A theoretical study of H2 O2 as the surrogate of dose in minibeam radiotherapy, with a diffusion model considering radical removal process.

BACKGROUND: Minibeam radiation therapy (MBRT) is an innovative dose delivery method with the potential to spare normal tissue while achieving similar tumor control as conventional radiotherapy. However, it is difficult to use a single dose parameter, such as mean dose, to compare different patterns of MBRT due to the spatially fractionated radiation. Also, the mechanism leading to the biological effects is still unknown. PURPOSE: This study aims to demonstrate that the hydrogen peroxide (H2 O2 ) distribution could serve as a surrogate of dose distribution when comparing different patterns of MBRT. METHODS: A free diffusion model (FDM) for H2 O2 developed with Fick's second law was compared with a previously published model based on Monte Carlo & convolution method. Since cells form separate compartments that can eliminate H2 O2 radicals diffusing inside the cell, a term describing the elimination was introduced into the equation. The FDM and the diffusion model considering removal (DMCR) were compared by simulating various dose rate irradiation schemes and uniform irradiation. Finally, the DMCR was compared with previous microbeam and minibeam animal experiments. RESULTS: Compared with a previous Monte Carlo & Convolution method, this analytical method provides more accurate results. Furthermore, the new model shows H2 O2 concentration distribution instead of the time to achieve a certain H2 O2 uniformity. The comparison between FDM and DMCR showed that H2 O2 distribution from FDM varied with dose rate irradiation, while DMCR had consistent results. For uniform irradiation, FDM resulted in a Gaussian distribution, while the H2 O2 distribution from DMCR was close to the dose distribution. The animal studies' evaluation showed a correlation between the H2 O2 concentration in the valley region and treatment outcomes. CONCLUSION: DMCR is a more realistic model for H2 O2 simulation than the FDM. In addition, the H2 O2 distribution can be a good surrogate of dose distribution when the minibeam effect could be observed.

Automated multi-criterial planning with beam angle optimization to establish non-coplanar VMAT class solutions for nasopharyngeal carcinoma.

PURPOSE: Complexity in selecting optimal non-coplanar beam setups and prolonged delivery times may hamper the use of non-coplanar treatments for nasopharyngeal carcinoma (NPC). Automated multi-criterial planning with integrated beam angle optimization was used to define non-coplanar VMAT class solutions (CSs), each consisting of a coplanar arc and additional 1 or 2 fixed, non-coplanar partial arcs. METHODS: Automated planning was used to generate a coplanar VMAT plan with 5 complementary computer-optimized non-coplanar IMRT beams (VMAT+5) for each of the 20 included patients. Subsequently, the frequency distribution of the 100 patient-specific non-coplanar IMRT beam directions was used to select non-coplanar arcs for supplementing coplanar VMAT. A second investigated CS with only one non-coplanar arc consisted of coplanar VMAT plus a partial arc at 90° couch angle (VMATCS90). Plans generated with the two VMATCSs were compared to coplanar VMAT. RESULTS: VMAT+5 analysis resulted in VMATCS60: two partial non-coplanar arcs at couch angles 60° and -60° to complement coplanar VMAT. Compared to coplanar VMAT, the non-coplanar VMATCS60 and VMATCS90 yielded substantial average dose reductions in OARs associated with xerostomia and dysphagia, i.e., parotids, submandibular glands, oral cavity and swallowing muscles (p < 0.05) for the same PTV coverage and without violating hard constraints. Impact of non-coplanar treatment and superiority of either VMACS60 and VMATCS90 was highly patient dependent. CONCLUSIONS: Compared to coplanar VMAT, dose to OARs was substantially reduced with a CS with one or two non-coplanar arcs. Preferences for coplanar or one or two additional arcs are highly patient-specific, balancing plan quality and treatment time.

Amygdala in Action: Functional Connectivity during Approach and Avoidance Behaviors.

Motivation is an important feature of emotion. By driving approach to positive events and promoting avoidance of negative stimuli, motivation drives adaptive actions and goal pursuit. The amygdala has been associated with a variety of affective processes, particularly the appraisal of stimulus valence that is assumed to play a crucial role in the generation of approach and avoidance behaviors. Here, we measured amygdala functional connectivity patterns while participants played a video game manipulating goal conduciveness through the presence of good, neutral, or bad monsters. As expected, good versus bad monsters elicited opposing motivated behaviors, whereby good monsters induced more approach and bad monsters triggered more avoidance. These opposing directional behaviors were paralleled by increased connectivity between the amygdala and medial brain areas, such as the OFC and posterior cingulate, for good relative to bad, and between amygdala and caudate for bad relative to good monsters. Moreover, in both conditions, individual connectivity strength between the amygdala and medial prefrontal regions was positively correlated with brain scores from a latent component representing efficient goal pursuit, which was identified by a partial least squares analysis determining the multivariate association between amygdala connectivity and behavioral motivation indices during gameplay. At the brain level, this latent component highlighted a widespread pattern of amygdala connectivity, including a dorsal frontoparietal network and motor areas. These results suggest that amygdala-medial prefrontal interactions captured the overall subjective relevance of ongoing events, which could consecutively drive the engagement of attentional, executive, and motor circuits necessary for implementing successful goal-pursuit, irrespective of approach or avoidance directions.

