Rust (Puccinia emaculata) Management and Impact on Biomass Yield in Switchgrass.

Rust, putatively caused by Puccinia emaculata, is a widespread and potentially damaging disease of switchgrass, a crop produced as feedstock for livestock and bioenergy. Azoxystrobin, chlorothalonil, and myclobutanil were applied at 1-, 2-, 3-, or 4-week intervals for 12 to 14 weeks to the vegetatively propagated switchgrass cultivar Cloud Nine to assess fungicide selection and application interval for the control of rust as well as the impact of this disease on switchgrass biomass yield. Although rust severity significantly differed among study years, azoxystrobin and myclobutanil were often equally and more effective than chlorothalonil at controlling rust, with superior disease control coming at shorter application intervals compared with extended application intervals. Year, product, application interval, and product × interval significantly impacted dry biomass yield, which was greatest in 2016 and lowest in 2014. Dry biomass yield protection was significantly better with azoxystrobin and myclobutanil applications than with chlorothalonil or no fungicide. Linear regression models with the final disease rating, as well as with the area under disease progress curve in each year, were significant, but coefficients of determination were low to moderate (0.21 < R2 < 0.60), indicating that rust response and subsequent disease impact on dry biomass yield were impacted by other factors. From our models, an estimated 3 to 5% biomass decline was calculated for each 10% increment in rust-related leaf necrosis observed at the final September rating date. With rust-related leaf necrosis ≥80% by 1 September in each of 4 study years, biomass yield may be reduced by 24 to 40% if rust problems are not managed in switchgrass crops.

Functionally weighted airway sparing (FWAS): a functional avoidance method for preserving post-treatment ventilation in lung radiotherapy.

Recent changes to the guidelines for screening and early diagnosis of lung cancer have increased the interest in preserving post-radiotherapy lung function. Current investigational approaches are based on spatially mapping functional regions and generating regional avoidance plans that preferentially spare highly ventilated/perfused lung. A potentially critical, yet overlooked, aspect of functional avoidance is radiation injury to peripheral airways, which serve as gas conduits to and from functional lung regions. Dose redistribution based solely on regional function may cause irreparable damage to the 'supply chain'. To address this deficiency, we propose the functionally weighted airway sparing (FWAS) method. FWAS (i) maps the bronchial pathways to each functional sub-lobar lung volume; (ii) assigns a weighting factor to each airway based on the relative contribution of the sub-volume to overall lung function; and (iii) creates a treatment plan that aims to preserve these functional pathways. To evaluate it, we used four cases from a retrospective cohort of SAbR patients treated for lung cancer. Each patient's airways were auto-segmented from a diagnostic-quality breath-hold CT using a research virtual bronchoscopy software. A ventilation map was generated from the planning 4DCT to map regional lung function. For each terminal airway, as resolved by the segmentation software, the total ventilation within the sub-lobar volume supported by that airway was estimated and used as a function-based weighting factor. Upstream airways were weighted based on the cumulative volumetric ventilation supported by corresponding downstream airways. Using a previously developed model for airway radiosensitivity, dose constraints were determined for each airway corresponding to a <5% probability of airway collapse. Airway dose constraints, ventilation scores, and clinical dose constraints were input to a swarm optimization-based inverse planning engine to create a 3D conformal SAbR plan (CRT). The FWAS plans were compared to the patients' prescribed CRT clinical plans and the inverse-optimized clinical plans. Depending on the size and location of the tumour, the FWAS plan showed superior preservation of ventilation due to airflow preservation through open pathways (i.e. cumulative ventilation score from the sub-lobar volumes of open pathways). Improvements ranged between 3% and 23%, when comparing to the prescribed clinical plans, and between 3% and 35%, when comparing to the inverse-optimized clinical plans. The three plans satisfied clinical requirements for PTV coverage and OAR dose constraints. These initial results suggest that by sparing pathways to high-functioning lung subregions it is possible to reduce post-SAbR loss of respiratory function.

Multiyear Regional Evaluation of Foliar Fungicide Applications for Cotton Target Spot Management in the Southeastern United States.

Fungicide programs for managing target spot of cotton caused by Corynespora cassiicola were evaluated over 15 site-years in the southeastern United States between 2014 and 2016. Two cultivars, hypothesized to vary in target spot susceptibility, PhytoGen 499WRF (PHY499) and Deltapine 1137B2RF (DPL1137), and four fungicides (azoxystrobin, flutriafol, pyraclostrobin, pyraclostrobin + fluxapyroxad) plus nontreated control, were compared. Fungicide programs consisted of 1) a single application at first flower or disease onset and 2) the first application followed by a second 14 days later. Treatments were applied in a factorial, randomized complete block design. Target spot onset and severity varied among site-years. Except when severity was low, target spot-associated defoliation was greater on PHY499 than on DP1137. Fungicides delayed disease development and defoliation, but application number had little impact. Based on a meta-analysis of 15 site-years, pyraclostrobin-based applications resulted in a 4 to 6% yield preservation, and yield preservation was greater at site-years with early disease onset and >40% target spot associated defoliation. Results suggest a single well-timed application of a pyraclostrobin-based fungicide reduces defoliation and protects cotton yield at locations with high target spot severity. Additional research is needed to identify risk factors for target spot-associated yield losses in cotton production systems.

Petrobactin Is Exported from Bacillus anthracis by the RND-Type Exporter ApeX.

Bacillus anthracis-a Gram-positive, spore-forming bacterium-causes anthrax, a highly lethal disease with high bacteremia titers. Such rapid growth requires ample access to nutrients, including iron. However, access to this critical metal is heavily restricted in mammals, which requires B. anthracis to employ petrobactin, an iron-scavenging small molecule known as a siderophore. Petrobactin biosynthesis is mediated by asb gene products, and import of the iron-bound (holo)-siderophore into the bacterium has been well studied. In contrast, little is known about the mechanism of petrobactin export following its production in B. anthracis cells. Using a combination of bioinformatics data, gene deletions, and laser ablation electrospray ionization mass spectrometry (LAESI-MS), we identified a resistance-nodulation-cell division (RND)-type transporter, termed ApeX, as a putative petrobactin exporter. Deletion of apeX abrogated export of intact petrobactin, which accumulated inside the cell. However, growth of ΔapeX mutants in iron-depleted medium was not affected, and virulence in mice was not attenuated. Instead, petrobactin components were determined to be exported through a different protein, which enables iron transport sufficient for growth, albeit with a slightly lower affinity for iron. This is the first report to identify a functional siderophore exporter in B. anthracis and the in vivo functionality of siderophore components. Moreover, this is the first application of LAESI-MS to sample a virulence factor/metabolite directly from bacterial culture media and cell pellets of a human pathogen.IMPORTANCEBacillus anthracis requires iron for growth and employs the siderophore petrobactin to scavenge this trace metal during infections. While we understand much about petrobactin biosynthesis and ferric petrobactin import, how apo-petrobactin (iron free) is exported remains unknown. This study used a combination of bioinformatics, genetics, and mass spectrometry to identify the petrobactin exporter. After screening 17 mutants with mutations of candidate exporter genes, we identified the apo-petrobactin exporter (termed ApeX) as a member of the resistance-nodulation-cell division (RND) family of transporters. In the absence of ApeX, petrobactin accumulates inside the cell while continuing to export petrobactin components that are capable of transporting iron. Thus, the loss of ApeX does not affect the ability of B. anthracis to cause disease in mice. This has implications for treatment strategies designed to target and control pathogenicity of B. anthracis in humans.

Inverse 4D conformal planning for lung SBRT using particle swarm optimization.

A critical aspect of highly potent regimens such as lung stereotactic body radiation therapy (SBRT) is to avoid collateral toxicity while achieving planning target volume (PTV) coverage. In this work, we describe four dimensional conformal radiotherapy using a highly parallelizable swarm intelligence-based stochastic optimization technique. Conventional lung CRT-SBRT uses a 4DCT to create an internal target volume and then, using forward-planning, generates a 3D conformal plan. In contrast, we investigate an inverse-planning strategy that uses 4DCT data to create a 4D conformal plan, which is optimized across the three spatial dimensions (3D) as well as time, as represented by the respiratory phase. The key idea is to use respiratory motion as an additional degree of freedom. We iteratively adjust fluence weights for all beam apertures across all respiratory phases considering OAR sparing, PTV coverage and delivery efficiency. To demonstrate proof-of-concept, five non-small-cell lung cancer SBRT patients were retrospectively studied. The 4D optimized plans achieved PTV coverage comparable to the corresponding clinically delivered plans while showing significantly superior OAR sparing ranging from 26% to 83% for D max heart, 10%-41% for D max esophagus, 31%-68% for D max spinal cord and 7%-32% for V 13 lung.

