Advanced maternal age (AMA) is known to reduce fertility, increases aneuploidy in oocytes and early embryos and leads to adverse developmental consequences which may associate with offspring lifetime health risks. However, investigating underlying effects of AMA on embryo developmental potential is confounded by the inherent senescence present in maternal body systems further affecting reproductive success. Here, we describe a new model for the analysis of early developmental mechanisms underlying AMA by the derivation and characterisation of mouse embryonic stem cell (mESC-like) lines from naturally conceived embryos. Young (7–8 weeks) and Old (7–8 months) C57BL/6 female mice were mated with young males. Preimplantation embryos from Old dams displayed developmental retardation in blastocyst morphogenesis. mESC lines established from these blastocysts using conventional techniques revealed differences in genetic, cellular and molecular criteria conserved over several passages in the standardised medium. mESCs from embryos from AMA dams displayed increased incidence of aneuploidy following Giemsa karyotyping compared with those from Young dams. Moreover, AMA caused an altered pattern of expression of pluripotency markers (Sox2, OCT4) in mESCs. AMA further diminished mESC survival and proliferation and reduced the expression of cell proliferation marker, Ki-67. These changes coincided with altered expression of the epigenetic marker, Dnmt3a and other developmental regulators in a sex-dependent manner. Collectively, our data demonstrate the feasibility to utilise mESCs to reveal developmental mechanisms underlying AMA in the absence of maternal senescence and with reduced animal use.

The systematic review examined the phenomenon of trust during public health emergency events. The literature reviewed was field studies done with people directly affected or likely to be affected by such events and included quantitative, qualitative, mixed-method, and case study primary studies in English (N = 38) as well as Arabic, Chinese, French, Russian, and Spanish (all non-English N = 30). Studies were mostly from high- and middle-income countries, and the event most covered was infectious disease. Findings from individual studies were first synthesized within methods and evaluated for certainty/confidence, and then synthesized across methods. The final set of 11 findings synthesized across methods identified a set of activities for enhancing trust and showed that it is a multi-faceted and dynamic concept.

Supporting designers is one of the main motivations for design research. However, there is an ongoing debate about the ability of design research to transfer its results, which are often provided in form of design methods, into practice. This article takes the position that the transfer of design methods alone is not an appropriate indicator for assessing the impact of design research by discussing alternative pathways for impacting design practice. Impact is created by different means – first of all through the students that are trained based on the research results including design methods and tools and by the systematic way of thinking they acquired that comes along with being involved with research in this area. Despite having a considerable impact on practice, this article takes the position that the transfer of methods can be improved by moving from cultivating method menageries to facilitating the evolution of method ecosystems. It explains what is understood by a method ecosystem and discusses implications for developing future design methods and for improving existing methods. This paper takes the position that efforts on improving and maturing existing design methods should be raised to satisfy the needs of designers and to truly support them.

Engagement of frontline staff, along with senior leadership, in competition-style healthcare-associated infection reduction efforts, combined with electronic clinical decision support tools, appeared to reduce antibiotic regimen initiations for urinary tract infections (P = .01). Mean monthly standardized infection and device utilization ratios also decreased (P < .003 and P < .0001, respectively).

The capacity of building services in many hospitals exceeds the requirements by significant amounts. Oversizing of building services has a direct impact on building efficiency and operational costs, ultimately impacting upon patient care, by diverting much needed funding. A key factor leading to the oversizing is the excessive and uncoordinated application of design margins across various project stages. Based on a hospital case study, this paper analyses the reasons for the overdesign of a replacement cooling system and raises the importance of managing margins activity to avoid overdesign.

Adverse programming of adult non-communicable disease can be induced by poor maternal nutrition during pregnancy and the periconception period has been identified as a vulnerable period. In the current study, we used a mouse maternal low-protein diet fed either for the duration of pregnancy (LPD) or exclusively during the preimplantation period (Emb-LPD) with control nutrition provided thereafter and postnatally to investigate effects on fetal bone development and quality. This model has been shown previously to induce cardiometabolic and neurological disease phenotypes in offspring. Micro 3D computed tomography examination at fetal stages Embryonic day E14.5 and E17.4, reflecting early and late stages of bone formation, demonstrated LPD treatment caused increased bone formation of relative high mineral density quality in males, but not females, at E14.5, disproportionate to fetal growth, with bone quality maintained at E17.5. In contrast, Emb-LPD caused a late increase in male fetal bone growth, proportionate to fetal growth, at E17.5, affecting central and peripheral skeleton and of reduced mineral density quality relative to controls. These altered dynamics in bone growth coincide with increased placental efficiency indicating compensatory responses to dietary treatments. Overall, our data show fetal bone formation and mineral quality is dependent upon maternal nutritional protein content and is sex-specific. In particular, we find the duration and timing of poor maternal diet to be critical in the outcomes with periconceptional protein restriction leading to male offspring with increased bone growth but of poor mineral density, thereby susceptible to later disease risk.

