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Ophelia syndrome or encephalitis with antibodies against the metabotropic glutamate receptor 5 (mGluR5) manifests with behavioral changes, memory deficits, and anxiety. To study the antibody pathogenicity, mice received continuous cerebroventricular infusion of patients' or controls' immunoglobulin G (IgG) for 14 days, followed by a 15-day washout. The effects on hippocampal mGluR5 clusters were determined by confocal microscopy. Animals infused with patients' IgG, but not controls' IgG, showed memory impairment, increased anxiety, and decreased neuronal surface mGluR5 clusters. After antibody clearance, both behavioral and molecular changes reversed to baseline conditions. These findings support the pathogenicity of these antibodies in anti-mGluR5 encephalitis. ANN NEUROL 2022;92:81-86.

The central nervous system (CNS) has emerged as a critical HIV reservoir. Thus, interventions aimed at controlling and eliminating HIV must include CNS-targeted strategies. Given the inaccessibility of the brain, efforts have focused on cerebrospinal fluid (CSF), aimed at defining biomarkers of HIV-disease in the CNS, including HIV-specific antibodies. However, how antibodies traffic between the blood and CNS, and whether specific antibody profiles track with HIV-associated neurocognitive disorders (HAND) remains unclear. Here, we comprehensively profiled HIV-specific antibodies across plasma and CSF from 20 antiretroviral therapy (ART) naive or treated persons with HIV. CSF was populated by IgG1 and IgG3 antibodies, with reduced Fc-effector profiles. While ART improved plasma antibody functional coordination, CSF profiles were unaffected by ART and were unrelated to HAND severity. These data point to a functional sieving of antibodies across the blood-brain barrier, providing previously unappreciated insights for the development of next-generation therapeutics targeting the CNS reservoir.

Background and Aims Electrocautery-tip lumen-apposing metal stents (EC-LAMSs) have extended the indications of therapeutic EUS. We aimed to retrospectively evaluate safety and technical and clinical success of a newly developed EC-LAMS, the Hot-Spaxus (Taewoong Medical Co, Gimpo, Korea), for various EUS-guided procedures. Methods We included and retrospectively analyzed consecutive patients at 8 tertiary care referral centers who had undergone EUS interventional procedures using the Hot-Spaxus between October 2018 and February 2021. Results Of 58 included patients (male-to-female, 36:22; mean age, 63.5 ± 14.9 years), 29 had undergone pancreatic fluid collection drainage (50%), 22 (37.9%) biliary drainage for malignant distal obstruction, 3 (5.1%) gallbladder drainage for acute cholecystitis, 3 gastroenteroanastomoses, and 1 (1.7%) pelvic collection drainage. Technical success was achieved in 54 of 58 patients (93.1%) and clinical success in all 58. Adverse events occurred in 6 patients (11.1%): 2 early (3.7%), 1 late (1.8%), and 3 long term (5.6%). The outcomes were similar to those observed in a control group of patients treated with the Hot-Axios (Boston Scientific, Marlborough, Mass, USA), the other available EC-LAMS. Conclusions Our study showed that the novel EC-LAMS has high technical and clinical success rates for various interventional EUS indications. Future multicenter prospective studies will better clarify the role of this new EC-LAMS for different indications.

Background: Radiosurgery has demonstrated good safety and efficacy in the treatment of multiple brain metastases (BMs). However, multi-target dose planning can be challenging and time-consuming. A recently developed real-time inverse treatment planning (IP) by convex optimization has been demonstrated to produce high-quality treatment plans with good conformity and selectivity in single-target plans. We intended to test the capacity of this IP to rapidly generate efficient plans while optimizing the preservation of normal tissue in multiple BM. Methods: Seventy-nine patients (mean age 62.4, age range 22–85) with a total of 272 BMs were treated by Gamma Knife Radiosurgery. All subjects were treated using a forward planning (FP) technique by an expert neurosurgeon. The new Intuitive Plan was applied and able to automatically generate an alternative plan for each patient. All planning variables were collected from the IP to be compared with the corresponding measurements obtained from the FP. A paired sample t test was applied to compare the 2 plans for the following variables: brain volumes receiving 10 Gy (V10) (primary endpoint), and 12 Gy (V12), planning indices (selectivity, coverage, gradient, and Paddick Conformity Index [PCI]), beam-on time (BOT), and integral doses. Additionally, the noninferiority margin for each item was calculated, and the 2 plans were compared for noninferiority using a paired t test. Results: The mean age of patients was 62.4 years old (age range 22–85), with a sex ratio of 1.02. The average number of lesions per patient was 3.4 (range 1–12). The mean prescription dose was 21.46 Gy (range 14–24 Gy). Noninferiority of the IP was concluded for V10, V12, prescription isodose volume, BOT, PCI, and selectivity. The V10 (and V12) was significantly lower with the IP (p < 0.001). These volumes were 8.69 cm3 ± 11.39 and 5.47 cm3 ± 7.03, respectively, for the FP and 7.57 cm3 ± 9.44 and 4.78 cm3 ± 5.86 for the IP. Only the coverage was significantly lower with the IP (−2.3%, p < 0.001), but both selectivity (+17%) and PCI (+15%) were significantly higher with the IP than FP (p < 0.001). Conclusion: This IP demonstrated its capacity to generate multi-target plans rapidly, with a dose to the brain (V10) and BOT noninferior to the one of a human expert planner. These results would benefit from confirmation in a larger prospective series.

Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of liver-related events (LREs). Here, we have assessed the ability of a composite score based on clinical features, metabolic comorbidities, and genetic variants to predict LREs. A total of 546 consecutive patients with NAFLD were recruited and stratified according to the fibrosis-4 (FIB-4) index. LREs were defined as occurrence of hepatocellular carcinoma or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LREs. The UK Biobank was used as the validation cohort, and severe liver disease (incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation) was used as the outcome. LREs were experienced by 58 patients, only one of whom was in the cohort of patients with a FIB-4 score < 1.3. Multivariate Cox regression analysis of 229 patients with a FIB-4 score ≥ 1.3 highlighted clinical variables independently associated with the development of LREs, including older age, low platelet count, low albumin, low high-density lipoprotein cholesterol, certain genetic factors, and interactions between genetic factors and sex or diabetes. The area under the curve (AUC) for the model was 0.87 at 1, 3, and 5 years. Our novel Genetic and Metabolic Staging (GEMS) scoring system was derived from the Cox model linear predictor, ranked from 0 to 10, and categorized into five classes (0-5, 5-6, 6-7, 7-8, and 8-10). The risk of LREs increased from 4% in patients in the best class (GEMS score 0-5) to 91% in the worst (GEMS score 8-10). GEMS score was associated with incident severe liver disease in the study population (hazard ratio, 1.56; 95% confidence interval, 1.48-1.65; P < 0.001) as well as in the UK Biobank cohort where AUCs for prediction of severe liver disease at 1, 3, and 5 years were 0.70, 0.69, and 0.67, respectively. Conclusion: The novel GEMS scoring system has an adequate ability to predict the outcome of patients with NAFLD.

