Medication error with methotrexate. / Feildosering av metotreksat.

Background: A woman in her seventies presented to the accident and emergency department (A&E) with shortness of breath that had increased over a period of three weeks. She had a history of COPD, hypertension and polymyalgia rheumatica. A medication error involving methotrexate, used for autoimmune diseases, was discovered during her medical history review. Case presentation: The patient arrived with stable vital signs, including 94 % oxygen saturation and a respiratory rate of 20 breaths/min. She had been taking 2.5 mg of methotrexate daily for the past three weeks instead of the prescribed weekly dose of 15 mg. Other examinations revealed no alarming findings, except for a slightly elevated D-dimer level. Interpretation: Considering her medical history and exclusion of other differential diagnoses, methotrexate toxicity was suspected. The patient was admitted to the hospital and intravenous folinic acid was initiated as an antidote treatment. Five days later, the patient was discharged with an improvement in the shortness of breath. This case underscores the importance of effective communication in health care, particularly in complex cases like this, where understanding dosages and administration is crucial. Medical history, clinical examinations and medication reviews, often involving clinical pharmacists, are vital in the A&E to reveal medication errors.

Impact of baseline coronary flow and its distribution on fractional flow reserve prediction.

Model-based prediction of fractional flow reserve (FFR) in the context of stable coronary artery disease (CAD) diagnosis requires a number of modelling assumptions. One of these assumptions is the definition of a baseline coronary flow, ie, total coronary flow at rest prior to the administration of drugs needed to perform invasive measurements. Here we explore the impact of several methods available in the literature to estimate and distribute baseline coronary flow on FFR predictions obtained with a reduced-order model. We consider 63 patients with suspected stable CAD, for a total of 105 invasive FFR measurements. First, we improve a reduced-order model with respect to previous results and validate its performance versus results obtained with a 3D model. Next, we assess the impact of a wide range of methods to impose and distribute baseline coronary flow on FFR prediction, which proved to have a significant impact on diagnostic performance. However, none of the proposed methods resulted in a significant improvement of prediction error standard deviation. Finally, we show that intrinsic uncertainties related to stenosis geometry and the effect of hyperemic inducing drugs have to be addressed in order to improve FFR prediction accuracy.

Semantic segmentation and detection of mediastinal lymph nodes and anatomical structures in CT data for lung cancer staging.

PURPOSE: Accurate lung cancer diagnosis is crucial to select the best course of action for treating the patient. From a simple chest CT volume, it is necessary to identify whether the cancer has spread to nearby lymph nodes or not. It is equally important to know precisely where each malignant lymph node is with respect to the surrounding anatomical structures and the airways. In this paper, we introduce a new data-set containing annotations of fifteen different anatomical structures in the mediastinal area, including lymph nodes of varying sizes. We present a 2D pipeline for semantic segmentation and instance detection of anatomical structures and potentially malignant lymph nodes in the mediastinal area. METHODS: We propose a 2D pipeline combining the strengths of U-Net for pixel-wise segmentation using a loss function dealing with data imbalance and Mask R-CNN providing instance detection and improved pixel-wise segmentation within bounding boxes. A final stage performs pixel-wise labels refinement and 3D instance detection using a tracking approach along the slicing dimension. Detected instances are represented by a 3D pixel-wise mask, bounding volume, and centroid position. RESULTS: We validated our approach following a fivefold cross-validation over our new data-set of fifteen lung cancer patients. For the semantic segmentation task, we reach an average Dice score of 76% over all fifteen anatomical structures. For the lymph node instance detection task, we reach 75% recall for 9 false positives per patient, with an average centroid position estimation error of 3 mm in each dimension. CONCLUSION: Fusing 2D networks' results increases pixel-wise segmentation results while enabling good instance detection. Better leveraging of the 3D information and station mapping for the detected lymph nodes are the next steps.

Uncertainty Quantification and Sensitivity Analysis for Computational FFR Estimation in Stable Coronary Artery Disease.

PURPOSE: The main objectives of this study are to validate a reduced-order model for the estimation of the fractional flow reserve (FFR) index based on blood flow simulations that incorporate clinical imaging and patient-specific characteristics, and to assess the uncertainty of FFR predictions with respect to input data on a per patient basis. METHODS: We consider 13 patients with symptoms of stable coronary artery disease for which 24 invasive FFR measurements are available. We perform an extensive sensitivity analysis on the parameters related to the construction of a reduced-order (hybrid 1D-0D) model for FFR predictions. Next we define an optimal setting by comparing reduced-order model predictions with solutions based on the 3D incompressible Navier-Stokes equations. Finally, we characterize prediction uncertainty with respect to input data and identify the most influential inputs by means of sensitivity analysis. RESULTS: Agreement between FFR computed by the reduced-order model and by the full 3D model was satisfactory, with a bias ([Formula: see text]) of [Formula: see text] at the 24 measured locations. Moreover, the uncertainty related to the factor by which peripheral resistance is reduced from baseline to hyperemic conditions proved to be the most influential parameter for FFR predictions, whereas uncertainty in stenosis geometry had greater effect in cases with low FFR. CONCLUSION: Model errors related to solving a simplified reduced-order model rather than a full 3D problem were small compared with uncertainty related to input data. Improved measurement of coronary blood flow has the potential to reduce uncertainty in computational FFR predictions significantly.

Fluoroscopy-free Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for controlling life threatening postpartum hemorrhage.

BACKGROUND: Severe postpartum hemorrhage occurs in 1/1000 women giving birth. This condition is often dramatic and may be life threatening. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has in recent years been introduced as a novel treatment for hemorrhagic shock. We present a series of fluoroscopy-free REBOA for controlling life threatening postpartum hemorrhage. METHODS: In 2008 an 'aortic occlusion kit' was assembled and used in three Norwegian university hospitals. The on-call interventional radiologist (IR) was to be contacted with a response time < 30 minutes in case of life threatening PPH. Demographics and characteristics were noted from the medical records. RESULTS: This retrospective study includes 36 patients treated with fluoroscopy-free REBOA for controlling severe postpartum hemorrhage in the years 2008-2015. The REBOA success rate was 100% and no patients died from REBOA related complications. Uterine artery embolization was performed in 17 (47%) patients and a hysterectomy in 16 (44%) patients. A short (11cm) introducer length was strongly associated with iliac artery thrombus formation (ρ = 0.50, P = 0.002). In addition, there was a strong negative correlation between uterine artery embolization and hysterectomy (ρ = -0.50, P = 0.002). CONCLUSIONS: Our Norwegian experience indicates the clinical safety and feasibility of REBOA in life threatening PPH. Also, REBOA can be used in an emergency situation without the use of fluoroscopy with a high degree of technical success. It is important that safety implementation of REBOA is established, especially through limited aortic balloon occlusion time and a thorough balloon deflation regime.

Differentiation at necropsy between in vivo gas embolism and putrefaction using a gas score.

Gas bubble lesions consistent with decompression sickness in marine mammals were described for the first time in beaked whales stranded in temporal and spatial association with military exercises. Putrefaction gas is a post-mortem artifact, which hinders the interpretation of gas found at necropsy. Gas analyses have been proven to help differentiating putrefaction gases from gases formed after hyperbaric exposures. Unfortunately, chemical analysis cannot always be performed. Post-mortem computed tomography is used to study gas collections, but many different logistical obstacles and obvious challenges, like the size of the animal or the transport of the animal from the stranding location to the scanner, limit its use in stranded marine mammals. In this study, we tested the diagnostic value of an index-based method for characterizing the amount and topography of gas found grossly during necropsies. For this purpose, putrefaction gases, intravenously infused atmospheric air, and gases produced by decompression were evaluated at necropsy with increased post-mortem time in New Zealand White Rabbits using a gas score index. Statistical differences (P<0.001) were found between the three experimental models immediately after death. Differences in gas score between in vivo gas embolism and putrefaction gases were found significant (P<0.05) throughout the 67h post-mortem. The gas score-index is a new and simple method that can be used by all stranding networks, which has been shown through this study to be a valid diagnostic tool to distinguish between fatal decompression, iatrogenic air embolism and putrefaction gases at autopsies.

Eccentric exercise 48 h prior to simulated diving has no effect on vascular bubble formation in rats.

