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Background: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. Objective: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. Methods: We enrolled 676 participants: a training cohort (n=346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n=330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. Results: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC]=0.93 [95% confidence interval, 0.89–0.98] and AUC=0.97 [0.93–1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC=0.92 [0.87–0.97]; PSP-P versus controls, AUC=0.94 [0.90–0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC=0.91 [0.84–0.97]). A strong correlation (r=0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. Conclusions: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The growing impact of extreme weather phenomena in different areas of the globe and the empirical evidence of the economic, social and environmental damage caused by global warming, urgently, calls for appropriate responses. Urban areas are part of the planet where the greatest social costs of global warming will be paid, and so it seems very important to take on the issue of climate change adaptation in land use and urban planning. In several cities, new planning instruments and projects have been developed that highlight a profound cultural change and approach to urban planning that we have known for the last two centuries. The lack of adequate management measures concerning increasingly frequent disasters lead to environmental, economic (e.g., exposure to risks and costs associated with extreme weather events), and social impacts (e.g., health impacts related to air quality, heat islands, etc., with an increase in chronic ailments and various diseases). As recognised by Sustainable Development Goal 11 (SDG11), the United Nations (UN) New Urban Agenda and the World Forum on Urban Forests, green and blue infrastructures (GBIs) and nature-based solutions (NBSs) can reduce these impacts by promoting population health shaping as an adaptation strategy to climate change. GBIs and NBSs for the sustainability, resilience and well-being of urban communities are increasingly considered efficient strategies to mitigate climate change-dependent disasters, but they are not yet considered in a systematic way within urban planning. The paper aims to investigate the role of GBIs and NBSs in the resilience of cities and urban communities against the risks associated with the climate crisis. Furthermore, the paper suggests how GBI and NBS could be interwoven into visions, urban planning, and design to create resilient places for people and resilient community behaviours.

Progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH) share several clinical and radiological features, making the differential diagnosis challenging. In this study, we aimed to differentiate between these two diseases using a machine learning approach based on cortical thickness and volumetric data.Twenty-three iNPH patients, 50 PSP patients and 55 control subjects were enrolled. All participants underwent a brain 3T-MRI, and cortical thickness and volumes were extracted using Freesurfer 6 on T1-weighted images and compared among groups. Finally, the performance of a machine learning approach with random forest using the extracted cortical features was investigated to differentiate between iNPH and PSP patients.iNPH patients showed cortical thinning and volume loss in the frontal lobe, temporal lobe and cingulate cortex, and thickening in the superior parietal gyrus in comparison with controls and PSP patients. PSP patients only showed mild thickness and volume reduction in the frontal lobe, compared to control subjects. Random Forest algorithm distinguished iNPH patients from controls with AUC of 0.96 and from PSP patients with AUC of 0.95, while a lower performance (AUC 0.76) was reached in distinguishing PSP from controls.This study demonstrated a more severe and widespread cortical involvement in iNPH than in PSP, possibly due to the marked lateral ventricular enlargement which characterizes iNPH. A machine learning model using thickness and volumetric data led to accurate differentiation between iNPH and PSP patients, which may help clinicians in the differential diagnosis and in the selection of patients for shunt procedures.

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ_PRS than controls [F(4,1319) = 20.4, P

Imaging studies investigating cerebellar gray matter (GM) in essential tremor (ET) showed conflicting results. Moreover, no large study explored the cerebellum in ET patients with resting tremor (rET), a syndrome showing enhanced blink reflex recovery cycle (BRrc).To investigate cerebellar GM in ET and rET patients using voxel-based morphometry (VBM) analysis.Seventy ET patients with or without resting tremor and 39 healthy controls were enrolled. All subjects underwent brain 3 T-MRI and BRrc recording. We compared the cerebellar GM volumes between ET (n = 40) and rET (n = 30) patients and controls through a VBM analysis. Moreover, we investigated possible correlations between cerebellar GM volume and R2 component of BRrc.rET and ET patients had similar disease duration. All rET patients and none of ET patients had enhanced BRrc. No differences in the cerebellar volume were found when ET and rET patients were compared to each other or with controls. By considering together the two tremor syndromes in a large patient group, the VBM analysis showed bilateral clusters of reduced GM volumes in Crus II in comparison with controls. The linear regression analysis in rET patients revealed a cluster in the left Crus II where the decrease in GM volume correlated with the R2BRrc increase.Our study suggests that ET and rET are different tremor syndromes with similar mild cerebellar gray matter involvement. In rET patients, the left Crus II may play a role in modulating the brainstem excitability, encouraging further studies on the role of cerebellum in these patients.

BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Este artículo resumirá los principales sustratos de las psicosis asociadas al cannabis. En primer lugar, se introducirá un marco epistemológico para apoyar la existencia de una “psicosis asociada al cannabis” específica como entidad nosológica distinta de la esquizofrenia idiopática y otros trastornos psicóticos. A continuación, se examinarán las principales características clínicas de las psicosis asociadas al cannabis. Por último, se presentarán los correlatos biológicos y genéticos de las psicosis asociadas al cannabis.

This paper will summarise the main substrates of cannabis-associated psychoses. First, an epistemological framework will be introduced to support the existence of a specific ‘cannabisassociated psychosis’ as a nosological entity distinct from idiopathic schizophrenia and other psychotic disorders. Then, the main clinical characteristics of cannabis-associated psychoses will be examined. Finally, the biological and genetic correlates of cannabis-associated psychosis will be presented.

Introduction There is some debate on the relationship between essential tremor with rest tremor (rET) and the classic ET syndrome, and only few MRI studies compared ET and rET patients. This study aimed to explore structural cortical differences between ET and rET, to improve the knowledge of these tremor syndromes. Methods Thirty-three ET patients, 30 rET patients and 45 control subjects (HC) were enrolled. Several MR morphometric variables (thickness, surface area, volume, roughness, mean curvature) of brain cortical regions were extracted using Freesurfer on T1-weighted images and compared among groups. The performance of a machine learning approach (XGBoost) using the extracted morphometric features was tested in discriminating between ET and rET patients. Results rET patients showed increased roughness and mean curvature in some fronto-temporal areas compared with HC and ET, and these metrics significantly correlated with cognitive scores. Cortical volume in the left pars opercularis was also lower in rET than in ET patients. No differences were found between ET and HC. XGBoost discriminated between rET and ET with mean AUC of 0.86 ± 0.11 in cross-validation analysis, using a model based on cortical volume. Cortical volume in the left pars opercularis was the most informative feature for classification between the two ET groups. Conclusion Our study demonstrated higher cortical involvement in fronto-temporal areas in rET than in ET patients, which may be linked to the cognitive status. A machine learning approach based on MR volumetric data demonstrated that these two ET subtypes can be distinguished using structural cortical features.

the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI) and FP7-HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN); and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS) (...), Pignon B, Peyre H, Ayrolles A, Kirkbride JB, Jamain S, Ferchiou A, Richard JR, Baudin G, Tosato S, Jongsma H, de Haan L, Tarricone I, Bernardo M, Velthorst E, Braca M, Arango C, Arrojo M, Bobes J, Del-Ben CM, Di Forti M, Gayer-Anderson C, Jones PB, La Cascia C, Lasalvia A, Menezes PR, Quattrone D, Sanjuán J, Selten JP, Tortelli A, Llorca PM, van Os J, Rutten BPF, Murray RM, Morgan C, Leboyer M, Szöke A, Schürhoff F

The EU-GEI Project was funded by grant agreement Health-F2-2010-241909 from the European Community’s Seventh Framework program. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation, D'Andrea, Giuseppe; Lal, Jatin; Tosato, Sarah;Gayer-Anderson, Charlotte;Jongsma, Hannah E.;Stilo, Simona A.; van der Ven, Els;Quattrone, Diego;Velthorst, Eva;Berardi, Domenico;Rossi Menezes, Paulo; Arango, Celso; Parellada, Mara; Lasalvia, Antonio; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Sideli, Lucia; Bobes, Julio; Bernardo, Miguel; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Marta Del-Ben, Cristina; Tripoli, Giada; Llorca, Pierre-Michel; de Haan, Lieuwe; Selten, Jean-Paul; Tortelli, Andrea; Szoke, Andrei; Muratori, Roberto; Rutten, Bart P.; van Os, Jim; Jones, Peter B.; Kirkbride, James B.; Murray, Robin M.; di Forti, Marta; Tarricone, Ilaria; Morgan, Craig

Background and Objectives: Patients undergoing cystoscopy can experience discomfort or pain during the procedure. In some cases, a urinary tract infection (UTI) with storage lower urinary tract symptoms (LUTS) may occur in the days following the procedure. This study aimed to assess the efficacy of D-mannose plus Saccharomyces boulardii in the prevention of UTIs and discomfort in patients undergoing cystoscopy. Materials and Methods: A single-center prospective randomized pilot study was conducted between April 2019 and June 2020. Patients undergoing cystoscopy for suspected bladder cancer (BCa) or in the follow-up for BCa were enrolled. Patients were randomized into two groups: D-Mannose plus Saccharomyces boulardii (Group A) vs. no treatment (Group B). A urine culture was prescribed regardless of symptoms 7 days before and 7 days after cystoscopy. The International Prostatic Symptoms Score (IPSS), 0–10 numeric rating scale (NRS) for local pain/discomfort, and EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) were administered before cystoscopy and 7 days after. Results: A total of 32 patients (16 per group) were enrolled. No urine culture was positive in Group A 7 days after cystoscopy, while 3 patients (18.8%) in Group B had a positive control urine culture (p = 0.044). All patients with positive control urine culture reported the onset or worsening of urinary symptoms, excluding the diagnosis of asymptomatic bacteriuria. At 7 days after cystoscopy, the median IPSS of Group A was significantly lower than that of Group B (10.5 vs. 16.5 points; p = 0.021), and at 7 days, the median NRS for local discomfort/pain of Group A was significantly lower than that for Group B (1.5 vs. 4.0 points; p = 0.012). No statistically significant difference (p > 0.05) in the median IPSS-QoL and EORTC QLQ-C30 was found between groups. Conclusions: D-Mannose plus Saccharomyces boulardii administered after cystoscopy seem to significantly reduce the incidence of UTI, the severity of LUTS, and the intensity of local discomfort.

Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Background: Rest tremor (RT) can be observed in several positions (seated, standing, lying down) but it is unknown whether the tremor features may vary across them. This study aimed to compare the RT electrophysiological features across different positions in tremor-dominant Parkinson's disease (PD) and essential tremor plus (ET with RT, rET). Methods: We consecutively enrolled 90 tremor-dominant PD and 24 rET patients. The RT presence was evaluated in three positions: with the patient seated, the arm flexed at 90°, the forearm supported against gravity, and the hand hanging down from the chair armrest (hand-hanging position), in lying down supine and in standing position. RT electrophysiological features (amplitude, frequency, burst duration, pattern) were compared between the two patient groups and across the different positions. Results: All PD and rET patients showed RT in hand-hanging position. Supine and standing RT were significantly more common in PD (67.8% and 75.6%, respectively) than in rET patients (37.5% and 45.8%, respectively). RT amplitude, frequency and pattern were significantly different between groups in hand-hanging position whereas only pattern was significantly different between PD and rET in both standing and supine positions. In each patient group, all RT electrophysiological features did not significantly vary across different recording positions (p > 0.05). Discussion: In our study, PD and rET showed RT in hand-hanging, supine, and standing positions. RT pattern was the only electrophysiological feature significantly different between PD and rET patients in all these positions, enabling clinicians to perform the RT analysis for diagnostic purposes in different tremor positions.

Objective: Comorbid depression is quite common in early psychosis and specifically related to suicidal behavior and poor long-term outcomes. However, Depressive Symptoms (DS) are often neglected in both research and treatment, especially at the psychosis onset. The goals of this investigation were: (a) to longitudinally explore DS levels in patients with First Episode Psychosis (FEP) during 24 months of follow-up, and (b) to investigate the associations of DS with psychopathology and intervention components of an “Early Intervention in Psychosis” (EIP) program across the follow-up period. Method: The Global Assessment of Functioning (GAF) and the Positive And Negative Syndrome Scale (PANSS) were completed by 266 FEP subjects. A linear regression analysis with DS as the dependent parameter and psychopathological and treatment characteristics as independent variables was performed (both at baseline and across the follow-up period). Results: DS had enduring associations with PANSS “Positive Symptoms” and “Negative Symptoms” subscores. During the investigation, FEP subjects significantly improved their DS severity levels. This was related to the number of individual psychotherapy meetings supplied within the EIP protocol, as well as to a higher antidepressant dose and a lower antipsychotic dose prescribed during the follow-up. Conclusions: DS are quite prominent in FEP, even at the recruitment time in EIP services. Nevertheless, DS severity tends to diminish overtime, especially with the provision of specialized EIP treatments.

