Resistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due ...to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients.
Background:
Patient-reported outcomes (PROs) are considered the gold standard when evaluating outcomes in a surgical population. While the psychometric properties of some PROs have been tested, the ...properties of newer PROs in patients undergoing hip arthroscopic surgery remain somewhat unknown.
Purpose:
To evaluate the reliability, validity, responsiveness, and interpretability of 5 PROs (Copenhagen Hip and Groin Outcome Score HAGOS, Hip Disability and Osteoarthritis Outcome Score HOOS, Hip Outcome Score HOS, International Hip Outcome Tool iHOT-33, and Modified Harris Hip Score MHHS) in a population undergoing hip arthroscopic surgery and also to provide a recommendation of the best PROs in patients undergoing hip arthroscopic surgery.
Study Design:
Cohort study (diagnosis); Level of evidence, 2.
Methods:
Study participants were adults (mean age, 37 ± 11 years) who had undergone hip arthroscopic surgery 12 to 24 months previously and pain-free, healthy age-matched controls (mean age, 35 ± 11 years). Baseline characteristics including age, height, weight, waist girth, physical activity, and occupation were collected for both groups. The hip arthroscopic surgery group completed the 5 PRO questionnaires on 3 occasions, while the healthy control group completed the PRO questionnaires on 1 occasion. The reliability (test-retest reliability intraclass correlation coefficient, or ICC and minimal detectable change MDC), validity (construct validity, ability to detect a difference between groups, acceptability including floor and ceiling effects), responsiveness, and interpretability (minimal important change MIC) of each measure were calculated.
Results:
The test-retest reliability of PROs was excellent (ICC, 0.91-0.97), with an MDC of <20%. The HOOS, HAGOS, and iHOT-33 had acceptable content validity. All PROs demonstrated construct validity and were able to detect a difference between the hip arthroscopic surgery and control groups. No measures demonstrated a floor effect; however, the MHHS and subscales relating to activities of daily living of the HOOS, HOS, and HAGOS demonstrated a ceiling effect. The HOOS, iHOT-33, and MHHS demonstrated adequate responsiveness, and the MIC for all measures was <11 points of a possible 100 points.
Conclusion:
The PROs of the HOOS and iHOT-33 demonstrate psychometric properties that may enable researchers and clinicians to use them with confidence in a population undergoing hip arthroscopic surgery. The psychometric properties of the MHHS, HOS, and some subscales of the HAGOS are reduced, and these PROs may be less valuable in this group.
The complexity of morphogenesis poses a fundamental challenge to understanding the mechanisms governing the formation of biological patterns and structures. Over the past century, numerous processes ...have been identified as critically contributing to morphogenetic events, but the interplay between the various components and aspects of pattern formation have been much harder to grasp. The combination of traditional biology with mathematical and computational methods has had a profound effect on our current understanding of morphogenesis and led to significant insights and advancements in the field. In particular, the theoretical concepts of reaction-diffusion systems and positional information, proposed by Alan Turing and Lewis Wolpert, respectively, dramatically influenced our general view of morphogenesis, although typically in isolation from one another. In recent years, agent-based modeling has been emerging as a consolidation and implementation of the two theories within a single framework. Agent-based models (ABMs) are unique in their ability to integrate combinations of heterogeneous processes and investigate their respective dynamics, especially in the context of spatial phenomena. In this review, we highlight the benefits and technical challenges associated with ABMs as tools for examining morphogenetic events. These models display unparalleled flexibility for studying various morphogenetic phenomena at multiple levels and have the important advantage of informing future experimental work, including the targeted engineering of tissues and organs.
The public health response to the current Coronavirus pandemic in long-term care communities, including assisted living, encompasses prohibiting visitors. This ban, which includes family members, has ...been criticized for being unfair, unhealthy, and unsafe. Against this backdrop, I examine the roles family play in residents' daily lives and care routines. I argue that classifying family as "visitors" rather than essential care partners overlooks their critical contributions and stems from taken-for-granted assumption about gender, families, and care work, and I demonstrate why families are more than visitors. Policies that ban family visits also reflect a narrow understanding of health that focuses on mitigating infection risk, but neglects overall health and well-being. This policy further stems from a limited comprehension of care relations. Research shows that banning family visits has negative consequences for residents, but also families themselves, and direct care workers. I argue that identifying ways to better understand and support family involvement is essential and demonstrate the utility of the Convoys of Care model for guiding the reconceptualization of family in long-term care research, policy, and practice during and beyond the pandemic.
The initiation of heterogeneity within a population of phenotypically identical progenitors is a critical event for the onset of morphogenesis and differentiation patterning. Gap junction ...communication within multicellular systems produces complex networks of intercellular connectivity that result in heterogeneous distributions of intracellular signaling molecules. In this study, we investigate emergent systems-level behavior of the intercellular network within embryonic stem cell (ESC) populations and corresponding spatial organization during early neural differentiation. An agent-based model incorporates experimentally-determined parameters to yield complex transport networks for delivery of pro-differentiation cues between neighboring cells, reproducing the morphogenic trajectories during retinoic acid-accelerated mouse ESC differentiation. Furthermore, the model correctly predicts the delayed differentiation and preserved spatial features of the morphogenic trajectory that occurs in response to intercellular perturbation. These findings suggest an integral role of gap junction communication in the temporal coordination of emergent patterning during early differentiation and neural commitment of pluripotent stem cells.
Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
Fake news exposure can negatively affect memory and beliefs, thus sparking debate about whether to repeat misinformation during corrections. The once-prevailing view was that repeating misinformation ...increases its believability and should thus be avoided. However, misinformation reminders have more recently been shown to enhance memory and belief accuracy. We replicated such reminder benefits in two experiments using news headlines and compared those benefits against the effects of veracity labeling. Specifically, we examined the effects of labeling real news corrections to enhance conflict salience (Experiment 1) and labeling fake news on its debut to encourage intentional forgetting (Experiment 2). Participants first viewed real and fake news headlines with some fake news labeled as false. Participants then saw labeled and unlabeled real news corrections; labeled corrections appeared alone or after fake news reminders. Reminders promoted the best memory and belief accuracy, whereas veracity labels had selective effects. Correction labels led to intermediate memory and belief accuracy, whereas fake news labels improved accuracy for beliefs more than memory. The extent that real and fake news details were recalled together correlated with overall memory and belief differences across conditions, implicating a critical role for integrative encoding that was promoted most by fake news reminders.
Hydrogen peroxide is appreciated as a cellular signaling molecule with second-messenger properties, yet the mechanisms by which the cell protects against intracellular H(2)O(2) accumulation are not ...fully understood. We introduce a network model of H(2)O(2) clearance that includes the pseudo-enzymatic oxidative turnover of protein thiols, the enzymatic actions of catalase, glutathione peroxidase, peroxiredoxin, and glutaredoxin, and the redox reactions of thioredoxin and glutathione. Simulations reproduced experimental observations of the rapid and transient oxidation of glutathione and the rapid, sustained oxidation of thioredoxin on exposure to extracellular H(2)O(2). The model correctly predicted early oxidation profiles for the glutathione and thioredoxin redox couples across a range of initial extracellular H(2)O(2) and highlights the importance of cytoplasmic membrane permeability to the cellular defense against exogenous sources of H(2)O(2). The protein oxidation profile predicted by the model suggests that approximately 10% of intracellular protein thiols react with hydrogen peroxide at substantial rates, with a majority of these proteins forming protein disulfides as opposed to protein S-glutathionylated adducts. A steady-state flux analysis predicted an unequal distribution of the intracellular anti-oxidative burden between thioredoxin-dependent and glutathione-dependent antioxidant pathways, with the former contributing the majority of the cellular antioxidant defense due to peroxiredoxins and protein disulfides.
Background
Phenylbutazone is often prescribed to manage pain caused by hyperinsulinemia‐associated laminitis, but in diabetic people nonsteroidal anti‐inflammatory drugs increase insulin secretion ...and pancreatic activity.
Hypothesis/Objectives
Investigate the effect of phenylbutazone administration on insulin secretion in horses. It was hypothesized that phenylbutazone will increase insulin secretion in horses with insulin dysregulation (ID).
Animals
Sixteen light breed horses, including 7 with ID.
Methods
Randomized cross‐over study design. Horses underwent an oral glucose test (OGT) after 9 days of treatment with phenylbutazone (4.4 mg/kg IV q24h) or placebo (5 mL 0.9% saline). After a 10‐day washout period, horses received the alternative treatment, and a second OGT was performed. Insulin and glucose responses were compared between groups (ID or controls) and treatments using paired t test and analyses of variance with P < .05 considered significant.
Results
In horses with ID, phenylbutazone treatment significantly decreased glucose concentration (P = .02), glucose area under the curve (2429 ± 501.5 vs 2847 ± 486.1 mmol/L × min, P = .02), insulin concentration (P = .03) and insulin area under the curve (17 710 ± 6676 vs 22 930 ± 8788 μIU/mL × min, P = .03) in response to an OGT. No significant effect was detected in control horses.
Conclusion and Clinical Importance
Phenylbutazone administration in horses with ID decreases glucose and insulin concentrations in response to an OGT warranting further investigation of a therapeutic potential of phenylbutazone in the management of hyperinsulinemia‐associated laminitis beyond analgesia.
While microscopy-based cellular assays, including microfluidics, have significantly advanced over the last several decades, there has not been concurrent development of widely-accessible techniques ...to analyze time-dependent microscopy data incorporating phenomena such as fluid flow and dynamic cell adhesion. As such, experimentalists typically rely on error-prone and time-consuming manual analysis, resulting in lost resolution and missed opportunities for innovative metrics. We present a user-adaptable toolkit packaged into the open-source, standalone Interactive Cellular assay Labeled Observation and Tracking Software (iCLOTS). We benchmark cell adhesion, single-cell tracking, velocity profile, and multiscale microfluidic-centric applications with blood samples, the prototypical biofluid specimen. Moreover, machine learning algorithms characterize previously imperceptible data groupings from numerical outputs. Free to download/use, iCLOTS addresses a need for a field stymied by a lack of analytical tools for innovative, physiologically-relevant assays of any design, democratizing use of well-validated algorithms for all end-user biomedical researchers who would benefit from advanced computational methods.
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