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Organization, time management, and planning (OTMP) skills are behavioral manifestations of executive functioning linked to academic outcomes. Interventions to improve OTMP skills have shown favorable outcomes. The Children's Organizational Skills Scale parent and teacher forms (COSS-P, COSS-T) are widely used for assessing OTMP skills, but there is limited research on this scale. This study examined the factor structure and construct validity of the COSS in a non-clinical and clinical sample of students in grades 2-8 (Study 1; n = 1138 COSS-T; 1155 COSS-P), and teacher-referred students with OTMP deficits in grades 3-5 (Study 2; n = 184). In Study 1, a bifactor model with a general factor and three subfactors demonstrated good fit for the COSS-P (RMSEA = 0.057) and COSS-T (RMSEA = 0.052). This model was replicated in Study 2. The general factor on both versions demonstrated an acceptable to high level of internal reliability. An acceptable degree of reliability was also identified for subfactor 1 (Task Planning). The COSS was shown to be effective in differentiating children with ADHD from a comparison group drawn primarily from the non-clinical sample (AUC = 0.84 COSS-P; 0.85 COSS-T). Sex differences of medium magnitude were identified on the total score of both COSS versions. Correlations between the COSS-P and COSS-T were variable across samples. The findings provide strong evidence for using the total score on the COSS-P and COSS-T as an index of overall OTMP skills deficits. Given variable cross-informant correlations on the COSS, multi-informant assessment of OTMP skills is strongly indicated.

We evaluate an adaptive optimisation methodology, Bayesian optimisation (BO), for designing a minimum weight explosive reactive armour (ERA) for protection against a surrogate medium calibre kinetic energy (KE) long rod projectile and surrogate shaped charge (SC) warhead. We perform the optimisation using a conventional BO methodology and compare it with a conventional trial-and-error approach from a human expert. A third approach, utilising a novel human-machine teaming framework for BO is also evaluated. Data for the optimisation is generated using numerical simulations that are demonstrated to provide reasonable qualitative agreement with reference experiments. The human-machine teaming methodology is shown to identify the optimum ERA design in the fewest number of evaluations, outperforming both the stand-alone human and stand-alone BO methodologies. From a design space of almost 1800 configurations the human-machine teaming approach identifies the minimum weight ERA design in 10 samples.

Machine learning (ML) is well suited for the prediction of high-complexity, high-dimensional problems such as those encountered in terminal ballistics. We evaluate the performance of four popular ML-based regression models, extreme gradient boosting (XGBoost), artificial neural network (ANN), support vector regression (SVR), and Gaussian process regression (GP), on two common terminal ballistics’ problems: (a) predicting the V50 ballistic limit of monolithic metallic armour impacted by small and medium calibre projectiles and fragments, and (b) predicting the depth to which a projectile will penetrate a target of semi-infinite thickness. To achieve this we utilise two datasets, each consisting of approximately 1000 samples, collated from public release sources. We demonstrate that all four model types provide similarly excellent agreement when interpolating within the training data and diverge when extrapolating outside this range. Although extrapolation is not advisable for ML-based regression models, for applications such as lethality/survivability analysis, such capability is required. To circumvent this, we implement expert knowledge and physics-based models via enforced monotonicity, as a Gaussian prior mean, and through a modified loss function. The physics-informed models demonstrate improved performance over both classical physics-based models and the basic ML regression models, providing an ability to accurately fit experimental data when it is available and then revert to the physics-based model when not. The resulting models demonstrate high levels of predictive accuracy over a very wide range of projectile types, target materials and thicknesses, and impact conditions significantly more diverse than that achievable from any existing analytical approach. Compared with numerical analysis tools such as finite element solvers the ML models run orders of magnitude faster. We provide some general guidelines throughout for the development, application, and reporting of ML models in terminal ballistics problems.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

