Predicting the future of our oceans-Evaluating genomic forecasting approaches in marine species.

Climate change is restructuring biodiversity on multiple scales and there is a pressing need to understand the downstream ecological and genomic consequences of this change. Recent advancements in the field of eco-evolutionary genomics have sought to include evolutionary processes in forecasting species' responses to climate change (e.g., genomic offset), but to date, much of this work has focused on terrestrial species. Coastal and offshore species, and the fisheries they support, may be even more vulnerable to climate change than their terrestrial counterparts, warranting a critical appraisal of these approaches in marine systems. First, we synthesize knowledge about the genomic basis of adaptation in marine species, and then we discuss the few examples where genomic forecasting has been applied in marine systems. Next, we identify the key challenges in validating genomic offset estimates in marine species, and we advocate for the inclusion of historical sampling data and hindcasting in the validation phase. Lastly, we describe a workflow to guide marine managers in incorporating these predictions into the decision-making process.

Genomic signatures and correlates of widespread population declines in salmon.

Global losses of biodiversity are occurring at an unprecedented rate, but causes are often unidentified. Genomic data provide an opportunity to isolate drivers of change and even predict future vulnerabilities. Atlantic salmon (Salmo salar) populations have declined range-wide, but factors responsible are poorly understood. Here, we reconstruct changes in effective population size (Ne) in recent decades for 172 range-wide populations using a linkage-based method. Across the North Atlantic, Ne has significantly declined in >60% of populations and declines are consistently temperature-associated. We identify significant polygenic associations with decline, involving genomic regions related to metabolic, developmental, and physiological processes. These regions exhibit changes in presumably adaptive diversity in declining populations consistent with contemporary shifts in body size and phenology. Genomic signatures of widespread population decline and associated risk scores allow direct and potentially predictive links between population fitness and genotype, highlighting the power of genomic resources to assess population vulnerability.

Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.

BACKGROUND: Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. DESIGN AND METHODS: In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. RESULTS AND CONCLUSIONS: We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.

Trans-oceanic genomic divergence of Atlantic cod ecotypes is associated with large inversions.

Chromosomal rearrangements such as inversions can play a crucial role in maintaining polymorphism underlying complex traits and contribute to the process of speciation. In Atlantic cod (Gadus morhua), inversions of several megabases have been identified that dominate genomic differentiation between migratory and nonmigratory ecotypes in the Northeast Atlantic. Here, we show that the same genomic regions display elevated divergence and contribute to ecotype divergence in the Northwest Atlantic as well. The occurrence of these inversions on both sides of the Atlantic Ocean reveals a common evolutionary origin, predating the >100 000-year-old trans-Atlantic separation of Atlantic cod. The long-term persistence of these inversions indicates that they are maintained by selection, possibly facilitated by coevolution of genes underlying complex traits. Our data suggest that migratory behaviour is derived from more stationary, ancestral ecotypes. Overall, we identify several large genomic regions-each containing hundreds of genes-likely involved in the maintenance of genomic divergence in Atlantic cod on both sides of the Atlantic Ocean.

Genomic evidence of hybridization between two independent invasions of European green crab (Carcinus maenas) in the Northwest Atlantic.

Invasive species have been associated with significant negative impacts in their introduced range often outcompeting native species, yet the long-term evolutionary dynamics of biological invasions are not well understood. Hybridization, either among waves of invasion or between native and introduced populations, could alter the ecological and evolutionary impacts of invasions yet has rarely been studied in marine invasive species. The European green crab (Carcinus maenas) invaded eastern North America twice from northern and southern locations in its native range. Here we examine the frequency of hybridization among these two distinct invasions at locations from New Jersey, USA to Newfoundland, Canada using restriction-site-associated DNA sequencing (RAD-seq), microsatellite loci and cytochrome c oxidase subunit I mitochondrial DNA (mtDNA) sequences. We used Bayesian clustering and hybrid assignment analyses to investigate hybridization between the northern and southern populations. Of the samples analyzed, six locations contained at least one hybrid individual, while two locations were characterized by extensive hybridization, with 95% of individuals collected from Placentia Bay, Newfoundland being hybrids (mostly F2) and 90% of individuals from Kejimkujik, Nova Scotia being classified as hybrids, mostly backcrosses to the northern ecotype. The presence of both F2 hybrids and backcrossed individuals suggests that these hybrids are viable and introgression is occurring between invasions. Our results provide insight into the demographic and evolutionary consequences of hybridization between independent invasions, and will inform the management of green crabs in eastern North America.