This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant [agreement HEALTH-F2-2009-241909 (Project EU-GEI)], São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London and the Wellcome Trust (grant 101272/Z/12/Z)., Tripoli, G., Quattrone, D., Ferraro, L., Gayer-Anderson, C., Rodriguez, V., La Cascia, C., La Barbera, D., Sartorio, C., Seminerio, F., Tarricone, I., Berardi, D., Szöke, A., Arango, C., Tortelli, A., Llorca, P.-M., De Haan, L., Velthorst, E., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Selten, J.-P., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., Lasalvia, A., Tosato, S., Richards, A., O'donovan, M., Rutten, B.P.F., Os, J.V., Morgan, C., Sham, P.C., Murray, R.M., Murray, G.K., Di Forti, M.

Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B=-0.12, 95% C.I. -0.18, -0.06, p

Objective. To study left ventricular (LV) function and blood pressure (BP) at a long-term follow-up in women after severe pre-eclampsia. Design. In this single-centre, cross-sectional study, 96 patients were eligible for inclusion. LV function was examined by transthoracic echocardiography including tissue Doppler echocardiography and speckle tracking. BP was measured at rest using repeated non-invasive techniques. Results. We compared 36 patients with early-onset and 33 patients with late-onset pre-eclampsia with 28 healthy controls. Mean age (40 ± 3 years) and median time since delivery (7 ± 2 years) were similar across the study groups. The patients had 18% higher systolic BP (139 ± 15 mmHg) and 24% higher diastolic BP (87 ± 19 mmHg) than controls (p

Spheroid image analysis, 3D invasion image analysis and antibodies list.

List of primary hits

In vivo imaging of SK-N-BE(2) tumor growth in NB orthotopic mice.

Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Mol Cancer Ther; 17(7); 1405–15. ©2018 AACR.

Validation of candidate FDA-approved drugs.

In vivo imaging of IMR-32 tumor growth in NB orthotopic mice.

Cell cycle and clonogenic profiles after treatments with ponatinib and axitinib.

AbtractStudies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = p < 0.001; neglect: OR = 2.27; p =

Background and purpose: Growing evidence suggests that Machine Learning (ML) models can assist the diagnosis of neurological disorders. However, little is known about the potential application of ML in diagnosing idiopathic REM sleep behavior disorder (iRBD), a parasomnia characterized by a high risk of phenoconversion to synucleinopathies. This study aimed to develop a model using ML algorithms to identify iRBD patients and test its accuracy. Methods: Data were acquired from 32 participants (20 iRBD patients and 12 controls). All subjects underwent a video-polysomnography. In all subjects, we measured the components of heart rate variability (HRV) during 24 h recordings and calculated night-to-day ratios (cardiac autonomic indices). Discriminating performances of single HRV features were assessed. ML models based on Logistic Regression (LR), Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) were trained on HRV data. The utility of HRV features and ML models for detecting iRBD was evaluated by area under the ROC curve (AUC), sensitivity, specificity and accuracy corresponding to optimal models. Results: Cardiac autonomic indices had low performances (accuracy 63–69%) in distinguishing iRBD from control subjects. By contrast, the RF model performed the best, with excellent accuracy (94%), sensitivity (95%) and specificity (92%), while XGBoost showed accuracy (91%), specificity (83%) and sensitivity (95%). The mean triangular index during wake (TIw) was the best discriminating feature between iRBD and HC, with 81% accuracy, reaching 84% accuracy when combined with VLF power during sleep using an LR model. Conclusions: Our findings demonstrated that ML algorithms can accurately identify iRBD patients. Our model could be used in clinical practice to facilitate the early detection of this form of RBD.