We present an inverse methodology for deriving viscoplasticity constitutive model parameters for use in explicit finite element simulations of dynamic processes using functional experiments, i.e., those which provide value beyond that of constitutive model development. The developed methodology utilises Bayesian optimisation to minimise the error between experimental measurements and numerical simulations performed in LS-DYNA. We demonstrate the optimisation methodology using high hardness armour steels across three types of experiments that induce a wide range of loading conditions: ballistic penetration, rod-on-anvil, and near-field blast deformation. By utilising such a broad range of conditions for the optimisation, the resulting constitutive model parameters are generalised, i.e., applicable across the range of loading conditions encompassed the by those experiments (e.g., stress states, plastic strain magnitudes, strain rates, etc.). Model constants identified using this methodology are demonstrated to provide a generalisable model with superior predictive accuracy than those derived from conventional mechanical characterisation experiments or optimised from a single experimental condition.

Fast radio bursts (FRBs) are short-time-scale transients of extragalactic origin. The number of detected FRBs has grown dramatically since their serendipitous discovery from archival data. Some FRBs have also been seen to repeat. The polarimetric properties of repeating FRBs show diverse behaviour and, at times, extreme polarimetric morphology, suggesting a complex magneto-ionic circumburst environment for this class of FRB. The polarimetric properties such as circular polarization behaviour of FRBs are crucial for understanding their surrounding magnetic-ionic environment. The circular polarization previously observed in some of the repeating FRB sources has been attributed to propagation effects such as generalized Faraday rotation (GFR), where conversion from linear to circular polarization occurs due to the non-circular modes of transmission in relativistic plasma. The discovery burst from the repeating FRB 20180301A showed significant frequency-dependent circular polarization behaviour, which was initially speculated to be instrumental due to a sidelobe detection. Here, we revisit the properties given the subsequent interferometric localization of the burst, which indicates that the burst was detected in the primary beam of the Parkes/Murriyang 20-cm multibeam receiver. We develop a Bayesian Stokes-Q, U, and V fit method to model the GFR effect, which is independent of the total polarized flux parameter. Using the GFR model we show that the rotation measure (RM) estimated is two orders of magnitude smaller and opposite sign (⁠|$\sim$| 28 rad m |$^{-2}$|⁠) than the previously reported value. We interpret the implication of the circular polarization on its local magnetic environment and reinterpret its long-term temporal evolution in RM. [ABSTRACT FROM AUTHOR]

A number of pulsar timing arrays have recently reported preliminary evidence for the existence of a nanohertz frequency gravitational wave background. These analyses rely on noise analyses, which are inherently complex due to the many astrophysical and instrumental factors. We investigate whether realistic systematic errors, stemming from misspecified noise models that fail to capture salient features of the pulsar timing noise, could bias the evidence for gravitational waves. We consider two plausible forms of misspecification: small instrumental pulse arrival time offsets and radio-frequency-dependent time-correlated noise. Using simulated data, we calculate the distribution of the commonly used optimal statistic with no signal present and using plausibly misspecified noise models. By comparing the optimal statistic distribution with the distribution created using "quasi-resampling" techniques (such as sky scrambles and phase shifts), we endeavour to determine the extent to which plausible misspecification might lead to a false positive. The results are reassuring: we find that quasi-resampling techniques tend to underestimate the significance of pure-noise data sets. We conclude that recent reported evidence for a nanohertz gravitational wave background is likely robust to the most obvious sources of systematic errors; if anything, the significance of the signal is potentially underestimated. [ABSTRACT FROM AUTHOR]

Introduction Access to a primary care provider is a key component of high-functioning healthcare systems. In Canada, 15% of patients do not have a regular primary care provider and are classified as ‘unattached’. In an effort to link unattached patients with a provider, seven Canadian provinces implemented centralised waitlists (CWLs). The effectiveness of CWLs in attaching patients to regular primary care providers is unknown. Factors influencing CWLs effectiveness, particularly across jurisdictional contexts, have yet to be confirmed.Methods and analysis A mixed methods case study will be conducted across three Canadian provinces: Ontario, Québec and Nova Scotia. Quantitatively, CWL data will be linked to administrative and provider billing data to assess the rates of patient attachment over time and delay of attachment, stratified by demographics and compared with select indicators of health service utilisation. Qualitative interviews will be conducted with policymakers, patients, and primary care providers to elicit narratives regarding the administration, use, and access of CWLs. An analysis of policy documents will be used to identify contextual factors affecting CWL effectiveness. Stakeholder dialogues will be facilitated to uncover causal pathways and identify strategies for improving patient attachment to primary care.Ethics and dissemination Approval to conduct this study has been granted in Ontario (Queens University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board, file number 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol number 40335), Québec (Centre intégré universitaire de santé et de services sociaux de l'Estrie, project number 2020–3446) and Nova Scotia (Nova Scotia Health Research Ethics Board, file number 1024979).

