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Purpose of ReviewPeripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV.Recent FindingsProgress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review.Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Although controversial, procurement kidney biopsies and histology are commonly used in kidney allocation from deceased donors. The long series of models developed for this question, incorporating a variety of clinical and histologic variables, failed to properly predict the long-term graft survival. This failure could be explained by many factors, including the lack of expertise in terms of skilled available nephropathologists in the urgent setting of biopsies assessment. Simulation-based learning is a form of experiential learning that provides learners with a real-world-like opportunity to develop and practice their knowledge and skills but in a simulated environment. Digital pathology with whole-slide imaging is a powerful tool for knowledge delivering, as it offers the opportunity to facilitate meeting of general pathologists with experts, with availability of second opinion consultation and tailored training on specific cases. In the back of these considerations, we report on the content of the web-meeting “Digital slide and simulation-based learning in pre-implantation kidney” which was fully dedicated to the evaluation of pre-implantation kidney biopsy, with a very practical approach and a direct interaction between two expert renal transplant pathologists and the audience of general pathologists.

Cardio-oncology is an increasingly important field of cardiology that focuses on the detection, monitoring, and treatment of cardiovascular disease (CVD) occurring during and after oncological treatments. The survival rate for childhood cancer patients has dramatically increased thanks to new treatment protocols and cardiovascular (CV) sequelae represent the third most frequent cause of mortality in surviving patients. This study aims to provide a complete and updated review of all the main aspects of cardio-oncology in childhood and to highlight the critical issues.The problem of CV complications in childhood cancer survivors raises the need to make an early diagnosis of cardiotoxicity by the new imaging and laboratory techniques in order to intervene promptly and to implement pharmacological strategies and lifestyle changes to reduce or even to prevent cardiac injury. Furthermore, a stratification of CV risk, also including new predisposing factors such as the presence of some genetic mutations, is of paramount importance before undertaking oncological treatments. Besides, a systematic and personalized planning of long-term follow-up is fundamental to ensure a transition from pediatric to adult hospital and to avoid missed or late diagnosis of cardiomyopathy. We reviewed the main risk factors for cardiotoxicity in children, both traditional and emerging ones: the mechanisms of toxicity of both old and new antineoplastic therapies, the techniques for detecting cardiac damage, and the current evidence regarding pharmacological cardioprotection. At the end, we focused our attention on the existing guidelines and strategies about the long-term follow-up of childhood cancer survivors.

Cone-beam CT (CBCT) scans now enable accurate measurements on foot skeletal structures with the advantage of observing these in 3D and in weight-bearing. Among the most common skeletal deformities, the varus/valgus of the hindfoot is the most complex to be represented, and a number of measure proposals have been published. This study aims to analyze and to compare these measurements from CBCT scans in a real clinical population with large such deformity. Ten patients with severe acquired adult fatfoot and indication for surgery underwent CBCT scans (Carestream, USA) while standing on that leg, before and after surgical correction. Corresponding 3D shape of each bone of the distal shank and hindfoot were defned (Materialise, Belgium). Six diferent techniques from the literature were used to calculate the varus/valgus deformity, i.e. the inclination of the hindfoot in the frontal plane of the shank. Standard clinical measurements by goniometers were taken for comparison. According to these techniques, and starting from a careful 3D reconstruction of the relevant foot skeletal structures, a large spectrum of measurements was found to represent the same hindfoot alignment angle. Most of them were very diferent from the traditional clinical measures. The assessment of the pre-operative valgus deformity and of the corresponding post-operative correction varied considerably. CBCT fnally allows 3D assessment of foot deformities in weight-bearing. Measurements from the diferent available techniques do not compare well, as they are based on very diferent approaches. It is recommended to be aware of the anatomical and functional concepts behind these techniques before clinical and surgical conclusions.

In this work we explore a new framework for approximate Bayesian inference in large datasets based on stochastic control. We advocate stochastic control as a finite time and low variance alternative to popular steady-state methods such as stochastic gradient Langevin dynamics. Furthermore, we discuss and adapt the existing theoretical guarantees of this framework and establish connections to already existing VI routines in SDE-based models.