Models of products and design processes are key to interacting with engineering designs and managing the processes by which they are developed. In practice, companies maintain networks of many interrelated models which need to be synthesised in the minds of their users when considering issues that cut across them. This article considers how information from product and design process models can be integrated with a view to help manage these complex interrelationships. A framework highlighting key issues surrounding model integration is introduced and terminology for describing these issues is developed. To illustrate the framework and terminology, selected modelling approaches that integrate product and process information are discussed and organised according to their levels and forms of integration. Opportunities for further work to advance integrated modelling in engineering design research and practice are discussed.

In many engineering design contexts models are indispensable. They offer decision support and help tackle complex and interconnected design projects, capturing the underlying structure of development processes or resulting products. Because managers and engineers base many decisions on models, it is crucial to understand their properties and how these might influence their behaviour. The level of detail, or granularity, of a model is a key attribute that results from how reality is abstracted in the modelling process. Despite the direct impact granularity has on the use of a model, the general topic has so far only received limited attention and is therefore not well understood or documented. This article provides background on model theory, explores relevant terminology from a range of fields and discusses the implications for engineering design. Based on this, a classification framework is synthesised, which outlines the main manifestations of model granularity. This research contributes to theory by scrutinising the nature of model granularity. It also illustrates how this may manifest in engineering design models, using Design Structure Matrices as an example, and discusses associated challenges to provide a resource for modellers navigating decisions regarding granularity.

Peer drinking norms are arguably one of the strongest correlates of adolescent drinking. Prospective studies indicate that adolescents tend to select peers based on drinking (peer selection) and their peers' drinking is associated with changes in adolescent drinking over time (peer socialization). The present study investigated whether the peer selection and socialization processes in adolescent drinking differed as a function of the dopamine receptor D4 (DRD4) variable number tandem repeat genotype in two independent prospective data sets. The first sample was 174 high school students drawn from a two-wave 6-month prospective study. The second sample was 237 college students drawn from a three-wave annual prospective study. Multigroup cross-lagged panel analyses of the high school student sample indicated stronger socialization via peer drinking norms among carriers, whereas analyses of the college student sample indicated stronger drinking-based peer selection in the junior year among carriers, compared to noncarriers. Although replication and meta-analytic synthesis are needed, these findings suggest that in part genetically determined peer selection (carriers of the DRD4 seven-repeat allele tend to associate with peers who have more favorable attitudes toward drinking and greater alcohol use) and peer socialization (carriers' subsequent drinking behaviors are more strongly associated with their peer drinking norms) may differ across adolescent developmental stages.

Al–12Si (80 vol%)–Ti52.4Al42.2Nb4.4Mo0.9B0.06 (at.%) (TNM) composites were successfully produced by the selective laser melting (SLM). Detailed structural and microstructural analysis shows the formation of the Al6MoTi intermetallic phase due to the reaction of the TNM reinforcement with the Al–12Si matrix during SLM. Compression tests reveal that the composites exhibit significantly improved properties (∼140 and ∼160 MPa higher yield and ultimate compressive strengths, respectively) compared with the Al–12Si matrix. However, the samples break at ∼6% total strain under compression, thus showing a reduced plasticity of the composites. Sliding wear tests were carried out for both the Al–12Si matrix and the Al–12Si–TNM composites. The composites perform better under sliding wear conditions and the wear rate increases with increasing loads. At high loads, the wear takes place at three different rates and the wear rate decreases with increasing experiment duration.

The early embryo and periconceptional period is a window during which environmental factors may cause permanent change in the pattern and characteristics of development leading to risk of adult onset disease. This has now been demonstrated across small and large animal models and also in the human. Most evidence of periconceptional ‘programming’ has emerged from maternal nutritional models but also other in vivo and in vitro conditions including assisted reproductive treatments, show consistent outcomes. This short review first reports on the range of environmental in vivo and in vitro periconceptional models and resulting long-term outcomes. Second, it uses the rodent maternal low protein diet model restricted to the preimplantation period and considers the stepwise maternal-embryonic dialogue that comprises the induction of programming. This dialogue leads to cellular and epigenetic responses by the embryo, mainly identified in the extra-embryonic cell lineages, and underpins an apparently permanent change in the growth trajectory during pregnancy and associates with increased cardiometabolic and behavioural disease in adulthood. We recognize the important advice of David Barker some years ago to investigate the sensitivity of the early embryo to developmental programming, an insight for which we are grateful.