Flying under the radar: The non-canonical biochemistry and molecular biology of petrobactin from Bacillus anthracis.

The dramatic, rapid growth of Bacillus anthracis that occurs during systemic anthrax implies a crucial requirement for the efficient acquisition of iron. While recent advances in our understanding of B. anthracis iron acquisition systems indicate the use of strategies similar to other pathogens, this review focuses on unique features of the major siderophore system, petrobactin. Ways that petrobactin differs from other siderophores include: A. unique ferric iron binding moieties that allow petrobactin to evade host immune proteins; B. a biosynthetic operon that encodes enzymes from both major siderophore biosynthesis classes; C. redundancy in membrane transport systems for acquisition of Fe-petrobactin holo-complexes; and, D. regulation that appears to be controlled predominately by sensing the host-like environmental signals of temperature, CO2 levels and oxidative stress, as opposed to canonical sensing of intracellular iron levels. We argue that these differences contribute in meaningful ways to B. anthracis pathogenesis. This review will also outline current major gaps in our understanding of the petrobactin iron acquisition system, some projected means for exploiting current knowledge, and potential future research directions.

Insect Damage, Aflatoxin Content, and Yield of Bt Corn in Alabama.

Isoline pairs of hybrid corn, similar except for presence or absence of a Bt trait, were planted at eight sites across Alabama over three years. This study evaluated insect damage, yield, and aflatoxin levels as affected by the Bt traits, YieldGard Corn Borer (expressing Cry1Ab), Herculex I (expressing Cry1F), Genuity VT Triple PRO (expressing Cry1A.105 and Cry2Ab2), Agrisure Viptera 3111 (expressing Vip3Aa20 and Cry1Ab), and Genuity SmartStax (expressing Cry1A.105, Cry2Ab2, and Cry1F). When examined over all sites and years, hybrids with any of the included Bt traits had lower insect damage and higher yields. However, insect damage was not consistently correlated to yield. Bt traits expressing multiple proteins provided greater protection from corn earworm feeding than did traits for single proteins. Yields and aflatoxin levels were highly variable among sites although irrigated sites had higher yields than nonirrigated sites. Aflatoxins commonly accumulate in corn in the southeastern United States because of prevailing high temperatures and frequent dry conditions. Aflatoxin levels were not consistently associated with any factors that were evaluated, including Bt traits.

First Report of Impatiens Downy Mildew Caused by Plasmopara obducens in Alabama.

