Evaluation of four-dimensional cone beam computed tomography ventilation images acquired with two different linear accelerators at various gantry speeds using a deformable lung phantom

We evaluated four-dimensional cone beam computed tomography (4D-CBCT) ventilation images (VI_CBCT) acquired with two different linear accelerator systems at various gantry speeds using a deformable lung phantom.The 4D-CT and 4D-CBCT scans were performed using a computed tomography (CT) scanner, an X-ray volume imaging system (Elekta XVI) mounted in Versa HD, and an On-Board Imager (OBI) system mounted in TrueBeam. Intensity-based deformable image registration (DIR) was performed between peak-exhale and peak-inhale images. VI_CBCT- and 4D-CT-based ventilation images (VI_CT) were derived by DIR using two metrics: one based on the Jacobian determinant and one on changes in the Hounsfield unit (HU). Three different DIR regularization values (λ) were used for VI_CBCT. Correlations between the VI_CBCT and VI_CT values were evaluated using voxel-wise Spearman’s rank correlation coefficient (r).In case of both metrics, the Jacobian-based VI_CBCT with a gantry speed of 0.6 deg/sec in Versa HD showed the highest correlation for all the gantry speeds (e.g., λ = 0.05 and r = 0.68). Thus, the r value of the Jacobian-based VI_CBCT was greater or equal to that of the HU-based VI_CBCT. In addition, the ventilation accuracy of VI_CBCT increased at low gantry speeds.Thus, the image quality of VI_CBCT was affected by the change in gantry speed in both the imaging systems. Additionally, DIR regularization considerably influenced VI_CBCT in both the imaging systems. Our results have the potential to assist in designing CBCT protocols, incorporating VI_CBCT imaging into the functional avoidance planning process.     

3D-printed patient-specific pelvis phantom for dosimetry measurements for prostate stereotactic radiotherapy with dominant intraprostatic lesion boost

AimDeveloping and assessing the feasibility of using a three-dimensional (3D) printed patient-specific anthropomorphic pelvis phantom for dose calculation and verification for stereotactic ablative radiation therapy (SABR) with dose escalation to the dominant intraprostatic lesions.Material and methodsA 3D-printed pelvis phantom, including bone-mimicking material, was fabricated based on the computed tomography (CT) images of a prostate cancer patient. To compare the extent to which patient and phantom body and bones overlapped, the similarity Dice coefficient was calculated. Modular cylindrical inserts were created to encapsulate radiochromic films and ionization chamber for absolute dosimetry measurements at the location of prostate and at the boost region. Gamma analysis evaluation with 2%/2mm criteria was performed to compare treatment planning system calculations and measured dose when delivering a 10 flattening filter free (FFF) SABR plan and a 10FFF boost SABR plan.ResultsDice coefficients of 0.98 and 0.91 were measured for body and bones, respectively, demonstrating agreement between patient and phantom outlines. For the boost plans the gamma analysis yielded 97.0% of pixels passing 2%/2mm criteria and these results were supported by the chamber average dose difference of 0.47 ± 0.03%. These results were further improved when overriding the bone relative electron density: 97.3% for the 2%/2mm gamma analysis, and 0.05 ± 0.03% for the ionization chamber average dose difference.ConclusionsThe modular patient-specific 3D-printed pelvis phantom has proven to be a highly attractive and versatile tool to validate prostate SABR boost plans using multiple detectors.     

