A Data-Driven Space-Time-Parameter Reduced-Order Model with Manifold Learning for Coupled Problems: Application to Deformable Capsules Flowing in Microchannels.

An innovative data-driven model-order reduction technique is proposed to model dilute micrometric or nanometric suspensions of microcapsules, i.e., microdrops protected in a thin hyperelastic membrane, which are used in Healthcare as innovative drug vehicles. We consider a microcapsule flowing in a similar-size microfluidic channel and vary systematically the governing parameter, namely the capillary number, ratio of the viscous to elastic forces, and the confinement ratio, ratio of the capsule to tube size. The resulting space-time-parameter problem is solved using two global POD reduced bases, determined in the offline stage for the space and parameter variables, respectively. A suitable low-order spatial reduced basis is then computed in the online stage for any new parameter instance. The time evolution of the capsule dynamics is achieved by identifying the nonlinear low-order manifold of the reduced variables; for that, a point cloud of reduced data is computed and a diffuse approximation method is used. Numerical comparisons between the full-order fluid-structure interaction model and the reduced-order one confirm both accuracy and stability of the reduction technique over the whole admissible parameter domain. We believe that such an approach can be applied to a broad range of coupled problems especially involving quasistatic models of structural mechanics.

Towards precise LET measurements based on energy deposition of therapeutic ions in Timepix3 detectors.

Objective.There is an increasing interest in calculating and measuring linear energy transfer (LET) spectra in particle therapy in order to assess their impact in biological terms. As such, the accuracy of the particle fluence energy spectra becomes paramount. This study focuses on quantifying energy depositions of distinct proton, helium, carbon, and oxygen ion beams using a silicon pixel detector developed at CERN to determine LET spectra in silicon.Approach.While detection systems have been investigated in this pursuit, the scarcity of detectors capable of providing per-ion data with high spatial and temporal resolution remains an issue. This gap is where silicon pixel detector technology steps in, enabling online tracking of single-ion energy deposition. The used detector consisted of a 300µm thick silicon sensor operated in partial depletion.Main results.During post-processing, artifacts in the acquired signals were identified and methods for their corrections were developed. Subsequently, a correlation between measured and Monte Carlo-based simulated energy deposition distributions was performed, relying on a two-step recalibration approach based on linear and saturating exponential models. Despite the observed saturation effects, deviations were confined below 7% across the entire investigated range of track-averaged LET values in silicon from 0.77 keVµm-1to 93.16 keVµm-1.Significance.Simulated and measured mean energy depositions were found to be aligned within 7%, after applying artifact corrections. This extends the range of accessible LET spectra in silicon to clinically relevant values and validates the accuracy and reliability of the measurements. These findings pave the way towards LET-based dosimetry through an approach to translate these measurements to LET spectra in water. This will be addressed in a future study, extending functionality of treatment planning systems into clinical routine, with the potential of providing ion-beam therapy of utmost precision to cancer patients.

Thermal neutron detection and track recognition method in reference and out-of-field radiotherapy FLASH electron fields using Timepix3 detectors.

Objective.This work presents a method for enhanced detection, imaging, and measurement of the thermal neutron flux.Approach. Measurements were performed in a water tank, while the detector is positioned out-of-field of a 20 MeV ultra-high pulse dose rate electron beam. A semiconductor pixel detector Timepix3 with a silicon sensor partially covered by a6LiF neutron converter was used to measure the flux, spatial, and time characteristics of the neutron field. To provide absolute measurements of thermal neutron flux, the detection efficiency calibration of the detectors was performed in a reference thermal neutron field. Neutron signals are recognized and discriminated against other particles such as gamma rays and x-rays. This is achieved by the resolving power of the pixel detector using machine learning algorithms and high-resolution pattern recognition analysis of the high-energy tracks created by thermal neutron interactions in the converter.Main results. The resulting thermal neutrons equivalent dose was obtained using conversion factor (2.13(10) pSv·cm2) from thermal neutron fluence to thermal neutron equivalent dose obtained by Monte Carlo simulations. The calibrated detectors were used to characterize scattered radiation created by electron beams. The results at 12.0 cm depth in the beam axis inside of the water for a delivered dose per pulse of 1.85 Gy (pulse length of 2.4µs) at the reference depth, showed a contribution of flux of 4.07(8) × 103particles·cm-2·s-1and equivalent dose of 1.73(3) nSv per pulse, which is lower by ∼9 orders of magnitude than the delivered dose.Significance. The presented methodology for in-water measurements and identification of characteristic thermal neutrons tracks serves for the selective quantification of equivalent dose made by thermal neutrons in out-of-field particle therapy.

Single proton LET characterization with the Timepix detector and artificial intelligence for advanced proton therapy treatment planning.

Objective.Protons have advantageous dose distributions and are increasingly used in cancer therapy. At the depth of the Bragg peak range, protons produce a mixed radiation field consisting of low- and high-linear energy transfer (LET) components, the latter of which is characterized by an increased ionization density on the microscopic scale associated with increased biological effectiveness. Prediction of the yield and LET of primary and secondary charged particles at a certain depth in the patient is performed by Monte Carlo simulations but is difficult to verify experimentally.Approach.Here, the results of measurements performed with Timepix detector in the mixed radiation field produced by a therapeutic proton beam in water are presented and compared to Monte Carlo simulations. The unique capability of the detector to perform high-resolution single particle tracking and identification enhanced by artificial intelligence allowed to resolve the particle type and measure the deposited energy of each particle comprising the mixed radiation field. Based on the collected data, biologically important physics parameters, the LET of single protons and dose-averaged LET, were computed.Main results.An accuracy over 95% was achieved for proton recognition with a developed neural network model. For recognized protons, the measured LET spectra generally agree with the results of Monte Carlo simulations. The mean difference between dose-averaged LET values obtained from measurements and simulations is 17%. We observed a broad spectrum of LET values ranging from a fraction of keVµm-1to about 10 keVµm-1for most of the measurements performed in the mixed radiation fields.Significance.It has been demonstrated that the introduced measurement method provides experimental data for validation of LETDor LET spectra in any treatment planning system. The simplicity and accessibility of the presented methodology make it easy to be translated into a clinical routine in any proton therapy facility.

Out-of-field measurements and simulations of a proton pencil beam in a wide range of dose rates using a Timepix3 detector: Dose rate, flux and LET.

Stray radiation produced by ultra-high dose-rates (UHDR) proton pencil beams is characterized using ASIC-chip semiconductor pixel detectors. A proton pencil beam with an energy of 220 MeV was utilized to deliver dose rates (DR) ranging from conventional radiotherapy DRs up to 270 Gy/s. A MiniPIX Timepix3 detector equipped with a silicon sensor and integrated readout electronics was used. The chip-sensor assembly and chipboard on water-equivalent backing were detached and immersed in the water-phantom. The deposited energy, particle flux, DR, and the linear energy transfer (LET(Si)) spectra were measured in the silicon sensor at different positions both laterally, at different depths, and behind the Bragg peak. At low-intensity beams, the detector is operated in the event-by-event data-driven mode for high-resolution spectral tracking of individual particles. This technique provides precise energy loss response and LET(Si) spectra with radiation field composition resolving power. At higher beam intensities a rescaling of LET(Si) can be performed as the distribution of the LET(Si) spectra exhibits the same characteristics regardless of the delivered DR. The integrated deposited energy and the absorbed dose can be thus measured in a wide range. A linear response of measured absorbed dose was obtained by gradually increasing the delivered DR to reach UHDR beams. Particle tracking of scattered radiation in data-driven mode could be performed at DRs up to 0.27 Gy/s. In integrated mode, the saturation limits were not reached at the measured out-of-field locations up to the delivered DR of over 270 Gy/s. A good agreement was found between measured and simulated absorbed doses.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy.

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets.Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with publishedin silicobiophysical models to elucidate the potential biological effects of collimated and uncollimated fields.Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keVµm-1in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keVµm-1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction.Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Quality assurance method for monitoring of lateral pencil beam positions in scanned carbon-ion radiotherapy using tracking of secondary ions.

PURPOSE: Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. METHODS: The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5 × 105 ions/s/cm2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3 Gy (RBE) and averaged dose rate of 0.27 Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter. RESULTS: The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. CONCLUSIONS: It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study.

Brain natriuretic peptide and impedance cardiography to assess volume status in peritoneal dialysis patients.

Assessment of volume status in patients with end-stage renal disease has long been a problem. Objective tools for estimating dry weight are necessary. The present study was designed to determine if better assessment of volume status could be achieved by measuring brain natriuretic peptide (BNP) and thoracic fluid content (TFC) by bioimpedance. We prospectively surveyed 51 medically stable peritoneal dialysis (PD) patients during their routine visits to our PD facility. There were no exclusion criteria. Clinical volume status was assessed by the attending nephrologist as hypovolemic, euvolemic, or hypervolemic. Once the clinical assessment was complete, plasma BNP concentration was measured. The TFC was determined by bioimpedance cardiography measured in the supine position. Of 51 patients, 19 (37.3%) were considered hypervolemic, 30 (58.8%) euvolemic, and 3 (5.9%) hypovolemic by clinical assessment. As defined by systolic blood pressure > or = 130 mmHg or diastolic pressure > or = 80 mmHg (or both), 57% were hypertensive. The hypovolemic group was excluded from the statistical analysis because of the small sample size. Logistic regression analysis did not show a significant correlation between clinical assessment of volume and BNP (p = 0.76) or TFC (p = 0.39). Our data demonstrate the limitations of BNP and thoracic impedance in helping with the clinical evaluation of volume status in a cohort of chronic PD patients.

A novel method for assessment of fragmentation and beam-material interactions in helium ion radiotherapy with a miniaturized setup.

Radiotherapy with protons and carbon ions enables to deliver dose distributions of high conformation to the target. Treatment with helium ions has been suggested due to their physical and biological advantages. A reliable benchmarking of the employed physics models with experimental data is required for treatment planning. However, experimental data for helium interactions is limited, in part due to the complexity and large size of conventional experimental setups. We present a novel method for the investigation of helium interactions with matter using miniaturized instrumentation based on highly integrated pixel detectors. The versatile setup consisted of a monitoring detector in front of the PMMA phantom of varying thickness and a detector stack for investigation of outgoing particles. The ion type downstream from the phantom was determined by high-resolution pattern recognition analysis of the single particle signals in the pixelated detectors. The fractions of helium and hydrogen ions behind the used targets were determined. As expected for the stable helium nucleus, only a minor decrease of the primary ion fluence along the target depth was found. E.g. the detected fraction of hydrogen ions on axis of a 220MeV/u 4He beam was below 6% behind 24.5cm of PMMA. Monte-Carlo simulations using Geant4 reproduce the experimental data on helium attenuation and yield of helium fragments qualitatively, but significant deviations were found for some combinations of target thickness and beam energy. The presented method is promising to contribute to the reduction of the uncertainty of treatment planning for helium ion radiotherapy.

A Novel Method for Fragmentation Studies in Particle Therapy: Principles of Ion Identification.

PURPOSE: In carbon ion beam radiation therapy, fragmentation processes within the patient lead to changes in the composition of the particle field with increasing depth. Consequences are alterations of the resulting dose distribution and its biological effectiveness. To enable accurate treatment planning, the characteristics of the ion spectra resulting from fragmentation processes need to be known for various ion energies and target materials. In this work, we present a novel method for ion type identification using a small and highly flexible setup based on a single detector and designed to simplify measurements and overcome current shortages in available fragmentation data. MATERIALS AND METHODS: The presented approach is based on the pixelated, semiconductor detector Timepix. The large number of pixels with small pitch, all individually calibrated for energy deposition, enables detection and visualization of single particle tracks. For discrimination among different ion species, the pattern recognition analysis of the detector signal is used. Fragmentation spectra resulting from a primary carbon ion beam at various depths of tissue-equivalent material were studied to identify different ion species in mixed particle fields. The performance of the method was evaluated quantitatively using reference data from an established technique. RESULTS: All ion species resulting from carbon ion fragmentation in tissue-equivalent material could be separated. For measurements behind a 158-mm-thick water tank, the relative fractions of H, He, Be, and B ions detected agreed with corresponding reference data within the limits of uncertainty. For the relatively rare lithium ions, the agreement was within 2.3 Δref (uncertainty of reference). CONCLUSION: For designated configurations, the presented ion type identification method enables studies of therapeutic carbon ion beams with a simple, small, and configurable detection setup. The technique is promising to enable online fragmentation studies over a wide range of beam and target parameters in the future.

Usefulness and validity of diagnostic nasogastric aspiration in patients without hematemesis.

