Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

Response: Special communication: Letters to the Editor-in-Chief [Vigorous exercise in clinical practice: balancing risks and benefits]

The effects of different exercise intensities on health have been investigated in several studies in recent years, in which some authors showed greater benefits for vigorous exercise (6) while others did not find any differences (8). An important issue regarding these conflicting results could be the fact that only a few of the studies controlled the effects of different exercise intensities for the overall volume of physical activity, making the evaluation of the available data difficult.

Mesospheric temperature response to variations in geomagnetic activity

Temperature data collected over several years from rocket grenade and other experiments at Point Barrow (Alaska), Fort Churchill (Canada) and Wallops Island (Virginia) have been analysed to determine the effect of geomagnetic activity on the neutral temperature in the mesosphere and to study the latitudinal variation of this effect. An analysis carried out has revealed almost certainly significant correlations between the temperature and the geomagnetic indicies Kp and Ap at Fort Churchill and marginally significant correlations at Barrow and Wallops. This has also been substantiated by a linear regression analysis. The results indicate two types of interdependence between mesospheric temperature and geomagnetic field variations. The first type is the direct heating effect, during a geomagnetic disturbance, which has been observed in the present analysis with a time lag of 3–15 hr at the high latitudes and 36 hr at the middle latitudes. The magnitude of this heating effect has been found to decrease at the lower altitudes. The second type of interrelation which has been observed is temperature perturbations preceding geomagnetic field variations, both presumably caused by a disturbance in atmospheric circulation at these levels.

The transient response of certain third-ordernon-linear systems

In this paper a method of solving certain third-order non-linear systems by using themethod of ultraspherical polynomial approximation is proposed. By using the method of variation of parameters the third-order equation is reduced to three partial differential equations. Instead of being averaged over a cycle, the non-linear functions are expanded in ultraspherical polynomials and with only the constant term retained, the equations are solved. The results of the procedure are compared with the numerical solutions obtained on a digital computer. A degenerate third-order system is also considered and results obtained for the above system are compared with numerical results obtained on the digital computer. There is good agreement between the results obtained by the proposed method and the numerical solution obtained on digital computer.

Plastic response of orthotropic spherical shells under blast loading

The plastic response of a segment of a simply supported orthotropic spherical shell under a uniform blast loading applied on the convex surface of the shell is presented. The blast is assumed to impart a uniform velocity to the shell surface initially. The material of the shell is orthotropic obeying a modified Tresca yield hypersurface conditions and the associated flow rules. The deformation of the shell is determined during all phases of its motion by considering the motion of plastic hinges in different regimes of flow. Numerical results presented include the permanent deformed configuration of the shell and the total time of shell response for different degrees of orthotropy. Conclusions regarding the plastic behaviour of spherical shells with circumferential and meridional stiffening under uniform blast load are presented.

Soil seed bank dynamics in response to an extreme flood event in a riparian habitat

A significantly increased water regime can lead to inundation of rivers, creeks and surrounding floodplains- and thus impact on the temporal dynamics of both the extant vegetation and the dormant, but viable soil-seed bank of riparian corridors. The study documented changes in the soil seed-bank along riparian corridors before and after a major flood event in January 2011 in southeast Queensland, Australia. The study site was a major river (the Mooleyember creek) near Roma, Central Queensland impacted by the extreme flood event and where baseline ecological data on riparian seed-bank populations have previously been collected in 2007, 2008 and 2009. After the major flood event, we collected further soil samples from the same locations in spring/summer (November–December 2011) and in early autumn (March 2012). Thereafter, the soils were exposed to adequate warmth and moisture under glasshouse conditions, and emerged seedlings identified taxonomically. Flooding increased seed-bank abundance but decreased its species richness and diversity. However, flood impact was less than that of yearly effect but greater than that of seasonal variation. Seeds of trees and shrubs were few in the soil, and were negatively affected by the flood; those of herbaceous and graminoids were numerous and proliferate after the flood. Seed-banks of weedy and/or exotic species were no more affected by the flood than those of native and/or non-invasive species. Overall, the studied riparian zone showed evidence of a quick recovery of its seed-bank over time, and can be considered to be resilient to an extreme flood event.

