Background and purpose: Automatic approaches are widely implemented to automate dose optimization in radiotherapy treatment planning. This study systematically investigates how to configure automatic planning in order to create the best possible plans. Materials and methods: Automatic plans were generated using protocol based automatic iterative optimization. Starting from a simple automation protocol which consisted of the constraints for targets and organs at risk (OAR), the performance of the automatic approach was evaluated in terms of target coverage, OAR sparing, conformity, beam complexity, and plan quality. More complex protocols were systematically explored to improve the quality of the automatic plans. The protocols could be improved by adding a dose goal on the outer 2 mm of the PTV, by setting goals on strategically chosen subparts of OARs, by adding goals for conformity, and by limiting the leaf motion. For prostate plans, development of an automated post-optimization procedure was required to achieve precise control over the dose distribution. Automatic and manually optimized plans were compared for 20 head and neck (H&N), 20 prostate, and 20 rectum cancer patients. Results: Based on simple automation protocols, the automatic optimizer was not always able to generate adequate treatment plans. For the improved final configurations for the three sites, the dose was lower in automatic plans compared to the manual plans in 12 out of 13 considered OARs. In blind tests, the automatic plans were preferred in 80% of cases. Conclusions: With adequate, advanced, protocols the automatic planning approach is able to create high-quality treatment plans.

There is ample evidence that systemic sympathetic neural activity contributes to the progression of chronic kidney disease, possibly by limiting renal blood flow and thereby inducing renal hypoxia. Up to now there have been no direct observations of this mechanism in humans. We studied the effects of systemic sympathetic activation elicited by a lower body negative pressure (LBNP) on renal blood flow (RBF) and renal oxygenation in healthy humans.

Renal hypoxia is thought to be an important pathophysiological factor in the progression of chronic kidney disease (CKD) and the associated hypertension. In a previous study among CKD patients, supplementation with 100% oxygen reduced sympathetic nerve activity (SNA) and lowered blood pressure (BP). We aimed to assess the underlying haemodynamic modulation and hypothesized a decreased systemic vascular resistance (SVR). To that end, 19 CKD patients were studied during 15-min intervals of increasing partial oxygen pressure (ppO2) from room air (0.21 ATA) to 1.0 ATA and further up to 2.4 ATA, while continuously measuring finger arterial blood pressure (Finapres). Off-line, we derived indexes of SVR, cardiac output (CO) and baroreflex sensitivity from the continuous BP recordings (Modelflow). During oxygen supplementation, systolic, and diastolic BP both increased dose-dependently from 128 ± 24 and 72 ± 19 mmHg respectively at baseline to 141 ± 23 (p < 0.001) and 80 ± 21 mmHg (p < 0.001) at 1.0 ATA oxygen. Comparing baseline and 1.0 ATA oxygen, SVR increased from 1440 ± 546 to 1745 ± 710 dyn·s/cm5 (p = 0.009), heart rate decreased from 60 ± 8 to 58 ± 6 bpm (p < 0.001) and CO from 5.0 ± 1.3 to 4.6 ± 1.1 L/min (p = 0.02). Baroreflex sensitivity remained unchanged (13 ± 13 to 15 ± 12 ms/mmHg). These blood pressure effects were absent in a negative control group of eight young healthy subjects. We conclude that oxygen supplementation in CKD patients causes a non-baroreflex mediated increased in SVR and blood pressure.

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In the kidneys, there is both blood flow through the capillaries and flow of pre-urine through the tubuli and collecting ducts. We hypothesized that diffusion-weighted (DW) MRI measures both blood and pre-urine flow when using a tri-exponential intravoxel incoherent motion (IVIM) model. Our aim was to systematically investigate and optimize tri-exponential IVIM-analysis for the kidney and test its sensitivity to renal perfusion changes in humans. The tri-exponential fit probes the diffusion coefficient (D), the intermediate (D*i) and fast (D*f) pseudo-diffusion coefficients, and their signal fractions, fD, fi and ff. First, we studied the effects of fixing the D*-coefficients of the tri-exponential fit using in silico simulations. Then, using a 3T MRI scanner, DW images were acquired in healthy subjects (18-24 years) and we assessed the within-subject coefficient of variation (wsCV, n=6). Then, renal perfusion was modulated by Angiotensin II infusion during which DW imaging of the kidneys and phase contrast MRI of the renal artery was performed (n=8). Radioisotope clearing tests were used to assess the glomerular filtration rate. Simulations showed that fixing the D*-coefficients - which could potentially increase the fit stability - in fact decreased the precision of the model. Changes in D*-coefficients were translated into the f-parameters instead. Fixing D*-coefficients resulted in a stronger response of the fit parameters to the intervention. Using this model, the wsCVs for D, fD, fi and ff were 2.4%, 0.8%, 3.5%, 19.4% respectively. fi decreased by 14% (p=0.059) and ff increased by 32% (p=0.004) between baseline and maximal Angiotensin II dose. ff inversely correlated to renal plasma flow (R=-0.70, p<0.01) and fi correlated to glomerular filtration rate (R=0.39, p=0.026). We validated a kidney-specific method for IVIM analysis using a tri-exponential model. The model is able to track renal perfusion changes induced by Angiotensin II.

