Influenza is a viral infection that primarily spreads via fluid droplets from an infected person's coughs and sneezes to others nearby. Social contact networks and the way people interact within them ...are thus important to its spread. We developed a method to characterize the social contact network for the potential transmission of influenza and then applied the method to school aged children and teenagers.
Surveys were administered to students in an elementary, middle and high-school in the United States. The social contact network of a person was conceptualized as a set of groups to which they belong (e.g., households, classes, clubs) each composed of a sub-network of primary links representing the individuals within each group that they contact. The size of the group, number of primary links, time spent in the group, and level of contact along each primary link (near, talking, touching, or kissing) were characterized. Public activities done by groups venturing into the community where random contacts occur (e.g., friends viewing a movie) also were characterized.
Students, groups and public activities were highly heterogeneous. Groups with high potential for the transmission of influenza were households, school classes, friends, and sports; households decreased and friends and sports increased in importance with grade level. Individual public activity events (such as dances) were also important but lost their importance when averaged over time. Random contacts, primarily in school passing periods, were numerous but had much lower transmission potential compared to those with primary links within groups. Students are highly assortative, interacting mainly within age class. A small number of individual students are identified as likely "super-spreaders".
High-school students may form the local transmission backbone of the next pandemic. Closing schools and keeping students at home during a pandemic would remove the transmission potential within these ages and could be effective at thwarting its spread within a community. Social contact networks characterized as groups and public activities with the time, level of contact and primary links within each, yields a comprehensive view, which if extended to all ages, would allow design of effective community containment for pandemic influenza.
Targeted social distancing to mitigate pandemic influenza can be designed through simulation of influenza's spread within local community social contact networks. We demonstrate this design for a ...stylized community representative of a small town in the United States. The critical importance of children and teenagers in transmission of influenza is first identified and targeted. For influenza as infectious as 1957-58 Asian flu (=50% infected), closing schools and keeping children and teenagers at home reduced the attack rate by >90%. For more infectious strains, or transmission that is less focused on the young, adults and the work environment must also be targeted. Tailored to specific communities across the world, such design would yield local defenses against a highly virulent strain in the absence of vaccine and antiviral drugs.
Antibodies targeting the Ebola virus surface glycoprotein (EBOV GP) are implicated in protection against lethal disease, but the characteristics of the human antibody response to EBOV GP remain ...poorly understood. We isolated and characterized 349 GP-specific monoclonal antibodies (mAbs) from the peripheral B cells of a convalescent donor who survived the 2014 EBOV Zaire outbreak. Remarkably, 77% of the mAbs neutralize live EBOV, and several mAbs exhibit unprecedented potency. Structures of selected mAbs in complex with GP reveal a site of vulnerability located in the GP stalk region proximal to the viral membrane. Neutralizing antibodies targeting this site show potent therapeutic efficacy against lethal EBOV challenge in mice. The results provide a framework for the design of new EBOV vaccine candidates and immunotherapies.
The US government proposes pandemic influenza mitigation guidance that includes isolation and antiviral treatment of ill persons, voluntary household member quarantine and antiviral prophylaxis, ...social distancing of individuals, school closure, reduction of contacts at work, and prioritized vaccination. Is this the best strategy combination? Is choice of this strategy robust to pandemic uncertainties? What are critical enablers of community resilience?
We systematically simulate a broad range of pandemic scenarios and mitigation strategies using a networked, agent-based model of a community of explicit, multiply-overlapping social contact networks. We evaluate illness and societal burden for alterations in social networks, illness parameters, or intervention implementation. For a 1918-like pandemic, the best strategy minimizes illness to <1% of the population and combines network-based (e.g. school closure, social distancing of all with adults' contacts at work reduced), and case-based measures (e.g. antiviral treatment of the ill and prophylaxis of household members). We find choice of this best strategy robust to removal of enhanced transmission by the young, additional complexity in contact networks, and altered influenza natural history including extended viral shedding. Administration of age-group or randomly targeted 50% effective pre-pandemic vaccine with 7% population coverage (current US H5N1 vaccine stockpile) had minimal effect on outcomes. In order, mitigation success depends on rapid strategy implementation, high compliance, regional mitigation, and rigorous rescinding criteria; these are the critical enablers for community resilience.
Systematic evaluation of feasible, recommended pandemic influenza interventions generally confirms the US community mitigation guidance yields best strategy choices for pandemic planning that are robust to a wide range of uncertainty. The best strategy combines network- and case-based interventions; network-based interventions are paramount. Because strategies must be applied rapidly, regionally, and stringently for greatest benefit, preparation and public education is required for long-lasting, high community compliance during a pandemic.
The translocator protein (TSPO) has been proven to have great potential as a target for the positron emission tomography (PET) imaging of glioblastoma. However, there is an ongoing debate about the ...potential various sources of the TSPO PET signal. This work investigates the impact of the inoculation-driven immune response on the PET signal in experimental orthotopic glioblastoma.
Serial
FGE-180 and
-(2-
Ffluoroethyl)-L-tyrosine (
FFET) PET scans were performed at day 7/8 and day 14/15 after the inoculation of GL261 mouse glioblastoma cells (n = 24) or saline (sham, n = 6) into the right striatum of immunocompetent C57BL/6 mice. An additional n = 25 sham mice underwent
FGE-180 PET and/or autoradiography (ARG) at days 7, 14, 21, 28, 35, 50 and 90 in order to monitor potential reactive processes that were solely related to the inoculation procedure. In vivo imaging results were directly compared to tissue-based analyses including ARG and immunohistochemistry.
We found that the inoculation process represents an immunogenic event, which significantly contributes to TSPO radioligand uptake.
FGE-180 uptake in GL261-bearing mice surpassed
FFET uptake both in the extent and the intensity, e.g., mean target-to-background ratio (TBR
) in PET at day 7/8: 1.22 for
FGE-180 vs. 1.04 for
FFET,
< 0.001. Sham mice showed increased
FGE-180 uptake at the inoculation channel, which, however, continuously decreased over time (e.g., TBR
in PET: 1.20 at day 7 vs. 1.09 at day 35,
= 0.04). At the inoculation channel, the percentage of TSPO/IBA1 co-staining decreased, whereas TSPO/GFAP (glial fibrillary acidic protein) co-staining increased over time (
< 0.001).
We identify the inoculation-driven immune response to be a relevant contributor to the PET signal and add a new aspect to consider for planning PET imaging studies in orthotopic glioblastoma models.
A comparison of the Potential Dermal Exposure (PDE) of workers to the insecticide deltamethrin was made as a function of crop type, in small agricultural production units in Argentina. Seven ...experiments were done with two different crops (maize and broccoli, treated area between 600 and 1000 m
2) with three different operators under typical field conditions using a lever operated knapsack. The methodology is based on the whole body dosimetry technique, presenting separately the data for mixing/loading and application activities. These results indicate a higher concentration of pesticide in lower body sections for broccoli and a wider distribution for maize. The risk inherent in these agricultural procedures is estimated through Margin of Safety (MOS) values and was found to be generally safe.
Preliminary results of a mass balance distribution of the pesticide between crop, soil and operator are also presented.
Local community networks can mitigate pandemic influenza in the absence of vaccine and antiviral drugs.
Targeted social distancing to mitigate pandemic influenza can be designed through simulation of ...influenza's spread within local community social contact networks. We demonstrate this design for a stylized community representative of a small town in the United States. The critical importance of children and teenagers in transmission of influenza is first identified and targeted. For influenza as infectious as 1957–58 Asian flu (≈50% infected), closing schools and keeping children and teenagers at home reduced the attack rate by >90%. For more infectious strains, or transmission that is less focused on the young, adults and the work environment must also be targeted. Tailored to specific communities across the world, such design would yield local defenses against a highly virulent strain in the absence of vaccine and antiviral drugs.
CHARGE syndrome is a complex of birth defects including coloboma, choanal atresia, ear malformations and deafness, cardiac defects, and growth delay. We have previously hypothesized that CHARGE ...syndrome could be caused by unidentified genomic microdeletion, but no such deletion was detected using short tandem repeat (STR) markers spaced an average of 5 cM apart. Recently, microdeletion at 8q12 locus was reported in two patients with CHARGE, although point mutation in CHD7 on chromosome 8 was the underlying etiology in most of the affected patients.
We have extended our previous study by employing a much higher density of SNP markers (3258) with an average spacing of approximately 800 kb. These SNP markers are diallelic and, therefore, have much different properties for detection of deletions than STRs.
A global error rate estimate was produced based on Mendelian inconsistency. One marker, rs431722 exceeded the expected frequency of inconsistencies, but no deletion could be demonstrated after retesting the 4 inconsistent pedigrees with local flanking markers or by FISH with the corresponding BAC clone. Expected deletion detection (EDD) was used to assess the coverage of specific intervals over the genome by deriving the probability of detecting a common loss of heterozygosity event over each genomic interval. This analysis estimated the fraction of unobserved deletions, taking into account the allele frequencies at the SNPs, the known marker spacing and sample size.
The results of our genotyping indicate that more than 35% of the genome is included in regions with very low probability of a deletion of at least 2 Mb.
CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this ...syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype.
Summary Altered glycosylation and/or expression of dystroglycan have been reported in forms of congenital muscular dystrophy as well as in cancers of the breast, colon, and oral epithelium. To date, ...however, there has been no study of the expression of dystroglycan in pediatric solid tumors. Using a combination of immunostaining on tissue microarrays and immunoblotting of snap-frozen unfixed tissues, we demonstrate a significant reduction in native α dystroglycan expression in pediatric alveolar rhabdomyosarcoma (RMS), embryonal RMS, neuroblastoma (NBL), and medulloblastoma, whereas expression of β dystroglycan, which is cotranslated with α dystroglycan, is largely unchanged. Loss of native α dystroglycan expression was significantly more pronounced in stage 4 NBL than in pooled samples of stage 1 and stage 2 NBL, suggesting that loss of native α dystroglycan expression increases with advancing tumor stage. Neuroblastoma and RMS samples with reduced expression of native α dystroglycan also showed reduced laminin binding in laminin overlay experiments. Expression of natively glycosylated α dystroglycan was not altered in several other pediatric tumor types when compared with appropriate normal tissue controls. These data provide the first evidence that α dystroglycan glycosylation and laminin binding to α dystroglycan are altered in certain pediatric solid tumors and suggest that aberrant dystroglycan glycosylation may contribute to tumor cell biology in patients with RMS, medulloblastoma, and NBL.
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