PURPOSE: Decompression sickness (DCS) caused by vascular bubble formation is a major risk when diving. Prior studies have shown that physical exercise has a significant impact in both reducing and increasing bubble formation. There is limited knowledge about the mechanisms, but there are indications that exercise-induced muscle injury prior to diving may cause increased bubble formation. The purpose of this study was to investigate the role of exercise-induced muscle injury as a possible mechanism of bubble formation during diving. METHODS: Muscle injury was induced by exposing female Sprague-Dawley rats (n = 30) to a single bout of eccentric exercise, 100 min intermittent, downhill (-16°) treadmill running. Forty-eight hours later, the animals were exposed to a 50-min simulated saturation dive (709 kPa) in a pressure chamber, when the degree of muscle injury and inflammation would be the most pronounced. Bubble formation after the dive was observed by ultrasonic imaging for 4 h. RESULTS: No difference in bubble loads was found between the groups at any time despite evident muscle injury. Maximum bubble loads (bubbles cm(-2) heart cycle(-1)) were not different, exercise: 1.6 ± 3.5 SD vs control: 2.2 ± 4.1 SD, P = 0.90, n = 15 in each group. CONCLUSIONS: Eccentric exercise performed 48 h prior to diving causes skeletal muscle injury but does not increase the amount of vascular bubbles in rats. The prevailing recommendation is that physical activity prior to diving is a risk factor of DCS. However, present and previous studies implicate that pre-dive physical activity does not increase the DCS risk.

Animal study assessing safety of an acoustic coupling fluid that holds the potential to avoid surgically induced artifacts in 3D ultrasound guided operations.

BACKGROUND: Use of ultrasound in brain tumor surgery is common. The difference in attenuation between brain and isotonic saline may cause artifacts that degrade the ultrasound images, potentially affecting resection grades and safety. Our research group has developed an acoustic coupling fluid that attenuates ultrasound energy like the normal brain. We aimed to test in animals if the newly developed acoustic coupling fluid may have harmful effects. METHODS: Eight rats were included for intraparenchymal injection into the brain, and if no adverse reactions were detected, 6 pigs were to be included with injection of the coupling fluid into the subarachnoid space. Animal behavior, EEG registrations, histopathology and immunohistochemistry were used in assessment. RESULTS: In total, 14 animals were included, 8 rats and 6 pigs. We did not detect any clinical adverse effects, seizure activity on EEG or histopathological signs of tissue damage. CONCLUSION: The novel acoustic coupling fluid intended for brain tumor surgery appears safe in rats and pigs under the tested circumstances.

Acute and potentially persistent effects of scuba diving on the blood transcriptome of experienced divers.

During scuba diving, the circulatory system is stressed by an elevated partial pressure of oxygen while the diver is submerged and by decompression-induced gas bubbles on ascent to the surface. This diving-induced stress may trigger decompression illness, but the majority of dives are asymptomatic. In this study we have mapped divers' blood transcriptomes with the aim of identifying genes, biological pathways, and cell types perturbed by the physiological stress in asymptomatic scuba diving. Ten experienced divers abstained from diving for >2 wk before performing a 3-day series of daily dives to 18 m depth for 47 min while breathing compressed air. Blood for microarray analysis was collected before and immediately after the first and last dives, and 10 matched nondivers provided controls for predive stationary transcriptomes. MetaCore GeneGo analysis of the predive samples identified stationary upregulation of genes associated with apoptosis, inflammation, and innate immune responses in the divers, most significantly involving genes in the TNFR1 pathway of caspase-dependent apoptosis, HSP60/HSP70 signaling via TLR4, and NF-κB-mediated transcription. Diving caused pronounced shifts in transcription patterns characteristic of specific leukocytes, with downregulation of genes expressed by CD8+ T lymphocytes and NK cells and upregulation of genes expressed by neutrophils, monocytes, and macrophages. Antioxidant genes were upregulated. Similar transient responses were observed after the first and last dive. The results indicate that sublethal oxidative stress elicits the myeloid innate immune system in scuba diving and that extensive diving may cause persistent change in pathways controlling apoptosis, inflammation, and innate immune responses.

Exercise-induced myofibrillar disruption with sarcolemmal integrity prior to simulated diving has no effect on vascular bubble formation in rats.

