Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach.

In this work, a stochastic computational model of microscopic energy deposition events is used to study for the first time damage to irradiated neuronal cells of the mouse hippocampus. An extensive library of radiation tracks for different particle types is created to score energy deposition in small voxels and volume segments describing a neuron's morphology that later are sampled for given particle fluence or dose. Methods included the construction of in silico mouse hippocampal granule cells from neuromorpho.org with spine and filopodia segments stochastically distributed along the dendritic branches. The model is tested with high-energy (56)Fe, (12)C, and (1)H particles and electrons. Results indicate that the tree-like structure of the neuronal morphology and the microscopic dose deposition of distinct particles may lead to different outcomes when cellular injury is assessed, leading to differences in structural damage for the same absorbed dose. The significance of the microscopic dose in neuron components is to introduce specific local and global modes of cellular injury that likely contribute to spine, filopodia, and dendrite pruning, impacting cognition and possibly the collapse of the neuron. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components. Going forward, this work can directly support the development of biophysical models of the modifications of spine and dendritic morphology observed after low dose charged particle irradiation by providing accurate descriptions of the underlying physical insults to complex neuron structures at the nano-meter scale.

Inflammatory Markers as Predictors of Atrial Fibrillation Recurrence: Exploring the C-Reactive Protein to Albumin Ratio in Cryoablation Patients.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac rhythm disorder associated with hemodynamic disruptions and thromboembolic events. While antiarrhythmic drugs are often recommended as the initial treatment, catheter ablation has emerged as a viable alternative. However, the recurrence of AF following ablation remains a challenge, and there is growing interest in exploring inflammatory markers as predictors of recurrence. METHODS: This retrospective, cross-sectional analysis included 249 patients who underwent cryoablation for paroxysmal AF. The relationship between the 'C-reactive protein (CRP) to albumin ratio (CAR)' and AF recurrence was examined. RESULTS: Two hundred and forty-nine patients with paroxysmal non-valvular atrial fibrillation were included. They were divided into two groups: those without recurrence (Group 1) and those with recurrence (Group 2). Significant differences were observed in age (57.2 ± 9.9 vs. 62.5 ± 8.4, p = 0.001) and left atrial size (4.0 ± 0.5 vs. 4.2 ± 0.7, p = 0.001) between the two groups. In blood parameters, significant differences were found in CRP (5.2 ± 1.3 vs. 9.4 ± 2.8, p < 0.001) and neutrophil counts (5.1 ± 2.2 vs. 6.7 ± 3.6, p = 0.001). In univariate regression analysis, age (OR: 1.058, CI: 1.024-1.093, p = 0.001), WBC count (OR: 1.201, CI: 1.092-1.322, p < 0.001), neutrophil count (OR: 1.239, CI: 1.114-1.378, p = 0.001), CAR (OR: 1.409, CI: 1.183-1.678, p < 0.001), and left atrial diameter (OR: 0.968, CI: 0.948-0.989, p = 0.002) showed significant associations with AF recurrence. CONCLUSIONS: Inflammation plays a crucial role in the initiation and progression of AF. This study demonstrated that along with age, the CAR can serve as an independent predictor of AF recurrence following cryoablation.

Increasing modified CHA2DS2-VASc risk score is associated with acute cardiac injury in hospitalised COVID-19 patients.

BACKGROUND: Prediction of hospital mortality in patients with COVID-19 by the CHA2DS2VASc (M-CHA2DS2VASc) has been recently shown. Because COVID-19 patients with acute cardiac injury have higher mortality compared to those without, we assumed that this risk score may also predict acute cardiac injury in these patients. METHODS: In this retrospective, single centre cohort study, we included 352 hospitalised patients with laboratory-confirmed COVID-19 and divided into three groups according to M-CHA2DS2VASc risk score which was created by changing gender criteria of the CHA2DS2VASc from female to male (Group 1, score 0-1 (n = 142); group 2, score 2-3 (n = 138) and group 3, score ≥4 (n = 72)). RESULTS: As the M-CHA2DS2VASc risk score increased, acute cardiac injury was also significantly increased (Group 1, 11.3%; group 2, 48.6%; group 3, 76%; p < 0.001). The higher M-CHA2DS2VASc tertile had higher prevalence of arrhythmias compared to lower tertile. The multivariate logistic regression analysis showed that M-CHA2DS2VASc risk score, admission to intensive care unit and invasive mechanical ventilation were independent predictors of acute cardiac injury (p = 0.001, odds ratio 1.675 per scale for M-CHA2DS2VASc). In receiver operating characteristic analysis, M-CHA2DS2VASc risk score was able to predict acute cardiac injury (Area under the curve value for acute cardiac injury was 0.80; p < 0.001). CONCLUSION: Admission M-CHA2DS2VASc risk score was associated with acute cardiac injury in hospitalised patients with COVID-19.