Comparing accelerometer, pedometer and a questionnaire for measuring physical activity in bronchiectasis: a validity and feasibility study?

BACKGROUND: There are challenges for researchers and clinicians to select the most appropriate physical activity tool, and a balance between precision and feasibility is needed. Currently it is unclear which physical activity tool should be used to assess physical activity in Bronchiectasis. The aim of this research is to compare assessment methods (pedometer and IPAQ) to our criterion method (ActiGraph) for the measurement of physical activity dimensions in Bronchiectasis (BE), and to assess their feasibility and acceptability. METHODS: Patients in this analysis were enrolled in a cross-sectional study. The ActiGraph and pedometer were worn for seven consecutive days and the IPAQ was completed for the same period. Statistical analyses were performed using SPSS 20 (IBM). Descriptive statistics were used; the percentage agreement between ActiGraph and the other measures were calculated using limits of agreement. Feedback about the feasibility of the activity monitors and the IPAQ was obtained. RESULTS: There were 55 (22 male) data sets available. For step count there was no significant difference between the ActiGraph and Pedometer, however, total physical activity time (mins) as recorded by the ActiGraph was significantly higher than the pedometer (mean ± SD, 232 (75) vs. 63 (32)). Levels of agreement between the two devices was very good for step count (97% agreement); and variation in the levels of agreement were within accepted limits of ±2 standard deviations from the mean value. IPAQ reported more bouted- moderate - vigorous physical activity (MVPA) [mean, SD; 167(170) vs 6(9) mins/day], and significantly less sedentary time than ActiGraph [mean, SD; 362(115) vs 634(76) vmins/day]. There were low levels of agreement between the two tools (57% sedentary behaviour; 0% MVPA10+), with IPAQ under-reporting sedentary behaviour and over-reporting MVPA10+ compared to ActiGraph. The monitors were found to be feasible and acceptable by participants and researchers; while the IPAQ was accepta ble to use, most patients required assistance to complete it. CONCLUSIONS: Accurate measurement of physical activity is feasible in BE and will be valuable for future trials of therapeutic interventions. ActiGraph or pedometer could be used to measure simple daily step counts, but ActiGraph was superior as it measured intensity of physical activity and was a more precise measure of time spent walking. The IPAQ does not appear to represent an accurate measure of physical activity in this population. TRIAL REGISTRATION: Clinical Trials Registration Number NCT01569009 : Physical Activity in Bronchiectasis.

Treatment of the axilla in patients with primary breast cancer and low burden axillary disease: Limitations of the evidence from randomised controlled trials.

Invasive breast cancer is the second most common cancer worldwide. It is known to metastasise to the regional axillary lymph nodes but there has been debate over what is the best way to stage and treat the axilla in patients presenting with primary breast cancer. Multiple trials over the last two decades have led to a change in practice from routine axillary lymph node dissection to sentinel lymph node biopsy in patients who are clinically lymph node negative preoperatively. This has resulted in new questions regarding subsequent treatment of some patients. This review will critically appraise the evidence on axillary treatment in patients with low burden axillary disease and highlight limitations of relevant randomised controlled trials.

First-trimester screening for trisomies 21, 18 and 13 by ultrasound and biochemical testing.

