Genomic organisation of extinct lineages can be inferred from extant chromosome-level genome assemblies. Here, we apply bioinformatic and molecular cytogenetic approaches to determine the genomic ...structure of the diapsid common ancestor. We then infer the events that likely occurred along this lineage from theropod dinosaurs through to modern birds. Our results suggest that most elements of a typical 'avian-like' karyotype (40 chromosome pairs, including 30 microchromosomes) were in place before the divergence of turtles from birds ~255 mya. This genome organisation therefore predates the emergence of early dinosaurs and pterosaurs and the evolution of flight. Remaining largely unchanged interchromosomally through the dinosaur-theropod route that led to modern birds, intrachromosomal changes nonetheless reveal evolutionary breakpoint regions enriched for genes with ontology terms related to chromatin organisation and transcription. This genomic structure therefore appears highly stable yet contributes to a large degree of phenotypic diversity, as well as underpinning adaptive responses to major environmental disruptions via intrachromosomal repatterning.
Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for ...disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.
Within palliative care, clear and open communication about death is encouraged. Euphemisms are discouraged as threats to promoting clear understanding of the prognosis; to opening communication about ...what a good death means to individual patients and families; and to fostering collaborative planning aimed at achieving this ‘good death’. Principles of patient-centred and culturally competent care, however, which reflect trends of individualisation, plurality and multiculturalism that are characteristic of late modernity, encourage respect for and support of patients' and families' preferences. These may include wishes to avoid open communication, preferences for euphemisms, and definitions of a ‘good death’ that vary from the practitioner's, and within families. The aim of this study was to examine how physicians navigate these competing priorities. Analysis is based on interviews with 23 doctors, ranging in experience from medical students through to senior palliative care specialists, and eight recorded observations of palliative care multidisciplinary team meetings with 52 clinicians collected in 2017 at two hospitals in one Australian metropolitan area. Findings show that synonyms familiar to clinicians are often used to communicate prognoses in multidisciplinary meetings. In communication with patients and families, doctors rely on emotional and cultural cues to decipher the preferred terminology and response. Drawing on a late modern re-imagination of emotion management, we conceptualise the work performed in this context as emotionally reflexive labour. These findings suggest that blanket protocols for direct communication overlook the complexity of end-of-life communication in an era where a ‘good death’ is understood to be culturally relative.
•Definitions of dying well in late modernity are individually and culturally relative.•Doctors perform emotionally reflexive labour to tailor communication.•In interactions with other clinicians, placeholders for death are widely used.•Blanket protocols for direct end-of-life communication may be inappropriate.
Undetected and untreated, low-levels of drug resistant (DR) subpopulations in clinical Mycobacterium tuberculosis (Mtb) infections may lead to development of DR-tuberculosis, potentially resulting in ...treatment failure. Current phenotypic DR susceptibility testing has a theoretical potential for 1% sensitivity, is not quantitative, and requires several weeks to complete. The use of "single molecule-overlapping reads" (SMOR) analysis with next generation DNA sequencing for determination of ultra-rare target alleles in complex mixtures provides increased sensitivity over standard DNA sequencing. Ligation free amplicon sequencing with SMOR analysis enables the detection of resistant allele subpopulations at ≥0.1% of the total Mtb population in near real-time analysis. We describe the method using standardized mixtures of DNA from resistant and susceptible Mtb isolates and the assay's performance for detecting ultra-rare DR subpopulations in DNA extracted directly from clinical sputum samples. SMOR analysis enables rapid near real-time detection and tracking of previously undetectable DR sub-populations in clinical samples allowing for the evaluation of the clinical relevance of low-level DR subpopulations. This will provide insights into interventions aimed at suppressing minor DR subpopulations before they become clinically significant.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical impact of peripheral arterial disease (PAD) is well characterized and is associated with significant morbidity and mortality. Health care-related expenditures among individuals with PAD, ...particularly for patients, are not well described.
Health care-related expenditure data from the 2011 to 2014 Agency for Healthcare Research and Quality Medical Expenditure Panel Surveys were analyzed for individuals with a diagnosis of PAD compared with U.S. adults 40 years of age and older. Weighted average annual expenditures were estimated using a multivariable generalized linear model. Subanalyses were also performed for out-of-pocket (OOP) expenditures by insurance type.
Adjusted for age, gender, and race, individuals with a diagnosis of PAD (weighted n = 640,098) had significantly higher average annual health care-related expenditures compared with the U.S. adult population as a whole (weighted n = 148,387,362). Average annual expenditures per individual for patients with PAD were $11,553 (95% confidence interval CI, $8137-$14,968) compared with only $4219 (95% CI, $4064-$4375; P < .001) for those without. Expenditures were driven by increased prescription medication expenditures as well as by expenditures for inpatient care, outpatient hospital-based care, and outpatient office-based care. Individuals with PAD had significantly higher OOP prescription medication expenditures ($386 95% CI, $258-$515 vs $192 95% CI, $183-$202; P = .003), which varied by insurance type, ranging from $179 (95% CI, $70-$288) for those with Medicare to $1196 (95% CI, $106-$2244) for those without insurance, although this difference did not reach significance.
