A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Hospital-wide healthcare-associated carbapenemase-producing Enterobacterales outbreak: risks of electric floor scrubbers in catering facilities and kitchens.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are associated with poor clinical outcomes and can spread rapidly in healthcare settings. Environmental reservoirs are increasingly recognized as playing an important part in some nosocomial outbreaks. AIM: To describe the investigation and control of a CPE outbreak, lasting several years, across two separate hospital sites within one organization. METHODS: Investigation of multiple ward-level CPE cross-transmissions with a number of sporadic cases. Environmental sampling of ward environments, catering facilities and electric floor scrubbers was undertaken. FINDINGS: Eleven patients over a 19-month period were identified as carrying healthcare-associated New Delhi metallo-beta-lactamase (NDM)-producing Enterobacter cloacae, and a further patient carried NDM Escherichia coli. E. cloacae isolates were indistinguishable on pulsed-field gel electrophoresis typing, supporting acquisition with a single point source. Environmental sampling found contamination of the electric floor scrubbers used for cleaning the hospital catering facilities and in the associated toilets. Standard outbreak response measures achieved control of ward outbreaks. Sporadic cases and hospital-wide cross-transmission were controlled after interventions on the central food-handling unit and by decommissioning affected floor scrubbers. Electric floor scrubbers were found to have the potential to disperse Gram-negative bacteria into the surrounding environment under experimental conditions. CONCLUSION: This outbreak report demonstrates that catering facilities and kitchens can be involved in widespread healthcare outbreaks of enteric organisms. This is also the first report of the potential role of electric floor scrubbers in causing significant environmental contamination with CPE which may indicate a role in nosocomial transmission.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

COVID-19: how prepared are front-line healthcare workers in England?

National efforts are underway to prepare the UK National Health Service (NHS) for the COVID-19 pandemic; however, the efficacy of these interventions is unknown. In view of this, a cross-sectional survey of front-line healthcare workers (HCWs) at two large acute NHS hospital trusts in England was undertaken to assess their confidence and perceived level of preparedness for the virus. The survey found that there has been moderate success in readying HCWs to manage COVID-19, but that more still needs to be done, particularly in relation to educating HCWs about laboratory diagnostics.

Petite mutation in aged and oxidatively stressed ale and lager brewing yeast.

AIMS: To determine the role of oxidative stress and chronological ageing on the propensity of brewing yeast strains to form respiratory deficient 'petites'. METHODS AND RESULTS: Four industrial yeast strains (two ale and two lager strains) were exposed to oxidative stress in the form of H(2)O(2) (5 mmol l(-1)) for two hours. Cell viability and occurrence of petites were determined by the slide culture and TTC-overlay techniques, respectively. Increases in petite frequency were observed but only in those strains sensitive to oxidative stress. Chronological ageing under aerobic conditions led to an increase in petites in strains sensitive to oxidative stress. No such increase was observed under anaerobic conditions. CONCLUSION: Ageing may contribute to mitochondrial DNA damage and increase the propensity of brewing yeast cells to become respiratory deficient. Tolerant strains may be less likely to generate petites as a result of serial re-pitching. SIGNIFICANCE AND IMPACT OF THE STUDY: Continuous re-use of brewing yeast is associated with an increase in the frequency of petites within brewery yeast slurries, a phenomenon resulting in reduced fermentative capacity. The cause of petite generation during brewery handling is unknown. We show that endogenous oxidative stress has the potential to generate petites within brewing yeast populations.

Outbreak of invasive group A streptococcus: investigations using agar settle plates detect perineal shedding from a healthcare worker.

BACKGROUND: Outbreaks of group A streptococcus (GAS) infections may occur in healthcare settings. Transmission to patients is sometimes linked to colonized healthcare workers (HCWs) and/or a contaminated environment. AIM: To describe the investigation and control of an outbreak of healthcare-associated GAS on an elderly care medical ward, over six months. METHODS: Four patients developed septicaemia due to GAS infection without a clinically obvious site of infection. The outbreak team undertook an investigation involving a retrospective review of GAS cases, prospective case finding, HCW screening and environmental sampling using both swabs and settle plates. Immediate control measures included source isolation and additional cleaning of the ward environment with a chlorine disinfectant and hydrogen peroxide. FINDINGS: Prospective patient screening identified one additional patient with throat GAS carriage. Settle plate positivity for GAS was strongly associated with the presence of one individual HCW on the ward, who was subsequently found to have GAS perineal carriage. Contamination of a fabric-upholstered chair in an office adjacent to the ward, used by the HCW, was also detected. In total, three asymptomatic HCWs had throat GAS carriage and one HCW had both perineal and throat carriage. All isolates were typed as emm 28. CONCLUSION: This is the first outbreak report demonstrating the use of settle plates in a GAS outbreak investigation on a medical ward, to identify the likely source of the outbreak. Based on this report we recommend that both throat and perineal sites should be sampled if HCW screening is undertaken during an outbreak of GAS. Fabric, soft furnishings should be excluded from clinical areas as well as any adjacent offices because pathogenic bacteria such as GAS may contaminate this environment.