Background Understanding and addressing the needs of frail patients has been identified as an important strategy by the Nova Scotia Health Authority (NSHA). Primary care (PC) providers are in a key position to aid in the identification of, and response to frailty as part of routine care. Unlike singular chronic conditions such as diabetes and hypertension which garner a disease-based approach and identification as part of standard practice, frailty is only just emerging as a concept for PC. The web-based Frailty Portal was developed to aid in the identification of, assessment and care planning for frail patients in PC practice. In this study we assess the implementation feasibility and impact of the Frailty Portal by: (1) identifying factors influencing the Frailty Portal’s use in community PC practice, and (2) examination of the immediate impact of the ‘Frailty Portal’ on frail patients, their caregivers and PC providers. Methods A convergent mixed method approach was implemented among PC providers in community-based practice in the NSHA, Central Zone. Quantitative and qualitative data were collected concurrently over a 9-month period. A sample of patients who underwent assessment and/or their caregiver were approached for survey participation. Results Fourteen community PC providers (10 family physicians, 4 nurse practitioners) completed 48 patient assessments and completed or begun 41 care plans; semi-structured interviews were conducted among 9 providers. Nine patients and 5 caregivers participated in the survey. PC providers viewed frailty as an important concept but implementation challenges were met, primarily with respect to the time required for use and lack of fit with traditional practice routines. Additional barriers included tool usability and accessibility, training and care planning steps, and privacy. Impacts of the tools use with respect to confidence and knowledge showed early promise. Conclusion This feasibility study highlights the need for added health system supports, resources and financial incentives for successful implementation of the Frailty Portal in community PC practice. We suggest future implementation integrate the Frailty Portal to practice electronic medical records (EMRs) and target providers with largely geriatric practice populations and those practicing within interdisciplinary, collaborative primary healthcare (PHC) teams.

n a gap in consistent application of system-level strategies that can effectively translate organizational policies around patient and family engagement into practice. Methods The broad objective of this initiative was to develop a system-level implementation strategy to include patient and family advisors (PFAs) at decision-making points in primary healthcare (PHC) based on wellestablished evidence and literature. In this opportunity sponsored by the Canadian Foundation for Healthcare Improvement (CFHI) a co-design methodology, also well-established was applied in identifying and developing a suitable implementation strategy to engage PFAs as members of quality teams in PHC. Diabetes management centres (DMCs) was selected as the pilot site to develop the strategy. Key steps in the process included review of evidence, review of the current state in PHC through engagement of key stakeholders and a co-design approach. Results The project team included a diverse representation of members from the PHC system including patient advisors, DMC team members, system leads, providers, Public Engagement team members and CFHI improvement coaches. Key outcomes of this 18-month long initiative included development of a working definition of patient and family engagement, development of a Patient and Family Engagement Resource Guide and evaluation of the resource guide. Conclusion This novel initiative provided us an opportunity to develop a supportive system-wide implementation plan and a strategy to include PFAs in decision-making processes in PHC. The well-established co-design methodology further allowed us to include value-based (customer driven quality and experience of care) perspectives of several important stakeholders including patient advisors. The next step will be to implement the strategy within DMCs, spread the strategy PHC, both locally and provincially with a focus on sustainability.

