Psychophysical Function in Age-related Maculopathy

Age-related macular degeneration (AMD), the late stage of age-related maculopathy (ARM), is the leading cause of blind registration in developed Countries. The Visual loss in AMD occurs due to dysfunction and death of photoreceptors (rods and cones) secondary to an atrophic or a neovascular event. The psychophysical tests of vision, which depend on the functional status of the photoreceptors, may detect subtle alterations in the macula before morphological fundus changes are apparent ophthalmoscopically, and before traditional measures of visual acuity exhibit deterioration, and may be a useful tool for assessing and monitoring patients with ARM. Furthermore, worsening of these visual functions over time may reflect disease progression, and some of these, alone or iti combination with other parameters, may act as a prognostic indicator for identifying eyes at, risk for developing neovascular AMD. Lastly, psychophysical tests often correlate with subjective and relatively undefined symptoms in patients With early ARM, and may reflect limitation of daily activities for ARM patients. However, clinical studies investigating psychophysical function have largely been cross-sectional in nature, with small sample sizes, and lack consistency in terms Of the grading and classification of ARM. This article aims to comprehensively review the literature germane to psychophysical tests in ARM, and to furnish the reader with an insight into this complex area of research. (Surv Ophdialmol 54:167-210, 2009. (C) 2009 Elsevier Inc. All rights reserved.)

Real-time error detection but not error correction drives automatic visuomotor adaptation

We investigated the role of visual feedback of task performance in visuomotor adaptation. Participants produced novel two degrees of freedom movements (elbow flexion-extension, forearm pronation-supination) to move a cursor towards visual targets. Following trials with no rotation, participants were exposed to a 60A degrees visuomotor rotation, before returning to the non-rotated condition. A colour cue on each trial permitted identification of the rotated/non-rotated contexts. Participants could not see their arm but received continuous and concurrent visual feedback (CF) of a cursor representing limb position or post-trial visual feedback (PF) representing the movement trajectory. Separate groups of participants who received CF were instructed that online modifications of their movements either were, or were not, permissible as a means of improving performance. Feedforward-mediated performance improvements occurred for both CF and PF groups in the rotated environment. Furthermore, for CF participants this adaptation occurred regardless of whether feedback modifications of motor commands were permissible. Upon re-exposure to the non-rotated environment participants in the CF, but not PF, groups exhibited post-training aftereffects, manifested as greater angular deviations from a straight initial trajectory, with respect to the pre-rotation trials. Accordingly, the nature of the performance improvements that occurred was dependent upon the timing of the visual feedback of task performance. Continuous visual feedback of task performance during task execution appears critical in realising automatic visuomotor adaptation through a recalibration of the visuomotor mapping that transforms visual inputs into appropriate motor commands.

The energy density of jellyfish: Estimates from bomb-calorimetry and proximate-composition

Two techniques are described to calculate energy densities for the bell, gonad and oral arm tissues of three scyphozoan jellyfish (Cyanea capillata, Rhizostoma octopus and Chrysaora hysoscella). First, bomb-calorimetry was used, a technique that is readily available and inexpensive. However, the reliability of this technique for gelatinous material is contentious. Second, further analysis involving the more labour intensive proximate-composition analysis (protein, fat and carbohydrate) was carried out on two species (C capillata and R. octopus). These proximate data were subsequently converted to energy densities. The two techniques (bomb-calorimetry and proximate-composition) gave very similar estimates of energy density. Differences in energy density were found both amongst different species and between different tissues of the same species. Mean ( +/- S.D.) energy density estimates for whole animals from bomb-calorimetry were 0.18 +/- 0.05, 0.11 +/- 0.04, and 0.10 +/- 0.03 kJ g wet mass(-1) for C. capillata, R. octopus, and C. hysoscella respectively. The implications of these low energy densities for species feeding on jellyfish are discussed. (c) 2007 Elsevier B.V. All rights reserved.