Learning from the COVID-19 lockdown in berlin: Observations and modelling to support understanding policies to reduce NO2.

Urban air pollution is a substantial threat to human health. Traffic emissions remain a large contributor to air pollution in urban areas. The mobility restrictions put in place in response to the COVID-19 pandemic provided a large-scale real-world experiment that allows for the evaluation of changes in traffic emissions and the corresponding changes in air quality. Here we use observational data, as well as modelling, to analyse changes in nitrogen dioxide, ozone, and particulate matter resulting from the COVID-19 restrictions at the height of the lockdown period in Spring of 2020. Accounting for the influence of meteorology on air quality, we found that reduction of ca. 30-50 % in traffic counts, dominated by changes in passenger cars, corresponded to reductions in median observed nitrogen dioxide concentrations of ca. 40 % (traffic and urban background locations) and a ca. 22 % increase in ozone (urban background locations) during weekdays. Lesser reductions in nitrogen dioxide concentrations were observed at urban background stations at weekends, and no change in ozone was observed. The modelled reductions in median nitrogen dioxide at urban background locations were smaller than the observed reductions and the change was not significant. The model results showed no significant change in ozone on weekdays or weekends. The lack of a simulated weekday/weekend effect is consistent with previous work suggesting that NOx emissions from traffic could be significantly underestimated in European cities by models. These results indicate the potential for improvements in air quality due to policies for reducing traffic, along with the scale of reductions that would be needed to result in meaningful changes in air quality if a transition to sustainable mobility is to be seriously considered. They also confirm once more the highly relevant role of traffic for air quality in urban areas.

On the Importance of Individualized, Non-Coplanar Beam Configurations in Mediastinal Lymphoma Radiotherapy, Optimized With Automated Planning.

BACKGROUND AND PURPOSE: Literature is non-conclusive regarding selection of beam configurations in radiotherapy for mediastinal lymphoma (ML) radiotherapy, and published studies are based on manual planning with its inherent limitations. In this study, coplanar and non-coplanar beam configurations were systematically compared, using a large number of automatically generated plans. MATERIAL AND METHODS: An autoplanning workflow, including beam configuration optimization, was configured for young female ML patients. For each of 25 patients, 24 plans with different beam configurations were generated with autoplanning: 11 coplanar CP_x plans and 11 non-coplanar NCP_x plans with x = 5 to 15 IMRT beams with computer-optimized, patient-specific configurations, and the coplanar VMAT and non-coplanar Butterfly VMAT (B-VMAT) beam angle class solutions (600 plans in total). RESULTS: Autoplans compared favorably with manually generated, clinically delivered plans, ensuring that beam configuration comparisons were performed with high quality plans. There was no beam configuration approach that was best for all patients and all plan parameters. Overall there was a clear tendency towards higher plan quality with non-coplanar configurations (NCP_x≥12 and B-VMAT). NCP_x≥12 produced highly conformal plans with on average reduced high doses in lungs and patient and also a reduced heart Dmean, while B-VMAT resulted in reduced low-dose spread in lungs and left breast. CONCLUSIONS: Non-coplanar beam configurations were favorable for young female mediastinal lymphoma patients, with patient-specific and plan-parameter-dependent dosimetric advantages of NCP_x≥12 and B-VMAT. Individualization of beam configuration approach, considering also the faster delivery of B-VMAT vs. NCP_x≥12, can importantly improve the treatments.

Computational imaging during video game playing shows dynamic synchronization of cortical and subcortical networks of emotions.

Emotions are multifaceted phenomena affecting mind, body, and behavior. Previous studies sought to link particular emotion categories (e.g., fear) or dimensions (e.g., valence) to specific brain substrates but generally found distributed and overlapping activation patterns across various emotions. In contrast, distributed patterns accord with multi-componential theories whereby emotions emerge from appraisal processes triggered by current events, combined with motivational, expressive, and physiological mechanisms orchestrating behavioral responses. According to this framework, components are recruited in parallel and dynamically synchronized during emotion episodes. Here, we use functional MRI (fMRI) to investigate brain-wide systems engaged by theoretically defined components and measure their synchronization during an interactive emotion-eliciting video game. We show that each emotion component recruits large-scale cortico-subcortical networks, and that moments of dynamic synchronization between components selectively engage basal ganglia, sensory-motor structures, and midline brain areas. These neural results support theoretical accounts grounding emotions onto embodied and action-oriented functions triggered by synchronized component processes.