Parathyroid Cystic Adenoma: A Systematic Review and Meta-Analysis

ObjectiveTo review diagnostic imaging modalities for parathyroid cystic adenomas (PCA). Since PCAs are a rare (0.5%-1%) subclass of parathyroid adenomas, and due to their cystic component, imaging modalities known to be efficient for diagnosing solid adenomas might fail in localizing them.MethodsWe conducted a systematic review using the PubMed and Cochrane databases for English articles on PCAs published between 1995 and 2020. A meta-analysis of the retrieved data was performed.ResultsOverall, 39 studies, reporting on a total of 160 patients, were included in the analysis. Two thirds (68%) of the patients were female, with a mean age of 53.9 years. A single cystic adenoma was detected in 98.1% of cases. The mean blood calcium corrected for albumin level was 12.6 ± 2.7 mg/dL, and the mean parathyroid hormone level was 565.5 ± 523.8 pg/mL. The mean PCA sizes as measured by ultrasound (US), computed tomography (CT), and ex vivo measurement were 4.8 ± 3.6, 5.2 ± 3.2, and 3.5 cm, respectively. The median weight was 8.1 g. PCA was detected in 86% of US examinations; 100% of US-guided fine needle aspiration, 4-dimensional computed tomography (4D-CT), or magnetic resonance imaging examinations; and 61% of 99m-technetium sestamibi scan with single-photon emission computed tomography ((99m)Tc-SPECT). (99m)Tc-SPECT showed a significantly lower diagnostic rate than US (odds ratio, 3.589), US-guided fine needle aspiration, CT combined with 4D-CT, and the combination of US, CT, 4D-CT, and magnetic resonance imaging (P < .001).ConclusionAlthough US and 4D-CT showed a significantly high rate in diagnosing PCA, (99m)Tc-SPECT showed a lower PCA diagnostic rate. These findings suggest that larger cystic lesions suspected as PCAs should be further evaluated using 4D-CT rather than (99m)Tc-SPECT.     

Commissioning and performance testing of the first prototype of AlignRT InBore™ a Halcyon™ and Ethos™-dedicated surface guided radiation therapy platform

PurposeTo commission and assess the performance of AlignRT InBore™, a Halcyon™ and Ethos™-dedicated Surface Guided Radiation Therapy (SGRT) platform which combines ceiling-mounted cameras for patient setup and bore-mounted cameras for in-bore tracking.MethodsTo check the potential impact of InBore™ cameras on dose delivery, 16 SRS, H&N, breast and pelvis patients’ quality assurance (QA) treatment plans were measured with/without AlignRT InBore™ and using ArcCHECK® and SRS MapCHECK®. Impact on image quality was determined using Catphan® 540 phantom and considering all available MV and CBCT protocols (head, breast, chest and pelvis). The stability, accuracy and overall performance of AlignRT InBore™ was assessed using an MV Cube and anthropomorphic phantoms.ResultsComparison of 2D dose distributions with/without AlignRT InBore™ showed no impact on treatment delivery for all 16 QA checks (p-value > 0.25). 2D and CBCT images showed no artefacts or change in the contrast-to-noise ratio, resolution and noise values measured with Catphan® 540. Anti-collision sensors were unaffected by the bore-mounted cameras. Additionally, AlignRT InBore™ cameras allowed for motion detection with sub-0.5 mm accuracy and sub-0.4 mm stability with surface coverage of >50 × 60 × 35 cc. Accurate transition (sub-0.3 mm) from virtual to treatment isocentres was achieved. Finally, Halcyon™ rotations during CBCT and beam delivery resulted in limited camera vibrations with translation uncertainty <0.5 mm in left-right and anterior-posterior directions and <0.1 mm in head-feet direction.ConclusionAlignRT InBore™ provides SGRT setup and intrafraction monitoring capabilities with a performance comparable to standard SGRT solutions while having no adverse effect on Halcyon™.     

Infrared cameras overestimate skin temperature during rewarming from cold exposure

ObjectiveThe primary aim of this study was to assess the accuracy of an infrared camera and that of a skin thermistor, both commercially available. The study aimed to assess the agreement over a wide range of skin temperatures following cold exposure.MethodsFifty-two males placed their right hand in a thin plastic bag and immersed it in 8 °C water for 30 min whilst seated in an air temperature of 30 °C. Following hand immersion, participants removed the bag and rested their hand at heart level for 10 min. Index finger skin temperature (T_sk) was measured with a thermistor, affixed to the finger pad, and an infrared camera measured 1 cm distally to the thermistor. Agreement between the infrared camera and thermistor was assessed by mean difference (infrared camera minus thermistor) and 95% limits of agreement analysis, accounting for the repeated measures over time. The clinically significant threshold for T_sk differences was set at ±0.5 °C and limits of agreement ±1 °C.ResultsAs an average across all time points, the infrared camera recorded T_sk 1.80 (SD 1.16) °C warmer than the thermistor, with 95% limits of agreement ranging from −0.46 °C to 4.07 °C.ConclusionCollectively, the results show the infrared camera overestimated T_sk at every time point following local cooling. Further, measurement of finger T_sk from the infrared camera consistently fell outside the acceptable level of agreement (i.e. mean difference exceeding ±0.5 °C). Considering these results, infrared cameras may overestimate peripheral T_sk following cold exposure and clinicians and practitioners should, therefore, adjust their risk/withdrawal criteria accordingly.     

