Understanding Mammalian Genetic Systems: The Challenge of Phenotyping in the Mouse

Understanding mammalian genetic systems is predicated on the determination of the relationship between genetic variation and phenotype. Several international programmes are under way to deliver mutations in every gene in the mouse genome. The challenge for mouse geneticists is to develop approaches that will provide comprehensive phenotype datasets for these mouse mutant libraries. Several factors are critical to success in this endeavour. It will be important to catalogue assay and environment and where possible to adopt standardised procedures for phenotyping tests along with common environmental conditions to ensure comparable datasets of phenotypes. Moreover, the scale of the task underlines the need to invest in technological development improving both the speed and cost of phenotyping platforms. In addition, it will be necessary to develop new informatics standards that capture the phenotype assay as well as other factors, genetic and environmental, that impinge upon phenotype outcome

Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI.

Gradient echo T2*-weighted MRI has high sensitivity in detecting cerebral microbleeds, which appear as small dot-like hypointense lesions. Microbleeds are strongly associated with intracerebral haemorrhage, hypertension, lacunar stroke and ischaemic small vessel disease, and have generated interest as a marker of bleeding-prone microangiopathy. Microbleeds have generally been considered to be clinically silent; however, since they are located in widespread cortical and basal ganglia regions and are histologically characterized by tissue damage, we hypothesized that they would cause cognitive dysfunction. We therefore studied patients with microbleeds (n = 25) and a non-microbleed control group (n = 30) matched for age, gender and intelligence quotient. To avoid the confounding effects of coexisting cerebrovascular disease, the groups were also matched for the extent of MRI-visible white matter changes of presumed ischaemic origin, location of cortical strokes, and for the proportion of patients with different stroke subtypes (including lacunar stroke). A battery of neuropsychological tests was used to assess current intellectual function, verbal and visual memory, naming and perceptual skills, speed and attention and executive function. Microbleeds were most common in the basal ganglia but were also found in frontal, parieto-occipital, temporal and infratentorial regions. There was a striking difference between the groups in the prevalence of executive dysfunction, which was present in 60% of microbleed patients compared with 30% of non-microbleed patients (P = 0.03). Logistic regression confirmed that microbleeds (but not white matter changes) were an independent predictor of executive impairment (adjusted odds ratio = 1.32, 95% confidence interval 1.01-1.70, P = 0.04). Patients with executive dysfunction had more microbleeds in the frontal region (mean count 1.54 versus 0.03; P = 0.002) and in the basal ganglia (mean 1.17 versus 0.32; P = 0.048). There was a modest correlation between the number of microbleeds and the number of cognitive domains impaired (r = 0.44, P = 0.03). This study provides novel evidence that microbleeds are associated with cognitive dysfunction, independent of the extent of white matter changes of presumed ischaemic origin, or the presence of ischaemic stroke. The striking effect of microbleeds on executive dysfunction is likely to result from associated tissue damage in the frontal lobes and basal ganglia. These findings have implications for the diagnosis of stroke patients with cognitive impairment, and for the appropriate use of antihypertensive and antiplatelet treatments in these patients

Neonatal morbidity associated with late preterm and early term birth: The roles of gestational age and biological determinants of preterm birth

Background: The aim of this study was to elucidate the role of gestational age in determining the risk of neonatal morbidity among infants born late preterm (34-36 weeks) and early term (37-38 weeks) compared with those born full term (39-41 weeks) by examining the contribution of gestational age within the context of biological determinants of preterm birth.Methods: This was a retrospective cohort study. The sample included singleton live births with no major congenital anomalies, delivered at 34-41 weeks of gestation to London-Middlesex (Canada) mothers in 2002-11. Data from a city-wide perinatal database were linked with discharge abstract data. Multivariable models used modified Poisson regression to directly estimate adjusted relative risks (aRRs). The roles of gestational age and biological determinants of preterm birth were further examined using mediation and moderation analyses.Results: Compared with infants born full term, infants born late preterm and early term were at increased risk for neonatal intensive care unit triage/admission [late preterm aRR = 6.14, 95% confidence interval (CI) 5.63, 6.71; early term aRR = 1.54, 95% CI 1.41, 1.68] and neonatal respiratory morbidity (late preterm aRR = 6.16, 95% CI 5.39, 7.03; early term aRR = 1.46, 95% CI 1.29, 1.65). The effect of gestational age was partially explained by biological determinants of preterm birth acting through gestational age. Moreover, placental ischaemia and other hypoxia exacerbated the effect of gestational age on poor outcomes.Conclusions: Poor outcomes among infants born late preterm and early term are not only due to physiological immaturity but also to biological determinants of preterm birth acting through and with gestational age to produce poor outcomes. © The Author 2013; all rights reserved

Hurricane Sandy Evacuation Among World Trade Center Health Registry Enrollees in New York City

Objective Timely evacuation is vital for reducing adverse outcomes during disasters. This study examined factors associated with evacuation and evacuation timing during Hurricane Sandy among World Trade Center Health Registry (Registry) enrollees. Methods The study sample included 1162 adults who resided in New York City’s evacuation zone A during Hurricane Sandy who completed the Registry’s Hurricane Sandy substudy in 2013. Factors assessed included zone awareness, prior evacuation experience, community cohesion, emergency preparedness, and poor physical health. Prevalence estimates and multiple logistic regression models of evacuation at any time and evacuation before Hurricane Sandy were created. Results Among respondents who evacuated for Hurricane Sandy (51%), 24% had evacuated before the storm. In adjusted analyses, those more likely to evacuate knew they resided in an evacuation zone, had evacuated during Hurricane Irene, or reported pre-Sandy community cohesion. Evacuation was less likely among those who reported being prepared for an emergency. For evacuation timing, evacuation before Hurricane Sandy was less likely among those with pets and those who reported 14 or more poor physical health days. Conclusions Higher evacuation rates were observed for respondents seemingly more informed and who lived in neighborhoods with greater social capital. Improved disaster messaging that amplifies these factors may increase adherence with evacuation warnings

