Designing and Implementing a Longitudinal Study of Children with Neurological, Genetic, or Metabolic Conditions: \u3cem\u3eCharting the Territory\u3c/em\u3e

Background: Children with progressive metabolic, neurological, or chromosomal conditions and their families anticipate an unknown lifespan, endure unstable and often painful symptoms, and cope with erratic emotional and spiritual crises as the condition progresses along an uncertain trajectory towards death. Much is known about the genetics and pathophysiology of these diseases, but very little has been documented about the trajectory of symptoms for children with these conditions or the associated experience of their families. A longitudinal study design will help to close this gap in knowledge. Methods/Design: Charting the Territory is a longitudinal descriptive, correlational study currently underway with children 0–19 years who are diagnosed with progressive neurological, metabolic, or chromosomal conditions and their families. The purpose of the study is to determine and document the clinical progression of the condition and the associated bio psychosocial spiritual experiences of these parents and siblings age 7–18 years. Approximately 300 families, both newly diagnosed children and those with established conditions, are being recruited in six Canadian cities. Children and their families are being followed for a minimum of 18 months, depending on when they enroll in the study. Family data collection will continue after the child’s death if the child dies during the study period. Data collection includes monthly parental assessment of the child’s symptoms; an annual functional assessment of the child; and completion of established instruments every 6 months by parents to assess family functioning, marital satisfaction, health status, anxiety, depression, stress, burden, grief, spirituality, and growth, and by siblings to assess coping and health. Impact of participation on parents is assessed after 1 year and at the end of the study. Chart reviews are conducted at enrollment and at the conclusion of the study or at the time of the child’s death. Discussion: Knowledge developed from this study will provide some of the first ever detailed descriptions of the clinical symptom trajectory of these non-curable progressive conditions and the bio-psychosocial spiritual aspects for families, from diagnosis through bereavement. Information about developing and implementing this study may be useful to other researchers who are interested in designing a longitudinal study

Development of a Molecular Tagging Velocimetry Technique for Non-Intrusive Velocity Measurements in Low-Speed Gas Flows

N2O molecular tagging velocimetry (N2O-MTV) is developed for use in very-high-temperature reactor environments. Tests were carried out to determine the optimum excitation wavelength, tracer concentration, and timing parameters for the laser system. Using NO tracers obtained from photo-dissociation of N2O, velocity profiles are successfully obtained in air, nitrogen, and helium for a large range of parameters: temperature from 295 to 781 K, pressure from 1 to 3 bars, with a velocity precision of 0.01 m/s. Furthermore, by using two read pulses at adjustable time delays, the velocity dynamic range can be increased. An unprecedented dynamic range of 5,000 has been obtained to successfully resolve the flow during a helium blowdown from 1000 m/s down to 0.2 m/s. This technique is also applied to the high-temperature test facility (HTTF) at Oregon State University (OSU) during a depressurized condition cooldown (DCC) event. Details of these measurements are presented in a companion paper. This technique shows a strong potential for fundamental understanding of gas flows in nuclear reactors and to provide benchmark experimental data to validate numerical simulations

Non-Intrusive Velocity Measurements with MTV During DCC Event in the HTTF

Velocity profiles are measured using molecular tagging velocimetry (MTV) in the high temperature test facility (HTTF) at Oregon State University during a depressurized conduction cooldown (DCC) event. The HTTF is a quarter scale electrically heated nuclear reactor simulator designed to replicate various accident scenarios. During a DCC, a double ended guillotine break results in the reactor pressure vessel (RPV) depressurizing into the reactor cavity and ultimately leading to air ingress in the reactor core (lock-exchange and gas diffusion). It is critical to understand the resulting buoyancy-driven flow to characterize the reactor self-cooling capacity through natural circulation. During tests conducted at ambient pressure and temperature, the RPV containing helium is opened (via the hot and cold legs) to a large vessel filled with nitrogen to simulate the atmosphere. The velocity profile on the hot leg pipe centerline is recorded at 10 Hz with MTV based on NO tracers. The precision of the velocimetry was measured to be 0.02 m/s in quiescent flow prior to the tests. A helium flow from the RPV is initially observed in the top quarter of the pipe. During the first 20 seconds of the event, helium flows out of the RPV with a maximum velocity below 2 m/s. The velocity profile transitions from parabolic to linear in character and decays slowly over the rest of the recording; peak velocities of 0.2 m/s are observed after 30 min. A counter-flow of nitrogen is also observed intermittently, which occurs at lower velocities (>0.1 m/s)