Nanoencapsulation of quercetin enhances its dietary efficacy in combating arsenic-induced oxidative damage in liver and brain of rats

AimsThis study was performed to evaluate the therapeutic efficacy of nanocapsulated flavonoidal quercetin (QC) in combating arsenic-induced reactive oxygen species (ROS)-mediated oxidative damage in hepatocytes and brain cells in a rat model.Main methodsHepatic and neuronal cell damage in rats was made by a single injection (sc) of sodium arsenite (NaAsO₂, 13 mg/kg b. wt. in 0.5 ml of physiological saline). A single dose of 500 µl of quercetin suspension (QC) (QC 8.98 µmol/kg) or 500 µl of nanocapsulated QC (NPQC) (QC 8.98 µmol/kg) was given orally to rats at 90 min prior to the arsenite injection.Key findingsInorganic arsenic depositions (182 ± 15.6 and 110 ± 12.8 ng/g protein) were found in hepatic and neuronal mitochondrial membranes. Antioxidant levels in hepatic and neuronal cells were reduced significantly by arsenic. NPQC prevented the arsenite-induced reduction in antioxidant levels in the liver and brain. Arsenic induced a substantial decrease in liver and brain cell membrane microviscosities, and NPQC treatment resulted in a unique protection against the loss. A significant correlation between mitochondrial arsenic and its conjugated diene level was observed both in liver and brain cells for all experimental rats.SignificanceArsenic-specific antidotes are used against arsenic-induced toxicity. However, the target site is poorly recognized and therefore achieving an active concentration of drug molecules can be a challenge. Thus, our objective was to formulate NPQC and to investigate its therapeutic potential in an oral route against arsenite-induced hepatic and neuronal cell damage in a rat model.     

Rates of intercalator-driven platination of DNA determined by a restriction enzyme cleavage inhibition assay

A restriction enzyme cleavage inhibition assay was designed to determine the rates of DNA platination by four non-cross-linking platinum–acridine agents represented by the formula [Pt(am₂)LCl](NO₃)₂, where am is a diamine nonleaving group and L is an acridine derived from the intercalator 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea (ACRAMTU). The formation of monofunctional adducts in the target sequence 5′-CGA was studied in a 40-base-pair probe containing the EcoRI restriction site GAATTC. The time dependence of endonuclease inhibition was quantitatively analyzed by polyacrylamide gel electrophoresis. The formation of monoadducts is approximately 3 times faster with double-stranded DNA than with simple nucleic acid fragments. Compound 1 (am₂ is ethane-1,2-diamine, L is ACRAMTU) reacts with a first-order rate constant of k _obs = 1.4 ± 0.37 × 10⁻⁴ s⁻¹ (t _1/2 = 83 ± 22 min). Replacement of the thiourea group in ACRAMTU with an amidine group (compound 2) accelerates the rate by fourfold (k _obs = 5.7 ± 0.58 × 10⁻⁴ s⁻¹, t _1/2 = 21 ± 2 min), and introduction of a propane-1,3-diamine nonleaving group results in a 1.5-fold enhancement in reactivity (compound 3, k _obs = 2.1 ± 0.40 × 10⁻⁴ s⁻¹, t _1/2 = 55 ± 10 min) compared with the prototype. Derivative 4, containing a 4,9-disubstituted acridine threading intercalator, was the least reactive compound in the series (k _obs = 1.1 ± 0.40 × 10⁻⁴ s⁻¹, t _1/2 = 104 ± 38 min). The data suggest a correlation may exist between the binding rates and the biological activity of the compounds. Potential pharmacological advantages of rapid formation of cytotoxic monofunctional adducts over the common purine–purine cross-links are discussed.     

The protective effect of montelukast sodium on carbon tetrachloride induced hepatopathy in rat

