A QTL for osteoporosis detected in an F2 population derived from White Leghorn chicken lines divergently selected for bone index

Osteoporosis, resulting from progressive loss of structural bone during the period of egg-laying in hens, is associated with an increased susceptibility to bone breakage. To study the genetic basis of bone strength, an F cross was produced from lines of hens that had been divergently selected for bone index from a commercial pedigreed White Leghorn population. Quantitative trait loci (QTL) affecting the bone index and component traits of the index (tibiotarsal and humeral strength and keel radiographic density) were mapped using phenotypic data from 372 F individuals in 32 F families. Genotypes for 136 microsatellite markers in 27 linkage groups covering ∼80% of the genome were analysed for association with phenotypes using within-family regression analyses. There was one significant QTL on chromosome 1 for bone index and the component traits of tibiotarsal and humeral breaking strength. Additive effects for tibiotarsal breaking strength represented 34% of the trait standard deviation and 7.6% of the phenotypic variance of the trait. These QTL for bone quality in poultry are directly relevant to commercial populations

Many quantitative trait loci for feather growth in an F broiler × layer cross collocate with body weight loci

1. A genome-wide scan of 467 F progeny of a broiler x layer cross was conducted to identify quantitative trait loci (QTL) affecting the rate of growth of the tail, wing and back feathers, and the width of the breast feather tract, at three weeks of age. 2. Correlations between the traits ranged from 0·36 to 0·61. Males had longer tail and wing feathers and shorter back feathers than females. Breast feather tract width was greater in females than males. 3. QTL effects were generally additive and accounted for 11 to 45% of sex average feather lengths of the breeds, and 100% of the breast feather tract width. Positive and negative alleles were inherited from both lines, whereas the layer allele was larger than the broiler allele after adjusting for body weight. 4. A total of 4 genome-significant and 4 suggestive QTL were detected. At three or 6 weeks of age, 5 of the QTL were located in similar regions as QTL for body weight. 5. Analysis of a model with body weight at three weeks as a covariate identified 5 genome significant and 6 suggestive QTL, of which only two were coincident with body weight QTL. One QTL for feather length at 148 cM on GGA1 was identified at a similar location in the unadjusted analysis. 6. The results suggest that the rate of feather growth is largely controlled by body weight QTL, and that QTL specific for feather growth also exist

Identification of the Amino Acids 300–600 of IRS-2 as 14-3-3 Binding Region with the Importance of IGF-1/Insulin-Regulated Phosphorylation of Ser-573

Phosphorylation of insulin receptor substrate (IRS)-2 on tyrosine residues is a key event in IGF-1/insulin signaling and leads to activation of the PI 3-kinase and the Ras/MAPK pathway. Furthermore, phosphorylated serine/threonine residues on IRS-2 can induce 14-3-3 binding. In this study we searched IRS-2 for novel phosphorylation sites and investigated the interaction between IRS-2 and 14-3-3. Mass spectrometry identified a total of 24 serine/threonine residues on IRS-2 with 12 sites unique for IRS-2 while the other residues are conserved in IRS-1 and IRS-2. IGF-1 stimulation led to increased binding of 14-3-3 to IRS-2 in transfected HEK293 cells and this binding was prevented by inhibition of the PI 3-kinase pathway and an Akt/PKB inhibitor. Insulin-stimulated interaction between endogenous IRS-2 and 14-3-3 was observed in rat hepatoma cells and in mice liver after an acute insulin stimulus and refeeding. Using different IRS-2 fragments enabled localization of the IGF-1-dependent 14-3-3 binding region spanning amino acids 300–600. The 24 identified residues on IRS-2 included several 14-3-3 binding candidates in the region 300–600. Single alanine mutants of these candidates led to the identification of serine 573 as 14-3-3 binding site. A phospho-site specific antibody was generated to further characterize serine 573. IGF-1-dependent phosphorylation of serine 573 was reduced by inhibition of PI 3-kinase and Akt/PKB. A negative role of this phosphorylation site was implicated by the alanine mutant of serine 573 which led to enhanced phosphorylation of Akt/PKB in an IGF-1 time course experiment. To conclude, our data suggest a physiologically relevant role for IGF-1/insulin-dependent 14-3-3 binding to IRS-2 involving serine 573

Logistic early warning scores to predict death, cardiac arrest or unplanned intensive care unit re-admission after cardiac surgery.

