Exome Sequencing of a Multigenerational Human Pedigree

Over the next few years, the efficient use of next-generation sequencing (NGS) in human genetics research will depend heavily upon the effective mechanisms for the selective enrichment of genomic regions of interest. Recently, comprehensive exome capture arrays have become available for targeting approximately 33 Mb or ∼180,000 coding exons across the human genome. Selective genomic enrichment of the human exome offers an attractive option for new experimental designs aiming to quickly identify potential disease-associated genetic variants, especially in family-based studies. We have evaluated a 2.1 M feature human exome capture array on eight individuals from a three-generation family pedigree. We were able to cover up to 98% of the targeted bases at a long-read sequence read depth of ≥3, 86% at a read depth of ≥10, and over 50% of all targets were covered with ≥20 reads. We identified up to 14,284 SNPs and small indels per individual exome, with up to 1,679 of these representing putative novel polymorphisms. Applying the conservative genotype calling approach HCDiff, the average rate of detection of a variant allele based on Illumina 1 M BeadChips genotypes was 95.2% at ≥10x sequence. Further, we propose an advantageous genotype calling strategy for low covered targets that empirically determines cut-off thresholds at a given coverage depth based on existing genotype data. Application of this method was able to detect >99% of SNPs covered ≥8x. Our results offer guidance for “real-world” applications in human genetics and provide further evidence that microarray-based exome capture is an efficient and reliable method to enrich for chromosomal regions of interest in next-generation sequencing experiments

Are the police embracing evidence-informed practice? A view from England and Wales

The What Works Centre for Crime Reduction (WWCCR) in the UK’s College of Policing has a key role in promoting the use of research in policing. Since 2014, the WWCCR has aimed to review - and make accessible - research to better inform and target crime reduction and to build police capacity to identify, evaluate and apply research evidence to practice. This comes amidst significant changes to entry requirements for policing in the UK as part of efforts to further professionalise the service and prepare for future challenges in policing. We report findings from in-depth interviews with senior police officers from forces across England and Wales, conducted as part of a three-year evaluation of the WWCCR. These interviews explored the traction of ‘evidence-based practice’ among senior officers and showed shifts over time in their accounts of the value placed on research and how it is promoted and used within their force. Additionally, an online survey across policing ranks, conducted in 2016, found differences by seniority in perceptions about the relevance of research for policing, and the level of organisational support for it. Findings are used to consider the status of research evidence in policing and its development within a policing profession

Dynamic Health Policies for Controlling the Spread of Emerging Infections: Influenza as an Example

The recent appearance and spread of novel infectious pathogens provide motivation for using models as tools to guide public health decision-making. Here we describe a modeling approach for developing dynamic health policies that allow for adaptive decision-making as new data become available during an epidemic. In contrast to static health policies which have generally been selected by comparing the performance of a limited number of pre-determined sequences of interventions within simulation or mathematical models, dynamic health policies produce “real-time” recommendations for the choice of the best current intervention based on the observable state of the epidemic. Using cumulative real-time data for disease spread coupled with current information about resource availability, these policies provide recommendations for interventions that optimally utilize available resources to preserve the overall health of the population. We illustrate the design and implementation of a dynamic health policy for the control of a novel strain of influenza, where we assume that two types of intervention may be available during the epidemic: (1) vaccines and antiviral drugs, and (2) transmission reducing measures, such as social distancing or mask use, that may be turned “on” or “off” repeatedly during the course of epidemic. In this example, the optimal dynamic health policy maximizes the overall population's health during the epidemic by specifying at any point of time, based on observable conditions, (1) the number of individuals to vaccinate if vaccines are available, and (2) whether the transmission-reducing intervention should be either employed or removed

Validating epilepsy diagnoses in routinely collected data

Purpose: Anonymised, routinely-collected healthcare data is increasingly being used for epilepsy research. We validated algorithms using general practitioner (GP) primary healthcare records to identify people with epilepsy from anonymised healthcare data within the Secure Anonymised Information Linkage (SAIL) databank in Wales, UK. Method: A reference population of 150 people with definite epilepsy and 150 people without epilepsy was ascertained from hospital records and linked to records contained within SAIL (containing GP records for 2.4 million people). We used three different algorithms, using combinations of GP epilepsy diagnosis and anti-epileptic drug (AED) prescription codes, to identify the reference population. Results: Combining diagnosis and AED prescription codes had a sensitivity of 84% (95% ci 77–90) and specificity of 98% (95–100) in identifying people with epilepsy; diagnosis codes alone had a sensitivity of 86% (80–91) and a specificity of 97% (92–99); and AED prescription codes alone achieved a sensitivity of 92% (70–83) and a specificity of 73% (65–80). Using AED codes only was more accurate in children achieving a sensitivity of 88% (75–95) and specificity of 98% (88–100). Conclusion: GP epilepsy diagnosis and AED prescription codes can be confidently used to identify people with epilepsy using anonymised healthcare records in Wales, U

Light Curves and Colors of the Ejecta from Dimorphos after the DART Impact

On 26 September 2022 the Double Asteroid Redirection Test (DART) spacecraft impacted Dimorphos, a satellite of the asteroid 65803 Didymos. Because it is a binary system, it is possible to determine how much the orbit of the satellite changed, as part of a test of what is necessary to deflect an asteroid that might threaten Earth with an impact. In nominal cases, pre-impact predictions of the orbital period reduction ranged from ~8.8 - 17.2 minutes. Here we report optical observations of Dimorphos before, during and after the impact, from a network of citizen science telescopes across the world. We find a maximum brightening of 2.29 $\pm$ 0.14 mag upon impact. Didymos fades back to its pre-impact brightness over the course of 23.7 $\pm$ 0.7 days. We estimate lower limits on the mass contained in the ejecta, which was 0.3 - 0.5% Dimorphos' mass depending on the dust size. We also observe a reddening of the ejecta upon impact.Comment: Accepted by Natur

