Multiple-period parallel group randomized trials (GRTs) analyzed with linear mixed models can represent time in mean models as continuous or categorical. If time is continuous, random effects are ...traditionally group- and member-level deviations from condition-specific slopes and intercepts and are referred to as random coefficients (RC) analytic models. If time is categorical, random effects are traditionally group- and member-level deviations from time-specific condition means and are referred to as repeated measures ANOVA (RM-ANOVA) analytic models. Longstanding guidance recommends the use of RC over RM-ANOVA for parallel GRTs with more than two periods because RC exhibited nominal type I error rates for both time parameterizations while RM-ANOVA exhibited inflated type I error rates when applied to data generated using the RC model. However, this recommendation was developed assuming a variance components covariance matrix for the RM-ANOVA, using only cross-sectional data, and explicitly modeling time × group variation. Left unanswered were how well RM-ANOVA with an unstructured covariance would perform on data generated according to the RC mechanism, if similar patterns would be observed in cohort data, and the impact of not modeling time × group variation if such variation was present in the data-generating model.
Continuous outcomes for cohort and cross-sectional parallel GRT data were simulated according to RM-ANOVA and RC mechanisms at five total time periods. All simulations assumed time × group variation. We varied the number of groups, group size, and intra-cluster correlation. Analytic models using RC, RM-ANOVA, RM-ANOVA with unstructured covariance, and a Saturated random effects structure were applied to the data. All analytic models specified time × group random effects. The analytic models were then reapplied without specifying random effects for time × group.
Results indicated the RC and saturated analytic models maintained the nominal type I error rate in all data sets, RM-ANOVA with an unstructured covariance did not avoid type I error rate inflation when applied to cohort RC data, and analytic models omitting time-varying group random effects when such variation exists in the data were prone to substantial type I error inflation unless the residual error variance is high relative to the time × group variance.
The time × group RC and saturated analytic models are recommended as the default for multiple period parallel GRTs.
The US Navy is developing a new suite of computational mechanics tools (Navy Enhanced Sierra Mechanics) for the prediction of ship response, damage, and shock environments transmitted to vital ...systems during threat weapon encounters. NESM includes fully coupled Euler-Lagrange solvers tailored to ship shock/damage predictions. NESM is optimized to support high-performance computing architectures, providing the physics-based ship response/threat weapon damage predictions needed to support the design and assessment of highly survivable ships. NESM is being employed to support current Navy ship design and acquisition programs while being further developed for future Navy fleet needs.
This patient seems to be a good candidate for treatment with an alarm, and he will be at least 13 times more likely to become dry if treated than if not treated. He has a good chance of remaining dry ...in the long term, but the treatment will require considerable effort and persistence.
Food Fraud can be an extremely profitable act even considering the capital investment of executing a complex and technologically challenging activity. This research was conducted to increase ...awareness of the economic motivation of Food Fraud through case studies that include commodity and finished goods pricing. The research objective was to establish a firm understanding of the economic drivers of Food Fraud. Examples provide insight on the macro- and micro-economic influences on the fraud opportunity. Specific case studies include: the Fraud Opportunity per One Shipment, Horsemeat in Beef, Selling Salmonella Contaminated Peanuts, Melamine in Wheat Gluten. An ingredient level review of a hypothetical food fraud example is also presented. Findings confirm that a single shipment of fraudulent food can result in tens of thousands of dollars in illegal profit. While the economic gain of a food fraud can be calculated based on an ingredient-level evaluation, the full economic impact of a food fraud incident is often incalculable.
•A single shipment of fraudulent food can result in tens of thousands of dollars in illegal profit.•The economic gain of a food fraud can be calculated but the full economic impact is often incalculable.•Factors influencing food fraud opportunities include both macro- and micro-economic influences.•Pennies worth of an adulterant-substance ingredient can produce thousands of dollars in profits.
The epidermal growth factor receptor (EGFR) is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. CP-358,774 is a directly acting inhibitor of human ...EGFR tyrosine kinase with an IC50 of 2 nM and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 nM. This inhibition is selective for EGFR tyrosine kinase relative to other tyrosine kinases we have examined, both in assays of isolated kinases and whole cells. At doses of 100 mg/kg, CP-358,774 completely prevents EGF-induced autophosphorylation of EGFR in human HN5 tumors growing as xenografts in athymic mice and of the hepatic EGFR of the treated mice. CP-358,774 inhibits the proliferation of DiFi human colon tumor cells at submicromolar concentrations in cell culture and blocks cell cycle progression at the G1 phase. This inhibitor produces a marked accumulation of retinoblastoma protein in its underphosphorylated form and accumulation of p27KIP1 in DiFi cells, which may contribute to the cell cycle block. Inhibition of the EGFR also triggers apoptosis in these cells as determined by formation of DNA fragments and other criteria. These results indicate that CP-358,774 has potential for the treatment of tumors that are dependent on the EGFR pathway for proliferation or survival.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for ...additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
Ce-bastnäsite is the single largest mineral source for light rare-earth elements. In view of the growing industrial importance of rare-earth minerals, it is critical to develop more efficient ...methods for separating the valuable rare-earth-containing minerals from the surrounding gangue. In this work, we employ a combination of periodic density functional theory (DFT) and molecular mechanics (MM) calculations together with the de novo molecular design program HostDesigner to identify bis-phosphinate ligands that preferentially bind to the (100) Ce-bastnäsite surface rather than the (104) calcite surface. DFT calculations for a simple phosphinate ligand were employed to qualitatively understand key behaviors involved in ligand–metal, ligand–solvent, and solvent–metal interactions. These insights were then used to guide the search for flexible, rigid, and semirigid hydrocarbon linkers to identify candidate bis-phosphinate ligands with the potential to bind preferentially to Ce-bastnäsite. Among the five most promising bis-phosphinate ligands suggested by theoretical studies, three ligands were synthesized and their adsorption characteristics to bastnäsite (100) interfaces were characterized using vibrational sum-frequency (vSFG) spectroscopy, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, and isothermal titration calorimetry (ITC). The efficacy of the selective interfacial molecular binding was demonstrated by identifying a bis-phosphinate ligand capable of providing an overall higher surface coverage of alkyl groups relative to a monophosphinate ligand. The results highlight the interplay between adsorption binding strength and maximum surface coverage in determining ligand efficiency to render the mineral surface hydrophobic. DFT calculations further indicate that all tested ligands have higher affinity for Ce-bastnäsite than for calcite. This is consistent with the ITC data showing stronger adsorption enthalpy to bastnäsite than to calcite, making these ligands promising candidates for selective flotation of Ce-bastnäsite.
Endophthalmitis is an infection of the posterior segment of the eye that frequently results in loss of vision. This devastating result occurs despite prompt and often aggressive therapeutic and ...surgical intervention. Over the past decade, research has centered on determining the bacterial and host factors involved in this potentially blinding disease. The initial focus on the bacterial factors responsible for intraocular virulence has recently expanded into analysis the inflammatory response to infection, including the molecular and cellular interactions between the pathogen and host. This review discusses the epidemiology and therapeutic challenges posed by endophthalmitis, as well as recent findings from the analysis of interactions between the host and pathogen. Based on these findings, a model for the pathogenesis of endophthalmitis is presented. A more comprehensive understanding of the molecular and cellular interactions taking place between pathogen and host during endophthalmitis will expose possible therapeutic targets designed to arrest the infection and prevent vision loss.
Background
Bypassing the emergency department and the computed tomography suite by directly transporting to the neuroangiography suite for imaging assessment and treatment may shorten reperfusion ...times while maintaining proper patient selection.
Objective
To determine whether flat-panel detector multiphase computed tomography angiography protocol is associated with reduced treatment times and a similar safety profile as the standard imaging protocol.
Methods
Single-center prospective study of consecutive patients with anterior circulation large vessel occlusion strokes transferred to our facility for consideration of endovascular therapy from May 2016 to December 2017. Those with basilar strokes and/or presenting to the emergency department were excluded. Patients were categorized into two groups: (1) flat-panel detector CT assessment in stroke to reduce times to intra-arterial treatment group, with patients transferred directly to the suite for multiphase computed tomography angiography; and (2) patients undergoing standard protocol including computed tomography ± computed tomography angiography/CT perfusion. The groups were matched for age, baseline National Institute of Health Stroke Scale, and pretreatment glucose. Baseline characteristics, time metrics, and outcomes were compared.
Results
Out of 419 patients who underwent endovascular therapy over the study period, 210 patients fit inclusion criteria, with 54 (25.7%) in the flat-panel detector CT assessment in stroke to reduce times to intra-arterial treatment group. After matching, 49 flat-panel detector CT assessment in stroke to reduce times to intra-arterial treatment/control pairs were generated and analyzed. Baseline characteristics were well balanced. Flat-panel detector CT assessment in stroke to reduce times to intra-arterial treatment patients had significantly shorter median door-to-puncture (33 26.5-47 vs. 55 44.5–66 min, p < 0.001), door-to-reperfusion (85 57.5–115.5 vs. 110 80–153, p = 0.005) and picture-to-puncture (18 13.5–22.5 vs. 42 32–47.5 min, p < 0.001) times. There were no differences in rates of successful reperfusion (modified thrombolysis in cerebral infarction 2b-3, 95.9% vs. 100%, p = 0.5), parenchymal hematomas type-2 (4.1% vs. 2%, p = 1.00), good outcome (90-day modified Rankin Scale 0–2, 44.9% vs. 40.8%, p = 0.68), and 90-day mortality (14.3% vs. 22.4%, p = 0.30).
Conclusion
Directly transferring patients to angiography and using multiphase computed tomography angiography to determine the eligibility for endovascular therapy is safe and may result in a significant reduction in treatment times. Future larger studies are warranted.
Loss of smell is an early and common presentation of COVID-19 infection. Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral ...infection causes injuries in the olfactory bulb region.
To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study.
This multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021.
(1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue.
Olfactory tissue from 23 deceased patients with COVID-19 (median IQR age, 62 49-69 years; 14 men 60.9%) and 14 control individuals (median IQR age, 53.5 33.25-65 years; 7 men 50%) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with COVID-19 and 1.198 (0.208) in controls (P < .001), whereas axon density was 2.973 (0.963) × 104/mm2 in patients with COVID-19 and 3.867 (0.670) × 104/mm2 in controls (P = .002). Concomitant endothelial injury of the microvasculature was also noted in olfactory tissue. The mean (SD) microvasculopathy score (range, 1-3) was 1.907 (0.490) in patients with COVID-19 and 1.405 (0.233) in control individuals (P < .001). Both the axon and microvascular pathology was worse in patients with COVID-19 with smell alterations than those with intact smell (mean SD axon pathology score, 2.260 0.457 vs 1.63 0.426; P = .002; mean SD microvasculopathy score, 2.154 0.528 vs 1.694 0.329; P = .02) but was not associated with clinical severity, timing of infection, or presence of virus.
This study found that COVID-19 infection is associated with axon injuries and microvasculopathy in olfactory tissue. The striking axonal pathology in some cases indicates that olfactory dysfunction in COVID-19 infection may be severe and permanent.
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