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Purpose: This study compared the classification performance of normalized apparent diffusion coefficient (nADC) with percentage T2-FLAIR mismatch-volume (%T2FM-volume) for differentiating between IDH-mutant astrocytoma (IDHm-A) and other glioma molecular subtypes., Methods: A total of 105 non-enhancing gliomas were studied. T2-FLAIR digital subtraction maps were used to identify T2FM and T2-FLAIR non-mismatch (T2FNM) subregions within tumor volumes of interest (VOIs). Median nADC from the whole tumor, T2FM, and T2NFM subregions and %T2FM-volume were obtained. IDHm-A classification analyses using receiver-operating characteristic curves and multiple logistic regression were performed in addition to exploratory survival analyses., Results: T2FM subregions had significantly higher nADC than T2FNM subregions within IDHm-A with ≥ 25% T2FM-volume (P < 0.0001). IDHm-A with ≥ 25% T2FM-volume demonstrated significantly higher whole tumor nADC compared to IDHm-A with < 25% T2FM-volume (P < 0.0001), and both IDHm-A subgroups demonstrated significantly higher nADC compared to IDH-mutant oligodendroglioma and IDH-wild-type gliomas (P < 0.05). For classification of IDHm-A vs. other gliomas, the area under curve (AUC) of nADC was significantly greater compared to the AUC of %T2FM-volume (P = 0.01, nADC AUC = 0.848, %T2FM-volume AUC = 0.714) along with greater sensitivity. In exploratory survival analyses within IDHm-A, %T2FM-volume was not associated with overall survival (P = 0.2), but there were non-significant trends for nADC (P = 0.07) and tumor volume (P = 0.051)., Conclusion: T2-FLAIR subtraction maps are useful for characterizing IDHm-A imaging characteristics. nADC outperforms %T2FM-volume for classifying IDHm-A amongst non-enhancing gliomas with preserved high specificity and increased sensitivity, which may be related to inherent diffusivity differences regardless of T2FM. In line with previous findings on visual T2FM-sign, quantitative %T2FM-volume may not be prognostic., Competing Interests: Declarations. Ethics approval: The study was performed in line with the principles of the Declaration of Helsinki and in compliance with the Health Insurance Portability and Accountability Act. Informed consent: All patients in the institutional cohort provided informed consent. Disclosures: BME is on the advisory board and is a paid consultant for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen Pharmaceuticals, Imaging Endpoints, Kazia, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Neosoma, Alpheus Medical, Sagimet Biosciences, Sapience Therapeutics, Orbus Therapeutics, and the Global Coalition for Adaptive Research (GCAR). TFC is cofounder, major stock holder, consultant and board member of Katmai Pharmaceuticals, holds stock for Erasca, member of the board and paid consultant for the 501c3 Global Coalition for Adaptive Research, holds stock in Chimerix and receives milestone payments and possible future royalties, member of the scientific advisory board for Break Through Cancer, member of the scientific advisory board for Cure Brain Cancer Foundation, has provided paid consulting services to Blue Rock, Vida Ventures, Lista Therapeutics, Stemline, Novartis, Roche, Sonalasense, Sagimet, Clinical Care Options, Ideology Health, Servier, Jubilant, Immvira, Gan & Lee, BrainStorm, Katmai, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Kintara, Bayer, Merck, Boehinger Ingelheim, VBL, Amgen, Kiyatec, Odonate Therapeutics QED, Medefield, Pascal Biosciences, Bayer, Tocagen, Karyopharm, GW Pharma, Abbvie, VBI, Deciphera, VBL, Agios, Genocea, Celgene, Puma, Lilly, BMS, Cortice, Novocure, Novogen, Boston Biomedical, Sunovion, Insys, Pfizer, Notable labs, Medqia, Trizel, Medscape and has contracts with UCLA for the Brain Tumor Program with Roche, VBI, Merck, Novartis, BMS, AstraZeneca, Servier. The Regents of the University of California (T.F.C. employer) has licensed intellectual property co-invented by TFC to Katmai Pharmaceuticals. PLN has received grants/contracts from ERASCA, Millenium, Children’s Tumor Foundation, Dept of Defense, GCAR, Springsworks, and BMS and has received payment/honoraria from Alexion. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s).)

