Common rats (Rattus rattus and Rattus norvegicus) and the house mouse (Mus musculus) are globally distributed synanthropic rodents, yet their tolerance to high altitude has never been assessed at a global scale. We combined worldwide occurrence records with climatic and elevational data to compare their observed and potential altitudinal ranges. Using more than 200,000 curated Global Biodiversity Information Facility (GBIF) records, we assigned elevation to each occurrence and built MaxEnt species distribution models incorporating elevation and four bioclimatic variables. Rats and mice overlapped broadly at low and mid elevations; however, both rat species showed a sharp and consistent decline in occurrence above ~ 2,500 m. Only 2.3-2.7% of rat records occurred above this threshold, compared with ~ 10% for M. musculus. Species distribution models corroborated this pattern, predicting high-altitude regions, including the Andean and Tibetan plateaus, and major mountain ranges in North America and Asia, as largely unsuitable for rats but suitable for mice. Minimum and maximum temperature were the strongest predictors of habitat suitability for all species, yet elevation exerted a markedly stronger negative effect on rats than on mice. These findings identify elevation as a major global constraint on the biogeography of common rats but not house mice, likely reflecting species-specific physiological limits related to hypoxia tolerance.

This study characterizes clinical and hematologic risk factors for retinopathy of prematurity (ROP) among preterm infants born at high altitude, where chronic environmental hypoxia represents a relevant physiological stressor but cannot be evaluated as an independent causal determinant. A retrospective cohort study was conducted in a tertiary neonatal intensive care unit located at 2240 m above sea level (Mexico City). Preterm infants with gestational age < 35 weeks and birthweight < 2000 g were included. Exclusion criteria were major congenital anomalies, death prior to ophthalmologic screening, and incomplete clinical data. Associations between clinical variables and ROP were assessed using univariate and multivariate logistic regression. Receiver operating characteristic (ROC) analyses were performed to identify cohort-specific exposure thresholds for respiratory support and transfusion burden. Among 76 infants, 22 (28.9%) developed ROP of any stage. Compared with infants without ROP, affected infants required longer supplemental oxygen therapy (median 42.5 vs. 20.0 days, p = 0.001), prolonged mechanical ventilation (17.0 vs. 5.0 days, p = 0.008), and more blood transfusions (6.0 vs. 2.0, p = 0.007). After reclassification, the incidence of necrotizing enterocolitis did not differ significantly between infants with and without ROP and was therefore retained only as a descriptive variable. Multivariate regression confirmed duration of oxygen exposure and transfusion burden as independent predictors of ROP. ROC analyses identified exposure thresholds associated with increased ROP risk: ≥ 35 days of oxygen therapy, ≥ 12 days of mechanical ventilation, and ≥ 6 transfusions. Preterm infants born and treated at high altitude exhibit clinically relevant associations between ROP and the duration and intensity of respiratory support and transfusion exposure. Although altitude itself cannot be evaluated as an independent risk factor in this single-cohort study, these findings underscore the importance of contextualized interpretation of established ROP risk factors in high-altitude neonatal care settings.

High altitude exposes the human fetus and newborn to chronic hypobaric hypoxia, markedly reducing oxygen availability during critical windows of development. While adults tolerate moderate hypoxia through well-described acclimatization mechanisms, neonates (particularly those born preterm) exhibit substantially greater vulnerability. Despite more than one million infants being born annually at high or very high altitude, neonatal care practices are still largely derived from sea-level evidence, often neglecting altitude-specific physiology. This review synthesizes current evidence on the effects of high-altitude hypobaric hypoxia on neonatal development, morbidity, and survival. We examine how reduced oxygen availability influences birth weight, prematurity, neonatal mortality, congenital heart disease, pulmonary hypertension, respiratory morbidity, retinopathy of prematurity, hematologic adaptations, infection susceptibility, and neurodevelopment. Across diverse populations and study designs, high altitude is consistently associated with lower birth weight, increased prematurity, higher neonatal mortality, and a greater burden of cardiopulmonary and ocular disease. Notably, many of these risks emerge at altitudes considered physiologically innocuous for adults. Mechanistically, hypobaric hypoxia disrupts oxygen homeostasis at systemic and cellular levels, affecting placental function, pulmonary vascular transition at birth, cerebral blood flow regulation, mitochondrial energy metabolism, and redox balance. Compensatory responses in the fetus and newborn, including increased hemoglobin concentration and erythropoietin production, may partially improve oxygen transport but can also contribute to secondary complications such as hyperbilirubinemia and altered vascular signaling. Importantly, high-altitude ancestry confers partial protection against fetal growth restriction, underscoring the potential influence of evolutionary and developmental context. Collectively, the evidence indicates that neonatal responses to hypobaric hypoxia are developmentally distinct from adult physiological adaptations. Altitude-adapted clinical thresholds, monitoring strategies, and therapeutic approaches grounded in neonatal physiology are urgently needed to improve outcomes for infants born and treated at high altitude worldwide.\.

