Meta-analysis: a unifying meta-likelihood approach framing unobserved heterogeneity, study covariates, publication bias, and study quality

OBJECTIVES: This contribution provides a unifying concept for meta-analysis integrating the handling of unobserved heterogeneity, study covariates, publication bias and study quality. It is important to consider these issues simultaneously to avoid the occurrence of artifacts, and a method for doing so is suggested here. METHODS: The approach is based upon the meta-likelihood in combination with a general linear nonparametric mixed model, which lays the ground for all inferential conclusions suggested here. RESULTS: The concept is illustrated at hand of a meta-analysis investigating the relationship of hormone replacement therapy and breast cancer. The phenomenon of interest has been investigated in many studies for a considerable time and different results were reported. In 1992 a meta-analysis by Sillero-Arenas et al. concluded a small, but significant overall effect of 1.06 on the relative risk scale. Using the meta-likelihood approach it is demonstrated here that this meta-analysis is due to considerable unobserved heterogeneity. Furthermore, it is shown that new methods are available to model this heterogeneity successfully. It is argued further to include available study covariates to explain this heterogeneity in the meta-analysis at hand. CONCLUSIONS: The topic of HRT and breast cancer has again very recently become an issue of public debate, when results of a large trial investigating the health effects of hormone replacement therapy were published indicating an increased risk for breast cancer (risk ratio of 1.26). Using an adequate regression model in the previously published meta-analysis an adjusted estimate of effect of 1.14 can be given which is considerably higher than the one published in the meta-analysis of Sillero-Arenas et al. In summary, it is hoped that the method suggested here contributes further to a good meta-analytic practice in public health and clinical disciplines.

Variation in the ovarian reserve Is linked to alterations in intrafollicular estradiol production and ovarian biomarkers of follicular differentiation and oocyte quality in cattle

The mechanisms whereby the high variation in numbers of morphologically healthy oocytes and follicles in ovaries (ovarian reserve) may have an impact onovarian function, oocyte quality, and fertility are poorly understood. The objective was to determine whether previously validated biomarkers for follicular differentiation and function, as well as oocyte quality differed between cattle with low versus a high antral follicle count (AFC). Ovaries were removed (n = 5 per group) near the beginning of the nonovulatory follicular wave, before follicles could be identified via ultrasonography as being dominant, from heifers with high versus a low AFC. The F1, F2, and F3 follicles were dissected and diameters determined. Follicular fluid and thecal, granulosal, and cumulus cells and the oocyte were isolated and subjected to biomarker analyses. Although the size and numerous biomarkers of differentiation, such as mRNAs for the gonadotropin receptors, were similar, intrafollicular concentrations of estradiol and the abundance of mRNAs for CYP19A1 in granulosal cells and ESR1, ESR2, and CTSB in cumulus cells were greater, whereas mRNAs for AMH in granulosal cells and TBC1D1 in thecal cells were lower for animals with low versus a high AFC during follicle waves. Hence, variation in the ovarian reserve may have an impact on follicular function and oocyte quality via alterations in intrafollicular estradiol production and expression of key genes involved in follicle-stimulating hormone action (AMH) and estradiol (CYP19A1) production by granulosal cells, function and survival of thecal cells (TBC1D1), responsiveness of cumulus cells to estradiol (ESR1, ESR2), and cumulus cell determinants of oocyte quality (CTSB).

Differential effects of temperature on fruit development and bean quality of contrasting genotypes of cacao (Theobroma cacao)