STUDY OBJECTIVE: We estimate the test characteristics of nasogastric aspiration to diagnose upper gastrointestinal tract hemorrhage in patients without hematemesis. METHODS: In this retrospective cohort study, medical records from patients admitted to 2 urban hospitals between 1997 and 2002 for gastrointestinal tract bleeding without hematemesis were reviewed. Positive nasogastric aspiration results were classified by the severity of hemorrhage, and negative results were classified by the presence or absence of bile. The reference standard for nasogastric aspiration was the source of bleeding-upper versus non--upper gastrointestinal tract--from the hospital discharge summary. Confidence intervals (CIs) for proportions and likelihood ratios (LRs) were calculated. RESULTS: Of 333 eligible patients, 235 were offered nasogastric aspiration, and 220 accepted the test. Results of 220 attempts were distributed as follows: negative, 158 (72%), including 9 (4%) with bile; nasogastric aspiration aborted, 13 (6%); and positive, 49 (23%), including 4 (2%) that were strongly positive (> or =450 mL red blood). Test characteristics of nasogastric aspiration to detect upper gastrointestinal tract bleeding in 213 patients with a reference standard diagnosis were as follows: sensitivity 42% (95% CI 32% to 51%), specificity 91% (95% CI 83% to 95%), negative predictive value 64% (95% CI 56% to 71%), and positive predictive value 92% (95% CI 79% to 97%). The nasogastric aspiration accurately predicted the source of bleeding in 66% of patients (95% CI 59% to 72%). The likelihood ratio of a positive nasogastric aspiration was 11 (95% CI 4 to 30), and the likelihood ratio of a negative nasogastric aspiration was 0.6 (95% CI 0.5 to 0.7). CONCLUSION: In patients without hematemesis, a positive nasogastric aspiration, seen in 23%, indicates probable upper gastrointestinal tract bleeding (LR+ 11), but a negative nasogastric aspiration, seen in 72%, provides little information (LR- 0.6).

Phosphate balance in peritoneal dialysis patients: role of ultrafiltration.

Current National Kidney Foundation's Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) recommend maintenance of serum phosphorus levels below 5.5 mg/dl. About 40% of patients maintained on chronic peritoneal dialysis (CPD) have phosphate levels above 5.5 mg%. The present study was designed to examine the relative contribution of ultrafiltration to phosphate removal in CPD patients. 24-hour dialysate collections were obtained in 28 CPD patients and the diffuse and ultrafiltration (UF) contributions to phosphate removal determined. 11% of phosphate removal was accounted for by UF. There was a highly significant correlation between UF rate and the % of phosphate removed by UF. The results of this study underscore the importance of individualizing the peritoneal dialysis prescription.

ED predictors of upper gastrointestinal tract bleeding in patients without hematemesis.

OBJECTIVES: In patients with gastrointestinal (GI) tract bleeding, the bleeding source is uncertain in the absence of hematemesis. We sought to identify clinical variables predictive of an upper GI bleeding source. METHODS: This retrospective cohort study involved patients admitted via the ED for GI tract bleeding without hematemesis, who underwent confirmatory testing. We used logistic regression analysis to identify clinical variables independently associated with an upper GI source. RESULTS: Among 325 patients, odds ratios for the strongest predictors were as follows: black stool, 16.6 (95% confidence interval [CI], 7.7-35.7); age less than 50 years, 8.4 (95% CI, 3.2-22.1); and blood urea nitrogen/creatinine ratio 30 or greater, 10.0 (95% CI, 4.0-25.6). Seven (5%) of 151 with none of these factors had an upper GI tract bleed, versus 63 (93%) of 68 with 2 or 3 factors. CONCLUSION: Black stool, age less than 50 years, and blood urea nitrogen/creatinine ratio of 30 or greater independently predict an upper GI tract bleeding source.

The sensitivity of room-air pulse oximetry in the detection of hypercapnia.

OBJECTIVE: To estimate the sensitivity of room-air pulse oximetry in the detection of moderate hypercapnia. METHODS: In this retrospective case-control study, charts were reviewed from patients with and without moderate hypercapnia (Pa co 2 >50 mm Hg), as determined by analysis of arterial blood gas samples obtained in the ED. Test characteristics (sensitivity, specificity, and likelihood ratios [LR) for room-air pulse oximetry < or = 96% to detect hypercapnia were calculated, as were confidence intervals. RESULTS: A total of 349 charts were eligible for abstraction-92 cases and 257 controls. A room-air pulse oximetry reading < or = 96% detected 88 of 92 cases of hypercapnia. Test characteristics were as follows (with 95% confidence interval): sensitivity, 0.96 (0.89-0.99); specificity, 0.39 (0.33-0.45), LR of a room-air pulse oximetry value >96%, 0.1 (0.04-0.3); and LR of a room-air pulse oximetry value < or = 96%, 1.6 (1.4-1.7). CONCLUSION: Room-air pulse oximetry detects moderate hypercapnia with high sensitivity.