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.

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.

Hemoglobin Istanbul: substitution of glutamine for histidine in a proximal histidine (F8(92) ).

A presumably spontaneous mutation has resulted in the formation of Hemoglobin (Hb) Istanbul in which glutamine is substituted for histidine in the proximal position of the beta-chain (F8(92)). The anemia and other physiological effects that occur in the presence of Hb Istanbul were much ameliorated by splenectomy. Hb Istanbul is a relatively unstable molecule which produces a rather moderate case of "unstable hemoglobin hemolytic anemia."In the determination of structure, a method of preferential cleavage of an aspartyl-proline bond at residues 99-100 of the beta-chain was used.

Hemoglobin Louisville (beta-42 (CD1) phe-leu): an unstable variant causing mild hemolytic anemia.

An unstable hemoglobin variant termed Hb Louisville, was found in four members of a Caucasian family, who were suffering from a mild hemolytic anemia. The variant showed a decreased stability upon warming at 65 degrees C and an increased tendency to dissociate in the presence of sulfhydryl group-blocking agents. The structural abnormality was identified as a replacement of phenylalanyl residue in position 42 (CD1) by a leucyl residue. Substitution of this phenylalanyl residue, which participates in the contact with heme, by a nonpolar leucyl residue has apparently less severe consequences than a replacement of the same residue by a polar seryl residue as in Hb Hammersmith. Oxygen equilibrium studies of total hemolysate from one Hb Louisville heterozygote indicated a decreased oxygen affinity, a marked decrease in heme-heme interaction, and a normal Bohr effect. Studies with isolated Hb Louisville were not made because it was not possible to separate the variant from normal Hb A.

Hemoglobin Savannah (B6(24) beta-glycine is greater than valine): an unstable variant causing anemia with inclusion bodies.

An abnormal hemoglobin, termed Hb Savannah, was found in red cell hemolysate of a young Caucasian girl with severe hemolytic anemia. The presence of this unstable variant became evident when inclusion bodies appeared rapidly upon exposure of red cells to redox dyes and a large percentage of hemoglobin in hemolysate precipitated on warming to 65 degrees C. Treatment of the hemoglobin with p-hydroxymercuribenzoate (PMB) caused a rapid dissociation into monomers; starch-gel electrophoresis of PMB-treated hemoglobin showed the presence of abnormal beta-chains. Data from structural studies of isolated beta-chains indicated substitution of a valyl residue for the normally occurring glycyl residue at position 24, which corresponds to helical residue B6. A similar substitution but with an arginine replacing the glycyl residue has been observed in Hb Riverdale-Bronx. The glycine to valine substitution will change the relationship of the B and the E helices which results in extensive conformational changes in the beta-chain. This change presumably causes an increased dissociation of the hemoglobin molecule into dimers and probably monomers, and a decreased stability of the alphabeta-dimers. The hemoglobin abnormality may be the result of a fresh mutation because the abnormality is not present in the parents nor in any of the seven siblings.

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.

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.

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.

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.

The chemical heterogeneity of human hemoglobin F. Direct evidence for the existence of three types of gamma chain, the G gamma I, A gamma I, and A gamma T chains.

Direct evidence is presented for the existence of three types of gamma chain of human hemoglobin F. A modification of a CM-cellulose chromatographic method has allowed the incomplete separation of these gamma chains while high pressure liquid chromatography and fingerprint analyses of tryptic peptides of zones of the isolated gamma chains, and amino acid analyses of isolated peptides were used to identify the chains. These studies have shown that the presence of a glycyl residue in position 136 (G gamma chain) is directly related to that of an isoleucyl residue in position 75 (I gamma chain), thus indicating the existence of an G gamma I chain, and that the presence of an alanyl residue in position 136 (A gamma chain) can be related to that of an isoleucyl residue in position 75, thus suggesting the existence of an A gamma I chain. When the isoleucyl residue at positive 75 is replaced by a threonyl residue, invariably it is related to the alanyl substitution at position 136 (A gamma T chain). These data support indirect evidence from case analyses and family studies which were published before, and indicate that the T gamma chain is an allele of the A gamma which should be renamed the A gamma T chain.