The effects of temperature and light integral on fruit growth and development of five cacao genotypes (Amelonado, AMAZ 15/15, SCA 6, SPEC 54/1 and UF 676) were studied in semi-controlled environment glasshouses in which the thermal regimes of cacao-growing regions of Brazil, Ghana and Malaysia were simulated. Fruit losses because of physiological will (cherelle will) were greater at higher temperatures and also differed significantly between genotypes, reflecting genetic differences in competition for assimilates between vegetative and reproductive components. Short-term measurements of fruit growth indicated faster growth rates at higher temperatures. In addition, a significant negative linear relationship between temperature and development time was observed. There was an effect of genotype on this relationship, such that time to fruit maturation at a given temperature was greatest for the clone UF 676 and least for AMAZ 15/15. Analysis of base temperatures, derived from these relationships indicated genetic variability in sensitivity of cacao fruit growth to temperature (base temperatures ranged from 7.5 degrees C for Amelonado and AMAZ 15/15 to 12.9 for SPEC 54/1). Final fruit size was a positive function of beam number for all genotypes and a positive function of light integral for Amelonado in the Malaysia simulated environment (where the temperature was almost constant). In simulated environments where temperature was the main variable (Brazil and Ghana) increases in temperature resulted in a significant decrease in final pod size for one genotype (Amelonado) in Brazil and for two genotypes (SPEC 54/1 and UF 676) in Ghana. It was hypothesised that pod growth duration (mediated by temperature), assimilation and beam number are all determinants of final pod size but that under specific conditions one of these factors may override the others. There was variability between genotypes in the response of beam size and beam lipid content to temperature. Negative relationships between temperature and bean size were found for Amelonado and UF 676. Lipid concentration was a curvilinear function of temperature for Amelonado and UF 676, with optimal temperatures of 23 degrees C and 24 degrees C, respectively. The variability observed here of different cacao genotypes to temperature highlights the need and opportunities for appropriate matching of planting material with local environments.

Artichoke leaf extract reduces symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers suffering from concomitant dyspepsia: a subset analysis

Objectives: Does artichoke leaf extract (ALE) ameliorate symptoms of Irritable bowel syndrome (IBS) in otherwise healthy volunteers suffering concomitant dyspepsia? Methods: A subset analysis of a previous dose-ranging, open, postal study, in adults suffering dyspepsia. Two hundred and eight (208) adults were identified post hoc as suffering with IBS. IBS incidence, self-reported usual bowel pattern, and the Nepean Dyspepsia Index (NDI) were compared before and after a 2-month intervention period. Results: There was a significant fall in IBS incidence of 26.4% (p<0.001) after treatment. A significant shift in self-reported usual bowel pattern away from "alternating constipation/diarrhea" toward "normal" (p<0.001) was observed. NDI total symptom score significantly decreased by 41% (p<0.001) after treatment. Similarly, there was a significant 20% improvement in the NDI total quality-of-life (QOL) score in the subset after treatment. Conclusion: This report supports previous findings that ALE ameliorates symptoms of IBS, plus improves health-related QOL.

Effect of dietary supplementation with selenium-enriched yeast or sodium selenite on selenium tissue distribution and meat quality in commercial-line turkeys

The objective of this study was to determine the concentration of total selenium (Se) and proportions of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys) in the tissues of female turkeys offered diets containing graded additions of selenized-enriched yeast (SY), or sodium selenite (SS). Oxidative stability and tissue glutathione peroxidase (GSH-Px) activity of breast and thigh muscle were assessed at 0 and 10 days post mortem. A total of 216 female turkey poults were enrolled in the study. A total of 24 birds were euthanized at the start of the study and samples of blood, breast, thigh, heart, liver, kidney and gizzard were collected for determination of total Se. Remaining birds were blocked by live weight and randomly allocated to one of four dietary treatments(n548 birds/treatment) that differed either in Se source (SY v. SS) or dose (Con [0.2 mg/kg total Se], SY-L and SS-L [0.3mg/kg total Se as SY and SS, respectively] and SY-H [0.45mg total Se/kg]). Following 42 and 84 days of treatment 24 birds per treatment were euthanized and samples of blood, breast, thigh, heart, liver, kidney and gizzard were retained for determination of total Se and the proportion of total Se comprised as SeMet or SeCys. Whole blood GSH-Px activity was determined at each time point. Tissue GSH-Px activity and thiobarbituric acid reactive substances were determined in breast and thigh tissue at the end of the study. There were responses (P,0.001) in all tissues to the graded addition of dietary Se, although rates of accumulation were highest in birds offered SY. There were notable differences between tissue types and treatments in the distribution of SeMet and SeCys, and the activity of tissue and erythrocyte GSH-Px (P,0.05). SeCys was the predominant form of Se in visceral tissue and SeMet the predominant form in breast tissue. SeCys contents were greater in thigh when compared with breast tissue. Muscle tissue GSH-Px activities mirrored SeCys contents. Despite treatment differences in tissue GSH-Px activity, there were no effects of treatment on any meat quality parameter.

