Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.

A Policy Analysis of Preparedness for Hurricane Evacuations in the United States, 1990 to 2019: Implementation in Coastal States.

Hurricane or typhoon evacuations in the United States are typically managed by state, territorial, or tribal emergency management officials with federal, state, and local agency operational support. The evacuation process may involve issuing mandatory or "voluntary" evacuation orders to alert the community and mitigate loss of life and injury. We conducted an analysis of state and local hurricane evacuation policies identified through a literature review (January 1990 to June 2019) and key informant interviews with state public health and emergency management officials in Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Texas in October and November 2019. Findings from the literature review show that most gaps in hurricane evacuation preparedness-based on 44 policy-related publications identified in the review-could be categorized into 4 themes: shelters, evacuation decisionmaking, at-risk populations, and transportation. Findings from key informant interviews for 7 states revealed that coastal states have been able to address most of these gaps since Hurricane Katrina in 2005. However, an important remaining gap in preparedness is providing timely warnings to at-risk populations during hurricane evacuations.

Structure Elucidation Using Gas Chromatography-Infrared Spectroscopy/Mass Spectrometry Supported by Quantum Chemical IR Spectrum Simulations.

An improved strategy for compound identification incorporating gas chromatography hyphenated with Fourier transform infrared spectroscopy and mass spectroscopy (GC-FTIR/MS) is reported. (Over)reliance on MS may lead either to ambiguous identity or to incorrect identification of a compound. However, the MS result is useful to provide a cohort of possible compounds. The IR result for each tentative compound match was then simulated using molecular modeling, to provide functional group and isomer differentiation information, and then compared with the experimental FTIR result, offering identification based on both MS and IR. Several basis sets were evaluated for IR simulations; Def2-TZVPP was a suitable basis set and correlated well with experimental data. The approach was applied to industrial applications, confirming the isomers of 2,3-bis(thiosulfanyl)-but-2-enedinitrile, bromination products of 1-bromo-2,3-dimethylbenzene, and autoxidative degradation of phenyl-di-tert-butylphosphine.

An Innovative United States-Mexico Community Outreach Initiative for Hispanic and Latino People in the United States: A Collaborative Public Health Network.

Collaborative partnerships are a useful approach to improve health conditions of disadvantaged populations. The Ventanillas de Salud (VDS) ("Health Windows") and Mobile Health Units (MHUs) are a collaborative initiative of the Mexican government and US public health organizations that use mechanisms such as health fairs and mobile clinics to provide health information, screenings, preventive measures (eg, vaccines), and health services to Mexican people, other Hispanic people, and underserved populations (eg, American Indian/Alaska Native people, geographically isolated people, uninsured people) across the United States. From 2013 through 2019, the VDS served 10.5 million people (an average of 1.5 million people per year) at Mexican consulates in the United States, and MHUs served 115 461 people from 2016 through 2019. We describe 3 community outreach projects and their impact on improving the health of Hispanic people in the United States. The first project is an ongoing collaboration between VDS and the Centers for Disease Control and Prevention (CDC) to address occupational health inequities among Hispanic people. The second project was a collaboration between VDS and CDC to provide Hispanic people with information about Zika virus infection and health education. The third project is a collaboration between MHUs and the University of Arizona to provide basic health services to Hispanic communities in Pima and Maricopa counties, Arizona. The VDS/MHU model uses a collaborative approach that should be further assessed to better understand its impact on both the US-born and non-US-born Hispanic population and the public at large in locations where it is implemented.

Hurricane Evacuation Laws in Eight Southern U.S. Coastal States - December 2018.

National Preparedness month is observed every September as a public service reminder of the importance of personal and community preparedness for all events; it coincides with the peak of the hurricane season in the United States. Severe storms and hurricanes can have long-lasting effects at all community levels. Persons who are prepared and well-informed are often better able to protect themselves and others (1). Major hurricanes can devastate low-lying coastal areas and cause injury and loss of life from storm surge, flooding, and high winds (2). State and local government entities play a significant role in preparing communities for hurricanes and by evacuating coastal communities before landfall to reduce loss of life from flooding, wind, and power outages (3). Laws can further improve planning and outreach for catastrophic events by ensuring explicit statutory authority over evacuations of communities at risk (4). State evacuation laws vary widely and might not adequately address information and communication flows to reach populations living in disaster-prone areas who are at risk. To understand the range of evacuation laws in coastal communities that historically have been affected by hurricanes, a systematic policy scan of the existing laws supporting hurricane evacuation in eight southern coastal states (Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Texas) was conducted. After conducting a thematic analysis, this report found that all eight states have laws to execute evacuation orders, traffic control (egress/ingress), and evacuation to shelters. However, only four of the states have laws related to community outreach, delivery of public education programs, and public notice requirements. The findings in this report suggest a need for authorities in hurricane-prone states to review how to execute evacuation policies, particularly with respect to community outreach and communication to populations at risk. Implementation of state evacuation laws and policies that support hurricane evacuation management can help affected persons avoid harm and enhance community resiliency (5). Newly emerging and re-emerging infectious diseases, such as SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), have and will continue to additionally challenge hurricane evacuations.