Introduction This case illustrates a unique challenge in neurocritical care at high altitude, where sea-level ventilation protocols can be detrimental. It adds novel clinical evidence by showing the pathophysiological consequences and therapeutic reversal of hypercapnia-induced cerebral hyperemia in a high-altitude native with traumatic brain injury (TBI). Main symptoms and findings A 25-year-old man, lifelong resident at 3600 m above sea level (m.a.s.l.), presented with moderate-to-severe TBI following a motor vehicle accident. He exhibited cerebral edema and hemorrhagic contusions on CT, with transcranial Doppler indicating cerebral hyperemia. Diagnosis, intervention, and outcomes Initial ventilation based on sea-level PaCO₂ norms led to iatrogenic hypercapnia and cerebral hyperemia. Upon adjusting the ventilatory targets to an altitude-appropriate PaCO₂ range (26–28 mmHg), cerebral blood flow normalized, as confirmed by Doppler. The patient rapidly recovered and was discharged neurologically intact. Conclusion In high-altitude settings, standard ventilation protocols may provoke secondary cerebral complications. This case highlights the critical importance of individualized, altitude-specific neurocritical strategies, with transcranial Doppler serving as a valuable bedside guide to optimize outcomes in altitude-acclimatized TBI patients.

IntroductionIn high-altitude cities located above 2,500 m, hospitals face a concerning mortality rate of over 50% among intensive care unit (ICU) patients with acute respiratory distress syndrome (ARDS). This elevated mortality rate is largely due to the absence of altitude-specific medical protocols that consider the unique physiological adaptations of high-altitude residents to hypoxic conditions. This study addresses this critical gap by analyzing demographic, clinical, sex-specific, and preclinical data from ICUs in Bogotá, Colombia (2,650 m) and El Alto, Bolivia (4,150 m).MethodsA cohort of seventy ARDS patients, aged 18 and older, was evaluated within 24 h of ICU admission. Data collected included demographic information (age, sex), clinical characteristics (primary pathology, weight, height), vital signs, respiratory variables, cardiorespiratory parameters, blood count results, inflammatory markers, severity assessment scores, and comorbidities. Advanced statistical analyses, such as multivariate logistic regression and principal component analysis, were utilized to identify key clinical predictors of ARDS-related mortality.ResultsOur findings indicate that in high-altitude ICUs, monitoring inflammatory markers may be more beneficial for improving ARDS survival rates than emphasizing respiratory failure markers. Unexpectedly, we found no significant differences in clinical outcomes between altitudes of 2,650 and 4,150 m or between male and female patients.ConclusionThe study concludes that, in high-altitude settings, ARDS patient survival in ICUs is more closely associated with managing inflammatory responses than with focusing solely on respiratory parameters. Further large-scale studies are recommended to validate the impact of inflammatory marker monitoring on survival outcomes in high-altitude ICUs.