Lady Beetle (Coleoptera: Coccinellidae) Communities in Soybean and Maize.

Coccinellids provide the most effective natural control of soybean aphid, but outbreaks remain common. Previous work suggests that native coccinellids are rare in soybean, potentially limiting soybean aphid control. We compared the coccinellid community in soybean with that of maize to identify differences in how coccinellid species use these habitats. As maize has long been used by coccinellids in the Americas, we hypothesized that coccinellids native to the Americas would use maize habitats, while exotic coccinellids would be more common in soybean. We identified and quantified aphids and all species and stages of coccinellids in a randomized complete block experiment with four blocks of 10 by 10 -m plots of soybean and maize in central Minnesota during 2008 and 2009. Coccinellid egg masses were identified by hatching in the laboratory. We used repeated-measures ANOVA to identify the dominant species in each habitat and compared species richness and Shannon's diversity with a paired t-test. Aphids and coccinellids had a similar phenology across habitats, but the coccinellid species composition differed significantly between soybean and maize. In soybean, the exotic, Harmonia axyridis Pallas, was the dominant species, while in maize, H. axyridis and the native, Coleomegilla maculata De Geer, were co-dominant. Eggs of H. axyridis were abundant in both habitats. In contrast, C. maculata eggs were very rare in soybean, despite being abundant in adjacent plots of maize. Species diversity was higher in maize. These findings were consistent with other published studies of coccinellid communities in these habitats.

Organization of the micronuclear genome of oxytricha nova.

In the hypotrichous ciliated protozoan Oxytricha nova, approximately 95% of the micronuclear genome, including all of the repetitive DNA and most of the unique sequence DNA, is eliminated during the formation of the macronuclear genome. We have examined the interspersion patterns of repetitive and unique and eliminated and retained sequences in the micronuclear genome by characterizing randomly selected clones of micronuclear DNA. Three major classes of clones have been defined: (1) those containing primarily unique, retained sequences; (2) those containing only unique, eliminated sequences; and (3) those containing only repetitive, eliminated sequences. Clones of type one and three document two aspects of organization observed previously: clustering of macronuclear destined sequences and the presence of a prevalent repetitive element. Clones of the second type demonstrate for the first time that eliminated unique sequence DNA occurs in long stretches uninterrupted by repetitive sequences. To further examine repetitive sequence interspersion, we characterized the repetitive sequence family that is present in 50% of the clones (class three above). A consensus map of this element was obtained by mapping approximately 80 phage clones and by hybridization to digests of micronuclear DNA. The repeat element is extremely large (approximately 24 kb) and is interspersed with both macronuclear destined sequences and eliminated unique sequences.

Natural history of the recombinant (8) syndrome.

The recombinant 8[Rec(8)] syndrome [rec(8), (8qter-->8q22.1::8p23.1-->8qter] is due to a parental inv(8)(8pter-->8p23.1::8q22.1-->8p23.1::8q22+ ++.1-->8qter). All inv(8) parents we have studied were of Hispanic origin. The Rec(8) phenotype consists of a characteristic set of minor facial anomalies, cardiovascular and other major malformations, and moderate to severe mental retardation. The clinical phenotype is relatively consistent in all published cases; however the natural history of the condition has remained unknown. Retrospective and prospective information on 42 propositi, spanning a period from 5 days to 23 years, allowed us to define the natural history of this syndrome, tabulate the frequency and the evolution of phenotypic abnormalities, and share our experience with different therapeutic approaches.

Hunter-McAlpine craniosynostosis phenotype associated with skeletal anomalies and interstitial deletion of chromosome 17q.

Hunter-McAlpine syndrome is an autosomal dominant disorder consisting of variable manifestations including craniosynostosis, almond-shaped palpebral fissures, small mouth, mild acral-skeletal anomalies, short stature, and mental deficiency. We report on a 9-year-old boy with this phenotype with more severe skeletal abnormalities than previously described. Chromosomes showed del(17)(q23.1-->q24.2); the more severe phenotype may be explained by the deletion. The deletion also suggests the possibility that the gene for Hunter-McAlpine syndrome might map to that region.

Peak nasal inspiratory flow measurement: an investigation in children.

Theoretically measurement of peak nasal inspiratory flow (PNIF) has promise as a method to objectively evaluate children with nasal airway obstruction. This study establishes normative data for children up to 8 years of age. PNIF increases linearly from a mean value of 30 l/min in early infancy up to a mean value of 80 l/min at age 8 years, apart from a dip at 3 years. There is a reasonably linear incremental rise with increasing height and weight. However, since results depend on both the degree of co-operation of the child and on the subjective impression of the observer as to when a maximal inspiratory effort has been made, there may be drawbacks to its use as a routine clinical method of nasal airway obstruction assessment.

Use of the Nottingham Health Profile to test the validity of census variables to proxy the need for health care.

BACKGROUND: Data on health or health service use are invariably used to test the validity of proxy measures of need, for use in resource allocation formulae. Perceived health state is a good measure to use in this respect, as it is closely linked to perceived need and the decision to consult health services. This being the case, a large community based study was undertaken which collected data on perceived health, using the Nottingham Health Profile (NHP), with the aim of testing the validity of a variety of Census based measures as proxy measures of the need for health care. METHOD: A postal questionnaire survey of 9565 people living in the former South East Thames Regional Health Authority was conducted and the relationship between their perceived health state and the socio-economic characteristics of their electoral ward of residence analysed. RESULTS: A relatively low response rate (59 per cent) weakened any conclusions to be drawn from the results. However, significant correlations between perceived health and a variety of the Census based indicators were found. The highly skewed distribution of responses to the NHP statements made the results difficult to analyse and interpret. CONCLUSIONS: Although the study gave an indication of those variables that might be incorporated into resource allocation formulae, the NHP is not a particularly efficient instrument to use in a community setting. It is argued that the appropriateness of an approach to determining appropriate needs weights in allocation formulae, which attempts to find one indicator of all health care needs at the District Health Authority level, must be questioned.

Tests for order restrictions in binary data.

In this article, a general procedure is presented for testing for equality of k independent binary response probabilities against any given ordered alternative. The proposed methodology is based on an estimation procedure developed in Hwang and Peddada (1994, Annals of Statistics 22, 67-93) and can be used for a very broad class of order restrictions. The procedure is illustrated through application to two data sets that correspond to three commonly encountered order restrictions: simple tree order, simple order, and down turn order.

Promoting clinically effective practice: general practitioners' awareness of sources of research evidence.

BACKGROUND: Practitioners are being encouraged to base their clinical practice on research evidence. In order to do this, they must be aware of and use the sources of evidence. METHODS: A questionnaire survey was undertaken to establish GPs' awareness of research evidence in their clinical practice and, in fundholding practices, its influence on purchasing plans. Questionnaires were sent to 360 lead fundholders in North Thames Region and 440 of a random sample of the remaining general practitioners in the region for comparison. RESULTS: Questionnaires were returned by 62% of lead fundholders and 63% of GPs in the random sample. There was limited use of the electronic sources of clinical effectiveness. There was greater reported awareness of published sources of research evidence and fundholding GPs were significantly more likely to have referred to publications summarizing research evidence. CONCLUSIONS: GPs seem to make more use of published clinical effectiveness sources than the electronic databases. Consequently, they need educational and technical support if they are to make full use of the available sources of research evidence available in other media.

Promoting clinical effective practice. Attitudes of fundholding general practitioners to the role of commissioning.

Aims to evaluate the acceptability of commissioning to improve clinical effectiveness in secondary care and explore the conditions under which fundholders would be willing to use commissioning in this way. Describes how fundholders in two contrasting districts in North Thames Region were interviewed in 1995-1996. Respondents were selected from a list of all fundholders in the district with few fundholding practices and from lists of fundholders holding contracts with specified hospitals in the district with many fundholders. Interviews were analysed using the constant comparison method of content analysis. All fundholders in the districts were eligible. The sample represented a broad range of fundholders, containing all fundholding waves and large and small practices. Managers and general practitioners from multifunds outside the districts were also interviewed to assess whether they faced different issues from single practice fundholders. Many respondents felt unable to use commissioning to improve clinically effectiveness despite their awareness of the policy. Reasons identified included the problem of agreeing complex commissioning arrangements to reflect clinical issues, and an unwillingness to use fundholding to challenge hospital practice. Respondents from early wave fundholding practices and those with training in critically appraising research literature expressed more readiness to review research evidence, but only a few early wave fundholders said they would consider evidence-based commissioning. Concludes that steps should be taken to educate fundholders in clinical effectiveness and provide appropriate information to them. Also, they must be persuaded that clinical effectiveness is not a politically-driven policy or they will resist it.