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored., Objectives: To investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD., Methods: We retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington's Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates., Results: Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate: β male/female =-3.462/-2.935, p<0.05; putamen: β male/female =-4.775/-3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score: β male/female =3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test : β male/female =-34.89/-38.91, p<0.0001), and greater functional decline (Total Functional Capacity: β male/female =-6.449/-6.817, p<0.05; Independence Scale: β male/female =-32.44/- 34.99, p<0.001)., Conclusions: The sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.

Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers., Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period., Results: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026)., Conclusions: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: Normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) computed from dynamic susceptibility contrast (DSC) perfusion imaging are useful biomarkers for differential diagnosis and treatment response assessment in brain tumors. However, their measurements are dependent on DSC acquisition factors, and CBV-optimized protocols technically differ from PSR-optimized protocols. This study aimed to generate "synthetic" DSC data with adjustable synthetic acquisition parameters using dual-echo gradient-echo (GE) DSC datasets extracted from dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI). Synthetic DSC was aimed at: 1) simultaneously create nrCBV and PSR maps using optimal sequence parameters, 2) compare DSC datasets with heterogeneous external cohorts, and 3) assess the impact of acquisition factors on DSC metrics., Materials and Methods: Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection and included in this cross-sectional study. Multiple synthetic DSC curves with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo GE data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation., Results: Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection, while PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman's ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p<0.0001), supporting a role of synthetic DSC for multicenter comparisons. Acquisition factors highly impacted PSR, and nrCBV without leakage correction also showed parameter-dependence, although less pronounced. However, this dependence was remarkably mitigated by post-hoc leakage correction., Conclusions: Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with one acquisition and a single contrast injection, facilitating the use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion metrics across heterogeneous multicenter datasets, as it facilitates post-hoc harmonization., Abbreviations: DSC = dynamic susceptibility contrast; FA = flip angle; GBCA = gadolinium-based contrast agent; GBM = glioblastoma; GE = gradient echo; IDH = isocitrate dehydrogenase; IDH m = IDH-mutant; IDH wt = IDH-wild-type; 1p19q cod = 1p19q codeleted; 1p19q int = 1p19q intact; MRI = magnetic resonance imaging; PCNSL = primary CNS lymphoma; PSR = percentage of signal recovery; Rec = recurrent; SAGE-EPI = spin-and-gradient-echo echoplanar imaging; CBV = cerebral blood volume; nrCBV = normalized relative CBV; ROI = region of interest; TE = echo time; TN = treatment-naïve; TR = repetition time., (© 2024 by American Journal of Neuroradiology.)

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers., (© 2024 John Wiley & Sons Ltd.)

Adeno-associated viruses (AAVs) are promising gene therapy vectors, but challenges arise when treating patients with preexisting neutralizing antibodies. Worldwide seroprevalence studies provide snapshots of existing immunity in diverse populations. Owing to the uniqueness of the Basque socio-geographical landscape, we investigated the seroprevalence of eight AAV serotypes in residents of the Basque Country. We found the highest seroprevalence of AAV3, and the lowest seroprevalence of AAV9. Additionally, less than 50% of the Basque population has neutralizing antibodies against AAV4, AAV6, and AAV9. Our findings provide insight into AAV infections in the Basque region, public health, and the development of AAV-based therapeutics., (© 2024. The Author(s).)

This paper presents the approach adopted by the EGI-ACE project for the setup and delivery of Data Spaces for various scientific domains. The work was implemented by members of the EGI e-infrastructure and of several European Research Infrastructures in the context of the European Open Science Cloud programme. Our results are several Data Space services that enable the reuse and exploitation of open, scientific big data for compute intensive use cases. The paper illustrates the EGI-ACE approach through two examples: (1) EMSO ERIC Data Portal for seafloor and water column research and (2) ENES Data Space for climate research., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Sipos G et al.)