Hemoglobin-A2-Coburg or alpha2delta2116Arg leads to His (G18).

Hemoglobin-A2-Coburg or alpha2delta2-116 Arg leads to His (G18) has been found in members of a family of Sicilian origin. The propositus is heterozygous for hemoglobin-A2-Coburg as well as for beta-thalassemia, and family data indicate that the gene for the delta-Coburg chain is in trans of the beta-thalassemia determinant.

Hb F-Forest Park, a new A gamma variant with two amino acid substitutions, 75(E19)Ile----Thr and 73(E17)Asp----Asn, which can be identified in adults by gene-mapping analysis.

The discovery is reported of a new fetal hemoglobin (Hb) variant which has an abnormal A gamma globin chain with two substitutions, namely 73(E17) Asp----Asn and 75(E19) Ile----Thr (the latter is also seen in the common A gamma T chain). This A gamma T variant was present in a female Caucasian newborn; its quantity at birth was 12.2% of the total Hb F (including F, F1 and F-Forest Park). Extensive gene-mapping analyses with a battery of restriction enzymes and probes identified normal globin gene arrangements in the baby and several relatives, but a -G gamma-G gamma-globin gene arrangement was present in the father, paternal grandmother and half-sister. The Hb F-Forest Park anomaly could be detected in the father, paternal grandfather, half-brother and the baby through digestion of their DNA's with SfaNI and hybridization with the gamma IVS-II probe, because the G----A base substitution at codon 73 leads to loss of a restriction site and to the occurrence of an abnormal fragment.

Hb A2-Wrens or alpha 2 delta 2 98(FG5) Val----Met, an unstable delta chain variant identified by sequence analysis of amplified DNA.

Data are reported for an 85-year-old black make who had an HPFH condition on one chromosome and a suspected 'delta-thalassemia' on the other. Sequence analysis of amplified DNA of an appropriate segment of the delta-globin gene identified a GTG to ATG mutation for codon 98 and thus a Val----Met replacement in the delta chain. This abnormality was confirmed by hybridization of amplified DNA with 32P-labeled synthetic probes and by the amino-acid composition of the isolated tryptic peptide delta T-11. Thus, the 'delta-thalassemia' is caused by the presence of an Hb A2 variant that is considered to be unstable to a similar extent as is Hb Köln, its beta chain counterpart.

Some physicochemical properties of hemoglobin-manitoba (alpha2 102Ser replaced by Arg (G9) beta2).

Hb-Manitoba was discovered in 1970 [1] in a Canadian family of British origin. Recently we observed the same variant in a second family, and found that the oxy-derivative of Hb-Manitoba is slightly unstable at 65 degrees C, dissociates less readily at alkaline pH than does Hb-A, and forms asymmetric hybrids with other hemoglobins which are readily detectable by electrophoresis.

Identification of hemoglobin G-Philadelphia (alpha 68 Asn replaced by Lys) and hemoglobin Matsue-Oki (alpha 75 Asp replaced by Asn) in a black infant.

Two alpha-chain variants, Hb G-Philadelphia and Hb Matsue-Oki, were present in members of a relatively large black family from South Carolina. The four Hb G-Philadelphia heterozygotes averaged 35.6% Hb G, suggesting the presence of an alpha-thalassemia-2 condition in cis to the Hb G mutation, which was confirmed by DNA structural analysis. The seven Hb Matsue-Oki heterozygotes averaged 22.2% Hb MO and likely have four active alpha-chain genes. One infant was a compound heterozygote for the two Hb variants which could not be separated from each other. The quantity of Hb G plus Hb MO was 58% by DEAE-cellulose chromatography and 69% by chain analyses. These results and the family data indicate that this child had three active alpha-chain genes, of which one regulated the synthesis of the normal alpha chain, one was mutated to give the alpha G chain, and one to give the alpha MO chain. The amino acid substitutions in Hb G-Philadelphia and Hb Matsue-Oki are located in the tryptic peptide alpha T-9, which is 29 amino acid residues long. Structural analyses of these abnormalities made use of high-pressure liquid chromatography for the separation of both tryptic and thermolytic peptides and of a highly sensitive ultra-micro sequencing procedure. Although the alpha 68 Asn replaced by Lys substitution is readily demonstrable in Hb G-Philadelphia the elucidation of the alpha 75 Asp replaced by Asn replacement in Hb Matsue-Oki was greatly facilitated by the use of these microprocedures.

