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Progress in high-energy physics has been closely tied to the development of high-performance electromagnetic calorimeters. Recent experiments have demonstrated the possibility to significantly accelerate the development of electromagnetic showers inside scintillating crystals typically used in homogeneous calorimeters based on scintillating crystals when the incident beam is aligned with a crystallographic axis to within a few mrad. In particular, a reduction of the radiation length has been measured when ultrarelativistic electron and photon beams were incident on a high-Z scintillator crystal along one of its main axes. Here, we propose the possibility to exploit this physical effect for the design of a new type of compact e.m. calorimeter, based on oriented ultra-fast lead tungstate (PWO-UF) crystals, with a significant reduction in the depth needed to contain electromagnetic showers produced by high-energy particles with respect to the state-of-the-art. We report results from tests of the crystallographic quality of PWO-UF samples via high-resolution X-ray diffraction and photoelastic analysis. We then describe a proof-of-concept calorimeter geometry defined with a Geant4 model including the shower development in oriented crystals. Finally, we discuss the experimental techniques needed for the realization of a matrix of scintillator crystals oriented along a specific crystallographic direction. Since the angular acceptance for e.m. shower acceleration depends little on the particle energy, while the decrease of the shower length remains pronounced at very high energy, an oriented crystal calorimeter will open the way for applications at the maximum energies achievable in current and future experiments. Such applications span from forward calorimeters, to compact beam dumps for the search for light dark matter, to source-pointing space-borne γ-ray telescopes, to decrease the size and the cost of the calorimeter needed to fully contain e.m. showers initiated by GeV to TeV particles.

Many research and application areas demand photon sources capable of producing quasi-monochromatic X-ray beams in the multi-keV energy range with reasonably high fluxes and compact footprints. Besides industrial, research, commercial and cultural heritage applications, various biomedical applications could benefit from the features of this type of X-ray sources. The main target of our proposal is the production of X-ray beams with energy range tunability, monochromaticity, flux and pulse duration, compatible with those required by various pre-clinical imaging modalities and material characterization techniques, through inverse Compton scattering. This kind of source involves an infrastructure much more compact than a large Synchrotron facility and can be realized on a laboratory scale enabling an easier access to a local community of users.

Abstract The ENUBET project is aimed at designing and experimentally demonstrating the concept of monitored neutrino beams. These novel beams are enhanced by an instrumented decay tunnel, whose detectors reconstruct large-angle charged leptons produced in the tunnel and give a direct estimate of the neutrino flux at the source. These facilities are thus the ideal tool for high-precision neutrino cross-section measurements at the GeV scale because they offer superior control of beam systematics with respect to existing facilities. In this paper, we present the first end-to-end design of a monitored neutrino beam capable of monitoring lepton production at the single particle level. This goal is achieved by a new focusing system without magnetic horns, a 20 m normal-conducting transfer line for charge and momentum selection, and a 40 m tunnel instrumented with cost-effective particle detectors. Employing such a design, we show that percent precision in cross-section measurements can be achieved at the CERN SPS complex with existing neutrino detectors.

Abstract The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: $${}^{36}\hbox {Ar}$$ 36 Ar , $${}^{38}\textrm{Ar}$$ 38 Ar , and $${}^{40}\textrm{Ar}$$ 40 Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019.

SiPM-based readouts are becoming the standard for light detection in particle detectors given their superior resolution and ease of use with respect to vacuum tube photo-multipliers. However, the contributions of noise detection such as the dark rate, cross-talk, and after-pulsing (AP) may significantly impact their performance. In this work, we present the development of highly reflective single-phase argon chambers capable of displaying light yields up to 32 photo-electrons per keV, with approximately 12 being primary photo-electrons generated by the argon scintillation, while the rest are accounted by optical cross-talk. Furthermore, the presence of compound processes results in a generalized Fano factor larger than 2 already at an over-voltage of 5 V. Finally, we present a parametrization of the optical cross-talk for the FBK NUV-HD-Cryo SiPMs at 87 K that can be extended to future detectors with tailored optical simulations.