Individuals with a diagnosis of PAD have higher health care-related expenditures and OOP expenses compared with other US adults. These expenditures compound lost wages, care by family members, and lost opportunity costs, increasing the burden carried by patients with PAD.
For the next generation of nuclear reactors, HTGRs specifically, an unlikely air ingress warrants inclusion in the license applications of many international regulators. Much research on oxidation ...rates of various graphite grades under a number of conditions has been undertaken to address such an event. However, consequences to the reactor result from the microstructural changes to the graphite rather than directly from oxidation. The microstructure is inherent to a graphite's properties and ultimately degradation to the graphite's performance must be determined to establish the safety of reactor design. To understand the oxidation induced microstructural change and its corresponding impact on performance, a thorough understanding of the reaction system is needed. This article provides a thorough review of the graphite-molecular oxygen reaction in terms of kinetics, mass and energy transport, and structural evolution: all three play a significant role in the observed rate of graphite oxidation. These provide the foundations of a microstructurally informed model for the graphite-molecular oxygen reaction system, a model kinetically independent of graphite grade, and capable of describing both the observed and local oxidation rates under a wide range of conditions applicable to air-ingress.
•Critical review of graphite oxidation relevant to a high-temperature gas-cooled reactor.•Assesses oxidation in terms of microstructure and its evolution.•Model is applicable to all nuclear graphites by using a grade independent kinetics model for the graphite-O2 reaction system.
Objective To investigate the relation between exposure to both air and noise pollution from road traffic and birth weight outcomes.Design Retrospective population based cohort study.Setting Greater ...London and surrounding counties up to the M25 motorway (2317 km2), UK, from 2006 to 2010.Participants 540 365 singleton term live births.Main outcome measures Term low birth weight (LBW), small for gestational age (SGA) at term, and term birth weight.Results Average air pollutant exposures across pregnancy were 41 μg/m3 nitrogen dioxide (NO2), 73 μg/m3 nitrogen oxides (NOx), 14 μg/m3 particulate matter with aerodynamic diameter <2.5 μm (PM2.5), 23 μg/m3 particulate matter with aerodynamic diameter <10 μm (PM10), and 32 μg/m3 ozone (O3). Average daytime (LAeq,16hr) and night-time (Lnight) road traffic A-weighted noise levels were 58 dB and 53 dB respectively. Interquartile range increases in NO2, NOx, PM2.5, PM10, and source specific PM2.5 from traffic exhaust (PM2.5 traffic exhaust) and traffic non-exhaust (brake or tyre wear and resuspension) (PM2.5 traffic non-exhaust) were associated with 2% to 6% increased odds of term LBW, and 1% to 3% increased odds of term SGA. Air pollutant associations were robust to adjustment for road traffic noise. Trends of decreasing birth weight across increasing road traffic noise categories were observed, but were strongly attenuated when adjusted for primary traffic related air pollutants. Only PM2.5 traffic exhaust and PM2.5 were consistently associated with increased risk of term LBW after adjustment for each of the other air pollutants. It was estimated that 3% of term LBW cases in London are directly attributable to residential exposure to PM2.5>13.8 μg/m3during pregnancy.Conclusions The findings suggest that air pollution from road traffic in London is adversely affecting fetal growth. The results suggest little evidence for an independent exposure-response effect of traffic related noise on birth weight outcomes.
Significance Mutations in titin are a major cause of heart failure, yet the functions of large parts of titin are not understood. Here we studied titin’s I-band/A-band junction that has been proposed ...to be crucial for thick filament length control. We made a mouse in which titin’s IA junction was deleted. Super-resolution microscopy (structured illumination microscopy) revealed that deleting the IA junction increases the strain on titin’s molecular spring elements without altering thick filament length. Single cell biomechanical measurements showed that this increases passive stiffness while functional studies at the whole animal level revealed diastolic dysfunction, exercise intolerance, and modest concentric cardiac hypertrophy—signature features of heart failure with preserved ejection fraction. Our studies support that titin is a promising therapeutic target for treating heart failure.
Titin, the largest protein known, forms a giant filament in muscle where it spans the half sarcomere from Z disk to M band. Here we genetically targeted a stretch of 14 immunoglobulin-like and fibronectin type 3 domains that comprises the I-band/A-band (IA) junction and obtained a viable mouse model. Super-resolution optical microscopy (structured illumination microscopy, SIM) and electron microscopy were used to study the thick filament length and titin’s molecular elasticity. SIM showed that the IA junction functionally belongs to the relatively stiff A-band region of titin. The stiffness of A-band titin was found to be high, relative to that of I-band titin (∼40-fold higher) but low, relative to that of the myosin-based thick filament (∼70-fold lower). Sarcomere stretch therefore results in movement of A-band titin with respect to the thick filament backbone, and this might constitute a novel length-sensing mechanism. Findings disproved that titin at the IA junction is crucial for thick filament length control, settling a long-standing hypothesis. SIM also showed that deleting the IA junction moves the attachment point of titin’s spring region away from the Z disk, increasing the strain on titin’s molecular spring elements. Functional studies from the cellular to ex vivo and in vivo left ventricular chamber levels showed that this causes diastolic dysfunction and other symptoms of heart failure with preserved ejection fraction (HFpEF). Thus, our work supports titin’s important roles in diastolic function and disease of the heart.
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