Recapitulation of human pathophysiology and identification of forensic biomarkers in a translational model of chlorine inhalation injury.

Chlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl2-induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl2-induced ALI in swine to understand toxico-pathophysiology and evaluate whether it is suitable for screening potential medical countermeasures and to identify biomarkers useful for forensic analysis. Specific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 (≤240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. Exposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Cl2 exposure resulted in increased total leucocyte and neutrophil counts in bronchoalveolar lavage fluid, vascular leakage, and pulmonary edema compared with the air-exposed group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-l-tyrosine and 3,5-dichloro-l-tyrosine) were detected in plasma and lung tissue after Cl2 exposure. In this study, we developed a translational swine model that recapitulates key features of human Cl2 inhalation injury and is suitable for testing medical countermeasures, and validated chlorinated fatty acids and protein adducts as biomarkers of Cl2 inhalation.NEW & NOTEWORTHY We established a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute lung injury and is suitable for screening potential medical countermeasures. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers of chlorine inhalation.

Montelukast in hospitalized patients diagnosed with COVID-19.

OBJECTIVE: Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. METHODS: We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. RESULTS: Patients receiving montelukast experienced significantly fewer events of clinical deterioration compared with patients not receiving montelukast (10% vs 32%, p = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. CONCLUSIONS: Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies.

Time constant to determine PEEP levels in mechanically ventilated COVID-19 ARDS: a feasibility study.

BACKGROUND: We hypothesized that the measured expiratory time constant (TauE) could be a bedside parameter for the evaluation of positive end-expiratory pressure (PEEP) settings in mechanically ventilated COVID-19 patients during pressure-controlled ventilation (PCV). METHODS: A prospective study was conducted including consecutively admitted adults (n = 16) with COVID-19-related ARDS requiring mechanical ventilation. A PEEP titration using PCV with a fixed driving pressure of 14 cmH2O was performed and TauE recorded at each PEEP level (0 to 18 cmH2O) in prone (n = 29) or supine (n = 24) positions. The PEEP setting with the highest TauE (TauEMAX) was considered to represent the best tradeoff between recruitment and overdistention. RESULTS: Two groups of patterns were observed in the TauE plots: recruitable (R) (75%) and nonrecruitable (NR) (25%). In the R group, the optimal PEEP and PEEP ranges were 8 ± 3 cmH2O and 6-10 cmH2O for the prone position and 9 ± 3 cmH2O and 7-12 cmH2O for the supine position. In the NR group, the optimal PEEP and PEEP ranges were 4 ± 4 cmH2O and 1-8 cmH2O for the prone position and 5 ± 3 cmH2O and 1-7 cmH2O for the supine position, respectively. The R group showed significantly higher optimal PEEP (p < 0.004) and PEEP ranges (p < 0.001) than the NR group. Forty-five percent of measurements resulted in the most optimal PEEP being significantly different between the positions (p < 0.01). Moderate positive correlation has been found between TauE vs CRS at all PEEP levels (r2 = 0.43, p < 0.001). CONCLUSIONS: TauE may be a novel method to assess PEEP levels. There was wide variation in patient responses to PEEP, which indicates the need for personalized evaluation.

Noninvasive ventilation in life-threatening asthma: A case series.