Funder: Università degli Studi di Padova, Evaluating the effects of neonicotinoids on forager bees in conditions as near as possible to those in nature presents a considerable challenge. Tackling this challenge is, however, necessary to establish their negative side effects on these pollinators. For instance, it is still under debate the mechanism by which bees seem to recognize low-level contaminations of neonicotinoid insecticides in nectar and pollen of the flowers they visit and limit collection to protect themselves and their hive from a possible intoxication. In this study, we propose an experimental system that involves the use of foragers in free flight foraging repeatedly on artificial feeders containing a sucrose solution contaminated with clothianidin, as well as foragers feeding at adjacent control feeders, allowing us to observe changes in their foraging activity. The progressive disappearance of foragers from the contaminated feeders became increasingly clear and rapid with the increase in clothianidin concentration. The lowest concentration at which we observed an effect was around 10 µg/L, which corresponds to the maximum residual concentration (10 ng/g) observed in pollen and nectar of flowers close to open fields sown with seeds coated with insecticides. At the highest concentrations tested (80 µg/L), there was an almost total abandonment of the feeders. The estimated quantity of contaminated sucrose solution collected by foragers showed an almost linear relationship inversely proportional to clothianidin concentration, whilst the estimated quantity of insecticide collected by a forager increased and then stabilised at the highest concentrations tested of 40 and 80 µg/L. Irregular mortality was not observed in front of the hives, furthermore, foragers did not show evident memory of the position of the treated units in the trials on the 2 consecutive days. The decrease in foraging activity in the presence of a few µg/L of insecticide in the sucrose solution appears to limit the introduction of elevated amounts of toxic substances into the hives, which would have serious consequences for the young bees and the brood. At the same time, in the absence of an alternative energy source, even reduced feeding of the hive can compromise colony health.

In the present report it is described the design, the manufacturing and the successful surgical implant of one of the first 3D custom titanium vertebra realized with Additive Manufacturing technique and its use for the spinal reconstruction after en-bloc resection for primary osteogenic sarcoma. Clinical case presentation and the design of the 3D custom titanium vertebra was reported. It was also described the complex procedures adopted to evaluate the retrieved device from the histological point of view, as a tumor relapse hit the patient, one year after the reconstruction procedure. The histological evaluation confirmed that the resection technique exerts an important role in promoting bone formation: vertebral body osteotomies favored the reconstruction procedure and maximized the contact area between host bone/vertebral prosthesis thus favoring the bone tissue penetration and device colonization. The sharing of these results is very important as they represent the starting point for improving the knowledge starting from the evidence obtained in a challenging clinical condition and with post-operative treatments that could be never reproduced in preclinical model.

Mathematical modeling and simulation are moving from being powerful development and analysis tools towards having increased roles in operational monitoring, control and decision support, in which models of specific entities are continually updated in the form of a digital twin. However, current digital twins are largely the result of bespoke technical solutions that are difficult to scale. We discuss two exemplar applications that motivate challenges and opportunities for scaling digital twins, and that underscore potential barriers to wider adoption of this technology. Development in digital-twin technology has been rapidly growing across a range of industries and disciplines. However, to ensure a wider and more robust adoption of such technology, various challenges must be addressed by the computational science community.

Purpose To investigate whether the World Health Organization Safety Surgical Checklist (SSC) is an effective tool to reduce complications in spinal surgery. Methods We retrospectively evaluated the clinical and radiological charts prospectively collected from patients who underwent a spinal surgery procedure from January 2010 to December 2012. The aim of this study was to compare the incidence of complications between two periods, from January to December 2010 (without checklist) and from January 2011 and December 2012 (with checklist), in order to assess the checklist’s effectiveness. Results The sample size was 917 patients with an average of 30-month follow-up. The mean age was 52.88 years. The majority of procedures were performed for oncological diseases (54.4%) and degenerative diseases (39.8%). In total, 159 complications were detected (17.3%). The overall incidence of complications for trauma, infectious pathology, oncology, and degenerative disease was 22.2%, 19.2%, 18.4%, and 15.3%, respectively. No correlation was observed between the type of pathology and the complication incidence. We observed a reduction in the overall incidence of complications following the introduction of the SSC: In 2010 without checklist, the incidence of complications was 24.2%, while in 2011 and 2012, following the checklist introduction, the incidence of complications was 16.7% and 11.7%, respectively (mean 14.2%). Conclusions The SSC seems to be an effective tool to reduce complications in spinal surgery. We propose to extend the use of checklist system also to the preoperative and postoperative phases in order to further reduce the incidence of complications. Graphic abstract These slides can be retrieved under Electronic Supplementary Material.

