Epithelial-fibroblast interactions in IPF: Lessons from in vitro co-culture studies.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial disease that is characterized by increased cellular proliferation and differentiation together with excessive extracellular matrix (ECM) deposition leading to buildup of scar tissue (fibrosis) and remodeling in the lungs. The activated and differentiated (myo)fibroblasts are one of the main sources of tissue remodeling in IPF and a crucial mechanism known to contribute to this feature is an aberrant crosstalk between pulmonary fibroblasts and the abnormal or injured pulmonary epithelium. This epithelial-fibroblast interaction mimics the temporal, spatial and cell-type specific crosstalk between the endoderm and mesoderm in the so-called epithelial-mesenchymal trophic unit (EMTU) during lung development that is proposed to be activated in healthy lung repair and dysregulated in various lung diseases including IPF. To study the dysregulated lung EMTU in IPF, various complex in vitro models have been established. Hence, in this review, we will provide a summary of studies that have used complex (3-dimensional) in vitro co-culture, and organoid models to assess how abnormal epithelial-fibroblast interactions in lung EMTU contribute to crucial features of the IPF including defective cellular differentiation, proliferation and migration as well as increased ECM deposition.

Glucose in prediabetic and diabetic range and outcome after stroke.

OBJECTIVES: Newly diagnosed disturbed glucose metabolism is highly prevalent in patients with stroke. Limited data are available on their prognostic value on outcome after stroke. We aimed to assess the association of glucose in the prediabetic and diabetic range with unfavourable short-term outcome after stroke. MATERIALS AND METHODS: We included 839 consecutive patients with ischemic stroke and 168 patients with intracerebral haemorrhage. In all nondiabetic patients, fasting glucose levels were determined on day 2-4. Prediabetic range was defined as fasting glucose of 5.6-6.9 mmol/L, diabetic range as ≥7.0 mmol/L, pre-existent diabetes as the use of anti-diabetic medication prior to admission. Outcome measures were poor functional outcome or death defined as modified Rankin Scale (mRS) score >2 and discharge not to home. The association of prediabetic range, diabetic range and pre-existent diabetes (versus normal glucose) with unfavourable outcome was expressed as odds ratios, estimated with multiple logistic regression, with adjustment for prognostic factors. RESULTS: Compared with normal glucose, prediabetic range (aOR 1.8; 95%CI 1.1-2.8), diabetic range (aOR 2.5; 95%CI 1.3-4.9) and pre-existent diabetes (aOR 2.6; 95%CI 1.6-4.0) were associated with poor functional outcome or death. Patients in the prediabetic range (aOR 0.6; 95%CI 0.4-0.9), diabetic range (aOR 0.4; 95%CI 0.2-0.9) and pre-existent diabetes (aOR 0.6; 95%CI 0.4-0.9) were more likely not to be discharged to home. CONCLUSIONS: Patients with glucose in the prediabetic and diabetic range have an increased risk of unfavourable short-term outcome after stroke. These findings illustrate the potential impact of early detection and treatment of these patients.

Appropriateness of blood product transfusion in the Obstetrics and Gynaecology (O&G) department of a tertiary hospital in West Africa.

BACKGROUND: Misuse of blood by clinicians was suggested to explain blood shortage in sub-Saharan Africa although based on little evidence. This study evaluated whether routine halving (restricted) of blood requests was justified. STUDY DESIGN AND METHODS: On alternated days for 3 months in 2011-2012, restricted or full blood product supply [whole blood (WB), red cell concentrate (RCC)] was provided to the Obstetrics & Gynaecology department (O&G). Patient age, haemoglobin (Hb) level pre- and post-transfusion, clinical condition, blood products request and supply, transfused and returned, clinical outcome were collated. RESULTS: Five hundred and nineteen patients (249 restricted and 270 full supply) received 1001 blood products (94.6% WB, 6.4% RCC). Clinical conditions were severe peri-partum bleeding (72.4%) requiring emergency transfusion (82%) whilst 27.6% of total transfusion was for anaemia, 18% being moderate (8-10 g dL(-1) ). Pre-transfusion Hb level was <6 g dL(-1) in 36.7%, 6-8 g dL(-1) 29.1% and ≥ 8 g dL(-1) in 33.2% of cases. Fifty-five percent of the transfused blood was stored ≤ 1 week. Restricted supply triggered additional request (40%) compared to 10% in full supply mode. Whether with restricted or full supply, blood requests, supply and units transfused/patient were similar (restricted 2.3 and 2.1 unit patient(-1) and full 2.9 and 2.3 unit patient(-1) , respectively). Fatal clinical outcome was 3.1% evenly distributed between supply modes and transfusion reactions 0.8%. CONCLUSIONS: O&G clinicians order blood according to clinical need and transfuse 85% of the products supplied. Product supply did not significantly affect use although appropriateness of transfusion was difficult to assess.