Abstract A large number of particle detectors employ liquid argon as their target material owing to its high scintillation yield and its ability to drift ionization charge over large distances. Scintillation light from argon is peaked at 128 nm and a wavelength shifter is required for its efficient detection. In this work, we directly compare the light yield achieved in two identical liquid argon chambers, one of which is equipped with polyethylene naphthalate (PEN) and the other with tetraphenyl butadiene (TPB) wavelength shifter. Both chambers are lined with enhanced specular reflectors and instrumented with SiPMs with a coverage fraction of approximately 1%, which represents a geometry comparable to the future large scale detectors. We measured the light yield of the PEN chamber to be 39.4 $$\,\pm \,$$ ± 0.4(stat) $$\,\pm \,$$ ± 1.9(syst)% of the yield of the TPB chamber. Using a Monte Carlo simulation this result is used to extract the wavelength shifting efficiency of PEN relative to TPB equal to 47.2 $$\,\pm \,$$ ± 5.7%. This result paves the way for the use of easily available PEN foils as a wavelength shifter, which can substantially simplify the construction of future liquid argon detectors.

Abstract Aria is a plant hosting a $${350}\,\hbox {m}$$ 350 m cryogenic isotopic distillation column, the tallest ever built, which is being installed in a mine shaft at Carbosulcis S.p.A., Nuraxi-Figus (SU), Italy. Aria is one of the pillars of the argon dark-matter search experimental program, lead by the Global Argon Dark Matter Collaboration. It was designed to reduce the isotopic abundance of $${^{39}\hbox {Ar}}$$ 39 Ar in argon extracted from underground sources, called Underground Argon (UAr), which is used for dark-matter searches. Indeed, $${^{39}\hbox {Ar}}$$ 39 Ar is a $$\beta $$ β -emitter of cosmogenic origin, whose activity poses background and pile-up concerns in the detectors. In this paper, we discuss the requirements, design, construction, tests, and projected performance of the plant for the isotopic cryogenic distillation of argon. We also present the successful results of the isotopic cryogenic distillation of nitrogen with a prototype plant.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell disease that presents with haemolytic anaemia, thrombosis and bone marrow failure. We report a case of a 51-year-old male with a history of PNH in treatment with Eculizumab admitted to our Hospital for acute chest pain and dyspnoea. The diagnosis was a triple vessel disease and patient was scheduled for coronary artery bypass grafting surgery. To balance the risk between thrombosis and bleeding in this particular clinical setting, we decided to use thromboelastography (TEG) as point of care solution and we used the R parameter as the target of our anticoagulant therapy. The R parameter between 11 and 14 sec can be used as a target value to balance the risk; in addition, there was no evidence of acute hemolysis during the surgery and supplemental dose of Eculizumab was administered in order to minimize any potential exacerbation of intravascular hemolysis.

Metasurfaces and, in particular, metalenses have attracted large interest and enabled various applications in the near-infrared and THz regions of the spectrum. However, the metalens design in the visible range stays quite challenging due to the smaller nanostructuring scale and the limited choice of lossless CMOS-compatible materials. We develop a simple yet efficient design of a polarization-independent, broadband metalens suitable for many CMOS-compatible fabrication techniques and materials and implement it for the visible spectral range using niobium pentoxide (Nb2O5). The produced metalens demonstrates high transmittance and focusing ability as well as a large depth of focus, which makes it a promising solution for a new generation of silicon photomultiplier photodetectors with reduced fill factor impact on the performance and reduced electron–hole generation regions, which altogether potentially leads to improved photodetection efficiency and other characteristics.

A 74-year-old male with diffuse large B-cell lymphoma, with an Ann Arbor stage IV-A, was submitted to immune-chemotherapy in 2014, with complete remission of the disease. Two years later, he presented with a left eye swelling leading to exophthalmos and blurred vision. A core biopsy was performed and revealed a local relapse of the disease. He was considered unfit for intensive salvage chemotherapy and was treated with a combination of rituximab and lenalidomide. After six courses of rituximab plus lenalidomide, the patient showed complete remission and was submitted to maintenance therapy with lenalidomide. After 24 months since the start of lenalidomide monotherapy, we did not observe any progression. In this experience, rituximab plus lenalidomide, without radiotherapy, was a safe and effective therapeutic combination in an elderly patient with a localized relapse of DLBCL who was unfit to receive more aggressive therapies.