AimThis study investigates the effects of montelukast sodium (MK) (CysLTLT1 receptor antagonist) on CCl₄induced hepatopathy on rat.Material and methodsWe worked on 4 groups of 10 Wistar male rats each. The groups received as follows: group I (control group) – saline, group II – MK 5 mg/kg/day i.p. for 5 days, group III – MK 5 mg/kg/day i.p., 1 day prior to and 4 days concomitantly with CCl₄ p.o., 0.3 ml/Kg/day and group IV – CCl₄, p.o., 0.3 ml/Kg/day for 4 days. One day after the last administration, samples of blood were taken and alanine aminotransferase (ALT), total bilirubin (TB), direct bilirubin (DB), malondialdehyde (MDA), catalase (CAT) as well as total antioxidant capacity (TAC) were determined. The histopathological exam was performed. We also determined superoxide dismutase (SOD), MDA, CAT and GSH in liver homogenate.ResultsCompared to group IV, group III exhibited statistically significant lower levels of ALT (318 ± 15.75 versus 203.14 ± 10.28 UI, p < 0.0001), TB (3.16 ± 0.30 versus 1.99 ± 0.08 mg/dl, p < 0.0001), MDA in blood and in liver homogenate (4.98 ± 1.71 versus 2.15 ± 1.18 nmol/ml, p = 0.0004) and higher levels of SOD and CAT. Histopathologically, group IV presented important macro- and micro-vesicular hepatic steatosis and group III preserved lobular histoarchitecture and had less severe cellular lesions.ConclusionMK exhibits a partial hepatoprotective effect on rats treated with CCl₄.     

Assessment of daily dose accumulation for robustly optimized intensity modulated proton therapy treatment of prostate cancer

PurposeTo implement a daily CBCT based dose accumulation technique in order to assess ideal robust optimization (RO) parameters for IMPT treatment of prostate cancer.MethodsTen prostate cancer patients previously treated with VMAT and having daily CBCT were included. First, RO-IMPT plans were created with ± 3 mm and ± 5 mm patient setup and ± 3% proton range uncertainties, respectively. Second, the planning CT (pCT) was deformably registered to the CBCT to create a synthetic CT (sCT). Both daily and weekly sampling strategies were employed to determine optimal dose accumulation frequency. Doses were recalculated on sCTs for both ± 3 mm/±3% and ± 5 mm/±3% uncertainties and were accumulated back to the pCT. Accumulated doses generated from ± 3 mm/±3% and ± 5 mm/±3% RO-IMPT plans were evaluated using the clinical dose volume constraints for CTV, bladder, and rectum.ResultsDaily accumulated dose based on both ± 3mm/±3% and ±5 mm/±3% uncertainties for RO-IMPT plans resulted in satisfactory CTV coverage (RO-IMPT_3mm/3% CTV_V95 = 99.01 ± 0.87% vs. RO-IMPT_5mm/3% CTV_V95 = 99.81 ± 0.2%, P = 0.002). However, the accumulated dose based on ± 3 mm/3% RO-IMPT plans consistently provided greater OAR sparing than ±5 mm/±3% RO-IMPT plans (RO-IMPT_3mm/3% rectum_V65Gy = 2.93 ± 2.39% vs. RO-IMPT_5mm/3% rectum_V65Gy = 4.38 ± 3%, P < 0.01; RO-IMPT_3mm/3% bladder_V65Gy = 5.2 ± 7.12% vs. RO-IMPT_5mm/3% bladder_V65Gy = 7.12 ± 9.59%, P < 0.01). The gamma analysis showed high dosimetric agreement between weekly and daily accumulated dose distributions.ConclusionsThis study demonstrated that for RO-IMPT optimization, ±3mm/±3% uncertainty is sufficient to create plans that meet desired CTV coverage while achieving superior sparing to OARs when compared with ± 5 mm/±3% uncertainty. Furthermore, weekly dose accumulation can accurately estimate the overall dose delivered to prostate cancer patients.     

Selenium in drinking water and cereal grains,and biomarkers of Se status in urine and fingernails of the Main Ethiopian Rift Valley population