BACKGROUND: The use of noninvasive ventilation (NIV) in severe acute asthma is controversial. A pH < 7.25, PaCO2 > 60 mmHg, and altered mental status have been described as contraindications to NIV in acute asthma. We hypothesized that NIV was safe and effective in asthma patients with a pH < 7.25 or PaCO2 > 60 mmHg. METHODS: Following institutional review board approval, the medical records of subjects who received NIV for acute asthma in the emergency department between January 2010 and July 2012 were reviewed. Subjects were included if they had a pH < 7.25 or PCO2 > 60 mmHg on either an arterial or venous blood gas. Primary outcome was need for endotracheal intubation. RESULTS: Sixty-two subjects received NIV for asthma, with 20 (mean age 42 ± 12 years, 62% male) meeting the inclusion criteria. Intubation was avoided in all 20 subjects, including nine (45%) with prior history of intubation due to asthma, eight (40%) who were obtunded, and three (15%) who were unresponsive upon arrival. Results are described as medians (ranges). Initial blood gas (80% venous) results were: pH 7.16 (6.89-7.27), PCO2 77 (65-144) mmHg, and HCO3 - 27 (20-32) mmol/L. Repeat blood gases (45% venous) performed a median of 117 minutes later were: pH 7.31 (7.22-7.45), PCO2 48 (31-63) mmHg, and HCO3 23 (19-31). Vomiting occurred in one patient; no other adverse events were noted. CONCLUSION: We identified a small series of asthma patients with severe respiratory acidosis or altered mental status in whom NIV was safe and effective.

Development and evaluation of a mechanical ventilator-sharing system.

Background: During the COVID-19 pandemic surge in the hospitalization of critically ill patients and the global demand for mechanical ventilators, alternative strategies for device sharing were explored. We developed and assessed the performance of a system for shared ventilation that uses clinically available components to individualize tidal volumes under a variety of clinically relevant conditions. The feasibility of remote monitoring of ventilators was also assessed. Methods: By using existing resources and off-the-shelf components, a ventilator-sharing system (VSS) that ventilates 2 patients simultaneously with a single device, and a ventilator monitoring system (VMS) that remotely monitors pulmonary mechanics were developed. The feasibility and effectiveness of VSS and VMS were evaluated in benchtop testing using 2 test lungs on a single ventilator, and then performance was assessed in translational swine models of normal and impaired lung function. Results: In benchtop testing, VSS and VMS delivered the set individualized parameters with minimal % errors in test lungs under pressure- and volume-regulated ventilation modes, suggesting the highest precision and accuracy. In animal studies, the VSS and VMS successfully delivered the individualized mechanical ventilation parameters within clinically acceptable limits. Further, we found no statistically significant difference between the target and measured values. Conclusion: The VSS adequately ventilated 2 test lungs or animals with variable lung conditions. The VMS accurately displayed mechanical ventilation settings, parameters, and alarms. Both of these systems could be rapidly assembled for scaling up to ventilate several critically ill patients in a pandemic or mass casualty disaster situations by leveraging off-the-shelf and custom 3D printed components.

Six methods to determine expiratory time constants in mechanically ventilated patients: a prospective observational physiology study.

BACKGROUND: Expiratory time constant (τ) objectively assesses the speed of exhalation and can guide adjustments of the respiratory rate and the I:E ratio with the goal of achieving complete exhalation. Multiple methods of obtaining τ are available, but they have not been compared. The purpose of this study was to compare six different methods to obtain τ and to test if the exponentially decaying flow corresponds to the measured time constants. METHODS: In this prospective study, pressure, flow, and volume waveforms of 30 postoperative patients undergoing volume (VCV) and pressure-controlled ventilation (PCV) were obtained using a data acquisition device and analyzed. τ was measured as the first 63% of the exhaled tidal volume (VT) and compared to the calculated τ as the product of expiratory resistance (RE) and respiratory system compliance (CRS), or τ derived from passive flow/volume waveforms using previously published equations as proposed by Aerts, Brunner, Guttmann, and Lourens. We tested if the duration of exponentially decaying flow during exhalation corresponded to the duration of the predicted second and third τ, based on multiples of the first measured τ. RESULTS: Mean (95% CI) measured τ was 0.59 (0.57-0.62) s and 0.60 (0.58-0.63) s for PCV and VCV (p = 0.45), respectively. Aerts method showed the shortest values of all methods for both modes: 0.57 (0.54-0.59) s for PCV and 0.58 (0.55-0.61) s for VCV. Calculated (CRS * RE) and Brunner's τ were identical with mean τ of 0.64 (0.61-0.67) s for PCV and 0.66 (0.63-069) s for VCV. Mean Guttmann's τ was 0.64 (0.61-0.68) in PCV and 0.65 (0.62-0.69) in VCV. Comparison of each τ method between PCV and VCV was not significant. Predicted time to exhale 95% of the VT (i.e., 3*τ) was 1.77 (1.70-1.84) s for PCV and 1.80 (1.73-1.88) s for VCV, which was significantly longer than measured values: 1.27 (1.22-1.32) for PCV and 1.30 (1.25-1.35) s for VCV (p < 0.0001). The first, the second and the third measured τ were progressively shorter: 0.6, 0.4 and 0.3 s, in both ventilation modes (p < 0.0001). CONCLUSION: All six methods to determine τ show similar values and are feasible in postoperative mechanically ventilated patients in both PCV and VCV modes.