FRB 20210912A is a fast radio burst (FRB), detected and localized to subarcsecond precision by the Australian Square Kilometre Array Pathfinder. No host galaxy has been identified for this burst despite the high precision of its localization and deep optical and infrared follow-up, to 5σ limits of R  = 26.7 mag and K s = 24.9 mag with the Very Large Telescope. The combination of precise radio localization and deep optical imaging has almost always resulted in the secure identification of a host galaxy, and this is the first case in which the line of sight is not obscured by the Galactic disc. The dispersion measure of this burst, DMFRB = 1233.696 ± 0.006 pc cm−3, allows for a large source redshift of z > 1 according to the Macquart relation. It could thus be that the host galaxy is consistent with the known population of FRB hosts, but is too distant to detect in our observations (z > 0.7 for a host like that of the first repeating FRB source, FRB 20121102A); that it is more nearby with a significant excess in DMhost, and thus dimmer than any known FRB host; or, least likely, that the FRB is truly hostless. We consider each possibility, making use of the population of known FRB hosts to frame each scenario. The fact of the missing host has ramifications for the FRB field: even with high-precision localization and deep follow-up, some FRB hosts may be difficult to detect, with more distant hosts being the less likely to be found. This has implications for FRB cosmology, in which high-redshift detections are valuable. [ABSTRACT FROM AUTHOR]

An increasing number of antibody-based therapies are being considered for controlling bacterial infections, including Clostridium difficile by targeting toxins A and B. In an effort to develop novel C. difficile immunotherapeutics, we previously isolated several single-domain antibodies (VHHs) capable of toxin A neutralization through recognition of the extreme C-terminal combined repetitive oligopeptides (CROPs) domain, but failed at identifying neutralizing VHHs that bound a similar region on toxin B. Here we report the isolation of a panel of 29 VHHs targeting at least seven unique epitopes on a toxin B immunogen composed of a portion of the central delivery domain and the entire CROPs domain. Despite monovalent affinities as high as KD = 70 pM, none of the VHHs tested were capable of toxin B neutralization; however, modest toxin B inhibition was observed with VHH-VHH dimers and to a much greater extent with VHH-Fc fusions, reaching the neutralizing potency of the recently approved anti-toxin B monoclonal antibody bezlotoxumab in in vitro assays. Epitope binning revealed that several VHH-Fcs bound toxin B at sites distinct from the region recognized by bezlotoxumab, while other VHH-Fcs partially competed with bezlotoxumab for toxin binding. Therefore, the VHHs described here are effective at toxin B neutralization when formatted as bivalent VHH-Fc fusions by targeting toxin B at regions both similar and distinct from the bezlotoxumab binding site.

Precision pulsar timing is integral to the detection of the nanohertz stochastic gravitational-wave background as well as understanding the physics of neutron stars. Conventional pulsar timing often uses fixed time and frequency-averaged templates to determine the pulse times of arrival, which can lead to reduced accuracy when the pulse profile evolves over time. We illustrate a dynamic timing method that fits each observing epoch using basis functions. By fitting each epoch separately, we allow for the evolution of the pulse shape epoch to epoch. We apply our method to PSR J1103−5403 and find evidence that it undergoes mode changing, making it the fourth millisecond pulsar to exhibit such behaviour. Our method, which is able to identify and time a single mode, yields a timing solution with a root-mean-square error of |$1.343$| µs, a factor of 1.78 improvement over template fitting on both modes. In addition, the white-noise amplitude is reduced 4.3 times, suggesting that fitting the full data set causes the mode changing to be incorrectly classified as white noise. This reduction in white noise boosts the signal-to-noise ratio of a gravitational-wave background signal for this particular pulsar by 32 per cent. We discuss the possible applications for this method of timing to study pulsar magnetospheres and further improve the sensitivity of searches for nanohertz gravitational waves. [ABSTRACT FROM AUTHOR]

