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Abstract Background Aspergillus niger is well-known for its high protein secretion capacity and therefore an important cell factory for homologous and heterologous protein production. The use of a strong promoter and multiple gene copies are commonly used strategies to increase the gene expression and protein production of the gene of interest (GOI). We recently presented a two-step CRISPR/Cas9-mediated approach in which glucoamylase (glaA) landing sites (GLSs) are introduced at predetermined sites in the genome (step 1), which are subsequently filled with copies of the GOI (step 2) to achieve high expression of the GOI. Results Here we show that in a ku70 defective A. niger strain (Δku70), thereby excluding non-homologous end joining (NHEJ) as a mechanism to repair double-stranded DNA breaks (DSBs), the chromosomal glaA locus or homologous GLSs can be used to repair Cas9-induced DSBs, thereby competing with the integration of the donor DNA containing the GOI. In the absence of exogenously added donor DNA, the DSBs are repaired with homologous chromosomal DNA located on other chromosomes (inter-chromosomal repair) or, with higher efficiency, by a homologous DNA fragment located on the same chromosome (intra-chromosomal repair). Single copy inter-chromosomal homology-based DNA repair was found to occur in 13–20% of the transformants while 80–87% of the transformants were repaired by exogenously added donor DNA. The efficiency of chromosomal repair was dependent on the copy number of the potential donor DNA sequences in the genome. The presence of five homologous DNA sequences, resulted in an increased number (35–61%) of the transformants repaired by chromosomal DNA. The efficiency of intra-chromosomal homology based DSB repair in the absence of donor DNA was found to be highly preferred (85–90%) over inter-chromosomal repair. Intra-chromosomal repair was also found to be the preferred way of DNA repair in the presence of donor DNA and was found to be locus-dependent. Conclusion The awareness that homologous chromosomal DNA repair can compete with donor DNA to repair DSB and thereby affecting the efficiency of multicopy strain construction using CRISPR/Cas9-mediated genome editing is an important consideration to take into account in industrial strain design.

Neurodevelopmental disorders such as attention deficit and/or hyperactivity disorder (ADHD) and schizophrenia are characterized by core impairment in executive functions (EF). Despite the development of various behavioral interventions to enhance EF, the evidence is still scarce. Alternatively, non-invasive brain stimulation tools such as transcranial alternating current stimulation (tACS) has emerged as a potential strategy to alleviate cognitive deficits. Previous studies have demonstrated the safety, feasibility, and efficacy of one single tACS session in different clinical populations. However, the effects of tACS appear limited and need to be sustained to be considered an effective cognitive neurorehabilitation tool. Recent studies have used home-based, repeated tACS sessions in individuals with neurodegenerative diseases. To our knowledge, the safety and feasibility of such an intensive protocol remains to be tested in a younger population with neurodevelopmental disorders. Using a randomized double-blind sham-controlled design, we administered home-based, repeated tACS sessions to seven individuals aged 14–25 with 22q11.2 deletion syndrome (22q11.2DS), which confers an increased risk for neurodevelopmental disorders. We aimed to assess the safety, tolerability, and feasibility of tACS. Findings from this ongoing clinical trial revealed a favorable safety profile, with frequent yet transient and mainly mild adverse effects. The intervention proved to be feasible, shown by very high adherence rates and positive user experiences. Future studies should therefore investigate whether prolonged exposure to tACS can lead to long-lasting cognitive outcomes.Clinical trial registrationClinicalTrials.gov, identifier NCT05664412.

IntroductionGram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering life-threatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gram-negative bacillary bacteremia.MethodsBy using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APC-like phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression.ResultsGM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK1/2 kinase-dependent manner.DiscussionThis study provides new insights into the signaling pathways that induce MHC class II expression in neutrophils, highlighting the potential for therapeutic targeting of JAK1/2 signaling in the treatment of gram-negative bacteremia and sepsis. Understanding these mechanisms may open up novel approaches for managing inflammatory responses during sepsis.

