The cost of Mycobacterium avium complex lung disease in Canada, France, Germany, and the United Kingdom: a nationally representative observational study.

BACKGROUND: Management of nontuberculous mycobacterial lung disease (NTMLD) consists of a long-term multi-drug antibiotic regimen, yet many patients do not achieve culture conversion. We estimated the NTMLD-related direct medical costs in Canada, France, Germany, and the United Kingdom (UK) among refractory patients who were infected with Mycobacterium avium complex (MAC), without concomitant cystic fibrosis, tuberculosis, or HIV. METHODS: We conducted a retrospective observational physician survey of nationally representative samples. The survey captured anonymized information about patients' treatment histories for NTMLD-related health care resource utilization over a 24-month period. We summarized NTMLD-related resource use and estimated the total economic burden, from each country's health care payer perspective. RESULTS: In total, 59 physicians provided data on 157 patients. The average person time observed during the 24-month period was 1.7 years (SD: 0.4); 17% of patients died by the end of the study period. The major components of NTMLD-related direct medical costs among refractory patients were hospitalizations (varying from 29% of total annual costs in the UK to 69% in France), outpatient visits (8% in Canada to 51% in the UK), and outpatient testing such as post-diagnostic sputum testing, bronchial wash/lavage, spirometry, biopsies, imaging, and electrocardiograms (5% in France to 35% in Canada). In this patient cohort, the average direct medical costs per person-year, in local currencies, were approximately $16,200 (Canada), €11,600 (Germany), €17,900 (France) and £9,700 (UK). CONCLUSIONS: Based on this study's findings, we conclude that managing patients with refractory NTMLD caused by MAC is associated with a substantial economic burden.

The use of large databases to inform the development of an intestinal scoring system for the poultry industry.

There is increasing interest among the poultry industry to develop a comprehensive index that can be used to evaluate overall intestinal health and impact on production performance. The Intestinal Integrity (I2) index is a quantitative measurement tool used to assess the intestinal health of flocks that use the Health Tracking System (HTSi), a global surveillance system developed by Elanco Animal Health that captures flock-level information on health and performance. To generate an I2 index score for a flock, the presence of 23 intestinal health conditions is assessed and recorded, then entered into a mathematical equation. The objective of this study was to use data from the HTSi dataset to investigate the association between health conditions contained within the I2 index and five performance outcomes: average daily gain (ADG), mortality during the first week, feed conversion ratio (FCR), European Production Efficiency Factor (EPEF), and percent livability. At the time of analysis, the HTSi dataset contained information from the years 2006-2015 on 921,646 individual bird necropsy records from over 153,576 flocks at 1,570 broiler production flows across 53 countries. Flock-level production data used for this study were available for a subset of this population, 33,212 total flocks representing 6 US and 4 UK production flows. A separate multivariable linear or logistic regression model, with farm as a random effect, was built for each of the five outcomes mentioned above. All models controlled for clustering of flocks within production flows. Significant associations were found between key performance indicators and ten intestinal conditions (gross E. acervulina, gross E. maxima, microscopic E. maxima, gizzard erosions, roundworms, excessive intestinal fluid, thin intestines, excessive intestinal mucus, feed passage, and necrotic enteritis) and two management parameters (production flow and down time). Results from this study demonstrate that large databases, such as the HTSi database, can be used to inform and evaluate changes that can optimize intestinal health, and hence welfare, productivity, and sustainability of the poultry industry. In addition, large databases can be used for monitoring and benchmarking intestinal health of poultry and informing the development of innovative indices such as the I2 index for scoring intestinal health and providing routine data for its calculation.

Weather and livestock risk factors for Escherichia coli O157 human infection in Alberta, Canada.

This study investigated the extent to which proximity to cattle and weather events in Alberta predispose human populations to E. coli O157 disease. Cases of human E. coli O157 infection in Alberta between 2004 and 2011 were obtained from the province's Communicable Disease Reporting System and Discharge Abstract Database. Regression models based on spatial area incorporated human infection data with livestock and weather covariates. A variety of regression models were applied (i.e. least squares, spatial lag/error, Poisson, negative binomial) to test the most appropriate approach. Ratios for the total number of calves, bulls and beef cows to human population were highlighted as significant cattle density variables in all final best-fitting models. Weather variables were not significant in final regression models averaged over the full study period. Our results provide evidence of a significant association between measures of cattle density and human E. coli O157 disease in Alberta.