Sustained effects of pleasant and unpleasant smells on resting state brain activity.

Research suggests that transient emotional episodes produces sustained effects on psychological functions and brain activity during subsequent resting state. In this fMRI study we investigated whether transient emotions induced by smells could impact brain connectivity at rest in a valence-specific manner. The results suggest a sustained reconfiguration of parts of the default mode network which become more connected with areas implicated in olfactory processing, emotional learning, and action control. We found lingering effects of odorants on subsequent resting state that predominantly involved connections of the precuneus with a network comprising the insula, amygdala, medial orbital gyrus. Unpleasant smells in particular predicted greater coupling between insula, hippocampal structures, and prefrontal cortex, possible reflecting enhanced aversive learning and avoidance motivation. More broadly, our study illustrates a novel approach to characterize the impact of smells on brain function and differentiate the neural signatures of their valence, during task-free rest conditions.

Transcranial magnetic stimulation of right inferior parietal cortex causally influences prefrontal activation for visual detection.

For effective interactions with the environment, the brain needs to form perceptual decisions based on noisy sensory evidence. Accumulating evidence suggests that perceptual decisions are formed by widespread interactions amongst sensory areas representing the noisy sensory evidence and fronto-parietal areas integrating the evidence into a decision variable that is compared to a decisional threshold. This concurrent transcranial magnetic stimulation (TMS)-fMRI study applied 10 Hz bursts of four TMS (or Sham) pulses to the intraparietal sulcus (IPS) to investigate the causal influence of IPS on the neural systems involved in perceptual decision-making. Participants had to detect visual signals at threshold intensity that were presented in their left lower visual field on 50% of the trials. Critically, we adjusted the signal strength such that participants failed to detect the visual stimulus on approximately 30% of the trials allowing us to categorise trials into hits, misses and correct rejections (CR). Our results show that IPS-relative to Sham-TMS attenuated activation increases for misses relative to CR in the left middle and superior frontal gyri. Critically, while IPS-TMS did not significantly affect participants' performance accuracy, it affected how observers adjusted their response times after making an error. We therefore suggest that activation increases in superior frontal gyri for misses relative to correct responses may not be critical for signal detection performance, but rather reflect post-decisional processing such as metacognitive monitoring of choice accuracy or decisional confidence.

Comparing TMS perturbations to occipital and parietal cortices in concurrent TMS-fMRI studies-Methodological considerations.

Neglect and hemianopia are two neuropsychological syndromes that are associated with reduced awareness for visual signals in patients' contralesional hemifield. They offer the unique possibility to dissociate the contributions of retino-geniculate and retino-colliculo circuitries in visual perception. Yet, insights from patient fMRI studies are limited by heterogeneity in lesion location and extent, long-term functional reorganization and behavioural compensation after stroke. Transcranial magnetic stimulation (TMS) has therefore been proposed as a complementary method to investigate the effect of transient perturbations on functional brain organization. This concurrent TMS-fMRI study applied TMS perturbation to occipital and parietal cortices with the aim to 'mimick' neglect and hemianopia. Based on the challenges and interpretational limitations of our own study we aim to provide tutorial guidance on how future studies should compare TMS to primary sensory and association areas that are governed by distinct computational principles, neural dynamics and functional architecture.

Concurrent TMS-fMRI Reveals Interactions between Dorsal and Ventral Attentional Systems.

Adaptive behavior relies on combining bottom-up sensory inputs with top-down control signals to guide responses in line with current goals and task demands. Over the past decade, accumulating evidence has suggested that the dorsal and ventral frontoparietal attentional systems are recruited interactively in this process. This fMRI study used concurrent transcranial magnetic stimulation (TMS) as a causal perturbation approach to investigate the interactions between dorsal and ventral attentional systems and sensory processing areas. In a sustained spatial attention paradigm, human participants detected weak visual targets that were presented in the lower-left visual field on 50% of the trials. Further, we manipulated the presence/absence of task-irrelevant auditory signals. Critically, on each trial we applied 10 Hz bursts of four TMS (or Sham) pulses to the intraparietal sulcus (IPS). IPS-TMS relative to Sham-TMS increased activation in the parietal cortex regardless of sensory stimulation, confirming the neural effectiveness of TMS stimulation. Visual targets increased activations in the anterior insula, a component of the ventral attentional system responsible for salience detection. Conversely, they decreased activations in the ventral visual areas. Importantly, IPS-TMS abolished target-evoked activation increases in the right temporoparietal junction (TPJ) of the ventral attentional system, whereas it eliminated target-evoked activation decreases in the right fusiform. Our results demonstrate that IPS-TMS exerts profound directional causal influences not only on visual areas but also on the TPJ as a critical component of the ventral attentional system. They reveal a complex interplay between dorsal and ventral attentional systems during target detection under sustained spatial attention. SIGNIFICANCE STATEMENT: Adaptive behavior relies on combining bottom-up sensory inputs with top-down attentional control. Although the dorsal and ventral frontoparietal systems are key players in attentional control, their distinct contributions remain unclear. In this TMS-fMRI study, participants attended to the left visual field to detect weak visual targets presented on half of the trials. We applied brief TMS bursts (or Sham-TMS) to the dorsal intraparietal sulcus (IPS) 100 ms after visual stimulus onset. IPS-TMS abolished the visual induced response suppression in the ventral occipitotemporal cortex and the response enhancement to visual targets in the temporoparietal junction. Our results demonstrate that IPS causally influences neural activity in the ventral attentional system 100 ms poststimulus. They have important implications for our understanding of the neural mechanisms underlying attentional control.