Dialysis patients experience frequent hospitalizations and a higher mortality rate compared to other Medicare populations, in whom hospitalizations are a major contributor to morbidity, mortality, and healthcare costs. Patients also typically remain on dialysis for the duration of their lives or until kidney transplantation. Hence, there is growing interest in studying the spatiotemporal trends in the correlated outcomes of hospitalization and mortality among dialysis patients as a function of time starting from transition to dialysis across the United States Utilizing national data from the United States Renal Data System (USRDS), we propose a novel multivariate spatiotemporal functional principal component analysis model to study the joint spatiotemporal patterns of hospitalization and mortality rates among dialysis patients. The proposal is based on a multivariate Karhunen-Loéve expansion that describes leading directions of variation across time and induces spatial correlations among region-specific scores. An efficient estimation procedure is proposed using only univariate principal components decompositions and a Markov Chain Monte Carlo framework for targeting the spatial correlations. The finite sample performance of the proposed method is studied through simulations. Novel applications to the USRDS data highlight hot spots across the United States with higher hospitalization and/or mortality rates and time periods of elevated risk., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

Patients with multiple myeloma (MM) have an increased risk of sepsis due to underlying disease- and treatment-related immunosuppression. However, data on sepsis incidence, causative pathogens, and impact on outcomes in newly diagnosed MM (NDMM) are limited. We conducted a retrospective observational study of 92 NDMM patients who developed sepsis between 2022 and 2023 at a tertiary care center in Italy. Patient characteristics, sepsis criteria [Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome (SIRS)], microbiology results, and associations with progression-free survival (PFS) were analyzed. In this cohort of 92 critically-ill patients, pathogenic organisms were identified via microbiological culture in 74 cases. However, among the remaining 18 culture-negative patients, 9 exhibited a SIRS score of 2 and another 9 had a SIRS score of 4, suggestive of a clinical presentation consistent with sepsis despite negative cultures. Common comorbidities included renal failure (60%), anemia (71%), and bone disease (83%). Gram-negative (28%) and Gram-positive (23%) bacteria were frequent causative organisms, along with fungi (20%). Cox Univariate analyses for PFS showed statically significant HR in patients with albumin ≥ 3.5 vs < 3.5 (HR = 5.04, p < 0.001), Karnofsky performance status ≥ 80 vs < 80 (HR = 2.01, p = 0.002), and early-stage vs late-stage disease by International Staging System (HR = 4.76 and HR = 12.52, both p < 0.001) and Revised International Staging System (R-ISS III vs R-ISS I, HR = 7.38, p < 0.001). Sepsis is common in NDMM and associated with poor outcomes. Risk stratification incorporating sepsis severity, comorbidities, and disease stage may help guide preventive strategies and optimize MM management., (© 2024. The Author(s).)

Background: Over the past decades, efforts have been made to improve the nutritional well-being of people with cystic fibrosis (pwCF). Due to the correlation observed between nutritional indices and lung function, prevailing recommendations consistently advocate for BMI percentile goals at or above the 50th percentile in pwCF. Recent global trends show a notable increase in overweight and obese statuses among pwCF. This study aims to explore the nutritional status of Italian pwCF. Methods: Data from the Italian CF Patient's Registry were analysed to assess the proportion of individuals categorized as underweight, target weight, overweight, and obese from 2010 to 2021. Patient-level comparison data from 2021 were also examined to identify the potential determinants of overweight and obesity. Results: Analysis spanning 2010 to 2021 reveals a decrease of approximately 40% in underweight status among adults, while the proportion of malnourished patients younger than 18 years remained stable. Conversely, there was a substantial increase of over 70% in overweight status and over 85% in obesity among adults, with minor fluctuations observed among children and adolescents. Patient factors associated with increased obesity incidence included age older than 45 years, male gender, pancreatic sufficiency, possession of at least one CFTR variant conferring residual function, ppFEV 1 > 90, and lower prevalence of Pseudomonas aeruginosa colonization. Conclusions: Our study confirms the evolving nutritional status landscape among Italian adult pwCF, with a significant shift towards overweight and obesity over the past decade. These trends highlight the need for proactive measures within CF standards of care to adapt and address the changing needs of patients.

Mixed membership models are an extension of finite mixture models, where each observation can partially belong to more than one mixture component. A probabilistic framework for mixed membership models of high-dimensional continuous data is proposed with a focus on scalability and interpretability. The novel probabilistic representation of mixed membership is based on convex combinations of dependent multivariate Gaussian random vectors. In this setting, scalability is ensured through approximations of a tensor covariance structure through multivariate eigen-approximations with adaptive regularization imposed through shrinkage priors. Conditional weak posterior consistency is established on an unconstrained model, allowing for a simple posterior sampling scheme while keeping many of the desired theoretical properties of our model. The model is motivated by two biomedical case studies: a case study on functional brain imaging of children with autism spectrum disorder (ASD) and a case study on gene expression data from breast cancer tissue. These applications highlight how the typical assumption made in cluster analysis, that each observation comes from one homogeneous subgroup, may often be restrictive in several applications, leading to unnatural interpretations of data features., Competing Interests: Disclosure The authors report that there are no competing interests to declare.

Objectives: About 10 million individuals in USA presented annually in the emergency department (ED) with chest pain or with signs and symptoms of acute coronary syndrome (ACS). The advent of point of care (POC) devices, able to measure high sensitivity troponin, are a very interesting tool in the ED setting for its rapid turnaround time (<10 min)., Methods: The present study evaluates the diagnostic performance of the Atellica VTLi (Siemens) in real life setting using the clinical data derived from integrated diagnoses of emergency room staff and cardiologist and in comparison with standard laboratory hs-cTnT assay (Cobas 8000, Elecsys, Roche). 966 patients admitted to the emergency department of "G. Mazzini Hospital" in Teramo, Italy, from July 27, 2022, through June 09, 2023, were enrolled., Results: The diagnostic performance of POC hs-cTnI was evaluated. An appropriate POC hs-cTnI threshold values <4 ng/L supplied a sensitivity and an NPV of 100 % (95 % CI: 99.5-100) in order to achieve rapid rule out for MI through a single measurement at patient presentation in the ED. Furthermore, a derivation POC hs-cTnI concentration >54 ng/L provided a specificity of 97.2 % (95 % CI: 95.9-98.1) and a PPV of 43.5 % (95 % CI: 40.3-46.7) for ruling in MI., Conclusions: This platform showed comparable diagnostic performance for myocardial infarction to the central laboratory. Our data suggest the possible use of the Atellica VTLi hs-cTnI POC assay either in emergency department of urban medical centre, either in rural hospital for triage and patient management., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group., Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness., Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (d max  = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (d max  = .47), crus I/II (d max  = .39), VIIIA (d max  = .45), and VIIIB (d max  = .40). Earlier age at seizure onset ( η ρ max 2  = .05) and longer epilepsy duration ( η ρ max 2  = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls., Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating from B, T, or NK lymphocytes. They represent approximately 4-5% of new cancer cases and are classified according to the revised WHO system based on cell lineage, morphology, immunophenotype, and genetics. Diagnosis requires adequate biopsy material, though integrated approaches are used for leukemic presentations. Molecular profiling is improving classification and identifying prognostic markers. Indolent NHLs, such as follicular lymphoma and marginal zone lymphoma, typically pursue a non-aggressive clinical course with long survival. Aggressive diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Recent studies have elucidated pathogenic mechanisms like MYC translocations and BCR pathway mutations. "Double hit" lymphomas with MYC and BCL2/BCL6 alterations confer a poor prognosis. Treatment approaches are evolving, with chemoimmunotherapy remaining standard for many indolent cases while intensified regimens and targeted agents show promise for refractory or high-risk aggressive disease. Continued elucidation of the genetic and microenvironmental underpinnings of lymphomagenesis is critical for developing personalized therapeutic strategies.

