Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.

Operando Investigation of Solid Electrolyte Interphase Formation, Dynamic Evolution, and Degradation During Lithium Plating/Stripping.

The solid electrolyte interphase (SEI) dictates the stability and cycling performance of highly reactive battery electrodes. Characterization of the thin, dynamic, and environmentally sensitive nature of the SEI presents a formidable challenge, which calls for the use of microscopic, time-resolved operando methods. Herein, we employ scanning electrochemical microscopy (SECM) to directly probe the heterogeneous surface electronic conductivity during SEI formation and degradation. Complementary operando electrochemical quartz crystal microbalance (EQCM) and ex situ X-ray photoelectron spectroscopy (XPS) provide comprehensive analysis of the dynamic size and compositional evolution of the complex interfacial microstructure. We have found that stable anode passivation occurs at potentials of 0.5 V vs Li/Li+, even in cases where anion decomposition and interphase formation occur above 1.0 V. We investigated the bidirectional relationship between the SEI and lithium plating-stripping, finding that plating-stripping ruptures the SEI. The current efficiency of this reaction is correlated to the anodic stability of the SEI, highlighting the interdependent relationship between the two. We anticipate this work will provide critical insights on the rational design of stable and effective SEI layers for safe, fast-charging, and long-lifetime lithium metal batteries.

Hydrogen-Atom-Transfer-Initiated Radical/Polar Crossover Annulation Cascade for Expedient Access to Complex Tetralins.

A radical/polar crossover annulation between allyl-substituted arenes and electron-deficient alkenes is described. Cobalt-catalyzed hydrogen atom transfer (HAT) facilitates tandem radical C-C bond formation that generates functionalized tetralin products in the face of potentially problematic hydrofluorination, hydroalkoxylation, hydrogenation, alkene isomerization, and radical polymerization reactions. The reactions proceed under mild conditions that tolerate many functional groups, leading to a broad substrate scope. This powerful ring-forming reaction very quickly assembles complex tetralins that are the formal products of the largely infeasible Diels-Alder cycloadditions of styrenes.

[Update on the management of intracranial hypertension syndrome]. / Actualización en el tratamiento del síndrome de hipertensión intracraneana.

Elevated intracranial pressure (ICP) is a devastating complication, with great impact on neurological status and high morbidity and mortality. Intracranial hypertension (ICH) has multiple etiologies. The natural history of this condition can lead to brain death. The successful management of patients with elevated ICP (> 20-25 mmHg) requires fast and timely recognition, judicious use of invasive monitoring and therapies aimed to reversing its underlying cause. Therefore, it must be managed as a neurological emergency. The objective of this review is to present in a friendly way the diagnostic approach and the management of ICH, focused on general practitioners.

Actualización en el tratamiento del síndrome de hipertensión intracraneana / Update on the management of intracranial hypertension syndrome

Elevated intracranial pressure (ICP) is a devastating complication, with great impact on neurological status and high morbidity and mortality. Intracranial hypertension (ICH) has multiple etiologies. The natural history of this condition can lead to brain death. The successful management of patients with elevated ICP (> 20-25 mmHg) requires fast and timely recognition, judicious use of invasive monitoring and therapies aimed to reversing its underlying cause. Therefore, it must be managed as a neurological emergency. The objective of this review is to present in a friendly way the diagnostic approach and the management of ICH, focused on general practitioners.

Stereocontrolled Synthesis and Structural Revision of Plebeianiol A.

We report the structural revision via synthesis of the abietane diterpenoid plebeianiol A. The synthesis was accomplished by a short and convergent sequence that featured our previously established cobalt-catalyzed hydrogen-atom-transfer-induced radical bicyclization. We further connected plebeianiol A as the likely biogenetic precursor to another previously reported ether-bridged abietane. Finally, we demonstrated that the key cyclization event is efficient with the A-ring diol protected as two different cyclic acetals or in unprotected form.

Porous protein crystals as scaffolds for enzyme immobilization.

Porous protein crystals provide a template for binding and organizing guest macromolecules. Peroxidase, oxidase, and reductase enzymes immobilized in protein crystals retained activity in single-crystal and bulk assay formats. Several binding strategies, including metal affinity and physical entrapment, were employed to encourage enzyme adsorption into the protein crystals and to retain the enzymes for multiple recycles. Immobilized enzymes had lower activity compared to free enzyme in solution, in part due to diffusion limitations of substrate within the crystal pores. However, the immobilized enzymes were long-term stable and showed increased thermal tolerance. The potential applications of enzyme-laden crystals as sensing devices, delivery capsules, and microreactors motivate future development of this technology.

Outbreak of Acute Respiratory Illness Associated with Adenovirus Type 4 at the U.S. Naval Academy, 2016.

