A comparison of four different approaches to measuring health utility in depressed patients.

BACKGROUND: A variety of instruments are used to measure health related quality of life. Few data exist on the performance and agreement of different instruments in a depressed population. The aim of this study was to investigate agreement between, and suitability of, the EQ-5D-3L, EQ-5D Visual Analogue Scale (EQ-5D VAS), SF-6D and SF-12 new algorithm for measuring health utility in depressed patients. METHODS: The intraclass correlation coefficient (ICC) and Bland and Altman approaches were used to assess agreement. Instrument sensitivity was analysed by: (1) plotting utility scores for the instruments against one another; (2) correlating utility scores and depressive symptoms (Beck Depression Inventory (BDI)); and (3) using Tukey's procedure. Receiver Operating Characteristic (ROC) analysis assessed instrument responsiveness to change. Acceptability was assessed by comparing instrument completion rates. RESULTS: The overall ICC was 0.57. Bland and Altman plots showed wide limits of agreement for each pair wise comparison, except between the SF-6D and SF-12 new algorithm. Plots of utility scores displayed 'ceiling effects' in the EQ-5D-3L index and 'floor effects' in the SF-6D and SF-12 new algorithm. All instruments showed a negative monotonic relationship with BDI, but the EQ-5D-3L index and EQ-5D VAS could not differentiate between depression severity sub-groups. The SF-based instruments were better able to detect changes in health state over time. There was no difference in completion rates of the four instruments. CONCLUSIONS: There was a lack of agreement between utility scores generated by the different instruments. According to the criteria of sensitivity, responsiveness and acceptability that we applied, the SF-6D and SF-12 may be more suitable for the measurement of health related utility in a depressed population than the EQ-5D-3L, which is the instrument currently recommended by NICE.The CoBalT study was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number: 06/ 404/02)

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters

This is the final version of the article. Available from Portland Press via the DOI in this record.There is another ORE record for this publication: http://hdl.handle.net/10871/32310Precise homoeostasis of the intracellular concentration of Cl- is achieved via the co-ordinated activities of the Cl- influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl- co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr1048)]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of 86Rb+ uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr5 in KCC1/KCC3 and Thr6 in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser96). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl- influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl- extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states.This work was supported by the Medical Research Council and the Wellcome Trust [grant number 091415] as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer). K.T.K. is supported by the Manton Center for Orphan Diseases at Children's Hospital Boston at Harvard Medical School, and the Harvard/MIT Joint Research Grants Program in Basic Neuroscience

Measuring Coverage in MNCH:A Validation Study Linking Population Survey Derived Coverage to Maternal, Newborn, and Child Health Care Records in Rural China

Accurate data on coverage of key maternal, newborn, and child health (MNCH) interventions are crucial for monitoring progress toward the Millennium Development Goals 4 and 5. Coverage estimates are primarily obtained from routine population surveys through self-reporting, the validity of which is not well understood. We aimed to examine the validity of the coverage of selected MNCH interventions in Gongcheng County, China.We conducted a validation study by comparing women's self-reported coverage of MNCH interventions relating to antenatal and postnatal care, mode of delivery, and child vaccinations in a community survey with their paper- and electronic-based health care records, treating the health care records as the reference standard. Of 936 women recruited, 914 (97.6%) completed the survey. Results show that self-reported coverage of these interventions had moderate to high sensitivity (0.57 [95% confidence interval (CI): 0.50-0.63] to 0.99 [95% CI: 0.98-1.00]) and low to high specificity (0 to 0.83 [95% CI: 0.80-0.86]). Despite varying overall validity, with the area under the receiver operating characteristic curve (AUC) ranging between 0.49 [95% CI: 0.39-0.57] and 0.90 [95% CI: 0.88-0.92], bias in the coverage estimates at the population level was small to moderate, with the test to actual positive (TAP) ratio ranging between 0.8 and 1.5 for 24 of the 28 indicators examined. Our ability to accurately estimate validity was affected by several caveats associated with the reference standard. Caution should be exercised when generalizing the results to other settings.The overall validity of self-reported coverage was moderate across selected MNCH indicators. However, at the population level, self-reported coverage appears to have small to moderate degree of bias. Accuracy of the coverage was particularly high for indicators with high recorded coverage or low recorded coverage but high specificity. The study provides insights into the accuracy of self-reports based on a population survey in low- and middle-income countries. Similar studies applying an improved reference standard are warranted in the future

Long-term effects of the Active for Life Year 5 (AFLY5) school-based cluster randomised controlled trial