Decompression sickness is initiated by gas bubbles formed during decompression, and it has been generally accepted that exercise before decompression causes increased bubble formation. There are indications that exercise-induced muscle injury seems to be involved. Trauma-induced skeletal muscle injury and vigorous exercise that could theoretically injure muscle tissues before decompression have each been shown to result in profuse bubble formation. Based on these findings, we hypothesized that exercise-induced skeletal muscle injury prior to decompression from diving would cause increase of vascular bubbles and lower survival rates after decompression. In this study, we examined muscle injury caused by eccentric exercise in rats prior to simulated diving and we observed the resulting bubble formation. Female Sprague-Dawley rats (n = 42) ran downhill (-16º) for 100 min on a treadmill followed by 90 min rest before a 50-min simulated saturation dive (709 kPa) in a pressure chamber. Muscle injury was evaluated by immunohistochemistry and qPCR, and vascular bubbles after diving were detected by ultrasonic imaging. The exercise protocol resulted in increased mRNA expression of markers of muscle injury; αB-crystallin, NF-κB, and TNF-α, and myofibrillar disruption with preserved sarcolemmal integrity. Despite evident myofibrillar disruption after eccentric exercise, no differences in bubble amounts or survival rates were observed in the exercised animals as compared to non-exercised animals after diving, a novel finding that may be applicable to humans.

Effects of hyperbaric oxygen preconditioning on cardiac stress markers after simulated diving.

Hyperbaric oxygen preconditioning (HBO-PC) can protect the heart from injury during subsequent ischemia. The presence of high loads of venous gas emboli (VGE) induced by a rapid ambient pressure reduction on ascent from diving may cause ischemia and acute heart failure. The aim of this study was to investigate the effect of diving-induced VGE formation on cardiac stress marker levels and the cardioprotective effect of HBO-PC. To induce high loads of VGE, 63 female Sprague-Dawley rats were subjected to a rapid ambient pressure reduction from a simulated saturation dive (50 min at 709 kPa) in a pressure chamber. VGE loads were measured for 60 min in anesthetized animals by the use of ultrasonography. The animals were divided into five groups. Three groups were exposed to either diving or to HBO-PC (100% oxygen, 38 min at 303 kPa) with a 45 or 180 min interval between HBO-PC and diving. Two additional groups were used as baseline controls for the measurements; one group was exposed to equal handling except for HBO-PC and diving, and the other group was completely unexposed. Diving caused high loads of VGE, as well as elevated levels of the cardiac stress markers, cardiac troponin T (cTnT), natriuretic peptide precursor B (Nppb), and αB-crystallin, in blood and cardiac tissue. There were strong positive correlations between VGE loads and stress marker levels after diving, and HBO-PC appeared to have a cardioprotective effect, as indicated by the lower levels of stress marker expression after diving-induced VGE formation.

Early genetic responses in rat vascular tissue after simulated diving.

Diving causes a transient reduction of vascular function, but the mechanisms behind this are largely unknown. The aim of this study was therefore to analyze genetic reactions that may be involved in acute changes of vascular function in divers. Rats were exposed to 709 kPa of hyperbaric air (149 kPa Po(2)) for 50 min followed by postdive monitoring of vascular bubble formation and full genome microarray analysis of the aorta from diving rats (n = 8) and unexposed controls (n = 9). Upregulation of 23 genes was observed 1 h after simulated diving. The differential gene expression was characteristic of cellular responses to oxidative stress, with functions of upregulated genes including activation and fine-tuning of stress-responsive transcription, cytokine/cytokine receptor signaling, molecular chaperoning, and coagulation. By qRT-PCR, we verified increased transcription of neuron-derived orphan receptor-1 (Nr4a3), plasminogen activator inhibitor 1 (Serpine1), cytokine TWEAK receptor FN14 (Tnfrsf12a), transcription factor class E basic helix-loop-helix protein 40 (Bhlhe40), and adrenomedullin (Adm). Hypoxia-inducible transcription factor HIF1 subunit HIF1-α was stabilized in the aorta 1 h after diving, and after 4 h there was a fivefold increase in total protein levels of the procoagulant plasminogen activator inhibitor 1 (PAI1) in blood plasma from diving rats. The study did not have sufficient power for individual assessment of effects of hyperoxia and decompression-induced bubbles on postdive gene expression. However, differential gene expression in rats without venous bubbles was similar to that of all the diving rats, indicating that elevated Po(2) instigated the observed genetic reactions.

A reliable and valid protocol for measuring maximal oxygen uptake in pigs.