Hb J-Antakya or alpha 2 beta (2)65(E9)Lys----Met in a Turkish family and Hb complutense or alpha 2 beta (2)127(H5)Gln----Glu in a Spanish family; correction of a previously published identification.

Almost 10 years ago we reported in this journal the characterization of Hb Hacettepe or alpha 2 beta (2)127(H5)Gln----Glu. Unfortunately, we have to conclude that the original characterization of this Turkish variant was in error. The corrected data are presented in this short communication. The variant (alpha 2 beta (2)65(E9)Lys----Met) was (re)named Hb J-Antakya, after the city where the family resides. An abnormal Hb, observed in a Spanish family and named Hb Complutense, had the beta 127 Gln----Glu substitution, erroneously assigned to the Turkish variant.

Heterozygosity for the IVS-I-5 (G-->C) mutation with a G-->A change at codon 18 (Val-->Met; Hb Baden) in cis and a T-->G mutation at codon 126 (Val-->Gly; Hb Dhonburi) in trans resulting in a thalassemia intermedia.

We have analyzed the hemoglobins of a young German patient with beta-thalassemia intermedia and of his immediate family and included in these studies an evaluation of possible nucleotide changes in the beta-globin genes through sequencing of amplified DNA. One chromosome of the propositus and one of his father's carried the GTG-->GGG mutation at codon 126 leading to the synthesis of Hb Dhonburi or alpha 2 beta (2)126(H4)Val-->Gly; this variant is slightly unstable and is associated with mild thalassemic features. His second chromosome and one of his mother's had the common IVS-I-5 (G-->C) mutation that leads to a rather severe beta(+)-thalassemia and the GTG-->ATG mutation at codon 18, resulting in the replacement of a valine residue by a methionine residue. This newly discovered beta-chain variant, named Hb Baden, was present for only 2-3% in both the patient and his mother. This low amount results from a decreased splicing of RNA at the donor splice-site of the first intron that is nearly completely deactivated by the IVS-I-5 (G-->C) thalassemic mutation. The chromosome with the codon 18 (GTG-->ATG) and the IVS-I-5 (G-->C) mutations has thus far been found only in this German family; analysis of 51 chromosomes from patients with the IVS-I-5 (G-->C) mutation living in different countries failed to detect the codon 18 (GTG-->ATG) change.

Hb natal or alpha 2(minus Tyr-Arg) beta 2: a high oxygen affinity alpha chain variant with a deleted carboxy-terminus resulting from a TAC----TAA (Tyr----terminating codon) mutation in codon alpha 140.

The discovery is reported of a fast-moving alpha chain variant (Hb Natal) which is characterized by a shortened alpha polypeptide chain because of the deletion of the Tyr-Arg carboxy-terminal residues. Through amplification of appropriate segments of DNA and hybridization with synthetic oligonucleotide probes, it was possible to detect a C----A mutation in codon 140 of the alpha 2 globin gene, which causes a change in the codon for tyrosine to a terminating codon. Hb Natal or alpha 2 (minus Tyr-Arg) beta 2 has a high affinity for oxygen without a Bohr effect and heme-heme interaction. These results provide direct evidence for the importance of the tyrosine residue at alpha 140 in the oxygenation-deoxygenation process.