Disaster healthcare disparities solutions: Part 3-Recovery and mitigation.

The purpose of this study was to explore the potential solutions for disaster healthcare disparities. This paper is the third of a three-part series that was written by the Disaster Healthcare Disparities Workgroup of the American College of Emergency Physicians Disaster Preparedness and Response Committee. The committee conducted a literature review and chose articles most representative and demonstrative of solutions to disaster healthcare disparities found in a past workgroup product. Many solutions for disaster healthcare disparities seen during recovery and mitigation were found. Some of these solutions have been successfully implemented and some remain theoretical. Solutions for disaster healthcare disparities seen during recovery and mitigation are achievable but there is still much work to do. Many of these solutions can be advocated for by nondisaster specialists.

Disaster healthcare disparities solutions: Part 2-Response.

The purpose of this study was to explore the potential solutions for disaster healthcare disparities. This paper is the second of a three-part series that was written by the Disaster Healthcare Disparities Workgroup of the American College of Emergency Physicians Disaster Preparedness and Response Committee. The committee conducted a literature review and chose articles most representative and demonstrative of solutions to disaster healthcare disparities found in a past workgroup product. Many solutions for disaster healthcare disparities during disaster response were found. Some of these solutions have been successfully implemented and some are hypothetical. Solutions for disaster healthcare disparities seen during response are achievable but there is still much work to do. A variety of the proposed solutions can be advocated for by nondisaster specialists leading to better care for all our patients.

Disaster healthcare disparities solutions: Part 1-Preparation.

The purpose of this study was to explore the potential solutions for disaster healthcare disparities. This paper is the first of a three-part series that was written by the Disaster Healthcare Disparities Workgroup of the American College of Emergency Physicians Disaster Preparedness and Response Committee. The committee workgroup conducted a literature review and chose articles most representative and demonstrative of solutions to disaster healthcare disparities found in a past workgroup product exploring disaster healthcare disparities seen in disaster. Many solutions for disaster healthcare disparities during preparation were found. Some of these solutions have been successfully implemented, while others are still theoretical. Solutions for disaster healthcare disparities seen in disaster preparation are achievable, but there is still much work to do. There are a variety of solutions that can be easily advocated for by disaster and nondisaster specialists, leading to better care for our patients.

Disparities in disaster healthcare: A review of past disasters.

OBJECTIVE: To review the literature on the effects seen after disaster on those with poor social determinants of health (SDOH) and individual social needs. DESIGN: The Disaster Preparedness and Response Committee of the American College of Emergency Physicians (ACEP) formed a work group to study healthcare disparities seen in disaster. This group was composed of six physicians on the committee, all of whom have extensive background in disaster medicine and the chair of the committee. A systematic literature review regarding past disasters and all the healthcare disparities seen was undertaken with the goal of organizing this information in one broad concise document looking at multiple disasters over history. The group reviewed multiple documents regarding SDOH and individual social needs for a complete understanding of these factors. Then, a topic list of healthcare disparities resulting from these factors was composed. This list was then filled out with subtopics falling under the header topics. Each member of the workgroup took one of these topics of healthcare disparity seen in disasters and completed a literature search. The databases reviewed include PubMed Central, Google Scholar, and Medline. The terms queried were disaster, healthcare disparities, disaster healthcare disparities, healthcare disparities associated with disasters, SDOH and disaster, special populations and disaster effects, and vulnerable populations and disaster effects. Each author chose articles they felt were most representative and demonstrative of the healthcare disparities seen in past disasters. These social determinant factors and individual social needs were then cross referenced in relation to past disasters for both their causes and the effect they had on various populations after disaster. This was presented to the ACEP board as a committee report. RESULTS: All the SDOH and individual social needs showed significant negative effects for the populations when combined with a disaster event. These SDOH cut across age, race, and gender affecting a wide swath of people. Previous disaster planning either did not plan or under planned for these marginalized populations during disaster events. CONCLUSIONS: Disparities in healthcare are a pervasive problem that effects many different groups. Disasters magnify and more fully expose these healthcare disparities. We have explored the healthcare disparities with past disasters. These disparities, although common, can be mitigated. The recognition of these poor determinants of health can lead to better and more comprehensive disaster planning for future disasters. Subsequent research is needed to explore these healthcare disparities exacerbated by disasters and to find methods for their mitigation.

Interventions to improve the psychological well-being of healthcare workers in disasters, pandemics, and mass casualty events.

