The impact generated by public and charity-funded research in the UK: A systematic literature review

Objective: To identify, synthesize and critically assess the empirical evidence of the impact generated by public and charity funded health research in the United Kingdom. Methods: We conducted a systematic literature review of the empirical evidence published in English in peer-reviewed journals between 2006 and 2017. Studies meeting the inclusion criteria were selected and their findings were analysed using the Payback Framework into five main categories: knowledge, benefits to future research and research use, benefits from informing policy and product development, health and health sector benefits and broader economic benefits. We assessed the studies for risk of selection, reporting and funding bias. Results: Thirteen studies met the inclusion criteria. The majority of the studies (10 out of 13) assessed impact at multiple domains including the main 5 key themes of the Payback Framework. All of them showed a positive impact of funded research on outcomes. Of those studies, one presented low risk of bias (8%), 6 studies were classified as presenting moderate risk of bias (46%) and 6 studies presented high risk of bias (46%). Conclusions: Empirical evidence on the impact of public and charity funded research is still limited and subject to funding and selection bias. More work is needed to establish the causal effects of funded research on academic outcomes, policy, practice and the broader economy

The Long Term Response of Birds to Climate Change: New Results from a Cold Stage Avifauna in Northern England

The early MIS 3 (55–40 Kyr BP associated with Middle Palaeolithic archaeology) bird remains from Pin Hole, Creswell Crags, Derbyshire, England are analysed in the context of the new dating of the site’s stratigraphy. The analysis is restricted to the material from the early MIS 3 level of the cave because the upper fauna is now known to include Holocene material as well as that from the Late Glacial. The results of the analysis confirm the presence of the taxa, possibly unexpected for a Late Pleistocene glacial deposit including records such as Alpine swift, demoiselle crane and long-legged buzzard with southern and/or eastern distributions today. These taxa are accompanied by more expected ones such as willow ptarmigan /red grouse and rock ptarmigan living today in northern and montane areas. Finally, there are temperate taxa normally requiring trees for nesting such as wood pigeon and grey heron. Therefore, the result of the analysis is that the avifauna of early MIS 3 in England included taxa whose ranges today do not overlap making it a non-analogue community similar to the many steppe-tundra mammalian faunas of the time. The inclusion of more temperate and woodland taxa is discussed in the light that parts of northern Europe may have acted as cryptic northern refugia for some such taxa during the last glacial. These records showing former ranges of taxa are considered in the light of modern phylogeographic studies as these often assume former ranges without considering the fossil record of those taxa. In addition to the anomalous combination of taxa during MIS 3 living in Derbyshire, the individuals of a number of the taxa are different in size and shape to members of the species today probably due to the high carrying capacity of the steppe-tundra

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

The assembly of developing motor neurons depends on an interplay between spontaneous activity, type II cadherins and gap junctions

A core structural and functional motif of the vertebrate central nervous system is discrete clusters of neurons or 'nuclei'. Yet the developmental mechanisms underlying this fundamental mode of organisation are largely unknown. We have previously shown that the assembly of motor neurons into nuclei depends on cadherin-mediated adhesion. Here, we demonstrate that the emergence of mature topography among motor nuclei involves a novel interplay between spontaneous activity, cadherin expression and gap junction communication. We report that nuclei display spontaneous calcium transients, and that changes in the activity patterns coincide with the course of nucleogenesis. We also find that these activity patterns are disrupted by manipulating cadherin or gap junction expression. Furthermore, inhibition of activity disrupts nucleogenesis, suggesting that activity feeds back to maintain integrity among motor neurons within a nucleus. Our study suggests that a network of interactions between cadherins, gap junctions and spontaneous activity governs neuron assembly, presaging circuit formation

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

Phenylketonuria, congenital hypothyroidism and haemoglobinopathies: public health issues for a Brazilian newborn screening program

