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Poor research integrity is increasingly recognised as a serious problem in science. We outline some evidence for this claim and introduce the Royal College of Psychiatrists (RCPsych) journals’ Research Integrity Group, which has been created to address this problem.
OBJECTIVES/GOALS: Few preclinical models exist to study how tumors transition from prolonged stable disease ('equilibrium') to progressive disease ('escape'). We characterized a new murine tumor model the exhibits such behavior, and sought to identify and validate the role of unique tumor-infiltrating immune cell subsets in this process. METHODS/STUDY POPULATION: We evaluated growth of NPK-C1 (originally LM7304; received from Dr. Cory Abate-Shen at Columbia University), a cell line developed from spontaneous prostate cancer lung metastases in NPK mice (Nkx3.1CreERT2/+Ptenflox/floxKrasLSL-G12D/+R26R-LSL-YFP/+), in immune competent (C57BL/6) and immune deficient mice (J/Nu). We determined the role of CD4 and CD8 T cells in regulating the 'equilibrium to escape’ growth dynamics of NPK-C1 via in vivo cell depletions at key inflection points of tumor growth. To deeply profile the immune contexture of NPK-C1 at these inflection points, we developed a 28-color immunophenotyping panel for use on a Cytek Aurora spectral flow cytometer. We performed dimensionality reduction and clustering analyses on these data using tSNE and FlowSOM algorithms within FlowJo (v10.6). RESULTS/ANTICIPATED RESULTS: We found that activated CD4 effector T cells are enriched in regressing NPK-C1 tumors, highlighting a role for CD4 T cells in antitumor immunity. CD8 T cells are also important for NPK-C1 control; specifically central memory-like cytotoxic CD8 T cells. Depletion of either CD4 or CD8 T cells during the equilibrium phase of NPK-C1 growth confirmed the role of these cells in antagonizing NPK-C1 escape. Tregs as a whole were counterintuitively enriched in regressing tumors, however high dimensional analysis reveals their significant phenotypic diversity, with a number of Treg subpopulations enriched in progressing tumors. In the myeloid compartment, we found that iNOS+ DC-like cells are enriched in regressing tumors, while CD103+ DCs are associated with late stage tumor progression. DISCUSSION/SIGNIFICANCE: In total, these analyses of the NPK-C1 model provide novel insights into the roles of lymphoid and myeloid populations throughout key phases of tumor/immune co-evolution, and highlight a role for multi-dimensional flow cytometry-based analyses to more deeply understand immune cell dynamics in the tumor microenvironment.
Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients.
Understanding the effects of acute feeding on body composition and metabolic measures is essential to the translational component and practical application of measurement and clinical use. To investigate the influence of acute feeding on the validity of dual-energy X-ray absorptiometry (DXA), a four-compartment model (4C) and indirect calorimetry metabolic outcomes, thirty-nine healthy young adults (n 19 females; age: 21·8 (sd 3·1) years, weight; 71·5 (sd 10·0) kg) participated in a randomised cross-over study. Subjects were provided one of four randomised meals on separate occasions (high carbohydrate, high protein, ad libitum or fasted baseline) prior to body composition and metabolic assessments. Regardless of macronutrient content, acute feeding increased DXA percent body fat (%fat) for the total sample and females (average constant error (CE):–0·30 %; total error (TE): 2·34 %), although not significant (P = 0·062); the error in males was minimal (CE: 0·11 %; TE: 0·86 %). DXA fat mass (CE: 0·26 kg; TE: 0·75 kg) and lean mass (LM) (CE: 0·83 kg; TE: 1·23 kg) were not altered beyond measurement error for the total sample. 4C %fat was significantly impacted from all acute feedings (avg CE: 0·46 %; TE: 3·7 %). 4C fat mass (CE: 0·71 kg; TE: 3·38 kg) and fat-free mass (CE: 0·55 kg; TE: 3·05 kg) exceeded measurement error for the total sample. RMR was increased for each feeding condition (TE: 1666·9 kJ/d; 398 kcal/d). Standard pre-testing fasting guidelines may be important when evaluating DXA and 4C %fat, whereas additional DXA variables (fat mass and LM) may not be significantly impacted by an acute meal. Measuring body composition via DXA under less stringent pre-testing guidelines may be valid and increase feasibility of testing in clinical settings.