Understanding fibroblast-immune cell interactions via co-culture models and their role in asthma pathogenesis.

Asthma is a chronic lung disease involving airway inflammation and fibrosis. Fibroblasts are the main effector cells important for lung tissue production which becomes abnormal in asthmatics and is one of the main contributors to airway fibrosis. Although fibroblasts were traditionally viewed solely as structural cells, they have been discovered to be highly active, and involved in lung inflammatory and fibrotic processes in asthma. In line with this, using 2D and 3D in vitro co-culture models, a complex interaction between lung fibroblasts and various immune cells important for the pathogenesis of asthma have been recently uncovered. Hence, in this review, we provide the first-ever summary of various studies that used 2D and 3D in vitro co-culture models to assess the nature of aberrant immune cell-fibroblast interactions and their contributions to chronic inflammation and fibrotic mechanisms in asthma pathogenesis.

Understanding the effects of pasture type and stocking rate on the hydrology of the Southern Great Plains.

Grassland is one of the major biomes in the United States (US) and the world. In the US, the majority of grasslands are concentrated in the Great Plains and has undergone through significant interventions or management changes over the last few decades. A key economy-driven intervention in the Southern Great Plains (SGP) include the introduction of new forage species and conversion of native grassland to introduced pasture to increase productivity and its nutritive value for improved cattle production. Since water is one of the fundamental resources needed to sustain grassland productivity, it is important to understand how such pasture conversion and prevailing cattle grazing practices affect water balance and biomass production in a given pasture system. In this study, the Nutrient Tracking Tool (NTT) with its core APEX (Agricultural Policy Environmental eXtender) model was used to assess the hydrological impacts of the pasture introduction, i.e., native pasture (little bluestem, Schizachyrium halapense) vs. introduced pasture (old world bluestem, Bothriochloa caucasica), and the stocking rate in the SGP. Monthly evapotranspiration (ET) and biomass estimates from NTT compared well with observed data at two USDA-ARS experimental pastures (native and introduced) near El Reno, Oklahoma, for the years 2015 and 2016. Simulated long-term average annual hydrologic fluxes (i.e., ET, runoff, and groundwater recharge) from the introduced pasture were slightly lower than the observed data but not significantly different than those from the native pasture under the current management conditions. NTT predicted higher water yield (runoff and recharge) and significantly lower ET for the introduced pasture than the native pasture. Results suggest that grazing has the potential to alter the hydrological balance in the SGP. For example, the increase in stocking rate within the carrying capacity of the farm decreases ET and increases runoff and groundwater recharge for both pastures. Comparison of estimated biomass production between native and introduced pastures indicated that introduced pastures are more efficient in using the available water and thus produce a higher forage biomass per unit of water in the SGP. This study highlighted the potential significance of considering hydrological and other biophysical impacts of new forage introduction and stocking rate changes for the sustainable management of grazing and pasture systems in the SGP.

Impaired fasting glucose is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase.