The treatment strategy for thoracolumbar burst fractures is still debated. The aim of this study is to evaluate clinical and radiologic outcomes of a 2-stage strategy with immediate posterior percutaneous instrumentation and delayed anterolateral fusion (group A) versus a single-stage open posterior instrumented fusion (group B).Demographics and clinical and surgical data of patients operated for AO Spine A3 and A4 fractures were prospectively collected. Vertebral height and deformity were evaluated before and after surgery. Visual analog scale score for back pain, Oswestry Disability Index, and 12-Item Short Form Health Survey results for quality-of-life assessment were collected during follow-up.Among the 110 patients enrolled, 66 were allocated to group A and 44 to group B; the most common fractured level was T12 (34%). Postoperative complications were higher in group B, especially the wound infection rate (18% vs. 3%), and pseudomeningocele (14% vs. 0%). The 2-stage approach allowed an average long-term gain of 15.8° at the local kyphosis of fractured vertebra and 5.8° at the regional level (Cobb angle), versus 15.4° and 5.5° in group B. At 2 years follow-up, both groups showed significant functional improvements; however, the visual analog scale and Oswestry Disability Index metrics seemed more favorable for group A patients (P0.0001 vs. P0.003). A complete fusion rate was obtained in 100% of group A vs. 65% of group B.Our study indicates that percutaneous instrumentation and anterior fusion or an expandable cage lead to excellent long-term clinical and radiologic outcomes with a lower complication rate and higher fusion rate than those of open posterior approaches.

International audience; INTRODUCTION: There is a growing interest in personality evaluation in Parkinson's disease (PD), following observations of specific temperaments in PD patients. Therefore, our objective was to evaluate personality dimensions from the Temperament and Character Inventory (TCI) in a cohort of fluctuating PD patients considered for deep brain stimulation. METHODS: Fluctuating PD patients from the PREDISTIM cohort were included. Description of TCI dimensions and comparison with a French normative cohort were performed. Pearson correlations between TCI dimensions and motor, behavioral and cognitive variables were investigated. Structural and internal consistency analysis of the TCI were further assessed. RESULTS: The 570 PD patients presented significant higher scores in Harm Avoidance, Reward Dependence, Persistence, Self-Directedness and Cooperativeness and significant lower scores in Self-Transcendence compared to the French normative cohort; only Novelty Seeking scores were not different. Harm Avoidance and Self-directedness scores were correlated with PDQ-39 total, HAMD, HAMA scores, and anxiolytic/antidepressant treatment. Novelty Seeking scores were correlated with impulsivity. Pearson correlations between TCI dimensions, principal component analysis of TCI sub-dimensions and Cronbach's alpha coefficients showed adequate psychometric proprieties. CONCLUSION: The TCI seems to be an adequate tool to evaluate personality dimensions in PD with good structural and internal consistencies. These fluctuating PD patients also have specific personality dimensions compared to normative French population. Moreover, Harm Avoidance and Self-Directedness scores are associated with anxio-depressive state or quality of life and, and Novelty Seeking scores with impulsivity.

IgG4-related disease (IgG4-RD) is still an underestimated disorder which affects multiple organs, and its recognition as a distinct clinical disease has been only proved in the recent decades. The renal involvement has been documented in approximately 15% of patients with IgG4-RD, and the typical manifestation is a tubulo-interstitial nephritis. The main histological findings in IgG4-RD are typically a dense tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and frequently elevated IgG4 serum levels. Herein we report our atypical and peculiar clinical presentation of an IgG4-related nephropathy (IgG4-RN) and the remarkable response to rituximab (RTX) treatment at the renal imaging with computerized tomography assessment. The current nephrological evidences support the renal function recovery after steroids or steroids plus RTX therapy, even if the renal imaging data are not always shown. In a complex and enigmatic clinical scenario such as the IgG4-RN, both the renal biopsy and the renal imaging before and after the immunosuppressive therapy become mandatory tools to thoroughly define the diagnosis, the management and the response to the immunological therapy.

Gamma Knife radiosurgery (GKRS) inverse dose planning is currently far from competing effectively with the quality of dose planning developed by experienced experts. A new inverse planning (IP) method based on « efficient convex optimization algorithms » is proposed, providing high-quality dose plans in real time. Eighty-six patients treated by GKRS for vestibular schwannomas (VS) were recruited. The treatment plans created by the first author, who has 27 years of experience and has developed and delivered more than 15,000 dose plans, served as reference. A first set of basic constraints determined by default led the IP for an initial real-time dose plan. Additional constraints were interactively proposed by the planner to take other parameters into account. A second optimized plan was then calculated by the IP. The primary endpoint was the Paddick Conformity Index (PCI). The statistical analysis was planned on a non-inferiority trial design. Coverage, selectivity, and gradient indexes, dose at the organ(s) at risk, and 12 Gy isodose line volume were compared. After a single run of the IP, the PCI was shown to be non-inferior to that of the “expert.” For the expert and the IP, respectively, the median coverage index was 0.99 and 0.98, the median selectivity index 0.92 and 0.90, the median gradient index 2.95 and 2.84, the median dose at the modiolus of the cochlea 2.83 Gy and 2.86 Gy, the median number of shots 14.31 and 24.13, and the median beam-on time 46.20 min and 26.77 min. In a few specific cases, advanced tools of the IP were used to generate a second run by adding new constraints either globally (for higher selectivity) or locally, in order to increase or decrease these constraints focally. These preliminary results showed that this new IP method based on « efficient convex optimization algorithms », called IntuitivePlan®, provided high-quality dose plans in real time with excellent coverage, selectivity, and gradient indexes with optimized beam-on time. If the new IP evaluated here is able to compete in real time with the quality of the treatment plans of an expert with extensive radiosurgical experience, this could allow new planners/radiosurgeons with limited or no experience to immediately provide patients with high-quality GKRS for benign and malignant lesions.