ABSTRACT IMPACT: Our research has the potential to impact human health by identifying a neural network that can be used to predict time to relapse in individuals with alcohol use disorder. OBJECTIVES/GOALS: Preoccupation towards alcohol use (e.g. craving, rumination, and poor executive control) is a maladaptive behavior associated with relapse risk. We investigated whether alterations in resting state networks known to mediate preoccupation could predict time to relapse in alcohol use disorder (AUD). METHODS/STUDY POPULATION: 50 participants with alcohol use disorder (AUD) (Age: M=41.76, SD=10.22, 19 females) were recruited from an addiction treatment program at ˜2 weeks of abstinence. fMRI data were preprocessed with the Human Connectome Project pipeline. Strength of resting state functional connectivity (RSFC) within two networks known to mediate the ‘Preoccupation go’ (PG) and ‘Preoccupation stop’ (PS) stages of addiction were calculated. T-tests were conducted to compare RSFC between subsequent abstainers and relapsers (after 4 months). Linear regressions were conducted to determine whether RSFC (of PG and PS networks) can predict time to relapse. Craving measures were included in the model. RESULTS/ANTICIPATED RESULTS: 19 AUD relapsed during the 4-month follow-up period. There were no RSFC group effects (subsequent abstainers and relapsers) in the PG or PS networks. Number of days to relapse could be predicted by PG RSFC (F(1,17)=14.90, p=0.001, r 2=0.47). Time to relapse increased by 13.19 days for each PG RSFC unit increase. Number of days to relapse could be predicted by PS RSFC (F(1,17)=9.39, p=0.002, r ²=0.36). Time to relapse increased by 12.94 days for each PS RSFC unit increase. After adding a self-report craving measure (i.e. Penn Alcohol Craving Scale) in the prediction model, both PG and PS RSFC still significantly predicted time to relapse. Craving metric did not predict time to relapse. DISCUSSION/SIGNIFICANCE OF FINDINGS: RSFC in preoccupation networks during short-term abstinence predicted time to relapse. These preliminary findings highlight promising targets for AUD neuromodulation interventions aimed to reduce relapse. Future larger scale studies that examine the effects of covariates and mediators are needed.
Clinical trials continue to face significant challenges in participant recruitment and retention. The Recruitment Innovation Center (RIC), part of the Trial Innovation Network (TIN), has been funded by the National Center for Advancing Translational Sciences of the National Institutes of Health to develop innovative strategies and technologies to enhance participant engagement in all stages of multicenter clinical trials. In collaboration with investigator teams and liaisons at Clinical and Translational Science Award institutions, the RIC is charged with the mission to design, field-test, and refine novel resources in the context of individual clinical trials. These innovations are disseminated via newsletters, publications, a virtual toolbox on the TIN website, and RIC-hosted collaboration webinars. The RIC has designed, implemented, and promised customized recruitment support for 173 studies across many diverse disease areas. This support has incorporated site feasibility assessments, community input sessions, recruitment materials recommendations, social media campaigns, and an array of study-specific suggestions. The RIC’s goal is to evaluate the efficacy of these resources and provide access to all investigating teams, so that more trials can be completed on time, within budget, with diverse participation, and with enough accrual to power statistical analyses and make substantive contributions to the advancement of healthcare.
Geographic range size and abundance are important determinants of extinction risk in fossil and extant taxa. However, the relationship between these variables and extinction risk has not been tested extensively during evolutionarily “quiescent” times of low extinction and speciation in the fossil record. Here we examine the influence of geographic range size and abundance on extinction risk during the late Paleozoic (Mississippian–Permian), a time of “sluggish” evolution when global rates of origination and extinction were roughly half those of other Paleozoic intervals. Analyses used spatiotemporal occurrences for 164 brachiopod species from the North American midcontinent. We found abundance to be a better predictor of extinction risk than measures of geographic range size. Moreover, species exhibited reductions in abundance before their extinction but did not display contractions in geographic range size. The weak relationship between geographic range size and extinction in this time and place may reflect the relative preponderance of larger-ranged taxa combined with the physiographic conditions of the region that allowed for easy habitat tracking that dampened both extinction and speciation. These conditions led to a prolonged period (19–25 Myr) during which standard macroevolutionary rules did not apply.