OBJECTIVES: Hyperglycemia on admission and diabetes mellitus type II are associated with unfavorable outcome in stroke patients. We studied whether impaired fasting glucose (IFG) is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase as well and if IFG is a stronger prognostic factor than hyperglycemia on admission. METHODS: We studied 220 consecutive patients with ischemic stroke treated with intravenous alteplase. In all nondiabetic patients, fasting glucose was determined on day 2-5. IFG was defined as fasting glucose level of ≥ 5.6 mmol/L, hyperglycemia on admission as glucose levels ≥ 7.9 mmol/L. The primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at 3 months, estimated with ordinal logistic regression, and adjusted for common prognostic factors. RESULTS: The fasting glucose levels were available in 194 and admission glucose levels in 215 patients. Sixty-three (32.5%) had IFG, 58 (27%) hyperglycemia on admission and 32 (14.6%) pre-existent diabetes. Patients with IFG showed a shift towards worse functional outcome compared with patients with normal fasting glucose levels (acOR 2.77; 95% CI 1.54-4.97), which was stronger than hyperglycemia on admission (acOR 1.75; 95% CI 0.91-3.4). CONCLUSIONS: IFG is associated with unfavorable outcome after treatment with intravenous alteplase for acute ischemic stroke. IFG predicts unfavorable outcome better than hyperglycemia on admission.

Increased admission and fasting glucose are associated with unfavorable short-term outcome after intra-arterial treatment of ischemic stroke in the MR CLEAN pretrial cohort.

BACKGROUND: Limited data are available on the impact of fasting glucose on outcome after intra-arterial treatment (IAT). We studied whether hyperglycemia on admission and impaired fasting glucose (IFG) are associated with unfavorable outcome after IAT in acute ischemic stroke. METHODS: Patients were derived from the pretrial registry of the MR CLEAN-trial. Hyperglycemia on admission was defined as glucose>7.8mmol/L, IFG as fasting glucose>5.5mmol/L in the first week of admission. Primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at discharge, estimated with ordinal logistic regression, adjusted for common prognostic factors. RESULTS: Of the 335 patients in which glucose on admission was available, 86 (26%) were hyperglycemic, 148 of the 240 patients with available fasting glucose levels (62%) had IFG. Median admission glucose was 6.8mmol/L (IQR 6-8). Increased admission glucose (acOR 1.2, 95%CI 1.1-1.3), hyperglycemia on admission (acOR 2.6, 95%CI 1.5-4.6) and IFG (acOR 2.8, 95%CI 1.4-5.6) were associated with worse functional outcome at discharge. CONCLUSION: Increased glucose on admission and IFG in the first week after stroke onset are associated with unfavorable short-term outcome after IAT of acute ischemic stroke.

EGSNRC Monte Carlo study of the effect of photon energy and field margin in phantoms simulating small lung lesions.

The dose distribution in small lung tumors (coin lesions) is affected by the combined effects of reduced attenuation of photons and extended range of electrons in lung. The increased range of electrons in low-density tissues can lead to loss of field flatness and increased penumbra width, especially at high energies. The EGSNRC Monte Carlo code, together with DOSXYZNRC, a three-dimensional voxel dose calculation module has been used to study the characteristics of the penumbra in the region of the target-lung interfaces for various radiation beam energies, lung densities, target-field edge distances, target size, and depth. The Monte Carlo model was validated by film measurements made in acrylic (simulating a tumor) imbedded in cork (simulating the lung). Beam profiles that are deemed to be acceptable are defined as those in which no point within the planning target volume (target volume plus 1 cm margin) received less than 95% of the dose prescribed to the center of the target. For parallel opposed beams and 2 cm cube target size, 6 MV photons produce superior dose distribution with respect to penumbra at the lateral, anterior, and posterior surfaces and midplane of the simulated target, with a target-field edge distance of 2.5 cm. A lesser target-field edge distance of 2.0 cm is required for 4 MV photons to produce acceptable dose distribution. To achieve equivalent dose distribution with 10 and 18 MV photons, a target-field edge distance of 3.0 and 3.5 cm, respectaively, is required. For a simulated target size of 4 cm cube, a target-field edge distance of 2, 2.5, and 3 cm is required for 6, 10, and 18 MV photons, respectively, to yield acceptable PTV coverage. The effect, which is predominant in determining the target dose, depends on the beam energy, target-field edge distance, lung density, and the depth and size of the target.

Fetal position and size data for dose estimation.