PURPOSE: This case series evaluates the surgical management of granular cell tumor (GCT) of the sellar region. This rare entity presents a unique diagnostic and surgical challenge. METHODS: Institutional neuropathology databases at Brigham and Women’s Hospital and Massachusetts General Hospital were searched for cases with a tissue diagnosis of GCT, and with a location in the sellar region. Patient, treatment, tumor, and follow-up data were extracted. RESULTS: Three patients had a diagnosis of GCT of the sellar region occurring over an 18-year period. All three patients were followed postoperatively at our multidisciplinary pituitary center (median follow-up=30 months; range=12–30 months). Hormonal disturbances, an incidental lesion requiring diagnosis, and neurological symptoms were indications for surgery in these patients. Two patients underwent a craniotomy and one underwent endoscopic transsphenoidal surgery. All three patients were free of tumor recurrence at last follow-up. In one case tested, positive thyroid transcription factor-1 (TTF-1) immunohistochemistry was observed. CONCLUSION: GCT is generally a benign tumor of the sellar region. Surgical resection is the standard treatment, more recently with transsphenoidal surgery when indicated. Surgical resection results in optimal outcome for patients.

Recently several variants of clotting factors have shown a peculiar behavior so that they appear as new defects. The factors involved are FII, FV and FIX. Prothrombin deficiency is usually associated with bleeding. Recently a few prothrombin abnormalities involving Arg396 mutations, have been demonstrated to show antithrombin resistance with the consequent appearance of a thrombophilic state and venous thromboses in young age. The same is true for an abnormal FIX (FIX Padua). The thrombotic manifestations in the latter condition are also venous. The abnormal FIX (FIX Padua) is characterized by a great increase in FIX activity whereas FIX antigen is only slightly increased. The condition is due to an Arg338Lys mutation. The increased intrinsic clotting activity of this abnormal FIX is being investigated as a useful therapeutic approach in homophile B patients. Another new clotting disorder is represented by two abnormal FV (FV East Texas and FV Amsterdam). These are characterized by a deletion of part of the B domain of FV resulting in a "short" FV. The condition is characterized by a mild bleeding tendency due to high levels of Tissue Factor pathway inhibitor. The "short" factor V is in fact resistant to the action of Tissue Factor pathway inhibitor which is sharply increased in these patients. These new clotting entities have again demonstrated that the study of patients who show a tendency to venous thrombosis or a mild bleeding condition that cannot be explained on the basis of our current concepts of blood coagulation, may represent "new" coagulation disorders. All persons interested in thrombotic or hemorrhagic disorders should be informed about these new clinical and laboratory conditions.

Funder: Università degli Studi di Padova, Systemic insecticides such as neonicotinoids are widely used in seed coating practices for pest control in many crops, e.g., corn. Their success is due to their ability to protect the whole plant, from the roots to the upper leaves, but their use at high amounts is causing possible adverse effects on non-target animals exposed to contaminated pollen, nectar, leaves, and dust emitted during sowing. In 2018, the European Union banned some neonicotinoids and fipronil as seed coating insecticides in open fields. Consequently, the methylcarbamate methiocarb and less-toxic neonicotinoids, e.g., thiacloprid, have been authorized and largely used as alternative pesticides for corn seed coating. Here, an analytical protocol based on QuEChERS extraction/purification procedure and analysis by liquid chromatography-mass spectrometry has been optimized for the identification and the quantification of methiocarb, thiamethoxam, thiacloprid, and their metabolites in guttation drops, the xylem fluid excreted at leaf margins, and in leaves of corn plants grown from coated seeds. Although methiocarb is a non-systemic pesticide, we unexpectedly found high concentrations of its metabolites in both guttations and leaves, whereas methiocarb itself was below detection limits in most of the samples. The methiocarb main metabolite, methiocarb sulfoxide, was found at a mean concentration of 0.61 ± 1.12 µg mL−1 in guttation drops and 4.4 ± 2.1 µg g−1 in leaves. Conversely, parent compounds of neonicotinoids (thiamethoxam, thiacloprid) are systemically distributed in corn seedlings. This result raises safety concerns given that methiocarb sulfoxide is more toxic than the parent compound for some non-target species.