To assess if the severity of nigrostriatal innervation loss affects the functional connectivity (FC) of the sensorimotor cortico-striato-thalamic-cortical loop (CSTCL) in Parkinson’s Disease (PD), Resting-State functional MRI and 18F-DOPA PET data, simultaneously acquired on a hybrid PET/MRI scanner, were retrospectively analyzed in 39 PD and 16 essential tremor patients. Correlations between posterior Putamen DOPA Uptake (pPDU) and the FC of the main CSTCL hubs were assessed separately in the two groups, analyzing the differences between the two groups by a group-by-pPDU interaction analysis of the resulting clusters’ FC. Unlike in essential tremor, in PD patients pPDU correlated inversely with the FC of the thalamus with the sensorimotor cortices, and of the postcentral gyrus with the dorsal cerebellum, and directly with the FC of pre- and post-central gyri with both the superior and middle temporal gyri and the paracentral lobule, and of the caudate with the superior parietal cortex. The interaction analysis confirmed the significance of the difference between the two groups in these correlations. In PD patients, the post-central cortex FC, in the clusters correlating directly with pPDU, negatively correlated with both UPDRS motor examination score and Hoehn and Yahr stage, independent of the pPDU, suggesting that these FC changes contribute to motor impairment. In PD, nigrostriatal innervation loss correlates with a decrease in the FC within the sensorimotor network and between the sensorimotor network and the superior temporal cortices, possibly contributing to motor impairment, and with a strengthening of the thalamo-cortical FC, that may represent ineffective compensatory phenomena.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.

Previous researchers have argued that material objects reproduce institutional logics on the basis of their durability, immutability and mobility. In this paper we analyse material objects that secure logics not because they reveal meanings and significations, but because they allow individuals and groups to confront the mystery of institutional values. Drawing on extensive historical sources, we analyse a small material object, a book entitled The Spiritual Exercises, and investigate the institutionalization of a practice for discovering what cannot be rendered material, the ineffable mystery of God’s will, as key component of the Jesuit beliefs system. We argue that religious logics require objects that present, rather than resolve, the mystery of institutional values. We extend the literature on institutional logics by considering how mystery enables institutions and their logics to embrace difference, adapt and endure for centuries. Our paper shows that institutional values and goods are ontologically mysterious no-things, ready to be interrogated through objects and procedural logics.

Funder: FP7 Ideas: European Research Council; doi: http://dx.doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2010-241909, Purpose: The EUropean Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study contains an unparalleled wealth of comprehensive data that allows for testing hypotheses about (1) variations in incidence within and between countries, including by urbanicity and minority ethnic groups; and (2) the role of multiple environmental and genetic risk factors, and their interactions, in the development of psychotic disorders. Methods: Between 2010 and 2015, we identified 2774 incident cases of psychotic disorders during 12.9 million person-years at risk, across 17 sites in 6 countries (UK, The Netherlands, France, Spain, Italy, and Brazil). Of the 2774 incident cases, 1130 cases were assessed in detail and form the case sample for case–control analyses. Across all sites, 1497 controls were recruited and assessed. We collected data on an extensive range of exposures and outcomes, including demographic, clinical (e.g. premorbid adjustment), social (e.g. childhood and adult adversity, cannabis use, migration, discrimination), cognitive (e.g. IQ, facial affect processing, attributional biases), and biological (DNA via blood sample/cheek swab). We describe the methodology of the study and some descriptive results, including representativeness of the cohort. Conclusions: This resource constitutes the largest and most extensive incidence and case–control study of psychosis ever conducted.

Introduction: Hyper-religiosity has been reported in patients affected by frontotemporal dementia (FTD) with asymmetrical, predominantly right-sided frontotemporal atrophy. Case report: We report a FTD patient carrying a double genetic variant (p.Cys139Arg and c.*78C > T) in the progranulin (GRN) gene who showed an unusual clinical phenotype characterized by hyper-religiosity behavior and visual hallucinations with exclusively religious content. Noteworthy, this patient exhibited a slow clinical and radiological rate of disease progression and a predominantly left-sided frontotemporal atrophy. Discussion and conclusion: The simultaneous presence of these GRN variants in our FTD patient with predominant atrophy in the left (dominant) hemisphere could determine the unusual phenotype with hyper-religiosity and visual hallucinations with exclusively religious content and influence the slow rate of disease progression.

