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Background The technical challenges associated with national data linkage, and the extent of cross-border population movements, are explored as part of a pioneering research project. The project involved linking state-based hospital admission records and death registrations across Australia for a national study of hospital related deaths. Methods The project linked over 44 million morbidity and mortality records from four Australian states between 1st July 1999 and 31st December 2009 using probabilistic methods. The accuracy of the linkage was measured through a comparison with jurisdictional keys sourced from individual states. The extent of cross-border population movement between these states was also assessed. Results Data matching identified almost twelve million individuals across the four Australian states. The percentage of individuals from one state with records found in another ranged from 3-5 %. Using jurisdictional keys to measure linkage quality, results indicate a high matching efficiency (F measure 97 to 99 %), with linkage processing taking only a matter of days. Conclusions The results demonstrate the feasibility and accuracy of undertaking cross jurisdictional linkage for national research. The benefits are substantial, particularly in relation to capturing the full complement of records in patient pathways as a result of cross-border population movements. The project identified a sizeable ‘mobile’ population with hospital records in more than one state. Research studies that focus on a single jurisdiction will under-enumerate the extent of hospital usage by individuals in the population. It is important that researchers understand and are aware of the impact of this missing hospital activity on their studies. The project highlights the need for an efficient and accurate data linkage system to support national research across Australia.

Background Record linkage techniques are widely used to enable health researchers to gain event based longitudinal information for entire populations. The task of record linkage is increasingly being undertaken by specialised linkage units (SLUs). In addition to the complexity of undertaking probabilistic record linkage, these units face additional technical challenges in providing record linkage ‘as a service’ for research. The extent of this functionality, and approaches to solving these issues, has had little focus in the record linkage literature. Few, if any, of the record linkage packages or systems currently used by SLUs include the full range of functions required. Methods This paper identifies and discusses some of the functions that are required or undertaken by SLUs in the provision of record linkage services. These include managing routine, on-going linkage; storing and handling changing data; handling different linkage scenarios; accommodating ever increasing datasets. Automated linkage processes are one way of ensuring consistency of results and scalability of service. Results Alternative solutions to some of these challenges are presented. By maintaining a full history of links, and storing pairwise information, many of the challenges around handling ‘open’ records, and providing automated managed extractions are solved. A number of these solutions were implemented as part of the development of the National Linkage System (NLS) by the Centre for Data Linkage (part of the Population Health Research Network) in Australia. Conclusions The demand for, and complexity of, linkage services is growing. This presents as a challenge to SLUs as they seek to service the varying needs of dozens of research projects annually. Linkage units need to be both flexible and scalable to meet this demand. It is hoped the solutions presented here can help mitigate these difficulties.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated a clear need for high-throughput, multiplexed and sensitive assays for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses and their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (mCARMEN), which combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable the identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants. A microfluidic CRISPR-based platform enables multiplexed and high-throughput identification of a wide range of respiratory viruses, including the ability to identify specific SARS-CoV-2 variants such as Delta and Omicron.

WRN helicase is an established synthetic lethal target for inhibition in the treatment of microsatellite instability-high (MSI-H) and mismatch repair deficient (MMRd) cancers. The identification of helicase inhibitors is challenging as high-throughput biochemical screening campaigns typically return few validated hits that are often inactive in cell-based assays. Herein, we highlight the power of non-covalent fragment-based lead discovery in locating new druggable allosteric sites on WRN, enabling us to bypass the challenging behavior of WRN during high-throughput screening hampering hit identification. During the fragment optimization process, structures of WRN with key prioritized fragments reveal multiple conformations of WRN with significant domain rotations up to 180°, including a WRN conformation not previously described. Rooted in a combination of biochemical, biophysical, and structural approaches, we present the detailed analyses of optimized chemical matter evolved from screening hits and the unique ability of WRN to accommodate diverse conformations as detailed by structural characterization. In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

The perihelion of the trans-Neptunian object (TNO) 2009 MS9 brings it close to the distance where some long-period comets are seen to become active. Knowing this, and the fact that this object appears to brighten in excess of its predicted nucleus brightness, suggests that 2009 MS9 has a delayed onset of activity brought on by the sublimation of a species more volatile than water. In this paper, we characterize 2009 MS9's physical properties and investigate potential outgassing through composite images, sublimation models, and measurements of spectral reflectivity. We find that deep composite images of the object at various epochs along its orbit show no evidence of dust yet place sensitive limits to the dust production. We estimate the nucleus radius to be 11.5 ± 3.5 km using thermal IR modeling from NEOWISE data and use this and data pre-perihelion to estimate a geometric albedo of 0.25. We compare a CO sublimation activity model to its post-perihelion heliocentric light curve and find that these data support an active fractional area of 5 × 10−6 assuming 2 μm–sized grains and other typical comet parameters. The spectral reflectivity of the surface materials obtained with the Gemini Observatory and CFHT at different epochs shows a reddening spectral slope. We compare the physical properties of 2009 MS9 to both TNO and comet populations and speculate that 2009 MS9's reddening may be due to the buildup of a dust mantle on the surface and could be an explanation of why TNOs exhibit a color bimodality.