BACKGROUND: Most knowledge about cellular and molecular adaptation in the heart after exercise training comes from rodent models, and this has substantially improved our knowledge about exercise-induced cardiac adaptations. However, in rodents, the electrophysiological properties of the heart are different from the human heart. Therefore, the need of exercise-training models in larger animal models is obvious. Physiological studies of cardio-respiratory fitness require training regimens that give robust and adequate testing procedures to quantify the outcome. METHODS: We developed a valid and reproducible protocol for measuring maximal oxygen uptake (VO2max) in young pigs. As previous studies have exercised pigs using horizontal treadmills, we determined whether treadmill inclination may influence the level of peak oxygen uptake (VO2peak) achieved, and whether the true VO2max was reached. Eight young pigs were used. Submaximal and VO2peak were tested at five different inclinations from 13 to 30 degrees . RESULTS: At submaximal VO2, there was an excellent test-retest at all treadmill inclinations (r = 0.99, coefficient of variation = 1.8%). The level of VO2peak was dependent upon treadmill inclination and the true VO2max, defined as a levelling-off of VO2 despite increased running speed, was only reached a treadmill inclination of 24 degrees . For VO2peak we only observed a significant test-retest correlation when using 19 and 24 degrees inclination of the treadmill (r = 0.88, coefficient of variation = 9.7%). CONCLUSION: The use of inappropriate treadmill inclination might hide training-induced adaptations if the true VO2max is not reached. This study shows that the present test protocol can be used in future studies of exercise on treadmill, when the aim is to measure submaximal and VO2max in pigs.

Recompression during decompression and effects on bubble formation in the pig.

INTRODUCTION: There is a relationship between gas bubble formation in the vascular system and serious decompression sickness. Hence, control of the formation of vascular bubbles should allow safer decompression procedures. METHODS: There were 12 pigs that were randomly divided into an experimental group (EXP) and a control group (CTR) of 6 animals each. The pigs were compressed to 500 kPa (5 ATA) in a dry hyperbaric chamber and held for 90 min bottom time breathing air. CTR animals were decompressed according to a modified USN dive profile requiring four stops. EXP followed the same profile except that a 5-min recompression of 50 kPa (0.5 ATA) was added at the end of each of the last three decompression stops before ascending to the next stop depth. RESULTS: All CTR animals developed bubbles, compared with only one animal in EXP. The number of bubbles detected during and after the dive was 0.02 +/- 0.02 bubbles x cm(-2) in CTR, while the number of bubbles detected in EXP were 0.0009 +/- 0.005 bubbles x cm(-2); the difference was highly significant. CONCLUSION: By brief recompression during late decompression stops, the amount of bubbles was reduced. Our findings give further support for a gas phase model of decompression.

Exercise ending 30 min pre-dive has no effect on bubble formation in the rat.

INTRODUCTION: We have previously shown that exercise performed 20 h before a dive significantly reduces bubble formation in both rats and humans. Furthermore, exercise performed closer to the dive did not prevent bubble formation. HYPOTHESIS: The present study was designed to determine whether exercise 30 min prior to a dive promotes bubble formation. The occurrence of many bubbles is linked to a higher risk of developing decompression sickness. METHODS: A total of 58 Sprague-Dawley rats were randomly divided into a sedentary control group (n = 29) and an exercise group (n = 29). Rats in the exercise group ran on a treadmill for a total of 90 min at variable intensity up to 85-90% of VO2max. Then, 30 min after exercise, one rat from each group rested in a pressure chamber at 700 kPa (7 atm) breathing air, performing a simulated dive. Bottom time was 45 min; decompression rate was 50 kPa x min(-1) (0.5 atm x min(-1)). Immediately after surfacing (100 kPa, 1 atm), the rats were anesthetized and bubbles were measured discontinuously for the next 60 min. RESULTS: There were no significant differences in survival (p = 0.55), median bubble grade (p = 0.67), survival time (p = 0.53), or the number of rats getting a bubble score > or = 2 (p = 0.79) between the groups. CONCLUSION: The same type and intensity of exercise that reduces bubble formation when performed 20 h prior to a dive neither promotes nor reduces bubble formation if performed 30 min before a dive. The present data indicate that exercise completed 30 min before a dive does not increase the risk of developing decompression sickness in the rat.