An intermediate-depth (1751 m) ice core was drilled at the South Pole between 2014 and 2016 using the newly designed US Intermediate Depth Drill. The South Pole ice core is the highest-resolution interior East Antarctic ice core record that extends into the glacial period. The methods used at the South Pole to handle and log the drilled ice, the procedures used to safely retrograde the ice back to the National Science Foundation Ice Core Facility (NSF-ICF), and the methods used to process and sample the ice at the NSF-ICF are described. The South Pole ice core exhibited minimal brittle ice, which was likely due to site characteristics and, to a lesser extent, to drill technology and core handling procedures.
The Expanded Program for Immunization Consortium – Human Immunology Project Consortium study aims to employ systems biology to identify and characterize vaccine-induced biomarkers that predict immunogenicity in newborns. Key to this effort is the establishment of the Data Management Core (DMC) to provide reliable data and bioinformatic infrastructure for centralized curation, storage, and analysis of multiple de-identified “omic” datasets. The DMC established a cloud-based architecture using Amazon Web Services to track, store, and share data according to National Institutes of Health standards. The DMC tracks biological samples during collection, shipping, and processing while capturing sample metadata and associated clinical data. Multi-omic datasets are stored in access-controlled Amazon Simple Storage Service (S3) for data security and file version control. All data undergo quality control processes at the generating site followed by DMC validation for quality assurance. The DMC maintains a controlled computing environment for data analysis and integration. Upon publication, the DMC deposits finalized datasets to public repositories. The DMC architecture provides resources and scientific expertise to accelerate translational discovery. Robust operations allow rapid sharing of results across the project team. Maintenance of data quality standards and public data deposition will further benefit the scientific community.
A cross-sectional survey study of inpatient prescribers in a university health system was performed to assess the importance they place on different clinical risk factors when making empiric antibiotic decisions. Our findings show that these clinical risk factors were weighted differently based on the clinical scenario and the type of prescriber.
No studies have investigated the associations between established plant-based diet indices and the metabolic syndrome (MetS). We evaluated the associations between an overall plant-based diet index (PDI), healthy PDI (hPDI), unhealthy PDI (uPDI) and the MetS in a nationally representative sample using data from 14 450 Korean adults (≥19 years) in the Korea National Health and Nutrition Examination Survey 2012–2016. Dietary intakes were assessed by a semi-quantitative FFQ. In the PDI, all plant foods received positive scores. In the hPDI, only healthy plant foods received positive scores. In the uPDI, only unhealthy plant foods received positive scores. All indices reverse scored animal food intake. Multivariable logistic regression models were used to examine the associations between three PDI and the MetS by sex, adjusting for potential risk factors. A total of 23·3 % of Korean adults had the MetS. In the overall study population, individuals in the highest quintile of uPDI had greater odds (OR 1·54, 95 % CI 1·28, 1·86, Ptrend < 0·001) of the MetS than those in the lowest quintile. Higher uPDI score was associated with higher odds of hypertriacylglycerolaemia in men and abdominal obesity, high fasting glucose and hypertriacylglycerolaemia in women. No significant associations were observed between PDI, hPDI and the MetS. Greater adherence to unhealthy plant-based diets was associated with greater odds of the MetS and its components suggesting the importance of the quality of plant-based diet in South Korean adults. Sex differences may be considered when recommending plant-based diets for the prevention and management of metabolic diseases.
To examine the predictors of suicidal ideation and self-harm in patients diagnosed with a depressive episode or an adjustment disorder, and to examine any difference in these predictors between the two diagnostic categories.
Patients referred to the liaison psychiatry services at two Dublin hospitals and diagnosed with either a depressive episode or an adjustment disorder were recruited to this study. They were interviewed at time of diagnosis, and again after six months, with a number of validated instruments to examine levels of suicidality or self-harm and their relationship to depressive symptoms, life events, social functioning and personality factors.
300 patients were recruited to the study, 154 of whom had a diagnosis of an adjustment disorder and the remainder diagnosed with a depressive episode. On univariate analysis there was no significant difference in the rates of suicidal ideation between the diagnoses of depressive episode and adjustment disorder. On logistic regression there were no significant predictors of suicidal ideation in adjustment disorder. A single marital status and low levels of social support were more predictive of suicidality in the subgroup with a diagnosis of depression.