Determining respiratory rate using measured expiratory time constant: A prospective observational study.

PURPOSE: Potential negative implications associated with high respiratory rate (RR) are intrinsic positive end-expiratory pressure (PEEPi) generation, cardiovascular depression and possibly ventilator induced lung injury. Despite these negative consequences, optimal RR remains largely unknown. We hypothesized that without consideration of dynamics of lung emptying (i.e., the expiratory time constant [RCEXP]) clinician settings of RR may exceed the frequency needed for optimal lung emptying. MATERIALS AND METHODS: This prospective multicenter observational study measured RCEXP in 56 intensive care patients receiving pressure-controlled ventilation. We compared set RR to the one predicted with RCEXP (RRP). Also, the subgroup of patients with prolonged RCEXP was analyzed. RESULTS: Overall, the absolute mean difference between the set RR and RRP was 2.8 bpm (95% CI: 2.3-3.2). Twenty-nine (52%) patients had prolonged RCEXP (>0.8 s), mean difference between set RR and RRP of 3.1 bpm (95% CI: 2.3-3.8; p < 0.0001) and significantly higher PEEPi compared to those with RCEXP ≤ 0.8 s: 4.4 (95% CI: 3.6-5.2) versus 1.5 (95% CI: 0.9-2.0) cmH2O respectively, p < 0.0001. CONCLUSIONS: Use of RRP based on measured RCEXP revealed that the clinician-set RR exceeded that predicted by RCEXP in the majority of patients. Measuring RCEXP appears to be a useful variable for adjusting the RR during mandatory mechanical ventilation.

Bias flow does not affect ventilation during high-frequency oscillatory ventilation in a pediatric animal model of acute lung injury.

OBJECTIVE: During high-frequency oscillatory ventilation, bias flow is the continuous flow of gas responsible for replenishing oxygen and removing CO(2) from the patient circuit. Bias flow is usually set at 20 L/min, but many patients require neuromuscular blockade at this flow rate. The need for neuromuscular blockade may be eliminated by increasing the bias flow rate, but CO(2) retention is a potential concern. We hypothesize that in a swine model of acute lung injury, increased bias flow rates will not affect CO(2) elimination. DESIGN: Prospective, randomized, experimental study. SETTING: Research laboratory at a university medical center. SUBJECTS: Sixteen juvenile swine. INTERVENTIONS: Sixteen juvenile swine (12-16.5 kg) were studied using a saline lavage model of acute lung injury. During high-frequency oscillatory ventilation, each animal was ventilated with bias flows of 10, 20, 30, and 40 L/min in random sequence. For ten animals, power was set at a constant level to maintain PaCO(2) 50-60 mm Hg, and amplitude was allowed to vary. For the remaining six animals, amplitude was kept constant to maintain PaCO(2) within the same range, while power was adjusted as needed with changes in bias flow. Linear regression was used for data analysis. MEASUREMENTS AND MAIN RESULTS: Median overall PaCO(2) was 53 mm Hg (range: 31-81 mm Hg). Controlling for both power and amplitude, there was no statistically significant change in PaCO(2) as bias flow varied from 10 to 40 L/min. CONCLUSIONS: Changes in bias flow during high-frequency oscillatory ventilation did not affect ventilation. Further clinical investigation is ongoing in infants and children with acute lung injury being managed with high-frequency oscillatory ventilation to assess the impact of alterations of bias flow on gas exchange, cardiopulmonary parameters, sedation requirements, and other clinical outcomes.