Evaluation of restoration of vegetation infested with cat's claw creeper vine (Dolichandra unguis-cati): soil seed bank response to herbicide and physical removal

Cat’s claw creeper vine, Dolichandra unguis-cati (L.) L.G.Lohmann (formerly known as Macfadyena unguis-cati (L.) A.H.Gentry), a Weed of National Significance (WoNS), is a structural woody parasite that is highly invasive along sensitive riparian corridors and native forests of coastal and inland eastern Australia. As part of evaluation of the impact of herbicide and mechanical/physical control techniques on the long-term reduction of biomass of the weed and expected return of native flora, we have set-up permanent vegetation plots in: (a) infested and now chemically/physically treated, (b) infested but untreated and (c) un-infested patches. The treatments were set up in both riparian and non-riparian habitats to document changes that occur in seed bank flora over a two-year post-treatment period. Response to treatment varied spatially and temporally. However, following chemical and physical removal treatments, treated patches exhibited lower seed bank abundance and diversity than infested and patches lacking the weed, but differences were not statistically significant. Thus it will be safe to say that spraying herbicides using the recommended rate does not undermine restoration efforts.

Quantifying the response of cotton production in eastern Australia to climate change

Abstract The paper evaluates the effect of future climate change (as per the CSIRO Mk3.5 A1FI future climate projection) on cotton yield in Southern Queensland and Northern NSW, eastern Australia by using of the biophysical simulation model APSIM (Agricultural Production Systems sIMulator). The simulations of cotton production show that changes in the influential meteorological parameters caused by climate change would lead to decreased future cotton yields without the effect of CO2 fertilisation. By 2050 the yields would decrease by 17 %. Including the effects of CO2 fertilisation ameliorates the effect of decreased water availability and yields increase by 5.9 % by 2030, but then decrease by 3.6 % in 2050. Importantly, it was necessary to increase irrigation amounts by almost 50 % to maintain adequate soil moisture levels. The effect of CO2 was found to have an important positive impact of the yield in spite of deleterious climate change. This implies that the physiological response of plants to climate change needs to be thoroughly understood to avoid making erroneous projections of yield and potentially stifling investment or increasing risk.

Promoting and maintaining physical activity in the transition to retirement: A systematic review of interventions for adults around retirement age

It has been argued that transition points in life, such as the approach towards, and early years of retirement present key opportunities for interventions to improve the health of the population. Research has also highlighted inequalities in health status in the retired population and in response to interventions which should be addressed. We aimed to conduct a systematic review to synthesise international evidence on the types and effectiveness of interventions to increase physical activity among people around the time of retirement. A systematic review of literature was carried out between February 2014 and April 2015. Searches were not limited by language or location, but were restricted by date to studies published from 1990 onwards. Methods for identification of relevant studies included electronic database searching, reference list checking, and citation searching. Systematic search of the literature identified 104 papers which described study populations as being older adults. However, we found only one paper which specifically referred to their participants as being around the time of retirement. The intervention approaches for older adults encompassed: training of health care professionals; counselling and advice giving; group sessions; individual training sessions; in-home exercise programmes; in-home computer-delivered programmes; in-home telephone support; in-home diet and exercise programmes; and community-wide initiatives. The majority of papers reported some intervention effect, with evidence of positive outcomes for all types of programmes. A wide range of different measures were used to evaluate effectiveness, many were self-reported and few studies included evaluation of sedentary time. While the retirement transition is considered a significant point of life change, little research has been conducted to assess whether physical activity interventions at this time may be effective in promoting or maintaining activity, or reducing health inequalities. We were unable to find any evidence that the transition to retirement period was, or was not a significant point for intervention. Studies in older adults more generally indicated that a range of interventions might be effective for people around retirement age.

Eurasian large mammal dynamics in response to changing environments during the Late Neogene

Nisäkkäiden levinneisyyteen, niiden morfologisiin ja ekologisiin piirteisiin vaikuttavat ympäristön sekä lyhyet että pitkäkestoiset muutokset, etenkin ilmaston ja kasvillisuuden vaihtelut. Työssä tutkittiin nisäkkäiden sopeutumista ilmastonmuutoksiin Euraasiassa viimeisen 24 miljoonan vuoden aikana. Tutkimuksessa keskityttiin varsinkin viimeiseen kahteen miljoonaan vuoteen, jonka aikana ilmasto muuttui voimakkaasti ja ihmisen toiminta alkoi tulla merkittäväksi. Tämän takia on usein vaikea erottaa, kummasta em. seikasta jonkin nisäkäslajin sukupuutto tai häviäminen alueelta johtui. Aineistona käytettiin laajaa venäjänkielistä kirjallisuutta, josta löytyvät tiedot ovat kääntämättöminä jääneet aiemmin länsimaisen tutkimuksen ulkopuolelle. Työssä käytettiin myös NOW-tietokantaa, jossa on fossiilisten nisäkkäiden löytöpaikat sekä niiden iät.