In this study, the frequency of detected congenital hypothyroidism, phenylketonuria and haemoglobinopathies in the State of Rio de Janeiro's (Brazil) Newborn Screening Program (NBSP) was analyzed between the years of 2005 and 2007. There were two Newborn Screening Reference Centers (named NSRC A and B) with programmatic differences. In 2007, overall detection coverage reached 80.7%. The increase in the incidence of congenital hypothyroidism (1:1,030 in 2007) was attributed to the reduction of neonatal TSH value limits over time. The incidence discrepancy of phenylketonuria between NSRC A (1:28,427) and B (1:16,522) might be partially explained by the small number of cases. The incidence of sickle cell disease and its traits were uniformly high (1:1,288 and 1:21, respectively). This was coherent with the ethnic composition of the population. The differences in laboratory methods and critical values, in addition to other programmatic issues, may explain the variances in the results and limited analysis of the role of biological and environmental determinants in the occurrence of these diseases.Neste estudo, foi analisada a frequência de detecção do hipotireoidismo congênito, fenilcetonúria e hemoglobinopatias no Programa de Triagem Neonatal do Estado do Rio de Janeiro, Brasil, entre 2005 e 2007. Havia dois Serviços de Referência em Triagem Neonatal (designados SRTN A e B) com diferenças programáticas. Em 2007, a cobertura alcançou 80,7%. O aumento na incidência do hipotireoidismo congênito (1:1.030 em 2007) foi atribuído à redução no valor de corte do TSH ao longo do tempo. As incidências discrepantes da fenilcetonúria entre os modelos (SRTN A - 1:28.427; SR-TN B - 1:16.522) podem ser parcialmente explicadas pelo pequeno número de casos. A incidência da doença falciforme e do traço falcêmico foi uniformemente elevada (1:1.288 e 1:21, respectivamente), sendo coerente com a composição étnica da população. As diferenças nos métodos laboratoriais e valores críticos, além de outras questões programáticas, podem explicar a variabilidade nos resultados e limitar a análise do papel dos determinantes biológicos e ambientais sobre a ocorrência das doenças

Epistasis and genotype-by-environment interaction of grain protein content in durum wheat

Parental, F1 , F 2 , BC 1 and BC 2 generations of four crosses involving four cultivars of durum wheat (Triticum durum Desf.) were evaluated at two sites in Tunisia. A three-parameter model was found inadequate for all cases except crosses Chili x Cocorit 71 at site Sidi Thabet and Inrat 69 x Karim at both sites. In most cases a digenic epistatic model was sufficient to explain variation in generation means. Dominance effects (h) and additive x additive epistasis (i) (when significant) were more important than additive (d) effects and other epistatic components. Considering the genotype-by-environment interaction, the non-interactive model (m, d, h, e) was found adequate. Additive variance was higher than environmental variance in three crosses at both sites. The estimated values of narrow-sense heritability were dependent upon the cross and the sites and were 0%-85%. The results indicate that appropriate choice of environment and selection in later generations would increase grain protein content in durum wheat

Reverse Engineering a Signaling Network Using Alternative Inputs

One of the goals of systems biology is to reverse engineer in a comprehensive fashion the arrow diagrams of signal transduction systems. An important tool for ordering pathway components is genetic epistasis analysis, and here we present a strategy termed Alternative Inputs (AIs) to perform systematic epistasis analysis. An alternative input is defined as any genetic manipulation that can activate the signaling pathway instead of the natural input. We introduced the concept of an “AIs-Deletions matrix” that summarizes the outputs of all combinations of alternative inputs and deletions. We developed the theory and algorithms to construct a pairwise relationship graph from the AIs-Deletions matrix capturing both functional ordering (upstream, downstream) and logical relationships (AND, OR), and then interpreting these relationships into a standard arrow diagram. As a proof-of-principle, we applied this methodology to a subset of genes involved in yeast mating signaling. This experimental pilot study highlights the robustness of the approach and important technical challenges. In summary, this research formalizes and extends classical epistasis analysis from linear pathways to more complex networks, facilitating computational analysis and reconstruction of signaling arrow diagrams

The incidence of smoking and risk factors for smoking initiation in medical faculty students: cohort study

BACKGROUND: Medical education requires detailed investigation because it is a period during which the attitudes and behaviors of physicians develop. The purpose of this study was to calculate the yearly smoking prevalence and incidence rates of medical faculty students and to identify the risk factors for adopting smoking behaviour. METHODS: This is a cohort study in which every student was asked about their smoking habits at the time of first registration to the medical faculty, and was monitored every year. Smoking prevalence, yearly incidence of initiation of smoking and average years of smoking were calculated in analysis. RESULTS: At the time of registration, 21.8% of the students smoked. At the end of six years, males had smoked for an average of 2.6 ± 3.0 years and females for 1.0 ± 1.8 years (p < 0.05). Of the 93 medical students who were not smokers at the time of registration, 30 (32.3%) were smokers at the end of the 6 years of the course. CONCLUSION: The first 3 years of medical education are the most risky period for initiation of smoking. We found that factors such as being male, having a smoking friend in the same environment and having a high trait anxiety score were related to the initiation of smoking. Targeted smoking training should be mandatory for students in the Medical Faculty