Intraparenchymal lung masses inaccessible through bronchoscopy or endobronchial ultrasound guidance pose a diagnostic challenge. Furthermore, some fragile or hypoxic patients may be poor candidates for transbronchial approaches. Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) offers a potential diagnostic approach to lung cancers adjacent to the esophagus. We aimed to evaluate the feasibility, accuracy, and safety of trans-esophageal EUS-FNA/FNB for tissue sampling of pulmonary nodules.We retrospectively analyzed data from patients with pulmonary lesions who underwent EUS-FNA/FNB between March 2015 and August 2021 at eight Italian endoscopic referral centers.A total of 47 patients (36 male; mean age 64.47 ± 9.05 years) were included (22 EUS-FNAs and 25 EUS-FNBs). Overall diagnostic accuracy rate was 88.9% (76.3-96.2%). The sensitivity and diagnostic accuracy were superior for EUS FNB sampling versus EUS-FNA (100% vs. 78.73%); P = 0.05, and (100% vs. 78.57%); P = 0.05, respectively. Additionally, sample adequacy was superior for EUS-FNB sampling versus EUS-FNA (100% vs. 78.5%); P = 0.05. Multivariate logistic regression analysis for diagnostic accuracy showed nodule size at the cutoff of 15 mm (OR 2.29, 1.04-5.5, P = 0.05) and use of FNB needle (OR 4.33, 1.05-6.31, P = 0.05) as significant predictors of higher diagnostic accuracy. There were no procedure-related adverse events.This study highlights the efficacy and safety of EUS-FNA/FNB as a minimally invasive procedure for diagnosing and staging peri-esophageal parenchymal lung lesions. The diagnostic yield of EUS-FNB was superior to EUS-FNA.

Background & Aims Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk for liver-related complications, such as decompensation, hepatocellular carcinoma (HCC), and death; the severity of liver fibrosis and metabolic comorbidities are the main risk factors. A single nucleotide polymorphism in patatin-like phospholipase domain-containing-3 (PNPLA3) gene is associated with higher prevalence of liver damage and HCC, but there are no data from prospective studies of outcomes of patients with this polymorphism. We investigated whether the common rs738409 variant in PNPLA3 gene associates with the occurrence of liver-related events and death in a large cohort of patients with NAFLD. Methods We followed 471 consecutive individuals at a hospital in Italy with a diagnosis of NAFLD based on histologic factors or a diagnosis of compensated NAFLD-related cirrhosis based on clinical factors for at least 6 months, from March 2004 through December 2018. We collected data on the occurrence of hepatic and extrahepatic outcomes, including decompensation and HCC, cardiovascular events and extrahepatic cancers, and overall and liver-related death. We detected the rs738409 G>C polymorphism in DNA from patient blood samples using the TaqMan assay. Results During a median follow-up time of 64.6 months (range 6.1–175 months) 26 cases of decompensation, 13 HCCs, and 16 deaths (12 liver-related) were recorded. All liver-related events, including liver-related death, occurred in patients with F3 fibrosis or cirrhosis. The prevalence of PNPLA3 rs738409 GG, GT, and TT genotypes was 31.8%, 45.6%, and 22.6%, respectively. After adjusting for clinical, metabolic, and histologic risk factors, PNPLA3 C>G variant was associated with a higher risk of decompensation (hazard ratio [HR], 2.10; 95% CI, 1.03–4.29; P = .04), HCC (HR, 2.68; 95% CI, 1.01–7.26; P = .04), and liver-related death (HR, 3.64; 95% CI, 1.18–11.2; P = .02) by multivariate Cox regression analysis. In the subgroup of 162 patients with F3 fibrosis or cirrhosis, we confirmed the independent association between the PNPLA3 variant and decompensation (HR, 2.00; 95% CI, 1.01–3.97; P = .04), HCC (HR, 2.66; 95% CI, 1.02–7.13; P = .04), and liver-related death (HR, 3.64, 95% CI, 1.18–11.2; P = .02). We found no association between PNPLA3 genotype and cardiovascular events, extrahepatic cancers, or overall mortality. Conclusions Patients with NAFLD carrying PNPLA3 rs738409 G>C variant are at higher risk of liver-related events and death.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise. Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed. Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.

Background In a previous article (10.1007/s00701-019-03888-3), preliminary results of a survey, aiming to shed light on the number of surgical procedures performed and assisted during neurosurgery residency in Europe were reported. We here present the final results and extend the analyses. Methods Board-certified neurosurgeons of European Association of Neurosurgical Societies (EANS) member countries were asked to review their residency case logs and participate in a 31-question electronic survey (SurveyMonkey Inc., San Mateo, CA). The responses received between April 25, 2018, and April 25, 2020, were considered. We excluded responses that were incomplete, from non-EANS member countries, or from respondents that have not yet completed their residency. Results Of 430 responses, 168 were considered for analysis after checking in- and exclusion criteria. Survey responders had a mean age of 42.7 ± 8.8 years, and 88.8% were male. Responses mainly came from surgeons employed at university/teaching hospitals (85.1%) in Germany (22.0%), France (12.5%), the United Kingdom (UK; 8.3%), Switzerland (7.7%), and Greece (7.1%). Most responders graduated in the years between 2011 and 2019 (57.7%). Thirty-eight responders (22.6%) graduated before and 130 responders (77.4%) after the European WTD 2003/88/EC came into effect. The mean number of surgical procedures performed independently, supervised or assisted throughout residency was 540 (95% CI 424–657), 482 (95% CI 398–568), and 579 (95% CI 441–717), respectively. Detailed numbers for cranial, spinal, adult, and pediatric subgroups are presented in the article. There was an annual decrease of about 33 cases in total caseload between 1976 and 2019 (coeff. − 33, 95% CI − 62 to − 4, p = 0.025). Variables associated with lesser total caseload during residency were training abroad (1210 vs. 1747, p = 0.083) and female sex by trend (947 vs. 1671, p = 0.111), whereas case numbers were comparable across the EANS countries (p = 0.443). Conclusion The final results of this survey largely confirm the previously reported numbers. They provide an opportunity for current trainees to compare their own case logs with. Again, we confirm a significant decline in surgical exposure during training between 1976 and 2019. In addition, the current analysis reveals that female sex and training abroad may be variables associated with lesser case numbers during residency.