A Probability-Based Investigation on the Setup Robustness of Pencil-beam Proton Radiation Therapy for Skull-Base Meningioma.

INTRODUCTION: The intracranial skull-base meningioma is in proximity to multiple critical organs and heterogeneous tissues. Steep dose gradients often result from avoiding critical organs in proton treatment plans. Dose uncertainties arising from setup errors under image-guided radiation therapy are worthy of evaluation. PATIENTS AND METHODS: Fourteen patients with skull-base meningioma were retrospectively identified and planned with proton pencil beam scanning (PBS) single-field uniform dose (SFUD) and multifield optimization (MFO) techniques. The setup uncertainties were assigned a probability model on the basis of prior published data. The impact on the dose distribution from nominal 1-mm and large, less probable setup errors, as well as the cumulative effect, was analyzed. The robustness of SFUD and MFO planning techniques in these scenarios was discussed. RESULTS: The target coverage was reduced and the plan dose hot spot increased by all setup uncertainty scenarios regardless of the planning techniques. For 1 mm nominal shifts, the deviations in clinical target volume (CTV) coverage D99% was -11 ± 52 cGy and -45 ± 147 cGy for SFUD and MFO plans. The setup uncertainties affected the organ at risk (OAR) dose both positively and negatively. The statistical average of the setup uncertainties had <100 cGy impact on the plan qualities for all patients. The cumulative deviations in CTV D95% were 1 ± 34 cGy and -7 ± 18 cGy for SFUD and MFO plans. CONCLUSION: It is important to understand the impact of setup uncertainties on skull-base meningioma, as the tumor target has complex shape and is in proximity to multiple critical organs. Our work evaluated the setup uncertainty based on its probability distribution and evaluated the dosimetric consequences. In general, the SFUD plans demonstrated more robustness than the MFO plans in target coverages and brainstem dose. The probability-weighted overall effect on the dose distribution is small compared to the dosimetric shift during single fraction.

Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are associated with cryptogenic stroke in patients with patent foramen ovale.

INTRODUCTION: Although most ischaemic strokes are due to cardioembolism, about 25-40% of strokes are cryptogenic. Patent foramen ovale has been associated with cryptogenic stroke; however, the precise mechanism of this association has not been demonstrated. The aim of this study was to evaluate the association between inflammatory markers and cryptogenic stroke in patients with patent foramen ovale. MATERIAL AND METHODS: We included 206 patients with patent foramen ovale. Ninety-four (45.63%) out of 206 patients had had stroke, and 112 (54.37%) had not had stroke. The ratio of the total neutrophil count to the total lymphocyte count was defined as the neutrophil to lymphocyte ratio, and the ratio of the absolute platelet count to the absolute lymphocyte count was determined as the platelet to lymphocyte count. RESULTS: The neutrophil to lymphocyte ratio was significantly higher in patients who had stroke than in those who did not (2.41 ±1.69 vs. 2.19 ±1.74, p = 0.047). Although the platelet to lymphocyte count was also higher in patients who had had stroke than in those who had not, it was not statistically significant (120.94 ±55.45 vs. 118.01 ±52.21, p = 0.729). 1.62 was the cut-off value for neutrophil to lymphocyte ratio to be associated with stroke with 73.4% sensitivity and 45.05% specificity (p = 0.042). CONCLUSIONS: This study demonstrated that elevated neutrophil to lymphocyte ratio and platelet to lymphocyte count could be associated with cryptogenic stroke in patients with patent foramen ovale.

Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.

Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors. We represented dendrites as cylindrical segments of varying diameter with unit aspect ratios, and developed a fast sampling method to consider the stochastic distribution of ED by δ rays (secondary electrons) around the path of heavy ions, to reduce computational times. We introduce probabilistic models with a small number of parameters to describe the induction of precursor lesions that precede dendritic snipping, denoted as snip sites. Predictions for oxygen (16O, 600 MeV/n) and titanium (48Ti, 600 MeV/n) particles with LET of 16.3 and 129 keV/µm, respectively, are considered. Morphometric parameters to quantify changes in neuron morphology are described, including reduction in total dendritic length, number of branch points and branch numbers. Sholl analysis is applied for single neurons to elucidate dose-dependent reductions in dendritic complexity. We predict important differences in measurements from imaging of tissues from brain slices with single neuron cell observations due to the role of neuron death through both soma apoptosis and excessive dendritic length reduction. To further elucidate the role of track structure, random segment excision (snips) models are introduced and a sensitivity study of the effects of the modes of neuron death in predictions of morphometric parameters is described. An important conclusion of this study is that δ rays play a major role in neuron morphological changes due to the large spatial distribution of damage sites, which results in a reduced dependence on LET, including modest difference between 16O and 48Ti, compared to damages resulting from ED in localized damage sites.

Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres.

Changes to cognition, including memory, following radiation exposure are a concern for cosmic ray exposures to astronauts and in Hadron therapy with proton and heavy ion beams. The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. A challenge for biophysical models of neuronal damage is the large sizes (> 100µm) and variability in volumes of possible dendritic segments and pre-synaptic elements (spines and filopodia). We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure. We investigate the optimal axis length of dendritic segments to evaluate microscopic ED and hit probabilities along the dendritic branches at a given macroscopic dose. Because of large computation times to analyze ED in volumes of varying sizes, we developed an analytical method to find the mean primary dose in spheres that can guide numerical methods to find the primary dose distribution for cylinders. Considering cylindrical segments of varying aspect ratio at constant volume, we assess the chord length distribution, mean number of hits and ED profiles by primary particles and secondary electrons (δ-rays). For biophysical modeling applications, segments on dendritic branches are proposed to have equal diameters and axes lengths along the varying diameter of a dendritic branch.

Space Radiation Quality Factors and the Delta Ray Dose and Dose-Rate Reduction Effectiveness Factor.

In this paper, the authors recommend that the dose and dose-rate effectiveness factor used for space radiation risk assessments should be based on a comparison of the biological effects of energetic electrons produced along a cosmic ray particles path in low fluence exposures to high dose-rate gamma-ray exposures of doses of about 1 Gy. Methods to implement this approach are described.

Safe days in space with acceptable uncertainty from space radiation exposure.

The prediction of the risks of cancer and other late effects from space radiation exposure carries large uncertainties mostly due to the lack of information on the risks from high charge and energy (HZE) particles and other high linear energy transfer (LET) radiation. In our recent work new methods were used to consider NASA's requirement to protect against the acceptable risk of no more than 3% probability of cancer fatality estimated at the 95% confidence level. Because it is not possible that a zero-level of uncertainty could be achieved, we suggest that an acceptable uncertainty level should be defined in relationship to a probability distribution function (PDF) that only suffers from modest skewness with higher uncertainty allowed for a normal PDF. In this paper, we evaluate PDFs and the number or "safe days" in space, which are defined as the mission length where risk limits are not exceeded, for several mission scenarios at different acceptable levels of uncertainty. In addition, we briefly discuss several important issues in risk assessment including non-cancer effects, the distinct tumor spectra and lethality found in animal experiments for HZE particles compared to background or low LET radiation associated tumors, and the possibility of non-targeted effects (NTE) modifying low dose responses and increasing relative biological effectiveness (RBE) factors for tumor induction. Each of these issues skew uncertainty distributions to higher fatality probabilities with the potential to increase central values of risk estimates in the future. Therefore they will require significant research efforts to support space exploration within acceptable levels of risk and uncertainty.