Electrochemical Behavior of Graphene in a Deep Eutectic Solvent.

Graphene electrodes and deep eutectic solvents (DESs) are two emerging material systems that have individually shown highly promising properties in electrochemical applications. To date, however, it has not been tested whether the combination of graphene and DESs can yield synergistic effects in electrochemistry. We therefore study the electrochemical behavior of a defined graphene monolayer of centimeter-scale, which was produced by chemical vapor deposition and transferred onto insulating SiO2/Si supports, in the common DES choline chloride/ethylene glycol (12CE) under typical electrochemical conditions. We measure the graphene potential window in 12CE and estimate the apparent electron transfer kinetics of an outer-sphere redox couple. We further explore the applicability of the 12CE electrolyte to fabricate nanostructured metal (Zn) and metalloid (Ge) hybrids with graphene by electrodeposition. By comparing our graphene electrodes with common bulk glassy carbon electrodes, a key finding we make is that the two-dimensional nature of the graphene electrodes has a clear impact on DES-based electrochemistry. Thereby, we provide a first framework toward rational optimization of graphene-DES systems for electrochemical applications.

Determining the Regiochemistry and Relative Stereochemistry of Small and Druglike Molecules Using an Alignment Algorithm for Infrared Spectra.

The relative stereochemistry and isomeric substitution pattern of organic molecules is typically determined using nuclear magnetic resonance spectroscopy (NMR). However, NMR spectra are sometimes nonconclusive, e.g., if spectra are extremely crowded, coupling patterns are not resolved, or if symmetry reasons preclude interpretation. Infrared spectroscopy (IR) can provide additional information in such cases, because IR represents a molecule comprehensively by depiction of the complete set of its normal vibrations. The challenge is thereby that diastereomers and substitution isomers often give rise to highly similar IR spectra, and visual distinction is insufficient and may be biased. Here we show the adaptation of an alignment algorithm, originally developed for vibrational circular dichroism (VCD) spectroscopy, to automatically match IR spectra and provide a quantitative measure of the goodness of fit, which can be used to distinguish isomers. The performance of the approach is demonstrated for different use cases: diastereomers of flexible druglike molecules, E/Z-isomers, and substitution isomers of pyrazine and naphthalene. It can be applied to IR spectra measured both in the gas phase (gas chromatography IR) and in solution.

Evolution of the Public Health Preparedness and Response Capability Standards to Support Public Health Emergency Management Practices and Processes.

In spring 2011, the Centers for Disease Control and Prevention (CDC) released Public Health Preparedness Capabilities: National Standards for State and Local Planning. The capability standards provide a framework that supports state, local, tribal, and territorial public health agency preparedness planning and response to public health threats and emergencies. In 2017, a project team at the CDC Division of State and Local Readiness incorporated input from subject matter experts, national partners, and stakeholders to update the 2011 capability standards. As a result, CDC released the updated capability standards in October 2018, which were amended in January 2019. The original structure of the 15 capability standards remained unchanged, but updates were made to capability functions, tasks, and resource elements to reflect advances in public health emergency preparedness and response practices since 2011. When the number of functions and tasks in the 2018 capability standards were compared to those in the 2011 capabilities, only 20% (3/15) of the capabilities had a decrease in function number. The majority of changes were at the task level (task numbers changed in 80%, or 12/15, capabilities) in the 2018 version. The capability standards provide public health agencies with a practical framework, informed by updated science and tools, which can guide prioritization of limited resources to strengthen public health agency emergency preparedness and response capacities.

Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography.

Aggregates of tau and beta amyloid (Aß) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aß plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.

School District Crisis Preparedness, Response, and Recovery Plans - United States, 2012.

