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What is this summary about? This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol–budesonide , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

A major focus for genomic prediction has been on improving trait prediction accuracy using combinations of algorithms and the training data sets available from plant breeding multi-environment trials (METs). Any improvements in prediction accuracy are viewed as pathways to improve traits in the reference population of genotypes and product performance in the target population of environments (TPE). To realize these breeding outcomes there must be a positive MET-TPE relationship that provides consistency between the trait variation expressed within the MET data sets that are used to train the genome-to-phenome (G2P) model for applications of genomic prediction and the realized trait and performance differences in the TPE for the genotypes that are the prediction targets. The strength of this MET-TPE relationship is usually assumed to be high, however it is rarely quantified. To date investigations of genomic prediction methods have focused on improving prediction accuracy within MET training data sets, with less attention to quantifying the structure of the TPE and the MET-TPE relationship and their potential impact on training the G2P model for applications of genomic prediction to accelerate breeding outcomes for the on-farm TPE. We extend the breeder’s equation and use an example to demonstrate the importance of the MET-TPE relationship as a key component for the design of genomic prediction methods to realize improved rates of genetic gain for the target yield, quality, stress tolerance and yield stability traits in the on-farm TPE.

The Tropical Conservativism Hypothesis and Biogeographical Conservativism Hypothesis were tested in forest millipedes. Latitudinal diversity gradient (LDG) was measured in the genus Sphaerotherium in order to distinguish between the two hypotheses. There was a significant correlation between the number of species and latitudinal degrees away from the equator (r=-0.8701, r2=0.7571, n=46, p

The Tropical Conservativism Hypothesis suggests processes of speciation, extinction and dispersal resulted in higher species richness at the tropics and declined away from the equator. Biogeographical Conservativism Hypothesis suggests that the processes invoked are not intrinsic to the tropics but were dependent on historical biogeography to determine the distribution of species richness. 77 valid species were identified as belonging to the genus Gnomeskelus in order to test between the two hypotheses. There was a significant correlation between the number of species and latitudinal degrees away from the equator (r=-0.7145, r2=0.5105, n=77, p

Abstract Background The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. Methods/design The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the “Guidelines for the content of statistical analysis plans in clinical trials” to support transparency and reproducibility of the trial findings. Discussion With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. Trial registration ANZCTR registry: ACTRN12617001187336 . Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.

Centrobolus typically has prolonged copulation as a form of syn-copula mateguarding. Variations in the copulation duration were calculated and analysed in four species of the millipede genus Centrobolus. Mean copulation durations differed between all four species but only two species were different intra-specifically. C. inscriptus was different from C. anulatus in copulation duration coefficient of variation (CV) (F=0.41490, d.f.=114, 7, p=0.04892) and C. fulgidus and C. anulatus were different in copulation duration CV (F=0.38912, d.f.=50, 7, p=0.04836). Copulation duration was variable intra-specifically but tends to be intermediate and determining evolutionarily (interspecifically). Copulation duration was significantly correlated (Spearman's Rho Calculator) with male and female volumes (r=1, p=0, n=4, 4; 4, 4). When I controlled for sex, I found copulation duration was significantly correlated with size (volumes) (r=0.6655, r2=0.4429, p=0.004897, n=8, 8). Larger male and female body size correlate with copulation duration both intra-specifically and interspecifically in millipedes, and perhaps in animals.

Dermatographism, also known as skin writing, is an immunological response that remains an enigma. It occurs when normal skin is stroked with a dull object causing it to become raised and inflamed, and assume the shape of the stroke. Here we present a case of dermatographia in a denervated deep inferior epigastric perforator flap used to reconstruct breast tissue following mastectomy. Keywords: Dermatographia, DIEP, Free Flap

Sexual Size Dimorphism (SSD) in the diplopod genus Centrobolus has a positive correlation with body size. Length, width and rings are the main components of interspecific variation in diplopod species. Interspecific variation in size was calculated in 6 species and data sets tested for skewness and kurtosis. 28 values were positively skew and had positive kurtosis while 8 were negatively skew and 4 had negative kurtosis. In 6 cases width was positively skewed and in four cases it was negatively skewed. Length was positively skewed in all 6 species except C. titanophilus. Longer males were thought to have increased reproductive success through female preference for larger size when there was size assortative mating behaviour.

