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A numerical investigation is undertaken on the development of linear disturbances in the rotating disk boundary layer, in which a time-periodic modulation is applied to the disk rotation rate. The model gives a prototypical example of a three-dimensional oscillatory boundary layer, by adding a Stokes layer to the von Kármán flow that develops on a steady disk. The study extends the Floquet analysis of Morgan et al. (J. Fluid Mech., vol. 925, 2021, A20), who showed that disk modulation stabilises the stationary convective instabilities found on the steady rotating disk. Using a radial homogeneous flow approximation, whereby the radial dependence of the basic state is ignored, disturbance development is simulated for several modulation settings, with flow conditions matched to both convective and absolute forms of linear instability. Disturbances excited via a stationary periodic wall forcing display behaviour consistent with that found using Floquet theory; time-periodic modulation stabilises the cross-flow instability by reducing the radial growth rate. In addition, convective and absolute instabilities, generated by an impulsive wall forcing, are both stabilised by the introduction of modulation to the disk rotation rate. Modulation establishes a significant reduction in both the temporal growth rate and the disturbance amplitude as it propagates away from the impulse origin. Moreover, greater stabilising control benefits are realised as the modulation amplitude increases.
While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need.
Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence.
Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age.
We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.
The climatic, hydrographic, and environmental regimes of terminal Pleistocene and Holocene northwestern Mongolia are reconstructed using archaeological and pedological data sets at Bayan Nuur, a lake on the northwestern perimeter of the Altan Els dune field in eastern Uvs Province, Mongolia. The archaeological data consist of land-use patterns controlled for time via time-sensitive, diagnostic artifacts. The pedological data consist of soil classifications and radiocarbon dating of paleosols that track lake levels and water table. These data are combined using a geographic information system (GIS) to ascertain site and paleosol geographic relationships to modern lake levels at Bayan Nuur. They point to a more xeric Younger Dryas than previously recognized, significant Holocene lake regressions, and to Mid- to Late Holocene lake standstills/transgressions, the scale of which had previously been unrecognized. Combined, these data point to a complex late Quaternary picture of paleoclimate and paleoenvironment across the region and the importance of using multiple proxies, including archaeological data, in paleoecological reconstructions.
Antibiotic treatment of asymptomatic bacteriuria (ASB) is considered inappropriate and may lead to adverse events. This 2-center, retrospective cohort study including emergency department or inpatient adults identified pyuria (odds ratio, 2.43; 95% confidence interval, 1.17–5.01; P = .02) as the only independent risk factor for antibiotic treatment of ASB.
The control of stationary convective instabilities in the rotating disk boundary layer via a time-periodic modulation of the disk rotation rate is investigated. The configuration provides an archetypal example of a three-dimensional temporally periodic boundary layer, encompassing both the von Kármán and Stokes boundary layers. A velocity–vorticity formulation of the governing perturbation equations is deployed, together with a numerical procedure that utilises the Chebyshev-tau method. Floquet theory is used to determine the linear stability properties of these time-periodic flows. The addition of a time-periodic modulation to the otherwise steady disk rotation rate establishes a stabilising effect. In particular, for a broad range of modulation frequencies, the growth of the stationary convective instabilities is suppressed and the critical Reynolds number for the onset of both the cross-flow and Coriolis instabilities is raised to larger values than that found for the steady disk without modulation. An energy analysis is undertaken, where it is demonstrated that time-periodic modulation induces a reduction in the Reynolds stress energy production and an increase in the viscous dissipation across the boundary layer. Comparisons are made with other control techniques, including distributed surface roughness and compliant walls.