Simulating medium-spectral-resolution exoplanet characterization with SCALES angular/reference differential imaging

SCALES (Slicer Combined with Array of Lenslets for Exoplanet Spectroscopy) is a 2 - 5 micron high-contrast lenslet-based integral field spectrograph (IFS) designed to characterize exoplanets and their atmospheres. The SCALES medium-spectral-resolution mode uses a lenslet subarray with a 0.34 x 0.36 arcsecond field of view which allows for exoplanet characterization at increased spectral resolution. We explore the sensitivity limitations of this mode by simulating planet detections in the presence of realistic noise sources. We use the SCALES simulator scalessim to generate high-fidelity mock observations of planets that include speckle noise from their host stars, as well as other atmospheric and instrumental noise effects. We employ both angular and reference differential imaging as methods of disentangling speckle noise from the injected planet signals. These simulations allow us to assess the feasibility of speckle deconvolution for SCALES medium resolution data, and to test whether one approach outperforms another based on planet angular separations and contrasts

Development of paediatric quality of inpatient care indicators for low-income countries - A Delphi study

BACKGROUND: Indicators of quality of care for children in hospitals in low-income countries have been proposed, but information on their perceived validity and acceptability is lacking. METHODS: Potential indicators representing structural and process aspects of care for six common conditions were selected from existing, largely qualitative WHO assessment tools and guidelines. We employed the Delphi technique, which combines expert opinion and existing scientific information, to assess their perceived validity and acceptability. Panels of experts, one representing an international panel and one a national (Kenyan) panel, were asked to rate the indicators over 3 rounds and 2 rounds respectively according to a variety of attributes. RESULTS: Based on a pre-specified consensus criteria most of the indicators presented to the experts were accepted: 112/137(82%) and 94/133(71%) for the international and local panels respectively. For the other indicators there was no consensus; none were rejected. Most indicators were rated highly on link to outcomes, reliability, relevance, actionability and priority but rated more poorly on feasibility of data collection under routine conditions. There was moderate to substantial agreement between the two panels of experts. CONCLUSIONS: This Delphi study provided evidence for the perceived usefulness of most of a set of measures of quality of hospital care for children proposed for use in low-income countries. However, both international and local experts expressed concerns that data for many process-based indicators may not currently be available. The feasibility of widespread quality assessment and responsiveness of indicators to intervention should be examined as part of continued efforts to improve approaches to informative hospital quality assessment

Being careful what we wish for? Challenges and opportunities afforded through engagement with business and management research

Despite the proliferation of work within construction management that draws upon management and organizational theory, two omissions stand out from the body of published work: the absence of any real debate about the values of rigour and relevance in research; and the under-use of dominant perspectives in business and management research (such as institutional theory) to frame construction management and organizational issues. Drawing specifically upon the ideas of institutional logics and institutional work, this paper explores the tensions, ironies and contradictions of the rigour-relevance debate; and the challenges and opportunities facing construction management research (CMR) and its institutions in furthering management and organizational research agendas. In doing so, attention is directed to the complex, contested and changing nature of the knowledge base within the business and management field; as well as key differences between that community of practice and CMR

Organisational and student characteristics, fidelity, funding models, and unit costs of recovery colleges in 28 countries:a cross-sectional survey

Background: Recovery colleges were developed in England to support the recovery of individuals who have mental health symptoms or mental illness. They have been founded in many countries but there has been little international research on recovery colleges and no studies investigating their staffing, fidelity, or costs. We aimed to characterise recovery colleges internationally, to understand organisational and student characteristics, fidelity, and budget. Methods: In this cross-sectional study, we identified all countries in which recovery colleges exist. We repeated a cross-sectional survey done in England for recovery colleges in 28 countries. In both surveys, recovery colleges were defined as services that supported personal recovery, that were coproduced with students and staff, and where students learned collaboratively with trainers. Recovery college managers completed the survey. The survey included questions about organisational and student characteristics, fidelity to the RECOLLECT Fidelity Measure, funding models, and unit costs. Recovery colleges were grouped by country and continent and presented descriptively. We used regression models to explore continental differences in fidelity, using England as the reference group. Findings: We identified 221 recovery colleges operating across 28 countries, in five continents. Overall, 174 (79%) of 221 recovery colleges participated. Most recovery colleges scored highly on fidelity. Overall scores for fidelity (β=–2·88, 95% CI 4·44 to –1·32; p=0·0001), coproduction (odds ratio [OR] 0·10, 95% CI 0·03 to 0·33; p&lt;0·0001), and being tailored to the student (OR 0·10, 0·02 to 0·39; p=0·0010), were lower for recovery colleges in Asia than in England. No other significant differences were identified between recovery colleges in England, and those in other continents where recovery colleges were present. 133 recovery colleges provided data on annual budgets, which ranged from €0 to €2 550 000, varying extensively within and between continents. From included data, all annual budgets reported by the college added up to €30 million, providing 19 864 courses for 55 161 students. Interpretation: Recovery colleges exist in many countries. There is an international consensus on key operating principles, especially equality and a commitment to recovery, and most recovery colleges achieve moderate to high fidelity to the original model, irrespective of the income band of their country. Cultural differences need to be considered in assessing coproduction and approaches to individualising support. Funding: National Institute for Health and Care Research.</p

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio