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BACKGROUND AND OBJECTIVES: Between December 31, 2018, and April 26, 2019, 72 confirmed cases of measles were identified in Clark County. Our objective was to estimate the economic burden of the measles outbreak from a societal perspective, including public health response costs as well as direct medical costs and productivity losses of affected individuals. METHODS: To estimate costs related to this outbreak from the societal perspective, 3 types of costs were collected or estimated: public health response (labor, material, and contractor costs used to contain the outbreak), direct medical (third party or patient out-of-pocket treatment costs of infected individuals), and productivity losses (costs of lost productivity due to illness, home isolation, quarantine, or informal caregiving). RESULTS: The overall societal cost of the 2019 Clark County measles outbreak was ∼$3.4 million ($47 479 per case or $814 per contact). The majority of the costs (∼$2.3 million) were incurred by the public health response to the outbreak, followed by productivity losses (∼$1.0 million) and direct medical costs (∼$76 000). CONCLUSIONS: Recent increases in incident measles cases in the United States and across the globe underscore the need to more fully understand the societal cost of measles cases and outbreaks and economic consequences of undervaccination. Our estimates can provide valuable inputs for policy makers and public health stakeholders as they consider budget determinations and the substantial value associated with increasing vaccine coverage and outbreak preparedness as well as the protection of society against vaccine-preventable diseases, such as measles, which are readily preventable with high vaccination coverage.

As a major human pathogen, RSV affects 3.4 million children worldwide annually. However, no effective antivirals or vaccines are available. An in-depth mechanistic understanding of the RSV RNA synthesis machinery remains a high priority among the NNS RNA viruses. There is a strong public health need for research on this virus, due to major fundamental gaps in our understanding of NNS RNA virus replication. As the key enzyme executing transcription and replication of the virus, the RSV RdRP is a logical target for novel antiviral drugs. Therefore, exploring the primer-dependent RNA elongation extends our mechanistic understanding of the RSV RNA synthesis. Further fine mapping of the promoter sequence paves the way to better understand the function and structure of the RSV polymerase., Respiratory syncytial virus (RSV) is a nonsegmented negative-sense (NNS) RNA virus and shares a similar RNA synthesis strategy with other members of NNS RNA viruses, such as measles, rabies virus, and Ebola virus. RSV RNA synthesis is catalyzed by a multifunctional RNA-dependent RNA polymerase (RdRP), which is composed of a large (L) protein that catalyzes three distinct enzymatic functions and an essential coenzyme phosphoprotein (P). Here, we successfully prepared highly pure, full-length, wild-type and mutant RSV polymerase (L-P) complexes. We demonstrated that the RSV polymerase could carry out both de novo and primer-based RNA synthesis. We defined the minimal length of the RNA template for in vitro de novo RNA synthesis using the purified RSV polymerase as 8 nucleotides (nt), shorter than previously reported. We showed that the RSV polymerase catalyzed primer-dependent RNA elongation with different lengths of primers on both short (10-nt) and long (25-nt) RNA templates. We compared the sequence specificity of different viral promoters and identified positions 3, 5, and 8 of the promoter sequence as essential to the in vitro RSV polymerase activity, consistent with the results previously mapped with the in vivo minigenome assay. Overall, these findings agree well with those of previous biochemical studies and extend our understanding of the promoter sequence and the mechanism of RSV RNA synthesis. IMPORTANCE As a major human pathogen, RSV affects 3.4 million children worldwide annually. However, no effective antivirals or vaccines are available. An in-depth mechanistic understanding of the RSV RNA synthesis machinery remains a high priority among the NNS RNA viruses. There is a strong public health need for research on this virus, due to major fundamental gaps in our understanding of NNS RNA virus replication. As the key enzyme executing transcription and replication of the virus, the RSV RdRP is a logical target for novel antiviral drugs. Therefore, exploring the primer-dependent RNA elongation extends our mechanistic understanding of the RSV RNA synthesis. Further fine mapping of the promoter sequence paves the way to better understand the function and structure of the RSV polymerase.

The respiratory syncytial virus (RSV) RNA polymerase, constituted of a 250 kDa large (L) protein and tetrameric phosphoprotein (P), catalyzes three distinct enzymatic activities — nucleotide polymerization, cap addition, and cap methylation. How RSV L and P coordinate these activities is poorly understood. Here, we present a 3.67 Å cryo-EM structure of the RSV polymerase (L:P) complex. The structure reveals that the RNA dependent RNA polymerase (RdRp) and capping (Cap) domains of L interact with the oligomerization domain (POD) and C-terminal domain (PCTD) of a tetramer of P. The density of the methyltransferase (MT) domain of L and the N-terminal domain of P (PNTD) is missing. Further analysis and comparison with other RNA polymerases at different stages suggest the structure we obtained is likely to be at an elongation-compatible stage. Together, these data provide enriched insights into the interrelationship, the inhibitors, and the evolutionary implications of the RSV polymerase., Respiratory syncytial virus (RSV) is a pathogenic non-segmented negative-sense RNA virus and active RSV polymerase is composed of a 250 kDa large (L) protein and tetrameric phosphoprotein (P). Here, the authors present the 3.67 Å cryo-EM structure of the RSV polymerase (L:P) complex.

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease with devastating changes in behavioral performance and social function. Mutations in the progranulin gene (GRN) are one of the most common causes of inherited FTD due to reduced progranulin expression or activity, including in brain where it is expressed primarily by neurons and microglia. Thus, efforts aimed at enhancing progranulin levels might be a promising therapeutic strategy. Bone marrow-derived cells are able to engraft in the brain and adopt a microglial phenotype under myeloablative irradiation conditioning. This ability makes bone marrow (BM)-derived cells a potential cellular vehicle for transferring therapeutic molecules to the central nervous system. Here, we utilized BM cells from Grn+/+ (wild type or wt) mice labeled with green fluorescence protein for delivery of progranulin to progranulin deficient (Grn−/−) mice. Our results showed that wt bone marrow transplantation (BMT) partially reconstituted progranulin in the periphery and in cerebral cortex of Grn−/− mice. We demonstrated a pro-inflammatory effect in vivo and in ex vivo preparations of cerebral cortex of Grn−/− mice that was partially to fully reversed five months after BMT. Our findings suggest that BMT can be administered as a stem cell-based approach to prevent or to treat neurodegenerative diseases.

The remains of ancient communities have been found at Wadi Ramm and Humayma, Jordan in the midst of what is now the Jordanian desert. In past times these sites were located along caravan routes and were populated by Nabataean, Roman, Byzantine, and early Islamic peoples. Despite the fact that these sites are located tens of kilometers from the seashore, seashells are frequently found in the layers associated with the different population groups. As of yet, shells from the 1996-1997 excavations at Wadi Ramm and from the 2008-2010 excavations at Humayma have not received in depth analyses allowing them to be correctly identified, quantified, and associated with significant archaeological contexts. Archaeomalacology (the study of molluscs in archaeological contexts) is a vital part of deciphering ancient human diet and activity. It is also critical in determining past environments and transportation systems. Clearly these shells came from the sea, but how did they get to these remote desert locales? Based on the preliminary descriptions provided by the field excavators, the photographs of the Wadi Ramm shells, and the actual Humayma shells which are at Queen’s, I am creating a catalogue to identify, describe, and quantify the variety of mollusc species present. This catalogue incorporates all of the significant data in one place, thus allowing me to look for patterns in the frequency, condition, and probable function of the shells. This analysis will lead to a better understanding of the diet and cultural practices of the different ancient inhabitants at Wadi Ramm and Humayma.

We used a novel approach to molecular quantification in standard fixed and embedded tissue to measure amyloid β 42 (Aβ(42)) and paired helical filament-τ (PHF-τ) in frontal, temporal, and parietal cortices from 325 consecutive brain autopsies collected as part of a population-based study of brain aging and incident dementia in the Seattle area. We observed significant effects of APOE ε4 on Aβ(42) levels in both diagnostic groups by disease stage and region. In contrast, we did not observe a significant effect of APOE ε4 on PHF-τ levels by disease stage in any region. Levels of Aβ(42) and PHF-τ in cerebral cortex were correlated more strongly in the Dementia group, and these measures had independent explanatory power for dementia beyond those of standard neuropathologic indices. Associations between Lewy body disease and Aβ(42) or PHF-τ levels and between Aβ(42) levels and microvascular brain injury suggested that these comorbid diseases enhanced the penetrance of Alzheimer disease. Our novel approach brings additional insights into the molecular pathogenesis of common causes of dementia and may serve as a platform for future studies pursuing associations between molecular changes in Alzheimer disease and genetic or environmental risk.

BACKGROUND: The human forearm biopsy model can evaluate the effect of novel agents on acute wounds. Bismuth subgallate/borneol (Suile) is a new product cleared by the Food and Drug Administration for treating partial-thickness wounds. Anecdotal reports suggest that Suile may be effective for full-thickness wounds because of its antimicrobial and hemostatic properties. METHODS: In a randomized, investigator-blinded study, 20 normal healthy volunteers underwent 2 6-mm full-thickness skin punch biopsies on the flexor surface of each forearm (2 wounds per subject). Biopsies were randomly assigned to control (bacitracin) and test article (Suile). Wounds were examined, measured by digital planimetry, and photographed daily until healed. Adverse events and pain levels were monitored. Time-to-complete closure was determined. RESULTS: Direct quantitative and qualitative comparisons of wound healing were made. The Suile group trended strongly toward more rapid healing (log-rank analysis). Individual subject arm analysis identified which biopsies healed first. Suile-treated biopsies healed more rapidly (P = .03, paired t-test). CONCLUSION: Although this study was powered to demonstrate equivalence, convincing evidence indicates that Suile is superior to bacitracin in this model. Based on the results, future studies in full-thickness wounds with Suile are warranted. The biopsy model provides these advantages: direct comparison within subjects, rapid study completion, good patient compliance, and experience with products before embarking on larger clinical trials in wounds.