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ObjectivesDescribing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers.DesignProspective cohort study.SettingMeasurements were performed in Leiden University Medical Center, the Netherlands.ParticipantsHealthy volunteers enrolled from July to September 2020.InterventionsTwo ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application.Primary and secondary outcome measuresAt each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint.ResultsIn 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time).ConclusionsThe mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application.Trial registrationClinicalTrials.gov with trial number NCT04626661.

IntroductionThe newly introduced Cellular Oxygen METabolism (COMET®) monitor enables the measurement of mitochondrial oxygen tension (mitoPO2) using the protoporphyrin IX triplet state lifetime technique (PpIX-TSLT). This study aims to investigate the feasibility and applicability of the COMET® measurements in the operating theatre and study the behavior of the new parameter mitoPO2 during stable operating conditions.MethodsIn this observational study mitochondrial oxygenation was measured in 20 patients during neurosurgical procedures using the COMET® device. Tissue oxygenation and local blood flow were measured by the Oxygen to See (O2C). Primary outcomes included mitoPO2, skin temperature, mean arterial blood pressure, local blood flow and tissue oxygenation.ResultsAll patients remained hemodynamically stable during surgery. Mean baseline mitoPO2 was 60 ± 19 mmHg (mean ± SD) and mean mitoPO2 remained between 40-60 mmHg during surgery, but tended to decrease over time in line with increasing skin temperature.ConclusionThis study presents the feasibility of mitochondrial oxygenation measurements as measured by the COMET® monitor in the operating theatre and shows the parameter mitoPO2 to behave in a stable and predictable way in the absence of notable hemodynamic alterations. The results provide a solid base for further research into the added value of mitochondrial oxygenation measurements in the perioperative trajectory.

In light of the associated risks, the question has been raised whether the decision to give a blood transfusion should solely be based on the hemoglobin level. As mitochondria are the final destination of oxygen transport, mitochondrial parameters are suggested to be of added value. The aims of this pilot study were to investigate the effect of a red blood cell transfusion on mitochondrial oxygenation as measured by the COMET device in chronic anemia patients and to explore the clinical usability of the COMET monitor in blood transfusion treatments, especially the feasibility of performing measurements in an outpatient setting. To correct the effect of volume load on mitochondrial oxygenation, a red blood cell transfusion and a saline infusion were given in random order. In total, 21 patients were included, and this resulted in 31 observations. If patients participated twice, the order of infusion was reversed. In both the measurements wherein a blood transfusion was given first and wherein 500 mL of 0.9% saline was given first, the median mitochondrial oxygen tension decreased after red blood cell transfusion. The results of this study have strengthened the need for further research into the effect of blood transfusion tissue oxygenation and the potential role of mitochondrial parameters herein.

ObjectiveAdequate oxygenation is essential for the preservation of organ function during cardiac surgery and cardiopulmonary bypass (CPB). Both hypoxia and hyperoxia result in undesired outcomes, and a narrow window for optimal oxygenation exists. Current perioperative monitoring techniques are not always sufficient to monitor adequate oxygenation. The non-invasive COMET® monitor could be a tool to monitor oxygenation by measuring the cutaneous mitochondrial oxygen tension (mitoPO2). This pilot study examines the feasibility of cutaneous mitoPO2 measurements during cardiothoracic procedures. Cutaneous mitoPO2 will be compared to tissue oxygenation (StO2) as measured by near-infrared spectroscopy.Design and MethodThis single-center observational study examined 41 cardiac surgery patients requiring CPB. Preoperatively, patients received a 5-aminolevulinic acid plaster on the upper arm to enable mitoPO2 measurements. After induction of anesthesia, both cutaneous mitoPO2 and StO2 were measured throughout the procedure. The patients were observed until discharge for the development of acute kidney insufficiency (AKI).ResultsCutaneous mitoPO2 was successfully measured in all patients and was 63.5 [40.0–74.8] mmHg at the surgery start and decreased significantly (p < 0.01) to 36.4 [18.4–56.0] mmHg by the end of the CPB run. StO2 at the surgery start was 80.5 [76.8–84.3]% and did not change significantly. Cross-clamping of the aorta and the switch to non-pulsatile flow resulted in a median cutaneous mitoPO2 decrease of 7 mmHg (p < 0.01). The cessation of the aortic cross-clamping period resulted in an increase of 4 mmHg (p < 0.01). Totally, four patients developed AKI and had a lower preoperative eGFR of 52 vs. 81 ml/min in the non-AKI group. The AKI group spent 32% of the operation time with a cutaneous mitoPO2 value under 20 mmHg as compared to 8% in the non-AKI group.ConclusionThis pilot study illustrated the feasibility of measuring cutaneous mitoPO2 using the COMET® monitor during cardiothoracic procedures. Moreover, in contrast to StO2, mitoPO2 decreased significantly with the increasing CPB run time. Cutaneous mitoPO2 also significantly decreased during the aortic cross-clamping period and increased upon the release of the clamp, but StO2 did not. This emphasized the sensitivity of cutaneous mitoPO2 to detect circulatory and microvascular changes.

The formation of the Isthmus of Panama stands as one of the greatest natural events of the Cenozoic, driving profound biotic transformations on land and in the oceans. Some recent studies suggest that the Isthmus formed many millions of years earlier than the widely recognized age of approximately 3 million years ago (Ma), a result that if true would revolutionize our understanding of environmental, ecological, and evolutionary change across the Americas. To bring clarity to the question of when the Isthmus of Panama formed, we provide an exhaustive review and reanalysis of geological, paleontological, and molecular records. These independent lines of evidence converge upon a cohesive narrative of gradually emerging land and constricting seaways, with formation of the Isthmus of Panama sensu stricto around 2.8 Ma. The evidence used to support an older isthmus is inconclusive, and we caution against the uncritical acceptance of an isthmus before the Pliocene.

Introduction: Ischemia and reperfusion are crucial in determining the outcome after cardiac arrest and can be influenced by extracorporeal cardiopulmonary resuscitation (ECPR). The effect of ECPR on the availability and level of oxygen in mitochondria remains unknown. The aim of this study was to find out if skin mitochondrial partial oxygen pressure (mitoPO2) measurements in cardiac arrest and ECPR are feasible and to investigate its course.Materials and Methods: We performed a feasibility test to determine if skin mitoPO2 measurements in a pig are possible. Next, we aimed to measure skin mitoPO2 in 10 experimental pigs. Measurements were performed using a cellular oxygen metabolism measurement monitor (COMET), at baseline, during cardiac arrest, and during ECPR using the controlled integrated resuscitation device (CIRD).Results: The feasibility test showed continuous mitoPO2 values. Nine experimental pigs could be measured. Measurements in six experimental pigs succeeded. Our results showed a delay until the initial spike of mitoPO2 after ECPR initiation in all six experimental tests. In two experiments (33%) mitoPO2 remained present after the initial spike. A correlation of mitoPO2 with mean arterial pressure (MAP) and arterial partial oxygen pressure measured by CIRD (CIRD-PaO2) seemed not present. One of the experimental pigs survived.Conclusions: This experimental pilot study shows that continuous measurements of skin mitoPO2 in pigs treated with ECPR are feasible. The delay in initial mitoPO2 and discrepancy of mitoPO2 and MAP in our small sample study could point to the possible value of additional measurements besides MAP to monitor the quality of tissue perfusion during cardiac arrest and ECPR.

About 3 million years ago (Ma), the Isthmus of Panama joined the Americas, forming a land bridge over which inhabitants of each America invaded the other-the Great American Biotic Interchange. These invasions transformed land ecosystems in South and Middle America. Humans invading from Asia over 12000 years ago killed most mammals over 44 kg, again transforming tropical American ecosystems. As a sea barrier, the isthmus induced divergent environmental change off its two coasts-creating contrasting ecosystems through differential extinction and diversification. Approximately 65 Ma invading marsupials and ungulates of North American ancestry, and xenarthrans of uncertain provenance replaced nearly all South America's non-volant mammals. There is no geological evidence for a land bridge at that time. Together with rodents and primates crossing from Africa 42 to 30 Ma, South America's mammals evolved in isolation until the interchange's first heralds less than 10 Ma. Its carnivores were ineffective marsupials. Meanwhile, North America was invaded by more competitive Eurasian mammals. The Americas had comparable expanses of tropical forest 55 Ma; later, climate change confined North American tropical forest to a far smaller area. When the isthmus formed, North American carnivores replaced their marsupial counterparts. Although invaders crossed in both directions, North American mammals spread widely, diversified greatly, and steadily replaced South American open-country counterparts, unused to effective predators. Invading South American mammals were less successful. South America's birds, bats, and smaller rainforest mammals, equally isolated, mostly survived invasion. Its vegetation, enriched by many overseas invaders, remained intact. This vegetation resists herbivory effectively. When climate permitted, South America's rainforest, with its bats, birds and mammals, spread to Mexico. Present-day tropical American vegetation is largely zoned by trade-offs between exploiting well-watered settings versus surviving droughts, exploiting fertile versus coping with poor soil, and exploiting lowland warmth versus coping with cooler altitudes. At the start of the Miocene, a common marine biota extended from Trinidad to Ecuador and western Mexico, which evolved in isolation from the Indo-Pacific until the Pleistocene. The seaway between the Americas began shoaling over 12 Ma. About 10 Ma the land bridge was briefly near-complete, allowing some interchange of land mammals between the continents. By 7 Ma, the rising sill had split deeper-water populations. Sea temperature, salinity and sedimentary carbon content had begun to increase in the Southern Caribbean, but not the Pacific. By 4 Ma, the seaway's narrowing began to extinguish Caribbean upwellings. By 2 Ma, upwellings remained only along Venezuela; Caribbean plankton, suspension-feeding molluscs and their predators had declined sharply, largely replaced by bottom-dwelling corals and calcareous algae and magnificent coral reefs. Closing the seaway extinguished the Eastern Pacific's reef corals (successors recolonized from the Indo-Pacific 6000 years ago), whereas many molluscs of productive waters that once thrived in the Caribbean now survive only in the Eastern Pacific. The present-day productive Eastern Pacific, with few, small coral reefs and a plankton-based ecosystem contrasts with the Caribbean, whose clear water favours expansive coral reefs and bottom-dwelling primary producers. These ecosystems reflect the trade-off between fast growth and effective defence with attendant longevity. Overfishing with new technologies during the last few centuries, however, has caused population crashes of ever-smaller marine animals, devastating Caribbean ecosystems.

Abstract Background Visible light spectroscopy (VLS) is a technique used to measure the mucosal oxygen saturation during upper gastrointestinal endoscopy to evaluate mucosal ischemia, however in vivo validation is lacking. We aimed to compare VLS measurements with a validated quantitative microvascular oxygen tension (μPO2) measurement technique. Methods Simultaneous VLS measurements and μPO2 measurements were performed on the small intestine of five pigs. First, simultaneous measurements were performed at different FiO2 values (18%–100%). Thereafter, the influence of bile was assessed by comparing VLS measurements in the presence of bile and without bile. Finally, simultaneous VLS and μPO2 measurements were performed from the moment a lethal dose potassium chloride intravenously was injected. Results In contrast to μPO2 values that increased with increasing FiO2, VLS values decreased. Both measurements correlated poorly with R2 = 0.39, intercept 18.5, slope 0.41 and a bias of − 16%. Furthermore, the presence of bile influenced VLS values significantly (median (IQR)) before bile application 57.5% (54.8–59.0%) versus median with bile mixture of the stomach 73.5% (66.8–85.8), p =

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. Measurements consisted of in vivo mitochondrial oxygenation and oxygen consumption, in vitro assessment of mitochondrial respiration in platelet-rich plasma (PRP) and peripheral blood mononuclear cells (PBMCs), and the ex vivo quantity of circulating cell-free mitochondrial DNA (mtDNA). The median mitoVO2 of COVID-19 patients on T1 and T2 was similar and tended to be lower than the mitoVO2 in the healthy controls, whilst the mitoVO2 in the general anesthesia group was significantly lower than that of all other groups. Basal platelet (PLT) respiration did not differ substantially between the measurements. PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the healthy controls. Cell-free mtDNA was eight times higher in the COVID-T1 samples when compared to the healthy controls samples. In the COVID-T2 samples, mtDNA was twofold lower when compared to the COVID-T1 samples. mtDNA levels were increased in COVID-19 patients but were not associated with decreased mitochondrial O2 consumption in vivo in the skin, and ex vivo in PLT or PBMC. This suggests the presence of increased metabolism and mitochondrial damage.

Current monitoring techniques in neonates lack sensitivity for hypoxia at cellular level. The recent introduction of the non-invasive Cellular Oxygen METabolism (COMET) monitor enables measuring in vivo mitochondrial oxygen tension (mitoPO2), based on oxygen-dependent quenching of delayed fluorescence of 5-aminolevulinic acid (ALA)-enhanced protoporphyrin IX. The aim is to determine the feasibility and safety of non-invasive mitoPO2 monitoring in surgical newborns. MitoPO2 measurements were conducted in a tertiary pediatric center during surgical repair of congenital diaphragmatic hernia or esophageal atresia. Intraoperative mitoPO2 monitoring was performed with a COMET monitor in 11 congenital diaphragmatic hernia and four esophageal atresia neonates with the median age at surgery being 2 days (IQR 1.25–5.75). Measurements were done at the skin and oxygen-dependent delayed fluorescence was measurable after at least 4 h application of an ALA plaster. Pathophysiological disturbances led to perturbations in mitoPO2 and were not observed with standard monitoring modalities. The technique did not cause damage to the skin, and seemed safe in this respect in all patients, and in 12 cases intraoperative monitoring was successfully completed. Some external and potentially preventable factors—the measurement site being exposed to the disinfectant chlorohexidine, purple skin marker, or infrared light—seemed responsible for the inability to detect an adequate delayed fluorescence signal. In conclusion, this is the first study showing it is possible to measure mitoPO2 in neonates and that the cutaneous administration of ALA to neonates in the described situation can be safely applied. Preliminary data suggests that mitoPO2 in neonates responds to perturbations in physiological status.

Introduction The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO2) in vivo at the bedside. MitoPO2might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study.Methods and analysis We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO2, which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods.Ethics and dissemination The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peer-reviewed journals and presented at scientific conferences.Trial registration number NCT03092297.

Teachers in primary education experience difficulties in teaching word problem solving in their mathematics classes. However, during controlled experiments with a metacognitive computer programme, students' problem-solving skills improved. Also without the supervision of researchers, metacognitive computer programmes can be beneficial in a natural class setting. In this study, we examined the effectiveness of a computer programme in such a setting. During 10 weeks, the Grade 5 students of the experimental condition (n = 280) practised with the programme while also working in their mathematical textbooks. The programme offered metacognitive hints to support them in solving the mathematical problems. The students of the control condition (n = 110) also worked in their textbooks for the 10-week period but had no access to the computer programme. The results indicate that the computer programme is suitable for implementation in practice and beneficial to the students in combination with their mathematics textbooks.

Telemedicine comprises different concepts aiming to close a spatial distance between practitioner, medical staff and patient. It's functionality can include mere data transmission but extend as well to triggering alarms or enable consultation and therapy suggestions. A special form of telemedicinal application is interventional decentralized telemonitoring. Here practitioner-patient communication is characterized by telemedicinial data collection driven therapy-control and -optimization. To identify feasible indications for the employment of telemonitoring a detailed definition of communicated parameters, alarm rules and algorithms of intervention are required as well as a benefit-cost analysis. The quality of the telemedical application is determined by the medical quality of the resulting actions.

Metacognitive monitoring and regulation play an essential role in mathematical problem solving. Therefore, it is important for researchers and practitioners to assess students' metacognition. One proven valid, but time consuming, method to assess metacognition is by using think-aloud protocols. Although valuable, practical drawbacks of this method necessitate a search for more convenient measurement instruments. Less valid methods that are easy to use are self-report questionnaires on metacognitive activities. In an empirical study in grade five (n = 39), the accuracy of students' performance judgments and problem visualizations are combined into a new instrument for the assessment of metacognition in word problem solving. The instrument was administered to groups of students. The predictive validity of this instrument in problem solving is compared to a well-known think-aloud measure and a self-report questionnaire. The results first indicate that the questionnaire has no relationship with word problem solving performance, nor the other two instruments. Further analyses show that the new instrument does overlap with the think-aloud measure and both predict problem solving. But, both instruments also have their own unique contribution to predicting word problem solving. The results are discussed and recommendations are made to further complete the practical measurement instrument. (Contains 1 figure and 3 tables.)