Correlates of diplopod size include diet, copulation duration, energy expense of copulation, oxygen consumption, precipitation, sex and temperature. Sexual Size Dimorphism (SSD) in the diplopod genus Centrobolus has a positive correlation with body size and copulation duration. Intraspecific variation in mass was calculated in forest millipedes and correlated with copulation duration (R2=0.68, d.f.=7, p=0.01). Interspecific variation in mass was calculated in forest millipede species and correlated with copulation duration (R=0.6711, R2=0.4504, p=0.144473, n= 3, 3).

A consistent effect of increasing precipitation (and resource abundance) on body size reductions is known as a water conservation hypothesis. Here a water conservation hypothesis was investigated in millipedes and a comparison made between high long-term mean annual precipitation of forest (750-1500 mm) and lower longterm mean annual precipitation of savanna (544 mm) biome species (n=29, 6). When the confounding effects of phylogeny, sexual dimorphism, sexual size dimorphism and size were controlled/removed, differences were found between six savanna species (Bicoxidens brincki, Doratogonus annulipes, Harpagophora spirobolina, Julomorpha hilaris, J. panda, Odontopyge tabulinus: 0,35975-2,632336 mm-1) and 29 forest species (Centrobolus: 0,000113-0,679931 mm-1; Sphaerotherium: 1,14271-3 mm-1) in the surface area: volume ratios. Savanna millipedes had size-independent surface area: volume ratios (0,519783 mm-1 in males and 0,823878 mm-1 in females). Differences occurred between size-independent savanna and size-dependent forest taxa in surface area: volume ratios (t=3.75191, p=0.000013, n=58,12) controlling for the derivation whereby length/width increase affected surface area equally. Female savanna millipedes were longer than female forest millipedes (t=2.26165, p=0.016156, n=22, 6).

Sexual Size Dimorphism (SSD) in the diplopod genera Bicoxidens, Doratogonus, Harpagophora, Julomorpha and Orthoporoides has length, width and rings as the main components of interspecific variation. Interspecific variation in size observed in B. bricki Schubart, 1966, D. annulipes Carl, 1917, H. spirobolina (Karsch, 1881), J. hilaris Attems, 1928, J. panda (Attems, 1928) and O. tabulinus (Attems, 1914) and the data sets were tested for normality. Male lengths differed from female lengths in all except J. hilaris which had different widths. Juliform millipedes appear to have decreased in size over evolutionary time and this study presents an interesting finding showing sexual dimorphism based on length in larger species and sexual dimorphism based on width in the smaller species. The reason for this has to do with the constraints imposed through a cylindrical body form which can be changed more powerfully through reducing width rather than length.

The diverse consequences of genotype-by-environment (GxE) interactions determine trait phenotypes across levels of biological organization for crops, challenging our ambition to predict trait phenotypes from genomic information alone. GxE interactions have many implications for optimizing both genetic gain through plant breeding and crop productivity through on-farm agronomic management. Advances in genomics technologies have provided many suitable predictors for the genotype dimension of GxE interactions. Emerging advances in high-throughput proximal and remote sensor technologies have stimulated the development of “enviromics” as a community of practice, which has the potential to provide suitable predictors for the environment dimension of GxE interactions. Recently, several bespoke examples have emerged demonstrating the nascent potential for enhancing the prediction of yield and other complex trait phenotypes of crop plants through including effects of GxE interactions within prediction models. These encouraging results motivate the development of new prediction methods to accelerate crop improvement. If we can automate methods to identify and harness suitable sets of coordinated genotypic and environmental predictors, this will open new opportunities to upscale and operationalize prediction of the consequences of GxE interactions. This would provide a foundation for accelerating crop improvement through integrating the contributions of both breeding and agronomy. Here we draw on our experience from improvement of maize productivity for the range of water-driven environments across the US corn-belt. We provide perspectives from the maize case study to prioritize promising opportunities to further develop and automate “enviromics” methodologies to accelerate crop improvement through integrated breeding and agronomic approaches for a wider range of crops and environmental targets.