Discovery of a meteoritic ejecta layer containing unmelted impactor fragments at the base of Paleocene lavas, Isle of Skye, Scotland

Evidence for meteorite impacts in the geological record may include the presence of shocked minerals, spherule layers, and geochemical anomalies. However, it is highly unusual to nd unmelted crystals from the actual impactor within an ejecta layer. Here we detail the rst recorded occurrence of vanadium-rich osbornite (TiVN) on Earth, from two sites on Skye, northwest Scotland, which are interpreted as part of a meteoritic ejecta layer. TiVN has only previously been reported as dust from comet Wild 2, but on Skye it has been identi ed as an unmelted phase. Both ejecta layer sites also contain niobium-rich osbornite (TiNbN), which has not previously been reported. An extraterrestrial origin for these deposits is strongly supported by the presence of reidite (a high-pressure zircon polymorph), which is only found naturally at sites of meteorite impact. Barringerite [(Fe,Ni)2P], baddeleyite (ZrO2), alabandite (MnS), and carbon-bearing native iron spherules, together with planar deformation features and diaplectic glass in quartz, further support this thesis. We demonstrate through eld relationships and Ar-Ar dating that the meteorite strike occurred during the mid-Paleocene. This is the rst recorded mid-Paleocene impact event in the region and is coincident with the onset of magmatism in the British Palaeogene Igneous Province (BPIP). The Skye ejecta layer deposits provoke important questions regarding their lateral extent at the base of the BPIP and the possibility of their presence elsewhere beneath the much larger North Atlantic Igneous Province

Mars Aerocapture Systems Study

Mars Aerocapture Systems Study (MASS) is a detailed study of the application of aerocapture to a large Mars robotic orbiter to assess and identify key technology gaps. This study addressed use of an Opposition class return segment for use in the Mars Sample Return architecture. Study addressed mission architecture issues as well as system design. Key trade studies focused on design of aerocapture aeroshell, spacecraft design and packaging, guidance, navigation and control with simulation, computational fluid dynamics, and thermal protection system sizing. Detailed master equipment lists are included as well as a cursory cost assessment

Recognizing, Evaluating, and Prioritizing the Fundamental Factors Influencing the Growing Prevalence of Transgender and Non-Binary Gender Identity in the Pediatric Population

This review observes the growing demographic of individuals identifying as transgender or non-binary, which currently represents approximately 1.3% (depending on the source) of the U.S. population. This population is shown to skew younger.Environmental xenobiotics, particularly those containing endocrine-disrupting chemicals (EDCs), are scrutinized for their role in affecting hormonal regulation crucial for gender identity differentiation. The research also highlights how exposure to pharmaceuticals with endocrine-disrupting properties may induce atypical patterns in gender identity development, suggesting that a variety of exogenous elements could impact neuroendocrine sexual differentiation.Medical disorders associated with altered androgen levels, such as congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS), are considered for their potential influence on gender identity from a biological perspective. Moreover, the role of diet and nutrition, particularly plant-based diets rich in phytoestrogens and conditions linked to obesity and metabolic syndrome, are explored for their effects on hormonal balance and, consequently, gender identity expression.This review acknowledges the significant impact of media representation and societal norms on shaping attitudes concerning gender expression and identity.The article points to psychological assessments and somatic markers as tools to explore prenatal hormone influences on gender identity, though emphasizing that they are not definitive. Furthermore, genetic and epigenetic findings offer a more in-depth understanding but lack diagnostic application. The identification and recognition of transgender and non-binary individuals continue to be self-determined processes that defy objective measurement by current medical standards

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Maternal and infant outcomes associated with lithium use in pregnancy

Background Concerns about teratogenicity and offspring complications limit use of lithium in pregnancy. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity and congenital malformations. Methods Meta-analysis of primary data analyzed using a shared protocol. Six study sites participated: Denmark, Canada, Netherlands, Sweden, UK, and US, totaling 727 lithium-exposed pregnancies compared to 21,397 reference pregnancies in mothers with a mood disorder, but unexposed to lithium. Main outcome measures included: (1) pregnancy complications, (2) delivery outcomes, (3) neonatal readmission to hospital within 28 days of birth, and (4) congenital malformations (major malformations and cardiac malformations). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were generated using logistic regression models. Site-specific prevalence rates and ORs were pooled using random-effects meta-analytic models. Findings Lithium exposure was not associated with any of the pre-defined pregnancy complications or delivery outcomes. There was an increased risk for neonatal readmission in lithium exposed (27·5%) versus reference group (14·3%) (Pooled aOR1·62; 95% CI: 1·12–2·33). Lithium exposure during first trimester was associated with increased risk of major malformations (7·4% versus 4·3%; pooled aOR 1·71, 95% CI: 1·07–2·72). Similarly, more lithium exposed children had major cardiac malformations, albeit not stasticially significant (2·1% versus 1·6%; pooled aOR 1·54, 95% CI: 0·64–3·70). Limitations in our study include: Serum lithium 5 levels were not available, hence no analyses related to dose-response effects could be performed, and residual confounding from e.g. substance abuse cannot be ruled out. Interpretation Treatment decisions must weigh the potential for increased risks, considering both effct sizes and the precision of the estimates, in particular associated with first-trimester lithium use against its effectiveness at reducing relapse