Coronary angiography is clinically used worldwide to diagnose diseases of coronary arteries. Despite its effectiveness, this technique is quite invasive and it is associated with significant risks due to the arterial catheterisation needed to inject the contrast agent. A valid alternative is using the K-edge subtraction (KES) method, which is based on the subtraction of two images acquired at energies bracketing the K-edge of the contrast element. The enhanced sensitivity of KES allows the intravenous injection of the contrast agent, thus reducing the risks of catheterisation. This technique can be effectively implemented by using intense and quasi-monochromatic x-ray beams. Synchrotron radiation has been proven to work well for this purpose, but its cost and size prevent a widespread clinical application. Inverse Compton sources are among the most promising innovative sources of intense and quasi-monochromatic x-rays. These sources are intrinsically more compact than those based on synchrotron radiation. In this work, the potential application of inverse Compton radiation to KES angiography is investigated. To this purpose, after a short review of the physics behind the inverse Compton process, an analytical framework is described. The proposed model is based on the application of the KES algorithm to calculate the SNR of details inside a suitable mathematical phantom. That allowed us to identify the characteristics of an inverse Compton source required for KES imaging. In particular, it was estimated that a photon fluence of 108 ph mm−2 is necessary to detect signals of clinical interest. Novel sources based on inverse Compton promise to achieve this requirement with an acquisition time of few hundreds of ms. This feature, together with compactness, broad two-dimensional radiation field, absence of harmonic contamination and the ability to deliver high photon fluxes also at high energies, makes this kind of sources promising for KES angiography and other diagnostic applications. [ABSTRACT FROM AUTHOR]

Purpose: This work aims at investigating, via in-silico evaluations, the noise properties of an innovative scanning geometry in cone-beam CT (CBCT): eCT. This scanning geometry substitutes each of the projections in CBCT with a series of collimated projections acquired over an oscillating scanning trajectory. The analysis focused on the impact of the number of the projections per period (PP) on the noise characteristics., Methods: In-silico eCT scanner was simulated with a GPU based Monte Carlo software. We employed two homogeneous PMMA phantoms with a diameter of 12 cm and 16 cm whose tomographic images were reconstructed via an in-house developed software. Noise properties of the reconstructed volumes were evaluated in terms of coefficient of variation (COV), non-uniformity index , noise power spectrum (NPS), and null-cone over the 3D NPS., Results: The beam narrowing at higher PP led to a significant reduction of cupping artifacts, with a non-uniformity index reducing of about 33% going from conventional CBCT to PP = 10. Oscillating scan orbits almost fully recovered missing data in conventional CBCT, with a narrowing of the null-cone in 3D NPS to below 2.5% for PP ≥ 5 compared to 11.0% in conventional CBCT at 6.5 cm from the orbit plane CONCLUSIONS: The work characterizes the noise in reconstructed 3D images in eCT, with particular focus on the NPS. The impact of the beam collimation on cupping artifacts reduction is outlined. Similarly, the missing data outlined by the null-cone is considerably narrowed in comparison to conventional CBCT, especially for portions of the FOV far from the middle-reconstructed plane., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

To understand how oncogenes affect genome organization, it is essential to visualize fundamental processes such as DNA replication and transcription at high resolution in intact cells. At the same time, it is important to determine the progression of the cell along the cell cycle, as cell cycle regulation is crucial for the control of cell proliferation and oncogenesis. Here, we present a super-resolution imaging-based method to analyze single cell nuclei sorted according to specific phases of the cell cycle. The sorting is based on the evaluation of the number and the intensity of pixels in the replication foci image and the colocalization analysis is based on image cross-correlation spectroscopy (ICCS). We evaluate the colocalization between replication and transcription, at different cell cycle phases, in a model of PML-RARα oncogene activation. We find that colocalization between replication and transcription is higher in cells in early S phase compared to cells in middle and late S phase. When we turn on the PML-RARα oncogene, this colocalization pattern is preserved but we detect an increase of colocalization between replication and transcription in the early S phase which points to an effect of the PML-RARα oncogene on the coordination between replication and transcription., (© 2024. The Author(s).)