OBJECTIVE: To examine the performance of screening for trisomies 21, 18 and 13 at 11-13 weeks' gestation using specific algorithms for these trisomies based on combinations of fetal nuchal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index for veins (DV PIV), and serum free ß-human chorionic gonadotropin (ß-hCG), pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP). METHODS: Model-based estimates of screening performance were produced for the distribution of maternal ages in England and Wales in 2011, and prospectively collected data on fetal NT, FHR, DV PIV, ß-hCG, PAPP-A, PLGF and AFP from singleton pregnancies undergoing aneuploidy screening. RESULTS: In screening by NT, FHR, free ß-hCG and PAPP-A, using specific algorithms for trisomy 21 and trisomies 18 and 13 at the risk cutoff of 1:100, the estimated detection rate (DR) was 87.0% for trisomy 21 and 91.8% for trisomies 18 and 13, at a false-positive rate (FPR) of 2.2%. Addition of PLGF, AFP and DV PIV increased the DR to 93.3% for trisomy 21 and 95.4% for trisomies 18 and 13 and reduced the FPR to 1.3%. CONCLUSIONS: Effective screening for trisomies can be achieved using specific algorithms based on NT, FHR, DV PIV, ß-hCG, PAPP-A, PLGF and AFP.

HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab.

BACKGROUND: Trastuzumab treatment improves survival of HER2-positive primary breast cancer. HER2 staining intensity varies widely in HER2-positive tumours. PATIENTS AND METHODS: We investigated whether differences in immunohistochemical (IHC) staining intensity for HER2 in HER2-positive tumors (IHC 3+ or FISH ratio ≥2.0) was associated with prognosis or benefit from trastuzumab treatment in patients randomized to 1 year or no trastuzumab in the HERceptin Adjuvant (HERA) trial. Median follow-up was 2 years. The nested case-control analysis, included 425 patients (cases) with a disease-free survival (DFS) event and two matched controls (no DFS event) per case. Tissue sections stained for HER2 were assessed for HER2 staining intensity by image analysis. RESULTS: HER2 staining intensity varied widely and correlated with HER2 gene copy number (Spearman, r = 0.498, P < 0.001) or less closely with HER2/CEP17 FISH ratio (r = 0.396, P < 0.001). We found no significant difference in DFS in the observation arm according to staining intensity (odds ratio [OR] change per 10 unit change in intensity: 1.015, 95% confidence interval [CI] 0.930-1.108) and no impact of staining intensity on benefit derived from 1-year trastuzumab (OR: 1.017, 95% CI 0.925-1.120). CONCLUSIONS: Variability in HER2 staining in HER2-positive tumours has no role in clinical management with adjuvant trastuzumab. HERA TRIAL NO: NCT00045032.

Factors associated with surgical management following neoadjuvant therapy in patients with primary HER2-positive breast cancer: results from the NeoALTTO phase III trial.

BACKGROUND: The NeoALTTO trial showed that dual HER2 blockade nearly doubles the rate of pathologic complete response (pCR) in patients with primary HER2-positive breast cancer. However, this did not translate into a higher rate of breast-conserving surgery (BCS). PATIENTS AND METHODS: In NeoALTTO, patients with HER2-positive breast cancer were randomly assigned to either trastuzumab, lapatinib or their combination with paclitaxel before surgery with pCR as the primary end point. We investigated the association between the surgery type and clinicopathological factors and response to treatment, adjusting for the treatment arm. RESULTS: Four hundred and twenty-nine patients were subjected to breast surgery. Two hundred and forty-two (56%) and 187 (44%) patients underwent mastectomy and BCS, respectively. In a logistic regression model, negative estrogen receptor (ER), multicentricity and the presence of a palpable mass before surgery were significantly associated with a low chance of BCS. Conversely, patients with small tumors and those eligible for BCS at diagnosis were managed more with BCS, independent of the treatment arm. Radiological response was not associated with the surgical decision. CONCLUSIONS: Tumor characteristics before neoadjuvant therapy play a main role in deciding the type of surgery calling for a clear consensus on the role of BCS in patients responding to neoadjuvant therapy.

Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.

OBJECTIVES: To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.

Structural and functional connectivity of marine fishes within a semi-enclosed Newfoundland fjord.

The interplay between structural connectivity (i.e. habitat continuity) and functional connectivity (i.e. dispersal probability) in marine fishes was examined in a coastal fjord (Holyrood Pond, Newfoundland, Canada) that is completely isolated from the North Atlantic Ocean for most of the year. Genetic differentiation was described in three species (rainbow smelt Osmerus mordax, white hake Urophycis tenuis and Atlantic cod Gadus morhua) with contrasting life histories using seven to 10 microsatellite loci and a protein-coding locus, PanI (G. morhua). Analysis of microsatellite differentiation indicated clear genetic differences between the fjord and coastal regions; however, the magnitude of difference was no more elevated than adjacent bays and was not enhanced by the fjord's isolation. Osmerus mordax was characterized by the highest structure overall with moderate differentiation between the fjord and St Mary's Bay (F(ST)c.0.047). In contrast, U. tenuis and G. morhua displayed weak differentiation (F(ST) < 0.01). Nonetheless, these populations did demonstrate high rates (< 75%) of Bayesian self-assignment. Furthermore, elevated differentiation was observed at the PanI locus in G. morhua between the fjord and other coastal locations. Interestingly, locus-specific genetic differentiation and expected heterozygosity were negatively associated in O. mordax, in contrast to the positive associations observed in U. tenuis and G. morhua. Gene flow in these species is apparently unencumbered by limited structural connectivity, yet the observed differentiation suggests that population structuring exists over small scales despite high dispersal potential.

Acupuncture for acute non-specific low back pain: a pilot randomised non-penetrating sham controlled trial.

OBJECTIVE: A pilot study to assess the feasibility of a trial to investigate the efficacy of acupuncture compared to placebo needling for the treatment of acute low back pain (LBP). As part of this, the study was designed to establish the credibility of the placebo control, and to provide data to inform a power analysis to determine numbers for a future trial. STUDY DESIGN: A pilot patient and assessor blinded randomized controlled trial. SETTING: Primary care health centre facility, South and East Belfast Trust, Northern Ireland. PATIENTS: Patients from the physiotherapy waiting list (n=48) with LBP of less than 12 weeks duration. OUTCOME MEASURES: Roland and Morris Disability Questionnaire (RMDQ), Visual Analogue Scale (VAS), medication use and an exit questionnaire were completed at baseline, end of treatment, and at 3 months follow up. RESULTS: Ninety-four percent (45/48) of patients completed assigned treatment, 83% (40/48) completed 3 months follow-up. The sham needle used here proved to be credible: 91.7% in the placebo group believed they had received acupuncture, compared to 95.8% in the verum acupuncture group. Differences in baseline characteristics were accounted for using ANCOVA. There was no significant difference between groups on the RMDQ over time. For pain, the only statistically significant difference was at the 3 months follow up (worst VAS, point estimate, 18.7, 95% CI 1.5-36.0, p=0.034). The majority of patients were taking some form of analgesic medication for LBP at the start of treatment (n=44; 92%), and at the end of treatment the verum acupuncture group were taking significantly fewer tablets of pain control medication (mean (S.D.): 1.0+/-0.3) than the placebo group (mean (S.D.): 4.2+/-0.6, p<0.05). Based upon these data, power analysis (power=90%, alpha=0.05, minimal clinically important difference (MCID) for RMDQ=2.5 points) indicated that 120 participants (60 per group) would be needed to complete an adequately powered randomized controlled trial. CONCLUSIONS: This study has demonstrated the feasibility of a randomized controlled trial of penetrating needle acupuncture compared to a non-penetrating sham for the treatment of acute LBP in primary care; 120 participants would be required in a fully powered trial. The placebo needle used in this study proved to be a credible form of control.

Estimating contemporary early life-history dispersal in an estuarine fish: integrating molecular and otolith elemental approaches.

Dispersal during the early life history of the anadromous rainbow smelt, Osmerus mordax, was examined using assignment testing and mixture analysis of multilocus genotypes and otolith elemental composition. Six spawning areas and associated estuarine nurseries were sampled throughout southeastern Newfoundland. Samples of adults and juveniles isolated by > 25 km displayed moderate genetic differentiation (F(ST) ~ 0.05), whereas nearby (< 25 km) spawning and nursery samples displayed low differentiation (F(ST) < 0.01). Self-assignment and mixture analysis of adult spawning samples supported the hypothesis of independence of isolated spawning locations (> 80% self-assignment) with nearby runs self-assigning at rates between 50 % and 70%. Assignment and mixture analysis of juveniles using adult baselines indicated high local recruitment at several locations (70-90%). Nearby (< 25 km) estuaries at the head of St Mary's Bay showed mixtures of individuals (i.e. 20-40% assignment to adjacent spawning location). Laser ablation inductively coupled mass spectrometry transects across otoliths of spawning adults of unknown dispersal history were used to estimate dispersal among estuaries across the first year of life. Single-element trends and multivariate discriminant function analysis (Sr:Ca and Ba:Ca) classified the majority of samples as estuarine suggesting limited movement between estuaries (< 0.5%). The mixtures of juveniles evident in the genetic data at nearby sites and a lack of evidence of straying in the otolith data support a hypothesis of selective mortality of immigrants. If indeed selective mortality of immigrants reduces the survivorship of dispersers, estimates of dispersal in marine environments that neglect survival may significantly overestimate gene flow.

Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) trial).

BACKGROUND: Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group. METHODS/DESIGN: This study was designed to test the feasibility of an assessor-blind randomised controlled trial which assess the effects on clinical outcomes and exercise adherence of adding manual auricular acupuncture to a personalised and supervised exercise programme (PEP) for CLBP. No sample size calculation has been carried out as this study aims to identify CLBP referral rates within the catchment area of the study site. The researchers aim to recruit four cohorts of n = 20 participants to facilitate a power analysis for a future randomised controlled trial. A computer generated random allocation sequence will be prepared centrally and used to allocate participants by cohort to one of the following interventions: 1) six weeks of PEP plus manual auricular acupuncture; 2) six weeks of PEP alone. Both groups will also complete a further six weeks of self-paced exercise with telephone follow-up support. In addition to a baseline and exit questionnaire at the beginning and end of the study, the following outcomes will be collected at baseline, and after 7, 13 and 25 weeks: pain frequency and bothersomeness, back-specific function, objective assessment and recall of physical activity, use of analgesia, perceived self-efficacy, fear avoidance beliefs, and beliefs about the consequences of back pain. Since this is a feasibility study, significance tests will not be presented, and treatment effects will be represented by point estimates and confidence intervals. For each outcome variable, analysis of covariance will be performed on the data, conditioning on the baseline value. DISCUSSION: The results of this study investigating the adjuvant effects of auricular acupuncture to exercise in managing CLBP will be used to inform the design of a future multi-centre randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94142364.

Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

OBJECTIVES: To assess the clinical effectiveness of positron emission tomography (PET) using 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) in breast, colorectal, head and neck, lung, lymphoma, melanoma, oesophageal and thyroid cancers. Management decisions relating to diagnosis, staging/restaging, recurrence, treatment response and radiotherapy (RT) planning were evaluated separately. DATA SOURCES: Major electronic databases were searched up to August 2005 and a survey of UK PET facilities was performed in February 2006. REVIEW METHODS: This assessment augments the systematic search undertaken in a previous review. Studies were limited to those using commercial dedicated PET or PET/computed tomography (CT) devices with FDG, in one of the eight cancers. RESULTS: The new search identified six systematic reviews and 158 primary studies. An economic model for England showed that in non-small cell lung cancer (NSCLC) FDG-PET was cost-effective in CT node-negative patients, but not in CT node-positive patients. A less robust model also showed that FDG-PET was cost-effective in RT planning for NSCLC. A model for Scotland showed that in late-stage Hodgkin's lymphoma (HL), FDG-PET was cost-effective for restaging after induction therapy. For staging/restaging colorectal cancer, FDG-PET changed patient management in a way that can impact on curative therapy. For detection of solitary pulmonary nodule (SPN) there was also impact on patient management, but the resulting effect on patient outcomes was unclear. FDG-PET had an impact on patient management across paediatric lymphoma decisions, but further study of individual management decisions is required. For other cancer management decisions, the evidence on patient management is weak. FDG-PET was accurate in detecting distant metastases across several sites, but sensitivity was variable for detection of lymph-node metastases and poor in early stage disease where sentinel lymph-node biopsy would be used and for small lesions. There were 61 studies of treatment response. These were generally small and covered all cancers except melanoma. They showed that FDG-PET imaging could be correlated with response, in some cases, but the impact on patient management was not documented. There were 17 small studies of RT planning in four cancers; here, FDG-PET led to alteration of RT volumes and doses, but the impact on patient outcomes was not studied. FDG-PET improved diagnostic accuracy compared with alternatives in a number of other cancer management decisions, but more comparative evidence is needed. There were 23 studies of PET/CT in six cancers (excluding breast and melanoma). In these FDG-PET/CT generally improved accuracy by 10-15% over PET, resolving some equivocal images. The survey of PET facilities in the UK showed that PET and PET/CT are being used for a variety of cancer indications. PET facilities are not distributed evenly across the UK and use is inconsistent. Various research studies are underway in most centres, but only a few of these are collaborative studies. There is major variation in throughput and cost per scan (635-1300 pounds). CONCLUSIONS: The strongest evidence for the clinical effectiveness of FDG-PET is in staging NSCLC, restaging HL, staging/restaging colorectal cancer and detection of SPN. Some of these may still require clinical audit to augment the evidence base. Other management decisions require further research to show the impact of FDG-PET on patient management or added value in the diagnostic pathway. It is likely that capital investment will be in the newer PET/CT technology, for which there is less evidence. However, as this technology appears to be slightly more accurate than PET/CT, the PET clinical effectiveness results presented here can be extrapolated to cover PET/CT. PET research could be undertaken on FDG-PET or FDG-PET/CT, using a standard cancer work-up process on typical patients who are seen within the NHS in England. For treatment response and RT planning, the need for larger studies using consistent methods across the UK is highlighted as a priority for all cancers. For all studies, consideration should be given to collaboration across sites nationally and internationally, taking cognisance of the work of the National Cancer Research Institute.

Acapella versus 'usual airway clearance' during acute exacerbation in bronchiectasis: a randomized crossover trial.

Devices such as the Acapella may facilitate independent airway clearance, however, few clinical trials have investigated the efficacy of Acapella. The aim of this study was to compare the effectiveness of Acapella to 'usual airway clearance' in adults during an acute exacerbation of bronchiectasis requiring oral antibiotic therapy. Twenty patients with bronchiectasis and an acute exacerbation requiring oral antibiotic therapy were recruited into a randomized crossover trial. Patients were allocated to one of two groups determined by concealed computer generated randomization. Group 1 (n=10): airway clearance session using Acapella at home twice daily during oral antibiotic therapy. Group 2 (n=10): 'usual' airway clearance sessions at home during oral antibiotic therapy. Patients recorded duration of each treatment session, volume of sputum produced and perception of breathlessness. An independent assessor performed outcome measures of spirometric lung function, pulse oximetry and breathlessness at the beginning and end of the study period. The mean volume of sputum expectorated during Acapella sessions was greater than for usual airway clearance sessions although this difference was not significant 2.61 ml (95% CI-1.62 to 6.84). Mean duration of Acapella sessions was greater than usual airway clearance sessions and approached significance. There were no significant between group differences in changes in lung function. This study demonstrates that the Acapella device may offer an acceptable, user-friendly method of airway clearance in patients with bronchiectasis.

Flight assessment in patients with respiratory disease: hypoxic challenge testing vs. predictive equations.

BACKGROUND: Predictive equations have been proposed as a simpler alternative to hypoxic challenge testing (HCT) for determining the risk of in-flight hypoxia. AIM: To assess agreement between hypoxic challenge testing (HCT) and predictive equations for assessment of in-flight hypoxia. DESIGN: Retrospective study. METHODS: Patients with chronic obstructive pulmonary disease (COPD) (n = 15), interstitial lung disease (ILD) (n = 15) and cystic fibrosis (CF) (n = 15) were studied. Spirometry was recorded prior to hypoxic inhalation and oxygen saturations (SpO2) were recorded before, after and during hypoxic inhalation. Blood gases were analysed before and after hypoxic inhalation and when SpO2 = 85%. An HCT was performed using the Ventimask method. The PaO2 at altitude was estimated for each group using four published predictive equations, which use values of PaO2 (ground) and lung function measurements to predict altitude PaO2. Results were interpreted using the BTS recommendations for prescription of in-flight oxygen post HCT. The Stuart Maxwell test of overall homogeneity was used to assess agreement between HCT results and each of the predictive equations. RESULTS: Ground PaO2 was significantly greater in patients with CF than either ILD or COPD (p < 0.05). PaO2 in all three groups significantly decreased following HCT. With the exception of equation 3, significantly fewer patients in each group would require in-flight O2 if prescription was based on HCT, compared to predictive equations (p < 0.05). DISCUSSION: Predictive equations considerably overestimate the need for in-flight O2, compared to HCT.

Predictors of mortality in adults with cystic fibrosis.

Assessment of prognostic indicators in patients with cystic fibrosis (CF) is important. The study's aim was to assess the relative contribution of gender, genetics and microbiology on survival in adults with CF. Adult patients were studied from 1995 to 2005 and data collected included FEV(1) (%predicted), body mass index (BMI), genetics, and microbiology. Data was available on 183 patients in 1995. Forty-five patients died in the subsequent 10 years. Patients who died during the study had lower mean (SD) FEV(1) %predicted in 1995 when compared to those remaining alive, 41.5 (15.2)% versus 69.8 (23.2)% predicted, respectively, P<0.001 and they had lower mean (SD) BMI in 1995, 19.2 (3.3) kg/m(2) in comparison to those remaining alive, 20.7 (3.4) kg/m(2), P=0.008. The proportion of patients infected with Pseudomonas aeruginosa and Burkholderia cepacia complex was higher in the group who died during the study compared to those remaining alive, odds ratio 20.9 P<0.0001 and 7.1 P<0.0001, respectively. The presence of the Delta F508 homozygous mutation did not alter survival, P=0.3. Patients infected with either P.aeruginosa or B.cepacia complex had reduced survival compared to those without infection, P=0.01 and P<0.0001, respectively. FEV(1)% (P<0.0001), infection with P.aeruginosa (P=0.005) or B.cepacia complex (P=0.03) were the only significant predictors of mortality. This study demonstrates adults who died were more likely to have worse lung function and be infected with either P.aeruginosa or B.cepacia complex. FEV(1)% and infection with P.aeruginosa or B.cepacia complex were the most significant predictors of survival in adults with CF.

Influence of habitual diet on antioxidant status: a study in a population of vegetarians and omnivores.

BACKGROUND: Antioxidant status can be used as a biomarker to assess chronic disease risk and diet can modulate antioxidant defence. OBJECTIVE: To examine effects of vegetarian diet and variations in the habitual intakes of foods and nutrients on blood antioxidants. SUBJECTS AND SETTING: Thirty-one vegetarians (including six vegans) and 58 omnivores, non-smokers, in Northern Ireland. DESIGN: A diet history method was used to assess habitual diet. Antioxidant vitamins, carotenoids, uric acid, zinc- and ferric-reducing ability of plasma (FRAP) were measured in fasting plasma and activities of glutathione peroxidase (GPX), superoxide dismutase (SOD) and glutathione S-transferase (GST) and level of reduced glutathione (GSH) were measured in erythrocytes. RESULTS: Vegetarians had approximately 15% higher levels of plasma carotenoids compared with omnivores, including lutein (P< or =0.05), alpha-cryptoxanthin P< or =0.05), lycopene (NS), alpha-carotene (NS) and beta-carotene (NS). The levels/activities of all other antioxidants measured were similar between vegetarians and omnivores. Total intake of fruits, vegetables and fruit juices was positively associated with plasma levels of several carotenoids and vitamin C. Intake of vegetables was positively associated with plasma lutein, alpha-cryptoxanthin, alpha-carotene and beta-carotene, whereas intake of fruits was positively associated with plasma beta-cryptoxanthin. Intake of tea and wine was positively associated with FRAP value, whereas intake of herbal tea associated positively with plasma vitamin C. Intakes of meat and fish were positively associated with plasma uric acid and FRAP value. CONCLUSIONS: The overall antioxidant status was similar between vegetarians and omnivores. Good correlations were found between intakes of carotenoids and their respective status in blood.