ObjectiveTo clinically characterize patients with anti-metabotropic glutamate receptor (mGluR) 1 encephalitis, to identify prognostic factors, and to study the immunoglobulin G (IgG) subclasses and effects of antibodies on neuronal mGluR1 clusters.MethodsClinical information on new and previously reported patients was reviewed. Antibodies to mGluR1 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays, and their effects on mGluR1 clusters were studied on rat hippocampal neurons.ResultsEleven new patients were identified (10 adults, 1 child);4 were female. In these and 19 previously reported cases (n = 30, median age 55 years), the main clinical manifestation was a subacute cerebellar syndrome that in 25 (86%) patients was associated with behavioral/cognitive changes or other neurologic symptoms. A tumor was found in 3 of 26 (11%). Brain MRI was abnormal in 7 of 19 (37%) at onset and showed cerebellar atrophy in 10 of 12 (83%) at follow-up. Twenty-five of 30 (83%) patients received immunotherapy. Follow-up was available for 25: 13 (52%) had clinical stabilization; 10 (40%) showed significant improvement; and 2 died. At the peak of the disease, patients with bad outcome at 2 years (modified Rankin Scale score > 2, n = 7) were more likely to have higher degree of initial disability, as reflected by a worse Scale for Assessment and Rating of Ataxia score, and more frequent need of assistance to walk. Antibodies to mGluR1 were mainly IgG1 and caused a significant decrease of mGluR1 clusters in cultured neurons.ConclusionsAnti-mGluR1 encephalitis manifests as a severe cerebellar syndrome, often resulting in long-term disability and cerebellar atrophy. The antibodies are pathogenic and cause significant decrease of mGluR1 clusters in cultured neurons.

Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far.A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration.This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

U.S. Army doctor Daniel Smith Lamb was a significant figure in the history of American pathology during its formative years. For 55 years (1865-1920), Lamb performed hundreds of autopsies in and around Washington, D.C. and personally collected over 1,500 gross pathology specimens for the Army Medical Museum. His work began at the close of the Civil War and continued on through World War I, contributing substantially to gross pathological and histological studies that documented wartime pathology, thus further contributing to the training of Army doctors. Specimens he collected also include material from autopsies he conducted on President James Garfield, his assassin Charles Guiteau, and other historical figures. Under the auspices of the Army Medical Museum, he conducted autopsies across the city of Washington for the museum's collection, many of which survive to this day at the National Museum of Health and Medicine. He served under 12 U.S. Army Surgeons General and 11 Museum Curators and was noted to be a steadying influence during a time of constant leadership changes at that institution. Lamb was known throughout Washington, D.C. as an advocate of medical education for African-Americans and women. While working at the Museum, he simultaneously served for 46 years as professor of anatomy at Howard University (1877-1923). He wrote seminal histories of the institutions with which he was associated and in so doing also contributed significantly to the study of the history of medicine.

Autoantibodies are increasingly recognized for their pathogenic potential in a growing number of neurological diseases. While myasthenia gravis represents the prototypic antibody (Ab)-mediated neurological disease, many more disorders characterized by Abs targeting neuronal or glial antigens have been identified over the past two decades. Depletion of humoral immune components including immunoglobulin G (IgG) through plasma exchange or immunoadsorption is a successful therapeutic strategy in most of these disease conditions. The neonatal Fc receptor (FcRn), primarily expressed by endothelial and myeloid cells, facilitates IgG recycling and extends the half-life of IgG molecules. FcRn blockade prevents binding of endogenous IgG to FcRn, which forces these antibodies into lysosomal degradation, leading to IgG depletion. Enhancing the degradation of endogenous IgG by FcRn-targeted therapies proved to be a powerful therapeutic approach in patients with generalized MG and is currently being tested in clinical trials for several other neurological diseases including autoimmune encephalopathies, neuromyelitis optica spectrum disorders, and inflammatory neuropathies. This review illustrates mechanisms of FcRn-targeted therapies and appraises their potential to treat neurological diseases.

INTRODUCTION: In the last years the Hepatitis C virus (HCV) infection was a relevant public health problem due to the large number of affected people worldwide and the impact on hepatic and extrahepatic complications. The availability of direct-acting antivirals (DAAs) and the very high rate of sustained virological response (SVR) after treatment has radically changed the course of HCV chronic infection. EVIDENCE ACQUISITION: We searched PubMed for articles published between January 1, 1995, through December 31, 2020, in English language. EVIDENCE SYNTHESIS: Robust evidence showed a close link between HCV infection and development of cardiovascular disease (CVD), as result of the atherogenic effect of the virus. CONCLUSIONS: This review aimed to explore the evidence linking HCV infection with cardiovascular disease and to evaluate the impact of SVR after DAAs on cardiovascular complications.

Hepatocellular carcinoma is diagnosed in more than half of all cases at unresectable stage when no potentially curative treatments are feasible. Since 2008, sorafenib had represented the only effective first line systemic therapy over the last decade until the approval of lenvatinib, who showed to be non-inferior to sorafenib. Recently, for the first time, a combination of immunotherapy and antiangiogenic drug, atezolizumab plus bevacizumab, was associated with a significantly longer overall survival and progression free survival compared to sorafenib, becoming the new best performing first-line approach for unresectable HCC. After several randomized controlled trials (RCTs) that have attempted to find an effective second-line therapy, regorafenib, cabozantinib, ramucirumab, nivolumab and pembrolizumab represent approved treatments for patients who failed first-line treatment. However, inclusion criteria of second-line RCTs are quite heterogeneous and no direct comparisons exist among these agents. Exciting opportunities have been found either in the combination or in the sequencing of these agents, but the optimal therapeutic strategy for these patients remains elusive. Moreover, the coexistence of cirrhosis and the competing risk of liver decompensation increase the complexity of the assessment of the net health benefit of the available therapeutic approaches. The aim of this review is to summarize the evidence on systemic treatments for unresectable HCC and to explore the future perspectives on this topic.

Background/aim The aim of the study was to investigate boost volume definition, doses, and delivery techniques for rectal cancer dose intensification. Patients and methods An online survey was made on 25 items (characteristics, simulation, imaging, volumes, doses, planning and treatment). Results Thirty-eight radiation oncologists joined the study. Twenty-one delivered long-course radiotherapy with dose intensification. Boost volume was delineated on diagnostic magnetic resonance imaging (MRI) in 18 centres (85.7%), and computed tomography (CT) and/or positron emission tomography-CT in 9 (42.8%); 16 centres (76.2%) performed co-registration with CT-simulation. Boost dose was delivered on gross tumor volume in 10 centres (47.6%) and on clinical target volume in 11 (52.4%). The most common total dose was 54-55 Gy (71.4%), with moderate hypofractionation (85.7%). Intensity-modulated radiotherapy (IMRT) was used in all centres, with simultaneous integrated boost in 17 (80.8%) and image-guidance in 18 (85.7%). Conclusion A high quality of treatment using dose escalation can be inferred by widespread multidisciplinary discussion, MRI-based treatment volume delineation, and radiation delivery relying on IMRT with accurate image-guided radiation therapy protocols.