Effects of parietal TMS on visual and auditory processing at the primary cortical level -- a concurrent TMS-fMRI study.

Accumulating evidence suggests that multisensory interactions emerge already at the primary cortical level. Specifically, auditory inputs were shown to suppress activations in visual cortices when presented alone but amplify the blood oxygen level-dependent (BOLD) responses to concurrent visual inputs (and vice versa). This concurrent transcranial magnetic stimulation-functional magnetic resonance imaging (TMS-fMRI) study applied repetitive TMS trains at no, low, and high intensity over right intraparietal sulcus (IPS) and vertex to investigate top-down influences on visual and auditory cortices under 3 sensory contexts: visual, auditory, and no stimulation. IPS-TMS increased activations in auditory cortices irrespective of sensory context as a result of direct and nonspecific auditory TMS side effects. In contrast, IPS-TMS modulated activations in the visual cortex in a state-dependent fashion: it deactivated the visual cortex under no and auditory stimulation but amplified the BOLD response to visual stimulation. However, only the response amplification to visual stimulation was selective for IPS-TMS, while the deactivations observed for IPS- and Vertex-TMS resulted from crossmodal deactivations induced by auditory activity to TMS sounds. TMS to IPS may increase the responses in visual (or auditory) cortices to visual (or auditory) stimulation via a gain control mechanism or crossmodal interactions. Collectively, our results demonstrate that understanding TMS effects on (uni)sensory processing requires a multisensory perspective.

Spread of extended-spectrum beta-lactamase CTX-M-producing escherichia coli clinical isolates in community and nosocomial environments in Portugal.

Of the 181 unduplicated Escherichia coli strains isolated in nine different hospitals in three Portuguese regions, 119 were extended-spectrum beta-lactamase (ESBL)-CTX-M producers and were selected for phenotype and genotype characterization. CTX-M producer strains were prevalent among community-acquired infections (56%), urinary tract infections (76%), and patients >/=60 years old (76%). In MIC tests, all strains were resistant to cefotaxime, 92% were resistant to ceftazidime, 93% were resistant to quinolones, 89% were resistant to aminoglycoside, and 26% were resistant to trimethoprim-sulfamethoxazole; all strains were sensitive to carbapenems, and 92% of the strains had a multidrug resistance phenotype. Molecular methods identified 109 isolates harboring a bla(CTX-M-15) gene, 1 harboring the bla(CTX-M-32) gene (first identification in the country), and 9 harboring the bla(CTX-M-14) gene. All isolates presented the ISEcp1 element upstream from the bla(CTX-M) genes; one presented the IS903 element (downstream of bla(CTX-M-14) gene), and none had the IS26 element; 85% carried bla(TEM-1B), and 84% also carried a bla(OXA-30). Genetic relatedness analysis based on pulsed-field gel electrophoresis defined five clusters and indicated that 76% of all isolates (from cluster IV) corresponded to a single epidemic strain. Of the 47 strains from one hospital, 41 belonged to cluster IV and were disseminated in three main wards. CTX-M-producing E. coli strains are currently a problem in Portugal, with CTX-M-15 particularly common. This study suggests that the horizontal transfer of bla(CTX-M) genes, mediated by plasmids and/or mobile elements, contributes to the dissemination of CTX-M enzymes to community and hospital environments. The use of extended-spectrum cephalosporins, quinolones, and aminoglycosides is compromised, leaving carbapenems as the therapeutic option for severe infections caused by ESBL producers.

CTX-M-3 and CTX-M-15 extended-spectrum beta-lactamases in isolates of Escherichia coli from a hospital in Algiers, Algeria.

Sixteen strains of Escherichia coli isolated between January and June 2005 in a hospital in Algiers carry the ISEcp1 element and the TEM and either CTX-M-3 (n=3) or CTX-M-15 (n=13) beta-lactamases. Fourteen of the isolates are multidrug resistant. Five isolates from the neonatal ward were indistinguishable by pulsed-field gel electrophoresis.