Male infertility represents a complex clinical condition that often challenges the ability of reproductive specialists to find its etiology and then propose an adequate treatment. The unexplained decline in sperm count, as well as the association between male infertility and mortality, morbidity, and cancer, has prompted researchers toward an urgent need to better understand the causes of male infertility. Therefore, molecular biologists are increasingly trying to study whether sperm epigenetic alterations may be involved in male infertility and embryo developmental abnormalities. In this context, research is also trying to uncover the hidden role of sperm RNAs, both coding and non-coding. This narrative review aims to thoroughly and comprehensively present the relationship between sperm epigenetics, sperm RNAs, and human fertility. We first focused on the technological aspects of studying sperm epigenetics and RNAs, relating to the complex role(s) played in sperm maturation, fertilization, and embryo development. Then, we examined the intricate connections between epigenetics and RNAs with fertility measures, namely sperm concentration, embryo growth and development, and live birth rate, in both animal and human studies. A better understanding of the molecular mechanisms involved in sperm epigenetic regulation, as well as the impact of RNA players, will help to tackle infertility., (© 2024. The Author(s).)

Extracellular vesicles (EVs) represent pivotal mediators in cell-to-cell communication. They are lipid-membranous carriers of several biomolecules, which can be produced by almost all cells. In the current Era of precision medicine, EVs gained growing attention thanks to their potential in both biomarker discovery and nanotherapeutics applications. However, current technical limitations in isolating and/or detecting EVs restrain their standard use in clinics. This review explores all the state-of-the-art analytical technologies which are currently overcoming these issues. On one end, several innovative optical-, electrical-, and spectroscopy-based detection methods represent advantageous label-free methodologies for faster EV detection. On the other end, microfluidics-based lab-on-a-chip tools support EV purification from low-concentrated samples. Altogether, these technologies will strengthen the routine application of EVs in clinics., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

X-ray sources based on the inverse Compton interaction between a laser and a relativistic electron beam are emerging as a promising compact alternative to synchrotron for the production of intense monochromatic and tunable radiation. The emission characteristics enable several innovative imaging techniques, including dual-energy K-edge subtraction (KES) imaging. The performance of these techniques is optimal in the case of perfectly monochromatic x-ray beams, and the implementation of KES was proven to be very effective with synchrotron radiation. Nonetheless, the features of inverse Compton scattering (ICS) sources make them good candidates for a more compact implementation of KES techniques. The energy and intensity distribution of the emitted radiation is related to the emission direction, which means different beam qualities in different spatial positions. In fact, as the polar angle increases, the average energy decreases, while the local energy bandwidth increases and the emission intensity decreases. The scope of this work is to describe the impact of the local energy distribution variations on KES imaging performance. By means of analytical simulations, the reconstructed signal, signal-to-noise ratio, and background contamination were evaluated as a function of the position of each detector pixel. The results show that KES imaging is possible with ICS x-ray beams, even if the image quality slightly degrades at the detector borders for a fixed collimation angle and, in general, as the beam divergence increases. Finally, an approach for the optimization of specific imaging tasks is proposed by considering the characteristics of a given source.

Dipeptidyl amino-peptidase 3 (DPP3) is an aminopeptidase that is released into circulation upon cell death. DPP3 is involved in the degradation of angiotensins, enkephalines, and endomorphines. It has been shown that circulating DPP3 (cDPP3) plasma concentration increases in cardiogenic shock (CS) patients and correlates with high mortality risk. Cardiogenic shock is a life-threatening syndrome associated with organ hypoperfusion. One of the common causes of CS is acute myocardial infarction (AMI). This study aimed to investigate if cDPP3 levels are associated with CS severity and the need for ventilation in patients suffering from CS. Fifteen patients with CS were included in this study. Six patients were invasively ventilated. The values of cDPP3 were higher in ventilated patients than in non-ventilated patients at admission, 3 h, and 24 h after admission in the intensive care unit. Patients with pulmonary hypertension at admission also showed high cDPP3 values at all time points. Furthermore, high cDPP3 levels were associated with reduced stroke volume. Our results suggest that cDPP3 could predict CS progression and guide therapy escalation.