COVID-19-related acute respiratory distress syndrome treated with veno-venous extracorporeal membrane oxygenation and programmed multi-level ventilation: a case report.

We report a patient with severe coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) and programmed multi-level ventilation (PMLV). VV ECMO as a treatment modality for severe ARDS has been described multiple times as a rescue therapy for refractory hypoxemia. It is well known that conventional ventilation can cause ventilator-induced lung injury. Protective ventilation during VV ECMO seems to be beneficial, translating to using low tidal volumes, prone positioning with general concept of open lung approach. However, mechanical ventilation is still required as ECMO per se is usually not sufficient to maintain adequate gas exchange due to hyperdynamic state of the patient and limitation of blood flow via VV ECMO. This report describes ventilation strategy using PMLV during "resting" period of the lung. In short, PMLV is a strategy for ventilating non-homogenous lungs that incorporates expiratory time constants and multiple levels of positive end-expiratory pressure. Using this approach, most affected acute lung injury/ARDS areas can be recruited, while preventing overdistension in healthy areas. To our knowledge, case report using such ventilation strategy for lung resting period has not been previously published.

Use of a Portable Electronic Interface Improves Clinical Handoffs and Adherence to Lung Protective Ventilation.

Background: Mechanical ventilation (MV) is used to support patients with respiratory impairment. Evidence supports the use of lung-protective ventilation (LPV) during MV to improve outcomes. However, studies have demonstrated poor adherence to LPV guidelines. We hypothesized that an electronic platform adapted to a hand-held tablet receiving real-time ventilatory parameters could increase clinician awareness of key LPV parameters. Furthermore, we speculated that an electronic shift-change tool could improve the quality of clinician handoffs. Methods: Using a specially designed Wi-Fi dongle to transmit data from three ventilators and a respiratory monitor, we implemented a system that displays data from all ventilators under the care of a Respiratory Care Practitioner (RCP) on an electronic tablet. In addition, the tablet created a handoff checklist to improve shift-change communication. In a simulated ICU environment, we monitored the performance of eight RCPs at baseline and while using the system. Results: Using the system, the time above guideline Pplat decreased by 74% from control, and the time outside the VT range decreased by 60% from control, p = 0.007 and 0.015, respectively. The handoff scores improved quality significantly from 2.8 to 1.6 on a scale of 1 to 5 (1 being best), p = 0.03. Conclusion: In a simulated environment, an electronic RT tool can significantly improve shift-change communication and increase the RCP's level of LPV adherence.

Development of a Pleural Pressure Catheter via Continuous Fiberoptic Esophageal Pressure Measurements.

There is growing research showing the importance of measuring esophageal pressure as a surrogate for pleural pressure for patients on mechanical ventilators. The most common measurement method uses a balloon catheter, whose accuracy can vary based on patient anatomy, balloon position, balloon inflation, and the presence of other tubes in the esophagus. The authors present the development and initial testing results of a new combination catheter, utilizing fiberoptic pressure sensing to provide more accurate esophageal pressure measurements and allowing for the incorporation of a feeding tube and temperature sensor.

Programmed multi-level ventilation in COVID-19-related acute respiratory distress syndrome: a multi-center retrospective observational study.