BackgroundSelenium (Se) plays an important role in human health, yet Se overexposure or deficiency can lead to deleterious health effects. This study aims to determine the concentration of Se in drinking water and staple cereal grain (maize, wheat, and teff) samples from the Main Ethiopian Rift (MER) Valley, and correspondingly, assesses Se biomarkers and their status as measured in the urine and fingernails of 230 individuals living in 25 MER communities.MethodThe concentration of Se in drinking water and cereal grain (maize, wheat, and teff) samples, and urine and fingernail samples were measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Demographic, anthropometric, and elemental concentrations were described by their quartiles and mean ± standard deviations. The 5th and 95th percentiles were used to describe the concentrations Se biomarkers ranges. The Se biomarker distributions in different study communities were further characterized according to Se levels found in drinking water, sex, and age using ANOVA, and multivariate regression. We conducted a correlation analysis (with Pearson correlation coefficient) and fitted a regression to evaluate the associations between these variables.ResultsThe mean concentration of Se in the drinking water samples was 0.66 (range: 0.015–2.64 µg/L; n = 25), and all samples were below the threshold value of 10 μg/L for Se in drinking water set by the World Health Organiation (WHO). In Ethiopia, most rural communities rely on locally produced cereal grains. We found mean Se concentrations (µg/kg) of 357 ± 190 (n = 14), 289 ± 123 (n = 14), and 145 ± 100 (n = 14) in wheat, teff, and maize, respectively. Furthermore, Se concentrations in drinking water showed no significant correlation with biomarker measures, indicating that the primary source of dietary Se is likely from local foods including staple grains. The mean±SD (5th–95th percentiles) of Se concentrations in fingernails and urine among study subjects were 1022 ± 320 (624–1551 µg/kg), and 38 ± 30 (1.9–100 µg/L), respectively.ConclusionA sizeable share of study participants (31%) fell below the lower limits of what is considered the currently accepted Se range of 20–90 µg/L in urine, though relatively few (only 4%) had similarly low fingernail levels. On the other hand, none of the samples reached Se toxicity levels, and the biomarker levels in this study are comparable to results from other studies that find adequate Se. Our results show that Se toxicity or deficiency is unlikely in the study population.     

Time and frequency to observe fiducial markers in MLC-modulated fields during prostate IMRT/VMAT beam delivery

ObjectiveThis work investigates the time and frequency to observe fiducial markers in MLC-modulated fields during intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) beam delivery for real-time prostate localization.MethodsThirty seven prostate patients treated with IMRT or VMAT were included in this retrospective study. DRR images were generated for all MLC segments/control points using the TPS. The MLC leaf pattern of each control point was overlaid on the DRR, and the number of fiducials within the MLC opening was analyzed. EPID images of fiducials in a pelvic phantom were obtained to demonstrate the fiducial visibility during modulated beam delivery.ResultsGold fiducials were visible on EPID images. The probability of seeing a number of fiducials within the MLC opening was analyzed. At least one fiducial was visible during 42 ± 2% and 52 ± 2% beam-on time for IMRT of the prostate with and without lymph nodes, and during 81 ± 4% and 80 ± 5% beam-on time for VMAT of the prostate with and without lymph nodes, respectively. The mean time interval to observe at least one fiducial was 8.4 ± 0.7 and 5.9 ± 0.5 s for IMRT of the prostate with and without the lymph nodes, respectively, and 1.6 ± 0.1 s for VMAT prostate patients. The estimated potential dosimetric uncertainty was 7% and 2% for IMRT and VMAT, respectively.ConclusionsOur results demonstrated that the time and frequency to observe fiducial markers in MLC-modulated fields during IMRT/VMAT beam delivery were adequate for real-time prostate localization. The beam’s eye view fiducial positions could be used for intrafractional target monitoring and motion correction in prostate radiotherapy.     

Enhancement of Hounsfield unit distribution in cone-beam CT images for adaptive radiation therapy: Evaluation of a hybrid correction approach

PurposeThis study aims to evaluate the accuracy of a hybrid approach combining the histogram matching (HM) and the multilevel threshold (MLT) to correct the Hounsfield Unit (HU) distribution in cone-beam CT (CBCT) images.Methods and MaterialsCBCT images acquired for ten prostate cancer patients were processed by matching their histograms to those of deformed planning CT (pCT) images obtained after applying a deformable registration (DR) process. Then, HU values corresponding to five tissue types in the pCT were assigned to the obtained CBCT images (CBCT_HM-MLT). Finally, the CBCT_HM-MLT images were compared to the deformed pCT visually and using different statistical metrics.ResultsThe visual assessment and the profiles comparison showed that the high discrepancies in the CBCT images were significantly reduced when using the proposed approach. Furthermore, the correlation values indicated that the CBCT_HM-MLT were in good agreement with the deformed pCT with correlation values ranging from 0.9893 to 0.9962. In addition, the root mean squared error (RMSE) over the entire volume was reduced from 64.15 ± 9.50 to 51.20 ± 6.76 HU. Similarly, the mean absolute error in specific tissue classes was significantly reduced especially in the soft tissue-air interfaces. These results confirmed that applying MLT after HM worked better than using only HM for which the correlation values were ranging from 0.9878 to 0.9955 and the RMSE was 55.95 ± 10.43 HU.ConclusionEvaluation of the proposed approach showed that the HM + MLT correction can improve the HU distribution in the CBCT images and generate corrected images in good agreement with the pCT.     