Background: Vertebral arthrodesis for degenerative pathology of the lumbar spine still remains burdened by clinical problems with significant negative results. The introduction of the sagittal balance assessment with the evaluation of the meaning of pelvic parameters and spinopelvic (PI-LL) mismatch offered new evaluation criteria for this widespread pathology, but there is a lack of consistent evidence on long-term outcome., Methods: The authors performed an extensive systematic review of literature, with the aim to identify all potentially relevant studies about the role and usefulness of the restoration or the assessment of Sagittal balance in lumbar degenerative disease. They present the study protocol RELApSE (NCT05448092 ID) and discuss the rationale through a comprehensive literature review., Results: From the 237 papers on this topic, a total of 176 articles were selected in this review. The analysis of these literature data shows sparse and variable evidence. There are no observations or guidelines about the value of lordosis restoration or PI-LL mismatch. Most of the works in the literature are retrospective, monocentric, based on small populations, and often address the topic evaluation partially., Conclusions: The RELApSE study is based on the possibility of comparing a heterogeneous population by pathology and different surgical technical options on some homogeneous clinical and anatomic-radiological measures aiming to understanding the value that global lumbar and segmental lordosis, distribution of lordosis, pelvic tilt, and PI-LL mismatch may have on clinical outcome in lumbar degenerative pathology and on the occurrence of adjacent segment disease., (© 2023 The Authors.)

The jugular venous pulse (JVP) is a one of the crucial parameters of efficient cardiovascular function. Nowadays, limited data are available regarding the response of JVP to exercise because of its complex and/or invasive assessment procedure. The aim of the present work is to test the feasibility of a non-invasive JVP plethysmography system to monitor different submaximal exercise condition. Twenty (20) healthy subjects (13M/7F mean age 25 ± 3, BMI 21 ± 2) underwent cervical strain-gauge plethysmography, acquired synchronously with the electrocardiogram, while they were carrying out different activities: stand supine, upright, and during the execution of aerobic exercise (2 km walking test) and leg-press machine exercise (submaximal 6 RM test). Peaks a and x of the JVP waveform were investigated since they reflect the volume of cardiac filling. To this aim, the Δax parameter was introduced, representing the amplitude differences between a and x peaks. Significant differences in the values of a, x, and Δax were found between static and exercise conditions (p < 0.0001, p < 0.0001, p < 0.0001), respectively. Particularly, the Δax value for the leg press was approximately three times higher than the supine, and during walking was even nine times higher. The exercise monitoring by means of the novel JVP plethysmography system is feasible during submaximal exercise, and it provides additional parameters on cardiac filling and cerebral venous drainage to the widely used heartbeat rate value.

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in healthy and diseased brain. In Parkinson's disease (PD)-characterized by selective dopaminergic neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)-astrocytes exert dual harmful/protective functions, with mechanisms not fully elucidated. Here, this study shows that astrocytes from the VMB-, STR-, and VMB/STR-depleted brains release a population of small EVs  in a region-specific manner. Interestingly, VMB-astrocytes secreted the highest rate of EVs, which is further exclusively increased in response to CCL3, a chemokine that promotes robust dopaminergic neuroprotection in different PD models. The neuroprotective potential of nigrostriatal astrocyte-EVs is investigated in differentiated versus undifferentiated SH-SY5Y cells exposed to oxidative stress and mitochondrial toxicity. EVs from both VMB- and STR-astrocytes counteract H 2 O 2 -induced caspase-3 activation specifically in differentiated cells, with EVs from CCL3-treated astrocytes showing a higher protective effect. High resolution respirometry further reveals that nigrostriatal astrocyte-EVs rescue neuronal mitochondrial complex I function impaired by the neurotoxin MPP + . Notably, only EVs from VMB-astrocyte fully restore ATP production, again specifically in differentiated SH-SY5Y. These results highlight a regional diversity in the nigrostriatal system for the secretion and activities of astrocyte-EVs, with neuroprotective implications for PD., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

The aim of this study was the preliminary assessment of a new cationic contrast agent, the CA4+, via the analysis of spatial distribution in cartilage of ex vivo bovine samples, at micrometer and millimeter scale. Osteochondral plugs ( n = 18) extracted from bovine stifle joints ( n = 2) were immersed in CA4+ solution up to 26 h. Planar images were acquired at different time points, using a microCT apparatus. The CA4+ distribution in cartilage and saturation time were evaluated. Tibial plates from bovine stifle joints ( n = 3) were imaged with CT, before and after 24 h-CA4+ bath immersion, at different concentrations. Afterward, potential CA4+ washout from cartilage was investigated. From microCT acquisitions, the CA4+ distribution differentiated into three distinct layers inside the cartilage, reflecting the spatial distribution of proteoglycans. After 24 h of diffusion, the iodine concentration reached in cartilage was approximately seven times that of the CA4+ bath. The resulting saturation time was 1.9 ± 0.9 h and 2.6 ± 2.9 h for femoral and tibial samples, respectively. Analysis of clinical CT acquisitions confirmed overall contrast enhancement of cartilage after 24 h immersion, observed for each CA4+ concentration. Distinct contrast enhancement was reached in different cartilage regions, depending on tissue's local features. Incomplete but remarkable washout of cartilage was observed. CA4+ significantly improved cartilage visualization and its qualitative analysis.

The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson's disease (PD), characterized by motor- and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright: © 2021 Leggio et al.)

Central nervous system tumors represent the most frequent solid malignancy in the pediatric population. Maximal safe surgical resection is a mainstay of treatment, with significant prognostic impact for the majority of histotypes. Intraoperative ultrasound (ioUS) is a widely available tool in neurosurgery to assist in intracerebral disease resection. Despite technical caveats, preliminary experiences suggest a satisfactory predictive ability, when compared to magnetic resonance imaging (MRI) studies. Most of the available evidence on ioUS applications in brain tumors derive from adult series, a scenario that might not be representative of the pediatric population. We present our preliminary experience comparing ioUS-assisted resection assessment to early post-operative MRI findings in 154 consecutive brain tumor resections at our pediatric neurosurgical unit. A high concordance was observed between ioUS and post-operative MRI. Overall ioUS demonstrated a positive predictive value of 98%, a negative predictive value of 92% in assessing the presence of tumor residue compared to postoperative MRI. Overall, sensibility and specificity were 86% and 99%, respectively. On a multivariate analysis, the only variable significantly associated to unexpected tumor residue on postoperative MRI was histology. Tumor location, patient positioning during surgery, age and initial tumor volume were not significantly associated with ioUS predictive ability. Our data suggest a very good predictive value of ioUS in brain tumor resective procedures in children. Low-grade glioma, high-grade glioma and craniopharyngioma might represent a setting deserving specific endeavours in order to improve intraoperative extent of resection assessment ability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carai, De Benedictis, Calloni, Onorini, Paternò, Randi, Colafati, Mastronuzzi and Marras.)

Background and Purpose: Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the prehospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage., Methods: Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized noninferiority trial design was used to assign rats to HDT15° or flat position (n = 64). HDT15° was applied for 1 h during the time window of hematoma expansion. The primary outcome was hematoma volume at 24 h. Secondary outcomes were mass effect, mortality, and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth, and cardiorespiratory parameters in separate sets of randomized animals (n = 32)., Results: HDT15° achieved the specified criteria of noninferiority for hematoma volume at 24 h. Mass effect, mortality, and functional deficit at 24 h showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pretreatment values (+2.91 ± 1.76 mmHg). HDT15° had a neutral effect on MRI-based analysis of hematoma growth and cardiorespiratory parameters., Conclusions: Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke., (© 2020 European Academy of Neurology.)

