Influence of pre-diagnostic cigarette smoking on colorectal cancer survival: overall and by tumour molecular phenotype.

BACKGROUND: Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis. METHODS: A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and other relevant data were collected by questionnaire after cancer diagnosis, using a referent period of '2 years before diagnosis' to capture pre-diagnosis information. Molecular analyses of microsatellite instability (MSI) status and BRAF V600E mutation status were performed in tumour tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major prognostic factors. RESULTS: Compared with never smokers, all-cause mortality (overall survival, OS) was higher for current (HR: 1.78; 95% CI: 1.04-3.06), but not for former (HR: 1.06; 95% CI: 0.71-1.59) smokers. The associations of cigarette smoking with the study outcomes were higher among patients with ≥40 pack-years of smoking (OS: HR: 1.72; 95% CI: 1.03-2.85; disease-free survival (DFS: HR: 1.99; 95% CI: 1.25-3.19), those who smoked ≥30 cigarettes per day (DFS: HR: 1.80; 95% CI: 1.22-2.67), and those with microsatellite stable (MSS) or MSI-low tumours (OS: HR: 1.38; 95% CI: 1.04-1.82 and DFS: HR: 1.32; 95% CI: 1.01-1.72). Potential heterogeneity was noted for sex (DFS HR: 1.68 for men and 1.01 for women: P for heterogeneity=0.04), and age at diagnosis (OS: HR: 1.11 for patients aged <60 and 1.69 for patients aged ≥60: P for heterogeneity=0.03). CONCLUSIONS: Pre-diagnosis cigarette smoking is associated with worsened prognosis among patients with CRC.

Monitoring of intratidal lung mechanics: a Graphical User Interface for a model-based decision support system for PEEP-titration in mechanical ventilation.

In mechanical ventilation, a careful setting of the ventilation parameters in accordance with the current individual state of the lung is crucial to minimize ventilator induced lung injury. Positive end-expiratory pressure (PEEP) has to be set to prevent collapse of the alveoli, however at the same time overdistension should be avoided. Classic approaches of analyzing static respiratory system mechanics fail in particular if lung injury already prevails. A new approach of analyzing dynamic respiratory system mechanics to set PEEP uses the intratidal, volume-dependent compliance which is believed to stay relatively constant during one breath only if neither atelectasis nor overdistension occurs. To test the success of this dynamic approach systematically at bedside or in an animal study, automation of the computing steps is necessary. A decision support system for optimizing PEEP in form of a Graphical User Interface (GUI) was targeted. Respiratory system mechanics were analyzed using the gliding SLICE method. The resulting shapes of the intratidal compliance-volume curve were classified into one of six categories, each associated with a PEEP-suggestion. The GUI should include a graphical representation of the results as well as a quality check to judge the reliability of the suggestion. The implementation of a user-friendly GUI was successfully realized. The agreement between modelled and measured pressure data [expressed as root-mean-square (RMS)] tested during the implementation phase with real respiratory data from two patient studies was below 0.2 mbar for data taken in volume controlled mode and below 0.4 mbar for data taken in pressure controlled mode except for two cases with RMS < 0.6 mbar. Visual inspections showed, that good and medium quality data could be reliably identified. The new GUI allows visualization of intratidal compliance-volume curves on a breath-by-breath basis. The automatic categorisation of curve shape into one of six shape-categories provides the rational decision-making model for PEEP-titration.

Tripal EUtils: a Tripal module to increase exchange and reuse of genome assembly metadata.

Data and metadata interoperability between data storage systems is a critical component of the FAIR data principles. Programmatic and consistent means of reconciling metadata models between databases promote data exchange and thus increases its access to the scientific community. This process requires (i) metadata mapping between the models and (ii) software to perform the mapping. Here, we describe our efforts to map metadata associated with genome assemblies between the National Center for Biotechnology Information (NCBI) data resources and the Chado biological database schema. We present mappings for multiple NCBI data structures and introduce a Tripal software module, Tripal EUtils, to pull metadata from NCBI into a Tripal/Chado database. We discuss potential mapping challenges and solutions and provide suggestions for future development to further increase interoperability between these platforms. Database URL: https://github.com/NAL-i5K/tripal_eutils.

Perceptions of health care providers concerning patient and health care provider strategies to limit out-of-pocket costs for cancer care.