Credentialing of vertebral stereotactic ablative body radiotherapy in a multi-centre trial

Purpose/objectiveStereotactic ablative body radiotherapy (SABR) in multi-centre trials requires rigorous quality assurance to ensure safe and consistent treatment for all trial participants. We report results of vertebral SABR dosimetry credentialing for the ALTG/TROG NIVORAD trial.Material/methodsCentres with a previous SABR site visit performed axial film measurement of the benchmarking vertebral plan in a local phantom and submitted radiochromic film images for analysis. Remaining centres had on-site review of SABR processes and axial film measurement of the vertebral benchmarking plan. Films were analysed for dosimetric and positional accuracy: gamma analysis (>90% passing 2%/2mm/10% threshold) and ≤ 1 mm positional accuracy at target-cord interface was required.Results19 centres were credentialed; 11 had on-site measurement. Delivery devices included linear accelerator, TomoTherapy and CyberKnife systems. Five centres did not achieve 90% gamma passing rate. Of these, three were out of tolerance (OOT) in low (<5Gy) dose regions and > 80% passing rate and deemed acceptable. Two were OOT over the full dose range: one elected not to remeasure; the other also had positional discrepancy greater than 1 mm and repeat measurement with a new plan was in tolerance. The original OOT was attributed to inappropriate MLC constraints. All centres delivered planned target-cord dose gradient within 1 mm.ConclusionCredentialing measurements for vertebral SABR in a multi-centre trial showed although the majority of centres delivered accurate vertebral SABR, there is high value in independent audit measurements. One centre with inappropriate MLC settings was detected, which may have resulted in delivery of clinically unacceptable vertebral SABR plans.     

The Added and Interpretative Value of CGM-Derived Parameters in Type 1 Diabetes Depends on the Level of Glycemic Control

ObjectiveIn type 1 diabetes mellitus (T1DM) management, continuous glucose monitoring (CGM)-derived parameters can provide additional insights, with time in range (TIR) and other parameters reflecting glycemic control and variability being put forward. This study aimed to examine the added and interpretative value of the CGM-derived indices TIR and coefficient of variation (CV%) in T1DM patients stratified according to their level of glycemic control by means of HbA1C.MethodsT1DM patients with a minimum disease duration of 10 years and without known macrovascular disease were enrolled. Patients were equipped with a blinded CGM device for 7 days. TIR and time spent in hypoglycemia and hyperglycemia were determined, and CV% was used as a parameter for glycemic variability. Pearson (r) and Spearman correlations (r_s) and a regression analysis were used to examine associations.ResultsNinety-five patients (age: 45 ± 10 years; HbA1C level: 7.7% ± 0.8% [61 ± 7 mmol/mol]) were included (mean blood glucose [MBG]: 159 ± 31 mg/dL; TIR: 55.8% ± 14.9%; CV%: 43.5% ± 7.8%) and labeled as having good (HbA1C level ≤7% [≤53 mmol/mol]; n = 20), moderate (7%-8%; n = 44), or poor (>8% [>64 mmol/mol]; n = 31) glycemic control. HbA1C was significantly associated with MBG (r_s = 0.48, P < .001) and time spent in hyperglycemia (total: r_s = 0.52; level 2: r = 0.46; P < .001) but not with time spent in hypoglycemia and CV%, even after an analysis of the HbA1C subgroups. Similarly, TIR was negatively associated with HbA1C (r = −0.53; P < .001), MBG (r_s = −0.81; P < .001), and time spent in hyperglycemia (total: r_s = −0.90; level 2: r_s = −0.84; P < .001) but not with time in hypoglycemia. The subgroup analyses, however, showed that TIR was associated with shorter time spent in level-2 hypoglycemia in patients with good (r_s = −0.60; P = .007) and moderate (r_s = −0.25; P = .047) glycemic control. In contrast, CV% was strongly positively associated with time in hypoglycemia (total: r_s = 0.78; level 2: r_s = 0.76; P < .001) but not with TIR or time in hyperglycemia in the entire cohort, although the subgroup analyses showed that TIR was negatively associated with CV% in patients with good glycemic control (r = −0.81, P < .001) and positively associated in patients with poor glycemic control (r = +0.47; P < .01).ConclusionThe CGM-derived metrics TIR and CV% are related to clinically important situations, TIR being strongly dependent on hyperglycemia and CV% being reflective of hypoglycemic risk. However, the interpretation and applicability of TIR and CV% and their relationship depends on the level of glycemic control of the individual patient, with CV% generally adding less clinically relevant information in those with poor control. This illustrates the need for further research and evaluation of composite measures of glycemic control in T1DM.     

