Rapid and Simple Buffer Exchange Using Cation-Exchange Chromatography to Improve Point-of-Care Detection of Pharmacological Agents.

The current COVID-19 pandemic has highlighted the power, speed, and simplicity of point-of-care (POC) diagnostics. POC diagnostics are available for a wide range of targets, including both drugs of abuse as well as performance-enhancing drugs. For pharmacological monitoring, minimally invasive fluids such as urine and saliva are commonly sampled. However, false positives or negatives caused by interfering agents excreted in these matrices may confound results. For example, false positives have, in most cases, prevented the use of POC diagnostics for pharmacological agent detection; the consequence is that centralized labs are instead tasked to perform these screenings, resulting in significant delays between sampling and testing. Thus, a rapid, simple, and inexpensive methodology for sample purification is required for the POC to reach a field-deployable tool for the pharmacological human health and performance assessments. Buffer exchange is a simple, rapid approach to remove interfering agents, but has traditionally been difficult to perform on small pharmacological molecules. Therefore, in this communication, we use salbutamol, a performance-enhancing drug, as a case example to demonstrate the efficacy of ion-exchange chromatography as a technique to perform buffer exchange for charged pharmacological agents. This manuscript demonstrates the efficacy of this technique leveraging a commercial spin column to remove interfering agents found in simulant urines, such as proteins, creatinine, and urea, while retaining salbutamol. The utility and efficacy of the method was then confirmed in actual saliva samples. The eluent was then collected and run on the lateral flow assays (LFAs), improving the reported limit of detection by over 5× (new lower limit of detection of 10 ppb compared to reported 60 ppb by the manufacturer) while simultaneously removing noise due to background interfering agents.

Central Sleep Apnea in Adults: Diagnosis and Treatment.

Background: While the literature has demonstrated a higher prevalence of moderate-to-severe obstructive sleep apnea (OSA) in the general population compared with central sleep apnea (CSA), more evidence is needed on the long-term clinical impact of and optimal treatment strategies for CSA. Observations: CSA is overrepresented among certain clinical populations, such as those with heart failure, stroke, neuromuscular disorders, and opioid use. The clinical concerns with CSA parallel those of OSA. The absence of respiration (apneas and hypopneas due to lack of effort) results in sympathetic surge, compromise of oxygenation and ventilation, sleep fragmentation, and elevation in blood pressure. Symptoms such as excessive daytime sleepiness, morning headaches, witnessed apneas, and nocturnal arrhythmias are shared between the 2 disorders. A systematic clinical approach should be used to identify and treat CSA. Conclusions: The purpose of this review is to familiarize the primary care community with CSA to aid in the identification and management of this breathing disturbance.

Detection of Asthma Inhaler Use via Terahertz Spectroscopy.

Inhaled medications are commonplace for administering bronchodilators, anticholinergics, and corticosteroids. While they have a defined legitimate use, they are also used in sporting events as performance-enhancing drugs. These performance enhancers can be acquired via both legal (i.e., at a pharmacy through over-the-counter medications or through a prescription) and illicit (i.e., black market and foreign pharmacies) means, thus making monitoring procurement impossible. While urine tests can detect these pharmacological agents hours after they have been inhaled, there is a significant lag time before they are observed in urine. Direct detection of these inhaled agents is complicated and requires a multiplexed approach due to the sheer number of inhaled pharmacological agents. Therefore, detection of propellants, which carry the drug into the lungs, provides a simpler path forward toward detection of broad pharmacological agents. In this paper, we demonstrate the first use of terahertz spectroscopy (THz) to detect inhaled medications in human subjects. Notably, we were able to detect and quantitate the propellant, HFA-134a, in breath up to 30 min after using an asthma inhaler, enabling the use of a point-of-care device to monitor exhaled breath for the presence of propellants. We also demonstrate via simulations that the same approach can be leveraged to detect and identify next-generation propellants, specifically HFA-152a. As a result, we provide evidence that a single point-of-care THz sensor can detect when individuals have used pressure-mediated dose inhalers (pMDIs) without further modification of the hardware.

Surveying the Genomic Landscape Supporting the Development of Precision Military Aerospace Medicine.

INTRODUCTION: Precision medicine is an approach to healthcare that is modifying clinical management by leveraging technological advances in genomics that assess a patient's genetic information to identify unique predispositions. While the civilian sector is integrating genomics widely to personalize diagnosis and treatment, the military medical environment has reacted more slowly. The operational requirements of military service encourage a tailored approach for focusing military precision medicine on occupation-specific conditions. Here, we present a survey of the genomic landscape related to military aerospace medicine.METHODS: We collated observations from genome-wide association studies (GWAS) relating genetic markers to conditions that may negatively influence flight operations and for which the U.S. Air Force School of Aerospace Medicine's Aeromedical Consult Service (ACS) provides aeromedical waiver guidance. Our sources for identifying relevant literature were the GWAS Catalog, the Atlas of GWAS Summary Statistics, and PubMed/Google Scholar searches.RESULTS: Using the ACS guidance as a starting point, we found 1572 papers describing 84 clinical conditions with genetic associations. The earliest aeromedical GWAS publication was in 2006, increasing to 225 publications in 2019. We identified 42,020 polymorphisms from more than 84 million participants across the studies.CONCLUSION: Our study revealed areas where deeper investigations into how genetic markers manifest in clinical diagnosis, prevention, or risk management could lead to increased medical readiness. Additionally, our results show those clinical areas for which guidance could include genetic risk considerations.Chapleau RR, Regn DD, de Castro MJ. Surveying the genomic landscape supporting the development of precision military aerospace medicine. Aerosp Med Hum Perform. 2022; 93(2):89-93.

Integrating the precision, sleep, and aerospace medicine fields: a systematic review of the genetic predisposition for obstructive sleep apnea in military aviation.

PURPOSE: Obstructive sleep apnea (OSA) is the most common pathologic sleep disorder with an estimated prevalence in the USA of up to 25% of adult males. With military aviation being heavily comprised of adult men, the impact of OSA on flying operations is concerning as OSA is disqualifying for all flying classes in the US Air Force. In order to minimize the impact of OSA on operations, early identification of at-risk patients is critical in disease management. Individuals could be identified for whom regular polysomnography testing may reveal OSA while mild or sub-clinical, at which point treatment may be initiated in order to promote continued medical qualification for duty and career retention. METHODS: We performed a keyword search of PubMed, EMBASE, and Google Scholar along with searches in the NHGRI/EBI GWAS Catalogue and the Atlas of GWAS Summary Statistics. We included primary research from candidate gene, GWAS, and meta-analyses. We also included other review articles in our search to confirm interpretations and implications of any genetic associations with OSA. Only studies related to OSA susceptibility or risk were included. RESULTS: We identified 134 publications reporting or reviewing genetic associations with OSA risk. These papers reported 301 variants, of which 195 were unique and 33 were replicated in at least two papers. With respect to the strength of association, 43 variants exhibited odds ratios greater than 2. Finally, there were 84 null results reported, 51 of which were in conflict with reported associations. CONCLUSION: There is ample evidence in the literature to confirm that genetics provide an important contribution to OSA development. The high number of strongly associated variants suggests that a polygenic risk model could be created with high predictive value for prognostic screening.

Comparison of virtual bronchoscopy to fiber-optic bronchoscopy for assessment of inhalation injury severity.

PURPOSE: Compare virtual bronchoscopy (VB) to fiberoptic bronchoscopy (FOB) for scoring smoke inhalation injury (SII). METHODS: Swine underwent computerized tomography (CT) with VB and FOB before (0) and 24 and 48 h after SII. VB and FOB images were scored by 5 providers off line. RESULTS: FOB and VB scores increased over time (p<0.001) with FOB scoring higher than VB at 0 (0.30±0.79 vs. 0.03±0.17), 24 h (4.21±1.68 vs. 2.47±1.50), and 48h (4.55±1.83 vs. 1.94±1.29). FOB and VB showed association with PaO2-to-FiO2 ratios (PFR) with areas under receiver operating characteristic curves (ROC): for PFR≤300, VB 0.830, FOB 0.863; for PFR≤200, VB 0.794, FOB 0.825; for PFR≤100, VB 0.747, FOB 0.777 (all p<0.001). FOB showed 80.3% specificity, 77% sensitivity, 88.8% negative-predictive value (NPV), and 62.3% positive-predictive value (PPV) for PFR≤300 and VB showed 67.2% specificity, 85.5% sensitivity, 91.3% NPV, and 53.4% PPV. CONCLUSIONS: VB provided similar injury severity scores to FOB, correlated with PFR, and reliably detected airway narrowing. VB performed during admission CT may be a useful screening tool specifically to demonstrate airway narrowing induced by SII.

Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine.

OBJECTIVE: The role of airway pressure release ventilation in the management of early smoke inhalation injury has not been studied. We compared the effects of airway pressure release ventilation and conventional mechanical ventilation on oxygenation in a porcine model of acute respiratory distress syndrome induced by wood smoke inhalation. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. PATIENTS: Thirty-three Yorkshire pigs. INTERVENTIONS: Smoke inhalation injury. MEASUREMENTS AND MAIN RESULTS: Anesthetized female Yorkshire pigs (n = 33) inhaled room-temperature pine-bark smoke. Before injury, the pigs were randomized to receive conventional mechanical ventilation (n = 15) or airway pressure release ventilation (n = 12) for 48 hrs after smoke inhalation. As acute respiratory distress syndrome developed (PaO2/Fio2 ratio <200), plateau pressures were limited to <35 cm H2O. Six uninjured pigs received conventional mechanical ventilation for 48 hrs and served as time controls. Changes in PaO2/Fio2 ratio, tidal volume, respiratory rate, mean airway pressure, plateau pressure, and hemodynamic variables were recorded. Survival was assessed using Kaplan-Meier analysis. PaO2/Fio2 ratio was lower in airway pressure release ventilation vs. conventional mechanical ventilation pigs at 12, 18, and 24 hrs (p < .05) but not at 48 hrs. Tidal volumes were lower in conventional mechanical ventilation animals between 30 and 48 hrs post injury (p < .05). Respiratory rates were lower in airway pressure release ventilation at 24, 42, and 48 hrs (p < .05). Mean airway pressures were higher in airway pressure release ventilation animals between 6 and 48 hrs (p < .05). There was no difference in plateau pressures, hemodynamic variables, or survival between conventional mechanical ventilation and airway pressure release ventilation pigs. CONCLUSIONS: In this model of acute respiratory distress syndrome caused by severe smoke inhalation in swine, airway pressure release ventilation-treated animals developed acute respiratory distress syndrome faster than conventional mechanical ventilation-treated animals, showing a lower PaO2/Fio2 ratio at 12, 18, and 24 hrs after injury. At other time points, PaO2/Fio2 ratio was not different between conventional mechanical ventilation and airway pressure release ventilation.

Respiratory dialysis: reduction in dependence on mechanical ventilation by venovenous extracorporeal CO2 removal.

OBJECTIVES: Mechanical ventilation is injurious to the lung. Use of lung-protective strategies may complicate patient management, motivating a search for better lung-replacement approaches. We investigated the ability of a novel extracorporeal venovenous CO2 removal device to reduce minute ventilation while maintaining normocarbia. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. SUBJECTS: Seven sedated swine. INTERVENTIONS: Tracheostomy, volume-controlled mechanical ventilation, and 72 hrs of round-the-clock intensive care unit care. A 15-F dual-lumen catheter was inserted in the external jugular vein and connected to the Hemolung, an extracorporeal pump-driven venovenous CO2 removal device. Minute ventilation was reduced, and normocarbia (Paco2 35-45 mm Hg) maintained. Heparinization was maintained at an activated clotting time of 150-180 secs. MEASUREMENTS AND MAIN RESULTS: Minute ventilation (L/min), CO2 removal by Hemolung (mL/min), Hemolung blood flow, O2 consumption (mL/min), CO2 production by the lung (mL/min), Paco2, and plasma-free hemoglobin (g/dL) were measured at baseline (where applicable), 2 hrs after device insertion, and every 6 hrs thereafter. Minute ventilation was reduced from 5.6 L/min at baseline to 2.6 L/min 2 hrs after device insertion and was maintained at 3 L/min until the end of the study. CO2 removal by Hemolung remained steady over 72 hrs, averaging 72 ± 1.2 mL/min at blood flows of 447 ± 5 mL/min. After insertion, O2 consumption did not change; CO2 production by the lung decreased by 50% and stayed at that level (p < .001). As the arterial PCO2 rose or fell, so did CO2 removal by Hemolung. Plasma-free hemoglobin did not change. CONCLUSIONS: Venovenous CO2 removal enabled a 50% reduction in minute ventilation while maintaining normocarbia and may be an effective lung-protective adjunct to mechanical ventilation.