The Politics of Surveillance and Response to Disease Outbreaks: The New Frontier for States and Non-state Actors

The capacity to conduct international disease outbreak surveillance and share information about outbreaks quickly has empowered both State and Non-State Actors to take an active role in stopping the spread of disease by generating new technical means to identify potential pandemics through the creation of shared reporting platforms. Despite all the rhetoric about the importance of infectious disease surveillance, the concept itself has received relatively little critical attention from academics, practitioners, and policymakers. This book asks leading contributors in the field to engage with five key issues attached to international disease outbreak surveillance - transparency, local engagement, practical needs, integration, and appeal - to illuminate the political effect of these technologies on those who use surveillance, those who respond to surveillance, and those being monitored.

Growth analysis and biomass partitioning of Cyperus iria in response to rice planting density and nitrogen rate

Cyperus iria is a weed of rice with widespread occurrence throughout the world. Because of concerns about excessive and injudicious use of herbicides, cultural weed management approaches that are safe and economical are needed. Developing such approaches will require a better understanding of weed biology and ecology, as well as of weed response to increases in crop density and nutrition. Knowledge of the effects of nitrogen (N) fertilizer on crop-weed competitive interactions could also help in the development of integrated weed management strategies. The present study was conducted in a screenhouse to determine the effects of rice planting density (0, 5, 10, and 20 plants pot−1) and N rate (0, 50, 100, and 150 kg ha−1) on the growth of C. iria. Tiller number per plant decreased by 73–88%, leaf number by 85–94%, leaf area by 85–98%, leaf biomass by 92–99%, and inflorescence biomass by 96–99% when weed plants were grown at 20 rice plants pot−1 (i.e., 400 plants m−2) compared with weed plants grown alone. All of these parameters increased when N rates were increased. On average, weed biomass increased by 118–389% and rice biomass by 121–275% with application of 50–150 kg N ha−1, compared to control. Addition of N favored weed biomass production relative to rice biomass. Increased N rates reduced the root-to-shoot weight ratio of C. iria. Rice interference reduced weed growth and biomass and completely suppressed C. iria when no N was applied at high planting densities (i.e., 20 plants pot−1). The weed showed phenotypic plasticity in response to N application, and the addition of N increased the competitive ability of the weed over rice at densities of 5 and 10 rice plants pot−1 compared with 20 plants pot−1. The results of the present study suggest that high rice density (i.e., 400 plants m−2) can help suppress C. iria growth even at high N rates (150 kg ha−1).

Identification of the sex pheromone of the tree infesting Cossid Moth Coryphodema tristis (Lepidoptera: Cossidae)

The cossid moth (Coryphodema tristis) has a broad range of native tree hosts in South Africa. The moth recently moved into non-native Eucalyptus plantations in South Africa, on which it now causes significant damage. Here we investigate the chemicals involved in pheromone communication between the sexes of this moth in order to better understand its ecology, and with a view to potentially develop management tools for it. In particular, we characterize female gland extracts and headspace samples through coupled gas chromatography electro-antennographic detection (GC-EAD) and two dimensional gas chromatography mass spectrometry (GCxGC-MS). Tentative identities of the potential pheromone compounds were confirmed by comparing both retention time and mass spectra with authentic standards. Two electrophysiologically active pheromone compounds, tetradecyl acetate (14:OAc) and Z9-tetradecenyl acetate (Z9-14:OAc) were identified from pheromone gland extracts, and an additional compound (Z9-14:OH) from headspace samples. We further determined dose response curves for the identified compounds and six other structurally similar compounds that are common to the order Cossidae. Male antennae showed superior sensitivity toward Z9-14:OAc, Z7-tetradecenyl acetate (Z7-14:OAc), E9-tetradecenyl acetate (E9-14:OAc), Z9-tetradecenol (Z9-14:OH) and Z9-tetradecenal (Z9-14:Ald) when compared to female antennae. While we could show electrophysiological responses to single pheromone compounds, behavioral attraction of males was dependent on the synergistic effect of at least two of these compounds. Signal specificity is shown to be gained through pheromone blends. A field trial showed that a significant number of males were caught only in traps baited with a combination of Z9-14:OAc (circa 95 of the ratio) and Z9-14:OH. Addition of 14:OAc to this mixture also improved the number of males caught, although not significantly. This study represents a major step towards developing a useful attractant to be used in management tools for C. tristis and contributes to the understanding of chemical communication and biology of this group of insects.

Response of Circular Footings to Vertical Vibrations

In this paper, analog solutions are presented for the response of a circular footing resting on an elastic half-space with uniform and parabolic contact pressure distributions and subjected to frequency dependent and frequency independent excitations. In addition, an analog solution to a rigid circular footing subjected to frequency dependent excitation is also presented. The results have been compared with the rigorous solution of Sung and the agreement is found to be good.