The structure and petrology of the Cnoc nan Cuilean Intrusion, Loch Loyal Syenite Complex, NW Scotland

In NW Scotland, several alkaline intrusive complexes of Silurian age intrude the Caledonian orogenic front. The most northerly is the Loch Loyal Syenite Complex, which is divided into three separate intrusions (Ben Loyal, Beinn Stumanadh and Cnoc nan Cuilean). Mapping of the Cnoc nan Cuilean intrusion shows two main zones: a Mixed Syenite Zone (MZ) and a Massive Leucosyenite Zone (LZ), with a gradational contact. The MZ forms a lopolith, with multiple syenitic lithologies, including early basic melasyenites and later felsic leucosyenites. Leucosyenite melts mixed and mingled with melasyenites, resulting in extreme heterogeneity within the MZ. Continued felsic magmatism resulted in formation of the relatively homogeneous LZ, invading western parts of the MZ and now forming the topographically highest terrane. The identification of pegmatites, microgranitic veins and unusual biotite-magnetite veins demonstrates the intrusion's complex petrogenesis. Cross-sections have been used to create a novel 3D GoCad™ model contributing to our understanding of the intrusion. The Loch Loyal Syenite Complex is known to have relatively high concentrations of rare earth elements (REEs), and thus the area has potential economic and strategic value. At Cnoc nan Cuilean, abundant REE-bearing allanite is present within melasyenites of the MZ. Extensive hydrothermal alteration of melasyenites here formed steeply dipping biotite-magnetite veins, most enriched in allanite and other REE-bearing accessories. This study has thus identified the area of greatest importance for further study of REE enrichment processes in the Cnoc nan Cuilean intrusion

Associations of screen time, sedentary time and physical activity with sleep in under 5s: a systematic review and meta-analysis

Sleep is crucial to children's health and development. Reduced physical activity and increased screen time adversely impact older children’s sleep, but little is known about these associations in children under 5 years. This systematic review examined the association between screen time/movement behaviors (sedentary behavior, physical activity) and sleep outcomes in infants (0-1 year); toddlers (1-2 years); and preschoolers (3-4 years). Evidence was selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and synthesized using vote counting based on the direction of association. Quality assessment and a Grading of Recommendations, Assessment, Development and Evaluation was performed, stratified according to child age, exposure and outcome measure. Thirty-one papers were included. Results indicate that screen time is associated with poorer sleep outcomes in infants, toddlers and preschoolers. Meta-analysis confirmed these unfavorable associations in infants and toddlers but not preschoolers. For movement behaviors results were mixed, though physical activity and outdoor play in particular were favorably associated with most sleep outcomes in toddlers and preschoolers. Overall, quality of evidence was very low, with strongest evidence for daily/evening screen time use in toddlers and preschoolers. Although high-quality experimental evidence is required, our findings should prompt parents, clinicians and educators to encourage sleep-promoting behaviors (e.g. less evening screen time) in the under 5s

Variability in remission in family therapy for anorexia nervosa.

ObjectiveThe evolution toward more stringent conceptualizations of remission in family therapy for adolescent anorexia nervosa (AN) has, with time, introduced variability in outcomes across randomized controlled trials (RCTs). An examination of remission across the history of research on family therapy for AN shows that earlier studies adopted lenient definitions and generally yielded higher rates of remission than studies of the past decade that have used stricter definitions of remission. In this study, we investigate the reactivity of remission rates to the application of different definitions of remission used within the family therapy for AN literature, within a single RCT data set.MethodWe conducted a secondary analysis of data from a single-site RCT which compared the relative efficacy of two formats of family therapy in a sample of 106 Australian adolescents with AN. Using end-of-treatment data, we compared remission rates using 11 definitions of remission that have been used in studies of family therapy for AN spanning more than three decades.ResultsWe found wide variability in remission rates (21.7-87.7%; Cochran's Q χ2 (10, N = 106) = 303.55, p = .000], depending on which definition of remission was applied. As expected, more lenient criteria produced higher remission rates than more stringent definitions.DiscussionApplying different criteria of remission to a single data set illustrates the impact of changing how remission is defined. Failure to consider the greater stringency of remission criteria in recent studies could result in false inferences concerning the efficacy of family therapy for AN over time

New Associations between Drug-Induced Adverse Events in Animal Models and Humans Reveal Novel Candidate Safety Targets.

