Changes in hypoxic and hypercapnic ventilatory responses at high altitude measured using rebreathing methods.

Ventilatory responses to hypoxia and hypercapnia play a vital role in maintaining gas exchange homeostasis, and in adaptation to high-altitude environments. This study investigates the mechanisms underlying sensitization of hypoxic and hypercapnic ventilatory responses (HVR and HCVR, respectively) in individuals acclimatized to moderate high altitude (3800 m). Thirty-one participants underwent chemoreflex testing using the Duffin modified rebreathing technique. Measures were taken at sea level and after 2 days of acclimatization to high altitude. Ventilatory recruitment thresholds (VRT), HCVR, and HVR were quantified. Acclimatization to high altitude resulted in increased HVR (p<0.001) and HCVR (p<0.001), as expected. We also observed that the decrease in VRT under hypoxic test conditions significantly contributed to the elevated HVR at high altitude since the change in VRT across hyperoxic and hypoxic test conditions was greater at high altitude compared to baseline sea level tests (p=0.043). Pre-VRT ventilation also increased at high altitude (p<0.001), but the change did not differ between oxygen conditions. Taken together, this data suggests that the increase in HVR at high altitude is at least partially driven by a larger decrease in the VRT in hypoxia versus hyperoxia at high altitude compared to sea level. This study highlights the intricacies of respiratory adaptations during acclimatization to moderate high altitude, shedding light on the roles of the VRT, baseline respiratory drive, and two-slope HCVR in this process. These findings contribute to our understanding of how the human respiratory control responds to hypoxic and hypercapnic challenges at high altitude.

Health disparities in COVID-19: immune and vascular changes are linked to disease severity and persist in a high-risk population in Riverside County, California.

BACKGROUND: Health disparities in underserved communities, such as inadequate healthcare access, impact COVID-19 disease outcomes. These disparities are evident in Hispanic populations nationwide, with disproportionately high infection and mortality rates. Furthermore, infected individuals can develop long COVID with sustained impacts on quality of life. The goal of this study was to identify immune and endothelial factors that are associated with COVID-19 outcomes in Riverside County, a high-risk and predominantly Hispanic community, and investigate the long-term impacts of COVID-19 infection. METHODS: 112 participants in Riverside County, California, were recruited according to the following criteria: healthy control (n = 23), outpatients with moderate infection (outpatient, n = 33), ICU patients with severe infection (hospitalized, n = 33), and individuals recovered from moderate infection (n = 23). Differences in outcomes between Hispanic and non-Hispanic individuals and presence/absence of co-morbidities were evaluated. Circulating immune and vascular biomarkers were measured by ELISA, multiplex analyte assays, and flow cytometry. Follow-up assessments for long COVID, lung health, and immune and vascular changes were conducted after recovery (n = 23) including paired analyses of the same participants. RESULTS: Compared to uninfected controls, the severe infection group had a higher proportion of Hispanic individuals (n = 23, p = 0.012) than moderate infection (n = 8, p = 0.550). Disease severity was associated with changes in innate monocytes and neutrophils, lymphopenia, disrupted cytokine production (increased IL-8 and IP-10/CXCL10 but reduced IFNλ2/3 and IFNγ), and increased endothelial injury (myoglobin, VCAM-1). In the severe infection group, a machine learning model identified LCN2/NGAL, IL-6, and monocyte activation as parameters associated with fatality while anti-coagulant therapy was associated with survival. Recovery from moderate COVID infection resulted in long-term immune changes including increased monocytes/lymphocytes and decreased neutrophils and endothelial markers. This group had a lower proportion of co-morbidities (n = 8, p = 1.0) but still reported symptoms associated with long COVID despite recovered pulmonary function. CONCLUSION: This study indicates increased severity of COVID-19 infection in Hispanic individuals of Riverside County, California. Infection resulted in immunological and vascular changes and long COVID symptoms that were sustained for up to 11 months, however, lung volume and airflow resistance was recovered. Given the immune and behavioral impacts of long COVID, the potential for increased susceptibility to infections and decreased quality of life in high-risk populations warrants further investigation.

The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes.

The Report of the 2021-2022 Professional Affairs Standing Committee: Resource Guide for the Integration of Clinical Pharmacy Faculty in Professional Practice Settings.

The 2021-22 Professional Affairs Committee was charged to (1) Develop a resource guide for member institutions and faculty regarding payment for the practice-related activities of pharmacy faculty; (2) Nominate at least one person for an elected AACP or Council Office; and (3) Consider ways that AACP can improve its financial health. This report describes the methodology and content utilized for the development of an online resource guide for member institutions, faculty, and practice sites regarding the integration of clinical faculties' patient care services into patient care settings, including models for payment and value-based payment structures that can be utilized to support the practice-related activities of faculty. The committee offers a revision to a current association policy statement, a proposed policy statement as well as recommendations to AACP and suggestions to colleges and schools of pharmacy pertaining to the committee charges.

Inflammatory gene expression during acute high-altitude exposure.

The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.

Hypoxia and Inflammation: Insights From High-Altitude Physiology.

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

Improvements in sleep-disordered breathing during acclimatization to 3800 m and the impact on cognitive function.

Sojourners to high altitude often experience poor sleep quality due to sleep-disordered breathing. Additionally, multiple aspects of cognitive function are impaired at high altitude. However, the impact of acclimatization on sleep-disordered breathing and whether poor sleep is a major contributor to cognitive impairments at high altitude remains uncertain. We conducted nocturnal actigraphy and polygraphy, as well as daytime cognitive function tests, in 15 participants (33% women) at sea level and over 3 days of partial acclimatization to high altitude (3800 m). Our goal was to determine if sleep-disordered breathing improved over time and if sleep-disordered breathing was associated with cognitive function. The apnea-hypopnea index and oxygen desaturation index increased on night 1 (adj. p = 0.026 and adj. p = 0.026, respectively), but both improved over the subsequent 2 nights. These measures were matched by poorer self-reported sleep quality on the Stanford Sleepiness Scale and PROMIS questionnaires following 1 night at high altitude (adj. p = 0.027 and adj. p = 0.022, respectively). The reaction time on the psychomotor vigilance task was slower at high altitude and did not improve (SL: 199 ± 27, ALT1: 224 ± 33, ALT2: 216 ± 41, ALT3: 212 ± 27 ms). The reaction times on the balloon analog risk task decreased at high altitude (SL: 474 ± 235, ALT1: 375 ± 159, ALT2: 291 ± 102, ALT3: 267 ± 90 ms), perhaps indicating increased risk-taking behavior. Finally, multiple cognitive function measures were associated with sleep-disordered breathing and measures of subjective sleep quality, rather than low daytime arterial oxygen saturation. These data indicate that sleep-disordered breathing at moderately high altitude improves with partial acclimatization and that some aspects of cognitive performance in unacclimatized sojourners may be impacted by poor sleep rather than hypoxemia alone.

Rates and Predictors of Vaccinations Among Inflammatory Bowel Disease Patients Receiving Anti-Tumor Necrosis Factor Agents.

BACKGROUND: As an important quality measure, the rates of recommended immunizations among immunocompromised inflammatory bowel disease (IBD) patients in community practice have not been well studied. AIMS: This study sought to investigate the rates and predictors of recommended immunizations and screening tests among IBD patients receiving anti-tumor necrosis factor (TNF) therapy in a large integrated healthcare organization. METHODS: We conducted a retrospective cohort study of 1401 IBD patients on anti-TNF therapy between 2010 and 2013 within the Kaiser Permanente Northern California healthcare system. The rates of vaccinations and screening tests were quantified, and the associated predictors were investigated. RESULTS: Vaccination rates for influenza and pneumococcus were 43.5 and 24.1%, respectively. The majority of patients (73.7%) received hepatitis B screening and/or vaccine. Patients receiving infliximab had higher rates of pneumococcal vaccine (P = 0.002), hepatitis B screening (P < 0.001), and tuberculin skin test (P < 0.001) compared with patients receiving adalimumab. Older patient age (≥50 years) was associated with higher likelihood of having HBsAg test (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0, P = 0.002), influenza vaccine (OR 2.6 [2.1-3.4], P < 0.001), and pneumococcal vaccine (OR 4.0 [3.0-5.3], P < 0.001). In contrast, older providers (≥50 years) were associated with significantly lower likelihood of their patients' having hepatitis A and B screening tests, and pneumococcal vaccination. CONCLUSIONS: The rates of immunizations for IBD patients receiving anti-TNF treatment were lower than recommended. Structured reminders for vaccinations and education for both patients and providers (older physicians in particular) may prove beneficial in improving immunization rates among immunocompromised IBD patients.

Drug shortages and implications for pediatric patients.

Drug shortages in the United States continue to be a significant problem that negatively impacts pediatric patients of all ages. These shortages have been associated with a higher rate of relapse among children with cancer, substitution of less effective agents, and greater risk for short- and long-term toxicity. Effective prevention and management of any drug shortage must include considerations for issues specific to pediatric patients; hence, the Pediatric Pharmacy Advocacy Group (PPAG) strongly supports the effective management of shortages by institutions caring for pediatric patients. Recommendations published by groups such as the American Society of Health-System Pharmacists and the American Society for Parenteral and Enteral Nutrition should be incorporated into drug shortage management policies. PPAG also supports the efforts of the Food and Drug Administration (FDA) to not only address but prevent drug shortages caused by manufacturing and quality problems, delays in production, and discontinuations. Prevention, mitigation, and effective management of drug shortages pose significant challenges that require effective communication; hence, PPAG encourages enhanced and early dialogue between the FDA, pharmaceutical manufacturers, professional organizations, and health care institutions.

Testing whether male age or high nutrition causes the cessation of reproductive aging in female Drosophila melanogaster populations.

Fecundity seems to stop declining and plateaus at low levels very late in Drosophila melanogaster populations. Here we test whether this apparent cessation of reproductive aging by a population, herein referred to as fecundity plateaus, is robust under various environmental influences: namely, male age and nutrition. The effect of male age on late age fecundity patterns was tested by supplying older females with young males before average population fecundity declined to plateau levels. The second possible environmental influence we tested was nutrition and whether late-life fecundity plateaus arise from a decline in the calories available for reproduction. This hypothesis was tested by comparing average daily female fecundity with both low- and high-lifetime nutrition. Both hypotheses were tested by measuring mid- and late-life fecundity for each cohort under the various environmental influences, and statistically testing whether fecundity stops declining and plateaus at late ages. These experiments demonstrate that mid- and late-life population fecundity patterns are significantly affected by the age of males and nutrition level. However, male age and nutrition level did not affect the existence of late-life fecundity plateaus, which demonstrates the robustness of our earlier findings. These results do not address any issue pertaining to the possible role, if any, of lifelong inter-individual heterogeneity in Drosophila fecundity.