BackgroundThe role of kidney hypoxia is considered pivotal in the progression of chronic kidney disease. A widely used method to assess kidney oxygenation is blood oxygen level dependent (BOLD)–magnetic resonance imaging (MRI), but its interpretation remains problematic. The BOLD‐MRI signal is the result of kidney oxygen consumption (a proxy of glomerular filtration) and supply (ie, glomerular perfusion). Therefore, we hypothesized that with pharmacological modulation of kidney blood flow, renal oxygenation, as assessed by BOLD‐MRI, correlates to filtration fraction (ie, glomerular filtration rate/effective renal plasma flow) in healthy humans. Methods and ResultsEight healthy volunteers were subjected to continuous angiotensin‐II infusion at 0.3, 0.9, and 3.0 ng/kg per minute. At each dose, renal oxygenation and blood flow were assessed using BOLD and phase‐contrast MRI. Subsequently, “gold standard” glomerular filtration rate/effective renal plasma flow measurements were performed under the same conditions. Renal plasma flow decreased dose dependently from 660±146 to 467±103 mL/min per 1.73 m2 (F[3, 21]=33.3, P<0.001). Glomerular filtration rate decreased from 121±23 to 110±18 mL/min per 1.73 m2 (F[1.8, 2.4]=6.4, P=0.013). Cortical transverse relaxation rate (R2*; increases in R2* represent decreases in oxygenation) increased by 7.2±3.8% (F[3, 21]=7.37, P=0.001); medullar R2* did not change. Cortical R2* related to filtration fraction (R2 0.46, P<0.001). ConclusionsBy direct comparison between “gold standard” kidney function measurements and BOLD MRI, we showed that cortical oxygenation measured by BOLD MRI relates poorly to glomerular filtration rate but is associated with filtration fraction. For future studies, there may be a need to include renal plasma flow measurements when employing renal BOLD‐MRI.

Background: It would be desirable to safely and continuously measure blood pressure noninvasively under hyperbaric and/or hyperoxic conditions, in order to explore haemodynamic responses in humans under these conditions.Methods: A systematic analysis according to `failure mode and effects analysis' principles of a commercially available beat-by- beat non-invasive blood pressure monitoring device was performed using specifications provided by the manufacturer. Possible failure modes related to pressure resistance and fire hazard in hyperbaric and oxygen-enriched environments were identified and the device modified accordingly to mitigate these risks. The modified device was compared to an unaltered device in five healthy volunteers under normobaric conditions. Measurements were then performed under hyperbaric conditions (243 kPa) in five healthy subjects.Results: Modifications required included: 1) replacement of the carbon brush motorized pump by pressurized air connected through a balanced pressure valve; 2) modification of the 12V power supply connection in the multiplace hyperbaric chamber, and 3) replacement of gas-filled electrolytic capacitors by solid equivalents. There was concurrence between measurements under normobaric conditions, with no significant differences in blood pressure. Measurements under pressure were achieved without problems and matched intermittent measurement of brachial arterial pressure.Conclusion: The modified system provides safe, stable, continuous non-invasive blood pressure trends under both normobaric and hyperbaric conditions.

For various (patho‐)physiological human study designs it would desirable to have a safe, noninvasive continuous blood pressure measurement for use under hyperbaric conditions. For this purpose we present the modifications to the Portapres™ system (Model 1) and its preliminary validation.The Portapres™ system was systematically analyzed according to “failure mode and effects analysis” principles. We identified possible failure modes related to pressure resistance and fire hazard in a hyperbaric and oxygen enriched environment, and adapted the device accordingly. 1) the carbon brush pump was replaced by a pressure reducing valve to be connected to a pressurized air supply. 2) gas‐filled electrolytic capacitors were replaced for solid equivalents. 3) the power supply was modified to fit the low voltage supply in the hyperbaric chamber.Preliminary validation of the modified system was performed in 5 healthy volunteers: against a standard Finapres® device (n=5) there was concurrence between measurements under normobaric conditions, with non‐significant (p > 0.2) mean differences of 1.03 and 4.93 mmHg in systolic and diastolic blood pressure. Hyperbaric measurements proceeded without problems in two of the healthy volunteers.The modified system seems to provide safe and reliable measurements both under normo‐ and hyperbaric conditions. Further validation is warranted.

IntroductionDonor-site morbidity, complications and availability remain concerns in autologous bone grafting today. The Reamer/Irrigator/Aspirator system (RIA) provides an alternative method to overcome these problems. According to literature, RIA graft possesses a higher osteogenic potency. This study compares iliac crest and RIA graft performance by determining their in vitro osteogenic capacity in a porcine model.MethodsOsteogenic capacity and cell content was determined in RIA and iliac crest bone grafts harvested from six female domestic white pigs. Cells initially washed off, and cells harvested with collagenase were analysed separately and in combination. Alkaline phosphatase expression (ALP) and cell numbers were evaluated after 7 and 14 days of culture. Matrix mineralisation was quantified after 14 days.ResultsCell cultures showed a significant increase of matrix mineralisation by RIA-derived cells compared to iliac crest bone graft (p=0.0313). The yield of collagenase derived cells was increased in the RIA group and a synergy between washed off and collagenase derived cells was observed. Cell proliferation was similar in both groups.DiscussionThe osteogenic differentiation capacity of cell populations isolated from the RIA derived bone graft surpasses that of iliac crest derived cells. It is proposed that the observed effect can be attributed to the origin of the cells and to the specific action of the RIA system. This study provides further evidence indicating that RIA bone graft provides superior osteogenic properties compared to iliac crest bone graft.