Investigating associations between COVID-19 mortality and population-level health and socioeconomic indicators in the United States: A modeling study

BackgroundWith the availability of multiple Coronavirus Disease 2019 (COVID-19) vaccines and the predicted shortages in supply for the near future, it is necessary to allocate vaccines in a manner that minimizes severe outcomes, particularly deaths. To date, vaccination strategies in the United States have focused on individual characteristics such as age and occupation. Here, we assess the utility of population-level health and socioeconomic indicators as additional criteria for geographical allocation of vaccines.Methods and findingsCounty-level estimates of 14 indicators associated with COVID-19 mortality were extracted from public data sources. Effect estimates of the individual indicators were calculated with univariate models. Presence of spatial autocorrelation was established using Moran’s I statistic. Spatial simultaneous autoregressive (SAR) models that account for spatial autocorrelation in response and predictors were used to assess (i) the proportion of variance in county-level COVID-19 mortality that can explained by identified health/socioeconomic indicators (R²); and (ii) effect estimates of each predictor.Adjusting for case rates, the selected indicators individually explain 24%–29% of the variability in mortality. Prevalence of chronic kidney disease and proportion of population residing in nursing homes have the highest R². Mortality is estimated to increase by 43 per thousand residents (95% CI: 37–49; p < 0.001) with a 1% increase in the prevalence of chronic kidney disease and by 39 deaths per thousand (95% CI: 34–44; p < 0.001) with 1% increase in population living in nursing homes. SAR models using multiple health/socioeconomic indicators explain 43% of the variability in COVID-19 mortality in US counties, adjusting for case rates. R² was found to be not sensitive to the choice of SAR model form. Study limitations include the use of mortality rates that are not age standardized, a spatial adjacency matrix that does not capture human flows among counties, and insufficient accounting for interaction among predictors.ConclusionsSignificant spatial autocorrelation exists in COVID-19 mortality in the US, and population health/socioeconomic indicators account for a considerable variability in county-level mortality. In the context of vaccine rollout in the US and globally, national and subnational estimates of burden of disease could inform optimal geographical allocation of vaccines.

Sasikiran Kandula and Jeffrey Shaman study population health and COVID-19 mortality in the United States.     

Auditory pre-experience modulates classification of affect intensity: evidence for the evaluation of call salience by a non-human mammal,the bat <Emphasis Type="Italic">Megaderma lyra</Emphasis>

Introduction

Immediate responses towards emotional utterances in humans are determined by the acoustic structure and perceived relevance, i.e. salience, of the stimuli, and are controlled via a central feedback taking into account acoustic pre-experience. The present study explores whether the evaluation of stimulus salience in the acoustic communication of emotions is specifically human or has precursors in mammals. We created different pre-experiences by habituating bats (Megaderma lyra) to stimuli based on aggression, and response, calls from high or low intensity level agonistic interactions, respectively. Then we presented a test stimulus of opposite affect intensity of the same call type. We compared the modulation of response behaviour by affect intensity between the reciprocal experiments.

Results

For aggression call stimuli, the bats responded to the dishabituation stimuli independent of affect intensity, emphasising the attention-grabbing function of this call type. For response call stimuli, the bats responded to a high affect intensity test stimulus after experiencing stimuli of low affect intensity, but transferred habituation to a low affect intensity test stimulus after experiencing stimuli of high affect intensity. This transfer of habituation was not due to over-habituation as the bats responded to a frequency-shifted control stimulus. A direct comparison confirmed the asymmetric response behaviour in the reciprocal experiments.

Conclusions

Thus, the present study provides not only evidence for a discrimination of affect intensity, but also for an evaluation of stimulus salience, suggesting that basic assessment mechanisms involved in the perception of emotion are an ancestral trait in mammals.

     

Trichoderma atroviride LU132 promotes plant growth but not induced systemic resistance to Plutella xylostella in oilseed rape

Several species of the fungus Trichoderma can promote plant health and are widely used as commercial biopesticides. Beneficial effects of this fungus are attributed to various mechanisms such as mycoparasitism, plant-growth promotion, increased stress tolerance and elicitation of induced systemic resistance against pathogens via jasmonic acid/ethylene-dependent pathways. Despite such well-established effects on pathogens, surprisingly little is known about the influence of Trichoderma on plant defences against herbivorous insects. This study investigated whether soil-supplementation of the established biocontrol agent Trichoderma atroviride LU132 affected the performance of oilseed rape (Brassica napus) and the development of Plutella xylostella caterpillars. Furthermore, induction and priming of defence-related phytohormones, genes and secondary metabolites by fungus and herbivore were assessed. Plants colonized by T. atroviride LU132 had significantly larger root and shoot biomass than controls. No effects of fungal inoculation were found on herbivore development. Leaf feeding of the herbivore induced higher jasmonic acid levels, but this was not influenced by fungal treatment. Similarly, the defence-related genes MYC2 and TPI were induced by herbivory but not primed or induced by T. atroviride. Expression of the gene PDF1.2 was repressed by herbivore feeding while no effects on the gene ACO and glucosinolates were observed. We conclude that T. atroviride LU132 has positive effects on the growth of oilseed but it does not enhance above-ground insect defences.     