OBJECTIVES: This information paper will describe the current research and recommendations for improving healthcare worker's (HCW) mental health. Individual and organizational goals will be outlined with items broken up into the time frames of predisaster, during a disaster, and post-disaster. METHODS: A team of subject matter experts reviewed the current literature utilizing a search of PubMed, Google Scholar, relevant article reference lists, and subject matter interviews. RESULTS: Thirty-six distinct recommendations were identified and distributed into the time frames of predisaster, during a disaster, and post-disaster. Twenty-one of these are pertaining to organizational goals and factors. Fifteen recommendations are identified for individual HCWs. CONCLUSIONS: Additional institutional and government policies supporting the protection of HCW's mental health are required to reduce the stigma and fear, preventing frontline workers from seeking help with the psychological effects of disasters, mass casualty incidents, and pandemics. Further research dealing with ways to ameliorate the negative effects of the stress related to the duties and responsibilities of HCWs, which are exacerbated by disasters, is needed.

A Medical Review of Fatal High-G U.S. Aerobatic Accidents.

INTRODUCTION: Exposure to high G force is a known safety hazard in military aviation as well as civilian aerobatic flight. Tolerance to high G forces has been well studied in military pilots, but there is little research directed at civilian pilots who may have medications or medical conditions not permitted in military pilots.METHODS: In this case-control study, we identified 89 fatal high-G aerobatic accidents and 4000 fatal control accidents from 1995 through 2018 from the NTSB accident database and the FAA autopsy database. We retrieved medications and medical conditions from the FAA's pilot medical databases. Logistic regression models were used to explore the associations of drugs, medical conditions, height, and medical waivers with high-G accidents.RESULTS: Seven drugs (alprazolam, clonidine, ethanol, meclizine, phentermine, triamterene, and zolpidem) reached statistical significance in our models, but had such small case counts that we consider these findings to be uncertain, except for ethanol, which was found in seven cases. Of these, only triamterene was known to the FAA. Statistically significant medical predictors included only alcohol abuse (seven cases) and liver disease (only two cases).DISCUSSION: Our analysis found that the drug ethanol and the condition alcohol abuse are significantly associated with high-G accidents. Seven other factors were statistically significant, but should only be considered as hypothesis generating due to very low case counts. Our study does not suggest that restricting pilots with otherwise permissible medications or medical conditions from aerobatics is warranted.Mills WD, Greenhaw RM, Wang JMP. A medical review of fatal high-G U.S. aerobatic accidents. Aerosp Med Hum Perform. 2019; 90(11):959-965.

HPLC method development, validation, and impurity characterization of a potent antitumor nucleoside, T-dCyd (NSC 764276).

An HPLC method for the assay of an anticancer nucleoside, 4'-thio-2'-deoxycytidine (T-dCyd, NSC 764276), has been developed and validated. The stress testing of T-dCyd was carried out in accordance with ICH guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of T-dCyd from its impurities and degradation products was achieved in 40min on a Luna® Phenyl-Hexyl column (150mm×4.6mm i.d., 3µm) with a gradient elution using ammonium phosphate buffer (pH 3.85) and methanol as the mobile phase. The gradient starts from 2% and ends at 80% of methanol. Detection is by UV at 282nm. LC-QTOF/MS was used to obtain mass data for characterization of impurities and degradation products. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.25-0.75mg/mL, r≥0.9998), accuracy (recovery 98.1-102.0%), precision (RSD≤1.5%), and sensitivity (LOD 0.1µg/mL). The developed method was suitable for the quality control and stability monitoring of the T-dCyd drug substance.

HPLC method development, validation, and impurity characterization of a potent antitumor indenoisoquinoline, LMP776 (NSC 725776).

An HPLC method for the assay of a DNA topoisomerase inhibitor, LMP776 (NSC 725776), has been developed and validated. The stress testing of LMP776 was carried out in accordance with International Conference on Harmonization (ICH) guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of LMP776 from its impurities and degradation products was achieved within 40 min on a Supelco Discovery HS F5 column (150 mm × 4.6 mm i.d., 5 µm) with a gradient mobile phase comprising 38-80% acetonitrile in water, with 0.1% trifluoroacetic acid in both phases. LC/MS was used to obtain mass data for characterization of impurities and degradation products. One major impurity was isolated through chloroform extraction and identified by NMR. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.25-0.75 mg/mL, r = 0.9999), accuracy (recovery 98.6-100.4%), precision (RSD ≤ 1.4%), and sensitivity (LOD 0.13 µg/mL). The validated method was used in the stability study of the LMP776 drug substance in conformance with the ICH Q1A (R2) guideline.

Characterization, HPLC method development and impurity identification for 3,4,3-LI(1,2-HOPO), a potent actinide chelator for radionuclide decorporation.