One of the major causes of morbidity and mortality in man and economically important animals is bacterial infections of the gastrointestinal (GI) tract. The emergence of difficult-to-treat infections, primarily caused by antibiotic resistant bacteria, demands for alternatives to antibiotic therapy. Currently, one of the emerging therapeutic alternatives is the use of lytic bacteriophages. In an effort to exploit the target specificity and therapeutic potential of bacteriophages, we examined the utility of bacteriophage tailspike proteins (Tsps). Among the best-characterized Tsps is that from the Podoviridae P22 bacteriophage, which recognizes the lipopolysaccharides of Salmonella enterica serovar Typhimurium. In this study, we utilized a truncated, functionally equivalent version of the P22 tailspike protein, P22sTsp, as a prototype to demonstrate the therapeutic potential of Tsps in the GI tract of chickens. Bacterial agglutination assays showed that P22sTsp was capable of agglutinating S. Typhimurium at levels similar to antibodies and incubating the Tsp with chicken GI fluids showed no proteolytic activity against the Tsp. Testing P22sTsp against the three major GI proteases showed that P22sTsp was resistant to trypsin and partially to chymotrypsin, but sensitive to pepsin. However, in formulated form for oral administration, P22sTsp was resistant to all three proteases. When administered orally to chickens, P22sTsp significantly reduced Salmonella colonization in the gut and its further penetration into internal organs. In in vitro assays, P22sTsp effectively retarded Salmonella motility, a factor implicated in bacterial colonization and invasion, suggesting that the in vivo decolonization ability of P22sTsp may, at least in part, be due to its ability to interfere with motility… Our findings show promise in terms of opening novel Tsp-based oral therapeutic approaches against bacterial infections in production animals and potentially in humans.

Forty-five years ago the late Professor Joseph L. Sax, the father of the modern public trust doctrine, published his seminal article, The Public Trust Doctrine in Natural Resource Law: Effective [...]

The rate of fast radio bursts (FRBs) in the direction of nearby galaxy clusters is expected to be higher than the mean cosmological rate if intrinsically faint FRBs are numerous. In this paper, we describe a targeted search for faint FRBs near the core of the Virgo Cluster using the Australian Square Kilometre Array Pathfinder telescope. During 300 h of observations, we discovered one burst, FRB 180417, with dispersion measure (DM) = 474.8 cm−3 pc. The FRB was promptly followed up by several radio telescopes for 27 h, but no repeat bursts were detected. An optical follow-up of FRB 180417 using the PROMPT5 telescope revealed no new sources down to an R -band magnitude of 20.1. We argue that FRB 180417 is likely behind the Virgo Cluster as the Galactic and intracluster DM contribution are small compared to the DM of the FRB, and there are no galaxies in the line of sight. The non-detection of FRBs from Virgo constrains the faint-end slope, α < 1.52 (at 68 per cent confidence limit), and the minimum luminosity, L min ≳ 2 × 1040 erg s−1 (at 68 per cent confidence limit), of the FRB luminosity function assuming cosmic FRB rate of 104 FRBs per sky per day with flux above 1 Jy located out to redshift of 1. Further FRB surveys of galaxy clusters with high-sensitivity instruments will tighten the constraints on the faint end of the luminosity function and, thus, are strongly encouraged. [ABSTRACT FROM AUTHOR]