Genomic prediction of complex traits across environments, breeding cycles, and populations remains a challenge for plant breeding. A potential explanation for this is that underlying non-additive genetic (GxG) and genotype-by-environment (GxE) interactions generate allele substitution effects that are non-stationary across different contexts. Such non-stationary effects of alleles are either ignored or assumed to be implicitly captured by most gene-to-phenotype (G2P) maps used in genomic prediction. The implicit capture of non-stationary effects of alleles requires the G2P map to be re-estimated across different contexts. We discuss the development and application of hierarchical G2P maps that explicitly capture non-stationary effects of alleles and have successfully increased short-term prediction accuracy in plant breeding. These hierarchical G2P maps achieve increases in prediction accuracy by allowing intermediate processes such as other traits and environmental factors and their interactions to contribute to complex trait variation. However, long-term prediction remains a challenge. The plant breeding community should undertake complementary simulation and empirical experiments to interrogate various hierarchical G2P maps that connect GxG and GxE interactions simultaneously. The existing genetic correlation framework can be used to assess the magnitude of non-stationary effects of alleles and the predictive ability of these hierarchical G2P maps in long-term, multi-context genomic predictions of complex traits in plant breeding.

Sexual Size Dimorphism (SSD) in the diplopod genus Centrobolus has a positive correlation with body size. Length, width and rings are the main components of interspecific variation in diplopod species. Interspecific variation in size was calculated in 6 species and data sets tested for normality. All data observed and tested were normal. Intersexual variation (coefficients of variation) in length and width was compared in 9 species using MEDCALC. In C. digrammus, C. inscriptus, and C. silvanus there was significant directional selection for slender males.

The present research aimed to study the sexual size dimorphism of Centrobolus titanophilus. Diplopoda illustrated reversed sexual size dimorphism (SSD) where one sex was larger than an other. The SSD of C. titanophilus was shown from data taken in the Cape Province, South Africa. The average size of C. titanophilus was 285 by 41.875 mm (n=8); the smaller sex was 276.6667 by 40.6667 mm (n=5) and the larger sex was 290 by 42.6 mm (n=3). Absolute size was estimated (x=418.3596 mm3; y=359.3327 mm3) and used to calculate the difference between the sexes based on differences in tergite width (t=1.85901, p=0.084172, n=8). The SSD ratio for C. titanophilus was 1.164268 which differed from 1 (t=2.70801, p=0.012845, n=8).

Forty-two studies on fire millipedes are reviewed in which mechanisms of selection; sperm competition and cryptic female choice were studied. Approaches to: (1) quantify size dimorphism and find the selection pressures operating on the sexes, (2) determine the functional significance of male and female genitalia, (3) understand why there should be a conflict of sexual interests in prolonged copulations, and (4) resolve the mechanisms of sperm competition and cryptic female choice in comparing male mating strategies to female mating strategies and sperm usage were included.

The present research aimed to study relative sexual size dimorphism of Centrobolus lawrencei compared to congenerics. Millipedes illustrated reversed sexual size dimorphism (SSD) as females were larger than males and broke the rule as this dimorphism increased with body size. SSD was calculated in 21 species of the genus Centrobolus and illustrated as a regression. The approximate relative position of C. lawrencei was shown from measurements taken in South Africa. The average size of C. lawrencei was 47.3333 * 4.82222 mm (n=9) and logged (x/y = 2.36132). Males were 47.875 * 4.6875 mm (n=8) and females 43 * 5.9 mm (n=1). The SSD index was 1.00201. Log volume measurements were (females/x = 2.36553 mm3; males/y = 2.36079 mm3). The difference between the correlation coefficients for the species and the genus were not highly significant (ra = 0.867365, rb = 0.7473; na = 9, nb = 21; Z = 0.75; P (one-tailed) = 0.2266, P (two-tailed) = 0.4533). The mean volume ratio for C. lawrencei was 1.00201 which did not differ from 1 (t=1.82574; p-value=0.097855; NS at p