There has been little prior research into the predictors of suicidal behaviour in patients with diagnoses of depression and adjustment disorders. Our finding that social support and marital status are protective against suicidality in this population is in keeping with the literature. The absence of any significant contribution of the severity of depressive symptoms to suicidality was unexpected.
Roughly half of the U.S. public thinks that torture can be acceptable in counterterrorism. According to recent research, dramatic depictions of torture increase public support for the practice. Yet we do not know how frequently—and in what context—torture is depicted across popular media. What messages about the acceptability and effectiveness of torture do Americans receive when they watch popular films? To address this question, we coded each incident of torture in the twenty top-grossing films each year from 2008 to 2017 to analyze how torture is portrayed in terms of its frequency, efficacy, and social acceptability. Results show that the majority of popular films—including films aimed toward children—have at least one torture scene. Across films, the messages sent about torture are fairly consistent. As expected, movies tend to depict torture as effective. Further, how movies portray torture is also a function of who is perpetrating it. Specifically, protagonists are more likely to torture for instrumental reasons or in response to threats and are more likely to do so effectively. In contrast, antagonists are more likely to use torture as punishment and to torture women. The frequency and nature of torture’s depiction in popular films may help explain why many in the public support torture in counterterrorism.
Vitamin B12 deficiency is common among older adults, even with dietary intakes well in excess of current recommendations. Severe clinical B12 deficiency (i.e. pernicious anaemia) leads to irreversible neurological damage, but once diagnosed, can be treated effectively with B12 injections. A much more common cause of low vitamin B12 status in older adults is food-bound malabsorption owing to atrophic gastritis. This in turn leads to reduced gastric acid secretion, thus limiting B12 absorption from food (given the essential role of gastric acid in releasing B12 from food proteins). Proton pump inhibitor (PPI) drugs reduce gastric acid secretion, similar to atrophic gastritis, thus there is a concern that these medications may lead to vitamin B12 malabsorption. Therefore, the aim of this study was to investigate biomarker status of vitamin B12 in relation to atrophic gastritis and PPI usage. Data were accessed from The Trinity Ulster Department of Agriculture (TUDA) Ageing Cohort Study, a cross-sectional study of community-dwelling adults (n 5186, ≥ 60 years) recruited across Northern Ireland and the Republic of Ireland (2008–2012). TUDA participants were classified into 3 groups; ‘healthy’ controls, atrophic gastritis and PPI users. Vitamin B12 status was assessed using a total of four biomarkers: serum total B12; serum holotranscobalamin, holoTC; plasma methylmalonic acid, MMA; plasma homocysteine. Atrophic gastritis was identified using pepsinogen analysis (via ELISA), with a pepsinogen I : II ratio of < 3 considered indicative of atrophic gastritis. Based on results from all four biomarkers, participants with atrophic gastritis were found to have significantly lower B12 status compared to healthy controls: e.g. mean (95% CI) serum total vitamin B12, 188 (156, 218) pmol/L vs. 262 (252, 272) pmol/L P < 0.001; holoTC, 46.0 (38.1, 53.8) pmol/L vs. 60.3 (57.8, 62.8) pmol/L P < 0.001; plasma MMA, 0.65 (0.52, 0.78) μmol/L vs. 0.37 (0.32, 0.42) μmol/L P = 0.001. No differences in B12 biomarker concentrations were observed between PPI users and healthy controls. Regular consumption of fortified foods (i.e. ≥ 5 portions per week) compared to non-regular consumption (i.e. 0–4 portions per week) impacted positively on B12 biomarker status in all participants. This effect however appeared insufficient to restore normal vitamin B12 status in those with atrophic gastritis. These results show that older adults with atrophic gastritis have significantly lower vitamin B12 biomarker status, particularly in those who did not regularly consume fortified foods. Further investigations of the effect of atrophic gastritis and PPI usage on B12 status are warranted.