Interference effects are included in the x-ray coherent scattering models used in Monte Carlo codes by modifying each material form factor through a proper interference function, which is obtained directly from the measured scattering pattern. This approach is effective for non-biological materials, but it is impractical for biological tissues, due the wide composition variability they can feature. Instead, a given biological sample can be considered as a proper mixture of four basis materials: fat, water, collagen and calcium hydroxyapatite. The sample form factor can then be obtained through a weighted mean of the form factors of the basis materials, which include interference effects. Here, we fully demonstrate the validity of the proposed segmentation method by applying it to 31 biological tissue samples whose form factors are available in the literature. The segmentation, namely the determination of the optimal weight of the basis components, was carried out through a multiple linear regression or, in some cases, by using a controlled trial and error sequence. The form factors of the basis materials were extracted from previous works and elaborated to include more scattering features. In particular, they were interpolated at a denser grid. Furthermore, the data measured separately in wide angle and small angle regimes, for fat and collagen, were merged. In general, a very good agreement was obtained between the original sample and the calculated mixture, being the mean relative difference of their scattering profiles and their attenuation coefficients ∼10%. The segmentation method is fully supported by our extension to the Geant4 model of x-ray coherent scattering, which was used to compare simulated scatter distributions with known experimental data. The developed Geant4 code and a series of molecular form factors, including those of the basis materials, are freely downloadable from a dedicated web repository.

MPP + is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson's disease models. Within the cells, MPP + accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP + is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP + treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP + , relevant for the standardization of studies that employ this neurotoxin as a disease model.

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor-ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson's disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood-brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

MariX is a research infrastructure conceived for multi-disciplinary studies, based on a cutting-edge system of combined electron accelerators at the forefront of the world-wide scenario of X-ray sources. The generation of X-rays over a large photon energy range will be enabled by two unique X-ray sources: a Free Electron Laser and an inverse Compton source, called BriXS (Bright compact X-ray Source). The X-ray beam provided by BriXS is expected to have an average energy tunable in the range 20-180 keV and intensities between 10 11 and 10 13 photon/s within a relative bandwidth ΔE/E=1-10%. These characteristics, together with a very small source size (~20 μm) and a good transverse coherence, will enable a wide range of applications in the bio-medical field. An additional unique feature of BriXS will be the possibility to make a quick switch of the X-ray energy between two values for dual-energy and K-edge subtraction imaging. In this paper, the expected characteristics of BriXS will be presented, with a particular focus on the features of interest to its possible medical applications., (Copyright © 2020. Published by Elsevier Ltd.)

Naturally occurring extracellular vesicles and artificially made vesicles represent important tools in nanomedicine for the efficient delivery of biomolecules and drugs. Since its first appearance in the literature 50 years ago, the research on vesicles is progressing at a fast pace, with the main goal of developing carriers able to protect cargoes from degradation, as well as to deliver them in a time- and space-controlled fashion. While natural occurring vesicles have the advantage of being fully compatible with their host, artificial vesicles can be easily synthetized and functionalized according to the target to reach. Research is striving to merge the advantages of natural and artificial vesicles, in order to provide a new generation of highly performing vesicles, which would improve the therapeutic index of transported molecules. This progress report summarizes current manufacturing techniques used to produce both natural and artificial vesicles, exploring the promises and pitfalls of the different production processes. Finally, pros and cons of natural versus artificial vesicles are discussed and compared, with special regard toward the current applications of both kinds of vesicles in the healthcare field., (© 2020 Wiley-VCH GmbH.)

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson's disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a "beneficial" or "destructive" phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD.

