Abstract I have been fortunate to work in two areas of extreme physiology and medicine: very high altitude and the microgravity of spaceflight. My introduction to high altitude medicine was as a member of Sir Edmund Hillary's Silver Hut Expedition in 1960–1961 when a small group of physiologists spent the winter and spring at an altitude of 5,800 m just south of Mt. Everest. The physiological objective was to obtain a better understanding of the acclimatization process of lowlanders during exposure to a very high altitude for several months. As far as we knew, no one had ever spent so long at such a high altitude before. The success of this expedition prompted me to organize the 1981 American Medical Research Expedition to Everest where the scientific objective was to determine the physiological changes that allow humans to survive in the extreme hypoxia of the highest point on earth. There is good evidence that this altitude is very near the limit of human tolerance to oxygen deprivation. Much novel information was obtained including an extraordinary degree of hyperventilation which reduced the alveolar partial pressure of carbon dioxide (Pco2) to about 8 mmHg (1.1 kPa) on the summit, and this in turn allowed the alveolar partial pressure of oxygen, PO2, to be maintained at a viable level of about 35 mmHg (4.7 kPa). The low Pco2 caused a severe degree of respiratory alkalosis with an arterial pH exceeding 7.7. These were the first physiological measurements to be made on the Everest summit, and essentially, none has been made since. The second extreme environment is microgravity. We carried out an extensive series of measurements on astronauts in the orbiting laboratory known as SpaceLab in the 1990s. Many aspects of pulmonary function are affected by gravity, so it was not surprising that many changes were found. However, overall gas exchange remained efficient. Some of the findings such as an anomalous behavior of inhaled helium and sulfur hexafluoride have still not been explained. Measurements made after astronauts were exposed to 6 months of microgravity in the International Space Station indicate that the function of the lung returns to its preexposure state within a few days.

Background

Climbers on the summit of Mt. Everest are exposed to extreme hypoxia, and the physiological implications are of great interest. Inferences have been made from alveolar gas samples collected on the summit, but arterial blood samples would give critical information. We propose a plan to insert an arterial catheter at an altitude of 8000 m, take blood samples above this using an automatic sampler, store the samples in glass syringes in an ice-water slurry, and analyze them lower on the mountain 4 to 6 hours later.

Results

A preliminary design of the automatic sampler was successfully tested at the White Mountain Research Station (altitude 3800 m-4300 m). To determine how much the blood gases changed over a long period, rabbit blood was tonometered to give a gas composition close to that expected on the summit (PO2 4.0 kPa (30 mmHg), PCO2 1.3 kPa (10 mmHg), pH 7.7) and the blood gases were measured every 2 hours for 8 hours both at sea level and 3800 m. The mean changes were PO2 +0.3 to +0.4 kPa (+2 to +3 mmHg), PCO2 0 to +0.13 kPa (+1 mmHg), pH -0.02 to +0.04, base excess -0.7 to +1.2 mM. In practice the delay before analysis should not exceed 4 to 6 hours. The small paradoxical rise in PO2 is presumably caused mainly by contamination of the blood with air.

Conclusion

We conclude that automatic arterial blood sampling at high altitude is technically feasible and that the changes in the blood gases over a period of several hours are acceptably small.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic magnified the importance of gas exchange abnormalities in early respiratory failure. Pulse oximetry (SpO2) has not been universally effective for clinical decision-making, possibly because of limitations. The alveolar gas monitor (AGM100) adds exhaled gas tensions to SpO2 to calculate the oxygen deficit (OD). The OD parallels the alveolar-to-arterial oxygen difference (AaDO2) in outpatients with cardiopulmonary disease. We hypothesized that the OD would discriminate between COVID-19 patients who require hospital admission and those who are discharged home, as well as predict need for supplemental oxygen during the index hospitalization. METHODS: Patients presenting with dyspnea and COVID-19 were enrolled with informed consent and had OD measured using the AGM100. The OD was then compared between admitted and discharged patients and between patients who required supplemental oxygen and those who did not. The OD was also compared to SpO2 for each of these outcomes using receiver operating characteristic (ROC) curves. RESULTS: Thirty patients were COVID-19 positive and had complete AGM100 data. The mean OD was significantly (p = 0.025) higher among those admitted 50.0 ± 20.6 (mean ± SD) vs. discharged 27.0 ± 14.3 (mean ± SD). The OD was also significantly (p < 0.0001) higher among those requiring supplemental oxygen 60.1 ± 12.9 (mean ± SD) vs. those remaining on room air 25.2 ± 11.9 (mean ± SD). ROC curves for the OD demonstrated very good and excellent sensitivity for predicting hospital admission and supplemental oxygen administration, respectively. The OD performed better than an SpO2 threshold of <94%. CONCLUSIONS: The AGM100 is a novel, noninvasive way of measuring impaired gas exchange for clinically important endpoints in COVID-19.