Regulation of basal and norepinephrine-induced cAMP and ICa in hiPSC-cardiomyocytes: Effects of culture conditions and comparison to adult human atrial cardiomyocytes

BackgroundThere is ongoing interest in generating cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) to study human cardiac physiology and pathophysiology. Recently we found that norepinephrine-stimulated calcium currents (I_Ca) in hiPSC-cardiomyocytes were smaller in conventional monolayers (ML) than in engineered heart tissue (EHT). In order to elucidate culture specific regulation of β₁-adrenoceptor (β₁-AR) responses we investigated whether action of phosphodiesterases (PDEs) may limit norepinephrine effects on I_Ca and on cytosolic cAMP in hiPSC-cardiomyocytes. Results were compared to adult human atrial cardiomyocytes.MethodsAdult human atrial cardiomyocytes were isolated from tissue samples obtained during open heart surgery. All patients were in sinus rhythm. HiPSC-cardiomyocytes were dissociated from ML and EHT. Förster-resonance energy transfer (FRET) was used to monitor cytosolic cAMP (Epac1-camps sensor, transfected by adenovirus). I_Ca was recorded by whole-cell patch clamp technique. Cilostamide (300 nM) and rolipram (10 μM) were used to inhibit PDE3 and PDE4, respectively. β₁-AR were stimulated with the physiological agonist norepinephrine (100 μM).ResultsIn adult human atrial cardiomyocytes, norepinephrine increased cytosolic cAMP FRET ratio by +13.7 ± 1.5% (n = 10/9, mean ± SEM, number of cells/number patients) and I_Ca by +10.4 ± 1.5 pA/pF (n = 15/10). This effect was not further increased in the concomitant presence of rolipram, cilostamide and norepinephrine, indicating saturation by norepinephrine alone. In ML hiPSC-cardiomyocytes, norepinephrine exerted smaller increases in cytosolic cAMP and I_Ca (FRET +9.6 ± 0.5% n = 52/21, number of cells/number of ML or EHT, and I_Ca + 1.4 ± 0.2 pA/pF n = 34/7, p < 0.05 each) and both were augmented in the presence of the PDE4 inhibitor rolipram (FRET +16.7 ± 0.8% n = 94/26 and I_Ca + 5.6 ± 1.4 pA/pF n = 11/5, p < 0.05 each). Cilostamide increased the response to norepinephrine on FRET (+12.7 ± 0.5% n = 91/19, p < 0.05), but not on I_Ca. In EHT hiPSC-cardiomyocytes, norepinephrine responses on both, FRET and I_Ca, were larger than in ML (FRET +12.1 ± 0.3% n = 87/32 and I_Ca + 3.3 ± 0.2 pA/pF n = 13/5, p < 0.05 each). Rolipram augmented the norepinephrine effect on I_Ca (+6.2 ± 1.6 pA/pF; p < 0.05 vs. norepinephrine alone, n = 10/4), but not on FRET.ConclusionOur results show culture-dependent differences in hiPSC-cardiomyocytes. In conventional ML but not in EHT, maximum norepinephrine effects on cytosolic cAMP depend on PDE3 and PDE4, suggesting immaturity when compared to the situation in adult human atrial cardiomyocytes. The smaller I_Ca responses to norepinephrine in ML and EHT vs. adult human atrial cardiomyocytes depend at least partially on a non-physiological large impact of PDE4 in hiPSC-cardiomyocytes.     