Previous studies on Gyrinicola batrachiensis indicate that these pinworms have distinct reproductive strategies dependent on the development time to metamorphosis of their anuran tadpole hosts. In tadpoles of amphibian species with short developmental periods (a few weeks), female nematodes reproduce parthenogenetically, and only produce thick-shelled eggs used as transmission agents from tadpole to tadpole. In contrast, nematodes in tadpoles with longer larval developmental periods (months to years) reproduce by haplodiploidy, and females produce thick-shelled as well as autoinfective thin-shelled eggs. However, recent investigations on the haplodiploidy strain of G. batrachiensis indicate that plasticity exists in the ability of these nematodes to produce thin-shelled autoinfective eggs when these nematodes infect tadpoles of co-occurring amphibian species. Yet, little information is available on the potential mechanism for this reproductive plasticity because few co-occurring amphibian species have been examined for the reproductive strategies of these nematodes. Therefore, our goals were to document field host specificity and reproductive strategies of nematode populations in tadpoles of five co-occurring amphibian species that varied in their larval developmental periods. Additionally, we evaluated adult worm morphology from each infected amphibian species to assess any differences in worm development and reproductive strategy of pinworm populations in different amphibian species. Of the five amphibian species examined, four were infected with the haplodiploid strain of G. batrachiensis. Prevalence of G. batrachiensis ranged from a high of 83% in Acris blandchardi to a low of 15% in Pseudacris clarkii; whereas mean intensity was highest for Rana sphenocephala (10 ± 10.36) and lowest for Hyla chrysoscelis (3.23 ± 3.35). Prevalence appeared to be controlled by tadpole ecology and life history, while mean intensity appeared to be controlled by tadpole physiology and worm reproductive strategy, but not necessarily the developmental period of each anuran species. G. batrachiensis observed in long developing tadpoles of R. sphenocephala had high mean intensities and conformed to the haplodiploidy reproductive strategy with both male and female worms being present, and females produced thick-shelled and thin-shelled eggs. In contrast, tadpoles of A. blanchardi, H. chrysoscelis, and P. clarkii, which varied in their developmental times from long to short, had relatively low mean intensities and contained both male and female G. batrachiensis. However, female worms only produced thick-shelled eggs in these hosts. Importantly, morphological differences existed among female worms recovered from R. sphenocephala and female worms recovered from A. blanchardi tadpoles with long developmental periods. These data strongly suggest that when the haplodiploidy strain of G. batrachiensis is shared by tadpoles of different amphibian species, species-specific differences in interactions between these nematodes and their development in different amphibian host species have a strong influence on the reproductive plasticity of these nematodes. [ABSTRACT FROM AUTHOR]

Background: Recent evidence shows that patient engagement is an important strategy in achieving a high performing healthcare system. While there is considerable evidence of implementation initiatives in direct care context, there is limited investigation of implementation initiatives in decision-making context as it relates to program planning, service delivery and developing policies. Research has also shown a gap in consistent application of system-level strategies that can effectively translate organizational policies around patient and family engagement into practice. Methods: The broad objective of this initiative was to develop a system-level implementation strategy to include patient and family advisors (PFAs) at decision-making points in primary healthcare (PHC) based on wellestablished evidence and literature. In this opportunity sponsored by the Canadian Foundation for Healthcare Improvement (CFHI) a co-design methodology, also well-established was applied in identifying and developing a suitable implementation strategy to engage PFAs as members of quality teams in PHC. Diabetes management centres (DMCs) was selected as the pilot site to develop the strategy. Key steps in the process included review of evidence, review of the current state in PHC through engagement of key stakeholders and a co-design approach. Results: The project team included a diverse representation of members from the PHC system including patient advisors, DMC team members, system leads, providers, Public Engagement team members and CFHI improvement coaches. Key outcomes of this 18-month long initiative included development of a working definition of patient and family engagement, development of a Patient and Family Engagement Resource Guide and evaluation of the resource guide. Conclusion: This novel initiative provided us an opportunity to develop a supportive system-wide implementation plan and a strategy to include PFAs in decision-making processes in PHC. The well-established co-design methodology further allowed us to include value-based (customer driven quality and experience of care) perspectives of several important stakeholders including patient advisors. The next step will be to implement the strategy within DMCs, spread the strategy PHC, both locally and provincially with a focus on sustainability. [ABSTRACT FROM AUTHOR]

Chronic vomiting in cats is a common presenting problem seen in veterinary practice today. The initial step when presented with a vomiting patient is to differentiate between vomiting and regurgitation or dysphagia. There are numerous causes for chronic vomiting in cats, and therefore a detailed and comprehensive patient history and a systematic diagnostic approach are key steps in determining the cause for vomiting and the most appropriate treatment plan. Common causes for chronic vomiting in cats may include inflammatory bowel disease, food allergy, gastrointestinal motility disorders, neoplasia, and extra-gastrointestinal diseases, such as renal disease, hepatobiliary disease, and hyperthyroidism. [ABSTRACT FROM AUTHOR]