During spring 2012, potted impatiens (Impatiens walleriana Hook.f.) plants with symptoms of a foliar disease were found in several commercial greenhouses in Mobile County, Alabama. Symptomatic leaves were chlorotic with no distinct lesions, and quickly wilted and abscised from erect green stems. In summer 2012 and 2013, numerous landscape impatiens plants with similar symptoms were observed in a large area from Mobile County north to Lee County, Alabama. A downy mildew was observed on the lower surfaces of symptomatic and abscised leaves from all locations. It consisted of hyaline, monopodial sporangiophores and ovoid, hyaline sporangia. Sporangiophores, which emerged from stomata, consisted of apical branches arranged at right angles to the supporting branches; they measured 69 to 90 µm long with individual branches measuring 7 to 14 µm long. Sporangia were borne on the tips of sporangiophore branches and measured 10 to 16.5 × 17 to 22.5 µm. No oospores were observed. In 2013, symptomatic plants were obtained from two separate locations in Alabama (Mobile and Tallapoosa counties). Total genomic DNA was extracted directly from symptomatic plant tissue and the large ribosomal subunit DNA was amplified by PCR using primers NL-1 and NL-4 (1). From both isolates, amplicons of 600 and 775 bp were obtained. DNA from each amplicon of both isolates was purified, sequenced, and the sequences were deposited in GenBank (Accession Nos. KF956518 to 21). The sequences of the 600-bp amplicons were 99% similar to that of I. walleriana (JX142135); the sequences of the 775-bp amplicons were 99% similar to Plasmopara obducens isolates from Florida (JX217746), Ohio (JX142134), Serbia (HQ246451), and the United Kingdom (AY587558). In pathogenicity tests, 10 potted impatiens plants, I. walleriana'Super Elfin,' were inoculated with a sporangial suspension (1 × 105 sporangia/ml washed from infected leaves) from the Mobile County isolate, by spraying until runoff. Controls were inoculated with sterile water. Plants were incubated in a moist chamber at 21°C for 48 h and then maintained in a greenhouse at 22 to 25°C until symptom development. All inoculated plants developed symptoms of downy mildew within 10 days. Microscopic examination of the symptomatic tissue revealed sporangiophores and sporangia similar to those observed in naturally infected plants. Control plants showed no symptoms. To our knowledge, this is the first report of downy mildew caused by P. obducens on impatiens in Alabama. This disease has been reported to have a significant economic impact for growers throughout the United States (2,3). Impatiens downy mildew is likely to be a recurring problem in Alabama. References: (1) K. O'Donnell. Curr. Genet. 22:213, 1992. (2) A. Palmateer et al. Plant Dis. 97:687, 2013. (3) S. Wegulo et al. Plant Dis. 88:909, 2004.

First Report of Corynespora cassiicola-Incited Target Spot on Cotton in Alabama.

Target spot symptoms were first observed on dryland and irrigated cotton (Gossypium hirsutum L.) statewide in Alabama in 2011. Leaf spots first appeared in the lower canopy and spread upward through the canopy toward the shoot tips. Individual leaf spots were roughly circular, formed concentric rings of alternating light and dark brown bands, and were up to 10 mm in diameter. Leaves with multiple lesions senesced prematurely. In 2012, target spot symptoms were observed as early as 68 days after planting in Tallapoosa County, Alabama. The possible combination of early disease onset and frequent showers/irrigation triggered rapid premature defoliation in some fields in excess of 75% in susceptible cultivars (Phytogen 499). Estimated yield losses in select cultivars (Deltapine 1050 and Phytogen 499) exceeded 336 kg/ha seed cotton. In 2012, symptomatic leaves were obtained from two separate locations in Alabama (Baldwin and Tallapoosa counties). The fungus was isolated from lesions by single spores plated on antibiotic V8 agar (1) and incubated at 21°C for 2 weeks under 12-h light cycles. Conidiophores arising from the gray, flocculose colonies were simple, erect, cylindrical, brown or olivaceous, unbranched, with two to seven septa. Conidia were borne singly, ranging from subhyaline to olivaceous, obclavate to cylindrical, straight to slightly curved, contained 4 to 15 pseudosepta, and were 50 to 209 µm long and 7 to 15 µm wide. These characteristics were consistent with the original description of Corynespora cassiicola on cotton (2). The internal transcribed spacer region (ITS) of two isolates, one representing each location, was amplified using primers 2234c and 3126t targeting a 550-bp region of the ITS1, 5.8S rRNA gene, and ITS2 (3). Sequences revealed 99% similarity to C. cassiicola in NCBI (Accession Nos. AY238606 and JQ717069). In greenhouse pathogenicity tests, 10 cotton seedlings (Phytogen 499) were inoculated by spraying a fungal suspension (2 × 104 spores/ml) of each of the two isolates prepared from 2-week-old cultures until runoff. Controls were inoculated with sterile water. Cotton seedlings were incubated in a moist chamber at 21°C for 72 h. All plants inoculated with the fungus developed leaf spot symptoms in 6 days. The fungus was reisolated from five inoculated plants. DNA was extracted from each isolate, amplified using primer pair 2234c/3126t, and sequenced. Sequences (550-bp) from all isolates shared 99% similarity to other C. cassiicola sequences in GenBank (Accession Nos. AY238606 and JQ717069). Nucleotide sequence data reported are available in GenBank under Accession Nos. KC544017 to 23. This pathogen has been reported previously to be economically important on a number of other hosts. To our knowledge, this is the first report of C. cassiicola on cotton in Alabama. Given the increasing prevalence of this disease in Alabama, its confirmation is a significant step toward developing management recommendations for growers. References: (1) L. J. Dixon et al. Phytopathology 99:1015, 2009. (2) J. P. Jones. Phytopathology 51:305, 1961. (3) J. Sequerra et al. Mycol. Res. 101:465, 1997.