The role of excessive airway constriction in the hyperresponsiveness to nebulized methacholine in mice with experimental asthma is still contentious. Yet, there have been very few studies investigating whether the increased in vivo response to methacholine caused by experimental asthma is associated with a corresponding increase in ex vivo airway constriction. Herein, the responses to nebulized methacholine in vivo and airway constriction in lung slices ex vivo were studied in 8- to 10-week-old male mice of two strains, BALB/c and C57BL/6. Experimental asthma was induced by administering house dust mites (HDM) intranasally, once daily, for 10 consecutive days. Complementary ex vivo studies were conducted with excised tracheas to measure and compare isometric force. As expected, the in vivo response to methacholine, and especially the hyperresponsiveness caused by HDM, was greater in BALB/c than in C57BL/6 mice. In contrast, there were no differences in maximal airway constriction between mouse strains, and the hyperresponsiveness to nebulized methacholine caused by HDM in both mouse strains was not associated with a corresponding increase in ex vivo airway constriction. The experiments with excised tracheas demonstrated no differences in isometric force between strains and between mice with and without experimental asthma. It is concluded that the hyperresponsiveness to nebulized methacholine in an acute mouse model of asthma induced by repeated HDM exposures is not associated with excessive airway constriction ex vivo.

Living at high altitude (HA) requires physiological and metabolic adjustments to sustain adequate homeostasis. Mitochondria play a key role in these adaptation processes as it consumes >85% of cellular O 2 to produce energy. In adults, HA hypoxia can induce structural changes in the electron transport chain (ETC) to optimize the use of O 2 . In newborn, postnatal development at HA results in slower growth rate and delayed development for some important homeostatic functions. While there is evidence that in species adapted to HA O 2 utilization is optimized, potential underlying plasticity of metabolic pathways during postnatal development is unknown. Because we already demonstrated that FVB mice are a good model to study HA adaptation, we used this laboratory strain to evaluate mitochondrial O 2 consumption rates (OCR) of liver samples during postnatal development and at adulthood at sea level (SL - Quebec, Canada) and in animals that have been raised at HA for >50 generations (La Paz, Bolivia, 3600m). Using the high-resolution oxygraph Oroboros O2k, we measured OCR in mice at postnatal day 7 (P7), 14 (P14), 21 (P21) and 60 (adults – P60) under states of maximum capacity (ET) with substrates for complex I (ET N – pyruvate, malate, glutamate), complex II (ET S – succinate), or I + II (maximal OCR - ET NS ). Our results show that ET N was considerably reduced at all ages in HA compared to SL mice (P7, -92%; P14, -86%; P21, -87%). Contrastingly, ET S was 32% higher in HA P21 mice while it was 30% lower in HA adults compared to SL. No difference was found for ET NS during postnatal development, but values were lower in HA adults compared with SL (101 ± 26 vs 167 ± 43 pmol/s*mg). We also calculated the relative contribution of CI and CII to maximal OCR (ET NS ). While CI contribution was substantially lower at all ages in HA mice compared to SL, CII participation was higher at P7 (+41%), P14 (+14%) and P21 (+16%) but was unchanged at adulthood. These results suggest that at HA, a development shift occurs from CI to CII, allowing maximal OCR (ET NS ) to remain unchanged between HA and SL. This shift might be a protective mechanism since the activity of CII is only dependent on the availability of its substrate (succinate), while CI is more sensitive to decreases in intracellular O 2 . This reprogramming was absent in adults; both CI and CII activity decreased at HA compared to SL. These differences highlight the distinct effect of HA hypoxia at different life stages. Funded by NSERC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

In addition to its hematopoietic function, erythropoietin (EPO) has demonstrated neuroprotective properties in preclinical studies, particularly in cases of reduced oxygenation or ischemia in the neonatal brain. While these findings have sparked optimism for its potential clinical application, the efficacy of EPO remains contentious in translational assays. Notably, while repeated administration of low doses of EPO has correlated with a decrease in adverse outcomes, the use of high EPO doses has shown either negligible or potentially detrimental effects on the incidence of brain injury. In this pilot study, we explored the effects of low and sustained doses of EPO (400 IU/kg) on the incidence of intraventricular hemorrhage (IVH) in premature infants. EPO was administered intravenously three times a week until the infants reached 32 weeks corrected gestational age. Our results indicate a significant decrease in the incidence of IVH with EPO treatment. Although, this study does not provide conclusive evidence on EPO's ability to reverse established IVH, these results strongly support the need for larger-scale clinical trials to further assess EPO's therapeutic potential.