In order to establish both positional and size data for estimation of fetal absorbed dose from radiological examinations, the depth from the mother's anterior surface to the mid-line of the fetal head and abdomen were measured from ultrasound scans in 215 pregnant women. Depths were measured along a ray path projected in the anteroposterior (AP) direction from the mother's abdomen. The fetal size was estimated from measurements of the fetal abdominal and head circumference, femur length and the biparietal diameter. The effects of fetal presentation, maternal bladder volume, placenta location, gestational age and maternal AP thickness on fetal depth and size were analysed. The fetal position from the anterior surface of the mother's abdomen is shorter for posterior placenta and empty bladder volume, but longer for anterior placenta and full bladder volume. Mean fetal depth (MFD) observed for all bladder volumes, fetal presentations and placenta locations increased from 6.5 +/- 0.5 cm to 10.2 +/- 0.7 cm over the duration of pregnancy. Similarly, mean fetal skull depth (FSD) increased from 6.6 +/- 0.6 cm to 9.8 +/- 0.6 cm over the period of pregnancy, but only from about 6.6 cm to 7.8 cm over the period (8-25 weeks) when damage to the developing brain has been observed to result in mental retardation. Using the range of mean fetal depth (4.7-13.9 cm) observed in this study and depth dose data at 75 kVp and 3.0 mmAl half value thickness (HVT), fetal absorbed dose would be overestimated by up to 66% or underestimated by up to 77% if the mean value of MFD (8.1 cm) is used rather than actual individual values. These errors increase with lower tube potential and filtration up to over 90% overestimation and up to 100% underestimation at 60 kVp and 1.0 mmAl filtration.

Fetal doses from radiological examinations.

There has been growing concern about radiation exposures in the case of pregnant women who undergo radiological examinations of the lower abdomen and pelvis, when the embryo/fetus is near or included in the X-ray field. This paper describes a retrospective study of 50 pregnant women accrued over a period of 10 years. Most of these women were not aware of pregnancy at the time of their radiological examinations. They subsequently discovered that they were pregnant and sought advice from their physicians on fetal dose and risk. They were then referred to a Radiation Protection Advisor for an estimation of the fetal dose. Radiation absorbed dose to the embryo/fetus was estimated from a knowledge of technique factors and examination details using normalized uterine doses published by the National Radiological Protection Board (NRPB). Doses to the embryo/fetus varied between less than 0.01 microGy and 117 mGy, depending on the examination. Gestational ages ranged between 2 and 24 weeks.

Equivalent dose to the fetus from occupational exposure of pregnant staff in diagnostic radiology.

The protection of the unborn children of pregnant women from ionizing radiations is very important because the fetus is particularly vulnerable to the effects of ionizing radiation. From the radiation protection perspective, the International Commission on Radiological Protection regards the unborn child as a member of the public when considering the occupational exposure of pregnant workers. The determination of the equivalent dose to the unborn child in diagnostic radiology is of interest as a basis for risk estimates from occupational exposures of the pregnant worker. In this paper, coefficients for converting dosemeter readings to equivalent dose to the fetus have been calculated using Monte Carlo simulation. X-ray transport was simulated by tracing individual photons through soft tissue phantoms. Equivalent dose to the uterus was used to simulate the equivalent dose to the fetus during the first 2 months of pregnancy. The Monte Carlo model was validated experimentally by direct measurements made in an Alderson female Rando phantom for a range of irradiation conditions. The two sets of data indicated good agreement with the Monte Carlo results, being relatively greater than the experimental results to a maximum of about 15%.

Stereotactic radiotherapy in the treatment of ocular melanoma: a noninvasive eye fixation aid and tracking system.

Ocular melanoma is frequently treated using brachytherapy implants (such as 125I and 60Co plaques or 184Ta wire), surgery, or external beam radiotherapy using small 60Co beams, high energy x-rays, or proton therapy. The last technique, though very expensive, provides improved dose distributions and dose localizations in the treatment of tumours adjacent to critical normal tissues. The technique of fractionated stereotactic radiotherapy is now being used at an increasingly large number of centers in the treatment of lesions in the brain, and the head and neck. This article describes the successful extension of the stereotactic technique to the treatment of ocular melanoma: an eye fixation aid is attached to a noninvasive, relocatable Gill-Thomas-Cosman head frame together with a simple eye-movement tracking system.

Risk ranking by perception.