Reciprocal coevolution between host and pathogen is widely seen as a major driver of evolution and biological innovation. Yet, to date, the underlying genetic mechanisms and associated trait functions that are unique to rapid coevolutionary change are generally unknown. We here combined experimental evolution of the bacterial biocontrol agent Bacillus thuringiensis and its nematode host Caenorhabditis elegans with large-scale phenotyping, whole genome analysis, and functional genetics to demonstrate the selective benefit of pathogen virulence and the underlying toxin genes during the adaptation process. We show that: (i) high virulence was specifically favoured during pathogen-host coevolution rather than pathogen one-sided adaptation to a nonchanging host or to an environment without host; (ii) the pathogen genotype BT-679 with known nematocidal toxin genes and high virulence specifically swept to fixation in all of the independent replicate populations under coevolution but only some under one-sided adaptation; (iii) high virulence in the BT-679-dominated populations correlated with elevated copy numbers of the plasmid containing the nematocidal toxin genes; (iv) loss of virulence in a toxin-plasmid lacking BT-679 isolate was reconstituted by genetic reintroduction or external addition of the toxins. We conclude that sustained coevolution is distinct from unidirectional selection in shaping the pathogen's genome and life history characteristics. To our knowledge, this study is the first to characterize the pathogen genes involved in coevolutionary adaptation in an animal host-pathogen interaction system.

Background Limited data exist collating most of the associated factors for strabismus in one analysis. The aim of this study was to assess the prevalence of strabismus and to analyse associated factors in former preterm and full-term infants. Methods In this cross-sectional study, 239 former preterm infants with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants with GA ≥ 37 weeks underwent detailed ophthalmologic examination in the age of 4–10 years and perinatal data assessment for risk factor analysis. Ophthalmologic examinations included cover testing, best corrected visual acuity, cycloplegic objective refraction, slit lamp as well as fundus examinations. For association analysis with strabismus, the following data was collected and included in multivariable analysis: sex, age at examination, anisometropia, myopic and hyperopic refractive error (≥ 3 dioptres), astigmatism, birth weight percentile, gestational age, retinopathy of prematurity occurrence, maternal age at childbirth, mother smoking, breastfeeding < 3 months, artificial ventilation, intraventricular bleeding, and other perinatal adverse events. Results Overall, 4/264 (2%) full-term infants, 15/125 (12%) preterm-infants with GA 29–32 weeks without ROP, 13/59 (22%) preterm infants with GA ≤ 28 weeks without ROP and 14/55 (26%) with GA ≤ 32 weeks with retinopathy of prematurity were affected by strabismus. In the multivariable regression model strabismus was associated with GA (OR = 0.84 per week; p  = 0.001), hyperopic refractive error (OR = 4.22; p  = 0.002) and astigmatism (OR = 1.68; p  = 0.02). Conclusion This investigation highlights that low gestational age and refraction of the eye are independent risk factors for strabismus, while the other factors show less independent influence.

Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) viral load and anti‐SARS‐CoV‐2 antibodies in coronavirus disease 2019 (COVID‐19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double‐blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID‐19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS‐CoV‐2 viral load and serum anti‐SARS‐CoV‐2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval CI] were 2.87 [1.57–5.25], 3.86 [2.23–6.68], and 0.23 [0.14–0.36], respectively, in COVACTA and 8.11 [2.95–22.26], 10.29 [4.5–23.55], and 0.21 [0.15–0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti‐SARS‐CoV‐2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59–4.08] for COVACTA and 1.54 [1.13–2.09] for REMDACTA). These results support the role of baseline SARS‐CoV‐2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID‐19.

Background: Undergraduate studies are challenging, and mental health issues can frequently occur in undergraduate students, straining campus resources that are already in demand for somatic problems. Cost-effective measures with ubiquitous devices, such as smartphones, offer the potential to deliver targeted interventions to monitor and affect lifestyle, which may result in improvements to student mental health. However, the avenues by which this can be done are not particularly well understood, especially in the Canadian context. Objective: The aim of this study is to deploy an initial version of the Smart Healthy Campus app at Western University, Canada, and to analyze corresponding data for associations between psychosocial factors (measured by a questionnaire) and behaviors associated with lifestyle (measured by smartphone sensors). Methods: This preliminary study was conducted as an observational app-based ecological momentary assessment. Undergraduate students were recruited over email, and sampling using a custom 7-item questionnaire occurred on a weekly basis. Results: First, the 7-item Smart Healthy Campus questionnaire, derived from fully validated questionnaires—such as the Brief Resilience Scale; General Anxiety Disorder-7; and Depression, Anxiety, and Stress Scale–21—was shown to significantly correlate with the mental health domains of these validated questionnaires, illustrating that it is a viable tool for a momentary assessment of an overview of undergraduate mental health. Second, data collected through the app were analyzed. There were 312 weekly responses and 813 sensor samples from 139 participants from March 2019 to March 2020; data collection concluded when COVID-19 was declared a pandemic. Demographic information was not collected in this preliminary study because of technical limitations. Approximately 69.8% (97/139) of participants only completed one survey, possibly because of the absence of any incentive. Given the limited amount of data, analysis was not conducted with respect to time, so all data were analyzed as a single collection. On the basis of mean rank, students showing more positive mental health through higher questionnaire scores tended to spend more time completing questionnaires, showed more signs of physical activity based on pedometers, and had their devices running less and plugged in charging less when sampled. In addition, based on mean rank, students on campus tended to report more positive mental health through higher questionnaire scores compared with those who were sampled off campus. Some data from students found in or near residences were also briefly examined. Conclusions: Given these limited data, participants tended to report a more positive overview of mental health when on campus and when showing signs of higher levels of physical activity. These early findings suggest that device sensors related to physical activity and location are useful for monitoring undergraduate students and designing interventions. However, much more sensor data are needed going forward, especially given the sweeping changes in undergraduate studies due to COVID-19.