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Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity.

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000–5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude‐related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2 = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues. [ABSTRACT FROM AUTHOR]

Background: The incidence, causes and impact of diaphragm thickness evolution in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock are unknown. Our study investigates its evolution during the first week of VA-ECMO and its relationship with sweep gas flow settings. Methods: We conducted a prospective monocentric observational study in a 12-bed ICU in France, enrolling patients on the day of the VA-ECMO implantation. The diaphragm thickness and the diaphragm thickening fraction (as index of contractile activity, dTF; dTF < 20% defined a low contractile activity) were daily measured for one week using ultrasound. Factors associated with diaphragm thickness evolution (categorized as increased, stable, or atrophic based on > 10% modification from baseline to the last measurement), early extubation role (< day4), and patients outcome at 60 days were investigated. Changes in diaphragm thickness, the primary endpoint, was analysed using a mixed-effect linear model (MLM). Results: Of the 29 included patients, seven (23%) presented diaphragm atrophy, 18 remained stable (60%) and 4 exhibited an increase (17%). None of the 13 early-extubated patients experienced diaphragm atrophy, while 7 (46%) presented a decrease when extubated later (p-value = 0.008). Diaphragm thickness changes were not associated with the dTF (p-value = 0.13) but with sweep gas flow (Beta = − 3; Confidence Interval at 95% (CI) [− 4.8; − 1.2]. p-value = 0.001) and pH (Beta = − 2; CI [− 2.9; − 1]. p-value < 0.001) in MLM. The dTF remained low (< 20%) in 20 patients (69%) at the study's end and was associated with sweep gas flow evolution in MLM (Beta = − 2.8; 95% CI [− 5.2; − 0.5], p-value = 0.017). Odds ratio of death at 60 days in case of diaphragm atrophy by day 7 was 8.50 ([1.4–74], p = 0.029). Conclusion: In our study, diaphragm thickness evolution was frequent and not associated with the diaphragm thickening fraction. Diaphragm was preserved from atrophy in case of early extubation with ongoing VA-ECMO assistance. Metabolic disorders resulting from organ failures and sweep gas flow were linked with diaphragm thickness evolution. Preserved diaphragm thickness in VA-ECMO survivors emphasizes the importance of diaphragm-protective strategies, including meticulous sweep gas flow titration. Key points: Question: How does the diaphragm thickness evolves during the first week of VA-ECMO treatment for a cardiogenic shock and is it associated with sweep gas flow settings? Findings: In patient receiving VA-ECMO for a cardiogenic shock, fewer progressive atrophy was described when early extubation was possible and associated with lower death rate at two months. The diaphragm thickness increased with the sweep gas flow and decreased with the acidosis. Diaphragm thickness evolution did not evolve parallel to the diaphragm thickening fraction. Meaning: In VA-ECMO-treated patients, we advocate for diaphragmatic-protective strategies through the careful titration of sweep gas flows, tight pH control, and the promotion of early extubation. [ABSTRACT FROM AUTHOR]

Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV1) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake ( V ˙ o2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43–0.90; P = 0.008) and 0.60 (0.48–0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection. [ABSTRACT FROM AUTHOR]

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity. [ABSTRACT FROM AUTHOR]