The study of people's perception and acceptability of risk is important in understanding the public reaction to technology and its environmental and health impact. The perception of risk depends on several factors, including early experiences, education, controllability of the risk, the type of consequence, and the type of person(s) who makes the judgment. This paper reviews some of the main factors influencing people's perception and acceptability of risk. Knowledge about which factors influence the perception of risk may enhance the understanding of different points of view brought into risk controversies, improve risk communication, and facilitate policy making. Results from a risk ranking by perception survey conducted in Ghana are also presented.

Poster - Thur Eve - 77: Coordinate transformation from DICOM to DOSXYZnrc.

DICOM format is the de facto standard for communications between therapeutic and diagnostic modalities. A plan generated by a treatment planning system (TPS) is often exported to DICOM format. BEAMnrc/DOSXYZnrc is a widely used Monte Carlo (MC) package for beam and dose simulations in radiotherapy. It has its own definition for beam orientation, which is not in compliance with the one defined in DICOM standard. Dose simulations using TPS generated plans require transformation of beam orientations to DOSXYZnrc coordinate system (c.s.) after extracting the necessary parameters from DICOM RP files. The transformation is nontrivial. There have been two studies for the coordinate transformations. The transformation equation sets derived have been helpful to BEAMnrc/DOSXYZnrc users. However, both the transformation equation sets are complex mathematically and not easy to program. In this study, we derive a new set of transformation equations, which are more compact, better understandable, and easier for computational implementation. The derivation of polar angle θ and azimuthal angle φ is similar to the existing studies by applying a series of rotations to a vector in DICOM patient c.s. The derivation of beam rotation Φcol for DOSXYZnrc, however, is different. It is obtained by a direct combination of the actual collimator rotation with the projection of the couch rotation to the collimator rotating plane. Verification of the transformation has been performed using clinical plans created with Eclipse. The comparison between Eclipse and MC results show exact geometrical agreement for field placements, together with good agreement in dose distributions.

Sci-Thur AM: Planning - 12: Comparative study of SBRT lung dose calculation using Eclipse and Monte Carlo.

Stereotactic Body Radiation Therapy (SBRT) is an option for early stage non-small cell lung cancer treatment. In SBRT treatment, high biological effective dose is delivered to the patient within a small number of fractions. High level of confidence in accuracy is required in the entire treatment procedure, from patient setup, tumour delineation, treatment simulation and planning, to the final dose delivery. SBRT lung treatment utilizes small fields that are incident on large tissue inhomogeneities within the patient. It is difficult for commercially available treatment planning systems (TPS) to model the lack of charged particle equilibrium and the dose near tissue-lung interfaces accurately. The Monte Carlo (MC) technique calculates the dose distribution from the first principles thereby providing a feasible tool for verifying the dose distribution computed from TPS. In this study, we compared the SBRT dose distribution between Eclipse 8.9 and BEAMnrc/DOSXYZnrc for both conformal and RapidArc plans. Calculation results for five clinical SBRT conformal lung plans were compared. Eclipse and MC results for each plan showed good agreement in dose received by organs at risk. MC simulation predicted uniformly hotter or similar PTV coverage for three cases with tumor either small or attached to the chest wall. When tumor is inside lung and at relatively medium to larger size for SBRT, MC predicted lower PTV coverage. The variation in dose coverage may depend on the tumour size and its position within the lung. Dose comparison for RapidArc plans shows similar dependence.

Poster - Thur Eve - 67: Clinical results of deep inspiration breath hold radiation treatment for the left breast patients.

Adjuvant radiotherapy for left breast cancers increases local tumor control, but also increases the risk of radiation-induced cardiac disease. Deep Inspiration Breath Hold (DIBH) can minimize dose to the heart for left breast patients where the heart is within the tangential field. In this study, we evaluated the dosimetric benefit of DIBH technique comparing to free breathing (FB) radiotherapy for left breast cancer patients. Five patients with left breast cancer treated with DIBH technique were selected randomly. The CT scans of breath hold (BH) and FB were taken for every DIBH patient. Standard clinical DIBH intensity-modulated radiotherapy (IMRT) plans were generated with BH scan dataset using the Varian Eclipse TP system. The prescription dose is 4250 cGy in 16 fractions. The BH plan was copied to the FB scan dataset and shifted accordingly to have the same coverage for the breast tissue, and the dose was re-calculated. Dose-volume histograms (DVH) of the heart and lung; mean dose and maximum dose of the heart were calculated and compared from the BH and FB plans for every patient. The lung volume is increased during BH and hence the heart is moved out of the field, resulting in the lower heart maximum dose. The mean dose is almost less than 1 Gy for all BH plans. The average mean heart dose is 0.8 Gy for BH plan compared to 1.6 Gy for FB plan. Patients benefit significantly from DIBH technique due to the very low heart dose.