OBJECTIVE: We aimed to describe the perceptions of health care providers concerning patient and health care provider strategies to limit out-of-pocket costs for cancer care. METHODS: We conducted semi-structured interviews with 21 cancer care providers (nurses, social workers, oncologists, surgeons, pharmacists, and dieticians) in Newfoundland and Labrador. RESULTS: Patients try to minimize costs by substituting or rationing medications, choosing radical treatments, lengthening the time between follow-up appointments, choosing inpatient care, and working during treatment to minimize loss of income. Providers respond to the financial concerns of patients by helping them to access financial assistance programs, by changing chemotherapy and supportive drug prescriptions, and by shortening radiation treatment protocols. They admit patients to hospital and arrange follow-up with physicians closer to a patient's home. CONCLUSIONS: Out-of-pocket costs resulting from cancer care are incurred at all phases of treatment and follow-up. These costs are substantial concerns for some patients and their health care providers. Encouraging communication between patients and their providers is needed to identify individuals at risk and to safely modify care plans. Tele-oncology and public drug, medical travel, and leave programs are needed to ensure that patients are better able to afford the costs related to cancer care.

Detection of thoracic vascular structures by electrical impedance tomography: a systematic assessment of prominence peak analysis of impedance changes.

OBJECTIVE: Electrical impedance tomography (EIT) is a non-invasive and radiation-free bedside monitoring technology, primarily used to monitor lung function. First experimental data shows that the descending aorta can be detected at different thoracic heights and might allow the assessment of central hemodynamics, i.e. stroke volume and pulse transit time. APPROACH: First, the feasibility of localizing small non-conductive objects within a saline phantom model was evaluated. Second, this result was utilized for the detection of the aorta by EIT in ten anesthetized pigs with comparison to thoracic computer tomography (CT). Two EIT belts were placed at different thoracic positions and a bolus of hypertonic saline (10 ml, 20%) was administered into the ascending aorta while EIT data were recorded. EIT images were reconstructed using the GREIT model, based on the individual's thoracic contours. The resulting EIT images were analyzed pixel by pixel to identify the aortic pixel, in which the bolus caused the highest transient impedance peak in time. MAIN RESULTS: In the phantom, small objects could be located at each position with a maximal deviation of 0.71 cm. In vivo, no significant differences between the aorta position measured by EIT and the anatomical aorta location were obtained for both measurement planes if the search was restricted to the dorsal thoracic region of interest (ROIs). SIGNIFICANCE: It is possible to detect the descending aorta at different thoracic levels by EIT using an intra-aortic bolus of hypertonic saline. No significant differences in the position of the descending aorta on EIT images compared to CT images were obtained for both EIT belts.

Very high incidence of familial colorectal cancer in Newfoundland: a comparison with Ontario and 13 other population-based studies.

Newfoundland has the highest rate of colorectal cancer (CRC) of any Canadian province. In order to investigate the factors, especially genetic components, responsible for CRC we established the Newfoundland Colorectal Cancer Registry. In a 5-year period we examined every case of CRC diagnosed under the age of 75 years and obtained consent from 730 cases. Careful analysis of family history was used to assign a familial cancer risk, based on established criteria. We observed that 3.7% of CRC cases came from families meeting the Amsterdam II criteria and a further 0.9% of cases involved familial adenomatous polyposis (FAP). An additional 43% of cases met one or more of the revised Bethesda criteria and 31% of all cases had a first-degree relative affected with CRC. We compared the Newfoundland data with data from the province of Ontario, where the same recruitment and risk-assessment criteria were used. In all categories, the indicators of familial risk were significantly higher in Newfoundland. These data were also compared to results published from 13 other population-based studies worldwide. In every category the proportion of Newfoundland cases meeting the criteria was higher than in any other population. The mean differences were: 3.5-fold greater for FAP, 2.8-fold higher for Amsterdam criteria, 2.0-fold higher for Bethesda criteria and 1.9-fold higher for the number of affected first-degree relatives. We conclude that the high incidence of CRC in Newfoundland may be attributable to genetic, or at least familial, factors. In the high-risk families we provide evidence for the involvement of founder mutations in the APC and MSH2 genes.

A comparison of the direct and indirect leukocyte migration tests in man.