The fluid–structure interactions (FSI) of compliant lifting surfaces is complicated by free-surface and multiphase flows such as cavitation and ventilation. This paper describes the dynamic FSI response of a flexible surface-piercing hydrofoil in dry, wetted, ventilating and cavitating conditions. Experimental modal analysis is used to quantify the resonant frequencies and damping ratios of the fluid–structure system in each flow regime. The generalized hydrodynamic stiffness, fluid damping and fluid added mass are also determined as ratios to the corresponding structural modal forces. Added mass increases with increasing partial immersion of the hydrofoil and decreases in the presence of gaseous cavities. In particular, modal frequencies were observed to increase significantly in fully ventilated flow compared to fully wetted flow. The modal frequencies varied non-monotonically with speed in fully wetted flow. Gaseous cavities reduced the modal added mass and reduced the fluid disturbing force. Modal damping increases non-monotonically with increasing immersion depth. Forward speed causes the fluid damping force to increase with an approximately quadratic functional behaviour, consistent with a series expansion of the Morison equation, although damping identification became increasingly difficult at high flow speeds. The results indicate that fluid damping is greater than the associated structural damping in a quiescent liquid, and increasingly so with increasing immersion, suggesting viscous dissipation as a dominant mechanism. A preliminary investigation of modal vibration as a means of controlling the size and stability of ventilated cavities indicates that low-order modes encourage the formation of ventilation, while higher-order modes encourage the washout and elimination of ventilation.
Compliant lift-generating surfaces have widespread applications as marine propellers, hydrofoils and control surfaces, and the fluid–structure interactions (FSI) of such systems have important effects upon their performance and stability. Multi-phase flows like cavitation and ventilation alter the hydrodynamic and hydroelastic behaviours of lifting surfaces in ways that are not yet completely understood. This paper describes experiments on one rigid and two flexible variants of a vertical surface-piercing hydrofoil in wetted, ventilating and cavitating conditions. Tests were conducted in a towing tank and a free-surface cavitation channel. This work, which is Part 1 of a two-part series, examines the passive, or flow-induced, fluid–structure interactions of the hydrofoils. Four characteristic flow regimes are described: fully wetted, partially ventilated, partially cavitating and fully ventilated. Hydroelastic coupling is shown to increase the hydrodynamic lift and yawing moments across all four flow regimes by augmenting the effective angle of attack. The effective angle of attack, which was derived using a beam model to account for the effect of spanwise twisting deflections, effectively collapses the hydrodynamic load coefficients for the three hydrofoils. A generalized cavitation parameter, using the effective angle of attack, is used to collapse the lift and moment coefficients for all trials at a single immersed aspect ratio, smoothly bridging the four distinct flow regimes. None of the hydrofoils approached the static divergence condition, which occurs when the hydrodynamic stiffness negates the structural stiffness, but theory and experiments both show that ventilation increases the divergence speed by reducing the hydrodynamic twisting moment about the elastic axis. Coherent vortex shedding from the blunt trailing edge of the hydrofoil causes vortex-induced vibration at an approximately constant Strouhal number of 0.275 (based on the trailing edge thickness), and leads to amplified response at lock-in, when the vortex-shedding frequency approaches one of the resonant modal frequencies of the coupled fluid–structure system.
The objective of this study was to assess the prospective association between diet quality, as well as a 6-year change in diet quality, and risk of incident CVD and diabetes in a community-based population.
We used Cox regression models to estimate the prospective association between diet quality, assessed using the Healthy Eating Index (HEI)-2015 and the Alternative HEI (AHEI)-2010 scores, as well as change in diet quality, and incident CVD and diabetes.
The ARIC Study recruited 15 792 black and white men and women (45–64 years) from four US communities.
We included 10 808 study participants who reported usual dietary intake via FFQ at visit 1 (1987–1989) and who had not developed CVD, diabetes, or cancer at baseline.
Overall, 3070 participants developed CVD (median follow-up of 26 years) and 3452 developed diabetes (median follow-up of 22 years) after visit 1. Higher diet score at the initial visit was associated with a significantly lower risk of CVD (HR per 10 % higher HEI-2015 diet quality score: 0·90 (95 % CI: 0·86, 0·95) and HR per 10 % higher AHEI-2010 diet quality score: 0·96 (95 % CI: 0·93, 0·99)). We did not observe a significant association between initial diet score and incident diabetes. There were no significant associations between change in diet score and CVD or diabetes risk in the overall study population.
Higher diet quality assessed using HEI-2015 and AHEI-2010 was strongly associated with lower CVD risk but not diabetes risk within a middle-aged, community-based US population.