3,4,3-LI(1,2-HOPO), 1,5,10,14-tetra(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14-tetraazatetradecane), is a potent octadentate chelator of actinides. It is being developed as a decorporation treatment for internal contamination with radionuclides. Conventional HPLC methods exhibited speciation peaks and bridging, likely attributable to the agent's complexation with residual metallic ions in the HPLC system. Derivatization of the target ligand in situ with Fe(III) chloride, however, provided a single homogeneous iron-complex that can readily be detected and analyzed by HPLC. The HPLC method used an Agilent Eclipse XDB-C18 column (150 mm × 4.6mm, 5 µm) at 25°C with UV detection at 280 nm. A gradient elution, with acetonitrile (11% to 100%)/buffer mobile phase, was developed for impurity profiling. The buffer consisted of 0.02% formic acid and 10mM ammonium formate at pH 4.6. An Agilent 1200 LC-6530 Q-TOF/MS system was employed to characterize the [Fe(III)-3,4,3-LI(1,2-HOPO)] derivative and impurities. The proposed HPLC method was validated for specificity, linearity (concentration range 0.13-0.35 mg/mL, r = 0.9999), accuracy (recovery 98.3-103.3%), precision (RSD ≤ 1.6%) and sensitivity (LOD 0.08 µg/mL). The LC/HRMS revealed that the derivative was a complex consisting of one 3,4,3-LI(1,2-HOPO) molecule, one hydroxide ligand, and two iron atoms. Impurities were also identified with LC/HRMS. The validated HPLC method was used in shelf-life evaluation studies which showed that the API remained unchanged for one year at 25°C/60% RH.

Aurora kinase A is a possible target of OSU­03012 to destabilize MYC family proteins.

OSU-03012, a 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitor, destabilizes MYCN and MYC proteins in neuroblastoma cells. However, AKT phosphorylation is barely detectable in neuroblastoma cells under normal culture conditions whether treated with OSU-03012 or not. This observation suggests that PDK1 is not the main target of OSU-03012 to destabilize MYC and MYCN in neuroblastoma cells. In the present study, we explored one of the possible mechanisms by which OSU-03012 destabilizes MYC and MYCN. Since Aurora kinase A is reported to phosphorylate GSK3ß, leading to its inactivation, we hypothesized that one of the targets of OSU-03012 is Aurora kinase A. Comparative analysis of OSU-03012 and VX-680, a potent and specific inhibitor of Aurora kinases, showed that both inhibitors destabilized MYC and MYCN and were significantly growth suppressive to neuroblastoma cell lines. In silico molecular docking analysis further showed that the calculated interaction energy between Aurora kinase A and OSU-03012 was -109.901 kcal/mol, which was lower than that (-89.273 kcal/mol) between Aurora kinase A and FXG, an Aurora kinase-specific inhibitor. Finally, an in vitro Aurora kinase A inhibition assay using a recombinant Aurora kinase A showed that OSU-03012 significantly inhibited Aurora kinase A, although it was weaker in potency than that of VX-680. Thus, OSU-03012 has a likelihood of binding to and inhibiting Aurora kinase A in vivo. These results suggest that OSU-03012 affects multiple cellular targets, including Aurora kinase A, to exhibit its growth suppressive and MYC and MYCN-destabilizing effects on neuroblastoma and other cancer cells.

HPLC method development, validation and impurity characterization for an antitumor Hsp90 inhibitor-PU-H71 (NSC 750424).

An HPLC method for the assay of the heat shock protein 90 inhibitor, PU-H71 (NSC 750424), has been developed and validated. The stress testing of PU-H71 was carried out in accordance with ICH guidelines Q1A (R2) under aqueous, acidic, alkaline, oxidative, thermolytic and photolytic conditions. The separation of PU-H71 from its impurities and degradation products was achieved within 50min on a Mac-Mod ACE 3 C18 column (150mm×4.6mm i.d., 3µm) with a gradient mobile phase comprising 20-95% acetonitrile in water, with 0.1% trifluroacetic acid in both phases. LC-quadrupole TOF/MS was used to obtain accurate mass data on various components as well as on their fragments for characterization of impurities and degradation products. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.1-0.3mg/mL, r≥0.9998), accuracy (recovery 99.7-101.1%), precision (intra-lab RSD≤1.39%, inter-lab RSD≤0.91%), sensitivity (LOD 0.08µg/mL), and ruggedness. The developed method was suitable for the assay and stability monitoring of PU-H71 drug substance.

A 78-year-old man with rapidly-progressing sarcomatoid renal cell carcinoma.

We report a case of metastatic sarcomatoid renal cell carcinoma (SRCC), which presented as nephrotic syndrome with diffuse peripheral edema. At the time of diagnosis, the metastatic disease involved bone, with peritoneal lymphadenopathy. The nephrotic syndrome did not improve after nephrectomy. Systemic disease progressed quickly postoperatively. The sarcomatoid renal cell carcinoma in this case had an aggressive clinical course. CNS metastasis quickly developed, and the patient passed away soon after.