ABSTRACT IMPACT: Circadian disruption is known to cause significant human pathology but has not been evaluated in pancreas cancer carcinogenesis; through understanding how disruption of circadian rhythms can lead to pancreas cancer development and spread, preventive and therapeutic strategies can be devised. OBJECTIVES/GOALS: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer due to early spread and poor response to therapy. Identifying factors driving PDAC growth could lead to new therapeutic strategies. Thus, we evaluated the extent to which circadian rhythm disruption, a factor strongly associated with cancer formation, contributes to PDAC pathogenesis. METHODS/STUDY POPULATION: To achieve the objective, we evaluated mice with pancreas lineage Kras-mutation (KC mice), which are predisposed to develop the full spectrum of pancreas cancer precursor lesions (pancreatic intra-epithelial neoplasia or PANIN-1, 2, 3) and PDAC. We subjected KC mice to a light-dark phase shift protocol known to induce circadian disruption (KCCD, n = 18), and another group to standard lighting conditions (KCNC, n = 31), with equal numbers of males and females in each group. The mice were allowed access to food and water ad libitum until sacrifice at age 9 months. Histopathologic evaluation of the pancreas was then performed to assess for pancreatic inflammation, pancreatic precursor lesions (PANIN) and PDAC. Fisher’s Exact Test was used to evaluate differences in incidence. RESULTS/ANTICIPATED RESULTS: As expected, both groups of mice demonstrated 100% incidence of chronic pancreatitis and PANIN-1 (low-grade precursor lesion) at age 9 months. This is consistent with the KC phenotype. However, the KCCD mice demonstrated a significant increase in acute pancreatic inflammation (61.1% vs 19.4%, p = 0.005) compared to KCNC mice. Furthermore, intermediate grade precursor lesions (PANIN-2) were also significantly increase in the KCCD mice (38.9% vs 6.5%, p = 0.006). Incidence of high-grade precursor lesions (PANIN-3, or carcinoma in situ: 22.2% vs 9.7%) and PDAC (27% vs 19%) were also increased, but these were not statistically significant. These results are notable given the established progression from higher grade premalignant PANIN lesions (PANIN-2, PANIN-3) to PDAC. DISCUSSION/SIGNIFICANCE OF FINDINGS: Insight into how circadian disruption leads to increased PANIN-2 formation and increase in acute inflammation may be advantageous for understanding circadian disruption in PDAC carcinogenesis. The circadian clock is present in immune cells and disruption can induce immune dysregulation. This mechanism will be evaluated in follow up studies.
This paper describes a computational investigation of multimode instability growth and multimaterial mixing induced by multiple shock waves in a high-energy-density (HED) environment, where pressures exceed 1 Mbar. The simulations are based on a series of experiments performed at the National Ignition Facility (NIF) and designed as an HED analogue of non-HED shock-tube studies of the Richtmyer–Meshkov instability and turbulent mixing. A three-dimensional computational modelling framework is presented. It treats many complications absent from canonical non-HED shock-tube flows, including distinct ion and free-electron internal energies, non-ideal equations of state, radiation transport and plasma-state mass diffusivities, viscosities and thermal conductivities. The simulations are tuned to the available NIF data, and traditional statistical quantities of turbulence are analysed. Integrated measures of turbulent kinetic energy and enstrophy both increase by over an order of magnitude due to reshock. Large contributions to enstrophy production during reshock are seen from both the baroclinic source and enstrophy–dilatation terms, highlighting the significance of fluid compressibility in the HED regime. Dimensional analysis reveals that Reynolds numbers and diffusive Péclet numbers in the HED flow are similar to those in a canonical non-HED analogue, but conductive Péclet numbers are much smaller in the HED flow due to efficient thermal conduction by free electrons. It is shown that the mechanism of electron thermal conduction significantly softens local spanwise gradients of both temperature and density, which causes a minor but non-negligible decrease in enstrophy production and small-scale mixing relative to a flow without this mechanism.
This SHEA white paper identifies knowledge gaps and challenges in healthcare epidemiology research related to coronavirus disease 2019 (COVID-19) with a focus on core principles of healthcare epidemiology. These gaps, revealed during the worst phases of the COVID-19 pandemic, are described in 10 sections: epidemiology, outbreak investigation, surveillance, isolation precaution practices, personal protective equipment (PPE), environmental contamination and disinfection, drug and supply shortages, antimicrobial stewardship, healthcare personnel (HCP) occupational safety, and return to work policies. Each section highlights three critical healthcare epidemiology research questions with detailed description provided in supplementary materials. This research agenda calls for translational studies from laboratory-based basic science research to well-designed, large-scale studies and health outcomes research. Research gaps and challenges related to nursing homes and social disparities are included. Collaborations across various disciplines, expertise and across diverse geographic locations will be critical.
Antibiotics are among the most common medications prescribed in nursing homes. The annual prevalence of antibiotic use in residents of nursing homes ranges from 47% to 79%, and more than half of antibiotic courses initiated in nursing-home settings are unnecessary or prescribed inappropriately (wrong drug, dose, or duration). Inappropriate antibiotic use is associated with a variety of negative consequences including Clostridioides difficile infection (CDI), adverse drug effects, drug–drug interactions, and antimicrobial resistance. In response to this problem, public health authorities have called for efforts to improve the quality of antibiotic prescribing in nursing homes.
Through diversity of composition, sequence, and interfacial structure, hybrid materials greatly expand the palette of materials available to access novel functionality. The NSF Division of Materials Research recently supported a workshop (October 17–18, 2019) aiming to (1) identify fundamental questions and potential solutions common to multiple disciplines within the hybrid materials community; (2) initiate interfield collaborations between hybrid materials researchers; and (3) raise awareness in the wider community about experimental toolsets, simulation capabilities, and shared facilities that can accelerate this research. This article reports on the outcomes of the workshop as a basis for cross-community discussion. The interdisciplinary challenges and opportunities are presented, and followed with a discussion of current areas of progress in subdisciplines including hybrid synthesis, functional surfaces, and functional interfaces.
