A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency

Background/Aims: Recessive mutations in the LHX3 homeodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3. Methods: Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized. Results: A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the a-glycoprotein and PRL target genes. Conclusion: The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene. copyright (C) 2012 S. Karger AG, Base

Decreasing the number of arthroscopies in knee osteoarthritis – a service evaluation of a de-implementation strategy

Background: The Personalised Knee Improvement Programme (P-KIP) was developed based on previously published work, with the hypothesis that surgeons would refer patients to a well-structured conservative management intervention instead of for arthroscopy (de-implementation of arthroscopy by substitution with P-KIP). This meets NICE guidelines and international recommendations but such programmes are not widely used in the UK. Our aim was to determine whether P-KIP would reduce the number of arthroscopies performed for knee osteoarthritis. Methods: P-KIP is a conservative care pathway including a group education session followed by individually tailored one-to-one dietician and physiotherapy sessions. Virtual clinic follow-up is conducted three to 6 months after completion of the programme. The service began in July 2015. The number of arthroscopies saved, measured from hospital level coding data, is the primary outcome measure. Interrupted time series analysis of coding data was conducted. As a quality assurance process, patient reported outcome measures (Oxford Knee Score; Euroqol 5D) were collected at baseline and at follow up. Results: Time series analysis demonstrates that the programme saved 15.4 arthroscopies a month (95% confidence interval 9–21; p < 0.001), equating to 184 arthroscopies a year in a single hospital. The PROMs data demonstrated improvements in patient reported outcome scores consistent with previous published reports of conservative interventions in similar patient populations. Conclusions: Results suggest that P-KIP reduces the number of arthroscopies performed, and patients who took part in P-KIP had an improvement in their knee and general health outcomes. P-KIP has the potential to deliver efficiency savings and relive pressure on operative lists, however replication in other sites is required

Habitat diversity and structure regulate British bird richness: implications of non-linear relationships for conservation

Spatial environmental heterogeneity (EH) is an important factor determining species richness among many taxa across spatial scales. Increased EH may support higher diversity mainly by providing a higher number of ecological niches. However, the shapes of the EH-diversity relationships and their influence on diversity measures at landscape scales are poorly understood. We used random forests regression models to assess the relationships between different components of EH and bird species richness across Great Britain. Bird data were obtained using BTO/JNCC/RSPB Breeding Bird Survey methods across 335 UK Countryside Survey (CS) 1-km squares in 2000. Data on components of EH, including; vegetation, habitat diversity, and habitat structure were collected in associated field surveys. Using the results of our EH component-bird richness models, we applied the case of the likely decline of the ash tree, a species of conservation concern and a key component of British landscape complexity, to create predictive scenarios of future bird richness. We found that EH components had a strong positive effect on bird richness and identified six key components that explained over 70% of variance in bird richness. Bird richness responses were strongly dependent on the specific EH components and were generally non-linear, especially for habitat structural variables, such as lines of trees and hedges. Our predictive scenarios showed a decrease in bird species richness only for simulated ash tree decreases within the habitat structural variables of over 90%, and only for areas where this tree species was a particularly abundant component of the landscape. Our findings, showing that bird richness responses differ for EH components, and that non-linear responses are common, could help the ‘design’ of landscapes that enhance bird diversity. In particular, our study indicates that, in some cases, increasing the occurrence of key structural components of habitat (such as ensuring a minimum of 700 m of managed hedges or a minimum of 70 individual trees per km square), could have disproportionally positive impacts on bird richness

Engineering higher order Van Hove singularities in two dimensions: the example of the surface layer of Sr2_2RuO4_4

The properties of correlated electron materials are often intricately linked to Van Hove singularities (VHs) in the vicinity of the Fermi energy. The class of these VHs is of great importance, with higher order ones -- with power-law divergence in the density of states -- leaving frequently distinct signatures in physical properties. We use a new theoretical method to detect and analyse higher order Van Hove singularities (HOVHs) in two-dimensional materials and apply it to the electronic structure of the surface layer of Sr$_2$RuO$_4$. We then constrain a low energy model of the VHs of the surface layer of Sr$_2$RuO$_4$ against angle-resolved photoemission spectroscopy and quasiparticle interference data to analyse the VHs near the Fermi level. We show how these VHs can be engineered into HOVHs.Comment: 8 pages including Supplemental Material, 5 figure