INTRODUCTION:A recent study on BALB/c and C57BL/6 mice demonstrated a clear lack of association between the in vivo response to nebulized methacholine and the degree of airway narrowing ex vivo in a model of asthma induced by a daily exposure to house dust mite over 10 consecutive days. This finding raises the question of which factors determine the methacholine response in vivo. METHODS:Herein, multiple linear regression analyses were used to determine which baseline physiological characteristics are associated with the methacholine response. RESULTS:Among the 10 baseline characteristics studied, and depending on how the methacholine response was monitored during a concentration-response, lung tissue compliance was the most commonly and robustly associated with the methacholine response. Inspiratory capacity was the second most frequently associated. CONCLUSION:These results suggest that lung tissue compliance and inspiratory capacity may be two important determinants of the methacholine response in BALB/c and C57BL/6 mice with and without experimental asthma.

Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood; however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats, are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex of both species across postnatal development and at adulthood at sea level (SL; Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600 m) after 50 generations of residency. At postnatal day (P)7, P14 and P21 and in adults (P60-90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway - OCRN), complex II (S pathway - OCRS) and complexes I+II (NS pathways - OCRNS). Our results showed: (1) at HA, rats exhibit higher OCR at P7, P14 and adulthood compared with their SL counterparts, and (2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance of studying HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.

Air trapping, often attested in humans by elevated residual volume (RV) and ratio of RV on total lung capacity (RV/TLC), is frequently observed in asthma. Confirming these alterations in experimental asthma would be important for translational purposes. Herein, lung volumes were investigated in a mouse model of pulmonary allergic inflammation. Eight- to 10-week-old male C57BL/6 and BALB/c mice were exposed once daily to intranasal house dust mite (HDM) for 10 consecutive days. All readouts were measured 24 h after the last exposure. Lung volumes were assessed with the flexiVent using a new automated method consisting of degassing the lungs followed by a full-range pressure–volume maneuver. The weight and the volume of the lungs were also measured ex vivo and a lobe was further processed for histological analyses. HDM exposure led to tissue infiltration with inflammatory cells, goblet cell hyperplasia, thickening of the airway epithelium, and elevated ex vivo lung weight and volume. It also decreased TLC and vital capacity but without affecting RV and RV/TLC. These observations were similar between the two mouse strains. Alterations of lung volumes in a murine model of pulmonary allergic inflammation are inconsistent with observations made in human asthma. These discrepancies reflect the different means whereby lung volumes are measured between species. The invasive method used herein enables RV to be measured more precisely and without the confounding effect of air trapping, suggesting that changes in RV and RV/TLC using this method in mice should be interpreted differently than in humans.

Chronic obstructive pulmonary disease (COPD) and asthma are major contributors to mortality resulting from respiratory diseases among sea-level populations. In high altitude environments, located between 2500 and 3600 meters, where oxygen availability decreases (hypoxia), pulmonary edema has been identified as the main cause of mortality among transient visitors to such high regions. However, despite the existence of physiological adaptations among permanent residents of high altitudes (characterized by increased ventilation, increased red blood cell counts, vasodilation, and an increased muscle contraction pump), extensive research on fatal respiratory diseases that prevalence in this demographic remains low. In this research effort, we analyzed 1,214 mortality records from 2017 in La Paz, Bolivia (located at 3,600 meters). Our results indicate that pneumonia is the leading cause of death in these high-altitude Bolivian cities. This is in stark contrast to pneumonia's position as the fourth leading cause of death at sea level, accentuating the distinctive health challenges faced by populations residing at high altitudes.