Idiopathic normal pressure hydrocephalus (iNPH) shares clinical and radiological features with progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD). Corpus callosum (CC) involvement in these disorders is well established on structural MRI and diffusion tensor imaging (DTI), but alterations overlap and lack specificity to underlying tissue changes. We propose a semi-automated approach to assess CC integrity in iNPH based on the spatial distribution of DTI-derived principal diffusion direction orientation (V1). We processed DTI data from 121 subjects (Site1: iNPH = 23, PSP = 27, controls = 14; ADNI: AD = 35, controls = 22) to obtain V1, fractional anisotropy (FA) and mean diffusivity (MD) maps. To increase the estimation accuracy of DTI metrics, analyses were restricted to the midsagittal CC portion (± 6 slices from midsagittal plane). Group-wise comparison of normalized altered voxel count in midsagittal CC was performed using Kruskal–Wallis tests, followed by post hoc comparisons (Bonferroni-corrected p

The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

Background and Objectives: Multiparametric magnetic resonance imaging (mpMRI) of the prostate and prostate-specific membrane antigen positron emission tomography (PSMA PET) are some examples of how the advancement of imaging techniques have revolutionized the diagnosis, staging, and consequently management of patients with prostate cancer (PCa). Although with less striking results, novel radiological modalities have also been proposed for bladder cancer (BCa) in recent years. Micro-ultrasound (MUS) is an imaging examination characterized by high real-time spatial resolution, recently introduced in the urological field. This article aimed to describe the current evidence regarding the application of MUS for the diagnosis and staging of PCa and BCa. Materials and Methods: We designed a narrative review. A comprehensive search in the MEDLINE, Scopus, and Cochrane Library databases was performed. Articles in English-language and published until July 2022 were deemed eligible. Retrospective and prospective primary clinical studies, as well as meta-analyses, were included. Results: MUS-guided prostate biopsy showed high sensitivity (0.91, 95% CI, 0.79–0.97) in the diagnosis of clinically significant PCa (csPCa). It was associated with a higher detection rate of csPCa than a systematic biopsy (1.18, 95% CI 0.83–1.68). No significant difference was found between MUS and mpMRI-guided biopsy in the total detection of PCa (p = 0.89) and in the detection of Grade Groups ≥ 2 (p = 0.92). The use of MUS to distinguish between non-muscle-invasive and muscle-invasive BCa was described, highlighting an up-staging with MUS only in a minority of cases (28.6%). Conclusions: Promising findings have emerged regarding the feasibility and accuracy of MUS in the diagnosis and staging of PCa and BCa. However, the available evidence is limited and should be considered preliminary.

This study aimed to investigate the structural covariance between the striatum and large-scale brain regions in patients with vascular parkinsonism (VP) compared to Parkinson’s disease (PD) and control subjects, and then explore the relationship between brain connectivity and the clinical features of our patients. Forty subjects (13 VP, 15 PD, and 12 age-and-sex-matched healthy controls) were enrolled in this study. They each underwent a careful clinical and neuropsychological evaluation, DAT-SPECT scintigraphy and 3T MRI scan. While there were no differences between PD and VP in the disease duration and severity, nor in terms of the DAT-SPECT evaluations, VP patients had a reduction in structural covariance between the bilateral corpus striatum (both putamen and caudate) and several brain regions, including the insula, thalamus, hippocampus, anterior cingulate cortex and orbito-frontal cortex compared to PD and controls. VP patients also showed lower scores on several neuropsychological tests. Interestingly, in the VP group, structural connectivity alterations were significantly related to cognitive evaluations exploring executive functions, memory, anxiety and depression. This compelling evidence suggests that structural disconnection in the basal ganglia circuits spreading in critical cortical regions may be involved in the pathophysiology of cognitive impairment in VP.