Trisomy 10p with clinical features of facio-auriculo-vertebral spectrum: a case report

We report a male child born with complete absence of his external ear, hemifacial microsomia of the right side, high arched palate, a down-turned upper lip and slightly upslanting palpebral fissures. The features were suggestive of facio-auriculo-vertebral spectrum. Investigations showed a tandem duplication of the short arm of one chromosome 10 with apparent breakpoints at p14 and p15. This case extends the list of chromosomal abnormalities associated with the facio-auriculo-vertebral phenotype and also adds useful clinical information to possible trisomy 10p phenotypes.

Does pre-operative estimation of oesophageal tumour metabolic length using F-18-fluorodeoxyglucose PET/CT images compare with surgical pathology length?

PURPOSE:
The aim of the study was to compare the pre-operative metabolic tumour length on FDG PET/CT with the resected pathological specimen in patients with oesophageal cancer.

METHODS:
All patients diagnosed with oesophageal carcinoma who had undergone staging PET/CT imaging between the period of June 2002 and May 2008 who were then suitable for curative surgery, either with or without neo-adjuvant chemotherapy, were included in this study. Metabolic tumour length was assessed using both visual analysis and a maximum standardised uptake value (SUV(max)) cutoff of 2.5.

RESULTS:
Thirty-nine patients proceeded directly to curative surgical resection, whereas 48 patients received neo-adjuvant chemotherapy, followed by curative surgery. The 95% limits of agreement in the surgical arm were more accurate when the metabolic tumour length was visually assessed with a mean difference of -0.05 cm (SD 2.16 cm) compared to a mean difference of +2.42 cm (SD 3.46 cm) when assessed with an SUV(max) cutoff of 2.5. In the neo-adjuvant group, the 95% limits of agreement were once again more accurate when assessed visually with a mean difference of -0.6 cm (SD 1.84 cm) compared to a mean difference of +1.58 cm (SD 3.1 cm) when assessed with an SUV(max) cutoff of 2.5.

CONCLUSION:
This study confirms the high accuracy of PET/CT in measuring gross target volume (GTV) length. A visual method for GTV length measurement was demonstrated to be superior and more accurate than when using an SUV(max) cutoff of 2.5. This has the potential of reducing the planning target volume with dose escalation to the tumour with a corresponding reduction in normal tissue complication probability.

The addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for advanced colorectal cancer: results of the MRC COIN trial.

Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3—29·2] in the control group vs 17·0 months [9·4—30·1] in the cetuximab group; HR 1·04, 95% CI 0·87—1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0—12·5] in the control group vs 8·6 months [5·1—13·8] in the cetuximab group; HR 0·96, 0·82—1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5—27·4); KRAS mutant, 14·4 months (8·5—24·0); all wild-type, 20·1 months (11·5—31·7).
Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4—26·1) in arm A and 14·4 months (8·0—24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008—1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0—28·1) in arm A and 18·0 months (12·1—29·3) in arm C (HR 1·087, 0·986—1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per µL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80—1·15, p=0·66), versus 1·54 (1·17—2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand—foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break.

Climate change, Hans Jonas and indirect investors

This article considers how corporate behaviour in relation to climate change might be reconfigured and the role that indirect investors might play in this reconfiguring. The article suggests that the consequences of climate change are serious enough that indirect investors might be prevailed upon, using a model of behaviour suggested by the work of Hans Jonas, to pressure institutional investors into demanding changes in corporate policy towards climate change. Jonas' work represents a plea for the recognition and acceptance of responsibility in the face of nature's vulnerability and humanity's power over technology. The article suggests that this ethic can be operationalised in relation to corporate governance by building on the changes in the pattern of investment holdings that have taken place in large public companies in the preceding two decades or so. The idea is to appeal to individuals who may perceive themselves as currently being outsiders – or at least only distant stakeholders in relation to the corporation – to realise the responsibility vested in them as beneficiaries through their interest in pension funds, life assurance policies, annuities and other arm's-length financial arrangements with corporations. The hope is that these individuals may, through the influence of a model of responsibility, become active investors and beneficiaries interested in corporate practices that impact on climate change and, encourage others to do likewise.