NHS England recently mandated that the National Early Warning Score of vital signs be used in all acute hospital trusts in the UK despite limited validation in the postoperative setting. We undertook a multicentre UK study of 13,631 patients discharged from intensive care after risk-stratified cardiac surgery in four centres, all of which used VitalPACTM to electronically collect postoperative National Early Warning Score vital signs. We analysed 540,127 sets of vital signs to generate a logistic score, the discrimination of which we compared with the national additive score for the composite outcome of: in-hospital death; cardiac arrest; or unplanned intensive care admission. There were 578 patients (4.2%) with an outcome that followed 4300 sets of observations (0.8%) in the preceding 24 h: 499 out of 578 (86%) patients had unplanned re-admissions to intensive care. Discrimination by the logistic score was significantly better than the additive score. Respective areas (95%CI) under the receiver-operating characteristic curve with 24-h and 6-h vital signs were: 0.779 (0.771-0.786) vs. 0.754 (0.746-0.761), p < 0.001; and 0.841 (0.829-0.853) vs. 0.813 (0.800-0.825), p < 0.001, respectively. Our proposed logistic Early Warning Score was better than the current National Early Warning Score at discriminating patients who had an event after cardiac surgery from those who did not

Quantitative trait loci for bone traits segregating independently of those for growth in an F-2 broiler X layer cross

An F broiler-layer cross was phenotyped for 18 skeletal traits at 6, 7 and 9 weeks of age and genotyped with 120 microsatellite markers. Interval mapping identified 61 suggestive and significant QTL on 16 of the 25 linkage groups for 16 traits. Thirty-six additional QTL were identified when the assumption that QTL were fixed in the grandparent lines was relaxed. QTL with large effects on the lengths of the tarsometatarsus, tibia and femur, and the weights of the tibia and femur were identified on GGA4 between 217 and 249 cM. Six QTL for skeletal traits were identified that did not co-locate with genome wide significant QTL for body weight and two body weight QTL did not coincide with skeletal trait QTL. Significant evidence of imprinting was found in ten of the QTL and QTL x sex interactions were identified for 22 traits. Six alleles from the broiler line for weight- and size-related skeletal QTL were positive. Negative alleles for bone quality traits such as tibial dyschondroplasia, leg bowing and tibia twisting generally originated from the layer line suggesting that the allele inherited from the broiler is more protective than the allele originating from the layer

"More than just a medical student”: a mixed methods exploration of a structured volunteering programme for undergraduate medical students

Background As a result of the COVID-19 pandemic Imperial College School of Medicine developed a structured volunteering programme involving 398 medical students, across eight teaching hospitals. This case study aims to illuminate the experiences of volunteers, mechanisms of learning and draw lessons for future emergencies and curriculum improvements. Methods Using an illuminative approach to evaluation we invited all volunteers and supervisors to complete a mixed-methods survey. This gathered nominal demographic information and qualitative data related to motivations, experiences, insights into learning, processual and contextual factors. Qualitative responses were coded, thematically organised, and categorised into an overarching framework. Mann-Whitney U tests determined whether volunteers’ overall rating of the experience varied according to demographic features and modulating factors. Spearman’s rank correlation assessed the relationship between aspects of induction and supervision, and overall volunteering rating. Follow up interviews were carried out with students to check back findings and co-create conclusions. Results Modulating factors identified through thematic analysis include altruistic motivation, engaged induction and supervision, feeling valued, having responsibility and freedom from the formal curriculum. Statistically significant positive correlations are identified between volunteers overall rating and being a year 1 or 2 student, ability to discuss role and ask questions during induction, being male, and having regular meetings and role support from supervisors. Qualitatively reported impacts include improved wellbeing, valuable contribution to service and transformative learning. Transformative learning effects included reframing of role within the multidisciplinary team, view of effective learning and view of themselves as competent clinicians. The number of weeks, number of shifts per week, and the role the volunteers performed, did not significantly impact experiences. Conclusions While acknowledging the uniqueness of the situation presented by the first wave COVID-19, we suggest the features of a successful service-learning programme include: a learner-centred induction, engaged and appreciative supervisors, and the entrustment of students with meaningful work with reciprocal benefits to services. Programmes in similar settings may find that 1) volunteering is best appreciated in years 1 or 2, 2) students with altruistic motivations and meaningful work may flourish without formal outcomes and assessments, and 3) that female volunteers may experience emergency learning differently to men