Intravesical chemotherapy may cause chemical cystitis and related lower urinary tract symptoms (LUTS). The aims of this study were to evaluate the efficacy and safety of an oral preparation of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin (Ialuril® Soft Gels) to reduce the severity of LUTS in patients with a history of bladder cancer (BCa) undergoing intravesical chemotherapy. We designed a monocentric, randomized, double-blind, placebo-controlled pilot trial. Patients referred to our institute between November 2016 and March 2018 were enrolled. All subjects had non-muscle-invasive BCa and received intravesical chemotherapy with mitomycin C (MMC). Patients were randomized 1:1 in two groups (intervention vs. control). All subjects underwent oral administration (Ialuril® Soft Gels or placebo) starting one week before the first weekly instillation and ending 30 days after the last one, subsequently starting one week before each monthly instillation and ending 14 days after it. International prostate symptom score (IPSS) and 0-100 visual analogue scale (VAS) were used to assess the efficacy of the treatment. Adverse events were also described. Patients were evaluated at baseline and after 1, 4, 7, and 13 months of intravesical chemotherapy. A total of 34 patients were enrolled. The median IPSS score was significantly lower in the intervention group compared to the control group at 4 (13 vs. 17 points; p = 0.038), 7 (10 vs. 18 points; p < 0.001), and 13 (10 vs. 17 points; p = 0.002) months. The median VAS score was significantly lower in the intervention group compared to the control group at 7 (22 vs. 37 points; p = 0.021) and 13 (20 vs. 35 points; p = 0.024) months. No AE specifically related to supplement or placebo was recorded. Oral formulation of HA, CS, quercetin, and curcumin could be an effective and safe supportive therapy against chemical cystitis in patients receiving intravesical chemotherapy for BCa.

Background There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. Methods We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. Results We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. Conclusions An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

The clinical differential diagnosis between Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) is often challenging. The description of milder PSP phenotypes strongly resembling PD, such as PSP-Parkinsonism, further increased the diagnostic challenge and the need for reliable neuroimaging biomarkers to enhance the diagnostic certainty. This review aims to summarize the contribution of a relatively simple and widely available imaging technique such as MR planimetry in the differential diagnosis between PD and PSP, focusing on the recent advancements in this field. The development of accurate MR planimetric biomarkers, together with the implementation of automated algorithms, led to robust and objective measures for the differential diagnosis of PSP and PD at the individual level. Evidence from longitudinal studies also suggests a role of MR planimetry in predicting the development of the PSP clinical signs, allowing to identify PSP patients before they meet diagnostic criteria when their clinical phenotype can be indistinguishable from PD. Finally, promising evidence exists on the possible association between MR planimetric measures and the underlying pathology, with important implications for trials with new disease-modifying target therapies.

Introduction Indocyanine green (ICG) is commonly used to visualize cerebral vasculature, particularly in the management of cerebral aneurysms. There have also been attempts to use ICG for visualization of tumors. Injection of ICG followed by immediate fluorescence microscopy is limited by the short time window for imaging and administration and restricted depth of imaging. Second Window Indocyanine Green (SWIG) addresses these issues by allowing for longer contrast times and the imaging of deeper regions of brain tissue. Biopsy of spinal cord lesions is often difficult for a variety of reasons, including the delicate nature of the tissue and differentiating normal from lesional tissue visually, especially in lesions with heterogeneous enhancement. Methods In this case report, we describe the use of second window ICG to facilitate the visualization of a spinal cord lesion and subsequent biopsy of the lesion. Results This patient is a 24-year-old female who had recurrence of a suprasellar germinoma. An MRI of the rest of the neuraxis was performed to assess for the presence of drop metastases. The spinal cord from C2-5 was expanded with areas of patchy enhancement; however, this lesion was asymptomatic. The patient's oncologist requested a biopsy of this lesion to help direct subsequent care of her recurrent germinoma. The day before surgery, the patient had an intravenous injection of ICG dye. She then underwent a C3-5 laminectomy for biopsy of her cervical intramedullary lesion. After opening of the dura, no visible abnormality of the spinal cord could be identified. A Stryker endoscope showed an area of ICG uptake in the cord at approximately the C3-4 level. A midline myelotomy was centered over the ICG demarcated area and several samples were taken for pathology. Final biopsy results determined the lesion to be spinal cord parenchyma with perivascular and intraparenchymal lymphocytes – not consistent with spinal cord tumor or germinoma. Conclusion Second Window ICG is effective in visualizing otherwise visually unremarkable spinal cord lesions. This technology can facilitate biopsy of these lesions and possibly their surgical resection.