Roche tomography of cataclysmic variables - V. A high-latitude star-spot on RU Pegasi

We present Roche tomograms of the secondary star in the dwarf nova system RU Pegasi derived from blue and red arm ISIS data taken on the 4.2-m William Herschel Telescope. We have applied the entropy landscape technique to determine the system parameters and obtained component masses of M1 = 1.06 Msun, M2 = 0.96 Msun, an orbital inclination angle of i = 43 degrees, and an optimal systemic velocity of gamma = 7 km/s. These are in good agreement with previously published values. Our Roche tomograms of the secondary star show prominent irradiation of the inner Lagrangian point due to illumination by the disc and/or bright spot, which may have been enhanced as RU Peg was in outburst at the time of our observations.We find that this irradiation pattern is axi-symmetric and confined to regions of the star which have a direct view of the accretion regions. This is in contrast to previous attempts to map RU Peg which suggested that the irradiation pattern was non-symmetric and extended beyond the terminator. We also detect additional inhomogeneities in the surface distribution of stellar atomic absorption that we ascribe to the presence of a large star-spot. This spot is centred at a latitude of about 82 degrees and covers approximately 4 per cent of the total surface area of the secondary. In keeping with the high latitude spots mapped on the cataclysmic variables AE Aqr and BV Cen, the spot on RU Peg also appears slightly shifted towards the trailing hemisphere of the star. Finally, we speculate that early mapping attempts which indicated non-symmetric irradiation patterns which extended beyond the terminator of CV donors could possibly be explained by a superposition of symmetric heating and a large spot.

Observation of ion temperatures exceeding background electron temperatures in petawatt laser-solid experiments

Neutron time of flight signals have been observed with a high resolution neutron spectrometer using the petawatt arm of the Vulcan laser facility at Rutherford Appleton Laboratory from plastic sandwich targets containing a deuterated layer. The neutron spectra have two elements: a high-energy component generated by beam-fusion reactions and a thermal component around 2.45 MeV. The ion temperatures calculated from the neutron signal width clearly demonstrate a dependence on the front layer thickness and are significantly higher than electron temperatures measured under similar conditions. The ion heating process is intensity dependent and is not observed with laser intensities on target below 10(20) W cm(-2). The measurements are consistent with an ion instability driven by electron perturbations.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Grading of age-related maculopathy:slit-lamp biomicroscopy versus an accredited grading center

To compare clinical age-related maculopathy (ARM) grading using slit-lamp biomicroscopy (SLB) versus photographic grading of stereoscopically captured fundus photographs (FP) using a high-resolution fundus camera.

AMD and micronutrient antioxidants

Age-related maculopathy (ARM) is a common clinical entity. The late-stage manifestations of ARM, which are known as age-related macular degeneration (AMD), have devastating consequences for vision. Various risk factors have been identified in the development of the condition, which are consistent with the premise that oxidative stress plays an important role in its pathogenesis. Thus, the possibility that antioxidant balance can be manipulated through diet or supplementation has created much interest. Associations between diet and nutrition and the clinical features of ARM have been described. Scrutiny of the literature shows consistency in the report of notable reductions in serum micronutrients in wet AMD, however, the evidence for causation is still circumstantial. In this comprehensive review of the clinical literature, we have assessed the evidence for a link between diet and nutrition as risk factors for the development of ARM and AMD. All published case control, population-based, and interventional studies on ARM were examined. Although initial support appeared to be moderate and somewhat contradictory, the evidence that lifetime oxidative stress plays an important role in the development of ARM is now compelling. The positive outcomes in the Age-Related Eye Diseases Study, a major controlled clinical trial, have given hope that modulation of the antioxidant balance through supplementation can help prevent progression of ARM to AMD.

Severity staging by early features of age-related maculopathy exhibits weak relationships with functional deficits on SWS grating acuity

To examine the relationship between short-wavelength-sensitive (SWS) resolution acuity and epidemiologically defined stages of early age-related maculopathy (ARM).