BACKGROUND AND AIMS Non-alcoholic fatty liver (NAFLD) is a major cause of liver disease worldwide leading also to a higher risk of cardiovascular events. We aimed to evaluate the impact of fatty liver and fibrosis on cardiovascular risk in a general population. METHODS Five hundred and forty-two subjects included in the community-based ABCD (Alimentazione, Benessere Cardiovascolare e Diabete) study were recruited. Steatosis (controlled attenuation parameter > 288 dB/m) and severe fibrosis (low risk, liver stiffness measurement [LSM]

How individuals interpret robots’ actions is a timely question in the context of the general approach to increase robot’s presence in human social environment in the decades to come. Facing robots, people might have a tendency to explain their actions in mentalistic terms, granting them intentions. However, how default or controllable this process is still under debate. In four experiments, we asked participants to choose between mentalistic (intentional) and mechanistic (non-intentional) descriptions to describe depicted actions of a robot in various scenarios. Our results show the primacy of mentalistic descriptions that are processed faster than mechanistic ones (experiment 1). This effect was even stronger under high vs low cognitive load when people had to decide between the two alternatives (experiment 2). Interestingly, while there was no effect of cognitive load at the later stages of the processing arguing for controllability (experiment 3), imposing cognitive load on participants at an early stage of observation resulted in a faster attribution of mentalistic properties to the robot (experiment 4). We discuss these results in the context of the idea that social cognition is a default system.

The anatomical collections at the National Museum of Health and Medicine (NMHM) contain skeletal specimens that highlight the history of military and civilian medicine dating from the American Civil War and the founding of the museum as the Army Medical Museum in 1862. Today, NMHM curates over 6400 gross skeletal specimens consisting primarily of pathological or anomalous single bone elements that display a variety of pathological conditions, including congenital anomalies, neoplasms, healed and unhealed trauma and infectious diseases, and surgical interventions such as amputations and excisions. In an effort to increase accessibility to these pathological specimens, NMHM is collaborating with Virginia Commonwealth University (VCU) and the Laboratory Division of the Federal Bureau of Investigation (FBI) to digitize and disseminate high-quality 3D models via online portals, enabling scholars and educators to manipulate, analyze, and 3D print the models from anywhere in the world. Many institutions with courses in paleopathology and forensic anthropology do not have reference collections or access to museum collections for hands-on teaching. Therefore a digital repository of osteological specimens can provide an unprecedented and unique resource of exemplars for scholars and educators. The sharing of these military medical assets improves historical knowledge and diagnostic capabilities in the fields of medicine and anthropology. This chapter outlines the digitization processes that are being utilized to increase access to these pathological skeletal specimens through multimodal 3D capture.

The non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease as well as the first cause of liver transplantation. NAFLD is commonly associated with metabolic syndrome (MetS), and this is the most important reason why it is extremely difficult to treat this disease bearing in mind the enormous amount of interrelationships between the liver and other systems in maintaining the metabolic health. The treatment of NAFLD is a key point to prevent NASH progression to advanced fibrosis, to prevent cirrhosis and to prevent the development of its hepatic complications (such as liver decompensation and HCC) and even extrahepatic one. A part of the well-known healthy effect of diet and physical exercise in this setting it is important to design the correct pharmaceutical strategy in order to antagonize the progression of the disease. In this regard, the current review has the scope to give a panoramic view on the possible pharmacological treatment strategy in NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver diseases worldwide, involving about 25% of people. NAFLD incorporates a large spectrum of pathological conditions, from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and its complications include hepatic decompensation and hepatocellular carcinoma (HCC). This progression occurs, over many years, in an asymptomatic way, until advanced fibrosis appears. Thus, the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis are key issues. To date, the histological assessment of fibrosis with liver biopsy is the gold standard, but obviously, invasiveness is the greater threshold. In addition, rare but potentially life-threatening complications, poor acceptability, sampling variability and cost maybe restrict its use. Furthermore, due to the epidemic of NAFLD worldwide and several limitations of liver biopsy evaluation, noninvasive assessment tools to detect fibrosis in NAFLD patients are needed.

Liver fibrosis is the main predictor of events in patients with nonalcoholic fatty liver disease (NAFLD),1 and its evolution is characterized by a nonlinear trend2,3 mostly affected by metabolic risk factors, severity of liver inflammation and steatosis, and weight loss.3 The rs738409 C>G common variant in PNPLA3 gene has been associated with severity of fibrosis and risk of liver-related events in NAFLD.4,5 Noninvasive tests as Fibrosis-4 (FIB-4) and liver stiffness measurement (LSM) are useful to rule-out advanced fibrosis and they could be reliable to predict fibrosis progression.2,6 We aimed to evaluate in patients with NAFLD whether PNPLA3 rs738409 C>G variant impacts on fibrosis progression, noninvasively assessed by FIB-4 and LSM.

We report the first case of a patient with severe, intractable Tourette Syndrome with comorbid Obsessive Compulsive disorder, who recovered from both disorders with gamma-knife (GK) stereotactic radiosurgery following deep brain stimulation (DBS). This case highlights the possible role of the internal capsule within the neural circuitries underlying both TS and OCD, and suggests that in cases of treatment-refractory TS and comorbid OCD, bilateral anterior capsulotomy using stereotactic radiosurgery may be a viable treatment option.

Objective According to A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) conservative treatment seems to be superior to any intervention for unruptured brain arteriovenous malformations (AVM). This study aims to evaluate safety and efficacy of upfront and repeated Gamma-Knife Radiosurgery (GKRS) in patients harbouring small AVM fulfilling the inclusion criteria of ARUBA. Methods A retrospective study was conducted to evaluate outcomes of unruptured naive brain AVM with a volume ⩽ 5cc eligible to ARUBA treated by GKRS with at least 3 years of follow-up. Results From 1992 to 2014, 249 patients were fulfilling the inclusion criteria of this study. The median age was 36 years [18-78]. The median treated volume of the nidus was 1.3 cc [0.4-5] and 63% of the AVM were in eloquent areas. Radiosurgery Based AVM score was 1-1.8 (76%), the Spetzler-Martin grade was II-III (73%), and the Virginia Radiosurgery AVM scale was ≤1point (75%). The overall AVM obliteration rate was 77.1% after up to 3 GKRS sessions. The median dose at the margin was 24 Gy [15-25] and the median follow-up was 45 months [36–205]. Eight patients (3.2%) experienced hemorrhage after GKRS, corresponding to a post-GKRS hemorrhage annual rate of 1.03%. Permanent symptomatic radio-induced changes rate was 2% (4 increased seizures, 1 neurological deficit). Conclusion The very low toxicity rate and the high occlusion rate are preaching in favor of upfront and repeated GKRS for unruptured small AVM (≤5cc).