Lanthanide-based time-resolved luminescence immunoassays.

The sensitive and specific detection of analytes such as proteins in biological samples is critical for a variety of applications, for example disease diagnosis. In immunoassays a signal in response to the concentration of analyte present is generated by use of antibodies labeled with radioisotopes, luminophores, or enzymes. All immunoassays suffer to some extent from the problem of the background signal observed in the absence of analyte, which limits the sensitivity and dynamic range that can be achieved. This is especially the case for homogeneous immunoassays and surface measurements on tissue sections and membranes, which typically have a high background because of sample autofluorescence. One way of minimizing background in immunoassays involves the use of lanthanide chelate labels. Luminescent lanthanide complexes have exceedingly long-lived luminescence in comparison with conventional fluorophores, enabling the short-lived background interferences to be removed via time-gated acquisition and delivering greater assay sensitivity and a broader dynamic range. This review highlights the potential of using lanthanide luminescence to design sensitive and specific immunoassays. Techniques for labeling biomolecules with lanthanide chelate tags are discussed, with aspects of chelate design. Microtitre plate-based heterogeneous and homogeneous assays are reviewed and compared in terms of sensitivity, dynamic range, and convenience. The great potential of surface-based time-resolved imaging techniques for biomolecules on gels, membranes, and tissue sections using lanthanide tracers in proteomics applications is also emphasized.

Trends in reported sun bed use, sunburn, and sun care knowledge and attitudes in a U.K. region: results of a survey of the Northern Ireland population.

BACKGROUND: Sunburn and sun bed use increase risk of malignant melanoma, the incidence of which continues to rise. OBJECTIVES: To document trends in reported sun bed use, sunburn, and sun care knowledge and attitudes in a U.K. region where there have been 20 years of sun-related health promotion campaigns. METHODS: In 2000, 2004 and 2008, a 'care in the sun' module was included in the Northern Ireland (NI) Omnibus survey. Each year 2200 subjects aged 16 years and over were randomly selected and invited to complete a sun-related questionnaire. Proportions of respondents were analysed by demographic and socioeconomic factors, with differences tested using z-tests and the χ(2) -squared test. RESULTS: In total, 3623 persons responded (response rate 50-59%). Skin cancer knowledge in 2008 was high at 97%. Skin type reporting was inaccurate and since 2000 has become weighted towards the darker Fitzpatrick skin types IV and V (χ(2) = 21·5, P = 0·006). Reported sunburn rose over the 8-year period to 60% in 2008, with 39% of those aged 16-24 years reporting sunburn at least once in the previous year. Twenty per cent reported sun bed use in 2008, a fall from 28% in 2004 (P = 0·01), with greater reported use among those aged 16-24 years (24%) and among women (31% vs. 9% men, P < 0·001). Tanning was reported to make respondents feel healthier (42%) and more attractive (47%), with these attitudes more likely among young women. CONCLUSIONS: Skin cancer and sun care knowledge is good among the NI population but reported behaviours of sun bed use and sunburn pose risks for further rises in skin cancer. Barriers for future sun care campaigns to address include poorer sun care knowledge among men, poor skin type awareness, and women's attitudes regarding the health and attractiveness of tanning. Sun bed use, although high, has fallen, possibly in response to recent campaigns.

Public at risk: a survey of sunbed parlour operating practices in Northern Ireland.