OBJECTIVE: We evaluated pressure-controlled ventilation (PCV) with multiple programmed levels of positive end expiratory pressure (programmed multi-level ventilation; PMLV) in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). METHODS: We conducted a multicenter, retrospective study from November 2020 to February 2021. PMLV was used with PCV in all patients with intensive care admission until improvement in oxygenation (fraction of inspired oxygen [FiO2] ≤0.50 and oxygen saturation [SpO2] >92%). The observed outcomes were improvement of hypoxemia, length of mechanical ventilation, partial pressure of carbon dioxide (PaCO2) stability, and adverse events. RESULTS: Of 188 mechanically ventilated patients with COVID-19-related ARDS, we analyzed 60 patients treated with PMLV. Hypoxemia improved in 55 (92%) patients, as measured by the change in partial pressure of oxygen/FiO2 and SpO2/FiO2 ratios on day 3 versus day 1, and in 32 (66%) ventilated patients on day 7 versus day 3. The median (interquartile range) length of mechanical ventilation for survivors and non-survivors was 8.4 (4.7-14.9) and 6.7 (3.6-10.3) days, respectively. CONCLUSIONS: PMLV appears to be a safe and effective ventilation strategy for improving hypoxemia in patients with COVID-19-related ARDS. Further studies are needed comparing the PMLV mode with the conventional ARDS ventilatory approach.

Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology.

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated a model promoter 40-80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response, whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular basis for the development of SARMs.

Inhaled medical gases: more to breathe than oxygen.

The mixture of oxygen and nitrogen is usually sufficient to achieve the therapeutic objective of supporting adequate gas exchange. Pediatric and neonatal patients have an assortment of physiologic conditions that may require adjunctive inhaled gases to treat the wide variety of diseases seen in this heterogeneous population. Inhaled nitric oxide, helium oxygen mixtures, inhaled anesthetics, hypercarbic mixtures, hypoxic mixtures, inhaled carbon monoxide, and hydrogen sulfide have been used to alter physiology in an attempt to improve patient outcomes. Balancing the therapeutic potential, possible adverse effects, and the complexity of the technical aspects of gas delivery, it is essential that clinicians thoroughly understand the application of medical gas therapy beyond the traditional nitrogen/oxygen mixture.

Cycling of the mechanical ventilator breath.

Patient-ventilator interaction is a key element in optimizing mechanical ventilation. The change from inspiration to expiration is a crucial point in the mechanically ventilated breath, and is termed "cycling." Patient-ventilator asynchrony may occur if the flow at which the ventilator cycles to exhalation does not coincide with the termination of neural inspiration. Ideally, the ventilator terminates inspiratory flow in synchrony with the patient's neural timing, but frequently the ventilator terminates inspiration either early or late. Most current mechanical ventilators include adjustable cycling features that, when used in conjunction with waveform graphics, can enhance patient-ventilator synchrony.

Orienting new respiratory therapists into the neonatal/pediatric environment: a survey of educators and managers.

BACKGROUND: Neonatal/pediatric respiratory care is recognized as a unique and complex area of clinical practice. Despite the substantial effort and costs associated with orienting neonatal/pediatric practitioners, few data exist related to the process of training respiratory therapists (RTs) in the acute neonatal/pediatric environment. To gain insight into the adequacy of preparation of RTs entering the neonatal/pediatric environment, the length of orientation necessary to achieve a base level of competency, and the methods used to train new neonatal/pediatric practitioners, we surveyed neonatal/pediatric respiratory care educators and managers. METHODS: The invitation to participate in the survey was distributed via e-mail to 1,259 members of the AARC education specialty section and 1,828 members of the AARC managers specialty section. The survey included 15 questions (not including the demographics questions), scored on 5-point Likert scale, and asked about: what type of degree program (associate's degree or bachelor's degree) better prepares new RTs for the neonatal/pediatric environment; experience requirements for orientation of neonatal/pediatric RTs; the role of simulation in training neonatal/pediatric RTs; and whether the neonatal/pediatric specialty credentialing exam should be used as a method of competency testing. There were 4 questions regarding simulation (the use of interactive full-body manikins in a realistic patient care environment), orientation times based on experience, and where the majority of the orientation time was spent. RESULTS: We received 251 responses (response rate 8%). The majority of respondents were either affiliated with or worked for urban, not-for-profit, non-government organizations. Sixty-three percent disagreed that an associate's degree respiratory therapy program, and 42% disagreed that a bachelor's degree program adequately prepares a new RT to work in the neonatal/pediatric critical care environment immediately after graduation. Seventy-one percent strongly agreed that children's hospital respiratory care departments should have a dedicated respiratory therapy educator. Seventy-six percent agreed that simulation is an effective tool for training RTs for neonatal/pediatric critical care. Sixty-five percent agreed that RTs should be required to take an exam at the end of the orientation period to verify competency. Fifty-nine percent strongly agreed that neonatal/pediatric RTs should have the National Board for Respiratory Care Registered Respiratory Therapist (RRT) credential. CONCLUSIONS: There appears to be a discrepancy in the educational preparation expected prior to entering the acute-care neonatal/pediatric environment and what training methods are most appropriate and cost-effective for orienting new RTs to this specialized environment. A dedicated respiratory therapy educator is valued. Simulation is considered an effective tool for training RTs and provides training opportunities that otherwise would not be available. The neonatal/pediatric specialty certification exam appears to be recognized as a valid method of determining mastery and verifying competence.