Poster - Thur Eve - 66: A planning comparison between RapidArc and intensity modulated radiotherapy for head and neck cancer.

Volumetric modulated arc therapy (VMAT) has recently been used to improve the dose distribution and efficiency of treatment delivery over the standard intensity-modulated radiotherapy (IMRT) technique. This study compares the dosimetry between RapidArc plan and standard IMRT plan for head and neck cancer. Three head and neck patients treated clinically with sliding window intensity-modulated radiotherapy (IMRT) technique at Grand River Regional Cancer Center were selected randomly and re-planned using RapidArc technique with 6 MV photon beams generated by a Varian 21EX linac with 120-leaf multileaf collimator. Three dose prescriptions were used to deliver 70 Gy, 63 Gy and 58.1 Gy to the regions of the primary tumors, intermediate-risk nodes and low-risk nodal level, respectively, in 35 fractions. Dosimetric comparison based on the dose-volume histogram, target coverage, organ at risk (OAR) dose sparing were studied between the RapidArc plan and IMRT plan. RapidArc technique from Varian Medical Systems showed superior target coverage, better OAR sparing, fewer monitor units per fraction with less treatment time over IMRT technique for head and neck cancers. The average homogeneity index, defined as the difference between the percentage dose covering 5% and 95% of the PTV, is 9.5 for RapidArc plan and 10.5 for IMRT plan. All RapidArc plans met the dose objectives for the primary OAR: spinal cord, brainstem, brain etc. Both parotid mean dose and D50% are lower for RapidArc plan than those of the IMRT plan. The technique is currently being used clinically at our cancer center.

Evaluation of daily online set-up errors and organ displacement uncertainty during conformal radiation treatment of the prostate.

We have studied and analysed the magnitude of interfraction set-up errors and gold seed marker and prostate displacement in 118 patients using three gold seeds implanted within the prostate. Set-up errors and gold seed marker displacements were determined from bony anatomy and gold seed marker mismatch between the electronic portal image and the simulation digitally reconstructed radiograph (DRR), respectively. Prostate displacement relative to bony anatomy was determined from the difference between gold seed marker and bony anatomy displacement. Daily online repositioning of patients was accomplished through image matching using Varian Portal-Vision software. A total of 4878 electronic portal images and 236 DRRs from 118 patients were acquired over the course of the study. The means and standard deviations of the systematic error of gold seed marker displacement of 118 patients were 2.1+/-2.7 mm for anteroposterior (AP), -0.5+/-1.7 mm for left-right (L-R), and 1.0+/-1.9 mm for superoinferior (SI) directions; the random errors were 3.2 mm (0.9-4.9 mm) for AP, 1.9 mm (0.7-5.3 mm) for L-R, and 2.1 mm (0.7-4.5 mm) for SI directions. The mean and standard deviation of the isocentre set-up systematic error of 20 patients was 1.2+/-2.2 mm for AP, -0.1+/-1.4 mm for L-R, and -0.8+/-2.6 mm for SI directions. The isocentre set-up random errors were 1.6 mm (1.2-4.8 mm) for AP, 1.3 mm (0.6-2.5 mm) for L-R and 1.3 mm (1.0-2.6 mm) for SI directions. The mean and standard deviation of the prostate displacement systematic error relative to bony anatomy was 0.0+/-1.4 mm for AP, 0.0+/-1.1 mm for L-R and -0.2+/-2.4 mm for SI directions. Prostate displacement random errors were 1.5 mm (1.2-3.3 mm) for AP, 0.9 mm (0.4-1.5 mm) for L-R and 1.4 mm (1.2-2.4 mm) for SI directions.