We examined Clostridioides difficile infection (CDI) prevention practices and their relationship with hospital-onset healthcare facility-associated CDI rates (CDI rates) in Veterans Affairs (VA) acute-care facilities.
From January 2017 to February 2017, we conducted an electronic survey of CDI prevention practices and hospital characteristics in the VA. We linked survey data with CDI rate data for the period January 2015 to December 2016. We stratified facilities according to whether their overall CDI rate per 10,000 bed days of care was above or below the national VA mean CDI rate. We examined whether specific CDI prevention practices were associated with an increased risk of a CDI rate above the national VA mean CDI rate.
All 126 facilities responded (100% response rate). Since implementing CDI prevention practices in July 2012, 60 of 123 facilities (49%) reported a decrease in CDI rates; 22 of 123 facilities (18%) reported an increase, and 41 of 123 (33%) reported no change. Facilities reporting an increase in the CDI rate (vs those reporting a decrease) after implementing prevention practices were 2.54 times more likely to have CDI rates that were above the national mean CDI rate. Whether a facility’s CDI rates were above or below the national mean CDI rate was not associated with self-reported cleaning practices, duration of contact precautions, availability of private rooms, or certification of infection preventionists in infection prevention.
We found considerable variation in CDI rates. We were unable to identify which particular CDI prevention practices (i.e., bundle components) were associated with lower CDI rates.
OBJECTIVES/SPECIFIC AIMS: 1) Determine the mutational landscape, including translocation, mutations and mutational signatures as well as copy number variations of pPCL and identify significant differences to non pPCL MM. 2) Determine whether genetic changes pertinent to pPCL could be explored as therapeutic targets to improve the dismal prognosis of this patient population. METHODS/STUDY POPULATION: Samples from overall 19 pPCL patients that presented to the Myeloma Center, UAMS between 2000-2018 were used for this study. We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. RESULTS/ANTICIPATED RESULTS: 1) GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. 2) The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36–77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. 3) Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. 4) The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. 5) Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. 6) Biallelic inactivation of TP53 – a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. DISCUSSION/SIGNIFICANCE OF IMPACT: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored.
Among adults in the US, bipolar disorder affects 2.6% or 5.7 million individuals; 83% of cases are considered to be severe. Even when an accurate diagnosis of bipolar disorder is established, its treatment remains suboptimal, and those with the disorder often fail to receive any care or evidence‐based care.
A continuing medical education (CME)-certified 25-item, multiple choice clinical practice assessment survey was developed to assess recognition and treatment of bipolar disorder, specifically, the use of LAIs in these patients.
The survey included knowledge- and case-based multiple-choice questions completed confidentially online. The survey was launched on December 20, 2017 and hosted on the Medscape Education website. Participant responses were collected through January 31, 2018. Confidentiality was maintained, and responses were de-identified and aggregated before analyses.
(n=1123 psychiatrists; 305 primary care physicians [PCPs]):
- When asked about assessment tools in bipolar disorder, only 43% of psychiatrists and 36% of PCPs could identify the correct use of the MDQ screening instrument, while only 64% of psychiatrists and 51% of PCPs knew that the use of the MDQ can improve recognition of bipolar disorder in patients with depression;
- Psychiatrists were more likely to correctly identify the symptoms that most strongly support a diagnosis of bipolar disorder compared to PCPs (76% vs 43%, respectively);
- When asked about laboratory testing in mood disorders, 52% of psychiatrists and 46% of PCPs knew that laboratory testing can help exclude alternative causes for mood symptoms;
- The majority of both healthcare professionals (73%–75%) did not know that diagnosis of bipolar I disorder relies heavily on changes in activity, energy, and mood;
- 87% of psychiatrists and 76% of PCPs did not identify oral aripiprazole as the only SGA not approved by the FDA for the maintenance treatment of bipolar I disorder;
- 49% of PCPs did not recognize lithium as the first choice for maintenance monotherapy for bipolar I disorder according to the guidelines;
- Only 19% of psychiatrists and 20% of PCPs correctly chose aripiprazole monohydrate and risperidone microspheres as the LAI SGAs indicated for use as monotherapy for patients with bipolar I disorder;
- When asked what is the most common barrier to prescribing LAI antipsychotics in patients with bipolar disorder, 34% of psychiatrists selected “Patients fear of injectables”
This educational research identified psychiatrists and PCPs’ current real-world clinical practices and gaps in the knowledge and competence in the diagnosis and assessment of bipolar disorder, and the treatment options for this condition. Further educational efforts tailored to address identified gaps for each audience are warranted.