Human-human and human-robot interaction are often compared with the overarching question of the differences in terms of cognitive processes engaged and what can explain these differences. However, research addressing this topic, especially in neuro-imagery, use extremely artificial interaction settings. Also, they neglect a crucial parameter of human social cognition: interaction is an adaptive (rather than fixed) process. Building upon the first fMRI paradigm requiring participants to interact online with both a human and a robot in a dyadic setting, we investigate the differences and changes of brain activity during the two type of interactions in a whole brain analysis. Our results show that, grounding on a common default level, the activity in specific neural regions associated with social cognition (e.g. Posterior Cingulate Cortex) increase in HHI while remaining stable in HRI. We discuss these results regarding the iterative process of deepening the social engagement facing humans but not robots.

Background Intracranial solitary fibrous tumors (ISFTs) are rare mesenchymal neoplasms originating in the meninges and characterized by very different biologic and clinical behaviors. Benign histotypes, such as hemangiopericytomas, are now considered a cellular phenotypic variant of this heterogeneous group of rare spindle-cell tumors. Owing to their rarity and resemblance to other, more common brain tumors, ISFTs are often poorly recognized and remain a diagnostic challenge. Methods We describe a surgical series of 29 patients treated for ISFTs confirmed histologically and through immunohistochemistry. We attempt to provide a focus on the natural history of these pathologies and the need for tailored management. Results This was a retrospective consecutive series of 29 patients with either solitary fibrous tumor (n = 14) or hemangiopericytoma (n = 15) over a 10-year period. Mean follow-up time was 37.71 months. Recurrence rate was 42.9% for solitary fibrous tumors versus 26.7% for hemangiopericytomas. STAT6 expression was 66.7% in hemangiopericytomas versus 42.9% in SFTs. Conclusions Histopathology and immunohistochemical staining (characterized by positive expression of mainly STAT6 but also CD34, Bcl-2 protein, and vimentin) are key in diagnosis and management of ISFTs. Although ISFTs are still considered benign lesions with very rare aggressive evolution, their clinical behavior is largely unpredictable. This study highlights the importance of relying on immunohistochemistry for a thorough definition of the management strategy.

Cardiovascular diseases are the leading life-threatening complications in hemodialysis patients. In this scenario, both tachy-arrhythmias and brady-arrhythmias are involved with related hemodialysis and nonhemodialysis-dependent mechanisms; moreover, those arrhythmias usually occur in different time intervals before sudden cardiac death (SCD). Furthermore, current evidence shows that the presence of advanced chronic kidney disease (CKD) reduces the benefits of implantable cardioverter--defibrillators (ICDs), which increases the risk of both arrhythmic and nonarrhythmic death, especially in patients with advanced stages of heart failure. Notably, patients with advanced CKD show a more severe degree of heart failure compared with mild CKD patients. However, the benefits of the ICD implantation in the primary prevention of hemodialysis patients is still controversial, and by now, no significant benefits have emerged compared with nonhemodialysis-dependent CKD patients. In secondary prevention, hemodialysis patients with ICD implantation have higher mortality rates compared with nonhemodialysis-dependent CKD patients with ICD. On the other hand, most articles include hemodialysis patients with reduced left ventricular ejection fraction, neglecting those with preserved systolic function. This review focuses on the epidemiology of SCD in the setting of hemodialysis and the current evidence on ICD implantation in patients on hemodialysis therapy analyzing novel strategies, which might reduce the risk of ICD placing.

Dogs were frequently employed as laboratory subjects during the era of atomic bomb testing (1950-1980), particularly in studies used to generate predictive data regarding the expected effects of accidental human occupational exposure to radiation. The bulk of these studies were only partly reported in the primary literature, despite providing vital information regarding the effects of radiation exposure on a model mammalian species. Herein we review this literature and summarize the biological effects in relation to the isotopes used and the method of radionuclide exposure. Overall, these studies demonstrate the wide range of developmental and physiological effects of exposure to radiation and radionuclides in a mid-sized mammal.

Background and purpose Consensus criteria for autoimmune limbic encephalitis (ALE) allow for a diagnosis even without neuronal antibodies (Abs), but it remains unclear which clinical features should prompt neuronal Ab screening in temporal lobe epilepsy patients. The aim of the study was to investigate whether patients with temporal lobe seizures associated with additional symptoms or signs of limbic involvement may harbor neuronal Abs, and which clinical features should prompt neuronal Ab screening in these patients. Methods We identified 47 patients from a tertiary epilepsy center with mediotemporal lobe seizures and additional features suggestive of limbic involvement, including either memory deficits, psychiatric symptoms, mediotemporal magnetic resonance imaging (MRI) hyperintensities or inflammatory cerebrospinal fluid (CSF). Neuronal Ab testing was carried out at two independent reference laboratories (Bielefeld-Bethel, Germany, and Barcelona, Spain). All brain MRI scans were assessed by two reviewers independently. Results Temporal lobe seizures were accompanied by memory deficits in 35/46 (76%), psychiatric symptoms in 27/42 (64%), and both in 19/42 patients (45%). Limbic T2/fluid-attenuated inversion recovery signal hyperintensities were found in 26/46 patients (57%; unilateral: n = 22, bilateral: n = 4). Standard CSF studies were abnormal in 2/37 patients (5%). Neuronal Abs were confirmed in serum and/or CSF in 8/47 patients (17%) and were directed against neuronal cell-surface targets (leucine-rich glioma inactivated protein 1: n = 1, contactin-associated protein-2: n = 1, undetermined target: n = 3) or glutamic acid decarboxylase in its 65-kD isoform (n = 3, all with high titers). Compared to Ab-negative patients, those who harbored neuronal Abs were more likely to have uni- or bilateral mediotemporal MRI changes (8/8, 100% vs. 18/38, 47%; p = 0.01, Fisher's exact test). Conclusions In patients with temporal lobe seizures and additional limbic signs, 17% had neuronal Abs affirming ALE diagnosis. Mediotemporal MRI changes were found in all Ab-positive cases and had a positive likelihood ratio of 2.11 (95% confidence interval 1.51-2.95).