An argument against the focus on Community Resilience in Public Health

Background - It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful? Discussion - Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. “Community resilience” might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified? One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us that a neighbourhood is resilient but not why it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary. There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Communityresilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital. Summary - Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience.</p

Accuracy of vascular tortuosity measures using computational modelling

Severe coronary tortuosity has previously been linked to low shear stresses at the luminal surface, yet this relationship is not fully understood. Several previous studies considered different tortuosity metrics when exploring its impact of on the wall shear stress (WSS), which has likely contributed to the ambiguous findings in the literature. Here, we aim to analyze different tortuosity metrics to determine a benchmark for the highest correlating metric with low time-averaged WSS (TAWSS). Using Computed Tomography Coronary Angiogram (CTCA) data from 127 patients without coronary artery disease, we applied all previously used tortuosity metrics to the left main coronary artery bifurcation, and to its left anterior descending and left circumflex branches, before modelling their TAWSS using computational fluid dynamics (CFD). The tortuosity measures included tortuosity index, average absolute-curvature, root-mean-squared (RMS) curvature, and average squared-derivative-curvature. Each tortuosity measure was then correlated with the percentage of vessel area that showed a < 0.4 Pa TAWSS, a threshold associated with altered endothelial cell cytoarchitecture and potentially higher disease risk. Our results showed a stronger correlation between curvature-based versus non-curvature-based tortuosity measures and low TAWSS, with the average-absolute-curvature showing the highest coefficient of determination across all left main branches (p < 0.001), followed by the average-squared-derivative-curvature (p = 0.001), and RMS-curvature (p = 0.002). The tortuosity index, the most widely used measure in literature, showed no significant correlation to low TAWSS (p = 0.86). We thus recommend the use of average-absolute-curvature as a tortuosity measure for future studies

Factors contributing to posttraumatic growth and its buffering effect in adult chidren of cancer patients undergoing treatment

This study examined relationships among demographic, clinical, and psychosocial variables in adult children of cancer patients. Two hundred and fourteen participants completed measures of posttraumatic growth (PTG), distress, posttraumatic stress disorder (PTSD) symptoms, social support, and family functioning. Significant gender differences in all PTG dimensions were found, as well as associations among PTG, gender, parental dependency, distress, PTSD, and family functioning. Social support was not a mediator in the relationship between gender and PTG. Gender, education, disease duration, dependency, distress, and family flexibility predicted PTG. Finally, PTG had amoderating effect in the relationship between distress and PTSD/social support. These results may guide psychosocial interventions in this population.Fundação para a Ciência e Tecnologia (FCT

Examining the geometry, age and genesis of buried Quaternary valley systems in the Midland Valley of Scotland, UK

Buried palaeo‐valley systems have been identified widely beneath lowland parts of the UK including eastern England, central England, south Wales and the North Sea. In the Midland Valley of Scotland palaeo‐valleys have been identified yet the age and genesis of these enigmatic features remain poorly understood. This study utilizes a digital data set of over 100 000 boreholes that penetrate the full thickness of deposits in the Midland Valley of Scotland. It identified 18 buried palaeo‐valleys, which range from 4 to 36 km in length and 24 to 162 m in depth. Geometric analysis has revealed four distinct valley morphologies, which were formed by different subglacial and subaerial processes. Some palaeo‐valleys cross‐cut each other with the deepest features aligning east–west. These east–west features align with the reconstructed ice‐flow direction under maximum conditions of the Main Late Devensian glaciation. The shallower features appear more aligned to ice‐flow direction during ice‐sheet retreat, and were therefore probably incised under more restricted ice‐sheet configurations. The bedrock lithology influences and enhances the position and depth of palaeo‐valleys in this lowland glacial terrain. Faults have juxtaposed Palaeozoic sedimentary and igneous rocks and the deepest palaeo‐valleys occur immediately down‐ice of knick‐points in the more resistant igneous bedrock. The features are regularly reused and the fills are dominated by glacial fluvial and glacial marine deposits. This suggests that the majority of infilling of the features happened during deglaciation and may be unrelated to the processes that cut them

Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism.

In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages

Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Objectives: This study sought to test the association between the rs9349379 genotype and SCAD. Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD

Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response

Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget