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The logarithmic law of the wall does not capture the mean flow when a boundary layer is subjected to a strong pressure gradient. In such a boundary layer, the mean flow is affected by the spatio-temporal history of the imposed pressure gradient; and accounting for history effects remains a challenge. This work aims to develop a universal mean flow scaling for boundary layers subjected to arbitrary adverse or/and favourable pressure gradients. We derive from the Navier–Stokes equation a velocity transformation that accounts for the history effects and maps the mean flow to the canonical law of the wall. The transformation is tested against channel flows with a suddenly imposed adverse or favourable pressure gradient, boundary layer flows subjected to an adverse pressure gradient, and Couette–Poiseuille flows with a streamwise pressure gradient. It is found that the transformed velocity profiles follow closely the equilibrium law of the wall.
A continuous-wave (CW) single-longitudinal-mode (SLM) Raman laser at 1240 nm with power of up to 20.6 W was demonstrated in a free-running diamond Raman oscillator without any axial-mode selection elements. The SLM operation was achieved due to the spatial-hole-burning free nature of Raman gain and was maintained at the highest available pump power by suppressing the parasitic stimulated Brillouin scattering (SBS). A folded-cavity design was employed for reducing the perturbing effect of resonances at the pump frequency. At a pump power of 69 W, the maximum Stokes output reached 20.6 W, corresponding to a 30% optical-to-optical conversion efficiency from 1064 to 1240 nm. The result shows that parasitic SBS is the main physical process disturbing the SLM operation of Raman oscillator at higher power. In addition, for the first time, the spectral linewidth of a CW SLM diamond Raman laser was resolved using the long-delayed self-heterodyne interferometric method, which is 105 kHz at 20 W.
Clinical trials provide the “gold standard” evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources – data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor.
Three examples of real-world trials that leverage different types of data sources – wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived.
Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity.
Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.
Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability toward psychopathology or confounded by unmeasured familial factors.
To examine whether the associations between psychiatric diagnoses and increased risk of cardiometabolic complications are attributable to a general liability toward psychopathology, or confounded by unmeasured familial factors.
We conducted a cohort study in Sweden and identified all individuals and their siblings born in Sweden 1955-1962 with follow-up through 2013. After excluding individuals who died or emigrated before 1987, the final sample consisted 672 823 individuals. We extracted ICD-coded diagnoses (recorded 1973-1987) for ten psychiatric conditions and criminal convictions when participants were aged 18-25 years, and ICD-coded diagnoses (recorded 1987-2013) for five cardiometabolic complications (obesity, hypertensive diseases, hyperlipidemia, type 2 diabetes mellitus, and cardiovascular diseases) when the participants were 51-58 years old. Logistic regression models were used to estimate the bivariate associations between psychiatric conditions or criminal convictions and cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the psychiatric conditions and criminal convictions. We then regressed the cardiometabolic complications on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs.
Each psychiatric conditions significantly increased the risk of cardiometabolic complications; however, most of these associations were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals’ general psychopathology and their siblings’ cardiometabolic complications, suggesting that the associations were not attributable to genetic or environmental confounding factors shared within families. The same pattern was evident for the specific internalizing and psychotic factors.
Individuals with mental disorders in early life had an increased long term risk of cardiometabolic complications, which appeared attributable to a general liability toward psychopathology. Sibling analyses suggested that the elevated risk could not be attributed to confounds shared within families.This highlights the importance of transdiagnostic and lifestyle based interventions to reduce the risk of cardiometabolic complications, particularly in patients with several mental disorders.
This study analyzes the linewidth narrowing characteristics of free-space-running Brillouin lasers and investigates the approaches to achieve linewidth compression and power enhancement simultaneously. The results show that the Stokes linewidth behavior in a free-space-running Brillouin laser cavity is determined by the phase diffusion of the pump and the technical noise of the system. Experimentally, a Stokes light output with a power of 22.5 W and a linewidth of 3.2 kHz was obtained at a coupling mirror reflectivity of 96%, which is nearly 2.5 times compressed compared with the linewidth of the pump (7.36 kHz). In addition, the theorical analysis shows that at a pump power of 60 W and a coupling mirror reflectivity of 96%, a Stokes output with a linewidth of 1.6 kHz and up to 80% optical conversion efficiency can be achieved by reducing the insertion loss of the intracavity. This study provides a promising technical route to achieve high-power ultra-narrow linewidth special wavelength laser radiations.
Background: Lower socioeconomic status is associated with worse outcomes after stroke. We evaluated the differences in acute revascularization treatments in patients with acute ischemic stroke (AIS) who were materially deprived compared to those who were not. Methods: In a population-based cohort study, we used linked administrative data to identify community-dwelling adults hospitalized for AIS between 2017-2022 in Ontario, Canada. The main exposure was neighborhood-level material deprivation quintiles. Multivariable logistic regression was used to obtain the adjusted odds ratio (aOR) of receiving revascularization treatments (thrombolysis or thrombectomy) for patients in each deprivation quintile compared to the least deprived quintile. Results: We identified 57,709 patients (median age 74 years; 45.9% female). Compared to patients in the least deprived quintile, those with higher deprivation were younger and more likely to have hypertension and diabetes, but less likely to have atrial fibrillation. Compared to patients in the least deprived quintile, fewer patients in the very deprived quintile (17.9% vs 19.6%, aOR 0.88, 95%CI [0.82,0.95]) and in the most deprived quintile (16.6% vs 19.6%, 0.77 [0.71,0.83]) received revascularization treatments. Conclusions: Our results suggest disparities in the use of acute ischemic stroke revascularization treatments by socioeconomic status despite access to universal health care.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
A high-load counter-rotating compressor is optimised based on the method of coupling aerodynamic optimisation technology and computational fluid dynamics, and the flow structures in the passage are analysed and evaluated by vorticity dynamics diagnosis. The results show that the aerodynamic performance of optimised compressor are obviously improved at both design point and off-design point. By comparing the distribution characteristics of vorticity dynamics parameters on the blade surface before and after the optimisation, it is found that BVF (boundary vorticity flux) and circumferential vorticity can effectively capture high flow loss regions such as shock waves and secondary flow in the passage. In addition, the BEF (Boundary enstrophy flux) diagnosis method based on the theory of boundary enstrophy flux is developed, which expands the application scenario of the boundary vorticity dynamics diagnosis method. The change of vorticity dynamics parameters shows blade geometric parameters’ influence on the passage’s viscous flow field, which provides a theoretical basis for the aerodynamic optimisation design.
Intimate partner violence (IPV) is a public health challenge negatively affecting victims’ health. Telomere length (TL), a marker for biological ageing, might be reflective of the mechanisms through which IPV leads to adverse health outcomes. The objective of the current study was to explore the association between IPV and leucocyte TL.
We conducted an analysis using a subset of the UK Biobank (N = 144 049). Physical, sexual and emotional IPV were reported by the participants. DNA was extracted from peripheral blood leukocytes. TL was assayed by quantitative polymerase chain reaction. We used multivariable linear regressions to test the associations between IPV and TL adjusted for age, sex, ethnicity, deprivation, education, as well as symptoms of depression and post-traumatic stress disorder in a sensitivity analysis.
After adjusting for sociodemographic factors, any IPV was associated with 0.02-s.d. shorter TL (β = −0.02, 95% CI −0.04 to −0.01). Of the three types of IPV, physical violence had a marginally stronger association (β = −0.05, 95% CI −0.07 to −0.02) than the other two types. The associations of numbers of IPV and TL showed a dose–response pattern whereby those who experienced all three types of IPV types had the shortest TL (β = −0.07, 95% CI −0.12 to −0.03), followed by those who experienced two types (β = −0.04, 95% CI −0.07 to −0.01). Following additional adjustment for symptoms of depression and PTSD, the associations were slightly attenuated but the general trend by number of IPVs remained.
Victims of IPV, particularly those exposed to multiple types of IPVs, had shorter TL indicative of accelerated biological ageing. Given that all three types of IPV are linked to TL, clinical practitioners need to comprehensively identify all types of IPV and those who received multiple types. Further studies should explore the association of violence with changes in TL over time, as well as to which extent biological ageing is a mechanistic factor.
This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.
A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors.
Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001).
Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.
In adults with Clostridioides difficile infection (CDI), higher stool concentrations of toxins A and B are associated with severe baseline disease, CDI-attributable severe outcomes, and recurrence. We evaluated whether toxin concentration predicts these presentations in children with CDI.
We conducted a prospective cohort study of inpatients aged 2–17 years with CDI who received treatment. Patients were followed for 40 days after diagnosis for severe outcomes (intensive care unit admission, colectomy, or death, categorized as CDI primarily attributable, CDI contributed, or CDI not contributing) and recurrence. Baseline stool toxin A and B concentrations were measured using ultrasensitive single-molecule array assay, and 12 plasma cytokines were measured when blood was available.
We enrolled 187 pediatric patients (median age, 9.6 years). Patients with severe baseline disease by IDSA-SHEA criteria (n = 34) had nonsignificantly higher median stool toxin A+B concentration than those without severe disease (n = 122; 3,217.2 vs 473.3 pg/mL; P = .08). Median toxin A+B concentration was nonsignificantly higher in children with a primarily attributed severe outcome (n = 4) versus no severe outcome (n = 148; 19,472.6 vs 429.1 pg/mL; P = .301). Recurrence occurred in 17 (9.4%) of 180 patients. Baseline toxin A+B concentration was significantly higher in patients with versus without recurrence: 4,398.8 versus 280.8 pg/mL (P = .024). Plasma granulocyte colony-stimulating factor concentration was significantly higher in CDI patients versus non-CDI diarrhea controls: 165.5 versus 28.5 pg/mL (P < .001).
Higher baseline stool toxin concentrations are present in children with CDI recurrence. Toxin quantification should be included in CDI treatment trials to evaluate its use in severity assessment and outcome prediction.
The mean velocity follows a logarithmic scaling in the surface layer when normalized by the friction velocity, i.e. a velocity scale derived from the wall-shear stress. The same logarithmic scaling exists for the mean temperature when one normalizes the temperature with the friction temperature, i.e. a scale derived from the wall heat flux. This temperature normalization poses challenges to adiabatic walls, for which the wall heat flux is zero, and the logarithmic temperature scaling becomes singular. This paper aims to establish a temperature transformation that applies to both isothermal walls and adiabatic walls. We show that by accounting for the diffusive flux, both the Van Driest transformation and the semi-local transformation (and other transformations alike) apply to adiabatic walls. We also show that the classic Walz equation works well for adiabatic walls because it models the diffusive flux, albeit in a rather crude way. For validation/testing, we conduct direct numerical simulations of supersonic Couette flows at Mach numbers $M=1$, 3 and 6, and various Reynolds numbers. The two walls are adiabatic, and a source term is included to cancel the aerodynamic heating in the domain. We show that the adiabatic wall data collapse onto the same incompressible logarithmic law of the wall like the isothermal wall data.
COVID-19 infection may lead to encephalopathy and various neurotrophic effects which can result in neuropsychiatric complications. Here, an asymptomatic adolescent female developed acute onset catatonia and psychosis manifesting during the resolution of Covid-19 infection.
Discuss differential diagnosis, medical workup, and initial treatment optimization for acute stabilization.
This 15-year-old female with no previous psychiatric history nor prodromal symptomatology was hospitalized secondary to Covid -19. During the immediate three-month recovery phase following resolution of Covid-19, the patient exhibited gradually increasing anxiety, paranoia, delusions, disorganized behavior, and weight loss leading to re-hospitalization secondary to catatonia. Negative workup included rapid strep test, urinalysis, chest and abdominal x-ray, EEG, and brain MRI. Lumbar puncture revealed elevated WBC of 18 but was unremarkable for NDMA receptor antibodies, CSF HSV, and encephalitis panel. IV steroids, IVIG, and Anakinra were all given without benefit. Inadequate response to olanzapine, clonidine, and lorazepam led to an Index Series of bilateral electroconvulsive therapy (ECT).
The provisional diagnosis of psychotic disorder secondary to COVID-19 infection responded robustly regarding sleep, behavior, and affect by session #6, yet positive symptoms of psychosis persist. Ongoing ECT, psychopharmacology, and narrowing of the differential diagnosis continue.
As more COVID-19 cases evolve during the pandemic, potential post-infectious neuropsychiatric complications should be considered as potentially contributory and kept in a thoughtful differential diagnosis. Regardless of ultimate causation, the acute symptom profile responded robustly to an initial Index Series of ECT.
This study assesses governments' long-term non-pharmaceutical interventions upon the coronavirus disease 2019 (COVID-19) pandemic in East Asia. It advances the literature towards a better understanding of when and which control measures are effective. We (1) provide time-varying case fatality ratios and focus on the elderly's mortality and case fatality ratios, (2) measure the correlations between daily new cases (daily new deaths) and each index based on multiple domestic pandemic waves and (3) examine the lead–lag relationship between daily new cases (daily new deaths) and each index via the cross-correlation functions on the pre-whitened series. Our results show that the interventions reduce COVID-19 infections for some periods before the period of the Omicron variant. Moreover, there is no COVID-19 policy lag in Taiwan between daily new confirmed cases and each index. As of March 2022, the case fatality ratios of the elderly group in Japan, Hong Kong and South Korea are 4.69%, 4.72% and 1.48%, respectively, while the case fatality ratio of the elderly group in Taiwan is 25.01%. A government's COVID-19 vaccination distribution and prioritisation policies are pivotal for the elderly group to reduce the number of deaths. Immunising this specific group as best as possible should undoubtedly be a top priority.