Beyond diffusion: Modelling local and long-distance dispersal for organisms exhibiting intensive and extensive search modes.

The distribution of foragers on the landscape has important consequences to, for example, the spread rate of an invasive species or the outcrossing levels between neighbouring crops. Since forager distribution can be difficult to measure directly, mathematical models are often used to predict the population density of dispersing foragers on the landscape. We model organism movement using a diffusion framework in which the foraging population is divided into two subpopulations engaged in intensive and extensive search modes respectively. Movement in the intensive search mode (ISM) is modeled by diffusion, and movement in the extensive search mode (ESM) is modeled by advection. We show that our model provides a superior fit to organism movement data than more traditional diffusion or diffusion-advection models in which the forager population is considered homogeneous. Our results have implications for the understanding of dispersal in a wide variety of applications.

The role of penicillin G potassium in managing Clostridium perfringens in broiler chickens.

The efficacy of penicillin G potassium (Pot-Pen) administered via drinking water to manage necrotic enteritis (NE) was investigated in a Clostridium perfringens (CP) challenge study using 1600 broiler chickens assigned to one of four treatment groups: nonchallenged, nonmedicated; challenged, nonmedicated; challenged, Pot-Pen 0.2 g/L; challenged, Pot-Pen 0.4 g/L. Overall mortality due to NE was significantly reduced among Pot-Pen-treated pens; mortality due to other causes did not differ among the treatment groups. Among all birds, growth performance parameters were significantly improved among Pot-Pen-treated pens. When considering birds randomly sacrificed 4 days post-Pot-Pen initiation, mean NE lesion scores were greatest among the challenged, nonmedicated pens; only one of 80 randomly sacrificed birds treated with Pot-Pen had NE lesions. Among the nonmedicated control pens, body weight (BW) was significantly greater among birds that did not have NE-associated lesions. When sacrificed birds were stratified by NE lesion score, there were no significant differences in BW among the treatment groups. Results of this study suggest that CP-associated subclinical disease can significantly reduce broiler performance. Furthermore, the positive effects of treatment with Pot-Pen appeared to be associated with the prevention and/or treatment of NE-specific lesions.

FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.

Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.

Distinct distribution of HPV types among cancer-free Afro-Caribbean women from Tobago.

Human papillomavirus (HPV), a sexually transmitted virus causes cervical carcinomas, and is associated with approximately 36% of oropharyngeal tumours where HPV16 is the predominant genotype. The cervical cancer incidence rate in Trinidad and Tobago is about two times higher than the worldwide rate. We have for the first time determined the prevalence and type distribution of cervical HPV infections among cancer-free Afro-Caribbean women from Tobago, and compared it with the HPV subtypes observed in their oral cavity. Thirty-five per cent of the women were cervical HPV positive. The most common high-risk type detected in the cervix was HPV45 rather than HPV16 and 18. The prevalence of HPV infection in the oral mucosa was 6.6%. The distribution of HPV genotypes in healthy Tobagonian women is different from that reported in studies conducted in European and North American populations. This may have important implications for vaccine introduction in this and other Afro-Caribbean countries.

Physicians to the Duke of Clarence.

Halliday and Beattie came from the small village of Dalton in Dumfriesshire and both became physicians to the Duke of Clarence, the King's brother. They had interesting and varied careers and accompanied their royal patron on his frequent visits to the Continent. Halliday served in the Peninsula War and at Waterloo while Beattie became a close friend and confident of the Duke. Based on his visits to the Continent, Beattie produced a beautifully illustrated series of travel books.

Burden and cost of gastroenteritis in a Canadian community.

This study estimated the health burden and costs associated with gastroenteritis in the City of Hamilton (Ontario, Canada). The number of cases, number of different resource units used, and cost per resource unit were represented by probability distributions and point estimates. These were subsequently integrated in a stochastic model to estimate the overall burden and cost in the population and to depict the uncertainty of the estimates. The estimated mean annual cost per capita was Can dollar 115. The estimated mean annual cost per case was Can dollar 1,089 and was similar to other published figures. Gastroenteritis represented a significant burden in the study population, with costs high enough to justify prevention efforts. These results, currently the most accurate available estimates for a Canadian population, can inform future economic evaluations to determine the most cost effective measures for reducing the burden and cost of gastroenteritis in the community.

Magnitude and distribution of acute, self-reported gastrointestinal illness in a Canadian community.

To estimate the magnitude and distribution of self-reported, acute gastrointestinal illness in a Canadian-based population, we conducted a retrospective, cross-sectional telephone survey of approximately 3500 randomly selected residents of the city of Hamilton (Ontario, Canada) from February 2001 to February 2002. The observed monthly prevalence was 10% (95 % CI 9.94-10.14) and the incidence rate was 1.3 (95 % CI 1.1-1.4) episodes per person-year; this is within the range of estimates from other developed countries. The prevalence was higher in females and in those aged < 10 years and 20-24 years. Overall, prevalence peaked in April and October, but a different temporal distribution was observed for those aged < 10 years. Although these data were derived from one community, they demonstrate that the epidemiology of acute gastrointestinal illness in a Canadian-based population is similar to that reported for other developed countries.

Risk factors for Salmonella typhimurium DT104 and non-DT104 infection: a Canadian multi-provincial case-control study.

To identify risk factors for sporadic Salmonella Typhimurium definitive phage-type 104 (DT104) and non-DT104 diarrhoeal illness in Canada, we conducted a matched case-control study between 1999 and 2000. Cases were matched 1:1 on age and province of residence. Multivariate analysis suggested that recent antibiotic use [odds ratio (OR) 5.2, 95% confidence interval (CI) 1.8-15.3], living on a livestock farm (OR 4.9, 95% CI 1.9-18.9), and recent travel outside Canada (OR 4.1, 95% CI 1.2-13.8) are independent risk factors for DT104 illness. Similar analyses suggested that recent travel outside North America is a sizable risk factor for non-DT104 illness (OR 66.8, 95% CI 6.7-665.3). No food exposure was a risk factor in either analysis. Educating health-care providers and the public about appropriate antibiotic use and antimicrobial resistance is important. Appropriate administration of antibiotics to livestock, particularly cattle, and hygienic measures such as handwashing after contact with farm animals may reduce risk. Travel represents an important and probably underestimated risk factor for sporadic illness with S. Typhimurium. Improved national surveillance and detailed investigation of travel-related illness are required.

The cold-water coral Lophelia pertusa (Scleractinia) and enigmatic seabed mounds along the north-east Atlantic margin: are they related?

In this study, an updated distribution of Lophelia pertusa between the Porcupine Seabight and Norwegian shelf is presented. It seems unlikely that enigmatic mound structures observed at water depths of more than 570 m during acoustic seabed surveys, particularly to the west of the Shetland Islands, are related to the occurrence of L. pertusa. At these depths in the Faroe-Shetland Channel, the predominant influence of cold Arctic water precludes its growth. Iceberg dumpsites are also considered unlikely explanations for the origin of these mounds, and they are interpreted as most likely to be related to the release of fluids at the seabed. When mound structures were investigated, no scleractinian corals were recovered at water depths >500 m. This study shows the importance of seabed temperature as an environmental control on cold-water coral distribution. The significance of cold-water coral habitats in sustaining high levels of local-scale biodiversity is now becoming apparent in parallel with increased hydrocarbon extraction and fishing activity beyond the shelf edge. There is growing evidence that these areas have been marked by the passage of deep-water trawls. It seems likely that trawling activity has already reduced the extent of cold-water coral distribution in this region of the north-east Atlantic.

The Chinese hamster FANCG/XRCC9 mutant NM3 fails to express the monoubiquitinated form of the FANCD2 protein, is hypersensitive to a range of DNA damaging agents and exhibits a normal level of spontaneous sister chromatid exchange.

Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane. Six FA genes have been cloned including a gene designated XRCC9 (for X-ray Repair Cross Complementing), isolated using a mitomycin C-hypersensitive Chinese hamster cell mutant termed UV40, and subsequently found to be identical to FANCG. A nuclear complex containing the FANCA, FANCC, FANCE, FANCF and FANCG proteins is needed for the activation of a sixth FA protein FANCD2. When monoubiquitinated, the FANCD2 protein co-localizes with the breast cancer susceptibility protein BRCA1 in DNA damage induced foci. In this study, we have assigned NM3, a nitrogen mustard-hypersensitive Chinese hamster mutant to the same genetic complementation group as UV40. NM3, like human FA cell lines (but unlike UV40) exhibits a normal spontaneous level of sister chromatid exchange. We show that both NM3 and UV40 are also hypersensitive to other DNA crosslinking agents (including diepoxybutane and chlorambucil) and to non-crosslinking DNA damaging agents (including bleomycin, streptonigrin and EMS), and that all these sensitivities are all corrected upon transfection of the human FANCG/XRCC9 cDNA. Using immunoblotting, NM3 and UV40 were found not to express the active monoubiquitinated isoform of the FANCD2 protein, although expression of the FANCD-L isoform was restored in the FANCG cDNA transformants, correlating with the correction of mutagen-sensitivity. These data indicate that cellular resistance to these DNA damaging agents requires FANCG and that the FA gene pathway, via its activation of FANCD2 and that protein's subsequent interaction with BRCA1, is involved in maintaining genomic stability in response not only to DNA interstrand crosslinks but also a range of other DNA damages including DNA strand breaks. NM3 and other "FA-like" Chinese hamster mutants should provide an important resource for the study of these processes in mammalian cells.

A descriptive analysis of giardiasis cases reported in Ontario, 1990-1998.

Cases of giardiasis in Ontario were described using notifiable disease data from the Ontario Ministry of Health for the years 1990-1998 inclusive. The mean annual age- and sex-adjusted incidence rate was 25.77 cases per 100,000 population for the 25,289 cases reported. Children under five years of age had the highest incidence of disease. Males had a higher mean annual incidence in all age groups. Four deaths occurred among cases. The most frequently reported symptoms were loose stools or watery diarrhea (50.1%). A seasonal pattern was noted, peaking in late summer and early autumn. The most frequently reported probable risk settings were the home (40.1%) and travel (39.1%). The study findings suggest that a high proportion of cases occur in urban areas and spatial analysis showed the highest incidence around Lake Huron and Georgian Bay. Unfiltered water and person-to-person contact are believed to be important sources of infection.

Epstein-Barr virus encoded latent membrane protein-1 induces epithelial cell proliferation and sensitizes transgenic mice to chemical carcinogenesis.

EBV is found to be associated with 100% of poorly or undifferentiated nasopharyngeal carcinomas, a tumor of epithelial origin. The latent membrane protein-1 (LMP1) of EBV, may play a causal role in the development of this disease. The experiments initiated here were designed to examine the activity of LMP1 in vivo in the epidermis of PyLMP1 transgenic mice in relation to its putative role in carcinogenesis. Transgenic positive epidermis showed a 2-3-fold increase in the mitotic index, coupled with an increased level of expression of proliferative cytokeratin markers (K6 and K14) over controls. These results provide direct evidence that LMP1 induces proliferation in otherwise normal epithelial cells in vivo. To assess the role of LMP1 in tumorigenic progression, transgenic mice were treated topically with chemical carcinogens. PyLMP1 mice were highly sensitive to chemical carcinogens, developing significantly more small papillomas at a faster rate than controls. Furthermore, LMP1 could substitute for 12-O-tetradecanoylphorbol-13-acetate treatment in tumor promotion. However, LMP1 inhibited expansion of the benign lesions and did not enhance progression of the lesions to carcinomas or the progression of these to the more malignant spindle cell carcinomas. These data demonstrate that, early in the carcinogenic process, LMP1 acts as a tumor promoter after chemical initiation; but, paradoxically, it may also introduce a hurdle against expansion or progression of a lesion.

Descriptive analysis of endemic cryptosporidiosis cases reported in Ontario, 1996-1997.

Endemic cryptosporidiosis in Ontario was studied using notifiable disease data from the Ontario Ministry of Health for the years 1996-1997 inclusive. For this study period, 451 endemic cases were identified, corresponding to a provincial mean annual age- and sex-adjusted incidence rate of 2.13 cases per 100,000. Children under five years of age had the highest incidence of disease. Males had a higher incidence than females, except for those 15-19 years of age. Five percent of cases were reported as HIV-positive or having AIDS. The proportion of cases occurring between July and November inclusive (63%) was significantly higher than expected (42%) assuming no seasonal variation (p < 0.01). The proportion of rural cases observed (29%) was significantly higher than expected (17%) based on the Ontario population (p < 0.01). Travel to or prior residence in an endemic area was identified in 22% of the cases where a risk setting was reported (n = 265).