Human adenoviruses (HAdVs) are known to cause respiratory illness outbreaks at basic military training (BMT) sites. HAdV type-4 and -7 vaccines are routinely administered at enlisted BMT sites, but not at military academies. During August-September 2016, U.S. Naval Academy clinical staff noted an increase in students presenting with acute respiratory illness (ARI). An investigation was conducted to determine the extent and cause of the outbreak. During 22 August-11 September 2016, 652 clinic visits for ARI were identified using electronic health records. HAdV-4 was confirmed by realtime polymerase chain reaction assay in 18 out of 33 patient specimens collected and 1 additional HAdV case was detected from hospital records. Two HAdV-4 positive patients were treated for pneumonia including 1 hospitalized patient. Molecular analysis of 4 HAdV-4 isolates identified genome type 4a1, which is considered vaccine-preventable. Understanding the impact of HAdV in congregate settings other than enlisted BMT sites is necessary to inform discussions regarding future HAdV vaccine strategy.

Expeditionary Force Health Protection for Global Health Engagement: Lessons Learned from Continuing Promise 2017.

Background: Global health engagement (GHE) is an important priority for the Military Health Service as such activities strengthen the health capabilities of partner nations and improve interoperability. By their very nature, GHE activities are predominantly conducted in low-resource areas with limited infrastructure and substantial humanitarian need. The Department of Defense is evaluating leaner, flexible force packages to accomplish GHE missions and better prepare uniformed medical providers to provide care in austere environments. Methods: Observations made during the execution of Continuing Promise 2017, a recurring civil-military humanitarian operation conducted in Central and South America, are offered herein. Descriptions of relevant force health protection (FHP) threats experienced by mission personnel and mitigation measures successfully employed to prevent illness are provided. Relevant Department of Defense instructions are reviewed and risk mitigation strategies are compared with published standards and expert recommendations. Findings: In addition to well-described sanitation, hygiene, and infectious disease challenges that traditionally accompany military field activities, providing health care services to host nation populations in low-resource settings generates unique FHP vulnerabilities. Public health expertise leveraged throughout the planning and execution of GHE activities is instrumental for successfully identifying and mitigating the numerous FHP risks present. Discussion: Experiences from Continuing Promise 2017 demonstrate the expeditionary public health practitioner's role as a force multiplier has never been more relevant. A variety of public health countermeasures are available to successfully mitigate FHP threats experienced during GHE events. The public health lessons learned from Continuing Promise 2017 assist mission planners, commanders, and health care providers ensure that GHE participants remain healthy enough to accomplish the mission and meet America's commitments to partner nations.

Molecular dynamics simulations of cellulase homologs in aqueous 1-ethyl-3-methylimidazolium chloride.

Pretreating biomass using ionic liquids (ILs) can decrease cellulose crystallinity and lead to improved hydrolysis. However, cellulase activity is often reduced in even low concentrations of ILs, necessitating complete washing between pretreatment and hydrolysis steps. To better understand how ILs interact with enzymes at the molecular scale, endoglucanase E1 from Acidothermus cellulolyticus was simulated in aqueous 1-ethyl-3-methylimidazolium chloride ([Emim]Cl). Homologs with differing surface charge were also simulated to assess the role of electrostatic interactions between the enzyme and the surrounding solvent. Chloride anions interacted with the enzyme surface via Coulomb or hydrogen bond interactions, while [Emim] cations primarily formed hydrophobic or ring stacking interactions. Cations strongly associated with the binding pocket of E1, potentially inhibiting the binding of substrate molecules. At elevated temperatures, cations also disrupted native hydrophobic contacts and caused some loss of secondary structure. These observations suggested that both cations and anions could influence enzyme behavior and that denaturing and inhibitory interactions might both be important in aqueous IL systems.

Service Member Completion of Laboratory Follow-Up After Emergency Transfusion With Freshly Collected Blood Products.

BACKGROUND: Transfusion of freshly collected blood products (FCBP) is sometimes necessary to save service member (SM) lives in austere deployed environments. Recipients of FCBPs are administratively tracked and offered serial serologic testing via the Armed Services Blood Program "Blood Look Back" (BLB) program to assure early detection of post-transfusion infections. OBJECTIVES: This study evaluates demographic and clinical features influencing SM completion of recommended BLB laboratory follow-up after transfusion with FCBPs. METHODS: Using BLB programmatic data, a retrospective cohort study was performed examining U.S. SM transfusion recipients of FCBPs from June 1, 2006, through December 31, 2012. Multivariate logistic regression was used to examine clinical and demographic factors influencing completion of BLB recommended follow-up. RESULTS: Of eligible subjects, 69% (n = 778) completed 12-month recommended BLB follow-up. As compared to other services, U.S. soldiers demonstrated greatest compliance with BLB recommendations with 71.7% completing recommended follow-up. As compared to the Army, SMs from the Air Force (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.15-0.85), Marine Corps (OR = 0.51, 95% CI = 0.37-0.71), and Navy (OR = 0.29, 95% CI = 0.11-0.74) were less likely to complete recommended follow-up; however, differences in follow-up among the services attenuated over time. Neither the type of FCBP (platelets versus whole blood) nor the volume of FCBP transfused significantly altered SM likelihood of competing recommended follow-up. CONCLUSIONS: More than 2 out of 3 SMs completed recommended 12-month BLB follow-up after transfusion with FCBPs with greater compliance in Army SMs compared to other services. Programmatic changes implemented by the BLB program were temporally associated with increased SM compliance with recommended follow-up as well as reduction of disparities in follow-up observed between the services.