LC/MS characterization of impurities and degradation products of a potent antitumor peptidic dimer, CU201.

Compound CU201 [SUIM-(d-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-d-Igl-Oic-Arg)(2), where SUIM=suberimidyl; Hyp=trans-4-hydroxyproline; Igl=alpha-(2-indanyl)-glycine; Oic=octahydroindole-2-carboxylic acid], is a dimeric analog of the potent bradykinin antagonist peptide B9430. It blocks the G(alphaq,11) signal of the heterotrimeric G proteins, stimulates c-Jun kinases, and induces apoptosis in lung cancer cells with neuroendocrine features. CU201 shows potent inhibition for small-cell lung cancer cells in vitro (ED(50)=0.15microM), as well as for small-cell lung cancer SHP-77 tumor growth in vivo. An HPLC method was developed, as part of a study supported by the National Cancer Institute's (NCI's) Rapid Access to Interventional Development (RAID) program, to assess the purity and stability of CU201. Impurities and degradation products were characterized by LC/MS. The identity of a major impurity, with 1 mass unit different from CU201, was confirmed by high resolution LC/MS and the investigation of model compounds. Susceptible linkages in the peptide chains were revealed by the degradation study.

Decellularization of bovine corneas for tissue engineering applications.

Scaffolds derived from processed tissues offer viable alternatives to synthetic polymers as biological scaffolds for regenerative medicine. Tissue-derived scaffolds provide an extracellular matrix (ECM) as the starting material for wound healing and the functional reconstruction of tissues, offering a potentially valuable approach for the replacement of damaged or missing tissues. Additionally, acellular tissue may provide a natural microenvironment for host-cell migration and the induction of stem cell differentiation to contribute to tissue regeneration. There are a number of processing methods that aim to stabilize and provide an immunologically inert tissue scaffold. Furthermore, these tissue-processing methods can often be applied to xenogenic transplants because the essential components of the ECM are often maintained between species. In this study, we applied several tissue-processing protocols to the cornea in order to obtain a decellularized cornea matrix that maintained the clarity and mechanical properties of the native tissue. Histology, mechanical testing and electron microscopy techniques were used to assess the cell extraction process and the organization of the remaining ECM. In vitro cell seeding experiments confirmed the processed corneas' biocompatibility.

Chromatographic analysis and decomposition product characterization of compound SR16157 (NSC 732011).

SR16157 (21-(2-N,N-diethylaminoethyl)oxy-7alpha-methyl-19-norpregna-1,3,5(10)-triene-3-O-sulfamate) is a novel, dual-acting estrone sulfatase inhibitor currently in preclinical development for use in breast cancer therapy. The compound has a dual mechanism of action: the sulfamate-containing parent compound SR16157 inhibits estrogen biosynthesis by irreversibly inhibiting the enzyme estrone sulfatase. The phenolic metabolite, SR16137, generated by the sulfatase enzyme is a potent antiestrogen in breast tissues and has beneficial effects in bone and the cardiovascular system. As part of the ongoing preclinical studies, an HPLC assay method has been developed and validated for SR16157. The assay method is specific, accurate (recovery=99.4-101.1), linear (r(2)> or =0.9999), precise (intraday R.S.D.< or =1.1%, intermediate R.S.D.< or =0.8%), and sensitive (limit of detection=1.0 microg/ml). It separates SR16157 from its impurities and forced decomposition products, which have been characterized by LC coupled with mass and UV spectral data. Major decomposition pathways are hydrolysis, hydroxylation, and oxidation.

Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture.

The interaction of a dietary excess of vitamin A (retinoid) and deficiency of methyl-donor compounds was examined in murine early-organogenesis embryonic development. Female mice were fed one of six diets from the time of vaginal plug detection until gestational d 8.0, when embryos were removed and grown in whole embryo culture for 46 h, using serum from rats fed the same diet for 36 d as the culture medium. The six diets were either methyl-donor deficient (designated -FCM: devoid of folic acid, choline and supplemental L-methionine, but having methionine as a component of the protein portion of the diet) or methyl-donor sufficient (designated +FCM: containing folic acid, choline and L-methionine supplementation), in combination with one of three concentrations of retinyl palmitate (0.016, 0.416 or 4.016 g/kg diet). The high dose of retinyl palmitate induced a failure of anterior neuropore closure and hypoplasia of the visceral arches, both of which were significantly ameliorated by simultaneous administration of the methyl-donor-deficient diet. The primary acidic retinoid detected in the rat serum was 9,13-di-cis-retinoic acid, although we hypothesize that teratogenic retinoids were formed by embryonic biotransformation of the retinyl esters to toxic metabolites. Biochemical measurements of metabolites in relevant pathways were performed. We propose that the amelioration of these malformations may be used to determine biochemical pathways critical for retinoid teratogenesis.