In the Direct Leukocyte Migration Test, as few as 10% mononuclear cells are sufficient to produce antigen-specific inhibition of polymorphonuclear leukocyte migration in the presence of 100 mug of excipient-free PPD per ml. A clear distinction between tuberculin-positive and tuberculin-negative donors can be made. The inhibition of migration is blocked by the presence of actinomycin D. In the Indirect Test, significant inhibition of migration of pure polymorphs is produced by supernatants from stimulated tuberculin-sensitive lymphocyte cultures. Inhibition is maximal at 6 h and is of a similar degree to that obtained in the direct test.

A decrease of intracellular ATP is compensated by increased respiration and acidification at sub-lethal parathion concentrations in murine embryonic neuronal cells: measurements in metabolic cell-culture chips.

We present a label-free in vitro method for testing the toxic potentials of chemical substances using primary neuronal cells. The cells were prepared from 16-day-old NMRI mouse embryos and cultured on silicon chips (www.bionas.de) under the influence of different parathion concentrations with sensors for respiration (Clark-type oxygen electrodes), acidification (pH-ISFETs) and cell adhesion (interdigitated electrode structures, IDES). After 12 days in vitro, the sensor readouts were simultaneously recorded for 350 min in the presence of parathion applying a serial 1:3 dilution. The parathion-dependent data was fitted by logistic functions. IC(50) values of approximately 105 µM, 65 µM, and 54 µM were found for respiration, acidification, and adhesion, respectively. An IC(50) value of approximately 36 µM was determined from the intracellular ATP-levels of cells, which were detected by an ATP-luminescence assay using micro-well plates. While the intracellular ATP level and cell adhesion showed no deviation from a simple logistic decay, increases of approximately 29% in the respiration and 15% in the acidification rates above the control values were found at low parathion concentrations, indicating hormesis. These increases could be fitted by a modified logistic function. We believe that the label-free, continuous, multi-parametric monitoring of cell-metabolic processes may have applications in systems-biology and biomedical research, as well as in environmental monitoring. The parallel characterization of IC(50) values and hormetic effects may provide new insights into the metabolic mechanisms of toxic challenges to the cell.

Effectiveness of a call/recall system in improving compliance with cervical cancer screening: a randomized controlled trial.

OBJECTIVE: To determine the effectiveness of a simple call/recall system in improving compliance with cervical cancer screening among women not screened in the previous 3 years. DESIGN: Prospective randomized controlled study. SETTING: Two family medicine clinics (1 urban, 1 rural) affiliated with Memorial University of Newfoundland, St. John's. PARTICIPANTS: A sample of women aged 18-69 years who were listed as patients of the clinics but who had not had a Papanicolaou test (Pap test) within the 3 years before the start of the study. Of 9071 women listed as patients 1360 (15.0%) had not undergone screening in the previous 3 years. A random sample of 650 were selected, 209 of whom were excluded because they had had a hysterectomy, had had a recent Pap test, had moved or had records containing clerical errors. This left 441 women for the study. INTERVENTION: The 221 women in the intervention group were sent a letter asking them to seek a Pap test and a reminder letter 4 weeks later. The 220 in the control group were sent no letters. MAIN OUTCOME MEASURES: Number of women who had a Pap test within 2 months and 6 months after the first letter was sent. RESULTS: Within 2 months, more women in the intervention group than in the control group had been screened (2.8% [5/178] and 1.9% (4/208] respectively). There was also a difference between the overall proportions at 6 months (10.7% [19/178] and 6.3% [13/208] respectively). None of the differences was statistically significant. CONCLUSION: A letter of invitation is not sufficient to encourage women who have never or have infrequently undergone a Pap test to come in for cervical cancer screening. The effectiveness of added recruitment methods such as opportunistic screening by physicians, follow-up by telephone and the offer of a specific appointment should be evaluated.

Lung cancer in Newfoundland, Canada.

In this study 1,466 cases of primary lung cancer diagnosed between 1974 and 1983 and reported to the Provincial Tumour Registry, were reviewed. The incidence of lung cancer in Newfoundland has been lower than that in Canada as a whole. The age-adjusted rates for Canadian males and females were 56 and 14 per 100,000 compared to 45 and 7 in Newfoundland. Census division rates showed no association with socioeconomic indicators. The rate in one census division was higher (63 vs 53) most probably because of the higher risk of men who worked in the St. Lawrence fluorspar mines. Although Newfoundland's current smoking rates (39% of men over 15 and 29% of women over 15) are high, this is not reflected in lung cancer rates. Smoking was not widely accepted in rural areas until the time of World War II, and Newfoundland's lower rates may be due to this delay in exposure.