BackgroundIn sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. VE-cadherin, an adherens junction protein, is the gatekeeper of endothelial cohesion. Kinins, released during sepsis, induce vascular leakage and vasodilation. They act via two G-protein coupled receptors: B1 (B1R) and B2 (B2R). B1R is inducible in the presence of pro-inflammatory cytokines, endotoxins or after tissue injury. It acts at a later stage of sepsis and elicits a sustained inflammatory response. The aim of our study was to investigate the relationships between B1R and VE-cadherin destabilization in vivo in a later phase of sepsis.MethodsExperimental, prospective study in a university research laboratory. We used a polymicrobial model of septic shock by cecal ligation and puncture in C57BL6 male mice or C57BL6 male mice that received a specific B1R antagonist (R-954). We studied the influence of B1R on sepsis-induced vascular permeability 30 h after surgery for several organs, and VE-cadherin expression in the lung and kidneys by injecting R-954 just before surgery. The 96-h survival was determined in mice without treatment or in animals receiving R-954 as a “prophylactic” regimen (a subcutaneous injection of 200 µg/kg, prior to CLP and 24 h after CLP), or as a “curative” regimen (injection of 100 µg/kg at H6, H24 and H48 post-surgery).ResultsB1R inactivation helps to maintain MAP above 65 mmHg but induces different permeability profiles depending on whether or not organ perfusion is autoregulated. In our model, VE-cadherin was destabilized in vivo during septic shock. At a late stage of sepsis, the B1R blockade reduced the VE-cadherin disruption by limiting eNOS activation. The survival rate for mice that received R-954 after sepsis induction was higher than in animals that received an antagonist as a prophylactic treatment.ConclusionsB1R antagonizing reduced mortality in our model of murine septic shock by limiting the vascular permeability induced by VE-cadherin destabilization through maintenance of the macrohemodynamics, consequently limiting organ dysfunctions.

Background: Large amounts of insecticide-containing dusts produced from abrasion of the seed dressing can be released into the atmosphere during sowing operations. Neonicotinoid pesticides, introduced in the 1990s for several crops, are the leading products for seed-coating treatments in many countries. Neonicotinoid containing dusts can be efectively intercepted by bees in fight over the sowing feld, inducing lethal acute efects, so that restrictions in the use of the main neonicotinoids have been adopted in the European Union. This led to the consequent introduction of replacement insecticides for seed-coating, i.e. methiocarb and thiacloprid, despite the lack of information on both the toxicity and the exposure scenarios for honeybees. Results: In this study, a laboratory apparatus was developed in order to quantify the toxicity of the dusts produced from the abrasion of the seed coating. This quantifcation is based on (i) an airstream transporting coating particles into an exposure chamber; (ii) exposure of bees to reproducible and measurable concentrations of insecticide, and (iii) direct measurement of the exposure dose on single bees. The method allowed us to perform in vivo experiments of honeybee exposure to provide toxicity data in more realistic exposure conditions. In fact, the formulation rather than the active principle alone can be tested, and the exposure is through dusts rather than a solution so that specifc absorption behavior can be studied in representative environmental conditions. The method was used to quantify the acute toxicity (LD50) of dusts obtained from the abrasion of corn seeds coated with clothianidin, thiacloprid and methiocarb. Conclusions: Our results show that, surprisingly, the replacement insecticide methiocarb has a toxicity (LD50=421– 693 ng/bee) in the same order of magnitude as clothianidin (LD50=113–451 ng/bee) through this specifc exposure route, while thiacloprid (LD50=16.9·103 ng/bee) has a signifcantly lower acute toxicity. Moreover, dusts containing methiocarb and clothianidin show a signifcant increase in toxicity when, after exposure, bees are kept under high humidity conditions. This suggests that the method here presented can be used to obtain complementary toxicity data in the risk assessment procedure for the authorization of new seed-coating insecticides or new formulations. Keywords: Systemic insecticides, Neonicotinoids, Methiocarb, Seed coating, Abrasion dusts, Honeybees, Pollinator insects, Acute toxicity, Exposure measurement

Primary melanocytic tumors of central nervous system represent rare tumors arising from melanocytes of the leptomeninges. These neoplasms include focal forms like melanocytoma and primary malignant melanoma and diffuse forms like leptomeningeal melanocytosis and primary leptomeningeal melanomatosis. The clinical diagnosis remains challenging, with clinical and radiologic features overlapping with other more common diseases. Here we present a case of a 38 years old male with primary diffuse leptomeningeal melanomatosis with presence of a NRASQ61K mutation without features of neurocutaneous melanosis.