We have tested a multiplex polymerase chain reaction (PCR) human papillomavirus (HPV) genotyping assay to fill the need for rapid and low-cost HPV detection in Sub-Saharan Africa. This method allows high throughput genotyping and simultaneous detection of 14 high-risk and two low-risk HPV types, by PCR amplification of HPV DNAs in a single reaction tube. In this study, we describe stepwise experiments to validate the multiplex HPV PCR assay for determination of HPV genotypes from 104 cervical brush samples from Tanzanian women. Assay performance was evaluated by determination of intra-laboratory reproducibility, sensitivity, and specificity. Further performance was assessed by comparison with the widely accepted and validated HPV My09/My11 amplification and hybridization assay. Statistics; the Cohen kappa (κ) and McNemar P values were used to analyze interobserver and intermethod agreement. Overall concordance between the multiplex and line blot hybridization assays was 99% (per sample) with a κ value equal to 0.95; and 96.49% (per detection event) with a κ value of 0.92. Interobserver reproducibility of the assay per sample was 95.76% with κ of 0.91. These results demonstrate that the multiplex HPV PCR assay has high analytical sensitivity and specificity in detecting as many as 16 different HPV genotypes and that its simplicity and low cost makes it well suited for sub-Saharan Africa.

Cancer registries routinely collect data on clinicopathologic factors, but rarely abstract anthropometric variables. We conducted a chart review study, examining the feasibility of abstracting weight, height, alcohol use, and smoking from medical records in women (n = 1,974) diagnosed with invasive breast cancer, and investigated the association between the abstracted variables with clinicopathologic features. Qualitative data were reviewed and categorized. Frequencies of the abstracted data, and demographic and clinicopathologic variables were calculated. Logistic regression models measured the relationship between the outcome variables, tumor size, stage of disease, and estrogen/progesterone (ER/PR) status with the abstracted variables. Data on current alcohol-use/no-use, current-smoker/non-smoker, and height/weight data were obtained on 96%, 97%, and 88-89% of the participants, respectively. The multivariate analysis showed that overweight (>or=25 kg/m(2)) women had significantly larger (>or=2 cm) tumor size compared with normal weight for both women <50 years (OR = 1.79; 95% CI = 1.14-2.81; p or=50 years at diagnosis (OR = 1.58; 95% CI = 1.19-2.09; p

Venous gas bubbles occur in recreational SCUBA divers in the absence of decompression sickness, forming venous gas emboli (VGE) which are trapped within pulmonary circulation and cleared by the lung without overt pathology. We hypothesized that asymptomatic VGE would transiently increase ventilation-perfusion mismatch due to their occlusive effects within the pulmonary circulation. Two sets of healthy volunteers (n = 11, n = 12) were recruited to test this hypothesis with a single recreational ocean dive or a baro-equivalent dry hyperbaric dive. Pulmonary studies (intrabreath V A/Q (iV/Q), alveolar dead space, and FVC) were conducted at baseline and repeat 1- and 24-h after the exposure. Contrary to our hypothesis V A/Q mismatch was decreased 1-h post-SCUBA dive (iV/Q slope 0.023 ± 0.008 ml−1 at baseline vs. 0.010 ± 0.005 NS), and was significantly reduced 24-h post-SCUBA dive (0.000 ± 0.005, p < 0.05), with improved V A/Q homogeneity inversely correlated to dive severity. No changes in V A/Q mismatch were observed after the chamber dive. Alveolar dead space decreased 24-h post-SCUBA dive (78 ± 10 ml at baseline vs. 56 ± 5, p < 0.05), but not 1-h post dive. FVC rose 1-h post-SCUBA dive (5.01 ± 0.18 l vs. 5.21 ± 0.26, p < 0.05), remained elevated 24-h post SCUBA dive (5.06 ± 0.2, p < 0.05), but was decreased 1-hr after the chamber dive (4.96 ± 0.31 L to 4.87 ± 0.32, p < 0.05). The degree of V A/Q mismatch in the lung was decreased following recreational ocean dives, and was unchanged following an equivalent air chamber dive, arguing against an impact of VGE on the pulmonary circulation.