Introduction: Previous studies of microtia epidemiology globally have demonstrated significant geographical and ethnic variation, cited broadly as affecting 3–5 in 10,000 live births. The aim of this study was to determine the incidence of microtia in a largely homogeneous ethnic population in the United Kingdom (Wales) and to identify factors, such as distance and socioeconomic status, which may influence the access to surgical intervention.Materials and Methods: A retrospective cohort study was conducted using data linkage to identify patients born between 2000 and 2018 with a diagnosis of microtia. Microtia incidence was calculated using annual and geographic birth rates. Surgical operation codes were used to classify patients into those that had no surgery, autologous reconstruction or prosthetic reconstruction. Sociodemographic attributes were compared using descriptive statistics to determine differences in access to each type of surgical intervention.Results: A total of 101 patients were identified, 64.4% were male and the median age was 12 (8–16). The mean annual incidence was 2.13 microtia cases per 10,000 births over the 19-year study period. Both temporal and geographic variation was noted. The majority of patients undergoing surgery opted for autologous reconstruction (72.9%) at a median age of 9 (7–10) compared to 7 (5–8) for prosthetic reconstruction. Autologous reconstruction had a higher median number of surgeries (2, 1–3) than prosthetic (1.5, 1–2) and a higher median socioeconomic status of 3 (2–4) compared to 2 (1–4) for the prosthetic cohort. There were no statistically significant differences in the distance traveled for surgery.Discussion: This study highlights a role for data linkage in epidemiological analyses and provides a revised incidence of microtia in Wales. Although the majority of patients opted for autologous reconstruction, demographic disparities in socioeconomic status warrant further investigation, emphasizing the importance of striving for equity in accessibility to surgical intervention.

This present research aims to study the relative sexual size dimorphism of Centrobolus (Cook) in 18 congenerics. Millipedes illustrated reversed sexual size dimorphism (SSD) where females were larger than males; and broke Rensch's rule as this dimorphism increased with body size. SSD was calculated in 18 species of the genus Centrobolus and illustrated was regressions; male versus female SSD and SSD vs body size. An allometric equation for Centrobolus was (1) ?=0.00051x-0.01071. SSD ranged from 0.63-2.89 (1.55±0.63; n not less than 18) and was not negatively correlated (R=0.70485; P=0.00109; n=18 spp.) with volume ranging from 284-2683 mm3 (1097.89±638.06; 18). The rejection of the rule appears consistent among arthropods.

Abstract Background Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients. Methods Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events. Results All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6–10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20–1.71], 1.64 [1.37–1.97], and 4.74 [3.86–5.82], respectively), macrovascular disease (1.43 [1.30–1.57], 2.04 [1.86–2.25], and 1.26 [1.06–1.51]) or both (2.01 [1.65–2.45], 2.92 [2.40–3.55], and 6.30 [4.93–8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002–0.008], p = 0.02) or macrovascular disease (0.005 [0.002–0.007], p

Genomic selection, enabled by whole genome prediction (WGP) methods, is revolutionizing plant breeding. Existing WGP methods have been shown to deliver accurate predictions in the most common settings, such as prediction of across environment performance for traits with additive gene effects. However, prediction of traits with non-additive gene effects and prediction of genotype by environment interaction (G×E), continues to be challenging. Previous attempts to increase prediction accuracy for these particularly difficult tasks employed prediction methods that are purely statistical in nature. Augmenting the statistical methods with biological knowledge has been largely overlooked thus far. Crop growth models (CGMs) attempt to represent the impact of functional relationships between plant physiology and the environment in the formation of yield and similar output traits of interest. Thus, they can explain the impact of G×E and certain types of non-additive gene effects on the expressed phenotype. Approximate Bayesian computation (ABC), a novel and powerful computational procedure, allows the incorporation of CGMs directly into the estimation of whole genome marker effects in WGP. Here we provide a proof of concept study for this novel approach and demonstrate its use with synthetic data sets. We show that this novel approach can be considerably more accurate than the benchmark WGP method GBLUP in predicting performance in environments represented in the estimation set as well as in previously unobserved environments for traits determined by non-additive gene effects. We conclude that this proof of concept demonstrates that using ABC for incorporating biological knowledge in the form of CGMs into WGP is a very promising and novel approach to improving prediction accuracy for some of the most challenging scenarios in plant breeding and applied genetics.

Breeding programs for rainfed lowland rice normally use large plot sizes for accurate estimation of yield. Resource requirements are reduced and more genotypes can be tested if a small plot size can be used. A total of 4 experiments was conducted at high and low soil fertility locations in Thailand to determine the influence of plot size and arrangement of tall and short genotypes in small plots on the estimation of yield of genotypes differing in height. Ten to sixteen genotypes were grown in different orders of tall and short genotypes within 2-row plots and also in random arrangements in 4-row, 6-row and 16-row plots. Results showed that taller genotypes tended to suppress the performance of the neighboring shorter genotypes. Consequently the yield results from 2-row plots, in which genotypes were randomly allocated, were unreliable at the high soil fertility location with more vigorous growth, although they were sufficient at the low soil fertility location. Thus plot sizes of 4 and 6-rows appear necessary for accurate estimation of yield across environments. However, when all short genotypes were grouped together and formed a block, and all tall genotypes grouped to form another block, yield results from 2-row plots showed a rather small effect of the competition between the neighbouring genotypes. The yield estimation was improved further by adjusting yield according to the height of each genotype by using covariance analysis. With these modifications, 2-row plots were found to be sufficient for accurate estimation of yield.

The transition from the vegetative to reproductive development is a critical event in the plant life cycle. The accurate prediction of flowering time in elite germplasm is important for decisions in maize breeding programs and best agronomic practices. The understanding of the genetic control of flowering time in maize has significantly advanced in the past decade. Through comparative genomics, mutant analysis, genetic analysis and QTL cloning, and transgenic approaches, more than 30 flowering time candidate genes in maize have been revealed and the relationships among these genes have been partially uncovered. Based on the knowledge of the flowering time candidate genes, a conceptual gene regulatory network model for the genetic control of flowering time in maize is proposed. To demonstrate the potential of the proposed gene regulatory network model, a first attempt was made to develop a dynamic gene network model to predict flowering time of maize genotypes varying for specific genes. The dynamic gene network model is composed of four genes and was built on the basis of gene expression dynamics of the two late flowering id1 and dlf1 mutants, the early flowering landrace Gaspe Flint and the temperate inbred B73. The model was evaluated against the phenotypic data of the id1 dlf1 double mutant and the ZMM4 overexpressed transgenic lines. The model provides a working example that leverages knowledge from model organisms for the utilization of maize genomic information to predict a whole plant trait phenotype, flowering time, of maize genotypes.

Quiet, shy and/or anxious children are found in every classroom and in every school and by their nature, tend to go 'under the radar'. These children present a variety of behaviours, such as being inhibited, lacking confidence, or appearing socially anxious. For some children, their shyness can be severe and may affect their access to learning, thus further understanding, support and nurture is needed. This study employed a targeted six week intervention programme entitled 'Special Me Time' (SMT) that supported the children with: vocalising their feelings; accessing classroom opportunities; communication, and developing friendships. The premise of the approach is that the children are withdrawn from the mainstream classroom and the session is led by a trained practitioner in a small group situation. The programme is aligned to and followed a nurture based approach. The SMT programme was conducted by school staff and Initial Teacher Education students in primary schools predominantly in South Wales, UK. Findings from the implementation of the programme highlighted that it benefited all children's personal and social development in a range of ways such as improving their confidence and self-esteem. Boys with English as an additional language (EAL) responded especially well to the programme. The results of this research study demonstrated the importance of using an intervention designed to understand and support quiet shy and/or anxious children and to develop their unique abilities in a medium where they were both seen and heard.