BACKGROUND:High-flow nasal cannula (HFNC) reduces the need for intubation in adult subject with acute respiratory failure. Changes in hypobaric hypoxemia have not been studied for subject with an HFNC in ICUs at altitudes > 2,600 m above sea level. In this study, we investigated the efficacy of HFNC treatment in subjects with COVID-19 at high altitudes. We hypothesized that progressive hypoxemia and the increase in breathing frequency associated with COVID-19 in high altitudes affect the success of HFNC therapy and may also influence the performance of the traditionally used predictors of success and failure. METHODS:This was a prospective cohort study of subjects >18 y with a confirmed diagnosis of COVID-19-induced ARDS requiring HFNC who were admitted to the ICU. Subjects were followed up during the 28 d of HFNC treatment or until failure. RESULTS:One hundred and eight subjects were enrolled. At admission to the ICU, FIO2 delivery between 0.5-0.8 (odds ratio 0.38 [95% CI 0.17-0.84]) was associated with a better response to HFNC therapy than oxygen delivery on admission between 0.8-1.0 (odds ratio 3.58 [95% CI 1.56-8.22]). This relationship continued during follow-ups at 2, 6, 12, and 24 h, with a progressive increase in the risk of failure (odds ratio 24 h 13.99 [95% CI 4.32-45.26]). A new cutoff for the ratio of oxygen saturation (ROX) index (ROX ≥ 4.88) after 24 h of HFNC administration was demonstrated to be the best predictor of success (odds ratio 11.0 [95% CI 3.3-47.0]). CONCLUSIONS:High-altitude subjects treated with HFNC for COVID-19 showed a high risk of respiratory failure and progressive hypoxemia when FIO2 requirements were > 0.8 after 24 h of treatment. In these subjects, personalized management should include continuous monitoring of individual clinical conditions (such as oxygenation indices, with cutoffs adapted to those corresponding to high-altitude cities).

Previous studies on the cardiac data of healthy permanent residents living in high-altitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600–4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts.

The neutrophil/lymphocyte ratio (NLR) and the lymphocyte/C-reactive protein ratio (LCR) are prognostic factors in inflammatory, cardiovascular, and oncological diseases. With the emergence of the COVID-19 pandemic, it has been recently shown that NLR and LCR are also useful for the prognosis of disease severity in patients infected with the SARS-CoV-2 virus at sea level. However, there are no studies demonstrating the reliability of NLR and LCR in high-altitude human populations (above 2,500 m). This is relevant because both the incidence and mortality from COVID-19 are decreased in high altitude. A possible explanation of this effect is a lower impact of this virus on the exaggerated inflammatory response induced by the viral infection. The aim of this study is to determine whether the NLR and LCR indices can be used as reliable predictive markers of COVID-19 severity in high-altitude permanent resident patients. Routine blood biochemistry and complete blood count were performed on 368 patients positive for the SARS-CoV-2 virus in Huaraz, Peru (3,050 m). Patients’ follow up was carried out until home discharge or fatal outcome. The results show that: 1) NLR values are higher in deceased patients admitted to the intensive care unit due to COVID-19; 2) NLR and LCR are reliable predictors of death in patients with COVID-19; and 3) NLR and LCR are reliable predictors of intensive care unit requirement in COVID-19 patients. We conclude that NLR and LCR are reliable biomarkers and prognostic factors of COVID-19 severity and can be used in high-altitude permanent resident patients.

Abstract Intraventricular hemorrhage (IVH) is the most frequent neurological complication in preterm infants, affecting 20-30% of infants born before 32 weeks of gestational age and/or weighing less than 1,500 grams. IVH can lead to long-term neurological sequelae, including cerebral palsy, seizures, posthemorrhagic hydrocephalus, and cognitive deficits. Therefore, mitigating the risk of IVH in neonates is a clinical priority. In this study, we have evaluated whether the hormone erythropoietin (EPO), known for its impact on neuroprotection and stimulation of brain maturation, can be used in IVH prevention in premature infants (<33 gestational weeks). So far, EPO's efficacy in treating preterm infants with IVH remains controversial. While repeated low doses of EPO showed a reduction in the incidence of adverse outcomes, high EPO doses showed no appreciable difference in the frequency of brain injury. In light of these divergent outcomes, in this pilot study, we tested whether low doses of EPO (400 IU/kg), administered intravenously three times per week until reaching 33 weeks of gestationally corrected age, can prevent IVH. Our results show that EPO reduces the odds of IVH among premature babies by 97%; however, it fails to reverse the condition once the injury has developed. These results have crucial clinical importance in preventing IVH in preterm infants.