Infection of cells with DNA viruses triggers innate immune responses mediated by DNA sensors. cGMP-AMP synthase (cGAS) is a key DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which binds to and activates stimulator of interferon genes (STING), leading to IFN production and an antiviral response. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. We report that KSHV infection activates the cGAS-STING pathway, and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. We screened KSHV proteins for their ability to inhibit this pathway and identified six viral proteins that block IFN-β activation through this pathway. This study is the first report identifying multiple viral proteins encoded by a human DNA virus that inhibit the cGAS-STING DNA sensing pathway. One such protein, viral interferon regulatory factor 1 (vIRF1), targets STING by preventing it from interacting with TANK binding kinase 1 (TBK1), thereby inhibiting STING's phosphorylation and concomitant activation, resulting in an inhibition of the DNA sensing pathway. Our data provide a unique mechanism for the negative regulation of STING-mediated DNA sensing. Moreover, the depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. The vIRF1-expressing cells also inhibited IFN-β production following infection with DNA pathogens. Collectively, our results demonstrate that gammaherpesviruses encode inhibitors that block cGAS-STING-mediated antiviral immunity, and that modulation of this pathway is important for viral transmission and the lifelong persistence of herpesviruses in the human population.

The goal of the extreme scale plasma turbulence studies described in this paper is to expedite the delivery of reliable predictions on confinement physics in large magnetic fusion systems by using world-class supercomputers to carry out simulations with unprecedented resolution and temporal duration. This has involved architecture-dependent optimizations of performance scaling and addressing code portability and energy issues, with the metrics for multi-platform comparisons being 'time-to-solution' and 'energy-to-solution'. Realistic results addressing how confinement losses caused by plasma turbulence scale from present-day devices to the much larger $25 billion international ITER fusion facility have been enabled by innovative advances in the GTC-P code including (i) implementation of one-sided communication from MPI 3.0 standard; (ii) creative optimization techniques on Xeon Phi processors; and (iii) development of a novel performance model for the key kernels of the PIC code. Results show that modeling data movement is sufficient to predict performance on modern supercomputer platforms.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with a progressive loss of cognitive abilities. In the present report, we assessed the relationship of memory and executive function with brain structure in a sample of 810 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, including 188 AD, 396 MCI, and 226 healthy older adults (HC). Composite scores of memory (ADNI-Mem) and executive function (ADNI-Exec) were generated by applying modern psychometric theory to item-level data from ADNI's neuropsychological battery. We performed voxel-based morphometry (VBM) and surface-based association (SurfStat) analyses to evaluate relationships of ADNI-Mem and ADNI-Exec with grey matter (GM) density and cortical thickness across the whole brain in the combined sample and within diagnostic groups. We observed strong associations between ADNI-Mem and medial and lateral temporal lobe atrophy. Lower ADNI-Exec scores were associated with advanced GM and cortical atrophy across broadly distributed regions, most impressively in the bilateral parietal and temporal lobes. We also evaluated ADNI-Exec adjusted for ADNI-Mem, and found associations with GM density and cortical thickness primarily in the bilateral parietal, temporal, and frontal lobes. Within-group analyses suggest these associations are strongest in patients with MCI and AD. The present study provides insight into the spatially unbiased associations between brain atrophy and memory and executive function, and underscores the importance of structural brain changes in early cognitive decline.

Background

Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer's disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study.

Objective

Determine the neuroanatomical correlates of plasma tau using voxel-based analysis.

Methods

Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42) and tau, and MRI variables. The relationship between plasma tau and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOEɛ4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL.

Results

Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus.

Conclusion

Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ-participants.