Early pandemic evaluation and enhanced surveillance of COVID-19 (EAVE II) : protocol for an observational study using linked Scottish national data

Introduction Following the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 and the ensuing COVID-19 pandemic, population-level surveillance and rapid assessment of the effectiveness of existing or new therapeutic or preventive interventions are required to ensure that interventions are targeted to those at highest risk of serious illness or death from COVID-19. We aim to repurpose and expand an existing pandemic reporting platform to determine the attack rate of SARS-CoV-2, the uptake and effectiveness of any new pandemic vaccine (once available) and any protective effect conferred by existing or new antimicrobial drugs and other therapies. Methods and analysis A prospective observational cohort will be used to monitor daily/weekly the progress of the COVID-19 epidemic and to evaluate the effectiveness of therapeutic interventions in approximately 5.4 million individuals registered in general practices across Scotland. A national linked dataset of patient-level primary care data, out-of-hours, hospitalisation, mortality and laboratory data will be assembled. The primary outcomes will measure association between: (A) laboratory confirmed SARS-CoV-2 infection, morbidity and mortality, and demographic, socioeconomic and clinical population characteristics; and (B) healthcare burden of COVID-19 and demographic, socioeconomic and clinical population characteristics. The secondary outcomes will estimate: (A) the uptake (for vaccines only); (B) effectiveness; and (C) safety of new or existing therapies, vaccines and antimicrobials against SARS-CoV-2 infection. The association between population characteristics and primary outcomes will be assessed via multivariate logistic regression models. The effectiveness of therapies, vaccines and antimicrobials will be assessed from time-dependent Cox models or Poisson regression models. Self-controlled study designs will be explored to estimate the risk of therapeutic and prophylactic-related adverse events. Ethics and dissemination We obtained approval from the National Research Ethics Service Committee, Southeast Scotland 02. The study findings will be presented at international conferences and published in peer-reviewed journals

Proceedings of the 2003 Winter Simulation Conference

In this paper we have applied an interval representation of time to represent and reason about activities, events, actions and situations relevant to the construction domain. The first part of the paper formally defines the situational simulation environment and develops a set of temporal axioms which can be used to 1) Express precedence constraints between time intervals and 2) Capture the causal relationships between actions and events. The second part of the paper looks at an agent reasoning mechanism used to perceive and predict actions and foresee future consequences of present actions within the simulation environment. Agent reasoning is based on awareness derived from a knowledge base of facts which captures the causal nature of events in the construction management domain

Dominant suppression of inflammation via targeted mutation of the mRNA destabilizing protein tristetraprolin

In myeloid cells, the mRNA-destabilizing protein tristetraprolin (TTP) is induced and extensively phosphorylated in response to LPS. To investigate the role of two specific phosphorylations, at serines 52 and 178, we created a mouse strain in which those residues were replaced by nonphosphorylatable alanine residues. The mutant form of TTP was constitutively degraded by the proteasome and therefore expressed at low levels, yet it functioned as a potent mRNA destabilizing factor and inhibitor of the expression of many inflammatory mediators. Mice expressing only the mutant form of TTP were healthy and fertile, and their systemic inflammatory responses to LPS were strongly attenuated. Adaptive immune responses and protection against infection by Salmonella typhimurium were spared. A single allele encoding the mutant form of TTP was sufficient for enhanced mRNA degradation and underexpression of inflammatory mediators. Therefore, the equilibrium between unphosphorylated and phosphorylated TTP is a critical determinant of the inflammatory response, and manipulation of this equilibrium may be a means of treating inflammatory pathologies