Self-selected fluid volume and flavor strength does not alter fluid intake,body mass loss,or physiological strain during moderate-intensity exercise in the heat

IntroductionThe purpose of this study was to determine the effects of ad libitum flavor and fluid intake on changes in body mass (BM) and physiological strain during moderate intensity exercise in the heat.MethodsTen subjects (24±3yrs, 7M/3F) performed 60 min of treadmill walking at 1.3 m/s and 7% grade in an environmental chamber set to 33 °C and 10% relative humidity while carrying a 22.7 kg pack on two different occasions. Subjects consumed either plain water or water plus flavor (Infuze), ad libitum, at each visit. Pre and post exercise, fluid consumption (change in fluid reservoir weight) and BM (nude) were measured. During exercise, heart rate (HR), systolic blood pressure (SBP), rate of perceived exertion (RPE), oxygen consumption (VO₂), respiratory exchange ratio (RER), core temperature (T_C), and physiological strain index (PSI) were recorded every 15 min during exercise.ResultsNo significant differences were observed for fluid consumption between fluid conditions (512 ± 97.2 mL water vs. 414.3 ± 62.5 mL Infuze). Despite a significant decrease from baseline, there were no significant differences in overall change of BM (Δ −1.18 vs. −0.64 Kg) or percent body weight loss for water and Infuze conditions, respectively (1.58 ± 0.6 and 0.79 ± 0.2%). Furthermore, there were no significant differences in HR (144 ± 6 vs. 143 ± 8 bpm), SBP (157 ± 5 vs. 155 ± 5 mmHg), RPE, VO₂ (27.4 ± 0.9 vs. 28.1 ± 1.2 ml/Kg/min), RER, T_C (38.1 ± 0.1 vs. 37.0 ± 0.1 °C), and peak PSI (5.4 ± 0.4 vs. 5.7 ± 0.8) between conditions.ConclusionsOffering individuals the choice to actively manipulate flavor strength did not significantly influence ad libitum fluid consumption, fluid loss, or physiological strain during 60 min of moderate intensity exercise in the heat.     

Comparison of different deep learning architectures for synthetic CT generation from MR images

PurposeAmong the different available methods for synthetic CT generation from MR images for the task of MR-guided radiation planning, the deep learning algorithms have and do outperform their conventional counterparts. In this study, we investigated the performance of some most popular deep learning architectures including eCNN, U-Net, GAN, V-Net, and Res-Net for the task of sCT generation. As a baseline, an atlas-based method is implemented to which the results of the deep learning-based model are compared.MethodsA dataset consisting of 20 co-registered MR-CT pairs of the male pelvis is applied to assess the different sCT production methods' performance. The mean error (ME), mean absolute error (MAE), Pearson correlation coefficient (PCC), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR) metrics were computed between the estimated sCT and the ground truth (reference) CT images.ResultsThe visual inspection revealed that the sCTs produced by eCNN, V-Net, and ResNet, unlike the other methods, were less noisy and greatly resemble the ground truth CT image. In the whole pelvis region, the eCNN yielded the lowest MAE (26.03 ± 8.85 HU) and ME (0.82 ± 7.06 HU), and the highest PCC metrics were yielded by the eCNN (0.93 ± 0.05) and ResNet (0.91 ± 0.02) methods. The ResNet model had the highest PSNR of 29.38 ± 1.75 among all models. In terms of the Dice similarity coefficient, the eCNN method revealed superior performance in major tissue identification (air, bone, and soft tissue).ConclusionsAll in all, the eCNN and ResNet deep learning methods revealed acceptable performance with clinically tolerable quantification errors.     

Resolution enhancement for lung 4D-CT based on transversal structures by using multiple Gaussian process regression learning

PurposeFour-dimensional computed tomography (4D-CT) plays a useful role in many clinical situations. However, due to the hardware limitation of system, dense sampling along superior–inferior direction is often not practical. In this paper, we develop a novel multiple Gaussian process regression model to enhance the superior-inferior resolution for lung 4D-CT based on transversal structures.MethodsThe proposed strategy is based on the observation that high resolution transversal images can recover missing pixels in the superior-inferior direction. Based on this observation and motived by random forest algorithm, we employ multiple Gaussian process regression model learned from transversal images to improve superior–inferior resolution. Specifically, we first randomly sample 3 × 3 patches from original transversal images. The central pixel of these patches and the eight-neighbour pixels of their corresponding degraded versions form the label and input of training data, respectively. Multiple Gaussian process regression model is then built on the basis of multiple training subsets obtained by random sampling. Finally, the central pixel of the patch is estimated based on the proposed model, with the eight-neighbour pixels of each 3 × 3 patch from interpolated superior-inferior direction images as inputs.ResultsThe performance of our method is extensively evaluated using simulated and publicly available datasets. Our experiments show the remarkable performance of the proposed method.ConclusionsIn this paper, we propose a new approach to improve the 4D-CT resolution, which does not require any external data and hardware support, and can produce clear coronal/sagittal images for easy viewing.