Investigating the persistence of tick-borne pathogens via the R0 model

In the epidemiology of infectious diseases, the basic reproduction number,R0, has a number of important applications, most notably it can be used to predict whether a pathogen is likely to become established, or persist, in a given area. We used the R0 model to investigate the persistence of 3 tick-borne pathogens; Babesia microti, Anaplasma phagocytophilum and Borrelia burgdorferi sensu lato in an Apodemus sylvaticus-Ixodes ricinus system. The persistence of these pathogens was also determined empirically by screening questing ticks and wood mice by PCR. All 3 pathogens behaved differently in response to changes in the proportion of transmission hosts on which I. ricinus fed, the efficiency of transmission between the host and ticks and the abundance of larval and nymphal ticks found on small mammals. Empirical data supported theoretical predictions of the R0 model. The transmission pathway employed and the duration of systemic infection were also identified as important factors responsible for establishment or persistence of tick-borne pathogens in a given tick-host system. The current study demonstrates how the R0 model can be put to practical use to investigate factors affecting tick-borne pathogen persistence, which has important implications for animal and human health worldwide

Beneficial ex vivo immunomodulatory and clinical effects of clarithromycin in COVID-19

INTRODUCTION: Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. METHODS: We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. RESULTS: Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). CONCLUSIONS: Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration

Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor

AbstractHFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 Å crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex

Preliminary Drop Testing Results to Validate an Analysis Methodology for Accidental Drop Events of Containers for Radioactive Materials

The National Spent Nuclear Fuel Program, operating from the Idaho National Engineering and Environmental Laboratory (INEEL), developed the standardized Department of Energy (DOE) spent nuclear fuel (SNF) canister. During the development of this canister, more than twenty drop tests were completed, evaluating high strain behavior, puncture resistance, maintenance of containment, and other canister responses. Computer analyses of these drop-test specimens/canisters employed the ABAQUS/Explicit software. A pre-drop analysis was performed for each test specimen to predict the deformed shape and resulting material straining. Typically, a postdrop analysis was also performed to better match actual test specifics (actual impact angle, test specimen material properties, etc.). The purpose for this analysis effort was to determine the capability of current analysis techniques to accurately predict the deformed shape of a standardized DOE SNF canister subjected to a defined drop event, without actually having to perform a drop test for every drop event of interest. Those analytical efforts yielded very accurate predictions for nearly all of the drop tests. However, it was noted, during one small-scale test, that the calculated deformed shape of the test specimen depended on the modeled frictional behavior as it impacted the essentially unyielding flat surface. In order to calculate the correct deformed shape, the modeled frictional behavior had to be changed to an unanticipated value. This paper will report the results of a preliminary investigation that determined the appropriate frictional modeling for a variety of impact angles. That investigation included drop testing performed at the INEEL from September 2000 to January 2001

Containment and Analysis Capability Insights Gained from Drop Testing Representative Spent Nuclear Fuel Containers

The National Spent Nuclear Fuel Program (NSNFP), operating from the Idaho National Engineering and Environmental Laboratory (INEEL), developed the standardized Department of Energy (DOE) spent nuclear fuel (SNF) canister. This canister is designed to be loaded with DOE SNF (including other radioactive materials) and then be used during interim storage, during transportation to the nation’s repository, and for final disposal at the repository without having to be reopened. The canister has been fully designed and has completed significant testing that clearly demonstrates that it can safely achieve its intended design goals. During 1999, nine 457-mm diameter test canisters were fabricated at the INEEL to represent the standardized DOE SNF canister design. Various "worst case" internals were incorporated. Seven of the test canisters were 4.57 m long and weighed approximately 2721 kg, while two were 3.00 m long and weighed approximately 1360 kg and 1725 kg. Seven of the test canisters were dropped from 9 m onto an essentially unyielding flat surface and one of the test canisters was dropped from 1 m onto a 15-cm diameter puncture post. The final test canister was dropped from 61 cm onto a 50.8 mm thick vertically oriented steel plate, and then fell over to impact another 50.8 mm thick vertically oriented steel plate. This last test represented a canister dropping onto another larger container such as a repository disposal container or waste package. The 1999 drop testing was performed at Sandia National Laboratories (SNL). The nine test canisters experienced varying degrees of damage to their skirts, lifting rings, and pressure boundary components (heads and main body). However, all of the canisters were shown to have maintained their pressure boundary (through pressure testing). Four heavily damaged canisters were also shown to be leaktight via helium leak testing. Pre- and post-drop finite element (FE) analyses were also performed. The results clearly indicated that accurate predictions of canister responses to the drop tests were achieved. The results achieved for the standardized canister can also be applicable to other well-constructed containers (canisters, casks, cans, vessels, etc.) subjected to similar loads. Properly designed containers can maintain a containment system after being subjected to dynamically induced high strains and FE computer analyses can accurately predict the resulting responses

Analytical Evaluation of Drop Tests Performed on Nine 18-Inch Diameter Standardized DOE Spent Nuclear Fuel Canisters

During fiscal year 1999, a total of nine 18-inch diameter test canisters were fabricated at the Idaho National Engineering & Environmental Laboratory (INEEL) to represent the standardized Department of Energy (DOE) Spent Nuclear Fuel (SNF) canister design. Various "worst case" internal loadings were incorporated. Seven of the test canisters were 15-foot long and weighed approximately 6000 pounds, while two were 10-foot long and weighed 3000 and 3800 pounds. Seven of the test canisters were dropped from thirty feet onto an essentially unyielding flat surface and one of the test canisters was dropped from 40-inches onto a 6-inch diameter puncture post. The final test canister was dropped from 24 inches onto a 2-inch thick vertically oriented steel plate, and then tipped over to impact another 2-inch thick vertically oriented steel plate. This last test was attempting to represent a canister dropping onto another larger container such as a repository disposal container. All drop testing was performed at Sandia National Laboratory (SNL). The nine test canisters experienced varying degrees of damage to their skirts, lifting rings, and pressure boundary components (heads and main body). However, all of the canisters were shown to have maintained their pressure boundary (through pressure testing), and the four worst damaged canisters were also shown to be leaktight (via helium leak testing performed at the INEEL). Pre-drop and post-drop test canister finite element modeling was performed at the INEEL in support of the canister drop test program. All model evaluations were performed using the ABAQUS/Explicit software. The finite element models representing the test canisters accurately (though at times, slightly conservatively) predicted the actual test canister responses during the defined drop events.This paper will discuss highlights of the drop testing program and will give detailed comparisons of analysis versus actual test results

The age-specific incidence of hospitalized paediatric malaria in Uganda.

BACKGROUND: Understanding the relationship between malaria infection risk and disease outcomes represents a fundamental component of morbidity and mortality burden estimations. Contemporary data on severe malaria risks among populations of different parasite exposures are scarce. Using surveillance data, we compared rates of paediatric malaria hospitalisation in areas of varying parasite exposure levels. METHODS: Surveillance data at five public hospitals; Jinja, Mubende, Kabale, Tororo, and Apac were assembled among admissions aged 1 month to 14 years between 2017 and 2018. The address of each admission was used to define a local catchment population where national census data was used to define person-year-exposure to risk. Within each catchment, historical infection prevalence was assembled from previously published data and current infection prevalence defined using 33 population-based school surveys among 3400 children. Poisson regression was used to compute the overall and site-specific incidences with 95% confidence intervals. RESULTS: Both current and historical Plasmodium falciparum prevalence varied across the five sites. Current prevalence ranged from < 1% in Kabale to 54% in Apac. Overall, the malaria admission incidence rate (IR) was 7.3 per 1000 person years among children aged 1 month to 14 years of age (95% CI: 7.0, 7.7). The lowest rate was described at Kabale (IR = 0.3; 95 CI: 0.1, 0.6) and highest at Apac (IR = 20.3; 95 CI: 18.9, 21.8). There was a correlation between IR across the five sites and the current parasite prevalence in school children, though findings were not statistically significant. Across all sites, except Kabale, malaria admissions were concentrated among young children, 74% were under 5 years. The median age of malaria admissions at Kabale hospital was 40 months (IQR 20, 72), and at Apac hospital was 36 months (IQR 18, 69). Overall, severe anaemia (7.6%) was the most common presentation and unconsciousness (1.8%) the least common. CONCLUSION: Malaria hospitalisation rates remain high in Uganda particularly among young children. The incidence of hospitalized malaria in different locations in Uganda appears to be influenced by past parasite exposure, immune acquisition, and current risks of infection. Interruption of transmission through vector control could influence age-specific severe malaria risk

Be stars: one ring to rule them all?

Aims. We report theoretical spectral energy distributions (SEDs), Br$\gamma$ line profiles and visibilities for two scenarios that can explain the disk dissipation of active hot stars an account for the transition from the Be to the B spectroscopic phase. Methods. We use the SIMECA code to investigate these two scenarios: the first one where the disk is formed by successive outbursts of the central star. A low-density region is developing above the star and slowly grows outward and forms a ring-like structure that will gradually excavate the disk. The second one, where a slowly decreasing mass loss, for instance due to a decrease of the radiative force through an opacity change at the base of the photosphere, may also be responsible for the vanishing of the circumstellar disk. Results. We obtain that a clear signature of the disk dissipation following the ring scenario will be the disappearance of the high velocity tails in the emission lines and a nearly constant peaks separation. Moreover, we found that following the ring-like scenario the visibilities must show an increasing second lobe, an increase of the value of the first zero and, assuming an unresolved central star, a first zero of the visibility curves that appends at shorter baselines as far as the disk is been excavate. We propose to use the AMBER instrument on the VLTI to probe if the the ring scenario is the one that rule the Be phenomenon.Comment: 10 page