Reproducibility and responsiveness of airway impedance measures derived from the forced oscillation technique across different operating lung volumes.

BACKGROUND: The forced oscillation technique (FOT) enables non-invasive measurement of respiratory system impedance. Limited data exists on how changes in operating lung volume (OLV) impact FOT-derived measures of airway resistance (Rrs) and reactance (Xrs). OBJECTIVES: This study examined the reproducibility and responsiveness of FOT-derived measures of Rrs and Xrs during simulated changes in OLV. METHODS: Participants simulated breathing at six OLVs: total lung capacity (TLC), ∼50% of inspiratory reserve volume (IRV50), ∼two-times tidal volume (VT2), tidal volume (VT), ∼50% of expiratory reserve volume (ERV50), and residual volume (RV), on a commercially available FOT device. Each simulated OLV manuever was performed in triplicate and in random order. Total Rrs and Xrs were recorded at 5, 11, and 19 Hz. RESULTS: Twelve healthy participants (2 female) completed the study (weight: 76.5 ± 13.6 kg, height: 178.6 ± 9.7 cm, body mass index: 23.9 ± 3.1 kg/m2). Reproducibility of Rrs and Xrs at VT, VT2 and IRV50 was good to excellent (Range: ICC: 0.89-0.98, 95% confidence interval (CI): 0.70-0.98), while reproducibility at TLC, RV, and ERV50 was poor to excellent (Range: ICC: 0.60-0.98, 95% CI: 0.36-0.97). Rrs and Xrs were not different between VT and VT2 at any frequency (P > .05). With lung hyperinflation from VT to TLC, Rrs and Xrs decreased at all three frequencies (e.g., At 5 Hz Rrs: mean difference (MD): - 0.89, 95%CI: - 0.03 to - 1.75, P = .04; Xrs: MD: - 0.56, 95%CI: - 0.25 to - 0.86, P < .01). With lung hypoinflated from VT to RV, Rrs increased, and Xrs decreased for all frequencies (e.g., MD at 5 Hz, Rrs: MD: 2.31, 95%CI: 0.94-3.67, P < .01; Xrs: MD: -2.53, 95%CI: -4.02 to -1.04, P < .01). CONCLUSION: FOT-derived measures of airway Rrs and Xrs are reproducible across a range of OLV's, and are responsive to hyper- and hypo-inflation of the lung. To further understand the impact of lung hyper- and hypo-inflation on FOT-derived airway impedance additional study is required in individuals with pathological variations in operating lung volume.

Outpatient intravenous diuresis in a rural setting: safety, efficacy, and outcomes.

Purpose: To evaluate the safety, efficacy, and outcomes of outpatient intravenous diuresis in a rural setting and compare it to urban outcomes. Methods: A single-center study was conducted on 60 patients (131 visits) at the Dartmouth-Hitchcock Medical Center (DHMC) from 1/2021-12/2022. Demographics, visit data, and outcomes were collected and compared to urban outpatient IV centers, and inpatient HF hospitalizations from DHMC FY21 and national means. Descriptive statistics, T-tests and chi-squares were used. Results: The mean age was 70 ± 13 years, 58% were male, and 83% were NYHA III-IV. Post-diuresis, 5% had mild-moderate hypokalemia, 16% had mild worsening of renal function, and 3% had severe worsening of renal function. No hospitalizations occurred due to adverse events. The mean infusion-visit urine output was 761 ± 521 ml, and post-visit weight loss was -3.9 ± 5.0 kg. No significant differences were observed between HFpEF and HFrEF groups. 30-day readmissions were similar to urban outpatient IV centers, DHMC FY21, and the national mean (23.3% vs. 23.5% vs. 22.2% vs. 22.6%, respectively; p = 0.949). 30-day mortality was similar to urban outpatient IV centers but lower than DHMC FY21 and the national means (1.7% vs. 2.5% vs. 12.3% vs. 10.7%, respectively; p < 0.001). At 60 days, 42% of patients had ≥1 clinic revisit, 41% had ≥1 infusion revisit, 33% were readmitted to the hospital, and two deaths occurred. The clinic avoided 21 hospitalizations, resulting in estimated cost savings of $426,111. Conclusion: OP IV diuresis appears safe and effective for rural HF patients, potentially decreasing mortality rates and healthcare expenses while mitigating rural-urban disparities.

Myocardial stunning secondary to erroneous administration of intravenous epinephrine.

Epinephrine is a commonly used medication for emergent conditions, such as anaphylaxis, respiratory distress, and shock. However, its versatility can also lead to iatrogenic errors in dosages, concentrations, and routes of administration. In this case, a 47-year-old female experiencing anaphylaxis received an intravenous dose of 0.3 mg (1:1000) epinephrine formulated for intramuscular injection, resulting in cardiac arrest and acute heart failure due to myocardial stunning, as diagnosed by echocardiography. Management included invasive ventilation and hemodynamic support until cardiac function recovered. This case highlights the potential dangers of epinephrine overdose, and to our knowledge, is the first reported case of iatrogenic epinephrine-induced Takotsubo cardiomyopathy in a rural area. In addition, we review the literature on iatrogenic epinephrine toxicity-associated cardiomyopathy and the epidemiology of epinephrine errors. Safety measures must be considered for improving communication in emergencies, increasing awareness via training, and changing epinephrine's antiquated packaging design.

Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies.

On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2's relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.

Accelerating massively parallel hemodynamic models of coarctation of the aorta using neural networks.

Comorbidities such as anemia or hypertension and physiological factors related to exertion can influence a patient's hemodynamics and increase the severity of many cardiovascular diseases. Observing and quantifying associations between these factors and hemodynamics can be difficult due to the multitude of co-existing conditions and blood flow parameters in real patient data. Machine learning-driven, physics-based simulations provide a means to understand how potentially correlated conditions may affect a particular patient. Here, we use a combination of machine learning and massively parallel computing to predict the effects of physiological factors on hemodynamics in patients with coarctation of the aorta. We first validated blood flow simulations against in vitro measurements in 3D-printed phantoms representing the patient's vasculature. We then investigated the effects of varying the degree of stenosis, blood flow rate, and viscosity on two diagnostic metrics - pressure gradient across the stenosis (ΔP) and wall shear stress (WSS) - by performing the largest simulation study to date of coarctation of the aorta (over 70 million compute hours). Using machine learning models trained on data from the simulations and validated on two independent datasets, we developed a framework to identify the minimal training set required to build a predictive model on a per-patient basis. We then used this model to accurately predict ΔP (mean absolute error within 1.18 mmHg) and WSS (mean absolute error within 0.99 Pa) for patients with this disease.

Relationship of Activity Patterns to Acute Mountain Sickness in South Pole Workers.

This study aimed to evaluate the influence of physical activity on incidence of acute mountain sickness (AMS) by continuous activity monitoring in a free-living sample of South Pole workers over the initial 72 h at altitude exposure of 2,840 m (9,318 ft). Body Media activity monitors were worn by 47 healthy participants. AMS was defined by the Lake Louise symptom questionnaire. Venous blood samples were taken at sea level and approximately 48 h after high altitude exposure. AMS incidence was 34% (n=16/47) over the first 48 h and 40% (n=19/47) over 72 h. On day 2 at high altitude, individuals with AMS demonstrated a significantly greater increase in the percent change in physical activity metrics from baseline: total energy expenditure 19±13 vs. 5±7%, total steps 65±51 vs. 10±18%, metabolic equivalent of tasks 21±13 vs. 7±13%, and time spent performing moderate to vigorous physical activity 114±79 vs. 26±27% for individuals with AMS vs. no AMS, respectively, p<0.05. In addition, erythropoietin and vascular endothelial growth factor were 1.69 and 1.75 times higher, respectively, in those with AMS. In conclusion, workers who engaged in increased physical activity and activity intensity during initial exposure to the South Pole were more susceptible to developing AMS.

Surrogate in vitro activation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens.

Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor-specific T-cells from peripheral blood. We hypothesized that antigen-driven T-cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by γ-chain cytokine-modulated T-cell hyperexpansion. Step 1 exposure to GM-CSF plus paired Toll-like receptor agonists (resiquimod and LPS), stimulated abundant IL-12 and IL-23 secretion, as well as upregulated co-stimulatory molecules and CD11c expression within the myeloid (CD33+) subpopulation. Added synthetic long peptides (>20aa) derived from widely expressed oncoproteins (MUC1, HER2/neu and CMVpp65), were reliably presented to CD4+ T-cells and cross-presented to CD8+ T-cells. Both presentation and cross-presentation demonstrated proteasomal and Sec61 dependence that could bypass the endoplasmic reticulum. Step 2 exposure to exogenous IL-7 or IL-7+IL-2 produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific T-cells with a predominant interferon-γ-producing T1-type, as well as the antigen-specific ability to lyse tumor targets. Other γ-chain cytokines and/or combinations were initially proliferogenic, but followed by a contractile phase not observed with IL-7 or IL-7+IL-2. Regulatory T-cells were minimally propagated under these culture conditions. This mechanistically rational culture sequence, effective even for unvaccinated donors, enables rapid preparation of T-cells recognizing tumor-associated antigens expressed by the majority of human cancers, including pancreatic cancers, breast cancers and glioblastomas.

A High Performance Pulsatile Pump for Aortic Flow Experiments in 3-Dimensional Models.

Aortic pathologies such as coarctation, dissection, and aneurysm represent a particularly emergent class of cardiovascular diseases. Computational simulations of aortic flows are growing increasingly important as tools for gaining understanding of these pathologies, as well as for planning their surgical repair. In vitro experiments are required to validate the simulations against real world data, and the experiments require a pulsatile flow pump system that can provide physiologic flow conditions characteristic of the aorta. We designed a newly capable piston-based pulsatile flow pump system that can generate high volume flow rates (850 mL/s), replicate physiologic waveforms, and pump high viscosity fluids against large impedances. The system is also compatible with a broad range of fluid types, and is operable in magnetic resonance imaging environments. Performance of the system was validated using image processing-based analysis of piston motion as well as particle image velocimetry. The new system represents a more capable pumping solution for aortic flow experiments than other available designs, and can be manufactured at a relatively low cost.

Does the degree of coarctation of the aorta influence wall shear stress focal heterogeneity?

The development of atherosclerosis in the aorta is associated with low and oscillatory wall shear stress for normal patients. Moreover, localized differences in wall shear stress heterogeneity have been correlated with the presence of complex plaques in the descending aorta. While it is known that coarctation of the aorta can influence indices of wall shear stress, it is unclear how the degree of narrowing influences resulting patterns. We hypothesized that the degree of coarctation would have a strong influence on focal heterogeneity of wall shear stress. To test this hypothesis, we modeled the fluid dynamics in a patient-specific aorta with varied degrees of coarctation. We first validated a massively parallel computational model against experimental results for the patient geometry and then evaluated local shear stress patterns for a range of degrees of coarctation. Wall shear stress patterns at two cross sectional slices prone to develop atherosclerotic plaques were evaluated. Levels at different focal regions were compared to the conventional measure of average circumferential shear stress to enable localized quantification of coarctation-induced shear stress alteration. We find that the coarctation degree causes highly heterogeneous changes in wall shear stress.