Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and ...adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.
To examine the effectiveness of a culturally and linguistically appropriate, patient-centered, target-driven lifestyle intervention with video education training in improving clinical outcomes, ...health literacy, and diabetic self-care practices in newly diagnosed patients in Nepal.
A total of 110 participants with newly and consequently diagnosed Type 2 were randomly allocated into intervention (mean age = 45 ± 9.7 years) and control (mean age = 47 ± 12.5 years) groups. Intervention group participants were trained on a culturally and linguistically appropriate diabetic video education program and were given a customized dietary and physical activity plan with specific targets to practice at home. Participants' compliance was monitored weekly
telephone calls. Both groups received the usual treatment from their doctor and were followed up after three months. Outcome measures included changes in: i. diabetic health literacy, diet, and physical activity measured using self-reported questionnaires; and ii. blood glucose (glycated hemoglobin, HbA1c), cholesterol, blood pressure, body mass index, and visual acuity. Clinical outcome measures were blinded from randomization and intervention allocation.
After three months, HbA1c decreased to 6.1% from the baseline value of 7.2% in the intervention group compared to 6.6% in the control group from the baseline value of 7.1% (p <0.05). The intervention group had mean total cholesterol and low-density lipoprotein of 174 and 95.5 mg/dL, which were significantly lower than 186 and 107.5 mg/dL in the control group. Daily white rice consumption decreased by 36.5% in the intervention vs. 4% in the control group (p <0.05). After three months, the intervention group participants exercised more than the control group (p <0.05). All intervention group participants self-initiated retinal screening checks since the baseline visit among which 13% showed early diabetic retinopathy signs compared to 0% in the control group. Health literacy improvement in the intervention group was found to be sustained after three months too.
A culturally appropriate, target-driven lifestyle intervention with video education training is effective in improving clinical outcomes, health literacy, and self-care practice in newly diagnosed diabetic patients in Nepal, i.e., at a time period when effective diabetes control is vital to prevent further complications. The training intervention could be rolled out nationwide in order to reduce the risk of diabetic-related complications and improve people's quality of life and productivity.
Highlights • Next generation sequencing detects germline and somatic variants. • Pathogenic variants (PVs) evaluated in individuals undergoing 25-gene panel testing. • Likely somatic PVs detected in ...0.06% of individuals, mostly in TP53 , CHEK2 , and ATM. • Likely somatic PVs accounted for 40% of PVs in TP53 ; <1% of PVs in most other genes. • Likely somatic PVs more frequently identified in older individuals (p < 0.001).
Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management ...decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA).
Sequencing and LR analysis were conducted in a consecutive series of 376,159 individuals who received clinical testing with a hereditary pan-cancer gene panel from September 2013 through May 2017. NGS dosage analysis was used to evaluate potential deletions or duplications, with controls in place to exclude pseudogene reads. Samples positive for a putative LR based on NGS were confirmed using a comprehensive approach that included targeted microarray-CGH and/or MLPA analysis, with further examination as needed to ascertain the nature of the LR.
A total of 3461 LRs were identified and classified as a deleterious mutation (DM), suspected deleterious mutation (SDM) or variant of uncertain significance. Pathogenic LRs (DM/SDM) accounted for the majority of LRs (67.7%), the largest proportion of which were deletions (86.1%), followed by duplications (11.3%), insertions (1.8%), triplications (0.5%), and inversions (0.3%). Several cases presented illustrate that the laboratory approach employed here can ensure consistent identification and accurate characterization of LRs. In the absence of this comprehensive testing strategy, 9% of LRs identified in this testing population might have been missed, potentially leading to inappropriate medical management in as many as 210 individuals referred for hereditary cancer testing.
These data show that copy number analysis using NGS coupled with confirmatory testing reliably detects and characterizes LRs. Further, LRs comprise a substantial proportion (7.2%) of pathogenic variants identified by the test. A robust and accurate LR identification strategy is an essential component of a high-quality genetic testing program, enabling clinicians to optimize patient medical management decisions.
Abstract
The stereophotoclinometry (SPC) software suite has been used to generate global digital terrain models (DTMs) of many asteroids and moons, and was the primary tool used by the Origins, ...Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission to model the shape of asteroid Bennu. We describe the dedicated preflight testing of SPC for the OSIRIS-REx mission using a synthetic “truth” asteroid model. SPC has metrics that determine the internal consistency of a DTM, but it was not known how these metrics are related to the absolute accuracy of a DTM, which was important for the operational needs of the mission. The absolute accuracy of an SPC-generated DTM cannot be determined without knowing the truth topography. Consequently, we developed a realistic, but synthetic, computer-generated representation of asteroid Bennu, photographed this synthetic truth model in an imaging campaign similar to that planned for the OSIRIS-REx mission, and then generated a global SPC DTM from these images. We compared the SPC DTM, which was represented by a radius every 70 cm across the asteroid surface, to the synthetic truth model to assess the absolute accuracy. We found that the internal consistency can be used to determine the 3D root-mean-square accuracy of the model to within a factor of two of the absolute accuracy.
Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% ...lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone.
Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history.
In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model.
Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.
Purpose - The purpose of this paper is to look to new opportunities that may be available to the nations comprising Central Asia. The region has recovered only slowly since the fall of the Soviet ...Union in 1991.Design methodology approach - Based on secondary data from reports by the UN, ADB and other NGOs, academic papers and the press, a quasi-mathematical equation is used to illustrate how infrastructure development is dependant on many factors. From this analysis the importance of the transportation sector for future growth is discerned. Historical detractors are noted and drivers for the future are discussed.Findings - The paper finds that Central Asia's future growth and prosperity would be based on a robust redevelopment of all its infrastructures but primarily on the implementation of Maglev high speed rail systems to move freight quickly internally and for Eurasian transit.Practical implications - Well-integrated transport infrastructures enhance local wellbeing. The interconnectedness and interdependence of globalised economies depend on transport, but other aspects of the total infrastructure local and regional must be integrated to achieve growth. In the case of Central Asia it is seen that an accord between the Presidents is needed to ensure regional cooperation, which will lead to Eurasian cooperation.Originality value - The region has been forgotten, to some extent, by the global community, yet it has great potential to become again an important transportation hub between Europe and Asia. The value of the paper is in noting the push of many NGOs towards regional integration, which may be best approached, we suggest, from an initial investment in its transportation infrastructure.
The Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) spacecraft arrived at the near-Earth asteroid (101955) Bennu in December 2018 and executed a ...science observation campaign to comprehensively characterize the asteroid. Proximity operations at Bennu included orbital phases and flyby phases with various viewing geometries and altitudes. The complexity of the mission plan, integrated instrument operations, and the challenges of spacecraft navigation in the microgravity environment required an intricate planning and implementation process that included participation and coordination among all mission elements. The Science Planning Team (SPT) and the Implementation Team (IpT) at the University of Arizona planned and implemented all science and most optical navigation observations. Prior to the formal planning process, science requirements were mapped to mission phases and observation geometry constraints. During development of the mission phases, the navigation team produced a spacecraft trajectory, and the SPT developed the pointing and attitude profile to meet the specified constraints. In the strategic planning process, which began three months prior to execution, the SPT conducted sensitivity analysis of the observation designs against a set of perturbed trajectories delivered by the navigation team to ensure that they were robust to navigational uncertainties. Planning of the specific observations to occur within each phase was divided into units of weeks, and the plans for each week were developed and implemented on a rolling eight-week tactical planning and implementation cycle, ending with execution and data downlink. This cycle included a standardized schedule of activities and gateways to ensure that every observation plan underwent a full suite of analysis, verification, and approval in the allocated timeframe. Checklists guided the SPT and IpT through the build and verification process to confirm plan safety and fidelity. The SPT led the first four weeks of the tactical process, with participation from the IpT and other stakeholders. During the first two weeks, the SPT gathered information from stakeholders, conducted preliminary planning to confirm the science observations were feasible and obeyed spacecraft constraints, and determined how to integrate instrument commanding with the spacecraft pointing profile. The SPT started the final observation design and planning six weeks prior to execution. Once complete, plan walkthroughs were conducted with stakeholders, which culminated in a go/no-go decision to proceed with implementation at the four-week point. In the last four weeks of the tactical planning and implementation process, the IpT led the final processing of science plans with participation from stakeholders. The IpT compiled the plans, performed comprehensive safety checks against established spacecraft and instrument flight rules, and generated flight products and artifacts. After IpT delivered the flight products, the spacecraft team integrated them with the spacecraft sequencing, performed ground testing, and produced an integrated report. IpT reviewed the report, verifying instrument health and safety and confirming nominal plan execution in the ground simulation. The final flight products were uplinked to the spacecraft a few days prior to the execution week. During execution, the IpT and other stakeholders monitored instrument performance and viewed science and navigation data. Resulting science data products were used for operational decisions and science investigations.
Fundamental changes within economies are needed to create arm's-length relations between governments, corporations, and banks. We are taking risks when investing in the future, and risk-taking ...demands openness and truthfulness from the agents we employ. If investors and accountants can concur on the degree of disclosure that is morally right we may come to some global agreement on what constitutes corruption - but to do this we have to bring together those who advocate profit-making with those who see this as usury; and we have to care for the future in novel ways - unknown in the past - so as to allow firms to be locally inefficient (apparently) while preserving the environment.This book looks widely at the prevailing situation in Asia and considers how little some governments are doing to guide their institutions towards probity and transparency. While fundamental changes are needed around the globe, it is in the developing nations that there is scope for radical change in the near future, as their institutions are re-created to meet the modern world. Once developed and functioning their managers will have the opportunity to facilitate and re-direct the institutions in the developed world, which happen to be more conservative than their own.Contents:The OECD Convention and Asia (E Quinones)The Asian Money Laundering Explosion (P Lilley)Corruption in Context (L Palmier)Monopoly Rights and Wrongs: Two Forms of Intellectual Property Rights Violations in Asia (H-B Cheah)Culture and Level of Industrialization as Determinants of Corruption in Asia (D Sculli)The Economy of Seepage and Leakage in Asia: The Most Dangerous Issue (G Etienne)Combating Corruption in Southeast Asia (C Wescott)The Nature of Corruption Hidden Culture: The Case of Korea (Y-L Moon & G N McLean)Comparative Study of Anti-Corruption Systems, Efforts and Strategies in Asian Countries: Focusing on Hong Kong, Singapore, Malaysia, and Korea (T Kim)and other papersReadership: Final-year undergraduates, master's and MBA students in ethics and social science; researchers on Asian topics, managers and policy-makers.
Abstract The OSIRIS-REx mission used stereophotoclinometry (SPC) to generate digital terrain models (DTMs) of its target asteroid, Bennu. Here we present a suite of preflight tests conducted to ...identify the observing geometry and number of images needed to create DTMs that would enable successful navigation around and to the surface of the asteroid. We demonstrate that high-quality DTMs can be generated by using only five images: four that are focused on topography, in which the spacecraft’s viewing geometry brackets the target (north, south, east, and west), and a fifth that measures the target’s albedo variation, taken from near local noon. We further show that the first 10 iterations of the SPC process can meaningfully improve DTM quality, including in the case of a suboptimal input image set, whereas after 10 iterations the DTM quality approaches an asymptotic maximum. We distill our findings into recommendations for observation planning that can be applied by other missions intending to use SPC to model the shape and terrain of their target.
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