Exploratory research into supply chain voids within Welsh priority business sectors

The paper reports the findings resulting from the initial stages of an exploratory investigation into Supply Chain Voids (SCV) in Wales. The research forms the foundations of a PhD thesis which is framed within the sectors designated as important by the Welsh Assembly Government (WAG) and indicates local supplier capability voids within their supply chains. This paper covers the stages of initial data gathering, analysis and results identified between June 2006 and April 2007, whilst addressing the first of four research questions. Finally, the approach to address future research is identified in order to explain how the PhD is to progress

Signalling adjustments to direct and indirect environmental effects on signal perception in meerkats.

The efficiency of communication between animals is determined by the perception range of signals. With changes in the environment, signal transmission between a sender and a receiver can be influenced both directly, where the signal's propagation quality itself is affected, and indirectly where the senders or receivers' behaviour is impaired, impacting for example the distance between them. Here we investigated how meerkats (Suricata suricatta) in the Kalahari Desert adjust to these challenges in the context of maintaining group cohesion through contact calls. We found that meerkats changed their calling rate when signal transmission was affected indirectly due to increased dispersion of group members as during a drought, but not under typical wet conditions, when signal transmission was directly affected due to higher vegetation density. Instead under these wetter conditions, meerkats remained within proximity to each other. Overall, both direct and indirect environmental effects on signal perception resulted in an increased probability of groups splitting. In conclusion, we provide evidence that social animals can flexibly adjust their vocal coordination behaviour to cope with direct and indirect effects of the environment on signal perception, but these adjustments have limitations

Ruling out a host-range expansion as the cause of the unpredicted non-target attack on tagasaste (Chamaecytisus proliferus) by Bruchidius villosus

Scotch broom (Cytisus scoparius) is a woody shrub of European origin that is an invasive weed in New Zealand. Bruchidius villosus was released in New Zealand in 1986 as a biological control agent of Scotch broom, after tests indicated that it was specific to this species. However, in 1999, B. villosus was discovered developing in the seeds of an unpredicted host, tagasaste or tree lucerne (Chamaecytisus proliferus). Although the original choice tests carried out in quarantine failed to predict acceptance of C. proliferus by ovipositing females, the current population in New Zealand clearly finds this species an acceptable host. An investigation of the original host-testing procedures revealed a number of possible limitations in the tests conducted in the 1980s. Concerns that a host-range expansion might have occurred in a weed biological control agent led to this study in which beetles from the original population (Silwood Park, United Kingdom) were reimported and the original handling and host choice tests were replicated. Despite showing a strong preference for Scotch broom, the beetles tested in this study accepted C. proliferus for oviposition. These results allow us to rule out the possibility that a hostrange expansion has occurred

Signalling adjustments to direct and indirect environmental effects on signal perception in meerkats

The efficiency of communication between animals is determined by the perception range of signals. With changes in the environment, signal transmission between a sender and a receiver can be influenced both directly, where the signal’s propagation quality itself is affected, and indirectly where the senders or receivers’ behaviour is impaired, impacting for example the distance between them. Here we investigated how meerkats (Suricata suricatta) in the Kalahari Desert adjust to these challenges in the context of maintaining group cohesion through contact calls. We found that meerkats changed their calling rate when signal transmission was affected indirectly due to increased dispersion of group members as during a drought, but not under typical wet conditions, when signal transmission was directly affected due to higher vegetation density. Instead under these wetter conditions, meerkats remained within proximity to each other. Overall, both direct and indirect environmental effects on signal perception resulted in an increased probability of groups splitting. In conclusion, we provide evidence that social animals can flexibly adjust their vocal coordination behaviour to cope with direct and indirect effects of the environment on signal perception, but these adjustments have limitations.Supplement 1: Additional information on results of the models fitted for the different analysis.Supplement 2: Additional analysis on change in group speed with regards to the different environmental conditions.The Swiss National Science Foundation, the University of Zurich, and the University of Cambridge.http://www.plosone.orgam2021Mammal Research Institut

Offspring mass variation in tree swallows : a case of bet‐hedging?

The evolution of reproductive strategies is affected by the ability of organisms to deal with future environmental conditions. When environments are temporally unpredictable, however, it is difficult to anticipate optimal offspring phenotype. Diversification of offspring phenotypes, a strategy called diversified bet‐hedging, may allow parents to maximize their fitness by reducing between‐year variation in reproductive success. The link between diversification of offspring phenotypes and individual reproductive success, however, has rarely been documented empirically. We used an eight‐year dataset (1215 broods, 870 females) on individually marked tree swallows ( Tachycineta bicolor ) to assess whether intra‐brood mass variation was compatible with a diversified bet‐hedging strategy. Intra‐brood mass variation was weakly, but significantly repeatable within females, suggesting consistent individual differences. Greater intra‐brood mass variation, however, was not associated with reduced between‐year variation in reproductive success or increased female reproductive success. Moreover, contrary to diversified bet‐hedging expectations, fledging success of large broods was greater when hatchlings had similar rather than variable masses. Our results suggest that intra‐brood mass variation may not result from diversified bet‐hedging, but rather from complex interactions between environmental, brood, and maternal characteristics

Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance

Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.Peer reviewe

The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers. DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990-2015 : a novel analysis from the Global Burden of Disease Study 2015

Background National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015. Methods We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure-the Healthcare Quality and Access (HAQ) Index-on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r= 0.88), an index of 11 universal health coverage interventions (r= 0.83), and human resources for health per 1000 (r= 0.77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time. Findings Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28.6 to 94.6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40.7 (95% uncertainty interval, 39.0-42.8) in 1990 to 53.7 (52.2-55.4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21.2 in 1990 to 20.1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73.8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015. Interpretation This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-systemcharacteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe