The cost of lower extremity fractures among active duty U.S. Army soldiers, 2017.

The estimated cost to the Army for lower extremity fractures in 2017 was approximately $116 million. Direct medical expenses totaled $24 million, and indirect medical costs totaled $92 million ($900 thousand lost duty; $91 million limited duty). Foot and toe fractures, along with lower leg and ankle fractures accounted for the majority of soldiers' initial visits for care (n=4,482; 91.6%), and more than $103 million (89.0%) of overall costs ($116 million). Costs varied by location of care. In outpatient settings, initial visits for foot and toe injuries accounted for the highest costs: $49 million overall. Direct medical costs totaled $1.2 million, and indirect medical costs (limited duty) were $48 million. Conversely, in inpatient settings, lower leg and ankle fractures accounted for slightly more than half of all costs (overall $9 million; $4.8 million in direct medical costs and $4.5 million in indirect medical costs). The finding that the majority of costs related to lower extremity fractures were due to estimated days of lost or limited duty and associated loss of productivity justifies the inclusion of indirect cost estimates as a part of overall injury cost calculations.

Mortality estimates among adult patients with severe acute respiratory infections from two sentinel hospitals in southern Arizona, United States, 2010-2014.

BACKGROUND: From October 2010 through February 2016, Arizona conducted surveillance for severe acute respiratory infections (SARI) among adults hospitalized in the Arizona-Mexico border region. There are few accurate mortality estimates in SARI patients, particularly in adults ≥ 65 years old. The purpose of this study was to generate mortality estimates among SARI patients that include deaths occurring shortly after hospital discharge and identify risk factors for mortality. METHODS: Patients admitted to two sentinel hospitals between 2010 and 2014 who met the SARI case definition were enrolled. Demographic data were used to link SARI patients to Arizona death certificates. Mortality within 30 days after the date of admission was calculated and risk factors were identified using logistic regression models. RESULTS: Among 258 SARI patients, 47% were females, 51% were white, non-Hispanic and 39% were Hispanic. The median age was 63 years (range, 19 to 97 years) and 80% had one or more pre-existing health condition; 9% died in hospital. Mortality increased to 12% (30/258, 30% increase) when electronic vital records and a 30-day post-hospitalization time frame were used. Being age ≥ 65 years (OR = 4.0; 95% CI: 1.6-9.9) and having an intensive care unit admission (OR = 7.4; 95% CI: 3.0-17.9) were independently associated with mortality. CONCLUSION: The use of electronic vital records increased SARI-associated mortality estimates by 30%. These findings may help guide prevention and treatment measures, particularly in high-risk persons in this highly fluid border population.

Structures of prostaglandin F synthase from the protozoa Leishmania major and Trypanosoma cruzi with NADP.

The crystal structures of prostaglandin F synthase (PGF) from both Leishmania major and Trypanosoma cruzi with and without their cofactor NADP have been determined to resolutions of 2.6 Å for T. cruzi PGF, 1.25 Å for T. cruzi PGF with NADP, 1.6 Å for L. major PGF and 1.8 Å for L. major PGF with NADP. These structures were determined by molecular replacement to a final R factor of less than 18.6% (Rfree of less than 22.9%). PGF in the infectious protozoa L. major and T. cruzi is a potential therapeutic target.

Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1.

Influenza A viruses cause the respiratory illness influenza, which can be mild to fatal depending on the strain and host immune response. The flu polymerase acidic (PA), polymerase basic 1 (PB1), and polymerase basic 2 (PB2) proteins comprise the RNA-dependent RNA polymerase complex responsible for viral genome replication. The first crystal structures of the C-terminal domain of PA (PA-CTD) in the absence of PB1-derived peptides show a number of structural changes relative to the previously reported PB1-peptide bound structures. The human A/WSN/1933 (H1N1) and avian A/Anhui1/2013 (H7N9) strain PA-CTD proteins exhibit the same global topology as other strains in the absence of PB1, but differ extensively in the PB1 binding pocket including a widening of the binding groove and the unfolding of a ß-turn. Both PA-CTD proteins exhibited a significant increase in thermal stability in the presence of either a PB1-derived peptide or a previously reported inhibitor in differential scanning fluorimetry assays. These structural changes demonstrate plasticity in the PA-PB1 binding interface which may be exploited in the development of novel therapeutics.

A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins.

Macrophage infectivity potentiators (Mips) are immunophilin proteins and essential virulence factors for a range of pathogenic organisms. We applied a structural biology approach to characterize a Mip from Burkholderia pseudomallei (BpML1), the causative agent of melioidosis. Crystal structure and nuclear magnetic resonance analyses of BpML1 in complex with known macrocyclics and other derivatives led to the identification of a key chemical scaffold. This scaffold possesses inhibitory potency for BpML1 without the immunosuppressive components of related macrocyclic agents. Biophysical characterization of a compound series with this scaffold allowed binding site specificity in solution and potency determinations for rank ordering the set. The best compounds in this series possessed a low-micromolar affinity for BpML1, bound at the site of enzymatic activity, and inhibited a panel of homologous Mip proteins from other pathogenic bacteria, without demonstrating toxicity in human macrophages. Importantly, the in vitro activity of BpML1 was reduced by these compounds, leading to decreased macrophage infectivity and intracellular growth of Burkholderia pseudomallei. These compounds offer the potential for activity against a new class of antimicrobial targets and present the utility of a structure-based approach for novel antimicrobial drug discovery.

Multi-target parallel processing approach for gene-to-structure determination of the influenza polymerase PB2 subunit.

Pandemic outbreaks of highly virulent influenza strains can cause widespread morbidity and mortality in human populations worldwide. In the United States alone, an average of 41,400 deaths and 1.86 million hospitalizations are caused by influenza virus infection each year (1). Point mutations in the polymerase basic protein 2 subunit (PB2) have been linked to the adaptation of the viral infection in humans (2). Findings from such studies have revealed the biological significance of PB2 as a virulence factor, thus highlighting its potential as an antiviral drug target. The structural genomics program put forth by the National Institute of Allergy and Infectious Disease (NIAID) provides funding to Emerald Bio and three other Pacific Northwest institutions that together make up the Seattle Structural Genomics Center for Infectious Disease (SSGCID). The SSGCID is dedicated to providing the scientific community with three-dimensional protein structures of NIAID category A-C pathogens. Making such structural information available to the scientific community serves to accelerate structure-based drug design. Structure-based drug design plays an important role in drug development. Pursuing multiple targets in parallel greatly increases the chance of success for new lead discovery by targeting a pathway or an entire protein family. Emerald Bio has developed a high-throughput, multi-target parallel processing pipeline (MTPP) for gene-to-structure determination to support the consortium. Here we describe the protocols used to determine the structure of the PB2 subunit from four different influenza A strains.