Skin and soft tissue infections (SSTIs) are the most common diseases caused by Staphylococcus aureus ( S. aureus ), which can progress to threatening conditions due to recurrences and systemic complications. Staphylococcal protein A (SpA) is an immunomodulator antigen of S. aureus , which allows bacterial evasion from the immune system by interfering with different types of immune responses to pathogen antigens. Immunization with SpA could potentially unmask the pathogen to the immune system, leading to the production of antibodies that can protect from a second encounter with S. aureus , as it occurs in skin infection recurrences. Here, we describe a study in which mice are immunized with a mutated form of SpA mixed with the Adjuvant System 01 (SpA mut /AS01) before a primary S. aureus skin infection. Although mice are not protected from the infection under these conditions, they are able to mount a broader pathogen-specific functional immune response that results in protection against systemic dissemination of bacteria following an S. aureus second infection (recurrence). We show that this "hidden effect" of SpA can be partially explained by higher functionality of induced anti-SpA antibodies, which promotes better phagocytic activity. Moreover, a broader and stronger humoral response is elicited against several S. aureus antigens that during an infection are masked by SpA activity, which could prevent S. aureus spreading from the skin through the blood., Competing Interests: AM was a PhD student of Università degli Studi di Siena Italy at the time of the study and supervised by GSK. GM was a student of Università di Bologna Italy at the time of the study and participated in an internship at GSK. AM is now an employee of GiGroup SpA, a contract employment organization contracted by GSK. GM is now an employee of GSK. DL and GB were employee of GSK at the time of the study. All the other authors are employee of GSK. FB, MB, GB, EC report ownership of GSK shares. FB is listed as inventor on patents concerning S. aureus vaccine development. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mandelli, Magri, Tortoli, Torricelli, Laera, Bagnoli, Finco, Bensi, Brazzoli and Chiarot.)

Introduction: Italian Cystic Fibrosis Registry (ICFR) collects data of patients with cystic fibrosis (CF) through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programmes, and resource allocation. Italian data are also compared at international level through the collaboration with the European CF Registry for sharing epidemiological data on general aspects like CF epidemiology and specific topics such as the use of CFTR modulators., Objectives: The purpose of this Report is to provide updated demographic and clinical data of the Italian FC population for the years 2021 and 2022, to contribute essential information for the implementation of projects aimed at improving the management of patients affected by this disease., Design: Analyses and results presented in this Report pertain to patients currently under care at Italian National Referral and Support Centres for Cystic Fibrosis and Paediatric Hospital 'Bambino Gesù' in the 2021-2022 period. Data were submitted by clinical Centres through a dedicated web-based software and underwent dual quality control (QC) measures: automated quantitative QC within the software and secondary QC at the European level before the integration into the European Cystic Fibrosis Registry. These measures ensure data completeness, accuracy, and longitudinal consistency with European core data., Setting and Participants: A total of 27 CF Centres, including referral and support centres, as well as 'Bambino Gesù' Children's Hospital CF centre, submitted their data to ICFR for the years 2021-2022. Althourgh CF Centres in Verona and Messina do not use the ICFR software, their data are centrally collected and subsequently forwarded to the European Registry. Data from service centres in Treviso and Rovereto are transmitted via the Verona CF Centre. Data from Sardinia Centre are currently unavailable., Results: The results section provides a comprehensive overview of various aspects of CF epidemiology and patient characteristics. 1.Demography: in 2021 and 2022, 5,977 and 6,077 CF patients were respectively included in the ICFR, with median ages of 23.3 and 23.7 years. The prevalence rates were 10.1 and 10.3 per 100,000 residents in Italy for the respective years, with males comprising 51.6% on average. The distribution by age showed a higher frequency among patients aged 7 to 35 years; adult patients constituted 63.5% on average in both years. 2. Diagnosis: most CF patients were diagnosed before the age of two (mean value 57.9%), with a significant percentage diagnosed in adult age (35.4% in 2021 and 25.6% in 2022). 3.New diagnoses: there were 113 new diagnoses in 2021 and 121 in 2022, with estimated incidences of 1 in 9,097 living births in 2021 and 1 in 6,232 in 2022. 4. Genetics: genetic analyses were conducted on 99.9% of patients, revealing CFTR gene mutations in over 98% of cases. The F508del mutation was the most common (44% of alleles in 2021), with 18% of patients having at least one "residual function" mutation. Gating mutations were present in 3.4% of Italian patients, while 20% had at least one-stop codon mutation. 5.Lung function: lung function, measured by percent predicted (pp)FEV1 (Forced Expiratory Volume in the first second) progressively declined before adulthood, with the majority of paediatric patients (92.8% in 2021 and 93.8% in 2022) maintaining a ppFEV1≥70%. 6.Nutrition: critical periods for nutrition were identified as the first 6 months of life and adolescence, with higher prevalence of malnourished male adolescents compared to females. Suboptimal BMI values were more common in adult females (28.7% in 2021 and 26.9% in 2022) compared to males (14.2% in 2021 and 12.6% in 2022). 7. Complications: CF-related liver disease without cirrhosis was prevalent in patients under 18 years (21.9% in 2021 and 21.2 in 2022), while CF-related diabetes was most frequent in adults (24.2%). 8.Transplantation: over the two-year period, 28 patients underwent double-lung transplantation, with median ages of 29.1 in 2021 and 35.3 in 2022, respectively. Median waiting times ranged from 9.4 to 11.6 months. 9.Microbiology: chronic Pseudomonas aeruginosa infection affected 37.2% of adult patients in 2021 and 36.0% in 2022, compared to 7.4% and 6.5% in paediatric patients. Staphylococcus aureus infection rates were 34.6% and 42.2% in 2021 among adults and 34.4% and 36.7% in 2022 among paediatric patients. 10. Mortality: a total of 34 patients died during the 2021-22 period (19 females, 15 males), with median ages at death of 43.7 years in 2021 and 46 years in 2022 (excluding transplanted patients)., Conclusions: The present Report is an update of the data published in the past years and summarizes the main epidemiological and clinical data regarding Italian CF subjects in the years 2021 and 2022. The number of patients registered in 2021 was 5,977, while in 2022 was 6,077. The population coverage estimates for 2022 to be around 97%. In 2020, 60.5% of patients were older than 18 years, in 2022 adult patients account for 63.5% of the Italian CF population. Over the years, therefore, an increase in the median age of Italian CF patients has been observed, reaching 23.7 years in 2022. The absolute number of new diagnoses per year remains substantially unchanged over the years (a total of 234 in the period under review). The median age at diagnosis in 2022 was 2.5 months, 62.6% of subjects are really diagnosed within the first year of life and almost 90% of them are diagnosed through neonatal screening. In 2022, almost all patients underwent genetic analysis (99.9%). Data collected confirm the great variability among Italian CF patients. As regards respiratory function, what is reported in previous reports is here confirmed, with an ever-increasing percentage of subjects under the age of 18 having normal respiratory function, moreover, less than 1% of paediatric patients has a severe lung function (ppFEV1<40). The marked improvement in this indicator in the adult population seems to be mainly due to the introduction from 2021 in Italy of therapy with highly effective CFTR modulators. At the same time, the close positive correlation between nutritional status and respiratory function is confirmed for the adult population. As regards chronic infection by Pseudomonas aeruginosa, in 2022, a reduction in the percentage of chronic infection is observed both among adults (36% vs 38.8% in 2020) and in paediatric patients (6.5% vs 7.6% in 2020). The most frequent complication in both paediatric and adult populations is liver disease (respectively, in 24.2% and 41.3% of subjects). In the two-year period, 34 patients died; their median age at death was between 43 and 46 years (transplant patients excluded); only two patients under the age of 18 died in the period 2021 and 2022, confirming once again that mortality in paediatric age is a rare event. The data presented in this Report shows how the register can be a national and international point of reference for CF patients and the scientific community, a tool for describing the Italian CF population over the years, and a starting point for planning epidemiological studies and clinical studies.

Background and Purpose: The T2-FLAIR mismatch sign on MR imaging is a highly specific imaging biomarker of isocitrate dehydrogenase ( IDH )-mutant astrocytomas, which lack 1p/19q codeletion. However, most studies using the T2-FLAIR mismatch sign have used visual assessment. This study quantified the degree of T2-FLAIR mismatch using digital subtraction of fluid-nulled T2-weighted FLAIR images from non-fluid-nulled T2-weighted images in human nonenhancing diffuse gliomas and then used this information to assess improvements in diagnostic performance and investigate subregion characteristics within these lesions., Materials and Methods: Two cohorts of treatment-naïve, nonenhancing gliomas with known IDH and 1p/19q status were studied ( n  = 71 from The Cancer Imaging Archive (TCIA) and n  = 34 in the institutional cohort). 3D volumes of interest corresponding to the tumor were segmented, and digital subtraction maps of T2-weighted MR imaging minus T2-weighted FLAIR MR imaging were used to partition each volume of interest into a T2-FLAIR mismatched subregion (T2-FLAIR mismatch, corresponding to voxels with positive values on the subtraction maps) and nonmismatched subregion (T2-FLAIR nonmismatch corresponding to voxels with negative values on the subtraction maps). Tumor subregion volumes, percentage of T2-FLAIR mismatch volume, and T2-FLAIR nonmismatch subregion thickness were calculated, and 2 radiologists assessed the T2-FLAIR mismatch sign with and without the aid of T2-FLAIR subtraction maps., Results: Thresholds of ≥42% T2-FLAIR mismatch volume classified IDH -mutant astrocytoma with a specificity/sensitivity of 100%/19.6% (TCIA) and 100%/31.6% (institutional); ≥25% T2-FLAIR mismatch volume showed 92.0%/32.6% and 100%/63.2% specificity/sensitivity, and ≥15% T2-FLAIR mismatch volume showed 88.0%/39.1% and 93.3%/79.0% specificity/sensitivity. In IDH -mutant astrocytomas with ≥15% T2-FLAIR mismatch volume, T2-FLAIR nonmismatch subregion thickness was negatively correlated with the percentage T2-FLAIR mismatch volume ( P  < .0001) across both cohorts. The percentage T2-FLAIR mismatch volume was higher in grades 3-4 compared with grade 2 IDH -mutant astrocytomas ( P  < .05), and ≥15% T2-FLAIR mismatch volume IDH- mutant astrocytomas were significantly larger than <15% T2-FLAIR mismatch volume IDH -mutant astrocytoma ( P  < .05) across both cohorts. When evaluated by 2 radiologists, the additional use of T2-FLAIR subtraction maps did not show a significant difference in interreader agreement, sensitivity, or specificity compared with a separate evaluation of T2-FLAIR and T2-weighted MR imaging alone., Conclusions: T2-FLAIR digital subtraction maps may be a useful, automated tool to obtain objective segmentations of tumor subregions based on quantitative thresholds for classifying IDH -mutant astrocytomas using the percentage T2 FLAIR mismatch volume with 100% specificity and exploring T2-FLAIR mismatch/T2-FLAIR nonmismatch subregion characteristics. Conversely, the addition of T2-FLAIR subtraction maps did not enhance the sensitivity or specificity of the visual T2-FLAIR mismatch sign assessment by experienced radiologists., (© 2024 by American Journal of Neuroradiology.)

Mixed membership models, or partial membership models, are a flexible unsupervised learning method that allows each observation to belong to multiple clusters. In this paper, we propose a Bayesian mixed membership model for functional data. By using the multivariate Karhunen-Loève theorem, we are able to derive a scalable representation of Gaussian processes that maintains data-driven learning of the covariance structure. Within this framework, we establish conditional posterior consistency given a known feature allocation matrix. Compared to previous work on mixed membership models, our proposal allows for increased modeling flexibility, with the benefit of a directly interpretable mean and covariance structure. Our work is motivated by studies in functional brain imaging through electroencephalography (EEG) of children with autism spectrum disorder (ASD). In this context, our work formalizes the clinical notion of "spectrum" in terms of feature membership proportions. Supplementary materials, including proofs, are available online. The R package BayesFMMM is available to fit functional mixed membership models.