Abstract The alloying process plays a pivotal role in the development of advanced multifunctional plasmonic materials within the realm of modern nanotechnology. However, accurate in silico predictions are only available for metal clusters of just a few nanometers, while the support of modelling is required to navigate the broad landscape of components, structures and stoichiometry of plasmonic nanoalloys regardless of their size. Here we report on the accurate calculation and conceptual understanding of the optical properties of metastable alloys of both plasmonic (Au) and magnetic (Co) elements obtained through a tailored laser synthesis procedure. The model is based on the density functional theory calculation of the dielectric function with the Hubbard-corrected local density approximation, the correction for intrinsic size effects and use of classical electrodynamics. This approach is built to manage critical aspects in modelling of real samples, as spin polarization effects due to magnetic elements, short-range order variability, and size heterogeneity. The method provides accurate results also for other magnetic-plasmonic (Au-Fe) and typical plasmonic (Au-Ag) nanoalloys, thus being available for the investigation of several other nanomaterials waiting for assessment and exploitation in fundamental sectors such as quantum optics, magneto-optics, magneto-plasmonics, metamaterials, chiral catalysis and plasmon-enhanced catalysis.

Electron paramagnetic resonance (EPR) spectroscopy is a powerful tool for in situ/operando tracking of catalytic reactions that involve paramagnetic species either as a catalyst (e.g. transition metal ions or defects), reaction intermediates (radicals) or poisoning agents such as coke. This article provides a summary of recent experimental examples and developments in resonator design as well as detection schemes that were carried out in our group. Opportunities for applying this technique are illustrated by examples, including studies of transition metal exchanged zeolites and metal-free zeolites as well as metal oxide catalysts. The inherent limitations of EPR applied at high temperatures are discussed, as well as strategies in reducing or lifting these restrictions are evaluated and ideas for future improvements and methodologies are discussed.

IntroductionIt is well known that young individuals often report pronounced negative perceptions and attitudes towards their own body or intense fear of being not muscular enough. There is much less data available, however, on the role of psychological mechanisms on these perceptions and attitudes, such as emotion regulation difficulties, correlates of alexithymia, and appearance-related rejection sensitivity.MethodsWe therefore set out to assess associations between these psychological mechanisms, and body image as well as muscle dysmorphic symptoms. Our sample was recruited as part of a larger-scale study aiming at assessing correlates of mental health (with a focus on eating disorder symptoms) in German speaking Switzerland. The first wave (T1), starting in April 2021, included 605 participants (80% female, 19.6 ± 2.5 years) who completed the online-questionnaire and were reassessed in a second wave (T2), one year later.ResultsResults indicated that at both waves, emotion regulation difficulties [DERS-SF] and appearance-based rejection sensitivity [ARS-D] were both positively cross-sectionally associated with body dissatisfaction [BSQ-8C] and muscle dysmorphic symptoms [MDDI] at the first assessment time-point and one year later at follow-up assessment. Moreover, alexithymia [TAS-20] was positively cross-sectionally associated with muscle dysmorphic symptoms at both waves. We further observed high absolute and relative level stabilities for all variables involved across the one-year study period.Discussion/ConclusionEven though the effects for some associations were rather small, our findings underline the relevance of such mechanisms in the development of body dissatisfaction and to a lesser extent of muscle dysmorphia symptoms over the period of one year. Additional research is necessary to replicate these findings in other youth samples.

Neurodevelopmental disorders such as attention deficit and/or hyperactivity disorder (ADHD) and schizophrenia are characterized by core impairment in executive functions (EF). Despite the development of various behavioral interventions to enhance EF, the evidence is still scarce. Alternatively, non-invasive brain stimulation tools such as transcranial alternating current stimulation (tACS) has emerged as a potential strategy to alleviate cognitive deficits. Previous studies have demonstrated the safety, feasibility, and efficacy of one single tACS session in different clinical populations. However, the effects of tACS appear limited and need to be sustained to be considered an effective cognitive neurorehabilitation tool. Recent studies have used home-based, repeated tACS sessions in individuals with neurodegenerative diseases. To our knowledge, the safety and feasibility of such an intensive protocol remains to be tested in a younger population with neurodevelopmental disorders. Using a randomized double-blind sham-controlled design, we administered home-based, repeated tACS sessions to seven individuals aged 14–25 with 22q11.2 deletion syndrome (22q11.2DS), which confers an increased risk for neurodevelopmental disorders. We aimed to assess the safety, tolerability, and feasibility of tACS. Findings from this ongoing clinical trial revealed a favorable safety profile, with frequent yet transient and mainly mild adverse effects. The intervention proved to be feasible, shown by very high adherence rates and positive user experiences. Future studies should therefore investigate whether prolonged exposure to tACS can lead to long-lasting cognitive outcomes. Clinical trial registration: ClinicalTrials.gov, identifier NCT05664412. [ABSTRACT FROM AUTHOR]

Introduction: Gram-negative bacillary bacteremia poses a significant threat, ranking among the most severe infectious diseases capable of triggering lifethreatening sepsis. Despite the unambiguous involvement of neutrophils in this potentially fatal disease, there are limited data about the molecular signaling mechanisms, phenotype, and function of human neutrophils during the early phase of gram-negative bacillary bacteremia. Methods: By using an unbiased proteomics and flow cytometry approach, we identified an antigen-presenting cell (APC)-like phenotype in human peripheral blood neutrophils (PMN) with MHC class II molecule expression in the early phase of bacteremia. Using an in-vitro model of GM-CSF-mediated induction of APClike phenotype in PMN, we investigated downstream signaling pathways leading to MHC class II expression. Results: GM-CSF stimulation of neutrophils leads to the activation of three major signaling pathways, the JAK-STAT, the mitogen-activated protein kinase (MAPK), and the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathways, while MHC class II induction is mediated by a MAPK-p38-MSK1-CREB1 signaling cascade and the MHC class II transactivator CIITA in a strictly JAK1/2 kinase-dependent manner. Discussion: This study provides new insights into the signaling pathways that induce MHC class II expression in neutrophils, highlighting the potential for therapeutic targeting of JAK1/2 signaling in the treatment of gram-negative bacteremia and sepsis. Understanding these mechanisms may open up novel approaches for managing inflammatory responses during sepsis. [ABSTRACT FROM AUTHOR]

The Southern Ocean is a high‐nutrient, low‐chlorophyll (HNLC) region characterized by incomplete nitrate (NO3−) consumption by phytoplankton in surface waters. During this incomplete consumption, phytoplankton preferentially assimilate the 14N‐ versus the 15N‐bearing form of NO3−, quantified as the NO3− assimilation isotope effect (15ε). Previous summertime estimates of the 15ε from HNLC regions range from 4 to 11‰. While culture work has shown that the 15ε varies among phytoplankton species, as well as with light and iron stress, we lack a systematic understanding of how and why the 15ε varies in the field. Here we estimate the 15ε from water‐column profile and surface‐water samples collected in the Indian sector of the Southern Ocean—the first leg of the Antarctic Circumnavigation Expedition (December 2016–January 2017) and the Crossroads transect (April 2016). Consistent with prior work in the mid‐to‐late summer Southern Ocean, we estimate a higher 15ε (8.9 ± 0.6‰) for the northern Subantarctic Zone and a lower 15ε (5.4 ± 0.9‰) at and south of the Subantarctic Front. We interpret our data in the context of coincident measurements of phytoplankton community composition and estimates of iron and light stress. Similar to prior work, we find a significant, negative relationship between the 15ε and the average mixed‐layer photosynthetically active radiation flux of 30–100 μmol m−2 s−1, while above 100 μmol m−2 s−1, 15ε increases again. In addition, while we observe no robust relationship of the 15ε to iron availability or phytoplankton community, mixed‐layer nitrification over the Kerguelen Plateau appears to strongly influence its magnitude. Plain Language Summary: The Southern Ocean, and the Subantarctic in particular, is an import region for global carbon cycling that is largely driven by microscopic algae, phytoplankton. Regarded as a high‐nutrient and low‐chlorophyll region, the Subantarctic surface nutrient essential for phytoplankton growth, nitrate, remains in high concentrations over the summertime growing season. During the consumption of nitrate, phytoplankton assimilates nitrate isotopes at varying ratios, likely due to environmental factors, and imparting isotopic signatures. During the Antarctic Circumnavigation Expedition and Crossroads transect, we collected samples from the Indian Sector of the Subantarctic during the mid‐to‐late summer. Here we use measurements of nitrate and its isotope ratios to better constrain these signatures and identify potential environmental drivers. While phytoplankton community composition and iron availability from coincident measurements may influence the nitrate isotopic assimilation ratios, we observe a strong, significant correlation between light stress across the upper ocean and isotopic signatures. This suggests that the influence of light availability for phytoplankton growth is the leading driver of nitrate isotopic ratios in the mid‐to‐late summer season of the Indian Sector of the Subantarctic. Key Points: Nitrate assimilation isotope effects are estimated for the Indian sector of the Subantarctic and Antarctic regions of the Southern OceanNitrate assimilation isotope effects increase with decreasing average mixed layer PAR flux within an optimal rangeDual nitrate isotopic composition profiles showed evidence of significant summertime nitrification on the Kerguelen Plateau [ABSTRACT FROM AUTHOR]

Background Marathon running poses unique cardiovascular challenges, sometimes leading to syncopal episodes. We present a case series of athletes who experienced pre-/syncope during the Zurich Marathon 2023, accompanied by elevated cardiac biomarkers. Case summary Eight athletes (2 females, 6 males) aged 21–35 years, with pre-/syncope and various additional diverse symptoms such as dizziness and palpitations during the (half-)marathon, were admitted to two emergency departments in Zurich, Switzerland. Clinical evaluations included electrocardiogram, echocardiography, telemetry, coronary computed tomography (CT) scans, and cardiac biomarker assessments. High-sensitive troponin T (hs-cTnT) was elevated in all cases at initial assessment and returned to normal at follow-up. All athletes who received CT scans had normal coronary and brain CT results. None of the eight athletes had underlying cardiovascular disease. Renal function normalized post-admission, and neurological symptoms resolved within hours. Creatinine levels indicated transient acute kidney injury. A common feature was inexperience in running, inadequate race preparation, particularly regarding fluid, electrolyte, and carbohydrate intake, along with pacing issues and lack of coping strategies with heat. Discussion From a clinician perspective, the case series highlights the challenge in the management of patients with a pre-/syncopal event during strenuous exercise and elevated cardiac biomarkers. Diverse initial symptoms prompted tailored investigations. Adequate training, medical assessments, and awareness of syncope triggers are essential for marathon participants. Caution and pacing strategies are crucial, especially among novices in competitive running. This information is pertinent given the growing popularity of marathon events and prompts a standardized diagnostic approach after these events. [ABSTRACT FROM AUTHOR]

Purpose: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration–resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. Methods: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021–01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan–Meier methodology (log-rank test). Results: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4–26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09–0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07–0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16–0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01–0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02–0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). Conclusion: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice. [ABSTRACT FROM AUTHOR]

The Southern Ocean accounts for ∼30% of the ocean's CO2 sink, partly due to its biological pump that transfers surface‐produced organic carbon to deeper waters. To estimate large‐scale Southern Ocean carbon export potential and characterize its drivers, we measured the carbon and nitrogen isotope ratios of surface suspended particulate matter (δ13CSPM, δ15NSPM) for samples collected in summer 2016/2017 during the Antarctic Circumnavigation Expedition (364 stations). Concurrent measurements of phytoplankton community composition revealed the dominance of large diatoms in the Antarctic and nano‐phytoplankton (mainly haptophytes) in open Subantarctic waters. As expected, δ13CSPM was strongly dependent on pCO2, with local deviations in this relationship explained by phytoplankton community dynamics. δ15NSPM reflected the nitrogen sources consumed by phytoplankton, with higher inferred nitrate (versus recycled ammonium) dependence generally coinciding with higher micro‐phytoplankton abundances. Using δ15NSPM and a two‐endmember isotope mixing model, we quantified the extent of nitrate‐ versus ammonium‐supported growth, which yields a measure of carbon export potential. We estimate that across the Southern Ocean, 41 ± 29% of the surface‐produced organic carbon was potentially exported below the seasonal mixed layer during the growth season, with maximum export potential (50%–99%) occurring in the Antarctic Circumpolar Current's southern Boundary Zone and near the (Sub)Antarctic islands, reaching a minimum in the Subtropical Zone (<33%). Alongside iron, phytoplankton community composition emerged as an important driver of the Southern Ocean's biological pump, with large diatoms dominating regions characterized by high nitrate dependence and elevated carbon export potential and smaller, mainly non‐diatom taxa proliferating in waters where recycled ammonium supported most productivity. Plain Language Summary: The Southern Ocean plays a crucial role in regulating climate by transferring atmospheric CO2 to the deep ocean. This transfer is partly facilitated by the biological pump, which involves organic matter production by phytoplankton in surface waters and the subsequent sinking of some of this material into the deep ocean. To estimate the fraction of newly produced organic carbon potentially exported to depth (i.e., biological pump strength) and determine the drivers thereof, we measured the carbon and nitrogen isotope ratios of surface organic matter and characterized the phytoplankton community at high resolution around Antarctica in summer. We found that nearly half of the carbon produced by Southern Ocean phytoplankton during their growth season was potentially exported. The biological pump was strongest in the southernmost waters of the Antarctic Ocean and near the (Sub)Antarctic islands where local processes supplied iron to phytoplankton and large diatoms dominated the community. Export potential was weakest in open Southern Ocean waters where iron limitation was pervasive and smaller phytoplankton were dominant. While it is well known that iron exerts a strong control on the Southern Ocean's biological pump, our study highlights the complementary role of phytoplankton community composition in modulating carbon export. Key Points: Phytoplankton community composition influences suspended particulate matter carbon and nitrogen isotope ratios across the Southern OceanThe nitrogen isotopes of particulate matter and a two‐endmember isotope mixing model can be used to estimate carbon export potential40% of summertime primary production is potentially exported, with a higher fraction exported near (Sub)Antarctic islands and melting ice [ABSTRACT FROM AUTHOR]