Epidemiology of epidermolysis bullosa in the antipodes: The Australasian epidermolysis bullosa registry with a focus on Herlitz junctional epidermolysis bullosa

To present epidemiologic and clinical data from the Australasian Epidermolysis Bullosa (EB) Registry, the first orphan disease registry in Australia. Design: Observational study (cross-sectional and longitudinal). Setting: Australian private dermatology practice, inpatient ward, and outpatient clinic. Patients: Systematic case finding of patients with EB simplex, junctional EB (JEB), and dystrophic EB and data collection were performed throughout Australia and New Zealand from January 1, 2006, through December 31, 2008. Patients were consecutively enrolled in the study after clinical assessment and laboratory diagnosis. Medical records were retrospectively examined, and physicians involved in EB care were contacted to obtain patient history. A Herlitz JEB case series was prepared from registry data. Main Outcome Measures: Demographics and prognosis of patients with Herlitz JEB. Results: A total of 259 patients were enrolled in the study: 139 with EBS, 91 with dystrophic EB, 28 with JEB, and 1 with Kindler syndrome. Most enrollees were Australian citizens (n=243), with an Australian prevalence rate of 10.3 cases per million. The age range in the registry was birth to 99 years, with a mean and median age of 24.1 and 18.0 years, respectively. Ages were similar in patients with EBS and dominant dystrophic EB but were markedly lower in patients with JEB. Patients with Herlitz JEB (n=10) had the highest morbidity and mortality rates, with a mean age at death of 6.8 months. Sepsis, failure to thrive, and tracheolaryngeal complications were the leading causes of death. Conclusions: The Australasian EB registry is the first registry in Australia and New Zealand to provide original data on age, sex, ethnicity, and geographical and disease subtype distribution. The Australasian Herlitz JEB cohort witnessed a high infant mortality rate and poor prognosis overall

The relative value of field survey and remote sensing for biodiversity assessment

1. The importance of habitat for biodiversity is well established, but the two most commonly used methods to measure habitat (field survey and remote sensing) have seldom been explicitly compared. 2. We compare high-resolution sample-based field survey (Countryside Survey) with medium-resolution remotely sensed habitat data (the highest resolution of Land Cover Map available) for Great Britain. Variation in abundance of 60 bird species from 335 1 km squares was modelled using habitat predictors from the two methods. Model comparisons assessed the explanatory power of (i) field survey vs. remotely sensed data and (ii) coarse information on habitat areas (Broad Habitats) vs. fine-grained information on Landscape Features. 3. Field survey data (combining Broad Habitat and Landscape Feature predictors) explained more variation in bird abundance than remotely sensed data (comprising Broad Habitat predictors only) for 57 species and had significantly higher mean explanatory power, averaged across 60 species models. The relative explanatory power of remote sensing, as a proportion of that provided by field data, was measured at 73%, aver aged across 60 species models. Predictions from field survey Broad Habitat data were more accurate than those from either remotely sensed Broad Habitat data or field survey Landscape Feature data, averaged across 60 species models. 4. High-resolution data generate more reliable models of predicted local population responses to land use change than lower resolution remotely sensed data. Collection of field data is typically costly in time, labour and resources, making use of remote sensing more feasible for assessment at larger spatial extents if data of equivalent value are produced, but the cost–benefit threshold between the two is likely to be context specific. However, integration of field survey with remotely sensed data provides accurate predictions of bird distributions, which suggests that both forms of data should be considered for future biodiversity surveys

The Dark Matter Halos of Moderate Luminosity X-ray AGN as Determined fromWeak Gravitational Lensing and Host Stellar Masses

Understanding the relationship between galaxies hosting active galactic nuclei (AGN) and the dark matter haloes in which they reside is key to constraining how black hole fuelling is triggered and regulated. Previous efforts have relied on simple halo mass estimates inferred from clustering, weak gravitational lensing, or halo occupation distribution modelling. In practice, these approaches remain uncertain because AGN, no matter how they are identified, potentially live a wide range of halo masses with an occupation function whose general shape and normalization are poorly known. In this work, we show that better constraints can be achieved through a rigorous comparison of the clustering, lensing, and cross-correlation signals of AGN hosts to the fiducial stellar-to-halo mass relation (SHMR) derived for all galaxies, irrespective of nuclear activity. Our technique exploits the fact that the global SHMR can be measured with much higher accuracy than any statistic derived from AGN samples alone. Using 382 moderate luminosity X-ray AGN at z < 1 from the COSMOS field, we report the first measurements of weak gravitational lensing from an X-ray-selected sample. Comparing this signal to predictions from the global SHMR, we find that, contrary to previous results, most X-ray AGN do not live in medium size groups – nearly half reside in relatively low mass haloes with M_(200b) ∼ 10^(12.5) M_⊙. The AGN occupation function is well described by the same form derived for all galaxies but with a lower normalization – the fraction of haloes with AGN in our sample is a few per cent. The number of AGN satellite galaxies scales as a power law with host halo mass with a power-law index α = 1. By highlighting the relatively ‘normal’ way in which moderate luminosity X-ray AGN hosts occupy haloes, our results suggest that the environmental signature of distinct fuelling modes for luminous quasars compared to moderate luminosity X-ray AGN is less obvious than previously claimed

