Hyperoxemia and hypoxemia impair cellular oxygenation:a study in healthy volunteers

Introduction: Administration of oxygen therapy is common, yet there is a lack of knowledge on its ability to prevent cellular hypoxia as well as on its potential toxicity. Consequently, the optimal oxygenation targets in clinical practice remain unresolved. The novel PpIX technique measures the mitochondrial oxygen tension in the skin (mitoPO2) which allows for non-invasive investigation on the effect of hypoxemia and hyperoxemia on cellular oxygen availability. Results: During hypoxemia, SpO2 was 80 (77–83)% and PaO2 45(38–50) mmHg for 15 min. MitoPO2 decreased from 42(35–51) at baseline to 6(4.3–9)mmHg (p &lt; 0.001), despite 16(12–16)% increase in cardiac output which maintained global oxygen delivery (DO2). During hyperoxic breathing, an FiO2 of 40% decreased mitoPO2 to 20 (9–27) mmHg. Cardiac output was unaltered during hyperoxia, but perfused De Backer density was reduced by one-third (p &lt; 0.01). A PaO2 &lt; 100 mmHg and &gt; 200 mmHg were both associated with a reduction in mitoPO2. Conclusions: Hypoxemia decreases mitoPO2 profoundly, despite complete compensation of global oxygen delivery. In addition, hyperoxemia also decreases mitoPO2, accompanied by a reduction in microcirculatory perfusion. These results suggest that mitoPO2 can be used to titrate oxygen support.</p

Breast cancer radiotherapy and the risk of acute coronary events - insights from a process oriented model

BACKGROUND AND PURPOSE: Acute coronary events (ACEs) are considered the most important side effect of radiotherapy (RT) for breast cancer but underlying mechanisms still have to be identified. Process oriented models mathematically describe the development of disease and provide a link between mechanisms and subsequent risk. Here, this link is exploited to learn about the underlying mechanisms from the observed age-time patterns of ACE risk. MATERIALS AND METHODS: A process oriented model of atherosclerosis and subsequent ACEs was applied to a contemporary breast cancer cohort of 810 patients with measurements of coronary artery calcification. Patients with prior ischemic heart disease were excluded. The process oriented model describes disease development as a series of different stages. Different variants of the model were fitted to the data. In each variant, one stage was assumed to be accelerated in relation to mean heart dose. RESULTS: During a mean follow up of 9.1 years, 25 ACEs occurred. The model reproduced the prevalence and associated risk of coronary calcifications. Mean heart dose significantly improved the fit only when implemented as affecting a late stage of atherosclerosis on already existing, complicated lesions (achieving p = 0.007). This can be understood by atherosclerosis being a slowly progressing disease. Therefore, an increase of ACEs few years after RT requires advanced atherosclerosis at the time of RT. CONCLUSION: Risk of ACE increases within few years in patients with advanced atherosclerosis at RT. Therefore, patients should be assessed for cardiovascular risk, and also elderly patients need to be considered for heart sparing techniques

A thematic analysis into the experiences of people with a mild intellectual disability during the COVID-19 lockdown period

Background. The COVID-19 pandemic is expected to have a substantial impact on people with an intellectual disability. The goal of the current study was to explore the experiences and needs of people with a mild intellectual disability during the COVID-19 lockdown period in the Netherlands. Method. A descriptive qualitative methodology was conducted, using semi-structured individual interviews with six people with a mild intellectual disability. Data were analysed thematically. Results. Three overarching themes were found: (i) Missing social contact and having people close; (ii) Being housebound has changed my daily life; and (iii) Hard to understand the preventive measures. Conclusions. Important insights into the experiences and needs of people with a mild intellectual disability during the COVID-19 lockdown period were gained. These insights are valuable with respect to a potential second COVID-19 wave or a future infection-outbreak

Sandbox university: Estimating influence of institutional action

The approach presented in this article represents a generalizable and adaptable methodology for identifying complex interactions in educational systems and for investigating how manipulation of these systems may affect educational outcomes of interest. Multilayer Minimum Spanning Tree and Monte-Carlo methods are used. A virtual Sandbox University is created in order to facilitate effective identification of successful and stable initiatives within higher education, which can affect students' credits and student retention - something that has been lacking up until now. The results highlight the importance of teacher feedback and teacher-student rapport, which is congruent with current educational findings, illustrating the methodology's potential to provide a new basis for further empirical studies of issues in higher education from a complex systems perspective

A simulation of skin mitochondrial PO2 in circulatory shock

Circulatory shock is the inadequacy to supply mitochondria with enough oxygen to sustain aerobic energy metabolism. A novel non-invasive bedside measurement was recently introduced to monitor the mitochondrial oxygen tension in the skin (mitoPO2). As the most downstream marker of oxygen balance in the skin, mitoPO2 may provide additional information to improve shock management. However, a physiological basis for the interpretation of mitoPO2 values has not been established yet. In this paper we developed a mathematical model of skin mitoPO2 using a network of parallel microvessels, based on Krogh's cylinder model. The model contains skin blood flow velocity, heterogeneity of blood flow, hematocrit, arteriolar oxygen saturation and mitochondrial oxygen consumption as major variables. The major results of the model show that normal physiological mitoPO2 is in the range of 40-60mmHg. The relationship of mitoPO2 with skin blood flow velocity follows a hyperbolic curve, reaching a plateau at high skin blood flow velocity, suggesting that oxygen balance remains stable whilst peripheral perfusion declines. The model shows that a critical range exists where mitoPO2 rapidly deteriorates if skin perfusion further decreases. The model intuitively shows how tissue hypoxia could occur in the setting of septic shock, due to the profound impact of microcirculatory disturbance on mitoPO2, even at sustained cardiac output. MitoPO2 is the result of a complex interaction between all factors of oxygen delivery and the microcirculation. This mathematical framework can be used to interpret mitoPO2 values in shock, with the potential to enhance personalized clinical trial design.</p

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

IMPORTANCE: Radiation-induced acute coronary events (ACEs) may occur as treatment-related late side effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remains to be determined. OBJECTIVE: The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in BC patients treated with radiotherapy (RT). DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOMES AND MEASURES: The study cohort consisted of 910 BC patients treated with postoperative RT after breast conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose (MHD), volume of the left ventricle receiving ≥ 5 Gy (LV-V5), mean LAD dose and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning CT-scans. Cox-regression analysis was used to analyse the effects on the cumulative incidence of ACEs. RESULTS: The median follow-up time was 9.2 years (range: 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n=163) the mean dose to the atherosclerotic plaque was the strongest predictor for ACE, even after correction for cardiovascular risk factors (HR: 1.269 (95% CI: 1.090-1.477), P=0.002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n=680) (hazard ratio (HR): 1.021 (95% CI: 1.003-1.039; P=0.023). CONCLUSION AND RELEVANCE: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in BC patients

ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis

ACE I/D polymorphism is associated with mortality in a cohort study of patients starting with dialysis.BackgroundIn dialysis patients, only a few follow-up studies have addressed the relationship between the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and mortality, but the available data are contradictory.MethodsA cohort of 453 consecutive patients starting dialysis between January 1999 and January 2002 and participating in a Dutch multicenter prospective study was examined. Patients who died within 3 months after the start of dialysis were excluded. Patients were followed until date of death or censoring in November 2003.ResultsThe ACE II, ID, and DD genotype frequencies were 24.3% (N = 110), 50.1% (N = 227), and 25.6% (N = 116). Besides a slightly higher number of Caucasians in the DD group, all other patient characteristics of the 3 ACE groups were similar at the start of dialysis. After adjustment for age, comorbidity, and ethnic background, patients with the ID and DD genotype showed an increased hazard ratio (HR) for all-cause mortality of 1.55 (95% CI 1.00-2.42) and 2.30 (95% CI 1.41-3.75), compared to patients with the II genotype. Slightly lower HRs were found for cardiovascular mortality. All groups of primary kidney disease showed a 2- to 3-fold increased adjusted HR for DD.ConclusionThe DD genotype identifies dialysis patients at an increased risk for mortality

Validation of separate multi-atlases for auto segmentation of cardiac substructures in CT-scans acquired in deep inspiration breath hold and free breathing

Background and purpose: Developing NTCP-models for cardiac complications after breast cancer (BC) radiotherapy requires cardiac dose-volume parameters for many patients. These can be obtained by using multi-atlas based automatic segmentation (MABAS) of cardiac structures in planning CT scans. We investigated the relevance of separate multi-atlases for deep inspiration breath hold (DIBH) and free breathing (FB) CT scans. Materials and methods: BC patients scanned in DIBH (n = 10) and in FB (n = 20) were selected to create separate multi-atlases consisting of expert panel delineations of the whole heart, atria and ventricles. The accuracy of atlas-generated contours was validated with expert delineations in independent datasets (n = 10 for DIBH and FB) and reported as Dice coefficients, contour distances and dose-volume differences in relation to interobserver variability of manual contours. Dependency of MABAS contouring accuracy on breathing technique was assessed by validation of a FB atlas in DIBH patients and vice versa (cross validation). Results: For all structures the FB and DIBH atlases resulted in Dice coefficients with their respective reference contours > 0.8 and average contour distances < 2 mm smaller than slice thickness of (CTs). No significant differences were found for dose-volume parameters in volumes receiving relevant dose levels (WH, LV and RV). Accuracy of the DIBH atlas was at least similar to, and for the ventricles better than, the interobserver variation in manual delineation. Cross-validation between breathing techniques showed a reduced MABAS performance. Conclusion: Multi-atlas accuracy was at least similar to interobserver delineation variation. Separate atlases for scans made in DIBH and FB could benefit atlas performance because accuracy depends on breathing technique