Objective Epileptic patients with hypothalamic hamartoma (HH) frequently present cognitive impairments. Surgical techniques aiming at HH can be very efficient for epilepsy relief and cognitive improvement but are also demonstrated to carry a significant risk of additional reduction in memory function in these already disabled patients. Gamma knife radiosurgery (GKS) offers an efficient minimally invasive procedure. We evaluated the effect of stereotactic radiosurgery on cognitive outcome. Methods We designed a prospective single-center case series study. Thirty-nine epileptic patients (median age = 17 years, range = 4-50) with HH underwent preoperative and postoperative testing of intelligence quotient (IQ; all patients), including a working memory component, and other memory function testing (for patients ≥16 years old). All patients were prospectively evaluated and underwent complete presurgical and postsurgical clinical, electrophysiological, endocrinal, and visual assessments. In all patients, the postoperative assessment was performed at least 3 years after radiosurgery. We explored what variables correlate with cognitive outcome. Literature review was done for other surgical techniques and their risks for cognitive complications after surgery. Results No decline was observed in intellectual ability (including working memory) after GKS, and no memory decline was seen in adults. We observed significant improvement (>1 SD in z-score) in working memory index (46%) and processing speed index (35%), as well as improvement in full-scale IQ (24%), verbal comprehension index (11%), perceptual organization index (21%), verbal learning (20%), and visual learning (33%). Before GKS, the probability of seizure cessation was higher in patients with higher cognitive performance. After GKS, the cognitive improvement was significantly higher in the seizure-free patients compared to the non-seizure-free patients. Significance We found clear cognitive improvement in a high percentage of patients but importantly no significant decline in intellectual ability (including working memory) and no decline in memory in adult patients 3 years after GKS. GKS compares favorably to the other surgical techniques in terms of cognitive outcome, with similar seizure freedom.

Xie et al. (1) report that a higher working memory (WM) capacity increases social-distancing compliance, even after accounting for relevant covariates (e.g., mood and personality traits), and that this effect is partly mediated by a facilitating benefit-over-cost analysis about social-distancing practice. In light of these findings, the authors suggest that interventions aiming to increase WM capacity might help to enhance compliance to social-distancing practice in times of crisis. After reanalyzing the data, we suggest that their conclusions should be nuanced with respect to 1) the disproportionate focus on WM capacity relative to other factors that equally explain the outcome and 2) the partial statistical control over factors’ indirect effects on social distancing. … [↵][1]1To whom correspondence may be addressed. Email: medhi.marot{at}etu.uca.fr. [1]: #xref-corresp-1-1

Background Spinal cord compression (SCC) is an uncommon, severe complication of Hodgkin lymphoma (HL), occurring in 0.2% of cases at the onset and in 6% during disease progression. We present a teenager with SCC with clinical onset of HL; her pre-existing neurological abnormalities covered the presence of an epidural mass, which could have misled us. Case presentation A 13-year-old girl presented with a three-month history of lower back pain and degrading ability to walk. She suffered from a chronic gait disorder due to her preterm birth. A magnetic resonance imaging of the spine revealed an epidural mass causing collapse of twelfth thoracic vertebra and thus compression and displacement of the spinal cord. Histological examination with immunohistochemical analysis of the epidural mass demonstrated a classic-type Hodgkin lymphoma. Early pathology-specific treatment allowed to avoid urgent surgery, achieve survival and restore of neurological function. Conclusions Children and adolescents with back pain and neurological abnormalities should be prioritized to avoid diagnostic delay resulting in potential loss of neurological function. SCC requires a prompt radiological assessment and an expert multidisciplinary management.

Odontoid fractures constitute the most common cervical fractures in elderly. External immobilization is the treatment of choice for Type I and III; there is still no wide consensus about the best management of Type II fractures. Observational multicenter study was conducted on a prospectively built database on elderly patients (> 75 years) with Type II odontoid fracture managed conservatively during the last 10 years. All patients underwent CT scan on admission and at 3 months; if indicated, selected patient had CT scan at 6 and 12 months. All patients were clinically evaluated by Neck Disability Index (NDI), Charlson Comorbidity Index (CCI), and American Society of Anaesthesiologists classification (ASA) on admission; NDI was assessed also at 6 weeks, 3, 6, 12, and 24 months; furthermore, a quality of life (QoL) assessment with the SF-12 form was performed at 3 and 12 months. Among the 260 patients enrolled, 177 (68%) were women and 83 (32%) men, with a median age of 83 years. Patients were followed up for a minimum of 24 months: 247 (95%) showed an excellent functional outcome within 6 weeks, among them 117 (45%) showed a good bony healing, whereas 130 (50%) healed in pseudo-arthrosis. The residual 5% were still variably symptomatic at 12 weeks; however, only 5 out of 13 (2% of the total cohort) required delayed surgery. This study showed that a conservative approach to odontoid Type II fracture in elderly is an effective and valid option, resulting in an excellent functional outcome (regardless of bony fusion) in the majority of cases. Failure of conservative treatment can be safely addressed with surgical fixation at a later stage.

Previous studies have shown that experiential avoidance (EA) is associated with physical and psychological well-being in medical and non-medical samples. The aims of the present study were to evaluate the reciprocal association between psychological well-being and EA over time among cardiac rehabilitation (CR) patients with moderately to severely low levels of psychological well-being. Pre-CR data on demographic characteristics, measures of psychological well-being, and cardiac-specific EA were collected from 915 CR patients, as well as post-CR psychological well-being and EA data, from 800 of these patients. A cross-lagged model was estimated to examine the relationship between EA and psychological well-being among patients with moderately to severely low levels of psychological well-being based on questionnaire scores. Both EA and psychological well-being significantly changed during CR and were negatively associated with each other at both pre- and post-CR. Results from cross-lagged structural equation modeling supported a nonreciprocal association between EA and psychological well-being during CR. Pre-CR assessment of EA in patients showing low levels of well-being at the beginning of CR could help to identify patients at risk for worse psychological outcomes. EA could be a promising target of psychological treatments administered during CR.

The purpose of this Individually Randomized Group Treatment Trial was to compare an Acceptance and Commitment Therapy-based (ACT) group intervention and a Cognitive Behavioral Therapy-based (CBT) group intervention for weight loss maintenance in a sample of adult patients with obesity seeking treatment for weight loss. One hundred and fifty-five adults (BMI: Kg/m2 = 43.8 [6.8]) attending a multidisciplinary rehabilitation program for weight loss were randomized into two conditions: ACT and CBT. Demographical, physical, and clinical data were assessed at the beginning of the program (t0), at discharge (t1), and at 6-month follow-up (t2). The following measures were administered: The Acceptance and Action Questionnaire-II (AAQ-II) and the Clinical Outcome in Routine Evaluation-Outcome Measure (CORE-OM). Generalized linear mixed models were performed to assess differences between groups. Moderation effects for gender and Eating Disorders (ED) have been considered. From baseline to discharge, no significant differences between interventions were found, with the only exception of an improvement in the CORE-OM total score and in the CORE-OM subjective wellbeing subscale for those in the CBT condition. From discharge to follow-up, ACT group participants showed significant results in terms of weight loss maintenance, CORE-OM total score, and CORE-OM and AAQ-II wellbeing, symptoms, and psychological problems subscales. Gender moderated the effects of time and intervention on the CORE-OM subscale reporting the risk for self-harm or harm of others. The presence of an eating disorder moderated the effect of time and intervention on the CORE-OM total score, on the CORE-OM symptoms and psychological problems subscales, and on the AAQ-II. Patients who received the ACT intervention were more likely to achieve a ≥5% weight loss from baseline to follow-up and to maintain the weight loss after discharge. The ACT intervention was thus effective in maintaining weight loss over time.