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18 % casein) or an isocaloric low-protein diet throughout gestation (LPD; 9 % casein), or fed the LPD exclusively during the pre-implantation period (3·5 d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P = 0·04 and P = 0·025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na+/K+ ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P = 0·044), whilst Emb-LPD males had elevated lung ACE activity (P = 0·001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected.

The clinical course and outcome of anorexia nervosa are presented in a 10-year followup study of 76 severely ill females with anorexia nervosa who met specific diagnostic criteria and had participated in a well-documented hospital treatment study. Information was obtained on 100% of the subjects. A comprehensive assessment was made in 93% of the living subjects in specific categories of weight, eating and weight control behaviours, menstrual function, anorexic attitudes, and psychological, sexual, social and vocational adjustment. Five subjects had died, which gives a crude mortality rate of 6·6%. Standardized mortality rates demonstrated an almost 13-fold increase in mortality in the anorexia nervosa subjects. Only eighteen (23·7%) were fully recovered. Sixty-four per cent developed binge-eating at some time during their illness, 57% at least weekly. Twenty-nine (41%) were still bulimic at follow-up. The high frequency and chronicity of the bulimic symptoms plus the high rate of weight relapse (42% during the first year after hospital treatment) suggest that intensive intervention is needed to help anorexics restore and maintain their weight within a normal range and to decrease abnormal eating and weight control behaviours.

For the sensitive detection of eggs of Echinococcus multilocularis in fox faeces by PCR we have evaluated a method based on the previous concentration of helminth eggs by a combination of sequential sieving of faecal samples and flotation of the eggs in zinc chloride solution. The eggs were microscopically detected in the fractions retained in 40 and 20µm mesh sieves. DNA of the taeniid eggs retained in the 20 µm sieve was obtained after alkaline lysis and PCR was performed using E. multilocularis species-specific primers. Compared to the parasitological findings after examination of the small intestines of the foxes, the specificity of the PCR was 100% (no false-positive result with 20 foxes free of E. multilocularis) and the sensitivity was 94% (33 positive results from total 35 foxes proven to be infected with E. multilocularis). Both false-negative results were obtained with faeces from foxes harbouring immature worms. Using faecal volumes between 2 and 20 ml, no inhibition of PCR was observed as was demonstrated by the amplification of size-modified target in parallel reactions. The tests were undertaken with fresh faeces stored in 70% ethanol, but egg detection by PCR was also possible after inactivation of eggs by freezing the faeces at −80°C for one week or by incubation at +70°C for 2 h.

SIV rats infected with a high dose (50000 oocysts) of Eimeria nieschulzi displayed clinical symptoms of coccidiosis such as diarrhoea (days 6 and 7 post-primary infection) and weight loss (days 6–8 post-primary infection) and were completely immune to challenge with a similar dose. The ability of rats to produce tumour necrosis factor (TNF) in vivo was enhanced during the period of oocyst excretion in the primary infection but significant production of TNF did not occur after challenge infection. Thus, TNF does not appear to be an important factor in resistance to infection with E. nieschulzi but may play some role in resistance to primary infection and in the pathology associated with E. nieschulzi infection. Parasite-specific serum IgM levels (measured by enzyme-linked immunosorbent assay) were also increased during primary infection but returned to background levels at the end of the patent period and were not affected by challenge infection. In contrast to TNF and IgM, serum concentrations of E. nieschulzi-specific IgGl, IgG2a, IgG2b, IgG2c and intestinal tissue levels of IgA did not begin to increase until after day 12 post-primary infection, reached peak levels between days 20 and 30 post-primary infection and were slightly increased by challenge infection.

Successful realization of large-scale product development programs is challenging because of complex product and process dependencies and complicated team interactions. Proficient teamwork is underpinned by knowledge of the manner in which tasks performed by different design participants fit together to create an effective whole. Based on an extensive industrial case study with a diesel engine company, this paper first argues that the overview and experience of senior designers play an important part in supporting teamwork by coordinating activities and facilitating proactive communication across large project teams. As experts move on and novices or contractors are hired, problems are likely to occur as tacit overview knowledge is lost. If informal, overview-driven processes break down, the risk of costly oversights will increase, and greater management overhead will be required to realize successful product designs. Existing process models provide a means to express the connectivity between tasks and components thus to compensate partially for the loss of tacit overview. This paper proposes the use of design confidence, a metric that reflects the designer's belief in the maturity of a particular design parameter at a given point in the process, to address the limitations of existing models. The applicability of confidence-based design models in providing overview, as well as their shortcomings, will be demonstrated through the example of a diesel engine design process. Confidence can be used to make overview knowledge explicit and convey additional information about the design artifact, thereby informing communication and negotiation between teams.