Health care worker follow-up compliance after occupational bloodborne pathogens exposure: A brief report.

A retrospective cohort study was conducted examining health care worker (HCW) compliance with Centers for Disease Control and Prevention recommendations following occupational bloodborne pathogen (BBP) exposure. HCWs with a BBP exposure from a known HIV- or hepatitis C virus-seropositive individual were less likely to complete recommended follow-up compared with HCWs with seronegative source patient exposures (adjusted odds ratio, 0.02 and 0.09, respectively). Continued targeted education and extra vigilance in performing postexposure surveillance are warranted in this higher-risk population.

In Situ Transformation of Chitosan Films into Microtubular Structures on the Surface of Nanoengineered Titanium Implants.

There is considerable interest in combining bioactive polymers such as chitosan with titanium bone implants to promote bone healing and address therapeutic needs. However, the fate of these biodegradable polymers especially on titanium implants is not fully explored. Here we report in situ formation of chitosan microtube (CMT) structures from chitosan films on the implant surface with titania nanotubes (TNTs) layer, based on phosphate buffer-induced transformation and precipitation process. We have comprehensively analyzed this phenomenon and the factors that influence CMT formation, including substrate topography, immersion solution and its pH, effect of coating thickness, and time of immersion. Significance of reported in situ formation of chitosan microtubes on the TNTs surface is possibly to tailor properties of implants with favorable micro and nano morphology using a self-ordering process after the implant's insertion.

Robust Superhydrophobic Graphene-Based Composite Coatings with Self-Cleaning and Corrosion Barrier Properties.

Superhydrophobic surfaces for self-cleaning applications often suffer from mechanical instability and do not function well after abrasion/scratching. To address this problem, we present a method to prepare graphene-based superhydrophobic composite coatings with robust mechanical strength, self-cleaning, and barrier properties. A suspension has been formulated that contains a mixture of reduced graphene oxide (rGO) and diatomaceous earth (DE) modified with polydimethylsiloxane (PDMS) that can be applied on any surface using common coating methods such as spraying, brush painting, and dip coating. Inclusion of TiO2 nanoparticles to the formulation shows further increase in water contact angle (WCA) from 159 ± 2° to 170 ± 2° due to the structural improvement with hierarchical surface roughness. Mechanical stability and durability of the coatings has been achieved by using a commercial adhesive to bond the superhydrophobic "paint" to various substrates. Excellent retention of superhydrophobicity was observed even after sandpaper abrasion and crosscut scratching. A potentiodynamic polarization study revealed excellent corrosion resistance (96.78%) properties, and an acid was used to provide further insight into coating barrier properties. The ease of application and remarkable properties of this graphene-based composite coating show considerable potential for broad application as a self-cleaning and protective layer.

Discriminating between stabilizing and destabilizing protein design mutations via recombination and simulation.

Accuracy of current computational protein design (CPD) methods is limited by inherent approximations in energy potentials and sampling. These limitations are often used to qualitatively explain design failures; however, relatively few studies provide specific examples or quantitative details that can be used to improve future CPD methods. Expanding the design method to include a library of sequences provides data that is well suited for discriminating between stabilizing and destabilizing design elements. Using thermophilic endoglucanase E1 from Acidothermus cellulolyticus as a model enzyme, we computationally designed a sequence with 60 mutations. The design sequence was rationally divided into structural blocks and recombined with the wild-type sequence. Resulting chimeras were assessed for activity and thermostability. Surprisingly, unlike previous chimera libraries, regression analysis based on one- and two-body effects was not sufficient for predicting chimera stability. Analysis of molecular dynamics simulations proved helpful in distinguishing stabilizing and destabilizing mutations. Reverting to the wild-type amino acid at destabilized sites partially regained design stability, and introducing predicted stabilizing mutations in wild-type E1 significantly enhanced thermostability. The ability to isolate stabilizing and destabilizing elements in computational design offers an opportunity to interpret previous design failures and improve future CPD methods.