Effect of elevated CO2 and high temperature on seed-set and grain quality of rice

Hybrid vigour may help overcome the negative effects of climate change in rice. A popular rice hybrid (IR75217H), a heat-tolerant check (N22), and a mega-variety (IR64) were tested for tolerance of seed-set and grain quality to high-temperature stress at anthesis at ambient and elevated [CO2]. Under an ambient air temperature of 29 °C (tissue temperature 28.3 °C), elevated [CO2] increased vegetative and reproductive growth, including seed yield in all three genotypes. Seed-set was reduced by high temperature in all three genotypes, with the hybrid and IR64 equally affected and twice as sensitive as the tolerant cultivar N22. No interaction occurred between temperature and [CO2] for seed-set. The hybrid had significantly more anthesed spikelets at all temperatures than IR64 and at 29 °C this resulted in a large yield advantage. At 35 °C (tissue temperature 32.9 °C) the hybrid had a higher seed yield than IR64 due to the higher spikelet number, but at 38 °C (tissue temperature 34–35 °C) there was no yield advantage. Grain gel consistency in the hybrid and IR64 was reduced by high temperatures only at elevated [CO2], while the percentage of broken grains increased from 10% at 29 °C to 35% at 38 °C in the hybrid. It is concluded that seed-set of hybrids is susceptible to short episodes of high temperature during anthesis, but that at intermediate tissue temperatures of 32.9 °C higher spikelet number (yield potential) of the hybrid can compensate to some extent. If the heat tolerance from N22 or other tolerant donors could be transferred into hybrids, yield could be maintained under the higher temperatures predicted with climate change.

The implications of the 2003 Common Agricultural Policy reforms for land use and landscape quality in England

The assessment of the potential landscape impacts of the latest Common Agricultural Policy reforms constitutes a challenge for policy makers and it requires the development of models that can reliably project the likely spatial distribution of land uses. The aim of this study is to investigate the impact of 2003 CAP reforms to land uses and rural landscapes across England. For this purpose we modified an existing economic model of agriculture, the Land-Use Allocation Model (LUAM) to provide outputs at a scale appropriate for informing a semi-quantitative landscape assessment at the level of ‘Joint Character Areas’ (JCAs). Overall a decline in the cereal and oilseed production area is projected but intensive arable production will persist in specific locations (East of England, East Midlands and South East), having ongoing negative effects on the character of many JCAs. The impacts of de-coupling will be far more profound on the livestock sector; extensification of production will occur in traditional mixed farming regions (e.g. the South West), a partial displacement of cattle by sheep in the upland regions and an increase in the sheep numbers is expected in the lowlands (South East, Eastern and East Midlands). This extensification process will affect positively those JCAs of mixed farming conditions, but it will have negative impacts on the JCAs of historically low intensity farming (e.g. the uplands of north-west) because they will suffer from under-management and land idling. Our analysis shows that the territorialisation between intensively and extensively agricultural landscapes will continue.

Study on indoor thermal environment and air quality of office rooms controlled by personal displacement ventilation using CFD

Three-dimensional computational simulations are performed to examine indoor environment and micro-environment around human bodies in an office in terms of thermal environment and air quality. In this study, personal displacement ventilation (PDV), including two cases with all seats taken and two middle seats taken, is compared with overall displacement ventilation (ODV) of all seats taken under the condition that supply temperature is 24℃ and air change rate is 60 l/s per workstation. When using PDV, temperature stratification, the characteristic of displacement ventilation, is obviously observed at the position of occupant’s head and clearer in the case with all seats taken. Verticalertical ertical temperature temperature temperature temperature temperature differences below height of the head areare under under under 2℃ in two cases in two cases in two cases in two cases in two cases in two cases in two cases in two cases with all seats taken，and the temperature with PDV is higher than that with ODV. Verticalertical ertical temperature temperature temperature temperature temperature temperature difference is under 3 under 3under 3 under 3℃ in the case in the case in the case in the case in the case in the case in the case with two middle seats taken. CO2 concentration is lower th is lower th is lower this lower this lower than 2 g/man 2 g/m an 2 g/man 2 g/man 2 g/man 2 g/m 3 in the breath zone. in the breath zone. in the breath zone. in the breath zone. in the breath zone. in the breath zone. in the breath zone. in the breath zone. in the breath zone. The results indicate that PDV can be used in the room with big change of occupants’ number to satisfy the need of thermal comfort and air quality. When not all seats are taken, designers should increase supply air requirement or reduce its temperature for thermal comfort. INDEX TERMS

The determination of total nitrogen and total phosphorus concentrations in freshwaters from land use, stock headage and population data: testing of a model for use in conservation and water quality management

1. Nutrient concentrations (particularly N and P) determine the extent to which water bodies are or may become eutrophic. Direct determination of nutrient content on a wide scale is labour intensive but the main sources of N and P are well known. This paper describes and tests an export coefficient model for prediction of total N and total P from: (i) land use, stock headage and human population; (ii) the export rates of N and P from these sources; and (iii) the river discharge. Such a model might be used to forecast the effects of changes in land use in the future and to hindcast past water quality to establish comparative or baseline states for the monitoring of change. 2. The model has been calibrated against observed data for 1988 and validated against sets of observed data for a sequence of earlier years in ten British catchments varying from uplands through rolling, fertile lowlands to the flat topography of East Anglia. 3. The model predicted total N and total P concentrations with high precision (95% of the variance in observed data explained). It has been used in two forms: the first on a specific catchment basis; the second for a larger natural region which contains the catchment with the assumption that all catchments within that region will be similar. Both models gave similar results with little loss of precision in the latter case. This implies that it will be possible to describe the overall pattern of nutrient export in the UK with only a fraction of the effort needed to carry out the calculations for each individual water body. 4. Comparison between land use, stock headage, population numbers and nutrient export for the ten catchments in the pre-war year of 1931, and for 1970 and 1988 show that there has been a substantial loss of rough grazing to fertilized temporary and permanent grasslands, an increase in the hectarage devoted to arable, consistent increases in the stocking of cattle and sheep and a marked movement of humans to these rural catchments. 5. All of these trends have increased the flows of nutrients with more than a doubling of both total N and total P loads during the period. On average in these rural catchments, stock wastes have been the greatest contributors to both N and P exports, with cultivation the next most important source of N and people of P. Ratios of N to P were high in 1931 and remain little changed so that, in these catchments, phosphorus continues to be the nutrient most likely to control algal crops in standing waters supplied by the rivers studied.

Cost effectiveness of mitigation measures for water security and water quality in the River Thames catchment: impacts of changing climate, land use and water scarcity

The catchment of the River Thames, the principal river system in southern England, provides the main water supply for London but is highly vulnerable to changes in climate, land use and population. The river is eutrophic with significant algal blooms with phosphorus assumed to be the primary chemical indicator of ecosystem health. In the Thames Basin, phosphorus is available from point sources such as wastewater treatment plants and from diffuse sources such as agriculture. In order to predict vulnerability to future change, the integrated catchments model for phosphorus (INCA-P) has been applied to the river basin and used to assess the cost-effectiveness of a range of mitigation and adaptation strategies. It is shown that scenarios of future climate and land-use change will exacerbate the water quality problems, but a range of mitigation measures can improve the situation. A cost-effectiveness study has been undertaken to compare the economic benefits of each mitigation measure and to assess the phosphorus reductions achieved. The most effective strategy is to reduce fertilizer use by 20% together with the treatment of effluent to a high standard. Such measures will reduce the instream phosphorus concentrations to close to the EU Water Framework Directive target for the Thames.

High night temperature induces contrasting responses for spikelet fertility, spikelet tissue temperature, flowering characteristics and grain quality in rice

Climate change is increasing night temperature (NT) more than day temperature (DT) in rice-growing areas. Effects of combinations of NT (24-35°C) from microsporogenesis to anthesis at one or more DT (30 or 35°C) at anthesis on rice spikelet fertility, temperature within spikelets, flowering pattern, grain weight per panicle, amylose content and gel consistency were investigated in contrasting rice cultivars under controlled environments. Cultivars differed in spikelet fertility response to high NT, with higher fertility associated with cooler spikelets (P < 0.01). Flowering dynamics were altered by high NT and a novel high temperature tolerance complementary mechanism, shorter flower open duration in cv. N22, was identified. High NT reduced spikelet fertility, grain weight per panicle, amylose content and gel consistency, whereas high DT reduced only gel consistency. Night temperature >27°C was estimated to reduce grain weight. Generally, high NT was more damaging to grain weight and selected grain quality traits than high DT, with little or no interaction between them. The critical tolerance and escape traits identified, i.e. spikelet cooling, relatively high spikelet fertility, earlier start and peak time of anthesis and shorter spikelet anthesis duration can aid plant breeding programs targeting resilience in warmer climates.