BACKGROUND: The International Agency for Research on Cancer has identified artificial ultraviolet (UV) radiation as a class 1 carcinogen. The contribution of sunbeds to malignant melanoma has been estimated at 100 deaths per year in the U.K. The sunbed industry is growing and claims self-regulation. OBJECTIVES: To explore the standards of operation and client protection for sunbed users. METHODS: An observational study of tanning parlour practices was conducted by Environmental Health Practitioners who made unannounced visits to the majority of known commercial tanning parlours in Northern Ireland (population 1.77 million) during July/August 2007. Descriptive statistics were produced and comparisons between groups were made using chi(2) analysis. RESULTS: All 332 premises visited cooperated with the survey. The UV type in machines was unknown in 71.2% of premises while 15.6% reported using type 4, high-dose UV devices; 36.2% of premises did not regularly service sunbeds or were unsure. Unsupervised use of sunbeds was reported in 8.6% of parlours and 3.4% provided a home sunbed service. Eye protection was available in 97.6% of premises but 34.6% charged for the service and only 79.6% sanitized these between use. Of the responders 15.9% were members of the Sunbed Association. These were more likely to have maintenance records and operating manuals but were also more likely to provide a home sunbed service. CONCLUSIONS: This study highlights the need for improved standards of regulation of the sunbed industry to protect clients from excessive and dangerous levels of UV radiation in a population where the numbers of melanomas continue to rise.

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review.

OBJECTIVES: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease. DATA SOURCES: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004. REVIEW METHODS: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. RESULTS: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY. CONCLUSIONS: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

Mutation analysis in Irish families with glomuvenous malformations.

BACKGROUND: Glomuvenous malformations (GVMs) are rare bluish lesions that can affect the skin and mucosal surfaces. They represent defects in vasculogenesis. Lesions can occur sporadically or in an autosomal dominant mode of inheritance. Recent studies have shown that mutations in the glomulin gene (GLMN) on chromosome 1p21-22 are responsible for familial GVMs. OBJECTIVES: To search for mutations in GLMN in Irish families with GVMs. METHODS: We identified four Irish families with GVMs and confirmed linkage to chromosome 1p21-22 in these cases. We sequenced the glomulin gene in all affected and unaffected members of the families. Results Linkage analysis showed that affected individuals from the families shared a common haplotype. Mutation analysis revealed a delAAGAA mutation in exon 3 of the glomulin gene in all four families with GVMs. CONCLUSIONS: We confirm that mutations in the glomulin gene are responsible for GVMs and suggest a founder Irish mutation in the glomulin gene in four Irish families.

Miliary neonatal hemangiomatosis with fulminant heart failure and cardiac septal hypertrophy in two infants.

Miliary neonatal hemangiomatosis is a rare, life-threatening condition associated with cutaneous and multiorgan involvement. We report two infants with this condition who had fulminant cardiac failure and cardiac septal hypertrophy. The first was a 5-day-old boy who presented with increasing numbers of cutaneous hemangiomata associated with worsening cardiac failure. Magnetic resonance imaging (MRI) showed extensive hepatic hemangioma. Despite treatment with systemic corticosteroids and subcutaneous interferon alfa-2b his disease progressed. Hepatic artery embolization was unsuccessful. The infant died of congestive cardiac failure at 6 weeks of age. Postmortem examination showed a massively enlarged cardiac interventricular septum and biventricular hypertrophy. The second patient was a 1-week-old girl who also had cutaneous hemangioma and cardiac decompensation. MRI showed extensive intrahepatic involvement. She was treated early with corticosteroids and interferon alpha, which resulted in involution of the cutaneous and hepatic lesions. Cardiac septal hypertrophy did not persist at late follow-up, and the association of miliary neonatal hemangiomatosis and cardiac septal hypertrophy has not yet been established.

Bayesian methods for design and analysis of cost-effectiveness trials in the evaluation of health care technologies.

We review the development of Bayesian statistical methods for the design and analysis of randomized controlled trials in the assessment of the cost-effectiveness of health care technologies. We place particular emphasis on the benefits of the Bayesian approach; the implications of skew cost data; the need to model the data appropriately to generate efficient and robust inferences instead of relying on distribution-free methods; the importance of making full use of quantitative and structural prior information to produce realistic inferences; and issues in the determination of sample size. Several new examples are presented to illustrate the methods. We conclude with a discussion of the key areas for future research.

Bayesian assessment of sample size for clinical trials of cost-effectiveness.

The authors present an analysis of the choice of sample sizes for demonstrating cost-effectiveness of a new treatment or procedure, when data on both cost and efficacy will be collected in a clinical trial. The Bayesian approach to statistics is employed, as well as a novel Bayesian criterion that provides insight into the sample size problem and offers a very flexible formulation.