To improve our ability to extrapolate preclinical toxicity to humans, there is a need to understand and quantify the concordance of adverse events (AEs) between animal models and clinical studies. In the present work, we discovered 3011 statistically significant associations between preclinical and clinical AEs caused by drugs reported in the PharmaPendium database of which 2952 were new associations between toxicities encoded by different Medical Dictionary for Regulatory Activities terms across species. To find plausible and testable candidate off-target drug activities for the derived associations, we investigated the genetic overlap between the genes linked to both a preclinical and a clinical AE and the protein targets found to interact with one or more drugs causing both AEs. We discuss three associations from the analysis in more detail for which novel candidate off-target drug activities could be identified, namely, the association of preclinical mutagenicity readouts with clinical teratospermia and ovarian failure, the association of preclinical reflexes abnormal with clinical poor-quality sleep, and the association of preclinical psychomotor hyperactivity with clinical drug withdrawal syndrome. Our analysis successfully identified a total of 77% of known safety targets currently tested in in vitro screening panels plus an additional 431 genes which were proposed for investigation as future safety targets for different clinical toxicities. This work provides new translational toxicity relationships beyond AE term-matching, the results of which can be used for risk profiling of future new chemical entities for clinical studies and for the development of future in vitro safety panels.This work was supported as part of the PhD project of K.A.G funded by the European Research Council and AstraZeneca Early Oncology TD

Pertussis Seroepidemiology in Women and Their Infants in Sarlahi District, Nepal.

Background Infants are at greatest risk for pertussis morbidity and mortality. Maternal vaccination during pregnancy has been shown to prevent pertussis in young infants in high- and middle-income countries. However, data on the levels of maternal pertussis antibodies and the efficiency of transplacental transfer in low-income South Asian settings are limited. Objective To estimate the prevalence of maternal pertussis antibodies and the efficiency of transplacental transfer in rural southern Nepal. Design/methods Paired maternal-infant blood samples were collected from a subsample of participants in a randomized, controlled trial of maternal influenza immunization (n = 291 pairs). Sera were tested by enzyme-linked immunosorbent assays for pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae. Maternal and infant pertussis antibody levels and transplacental transfer efficiency were determined and potential factors associated with both were assessed. Results Elevated maternal antibodies to pertussis toxin, suggesting recent pertussis infection, were rarely detected (4%, tested n = 305). However, paired maternal-cord sera were highly correlated across all antibodies; transplacental antibody transfer ratios for pertussis toxin were 1.14 (n = 291, 95% CI 1.07–1.20); filamentous hemagglutinin 1.10 (n = 120, 95% CI: 1.01–1.20); fimbriae 2/3 1.05 (n = 120, 95% CI: 0.96–1.15) and pertactin 0.96 (n = 289, 95% CI: 0.91–1.00). Older gestational age was associated with increased pertussis toxin and decreased fimbriae 2/3 antibody transport. Conclusions A low prevalence of maternal antibody to all four pertussis antigens was noted in Nepal, but transplacental antibody transfer was efficient. No consistent demographic factors were associated with elevated maternal antibody levels or efficiency of transplacental transfer. If an increase in infant pertussis disease burden was detected in this population, maternal immunization could be an effective intervention to prevent disease in early infancy

Investigating the effects of mobile bottom fishing on benthic biota:A systematic review protocol

Background Mobile bottom fishing, such as trawling and dredging, is the most widespread direct human impact on marine benthic systems. Knowledge of the impacts of different gear types on different habitats, the species most sensitive to impacts and the potential for habitats to recover are often needed to inform implementation of an ecosystem approach to fisheries and strategies for biodiversity conservation. This knowledge helps to identify management options that maximise fisheries yield whilst minimising negative impacts on benthic systems. Methods/design The methods are designed to identify and collate evidence from experimental studies (e.g. before/after, control/impact) and comparative studies (spanning a gradient of fishing intensity) to identify changes in state (numbers, biomass, diversity etc.) of benthic biota (flora and fauna), resulting from a variety of mobile bottom fishing scenarios. The primary research question that the outputs will be used to address is: “to what extent does a given intensity of bottom fishing affect the abundance and/or diversity of benthic biota?” Due to the variety of gear and habitat types studied, the primary question will be closely linked with secondary questions. These include: “how does the effect of bottom fishing on various benthic biota metrics (species, faunal type, trait, taxon etc.) vary with (1) gear type and (2) habitat, and (3) gear type-habitat interactions?” and (4) “how might properties of the community and environment affect the resilience (and recovery potential) of a community to bottom fishing?

Lentiviral-mediated gene transfer to the sheep brain: Implications for gene therapy in batten disease

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are inherited neurodegenerative lysosomal storage diseases with common clinical features of blindness and seizures culminating in premature death. Gene-therapy strategies for these diseases depend on whether the missing activity is a secreted lysosomal protein taken up by neighboring cells, or an intramembrane protein that requires careful targeting. Therapies are best developed in animal models with large complex human-like brains. Lentiviral-mediated gene delivery to neural cell cultures from normal sheep and sheep affected with an NCL resulted in green fluorescent protein (GFP) expression in neurons and neuroblasts, more efficiently than in astrocytes. Similar transgene expression was obtained from two constitutive promoters, the viral MND promoter and the human EF1α promoter. In vivo studies showed stable and persistent GFP expression throughout the cell bodies, axons, and dendrites from intracortical injections and indicated ependymal and subependymal transduction. The sheep showed no ill effects from the injections. These data support continuing gene-therapy trials in the sheep models of Batten disease

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative