Predictions from standard epidemiological models of consequences of segregating and isolating vulnerable people into care facilities.

OBJECTIVES: Since the declaration of the COVID-19 pandemic, many governments have imposed policies to reduce contacts between people who are presumed to be particularly vulnerable to dying from respiratory illnesses and the rest of the population. These policies typically address vulnerable individuals concentrated in centralized care facilities and entail limiting social contacts with visitors, staff members, and other care home residents. We use a standard epidemiological model to investigate the impact of such circumstances on the predicted infectious disease attack rates, for interacting robust and vulnerable populations. METHODS: We implement a general susceptible-infectious-recovered (SIR) compartmental model with two populations: robust and vulnerable. The key model parameters are the per-individual frequencies of within-group (robust-robust and vulnerable-vulnerable) and between-group (robust-vulnerable and vulnerable-robust) infectious-susceptible contacts and the recovery times of individuals in the two groups, which can be significantly longer for vulnerable people. RESULTS: Across a large range of possible model parameters including degrees of segregation versus intermingling of vulnerable and robust individuals, we find that concentrating the most vulnerable into centralized care facilities virtually always increases the infectious disease attack rate in the vulnerable group, without significant benefit to the robust group. CONCLUSIONS: Isolated care homes of vulnerable residents are predicted to be the worst possible mixing circumstances for reducing harm in epidemic or pandemic conditions.

Viral Respiratory Epidemic Modeling of Societal Segregation Based on Vaccination Status.

BACKGROUND: Societal segregation of unvaccinated people from public spaces has been a novel and controversial coronavirus disease 2019 (COVID-19)-era public health practice in many countries. Models exploring potential consequences of vaccination-status-based segregation have not considered how segregation influences the contact frequencies in the segregated groups. We systematically investigate implementing effects of segregation on population-specific contact frequencies and show this critically determines the predicted epidemiological outcomes, focusing on the attack rates in the vaccinated and unvaccinated populations and the share of infections among vaccinated people that were due to contacts with infectious unvaccinated people. METHODS: We describe a susceptible-infectious-recovered (SIR) two-population model for vaccinated and unvaccinated groups of individuals that transmit an infectious disease by person-to-person contact. The degree of segregation of the two groups, ranging from zero to complete segregation, is implemented using the like-to-like mixing approach developed for sexually transmitted diseases, adapted for presumed severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) transmission. We allow the contact frequencies for individuals in the two groups to be different and depend, with variable strength, on the degree of segregation. RESULTS: Segregation can either increase or decrease the attack rate among the vaccinated, depending on the type of segregation (isolating or compounding), and the contagiousness of the disease. For diseases with low contagiousness, segregation can cause an attack rate in the vaccinated, which does not occur without segregation. INTERPRETATION: There is no predicted blanket epidemiological advantage to segregation, either for the vaccinated or the unvaccinated. Negative epidemiological consequences can occur for both groups.

Production of large, defined genome modifications in rats by targeting rat embryonic stem cells.

Rats were more frequently used than mice to model human disease before mouse embryonic stem cells (mESCs) revolutionized genetic engineering in mice. Rat ESCs (rESCs) were first reported over 10 years ago, yet they are not as frequently used as mESCs. CRISPR-based gene editing in zygotes is widely used in rats but is limited by the difficulty of inserting or replacing DNA sequences larger than about 10 kb. We report here the generation of germline-competent rESC lines from several rat strains. These rESC lines maintain their potential for germline transmission after serial targeting with bacterial artificial chromosome (BAC)-based targeting vectors, and CRISPR-Cas9 cutting can increase targeting efficiency. Using these methods, we have successfully replaced entire rat genes spanning up to 101 kb with the human ortholog.

Adversity, Emotional Arousal, and Problem Behaviour in Adolescence: The Role of Non-Verbal Cognitive Ability as a Resilience Promoting Factor.

BACKGROUND: To test whether emotional arousal mediates the moderator effect of non-verbal cognitive ability on the association between cumulative contextual risk (number of proximal and distal adverse life events) and adolescent problem behaviour. METHOD: Data from a UK community sample of secondary school aged children were used. The study sample comprised 207 children with a mean age of 13.44 years (SD = 1.45). Problem behaviour was assessed with the Strengths and Difficulties Questionnaire, non-verbal cognitive ability was assessed with Raven's Standard Progressive Matrices Plus, and emotional arousal was measured with the Acting Out Emotions Scale of the Emotion Awareness Questionnaire. Adjustment was made for gender, age, family structure, and socio-economic disadvantage. RESULTS: Non-verbal cognitive ability moderated the effect of cumulative contextual risk on overall problem behaviour, and emotional arousal mediated this moderator effect. That is, risk predicted emotional arousal, which predicted overall problem behaviour, but emotional arousal was more strongly related to overall problem behaviour among children of low non-verbal cognitive ability than among children of high non-verbal cognitive ability. CONCLUSIONS: These findings are important for both theory development and intervention design. They advance theory because they suggest that non-verbal cognitive ability buffers the effect of risk on overall problem behaviour by strengthening control over emotions. They have implications for intervention design because they suggest that interventions carried out to enhance children's emotion regulation skills in the presence of multiple adversity might be more effective if they target children who score low on non-verbal cognitive ability.

Mouse fibroblast cell adhesion studied by neutron reflectometry.

Neutron reflectometry (NR) was used to examine live mouse fibroblast cells adherent on a quartz substrate in a deuterated phosphate-buffered saline environment at room temperature. These measurements represent the first, to our knowledge, successful visualization and quantization of the interface between live cells and a substrate with subnanometer resolution using NR. NR data, attributable to the adhesion of live cells, were observed and compared with data from pure growth medium. Independently of surface cell density, the average distance between the center of the cell membrane region and the quartz substrate was determined to be approximately 180 A. The membrane region ( approximately 80 A thick) contains the membranes of cells that are inhomogeneously distributed or undulating, likely conforming to the nonplanar geometry of the supporting adherence proteins. A second region of cell membranes at a greater distance from the substrate was not detectable by NR due to the resolution limits of the technique employed. Attachment of the live cell samples was confirmed by interaction with both distilled water and trypsin. Distinct changes in the NR data after exposure indicate the removal of cells from the substrate.

F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analyses.

A useful approach for exploring gene function involves generating mutant mice from genetically modified embryonic stem (ES) cells. Recent advances in genetic engineering of ES cells have shifted the bottleneck in this process to the generation of mice. Conventional injections of ES cells into blastocyst hosts produce F0 generation chimeras that are only partially derived from ES cells, requiring additional breeding to obtain mutant mice that can be phenotyped. The tetraploid complementation approach directly yields mice that are almost entirely derived from ES cells, but it is inefficient, works only with certain hybrid ES cell lines and suffers from nonspecific lethality and abnormalities, complicating phenotypic analyses. Here we show that laser-assisted injection of either inbred or hybrid ES cells into eight cell-stage embryos efficiently yields F0 generation mice that are fully ES cell-derived and healthy, exhibit 100% germline transmission and allow immediate phenotypic analysis, greatly accelerating gene function assignment.

An initial investigation of serum cytokine levels in patients with gadolinium retention.

OBJECTIVE: To determine whether individuals with proposed gadolinium deposition disease (GDD) have elevated serum levels of pro-inflammatory and pro-fibrotic cytokines, and whether specific cytokines are correlated with certain symptoms. MATERIALS AND METHODS: Twenty-four participants recruited between May 2016 and June 2017 met GDD diagnostic criteria. The 64 control subjects provided serum samples before prophylactic flu vaccination. Serum cytokine levels were obtained with Luminex serum cytokine assay using eBiosciences/Affymetrix human 62-plex kits. Wilcoxon rank-sum tests were performed to assess the difference between the median fluorescence intensity values for the participants and the control group. Generalized linear models were built to evaluate the association between each cytokine of interest and selected participant symptoms. RESULTS: Serum levels of 14 cytokines, including nine pro-inflammatory cytokines, were statistically significantly elevated compared to controls (p ≤ 0.05). Hypotheses regarding pro-fibrotic cytokines and cytokine links to specific symptoms' intensity were not confirmed. CONCLUSION: The statistically significantly elevated cytokines may be markers of susceptibility to GDD or agents of symptom induction. These findings suggest that individuals developing symptoms characteristic of GDD after a contrast-assisted magnetic resonance imaging should be studied to investigate whether gadolinium retention and elevated cytokines may be related to their symptoms.

OBJETIVO: Determinar se indivíduos com doença de deposição de gadolínio (DDG) apresentam níveis séricos elevados de citocinas pró-inflamatórias e pró-fibróticas e se citocinas específicas estão correlacionadas com determinados sintomas. MATERIAIS E MÉTODOS: Vinte e quatro participantes recrutados entre maio/2016 e junho/2017 cumpriram os critérios de diagnóstico de DDG. Amostras de soro de 64 indivíduos controles foram obtidas antes de vacinação profilática contra a gripe. Os níveis de citocinas séricas foram mensurados com o ensaio Luminex usando kits 62-plex humanos. Foram realizados testes de Wilcoxon para avaliar a diferença dos valores médios de intensidade de fluorescência entre os participantes e o grupo controle. Foram construídos modelos lineares generalizados para avaliar a associação entre cada citocina de interesse e os sintomas dos participantes selecionados. RESULTADOS: Níveis séricos de 14 citocinas, incluindo 9 citocinas pró-inflamatórias, foram estatisticamente significantes em comparação aos controles (p ≤ 0,05). Hipóteses sobre as citocinas pró-fibróticas e associação das citocinas com a intensidade de sintomas específicos não foram confirmadas. CONCLUSÃO: Citocinas estatisticamente elevadas podem ser marcadores de suscetibilidade para DDG ou agentes de indução de sintomas. Esses achados sugerem que indivíduos que desenvolvem sintomas da DDG após ressonância magnética com contraste devem ser estudados para investigar se a retenção de gadolínio e citocinas elevadas podem estar relacionadas aos seus sintomas.

Self-organization and time-stability of social hierarchies.

The formation and stability of social hierarchies is a question of general relevance. Here, we propose a simple generalized theoretical model for establishing social hierarchy via pair-wise interactions between individuals and investigate its stability. In each interaction or fight, the probability of "winning" depends solely on the relative societal status of the participants, and the winner has a gain of status whereas there is an equal loss to the loser. The interactions are characterized by two parameters. The first parameter represents how much can be lost, and the second parameter represents the degree to which even a small difference of status can guarantee a win for the higher-status individual. Depending on the parameters, the resulting status distributions reach either a continuous unimodal form or lead to a totalitarian end state with one high-status individual and all other individuals having status approaching zero. However, we find that in the latter case long-lived intermediary distributions often exist, which can give the illusion of a stable society. As we show, our model allows us to make predictions consistent with animal interaction data and their evolution over a number of years. Moreover, by implementing a simple, but realistic rule that restricts interactions to sufficiently similar-status individuals, the stable or long-lived distributions acquire high-status structure corresponding to a distinct high-status class. Using household income as a proxy for societal status in human societies, we find agreement over their entire range from the low-to-middle-status parts to the characteristic high-status "tail". We discuss how the model provides a conceptual framework for understanding the origin of social hierarchy and the factors which lead to the preservation or deterioration of the societal structure.

Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients.

OBJECTIVES: The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). MATERIALS AND METHODS: Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. RESULTS: Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. CONCLUSIONS: Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

Electric field mediated DNA motion model.

Understanding the motion and the governing equations of a molecule's path in tissue is an ultimate requirement for the repeatable, site specific delivery of molecules [Joseph D. Hickey. Modelling the Motion of Ions and Molecules in Electroporation and Electrophoresis Field Conditions. University of South Florida, College of Arts and Sciences, Department of Physics, Tampa, Florida, 2003., Joseph D. Hickey and Richard Gilbert. Modeling the electromobility of ions in a target tissue. DNA and Cell Biology, 22 (12) (2003) 823-828.]. This paper describes a computationally efficient mathematical model and simulation technique for the examination of DNA fragments in a 1% agarose gel. The speed of the individual DNA fragments through the agarose gel was described through two parts. The maximum velocity was calculated using the Coulombic force divided by Stoke's law and that value was retarded by an exponential rate equation. The simulation utilizes previously published techniques modified for this specific application [Joseph D. Hickey and Richard Gilbert. Fluid flow electrophoresis model. Bioelectrochemistry, 63 (2) (2004) 365-367., Joseph D. Hickey and Richard Gilbert. Modeling the electromobility of ions in a target tissue. DNA and Cell Biology, 22 (12) (2003) 823-828.]. Five representative DNA fragment sizes that span the resolution of a 1% agarose gel were chosen for this analysis. The speeds corresponding to these five DNA fragment sizes were converted into discrete values and used in a 50 step simulation. The resultant error comparing the simulation with experimental distance was 7.76%. Through a 1-D optimization procedure, this error was reduced to 3.02% for a 52 step simulation.

An initial investigation of serum cytokine levels in patients with gadolinium retention / Uma investigação inicial dos níveis séricos de citocinas em pacientes com retenção de gadolínio

Abstract Objective: To determine whether individuals with proposed gadolinium deposition disease (GDD) have elevated serum levels of pro-inflammatory and pro-fibrotic cytokines, and whether specific cytokines are correlated with certain symptoms. Materials and Methods: Twenty-four participants recruited between May 2016 and June 2017 met GDD diagnostic criteria. The 64 control subjects provided serum samples before prophylactic flu vaccination. Serum cytokine levels were obtained with Luminex serum cytokine assay using eBiosciences/Affymetrix human 62-plex kits. Wilcoxon rank-sum tests were performed to assess the difference between the median fluorescence intensity values for the participants and the control group. Generalized linear models were built to evaluate the association between each cytokine of interest and selected participant symptoms. Results: Serum levels of 14 cytokines, including nine pro-inflammatory cytokines, were statistically significantly elevated compared to controls (p ≤ 0.05). Hypotheses regarding pro-fibrotic cytokines and cytokine links to specific symptoms' intensity were not confirmed. Conclusion: The statistically significantly elevated cytokines may be markers of susceptibility to GDD or agents of symptom induction. These findings suggest that individuals developing symptoms characteristic of GDD after a contrast-assisted magnetic resonance imaging should be studied to investigate whether gadolinium retention and elevated cytokines may be related to their symptoms.

Resumo Objetivo: Determinar se indivíduos com doença de deposição de gadolínio (DDG) apresentam níveis séricos elevados de citocinas pró-inflamatórias e pró-fibróticas e se citocinas específicas estão correlacionadas com determinados sintomas. Materiais e Métodos: Vinte e quatro participantes recrutados entre maio/2016 e junho/2017 cumpriram os critérios de diagnóstico de DDG. Amostras de soro de 64 indivíduos controles foram obtidas antes de vacinação profilática contra a gripe. Os níveis de citocinas séricas foram mensurados com o ensaio Luminex usando kits 62-plex humanos. Foram realizados testes de Wilcoxon para avaliar a diferença dos valores médios de intensidade de fluorescência entre os participantes e o grupo controle. Foram construídos modelos lineares generalizados para avaliar a associação entre cada citocina de interesse e os sintomas dos participantes selecionados. Resultados: Níveis séricos de 14 citocinas, incluindo 9 citocinas pró-inflamatórias, foram estatisticamente significantes em comparação aos controles (p ≤ 0,05). Hipóteses sobre as citocinas pró-fibróticas e associação das citocinas com a intensidade de sintomas específicos não foram confirmadas. Conclusão: Citocinas estatisticamente elevadas podem ser marcadores de suscetibilidade para DDG ou agentes de indução de sintomas. Esses achados sugerem que indivíduos que desenvolvem sintomas da DDG após ressonância magnética com contraste devem ser estudados para investigar se a retenção de gadolínio e citocinas elevadas podem estar relacionadas aos seus sintomas.

Modeling the electromobility of ions in a target tissue.

Electroporation is a clinical and laboratory technique for the delivery of molecules to cells. This method imposes electric fields onto cells or tissues through the use of electrodes and a set of electrical parameters to ultimately incorporate molecules into the cells. Clinical applications may include using directional fields to bring therapeutics to the target tissues before triggering an electroporation event. The choice of applicator may also have a significant influence on this molecular flow. Modeling ionic flow in tissues will yield insight into selecting the appropriate parameters or electroporation signature for a desired target application. In this paper, the motion of tissue injected ions was modeled for two common electroporation applicator configurations-the parallel plate, and the four needle electrodes. This electric field induced fluid flow model predicts that the parallel plate applicator ultimately directs the movement of an ionic therapeutic in a forward manner with side motion due only to obstruction, while the four-needle applicator directs anisotropic flow within the field ultimately forcing the therapeutic into a mound at the fringes of the induced electric field.

Fluid flow electrophoresis model.

Molecular delivery via electroporation is typically done via molecular diffusion and tissue perfusion. The inherent variability in those distribution methods limits the efficacy of this medical and laboratory technique. Electrophoresis has been shown to improve the distribution and placement of the molecule [Gene Therapy 9 (2002) 1286]. This paper presents a fluid flow model for electrophoresis in tissues. Parallel plate and four-needle needle array electrodes are the electrodes modeled as the delivery devices. The parallel plate electrode produces a homogeneous distribution of the analyte but the needle array electrode creates a peak where the electric field effects diminish.

Classical nucleation theory with a radius-dependent surface tension: a two-dimensional lattice-gas automata model.

The constant surface tension assumption of the Classical Nucleation Theory (CNT) is known to be flawed. In order to probe beyond this limitation, we consider a microscopic, two-dimensional Lattice-Gas Automata (LGA) model of nucleation in a supersaturated system, with model input parameters E(ss) (solid particle-to-solid particle bonding energy), E(sw) (solid particle-to-water bonding energy), η (next-to-nearest-neighbor bonding coefficient in solid phase), and C(in) (initial solute concentration). The LGA method has the advantages of easy implementation, low memory requirements, and fast computation speed. Analytical results for the system's concentration and the crystal radius as functions of time are derived and the former is fit to the simulation data in order to determine the equilibrium concentration. The "Mean First-Passage Time" technique is used to obtain the nucleation rate and critical nucleus size from the simulation data. The nucleation rate and supersaturation data are evaluated using a modification to the CNT that incorporates a two-dimensional radius-dependent surface tension term. The Tolman parameter, δ, which controls the radius dependence of the surface tension, decreases (increases) as a function of the magnitude of E(ss) (E(sw)), at fixed values of η and E(sw) (E(ss)). On the other hand, δ increases as η increases while E(ss) and E(sw) are held constant. The constant surface tension term of the CNT, Σ(0), increases (decreases) with increasing magnitudes of E(ss) (E(sw)) at fixed values of E(sw) (E(ss)) and increases as η is increased. Σ(0) increases linearly as a function of the change in energy during an attachment or detachment reaction, |ΔE|, however, with a slope less than that predicted for a crystal that is uniformly packed at maximum density. These results indicate an increase in the radius-dependent surface tension, Σ, with respect to increasing magnitude of the difference between E(ss) and E(sw).

Clinical use of a carbohydrate-restricted diet to treat the dyslipidemia of the metabolic syndrome.

BACKGROUND: The metabolic syndrome is characterized by an atherogenic dyslipidemia identifiable using lipoprotein subclass analysis. This study assesses the effect of a carbohydrate-restricted diet on the dyslipidemia of the metabolic syndrome in a clinical setting. METHODS: This is a retrospective chart review of patients attending a preventive medicine clinic using lipoprotein subclass analysis (by NMR spectroscopy) to identify the atherogenic dyslipidemia. If present, patients were counseled to begin a carbohydrate-restricted diet (< 20 g/day). Patients already on statin therapy were included only if the medication dose was not changed. The outcomes were changes in body weight, fasting serum lipid profiles and serum lipoprotein subclasses. RESULTS: Of 122 patients identified, 80 patients had complete pre- and post-treatment data. The mean (+/-SD) age was 66 +/- 9 years, baseline weight was 85 +/- 12 kg, BMI was 28.1 +/- 3.6, 73% were male, 99% were Caucasian. Sixty-five percent were taking statin medication. Carbohydrate-restriction led to a 13% reduction in total cholesterol, 16% reduction in LDL cholesterol, 38% reduction in triglycerides, and a 13% increase in HDL cholesterol (all p values < 0.001). Carbohydrate-restriction also led to a reduction in LDL particle concentration of 28%, a reduction in small LDL of 82%, a reduction of large VLDL of 62%, and an increase in large HDL of 30% (all p values < 0.001). CONCLUSIONS: A carbohydrate-restricted diet recommendation led to improvements in lipid profiles and lipoprotein subclass traits of the metabolic syndrome in a clinical outpatient setting, and should be considered as a treatment for the metabolic syndrome.