In the centenary year of Einstein's General Theory of Relativity, this paper reviews the current status of gravitational wave astronomy across a spectrum which stretches from attohertz to kilohertz frequencies. Sect. 1 of this paper reviews the historical development of gravitational wave astronomy from Einstein's first prediction to our current understanding the spectrum. It is shown that detection of signals in the audio frequency spectrum can be expected very soon, and that a north-south pair of next generation detectors would provide large scientific benefits. Sect. 2 reviews the theory of gravitational waves and the principles of detection using laser interferometry. The state of the art Advanced LIGO detectors are then described. These detectors have a high chance of detecting the first events in the near future. Sect. 3 reviews the KAGRA detector currently under development in Japan, which will be the first laser interferometer detector to use cryogenic test masses. Sect. 4 of this paper reviews gravitational wave detection in the nanohertz frequency band using the technique of pulsar timing. Sect. 5 reviews the status of gravitational wave detection in the attohertz frequency band, detectable in the polarisation of the cosmic microwave background, and discusses the prospects for detection of primordial waves from the big bang. The techniques described in sects. 1-5 have already placed significant limits on the strength of gravitational wave sources. Sects. 6 and 7 review ambitious plans for future space based gravitational wave detectors in the millihertz frequency band. Sect. 6 presents a roadmap for development of space based gravitational wave detectors by China while sect. 7 discusses a key enabling technology for space interferometry known as time delay interferometry. [ABSTRACT FROM AUTHOR]

Introduction: Ipsilateral nonstenotic (<50%) internal carotid artery (ICA) plaque, cardiac atriopathy, and patent foramen ovale (PFO) may account for a substantial proportion of embolic stroke of undetermined source (ESUS).Methods: Consecutive stroke patients at our center (2019-2021) with unilateral, anterior circulation ESUS were categorized into the following mutually exclusive etiologies: (1) nonstenotic ipsilateral ICA plaque (NSP, ≥3mm in maximal axial diameter), (2) sex-adjusted mod-to-severe left atrial enlargement (LAE), (3) PFO, and (4) "occult ESUS" (patients who failed to meet criteria for these 3 groups). Descriptive statistics and multivariable logistic regression were used to model group characteristics.Results: Of 132 included patients, the median age was 65 (IQR 56-73), 74 (56%) of whom were White, and 54 (41%) were female. Twenty-one patients (16%) had NSP proximal to the infarct territory, 17 (13%) had LAE, 9 (7%) had a PFO, and 85 (64%) had no other mechanism. Patients with LAE were older (p=0.004), and had more frequent intracranial occlusions of the internal carotid and proximal middle cerebral artery (p=0.048), while tobacco use was most commonly found among patients with NSP (75%) when compared to other ESUS groups (p=0.02). Five of 9 patients with LAE who underwent outpatient telemetry had paroxysmal atrial fibrillation (56%), while zero patients with PFO or NSP had paroxysmal atrial fibrillation (p=0.005). Older age (adjusted OR [aOR] 1.05, 95%CI 1.03-1.07), coronary artery disease (aOR 3.22, 95%CI 1.61-6.44) and hypertension (aOR 2.16, 95%CI 1.14-4.06) were independently associated with LAE, while only tobacco use was associated with NSP when compared to other ESUS subclassifiers (OR 3.18, 95%CI 1.08-0.42). Age and tobacco use were both inversely associated with PFO (aOR 0.93, 95%CI 0.88-0.98, and aOR 0.10, 95%CI 0.02-0.90, respectively).Conclusions: Certain clinical and radiographic features may be useful in predicting the proximal source of occult cerebral emboli, and can be used for cost-effective outpatient diagnostic testing. [ABSTRACT FROM AUTHOR]

PAHdb, a legacy of and resource in genetics, is a relational locus-specific database ( http://www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n = 439, putative disease-causing) and benign alleles (n = 41, putative untranslated polymorphisms) at the human phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or by in vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are point mutations causing missense in translation of which few have a primary effect on PAH enzyme kinetics. Most apparently have a secondary effect on its function through misfolding, aggregation, and intracellular degradation of the protein. Some point mutations create new splice sites. A subset of primary PAH mutations that are tetrahydrobiopterin-responsive is highlighted on a Curators' Page. A clinical module describes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylketonuria [PKU]), their inheritance, and their treatment. PAHdb contains data on the mouse gene (Pah) and on four orthologous mutant mouse models and their use (for example, in research on oral treatment of PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]). Hum Mutat 21:333–344, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