The unique characteristics of children dictate the need for school-based all-hazards response plans during natural disasters, emerging infectious diseases, and terrorism (1-3). Schools are a critical community institution serving a vulnerable population that must be accounted for in public health preparedness plans; prepared schools are adopting policies and plans for crisis preparedness, response, and recovery (2-4). The importance of having such plans in place is underscored by the development of a new Healthy People 2020 objective (PREP-5) to "increase the percentage of school districts that require schools to include specific topics in their crisis preparedness, response, and recovery plans" (5). Because decisions about such plans are usually made at the school district level, it is important to examine district-level policies and practices. Although previous reports have provided national estimates of the percentage of districts with policies and practices in place (6), these estimates have not been analyzed by U.S. Census region* and urbanicity.(†) Using data from the 2012 School Health Policies and Practices Study (SHPPS), this report examines policies and practices related to school district preparedness, response, and recovery. In general, districts in the Midwest were less likely to require schools to include specific topics in their crisis preparedness plans than districts in the Northeast and South. Urban districts tended to be more likely than nonurban districts to require specific topics in school preparedness plans. Southern districts tended to be more likely than districts in other regions to engage with partners when developing plans. No differences in district collaboration (with the exception of local fire department engagement) were observed by level of urbanicity. School-based preparedness planning needs to be coordinated with interdisciplinary community partners to achieve Healthy People 2020 PREP-5 objectives for this vulnerable population.

Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone.

Immunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine for serogroups A, C, W, and Y (MenACWY) administered alone (n = 41) or concomitantly with other vaccines (n = 279) to U.S. military personnel (mean age, 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, and various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and postvaccination sera for Neisseria meningitidis serogroups C and Y 1 to 12 months (mean, 4.96 months) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG concentration in serum, ≥2 µg/ml; rSBA titer, ≥8) corresponding to an immunologic response was higher postvaccination than at baseline (P < 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (range of odds ratios [ORs], 1.5 to 21.7) and more of them seroconverted (OR range, 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to U.S. military personnel.

The content of goals in individual educational programs for students with complex communication needs.

The aim of the study was to explore the contents of communication-related goals in individualized education programs (IEPs) for students with complex communication needs. Goals in 43 IEPs were linked to the International Classification of Functioning, Disability and Health, Children and Youth version (ICF-CY). The results show that the communication-related IEP goals contain information on multiple domains of functioning in the ICF-CY. However, judging by the amount of codes linked to ICF-CY chapters, the IEPs contain a relatively small proportion of goals that focus on interaction with others, or participation in classroom and leisure activities. Special education teachers and speech-language pathologists working with students with complex communication needs may need support to formulate communication-related IEP goals with a focus on interaction and participation in school activities.

The Communication Supports Inventory-Children & Youth (CSI-CY), a new instrument based on the ICF-CY.

PURPOSE: Two studies are presented that evaluated the Communication Supports Inventory-Children & Youth (CSI-CY), an instrument designed to facilitate the development of communication-related educational goals for students with complex communication needs (CCN). The CSI-CY incorporates a code set based on the ICF-CY. The studies were designed to determine the effect of using the CSI-CY on IEP goals for students with CCN and to evaluate consumer satisfaction. METHOD: In Study 1, sixty-one educators and speech-language pathologists were randomly assigned to either (a) provide a student's current IEP (control group) or (b) complete the CSI-CY prior to preparing a student's next IEP and to submit the new IEP (experimental group). Study 2 was a field test to generate consumer satisfaction data. RESULTS: Study 1 showed that IEP goals submitted by participants in the experimental group referenced CSI-CY-related content significantly more frequently than did those submitted by control participants. Study 2 revealed high satisfaction with the instrument. CONCLUSIONS: The code set basis of the CSI-CY extends the common language of the ICF-CY to practical educational use for children with CCN across diagnostic groups. The CSI-CY is well regarded as an instrument to inform the content of communication goals related to CCN. Implications for Rehabilitation The CSI-CY will guide rehabilitation professionals to develop goals for children with complex communication impairments. The CSI-CY is a new instrument that is based on the ICF-CY for documentation of communication goals.

Naturally acquired antibodies against Haemophilus influenzae type a in Aboriginal adults, Canada.

In the post-Haemophilus influenzae type b (Hib) vaccine era that began in the 1980's, H. influenzae type a (Hia) emerged as a prominent cause of invasive disease in North American Aboriginal populations. To test whether a lack of naturally acquired antibodies may underlie increased rates of invasive Hia disease, we compared serum bactericidal activity against Hia and Hib and IgG and IgM against capsular polysaccharide between Canadian Aboriginal and non-Aboriginal healthy and immunocompromised adults. Both healthy and immunocompromised Aboriginal adults exhibited significantly higher bactericidal antibody titers against Hia than did non-Aboriginal adults (p = 0.042 and 0.045 respectively), with no difference in functional antibody activity against Hib. IgM concentrations against Hia were higher than IgG in most study groups; the inverse was true for antibody concentrations against Hib. Our results indicate that Aboriginal adults possess substantial serum bactericidal activity against Hia that is mostly due to IgM antibodies. The presence of sustained IgM against Hia suggests recent Hia exposure.