Negative symptoms (NS) severely interfere with real-world performance, already at the onset of schizophrenia and in "clinical high risk" mental states. However, most of the empirical studies specifically examining treatment effectiveness on NS included patients with stable, prolonged schizophrenia. Moreover, research on psychosocial interventions for NS in early schizophrenia is still relatively scarce. Thus, the aims of this study were (1) to longitudinally monitor the NS stability in young individuals with First Episode Schizophrenia (FES) across a 2-year follow-up period, and (2) to investigate any significant association of NS with functioning, other aspects of FES psychopathology and the specific treatment component effects on NS of an "Early Intervention in Psychosis" (EIP) program during the 2 years of follow-up. At entry, 159 FES participants (aged 12-35 years) completed the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Spearman's correlations and multiple linear regression analyses were performed. NS had relevant enduring associations with PANSS disorganization scores and GAF functioning decline. Across the follow-up, FES individuals showed a significant improvement in NS levels. This was specifically associated with the number of individual psychotherapy and intensive case management sessions provided during the 2 years of our EIP program, as well as with the antipsychotic dosage at entry. NS are clinically relevant in FES, already at the enrollment in specialized EIP services. However, their clinical severity seems to decrease over time, together with the delivery of specific, patient-tailored EIP interventions.

Infections represent one of the most frequent complications during the treatment of patients with Acute Lymphoblastic Leukemia (ALL): of these, almost half develop an infectious event in the majority of cases in induction. The new monoclonal and bispecific antibodies and CAR-T, besides offering new perspectives in the overall survival and disease-free survival of patients, may also transform the epidemiology of infections in ALL by improving the toxicity of treatments. In this review, we examined studies published in the literature over the past 12 years and described the infectious complications of therapy with Blinatumomab, Inotuzumab, Rituximab and CAR-T in adult and pediatric patients with ALL. Infections are less frequent than in traditional chemotherapy treatment with vincristine, corticosteroids and anthracyclines, which has been the backbone of therapy for patients with ALL for years. On the other hand, the infection scenario in the CAR-T setting is quite peculiar: In these patients, infections are more frequent in the first month after infusion and are predominantly bacterial. As the time moves away from day zero, viral infections become more frequent, occurring mainly in patients who have had prolonged cytopenia and major cytokine release syndrome.

BackgroundOverexpression of human epidermal growth factor receptor type 2 (HER2) occurs in almost 25-30% of androgen receptor (AR)-positive salivary gland carcinomas (SGCs), notably salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS). In the last years, several studies have reported the clinical benefit of HER2 directed therapies in this setting. This work aims at describing the natural history of AR-positive recurrent/metastatic (R/M) SGC patients, based on HER2 amplification status.MethodsConsecutive R/M AR-positive SGC patients accessing our Institution from 2010 to 2021 were analyzed. Descriptive statistics and survival analyses were performed to present the clinical characteristics of the selected patients and the outcomes, based on HER2 status. A specific focus was dedicated to patients developing metastases to the central nervous system (CNS).ResultsSeventy-four R/M AR-positive SGC patients (72 men) were analyzed. Median follow-up was 36.18 months (95% CI 30.19-42.66). HER2 status was available in 62 cases (84%) and in 42% the protein was overexpressed (HER2+). Compared with patients with HER2- SGCs, in patients with HER2+ disease, HR for disease recurrence was 2.97 (95% CI 1.44-6.1, p=0.003), and HR for death from R/M disease was 3.22 (95% CI 1.39-7.49, p=0.007). Moreover, the HER2+ group showed a non-significant trend towards a higher prevalence of CNS metastases (40% vs. 24%, p=0.263). Patients developing CNS metastases had shorter survival than those who did not; at bivariate analysis (covariates: CNS disease and HER2 status), HER2 status demonstrated its independent prognostic significance.DiscussionIn our patient population, HER2 amplification was a negative prognostic factor, and it was associated with a non-statistically significant higher risk of developing CNS metastasis. Further studies are needed to explore the potential clinical benefit of tackling the two biological pathways (AR and HER2) in patients affected by this rare and aggressive malignancy.