Inflammatory factors produced by sensitized guinea-pig peripheral blood lymphocytes.

The supernatants obtained from stimulated tuberculin-sensitive guinea-pig peripheral blood lymphocytes contain factors that induce a cutaneous inflammatory response in normal guinea-pigs similar to the tuberculin reaction and inhibit the migration of normal guinea-pigs peritoneal exudate cells. There appears to be a correlation between the presence of in vitro migration inhibitory activity and inflammatory activity in vivo.

Inflammation-inducing factors from human lymphocytes. Correlation with polymorphonuclear leucocyte migration enhancement of inhibition.

Factors capable of inducing inflammatory reactions in the skin of normal guinea pigs have been demonstrated in culture supernatants from PPD-stimulated human mononuclear cells from tuberculin-positive donors. The reaction is characterised by erythema, induration and infiltration with mononuclear cells and some polymorphonuclear leucocytes. These supernatants either enhance or do not affect polymorph migration in the leucocyte migration test. Supernatants that inhibit migration in vitro produce a marked polymorph infiltration upon intradermal injection.

A comparison of PAH, PCB, and pesticide concentrations in air at two rural sites on Lake Superior.

Atmospheric concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and pesticides were compared at Brule River and Eagle Harbor, two rural sites on Lake Superior that are part of the Integrated Atmospheric Deposition Network (IADN). Brule River lies 40 km southwest of Duluth, MN, a small industrial city, and Eagle Harbor is in Michigan's upper peninsula, 400 km east of Brule River. Pesticide and PCB concentrations were similar at both sites. Day-by-day regression analyses of the data showed that PAH concentrations, an indication of urban contamination, were significantly higher at Brule Riverthan at Eagle Harbor. Concentration ranges for all compounds at both sites were well within global background levels, despite the differences observed between the two sites. Clearly, pollution from Duluth is influencing PAH concentrations at Brule River more than at Eagle Harbor.

HLA haplotypes in a genetic isolate in Newfoundland. A population showing 8% homozygosity and a familial aggregate of lymphoma and immunodeficiency cases.

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28,Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18,HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 20 HLA homozygous individuals, of these 15 were HLA-A2, b12/a2, b12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.

HLA in familial Hodgkin's disease. Results and a new hypothesis;.

A familial aggregate of seven cases of Hodgkin's disease (HD) has been investigated by HLA typing. Over 600 people in the immediate population (i.e. about half) have been HLA typed and haplotypes have been obtained for 95% of them. It was expected that the cases would share a particular HLA haplotype or at least that they would have one or two HLA antigens of the same series in common. However, this was not the case so no simple idea of association of HLA with HD cases was upheld. When antigen frequencies were examined in the whole population, it was found that HLA B18 increased progressively in incidence from 0.08 to 0.4 in successive groups of individuals each one more closely related to the HD cases. Similarly the community with the highest incidence of HD also had the highest incidence of B18. Thus B18, which in the world figures carries the highest relative risk, emerged as important in this study. Of four proposed interpretations of the data, we are most interested in the idea that the important HLA association is at a population level rather than at the level of the individual patient. A hypothesis, based on the concept of a "healthy carrier" for the HD agent, explains how such an association might operate. It is possible that B18-linked complement deficiency could be the basis for such a carrier state.

Atlantic Breast Cancer Information Project: formation of a "town-gown" partnership.

The Atlantic Breast Cancer Information Project (ABCIP) is one of 5 breast cancer information exchange projects funded by Health Canada. This article describes the development of ABCIP and thereby contributes to the limited knowledge on successful partnership formation in the face of restraints but with support from enabling factors. Partnership formation is presented in the context of alliances in management, coalitions in health promotion, and social movements. The restraining factors were the inertia of the status quo, provincial structures and concerns about empowering others. The enabling factors fell into 3 categories: timely logistics, roles of individuals who participated at critical points in the process, and the evolution of a supportive cultural environment. The article outlines ABCIP's achievements to date.

An immunoglobulin in Newfoundland with the genetic marker Glm/z) without Glm(a) in five siblings: a possible hybrid molecule.

Inheritance of Glm(z) without Glm(a) was found in five members of a Newfoundland family. The investigations were suggestive for the transmission of a Gm haplotype (z;n-;g) coding for Glm(z) and nGlm(a) at the Fd and Fc parts, respectively, of the IgGl heavy chain.