Effect of multiple, simultaneous vaccines on polio seroresponse and associated health outcomes.

BACKGROUND: Administration of multiple simultaneous vaccines to infants, children, and military recruits is not uncommon. However, little research exists to examine associated serological and health effects, especially in adults. METHOD: We retrospectively examined 416 paired serum specimens from U.S. military subjects who had received the inactivated polio vaccine (IPV) alone or in combination with either 1 other vaccine (<3 group) or 4 other vaccines (>4 group). Each of the 2 groups was subdivided into 2 subgroups in which Tdap was present or absent. RESULTS: The >4 group was associated with a higher proportion of polio seroconversions than the <3 group (95% vs. 58%, respectively, p<0.01). Analysis of the <3 subgroup that excluded Tdap vs. the >4 subgroup that excluded Tdap showed no difference between them (p>0.1). However, the >4 subgroup that included Tdap had significantly more seroconversions than either the <3 subgroup that excluded Tdap or the >4 subgroup that excluded Tdap (p<0.01). Overall, at least 98% of subjects were at or above the putative level of seroprotection both pre- and post-vaccination, yet at least 81% of subjects seroconverted. In an analysis of 400 of the subjects in which clinic in- and outpatient encounters were counted over the course of 1 year following vaccinations, there was no significant difference between the 2 groups (p>0.1). CONCLUSION: A combination of >4 vaccines including IPV appeared to have an immunopotentiation effect on polio seroconversion, and Tdap in particular was a strong candidate for an important role. The dose of IPV we studied in our subjects, who already had a high level of seroprotection, acted as a booster. In addition, there appear to be no negative health consequences from receiving few versus more multiple simultaneous vaccinations.

Persistence of serogroup C antibody responses following quadrivalent meningococcal conjugate vaccination in United States military personnel.

Serogroup C meningococcal (MenC) disease accounts for one-third of all meningococcal cases and causes meningococcal outbreaks in the U.S. Quadrivalent meningococcal vaccine conjugated to diphtheria toxoid (MenACYWD) was recommended in 2005 for adolescents and high risk groups such as military recruits. We evaluated anti-MenC antibody persistence in U.S. military personnel vaccinated with either MenACYWD or meningococcal polysaccharide vaccine (MPSV4). Twelve hundred subjects vaccinated with MenACYWD from 2006 to 2008 or MPSV4 from 2002 to 2004 were randomly selected from the Defense Medical Surveillance System. Baseline serologic responses to MenC were assessed in all subjects; 100 subjects per vaccine group were tested during one of the following six post-vaccination time-points: 5-7, 11-13, 17-19, 23-25, 29-31, or 35-37 months. Anti-MenC geometric mean titers (GMT) were measured by rabbit complement serum bactericidal assay (rSBA) and geometric mean concentrations (GMC) by enzyme-linked immunosorbent assay (ELISA). Continuous variables were compared using the Wilcoxon rank sum test and the proportion of subjects with an rSBA titer ≥ 8 by chi-square. Pre-vaccination rSBA GMT was <8 for the MenACWYD group. rSBA GMT increased to 703 at 5-7 months post-vaccination and decreased by 94% to 43 at 3 years post-vaccination. GMT was significantly lower in the MenACWYD group at 5-7 months post-vaccination compared to the MPSV4 group. The percentage of MenACWYD recipients achieving an rSBA titer of ≥ 8 decreased from 87% at 5-7 months to 54% at 3 years. There were no significant differences between vaccine groups in the proportion of subjects with a titer of ≥ 8 at any time-point. GMC for the MenACWYD group was 0.14 µg/mL at baseline, 1.07 µg/mL at 5-7 months, and 0.66 µg/mL at 3 years, and significantly lower than the MPSV4 group at all time-points. Anti-MenC responses wane following vaccination with MenACYWD; a booster dose is needed to maintain protective levels of circulating antibody.

Molecular signatures of antibody responses derived from a systems biology study of five human vaccines.

Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling.

Structured water molecules in the binding site of bromodomains can be displaced by cosolvent.

Bromodomains are α-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2-5 ns, and 10-30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50-500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol.

Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B.

Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.