Non-invasive muscle contraction assay to study rodent models of sarcopenia.

BACKGROUND: Age-related sarcopenia is a disease state of loss of muscle mass and strength that affects physical function and mobility leading to falls, fractures, and disability. The need for therapies to treat age-related sarcopenia has attracted intensive preclinical research. To facilitate the discovery of these therapies, we have developed a non-invasive rat muscle functional assay system to efficiently measure muscle force and evaluate the efficacy of drug candidates. METHODS: The lower leg muscles of anesthetized rats are artificially stimulated with surface electrodes on the knee holders and the heel support, causing the lower leg muscles to push isometric pedals that are attached to force transducers. We developed a stimulation protocol to perform a fatigability test that reveals functional muscle parameters like maximal force, the rate of fatigue, fatigue-resistant force, as well as a fatigable muscle force index. The system is evaluated in a rat aging model and a rat glucocorticoid-induced muscle loss model RESULTS: The aged rats were generally weaker than adult rats and showed a greater reduction in their fatigable force when compared to their fatigue-resistant force. Glucocorticoid treated rats mostly lost fatigable force and fatigued at a higher rate, indicating reduced force from glycolytic fibers with reduced energy reserves. CONCLUSIONS: The involuntary contraction assay is a reliable system to assess muscle function in rodents and can be applied in preclinical research, including age-related sarcopenia and other myopathy.

Impact of a Formal Research Committee on Respiratory Therapists' Publications.

BACKGROUND: Presenting research at national and international meetings is an important aspect of the practice of respiratory care. Our department regularly presented abstracts but few projects were written up as manuscripts. We also noted that we did not have a centralized strategy to evaluate individual projects and provide mentorship. To address these challenges, we formed a Research Committee that meets monthly. We hypothesized that the formation of this committee would be associated with an increase in published manuscripts. METHODS: We evaluated all original research abstracts authored or co-authored by Duke respiratory therapists presented at the AARC Open Forum between 2009 and 2019. Abstracts were grouped into two time periods; 1) 2009-2013 (before the formation of the research committee) and 2) 2014-2019 (after the formation of the research committee). Abstracts were evaluated based on authors, type of study, patient population, and whether the abstract resulted in a manuscript. Primary outcome was the percentage of abstracts published as manuscripts. RESULTS: A total of 56 abstracts were presented by 23 different lead authors, with 16 (29%) published as manuscripts. After formation of the committee, fewer abstracts per year were presented, but these abstracts were more likely to be published as manuscripts (53% vs 18%, P = .02). For abstracts published as manuscripts, there was a significant difference in the type of study before and after committee formation (P = .042), but there were no differences in lead author credentials, senior author credentials, author gender, or patient population. CONCLUSIONS: The formation of a research committee was associated with an increase in the percentage of abstracts published as manuscripts.

Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands.

Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.