In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonography with or without alpha-fetoprotein (AFP) in patients with advanced fibrosis. Furthermore, the use of non-invasive tools could represent a strategy to implement surveillance performance. In this review, we analyzed the main risk factors of NAFLD-related HCC, the validated screening methods and the future perspectives.

Therapeutic options for end-stage organ failure are often limited to whole organ transplantation. The tolerance or rejection of the transplanted organ is driven by both early non-specific innate and specific adaptive responses. The use of mesenchymal stromal cells (MSCs) is considered a promising tool in regenerative medicine. Human umbilical cord (HUC) is an easily available source of MSCs, without relevant ethical issues. Moreover, Wharton's jelly-derived MSCs (WJ-MSCs), showed consistent immunomodulatory features that may be useful to promote immune tolerance in the host after transplantation. Few data are available on the phenotype of WJ-MSCs in situ. We investigated the expression of immune-related molecules, such as HLAs, IDO, CD276/B7-H3, and others, both in situ (HUC) and in in vitro-cultured WJ-MSCs. Morphological and biochemical techniques were used to define the expression of such molecules. In addition, we focused on the possible role of CD276/B7-H3 on T cells proliferation inhibition. We assessed CD276/B7-H3 expression by WJ-MSCs both in situ and alongside cell culture. WJ-MSCs were able to suppress T cell proliferation in mixed lymphocyte reaction (MLR). Moreover, we describe for the first time a specific role for CD276/B7-H3, since the immunomodulatory ability of WJ-MSCs was abolished upon anti-CD276/B7-H3 antibody addition to the MLR. These results further detail the immune regulation properties and tolerance induction exerted by human WJ-MSCs, in particular pointing to CD276/B7-H3 as one of the main involved factors. These data further suggest WJ-MSCs as potent tools to modulate local immune response in "support-type" regenerative medicine approaches.

The benefits from cardiovascular implantable electronic devices (CIED) implantation in hemodialysis (HD) patients are still far to be thoroughly defined, especially on primary prevention. In addition, CIED placement is not a risk-free procedure, because it could be followed by a not negligible burden of complications that could compromise the health and the vascular access of HD patients. In fact, the arteriovenous fistula (AVF) dysfunction following CIED implantation is usually due to a hemodynamically significant alteration of blood flow. This condition could lead to a potential decrease of dialysis efficacy and a raised risk of thrombosis of both the central vein and the efferent vein of the AVF.The pathological pathway that leads to AVF dysfunction after CIED implantation may involve the irritating actions of the CIED and their leads to the vascular wall in HD patients that are more prone to show previous vascular diseases.The aim of this review is to focus the physiopathology of the CIED-induced AVF dysfunction, the current treatment strategies and the novel perspectives that could be taken into consideration and offered to the HD population to preserve both their AVF and their quality of life.

Altres ajuts: Project Integrative of Excellence (PIE 16/00014); Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; #CB15/00010); "La Caixa" Foundation (ID 100010434, under the agreement LCF/PR/HR17/52150001); The Safra Foundation (J.D.), and Fundació CELLEX (J.D.); Centres de Recerca de Catalunya (CERCA) program by La Generalitatde Catalunya (J.R.); Pla Estratègic de Recerca i Innovació en Salut (PERIS, SLT002/16/00346, J.P.); Basque Government Doctoral Fellowship Program (PRE_ 2019_1_0255; E.M.) To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies. Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects. In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood. In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy.

The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by Ecto-5ʹ-nucleotidase/CD73 to immunosuppressive adenosine. Directly inhibiting the enzymatic function of CD39 via an antibody has the potential to unleash an immune-mediated anti-tumor response via two mechanisms: 1) increasing the availability of immunostimulatory extracellular ATP released by damaged and/or dying cells, and 2) reducing the generation and accumulation of suppressive adenosine within the TME. Tizona Therapeutics has engineered a novel first-in-class fully human anti-CD39 antibody, TTX-030, that directly inhibits CD39 ATPase enzymatic function with sub-nanomolar potency. Further characterization of the mechanism of inhibition by TTX-030 using CD39+ human melanoma cell line SK-MEL-28 revealed an uncompetitive allosteric mechanism (α

Introduction Evidence exists for the role of the hypothalamic hamartoma’s topography as a determinant for the clinical presentation. How the hamartoma relation to the hypothalamic structures can make clinical presentations, severity and surgery outcomes different from patient to patient is largely unknown. Our aim was to analyze the effect of fine anatomical topography on clinical spectrum and radiosurgery outcome. Methods Forty-eight epileptic patients with hypothalamic hamartoma were treated by Gamma Knife Surgery and were reviewed for fine topography and morphology using magnetic resonance neuroimaging. We evaluated different topographic patterns; contact to prominent structures (the mammillary body, tuber cinereum and pituitary stalk), the degree of involvement within sagittally-oriented regions, (mammillary, tuberal, and supra optic) coronally-oriented zones (periventricular, medial, and lateral), lesion dimensions (length, width, and height),and volumes (total, intra-hypothalamic, and extra-hypothalamic volumes). This data were statistically analysed for correlation with all clinical variables and epilepsy surgery outcome. We reviewed all the classification protocols in the literature. Results Focal onset impaired awareness seizures started at an earlier age of onset with larger hypothalamic hamartoma volume and dimensions. Lateral extension within the hypothalamus was associated with more severe epilepsy, higher seizure frequency, more severe psychiatric comorbidity, hetero-aggression, hyperkinesia, and school difficulties. Presence of precocious puberty was positively correlated to anterior-posterior extension; tuberal region involvement, hypothalamic hamartoma volume, and type III-VI. Larger hypothalamic hamartoma presented precocious puberty at an earlier age of onset. After Gamma Knife Surgery, epilepsy outcome was better and rapid when lesion is smaller. Post-radiosurgical transient increased seizures were present when the mammillary region was more involved. Conclusion Clinical presentation of epileptic hypothalamic hamartoma is significantly affected by fine topography patterns and invaded hypothalamic areas. Gamma Knife Radiosurgery effect is better and rapid in smaller hamartoma (Type I-III) and seizure outcome was not affected by the invaded hypothalamic areas.

Dear Editor,Covid-19 infection is causing a severe health emergency all over the world. In Italy the first Covid-19 patient was diagnosed on 21 February 2020. The number of cases has dramatically i...