Background: Cerebellar ectopy is a rare finding, with few cases previously reported. Intraventricular localized cerebellar ectopy was described in only 1 case within the fourth ventricle., Case Description: A 9-year-old girl suffered for 2 years from bilateral frontoparietal headaches, sometimes accompanied by vomiting and photophobia. Magnetic resonance imaging demonstrated an oval-shaped lesion within the left lateral ventricle, characterized by well-defined margins without a clear cleavage plane from the adjacent choroid plexus. The mass presented an intermediate signal on T1- and T2-weighted sequences, similar to gray matter, and reduced ADC values on ADC maps compared with white matter, with no enhancement after gadolinium-based contrast injection. After resection, macroscopic examination revealed an organoid structure with leptomeningeal lining and a clear-cut cortex and white matter components. Histology demonstrated normal cerebellum with a double-layered cortex and normal underlying white matter. The cerebellar ectopy was focally covered by bundles of capillary vascular structures covered by a monostratified ependymal cell lining, consistent with choroid plexus., Conclusions: We describe, for the first time to our knowledge, the case of a child with ectopic cerebellar tissue harboring the supratentorial ventricular system. Plausible etiologic mechanism consists in the herniation of the cerebellar germinal tissue into the ventricular system through the ependyma, allowing cell migration to the supratentorial compartment, followed by maturation into the normal cerebellum., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An extension to Geant4 Monte Carlo code was developed to take into account inter-atomic (molecular) interference effects in X-ray coherent scattering. Based on our previous works, the developed code introduces a set of form factors including interference effects for a selected variety of amorphous materials useful for medical applications, namely various tissues and plastics used to build phantoms. The code is easily upgradable in order to include new materials and offers the possibility to model a generic tissue as a combination of a set of four basic components. A dedicated Geant4 application for the simulation of X-ray diffraction experiments was created to validate the proposed upgrade of Rayleigh scattering model. A preliminary validation of the code obtained through a comparison with EGS4 and an experiment is presented, showing a satisfactory agreement., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Advanced applications of digital mammography such as dual-energy and tomosynthesis require multiple exposures and thus deliver higher dose compared to standard mammograms. A straightforward manner to reduce patient dose without affecting image quality would be removal of the anti-scatter grid, provided that the involved reconstruction algorithms are able to take the scatter figure into account [1]. Monte Carlo simulations are very well suited for the calculation of X-ray scatter distribution and can be used to integrate such information within the reconstruction software. Geant4 is an open source C++ particle tracking code widely used in several physical fields, including medical physics [2,3]. However, the coherent scattering cross section used by the standard Geant4 code does not take into account the influence of molecular interference. According to the independent atomic scattering approximation (the so-called free-atom model), coherent radiation is indistinguishable from primary radiation because its angular distribution is peaked in the forward direction. Since interference effects occur between x-rays scattered by neighbouring atoms in matter, it was shown experimentally that the scatter distribution is affected by the molecular structure of the target, even in amorphous materials. The most important consequence is that the coherent scatter distribution is not peaked in the forward direction, and the position of the maximum is strongly material-dependent [4]. In this contribution, we present the implementation of a method to take into account inter-atomic interference in small-angle coherent scattering in Geant4, including a dedicated data set of suitable molecular form factor values for several materials of clinical interest. Furthermore, we present scatter images of simple geometric phantoms in which the Rayleigh contribution is rigorously evaluated., (Copyright © 2017.)

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm 3 absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

Background: Excessively long clamping time and suboptimal position of stitches can influence the anastomosis patency and the clinical outcome in cerebral bypass surgery. Coronary intravascular micro-shunts could represent an innovative solution for neurosurgical bypass, but the hemodynamic properties of these devices should be extensively studied before their translational application. We created an experimental in-vivo model and we analyzed the blood flow and pressure modification induced by the micro-shunt., Methods: After laparotomy, an intravascular micro-shunt was placed into the aorta of 8 adult rats, simulating a neurosurgical setting in which the shunt is temporary placed inside the receiving cerebral vessel. A fiber-optic pressure sensor was placed in the femoral artery and the blood pressure continuously recorded during the procedure. Using an ultrasound vascular probe, blood flow velocity in aorta was measured at baseline and both proximally and distally to the shunt., Results: After shunt positioning, no significant decrease in blood pressure was observed (mean value 68.57 versus 80.00 mmHg; P=0.48). Distal aortic blood flow, expressed as peak systolic velocity, showed a significant decrease after shunt positioning (mean value 51.88 versus 86.88 cm/sec; P=0.04), with a mean residual blood flow of 63%. Blood flow values recorded immediately upstream to the shunt did not differ from baseline., Conclusions: This is the first in-vivo experimental study concerning the hemodynamic properties of an intravascular micro-shunt. Our results demonstrate that this device provides a considerable blood out-flow without significant changes in blood pressure, suggesting that specific neurosurgical micro-shunts might be developed.

Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)