Objective: To investigate the long-term effectiveness of a school-based intervention to improve physical activity and diet in children. Design: Cluster-randomised controlled trial. Setting: 60 primary schools in the southwest of England. Participants: Primary school children who were aged 8-9 years at recruitment, 9-10 years during the intervention and 10-11 years at the long-term follow-up assessment. Intervention: Teacher training, provision of lesson and child-parent interactive homework plans and teaching materials. Main Outcome Measures: Primary outcomes were accelerometer-assessed minutes of moderate to vigorous physical activity (MVPA) per day, accelerometer-assessed minutes of sedentary behaviour per day and reported daily consumption of servings of fruit and vegetables. Results: 60 schools with 2221 eligible children were recruited. As in the previously published assessment immediately after the end of the intervention, none of the three primary outcomes differed between children in schools allocated to the intervention, compared with those in control schools at the end of the long-term follow-up (1 year after the end of the intervention). Differences in secondary outcomes were consistent with those at the immediate follow-up, with no evidence that these had diminished over time. Comparing intervention with control schools, the difference in mean child-reported screen viewing at the weekend was -16.03 min (95% CI -32.82 to 0.73), for servings of snacks per day, the difference was -0.11 (95% CI -0.39 to 0.06), in servings of high-energy drinks per day -0.20 (95% CI -0.39 to -0.01) and in servings of high-fat foods per day -0.12 (95% CI -0.39 to 0.00). None of these reached our predefined level of statistical significance, especially after accounting for multiple testing. Conclusions: School-based curriculum interventions alone are unlikely to have a major public health impact on children's diet and physical activity.Emma L Anderson, Laura D Howe, Ruth R Kipping, Rona Campbell, Russell Jago, Sian M Noble, Sian Wells, Catherine Chittleborough, Tim J Peters, Debbie A Lawlo

Does anxiety moderate the effectiveness of mirtazapine in patients with treatment-resistant depression? A secondary analysis of the MIR trial

BACKGROUND: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. METHODS: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11-15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. RESULTS: Baseline generalized anxiety moderated mirtazapine's effect as measured by GAD-7 (p = 0.041) and BDI-II (p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) -2.82, 95% confidence interval (CI) -0.69 to -4.95) and larger decreases in BDI-II score (ADM -6.36, 95% CI -1.60 to -10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI -1.05 to 1.60) or antidepressant benefit (ADM -0.17, 95% CI -3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. CONCLUSIONS: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis

Is the Shroud of Turin in Relation to the Old Jerusalem Historical Earthquake?

Phillips and Hedges suggested, in the scientific magazine Nature (1989), that neutron radiation could be liable of a wrong radiocarbon dating, while proton radiation could be responsible of the Shroud body image formation. On the other hand, no plausible physical reason has been proposed so far to explain the radiation source origin, and its effects on the linen fibres. However, some recent studies, carried out by the first author and his Team at the Laboratory of Fracture Mechanics of the Politecnico di Torino, found that it is possible to generate neutron emissions from very brittle rock specimens in compression through piezonuclear fission reactions. Analogously, neutron flux increments, in correspondence to seismic activity, should be a result of the same reactions. A group of Russian scientists measured a neutron flux exceeding the background level by three orders of magnitude in correspondence to rather appreciable earthquakes (4th degree in Richter Scale). The authors consider the possibility that neutron emissions by earthquakes could have induced the image formation on Shroud linen fibres, trough thermal neutron capture by Nitrogen nuclei, and provided a wrong radiocarbon dating due to an increment in C(14,6)content. Let us consider that, although the calculated integral flux of 10^13 neutrons per square centimetre is 10 times greater than the cancer therapy dose, nevertheless it is100 times smaller than the lethal dose.Comment: 13 pages, 1 figur

Black Stork Down: Military Discourses in Bird Conservation in Malta

Tensions between Maltese hunters and bird conservation NGOs have intensified over the past decade. Conservation NGOs have become frustrated with the Maltese State for conceding to the hunter lobby and negotiating derogations from the European Union’s Bird Directive. Some NGOs have recently started to organize complex field-operations where volunteers are trained to patrol the landscape, operate drones and other surveillance technologies, detect illegalities, and lead police teams to arrest poachers. We describe the sophisticated military metaphors which conservation NGOs have developed to describe, guide and legitimize their efforts to the Maltese public and their fee-paying members. We also discuss why such groups might be inclined to adopt these metaphors. Finally, we suggest that anthropological studies of discourse could help understand delicate contexts such as this where conservation NGOs, hunting associations and the State have ended in political deadlock

Coherent coupling between radio frequency, optical, and acoustic waves in piezo-optomechanical circuits

The interaction of optical and mechanical modes in nanoscale optomechanical systems has been widely studied for applications ranging from sensing to quantum information science. Here, we develop a platform for cavity optomechanical circuits in which localized and interacting 1550 nm photons and 2.4 GHz phonons are combined with photonic and phononic waveguides. Working in GaAs facilitates manipulation of the localized mechanical mode either with a radio frequency field through the piezo-electric effect, or optically through the strong photoelastic effect. We use this to demonstrate a novel acoustic wave interference effect, analogous to coherent population trapping in atomic systems, in which the coherent mechanical motion induced by the electrical drive can be completely cancelled out by the optically-driven motion. The ability to manipulate cavity optomechanical systems with equal facility through either photonic or phononic channels enables new device and system architectures for signal transduction between the optical, electrical, and mechanical domains