Impact of opioid substitution therapy on antiretroviral therapy outcomes:a systematic review and meta-analysis

BACKGROUND: Human immunodeficiency virus (HIV)-infected people who inject drugs (PWID) frequently encounter barriers accessing and remaining on antiretroviral therapy (ART). Some studies have suggested that opioid substitution therapy (OST) could facilitate PWID's engagement with HIV services. We conducted a systematic review and meta-analysis to evaluate the impact of concurrent OST use on ART-related outcomes among HIV-infected PWID. METHODS: We searched Medline, PsycInfo, Embase, Global Health, Cochrane, Web of Science, and Social Policy and Practice databases for studies between 1996 to November 2014 documenting the impact of OST, compared to no OST, on ART outcomes. Outcomes considered were coverage and recruitment onto ART, adherence, viral suppression, attrition from ART, and mortality. Meta-analyses were conducted using random-effects modeling, and heterogeneity assessed using Cochran Q test and I2 statistic. RESULTS: We identified 4685 articles, and 32 studies conducted in North America, Europe, Indonesia, and China were included. OST was associated with a 69% increase in recruitment onto ART (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.32-2.15), a 54% increase in ART coverage (odds ratio [OR], 1.54; 95% CI, 1.17-2.03), a 2-fold increase in adherence (OR, 2.14; 95% CI, 1.41-3.26), and a 23% decrease in the odds of attrition (OR, 0.77; 95% CI, .63-.95). OST was associated with a 45% increase in odds of viral suppression (OR, 1.45; 95% CI, 1.21-1.73), but there was limited evidence from 6 studies for OST decreasing mortality for PWID on ART (HR, 0.91; 95% CI, .65-1.25). CONCLUSIONS: These findings support the use of OST, and its integration with HIV services, to improve the HIV treatment and care continuum among HIV-infected PWID

The identification of informative genes from multiple datasets with increasing complexity

Background In microarray data analysis, factors such as data quality, biological variation, and the increasingly multi-layered nature of more complex biological systems complicates the modelling of regulatory networks that can represent and capture the interactions among genes. We believe that the use of multiple datasets derived from related biological systems leads to more robust models. Therefore, we developed a novel framework for modelling regulatory networks that involves training and evaluation on independent datasets. Our approach includes the following steps: (1) ordering the datasets based on their level of noise and informativeness; (2) selection of a Bayesian classifier with an appropriate level of complexity by evaluation of predictive performance on independent data sets; (3) comparing the different gene selections and the influence of increasing the model complexity; (4) functional analysis of the informative genes. Results In this paper, we identify the most appropriate model complexity using cross-validation and independent test set validation for predicting gene expression in three published datasets related to myogenesis and muscle differentiation. Furthermore, we demonstrate that models trained on simpler datasets can be used to identify interactions among genes and select the most informative. We also show that these models can explain the myogenesis-related genes (genes of interest) significantly better than others (P < 0.004) since the improvement in their rankings is much more pronounced. Finally, after further evaluating our results on synthetic datasets, we show that our approach outperforms a concordance method by Lai et al. in identifying informative genes from multiple datasets with increasing complexity whilst additionally modelling the interaction between genes. Conclusions We show that Bayesian networks derived from simpler controlled systems have better performance than those trained on datasets from more complex biological systems. Further, we present that highly predictive and consistent genes, from the pool of differentially expressed genes, across independent datasets are more likely to be fundamentally involved in the biological process under study. We conclude that networks trained on simpler controlled systems, such as in vitro experiments, can be used to model and capture interactions among genes in more complex datasets, such as in vivo experiments, where these interactions would otherwise be concealed by a multitude of other ongoing events