Characterization of the target of ivermectin, the glutamate-gated chloride channel, from Anopheles gambiae.

The use of insecticide-treated nets and indoor residual insecticides targeting adult mosquito vectors is a key element in malaria control programs. However, mosquito resistance to the insecticides used in these applications threatens malaria control efforts. Recently, the mass drug administration of ivermectin (IVM) has been shown to kill Anopheles gambiae mosquitoes and disrupt Plasmodium falciparum transmission in the field. We cloned the molecular target of IVM from A. gambiae, the glutamate-gated chloride channel (AgGluCl), and characterized its transcriptional patterns, protein expression and functional responses to glutamate and IVM. AgGluCl cloning revealed an unpredicted fourth splice isoform as well as a novel exon and splice site. The predicted gene products contained heterogeneity in the N-terminal extracellular domain and the intracellular loop region. Responses to glutamate and IVM were measured using two-electrode voltage clamp on Xenopus laevis oocytes expressing AgGluCl. IVM induced non-persistent currents in AgGluCl-a1 and did not potentiate glutamate responses. In contrast, AgGluCl-b was insensitive to IVM, suggesting that the AgGluCl gene could produce IVM-sensitive and -insensitive homomultimers from alternative splicing. AgGluCl isoform-specific transcripts were measured across tissues, ages, blood feeding status and sex, and were found to be differentially transcribed across these physiological variables. Lastly, we stained adult, female A. gambiae for GluCl expression. The channel was expressed in the antenna, Johnston's organ, supraesophageal ganglion and thoracic ganglia. In summary, we have characterized the first GluCl from a mosquito, A. gambiae, and described its unique activity and expression with respect to it as the target of the insecticide IVM.

Risk of alcohol use disorder or other drug use disorder among U.S. Service members following traumatic brain injury, 2008-2011.

OBJECTIVES: Evaluate the risk of developing an alcohol use disorder (AUD) or other drug use disorder (ODUD) in U.S. service members (SMs) after incident traumatic brain injury (TBI) in both the deployed and the nondeployed setting. PARTICIPANTS AND METHODS: Retrospective cohort study of U.S. SMs who served on active duty from January 1, 2008 to December 31, 2010. The exposed cohort consisted of SMs who received an incident diagnosis of TBI during the exposure period. The unexposed cohort was populated with a 10% random sample of SMs with any other medical diagnosis over the exposure period. RESULTS: After adjusting for various demographic factors, TBI severity, historic diagnosis of post-traumatic stress disorder (PTSD), comorbid PTSD, and comorbid mental health outcomes, the TBI cohort (n = 53,817) demonstrated elevated incident rate ratio of developing AUD (adjusted incidence rate ratios (IRR) 1.5, 95% confidence interval (CI) 1.4, 1.6, p < 0.0001) as compared to an unexposed cohort (n = 151,776). The TBI cohort did not demonstrate elevated risk of ODUD as compared to the unexposed cohort (adjusted IRR 1.0, 95% CI 1.0, 1.2, p = 0.178). CONCLUSIONS: U.S. SMs diagnosed with incident TBI demonstrated increased risk of developing an AUD within 1 year of incident TBI as compared to SMs without diagnosed TBI.

Notes from the field: investigation of contacts of a health care worker who worked while ill with pertussis--Maryland, August-September 2014.

On September 5, 2014, the public health department of a Maryland hospital was notified of a case of Bordetella pertussis infection confirmed by polymerase chain reaction (PCR) in a staff health care worker (HCW). The HCW experienced onset of diarrhea and malaise (nonrespiratory symptoms atypical of the catarrhal phase of pertussis) on August 26. By September 2, paroxysms of coughing led the HCW to consult a colleague, who ordered the PCR test, prescribed a 5-day course of azithromycin, and advised avoidance of patient care until treatment completion. Contrary to the hospital's infection control policy, neither the HCW nor the colleague reported the presumptive diagnosis of pertussis to the hospital's public health department. The HCW continued to work in the outpatient department until the positive PCR result was received on September 5, at which time the hospital's public health department was first notified. The hospital barred the HCW from further work at the hospital while ill, and, in collaboration with local and state public health counterparts, began a contact investigation and stratified patient and HCW contacts by level of exposure.

Tuberculosis contact investigation in a military health care setting: case report and evidence review.

Tuberculosis (TB) remains a global threat to the U.S. armed forces. A single individual with TB disease exerts an immediate and disruptive impact upon patients' lives, military operations, and daily functioning at military treatment facilities. Medical personnel in operational or limited-resource settings are sometimes challenged to perform a TB outbreak investigation with minimal specialized training or limited logistic assistance. This article presents a case of a patient with TB disease presenting to a large military treatment facility and outlines the current, evidence-based recommendations for performing a TB outbreak investigation.