Polymorphism of CYP3A4*2 and eNOS genes in the diabetic patients with hyperlipidemia undergoing statin treatment

In individuals with diabetes, a log linear relationship exists between cholesterol levels and cardiovascular disease. Type 2 diabetes (T2D) and Statins, a cholesterol lowering drug, have a complex relationship. Statins are potent modulators of CYP3A4*2 enzyme and endothelial nitric oxide synthase (eNOS) functions in a number of cholesterol-independent, cardio protective actions in T2D. The aim of this study was to evaluate the CYP3A4*2 and eNOS gene mutations in a large number of T2D patients undergoing statin treatments. Blood samples were collected from 386 subjects in which 196 diabetic patients with hyperlipidemia were undergoing statin treatment (108 females and 88 males). The 190 healthy non-diabetic volunteers formed the control group. We investigated single nucleotide polymorphisms in diabetic patients and controls, and found that the statin therapy was not found to be effective in lowering LDL-cholesterol levels. Statistical analysis showed that T2D patients had significantly higher values of not only glucose levels but also a very high value of Triglycerides and cholesterol at the time of presentation. Our results for CYP3A4*2 showed that the genotype TT (wild type) had lower LDL when compared to TC (heterozygous). Similarly, the genotype TC (heterozygous) had lower LDL when compared to CC (homozygous). A similar trend was observed in the GG (wild type) and GT (heterozygous) of eNOS. In conclusion, we have described for the first time a significant correlation of statin treatment and CYP3A4*2 and eNOS gene polymorphisms in T2D, suggesting a new genetic susceptibility factor for insulin resistance and hyperlipidemia in T2D.     

Cytotoxic effect of Green synthesized silver nanoparticles using Melia azedarach against in vitro HeLa cell lines and lymphoma mice model

This communication explains the biosynthesis of stable silver nanoparticles (AgNPs) from Melia azedarach and its cytotoxicity against in vitro HeLa cells and in vivo Dalton's ascites lymphoma (DAL) mice model. The AgNPs synthesis was determined by UV–visible spectrum and it was further characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS) and X-ray diffraction (XRD) analysis. Zeta potential analysis revealed stable AgNPs at ?24.9 mV. UV visible spectrum indicated an absorption peak at 436 nm which reflects its specific Surface Plasmon Resonance (SPR). Biosynthesized AgNPs were predominantly cubical and spherical with an average particle size of 78 nm approximately as observed through SEM and DLS analysis, respectively. Cytotoxicity of biosynthesized AgNPs against in vitro Human epithelial carcinoma cell line (HeLa) showed a dose–response activity. Lethal dose (LD₅₀) value was found to be 300 μg/mL of AgNPs against HeLa cell line. Cytotoxicity against normal continuous cell line human breast lactating, donor 100 (HBL 100) was found only in increased concentration of both AgNPs and 5-FU. In addition, in vivo DAL mice model showed significant increase in life span, induction of apoptosis was evidenced by acridine orange and ethidium bromide (AO and EB) staining.     

A Bivalve Biomineralization Toolbox

Mollusc shells are a result of the deposition of crystalline and amorphous calcite catalyzed by enzymes and shell matrix proteins (SMP). Developing a detailed understanding of bivalve mollusc biomineralization pathways is complicated not only by the multiplicity of shell forms and microstructures in this class, but also by the evolution of associated proteins by domain co-option and domain shuffling. In spite of this, a minimal biomineralization toolbox comprising proteins and protein domains critical for shell production across species has been identified. Using a matched pair design to reduce experimental noise from inter-individual variation, combined with damage-repair experiments and a database of biomineralization SMPs derived from published works, proteins were identified that are likely to be involved in shell calcification. Eighteen new, shared proteins likely to be involved in the processes related to the calcification of shells were identified by the analysis of genes expressed during repair in Crassostrea gigas, Mytilus edulis, and Pecten maximus. Genes involved in ion transport were also identified as potentially involved in calcification either via the maintenance of cell acid–base balance or transport of critical ions to the extrapallial space, the site of shell assembly. These data expand the number of candidate biomineralization proteins in bivalve molluscs for future functional studies and define a minimal functional protein domain set required to produce solid microstructures from soluble calcium carbonate. This is important for understanding molluscan shell evolution, the likely impacts of environmental change on biomineralization processes, materials science, and biomimicry research.     

A high-throughput approach to developing and optimizing mixed-mode membrane chromatography for protein purification

Membrane chromatography has been established as a viable alternative to packed-bed column chromatography for the purification of therapeutic proteins. Purification via membrane chromatography offers key advantages, including higher productivity and reduced buffer usage. Unlike column chromatography purification, the utilization of high-throughput screening in order to reduce development times and material requirements has been a challenge for membrane chromatography. This research focused on the development of a new, high-throughput screening technique for use in screening membrane chromatography conditions for monoclonal antibody purification. The developed screen utilizes a 96-well plate format, thereby allowing for the screening of multiple different membrane conditions at once. For this study, four mixed-mode cation exchange membranes and one cation exchange membrane were evaluated on the plate. The screen is performed in a similar manner to that of a resin slurry plate screen, however, instead of a single loading step, the antibody feed was loaded in 50 mg/ml increments up to a maximum loading of 450 mg/ml. Performing a similar, incremental loading on a resin plate would be impractical, as mixing times are substantially longer due to pore diffusion limitations. However, due to the significantly faster rate of mass transfer for membranes relative to resin, mixing times could be reduced by up to a factor of sixty on the membrane plate. Additional optimization showed that higher hydrophobicity can potentially lead to slower kinetics and mixing times that may need to be adjusted accordingly. The end result is a screen that has been proven to provide results comparable to those obtained on larger-scale membrane purification runs while also enabling exploration of a much greater operating space and significantly reducing the feed materials required.     

Abdominal lymphatic pump treatment increases leukocyte count and flux in thoracic duct lymph

BACKGROUND: Previous studies suggest that rhythmic compression of the abdomen (abdominal lymphatic pump techniques, LPT) enhances immunity and resistance to infectious disease, but direct evidence of this has not been documented. In this study, the thoracic duct of eight anesthetized mongrel dogs was catheterized, so the immediate effects of LPT on lymph flow and leukocyte output could be measured. METHODS AND RESULTS: Lymph flow was measured by timed collection or ultrasonic flowmeter, and lymph was collected over ice under 1) resting (baseline) conditions, and 2) during application of LPT. The baseline leukocyte count was 4.8 +/- 1.7 x 10(6) cells/ml of lymph, and LPT significantly increased leukocytes to 11.8 +/- 3.6 x 10(6) cells/ml. Flow cytometry and differential cell staining revealed that numbers of macrophages, neutrophils, total lymphocytes, T cells and B cells were similarly increased during LPT. Furthermore, LPT significantly enhanced lymph flow from 1.13 +/- 0.44 ml/min to 4.14 +/- 1.29 ml/min. Leukocyte flux, computed from the product of lymph flow and cell count, was increased by LPT from 8.2 +/- 4.1 x 10(6) to 60 +/- 25 x 10(6) total cells/min. Similar trends were observed in macrophages, neutrophils, total lymphocytes, T cells and B cells during LPT. CONCLUSIONS: LPT significantly increased both thoracic duct lymph flow and leukocyte count, so lymph leukocyte flux was markedly enhanced. Increased mobilization of immune cells is likely and important mechanism responsible for the enhanced immunity and recovery from infection of patients treated with LPT.     

Refolding and Purification of Zymomonas mobilis Levansucrase Produced as Inclusion Bodies in Fed-Batch Culture of Recombinant Escherichia coli

Zymomonas mobilis levansucrase was overproduced by the fed-batch culture of recombinant Escherichia coli harboring a novel expression system that is constitutively expressed by the promoter from the Rahnella aquatilis levansucrase gene. Most of the levansucrase was produced as inclusion bodies in the bacterial cytoplasm, accounting for approximately 20% of the total cellular protein. Refolding after complete denaturation by high concentrations of urea or guanidine hydrochloride was not successful, resulting in large amounts of insoluble aggregates. During the development of the refolding method, it was found that direct solubilization of the inclusion bodies with Triton X-100 reactivated the enzyme, with a considerable refolding efficiency. About 65% of inclusion body levansucrase was refolded into active levansucrase in the renaturation buffer containing 4% (v/v) Triton X-100. The in vitro refolded enzyme was purified to 95% purity by single-step DEAE–Sepharose ion exchange chromatography. Triton X-100 was removed by this ion exchange chromatography.