PAHdb, a legacy of and resource in genetics, is a relational locus?specific database (http://www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n = 439, putative disease?causing) and benign alleles (n = 41, putative untranslated polymorphisms) at the human phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.16.1) or by in vitro expression analysis. The majority (63%) of the putative pathogenic PAH alleles are point mutations causing missense in translation of which few have a primary effect on PAH enzyme kinetics. Most apparently have a secondary effect on its function through misfolding, aggregation, and intracellular degradation of the protein. Some point mutations create new splice sites. A subset of primary PAH mutations that are tetrahydrobiopterin?responsive is highlighted on a Curators' Page. A clinical module describes the corresponding human clinical disorders (hyperphenylalaninemia [HPA] and phenylketonuria [PKU]), their inheritance, and their treatment. PAHdb contains data on the mouse gene (Pah) and on four orthologous mutant mouse models and their use (for example, in research on oral treatment of PKU with the enzyme phenylalanine ammonia lyase [EC 4.3.1.5]). Hum Mutat 21:333–344, 2003. © 2003 Wiley?Liss, Inc. [ABSTRACT FROM AUTHOR]

This paper describes why financial services companies are uniquely placed to use direct marketing and how they need to overcome a number of issues in order to maximise its potential. It weighs up practical limitations such as the Data Protection Act and industry regulations as well as examining softer issues such as the drawbacks of a traditional financial services culture and the need to protect credibility through maintaining sufficient levels of customer confidentiality and trust. A discussion of practical recommendations and how they can be best implemented explores possible solutions to the challenges. [ABSTRACT FROM AUTHOR]

The article discusses disasters and dangers faced by men and ships that participated in springtime sealing in Newfoundland's seal fisheries up to 1914. It comments on perils such as storms, becoming stuck in the ice, and running ashore or striking rocks. The author considers specific disasters such as a loss of men from the ship the Greenland by storm in 1898, the loss of men from the ship Newfoundland by storm in 1914, and the disappearance of the ship Erna in 1912. The loss of both sailing ships and steamships is addressed.

The frequency dependence of normal pulsar radio emission is typically observed to be a power law, with some indications of a flattening or turnover at low frequencies (≲ 100 MHz). The spectrum of the Crab pulsar's giant pulse emission has not been examined as closely. We conducted simultaneous wideband observations of the Crab pulsar, with the Parkes radio telescope and the Murchison Widefield Array, to study the spectral behaviour of its giant pulses. Our analysis shows that the mean spectral index of Crab giant pulses flattens at low frequencies, from −2.6 ± 0.5 between the Parkes bands, to −0.7 ± 1.4 between the lowest MWA subbands. [ABSTRACT FROM AUTHOR]

An introduction in presented in which the author discusses several reports published within the issue on topics including use of public trust doctrine to fossil fuel corporations liable for the damage, implications of property law on democratic political theory, and environmental rights.

The direct detection of gravitational waves will usher in a new era of astrophysics, enabling the study of regions of the universe opaque to electromagnetic radiation or electromagnetically quiet. An ensemble of pulsars (referred to as a pulsar timing array) provides a set of clocks distributed across the Galaxy sensitive to gravitational waves with periods on the order of five years (frequencies of many nanohertz). Plausible source of gravitational waves in this frequency band include massive black hole binaries in the throes of mergers and oscillating cosmic strings. The stochastic gravitational wave background, the sum of gravitational waves emitted throughout the universe, is the most likely signal to be detected by a pulsar timing array.While the detection of gravitational waves will be a milestone in pulsar astronomy, a constraining limit on the strength of the gravitational wave background can be used to constrain cosmological models and early Universe physics. Here we present a new algorithm that can be used to constrain the strength of the GWB with a pulsar timing array. We then apply this technique to Parkes Pulsar Timing Array observations and place a new limit on the strength of the GWB. We conclude by discussing the astrophysical implications of this limit and the prospects for detecting gravitational waves with pulsars. [ABSTRACT FROM PUBLISHER]