This article discusses the adverse events and the effect of oxygen therapy on stable-treated patients with pulmonary vascular disease (PVD) who are exposed to high altitude. The study involved investigating PVD patients at low altitude and high altitude during a 30-hour overnight stay. The main outcomes measured were severe hypoxemia, acute mountain sickness, and the therapeutic effect of supplemental oxygen therapy. The results showed that some patients experienced adverse events at high altitude, primarily severe hypoxemia, which was effectively treated with supplemental oxygen therapy. The study suggests that stable, low-risk PVD patients can tolerate short-term stays at high altitude but may require supplemental oxygen therapy in certain cases. [Extracted from the article]

Importance: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO 2 ) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO 2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown., Objective: To provide an effect size estimate for the decline in PaO 2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938., Data Sources: A systematic search of PubMed and Embase was performed from inception to May 30, 2023., Study Selection: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude., Data Extraction and Synthesis: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis., Main Outcome and Measures: Relative risk estimates and 95 % confidence intervals for the association between PaO 2 and altitude in patients with COPD., Results: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO 2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I 2 =65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO 2 , age and time spent at altitude were predictors for PaO 2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO 2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001)., Conclusions and Relevance: This meta-analysis, providing altitude-related decrease in PaO 2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO 2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide., Competing Interests: Conflicts of interest The authors declare no conflict of interest concerning this work., (Copyright © 2024 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Our objective was to investigate the effect of a day-long exposure to high altitude on peak exercise capacity and safety in stable patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: In a randomised controlled crossover trial, stable patients with PAH or distal CTEPH without resting hypoxaemia at low altitude performed two incremental exercise tests to exhaustion: one after 3-5 h at high altitude (2500 m) and one at low altitude (470 m)., Results: In 27 patients with PAH/CTEPH (44% females, mean±sd age 62±14 years), maximal work rate was 110±64 W at 2500 m and 123±64 W at 470 m (-11%, 95% CI -16- -11%; p<0.001). Oxygen saturation measured by pulse oximetry and arterial oxygen tension at end-exercise were 83±6% versus 91±6% and 6.1±1.9 versus 8.6±1.9 kPa (-8% and -29%; both p<0.001) at 2500 versus 470 m, respectively. Maximal oxygen uptake was 17.8±7.5 L·min -1 ·kg -1 at high altitude versus 20±7.4 L·min -1 ·kg -1 at low altitude (-11%; p<0.001). At end-exercise, the ventilatory equivalent for carbon dioxide was 43±9 at 2500 m versus 39±9 at 470 m (9%, 95% CI 2-6%; p=0.002). No adverse events occurred during or after exercise., Conclusions: Among predominantly low-risk patients with stable PAH/CTEPH, cycling exercise during the first day at 2500 m was well tolerated, but peak exercise capacity, blood oxygenation and ventilatory efficiency were lower compared with 470 m., Competing Interests: Conflict of interest: None of the authors have any conflicts of interest in relation to this manuscript., (Copyright ©The authors 2024.)