG-vaccinated young adults in Northern Malawi.

SETTING: Rural northern Malawi, where vaccination with BCG Glaxo (1077) provides protection against leprosy but not against pulmonary tuberculosis. OBJECTIVE: To evaluate the patterns of responsiveness to purified protein derivative of Mycobacterium tuberculosis (PPD) in terms of delayed type hypersensitivity (DTH) and interferon-gamma (IFN-gamma) production. DESIGN: IFN-gamma was measured in 6 day whole blood cultures diluted 1 in 10, stimulated with PPD RT48, and the results compared to the DTH response to PPD RT23. A total of 633 individuals aged 12 to 28 years, without prior BCG vaccination, were recruited. RESULTS: Overall, 63% of subjects made a positive IFN-gamma response (defined as >62 pg/ml), and 37% gave a DTH induration of >5 mm. A strong correlation between skin test and IFN-gamma responses was observed, although with interesting exceptions: 13/270 individuals with zero DTH showed IFN-gamma responses >500 pg/ml, and 7/53 individuals with >10 mm induration showed IFN-gamma responses < or = 62 pg/ml. The prevalence of skin test responsiveness increased with age, and was higher among older males than females; age-sex patterns were less clear for IFN-gamma production. CONCLUSION: The 6 day IFN-gamma response to PPD correlates well with Mantoux skin test induration. The discordant individuals may represent important subsets in terms of protective immunity and risk of clinical tuberculosis.

Culturally sensitive assessment of narrative skills in children.

The clinical legacy of William Labov's narrative analysis framework is explored. In recent years, the importance of narration for children's developing literacy and discourse skills has been widely recognized. This article describes a three-step process for assessing children's narrative discourse: elicitation, coding, and scoring. The influences of cultural differences on narration are also presented, with implications and suggestions for culturally sensitive assessment.

BCG scars in northern Malawi: sensitivity and repeatability of scar reading, and factors affecting scar size.

SETTING: Karonga district, northern Malawi. OBJECTIVE: To assess the sensitivity and repeatability of BCG scar reading, and factors affecting scar size. DESIGN: Follow-up of individuals aged > 3 months who were recruited into a BCG vaccine trial (1986-1989), and of infants vaccinated in health centres (1989-1991), who were examined for presence and size of BCG scars in subsequent years. All examinations were carried out blind of information on true vaccination status or the results of previous examinations. RESULTS: For trial individuals who were considered scar negative at recruitment and received BCG, the sensitivity of scar reading was > or = 93%, repeatability was > or = 94% for those < 60 years old at vaccination, and only around 1% were assessed as having > 1 BCG scar post-vaccination. For infants vaccinated when < 1 month old in health centres, the proportion who still had recognisable scars 4 years later was < 80%. Scars were larger in individuals with a prior BCG vaccination, and for those aged 15-59 at vaccination the scars were approximately 1 mm larger for males than for females. CONCLUSIONS: A BCG scar is a highly sensitive and repeatable indicator of vaccination status when the vaccine is properly handled, delivered appropriately, and given at over 3 months of age, but not for vaccinations given within 1 month of birth. Given that most vaccinations in the world are given soon after birth, this low sensitivity will lead to both vaccine coverage and vaccine efficacy being underestimated in studies in which vaccination status is inferred from the presence/absence of a distinctive BCG scar. Age-sex patterns identified for scar size show important similarities to those found with skin test responses to tuberculin.

International developments in abortion law from 1988 to 1998.

OBJECTIVES: In 2 successive decades since 1967, legal accommodation of abortion has grown in many countries. The objective of this study was to assess whether liberalizing trends have been maintained in the last decade and whether increased protection of women's human rights has influenced legal reform. METHODS: A worldwide review was conducted of legislation and judicial rulings affecting abortion, and legal reforms were measured against governmental commitments made under international human rights treaties and at United Nations conferences. RESULTS: Since 1987, 26 jurisdictions have extended grounds for lawful abortion, and 4 countries have restricted grounds. Additional limits on access to legal abortion services include restrictions on funding of services, mandatory counseling and reflection delay requirements, third-party authorizations, and blockades of abortion clinics. CONCLUSIONS: Progressive liberalization has moved abortion laws from a focus on punishment toward concern with women's health and welfare and with their human rights. However, widespread maternal mortality and morbidity show that reform must be accompanied by accessible abortion services and improved contraceptive care and information.

Narrative Assessment Profile: discourse analysis for school-age children.

The assessment of narrative skills of school-age children is described using a comprehensive discourse analysis approach, the Narrative Assessment Profile. The following dimensions of narration are evaluated: topic maintenance, event sequencing, explicitness, referencing, conjunctive cohesion, and fluency. The purpose of this article is to describe the development of these six dimensions and their symptoms in impaired narrative discourse. Assessment and intervention guidelines are presented.

Household and dwelling contact as risk factors for leprosy in northern Malawi.

Data on household and dwelling contact with known leprosy cases were available on more than 80,000 initially disease-free individuals followed up during the 1980s in a rural district of northern Malawi. A total of 331 new cases of leprosy were diagnosed among them. Individuals recorded as living in household or dwelling contact with multibacillary patients at the start of follow-up were at approximately five- to eightfold increased risk of leprosy, respectively, compared with individuals not living in such households or dwellings. Individuals living in household or dwelling contact with paucibacillary cases were both at approximately twofold increased risk. The higher risk associated with multibacillary contact and the fact that dwelling contact entailed a greater risk than household contact if the association was with multibacillary, but not with paucibacillary, disease suggest that paucibacillary cases may not themselves be sources of transmission, but rather just markers that a household has had contact with some (outside) source of infection. When household contact was considered alone, the risks of disease were appreciably higher for younger than for older contacts and for male compared with female contacts. Despite the elevated risk of leprosy associated with household or dwelling contact, only 15% of all incidence cases arose among recognized household contacts. Given the dynamic nature of household membership and consequent misclassification of contact status, the true contribution to overall incidence of contact within household or dwelling settings is likely to be much higher than this, perhaps 30% or higher. Considering the predilection of males for infectious multibacillary forms of the disease, the transmission of Mycobacterium leprae at an early age, in particular to males, may be of particular importance for the persistence of leprosy in endemic communities. Although residential contact with a multibacillary case is the strongest known determinant of leprosy risk, the vast majority of such contacts never manifest disease, which indicates a crucial role for genetic and/or environmental factors in the transmission of M. leprae infection and/or the pathogenesis of clinical leprosy.