Background: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH)., Methods: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide., Results: She died due to severe sepsis complications., Conclusion: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background : Patients with refractory metastatic colorectal cancer (mCRC) rarely receive third-line or further treatment. In this context, regorafenib (R) and trifluridine/tipiracil (T) are two important novel therapeutic choices with statistically significant increases in overall survival (OS), progression-free survival (PFS), and disease control, with different toxicity profiles. This study is a subgroup analysis of our larger retrospective study, already published, whose objective was to assess the outcomes of patients when R and T were given sequentially. Patients and Methods : The study involved thirteen Italian cancer centers on a 10-year retrospective observation (2012-2022). In this subgroup analysis, we focused our attention on the correlation between the first drug treatment duration (<3 months, 3 to <6 months and ≥6 months) and survival outcomes in patients who had received the sequence regorafenib-to-trifluridine/tipiracil, or vice versa. Results : The initial study included 866 patients with mCRC who received sequential T/R, or R/T, or T or R alone. This analysis is focused on evaluating the impact of the duration of the first treatment in the sequence on clinical outcomes (OS, PFS) and includes 146 and 116 patients of the T/R and R/T sequences, respectively. Based on the duration of the first drug treatment, subgroups for the T/R sequence included 27 patients (18.4%) who received T for <3 months, 86 (58.9%) treated for 3 to <6 months, and 33 (22.6%) treated for ≥6 months; in the reverse sequence (R as the first drug), subgroups included 18 patients (15.5%) who received their first treatment for <3 months, 62 (53.4%) treated for 3 to <6 months, and 35 (31.0%) treated for ≥6 months. In patients who received their first drug treatment for a period of 3 to <6 months, the R/T sequence had a significantly longer median OS (13.7 vs. 10.8 months, p = 0.0069) and a longer median PFS (10.8 vs. 8.5 months, p = 0.0003) than the T/R group. There were no statistically significant differences between groups with first drug treatment durations of <3 months and ≥6 months. Conclusions : Our analysis seems to suggest that the administration of R for a period of 3 to <6 months before that of T can prolong both OS and PFS, as compared to the opposite sequence.

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF., Conclusions:  Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications., What Is Known: • Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy. • There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis., What Is New: • Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications. • Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

After recovering from the acute COVID-19 illness, a substantial proportion of people continue experiencing post-acute sequelae of COVID-19 (PASC), also termed "long COVID". Their quality of life is adversely impacted by persistent cognitive dysfunction and affective distress, but the underlying neural mechanisms are poorly understood. The present study recruited a group of mostly young, previously healthy adults (24.4 ± 5.2 years of age) who experienced PASC for almost 6 months following a mild acute COVID-19 illness. Confirming prior evidence, they reported noticeable memory and attention deficits, brain fog, depression/anxiety, fatigue, and other symptoms potentially suggestive of excitation/inhibition imbalance. Proton magnetic resonance spectroscopy ( 1 H-MRS) was used to examine the neurochemical aspects of cell signaling with an emphasis on GABA levels in the occipital cortex. The PASC participants were compared to a control (CNT) group matched in demographics, intelligence, and an array of other variables. Controlling for tissue composition, biological sex, and alcohol intake, the PASC group had lower GABA+/water than CNT, which correlated with depression and poor sleep quality. The mediation analysis revealed that the impact of PASC on depression was partly mediated by lower GABA+/water, indicative of cortical hyperexcitability as an underlying mechanism. In addition, N-acetylaspartate (NAA) tended to be lower in the PASC group, possibly suggesting compromised neuronal integrity. Persistent neuroinflammation may contribute to the pathogenesis of PASC-related neurocognitive dysfunction.

Objective: The aim of the study is to describe the radiological spectrum of appearances of ovarian lymphoma (OL). The manuscript describes the radiological aspects of OL to assist the radiologist in achieving correct orientation of the diagnosis., Methods: We conducted a retrospective evaluation of imaging studies of 98 cases of non-Hodgkin's lymphoma, with extra-nodal localisation (ovaries) in three cases (1 primary, 2 secondary). A literature review was also performed., Results: Of the three evaluated women, one had a primary ovarian involvement and two had a secondary ovarian involvement. The most common lesion characteristics were a well-defined, solid homogeneous and hypoechoic mass at US. CT depicts OL as a well-defined, non-infiltrating, homogeneous hypodense solid mass, with mild contrast enhancement. On T1-weight MRI, OL appears as a homogeneous mass of low signal intensity, which enhances avidly following intravenous gadolinium., Conclusion: Clinical and serological presentation of OL can be similar to that of primary ovarian cancer. As imaging plays a central role in the diagnosis of OL, the radiologist should be familiar with US, CT and MRI appearances of this condition to correctly orient the diagnosis and so avoid unnecessary adnexectomy., (© 2023. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Purpose: Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy., Experimental Design: N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival., Results: Optimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth., Conclusions: Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma., (©2023 American Association for Cancer Research.)

Bayesian methods provide direct inference in functional data analysis applications without reliance on bootstrap techniques. A major tool in functional data applications is the functional principal component analysis which decomposes the data around a common mean function and identifies leading directions of variation. Bayesian functional principal components analysis (BFPCA) provides uncertainty quantification on the estimated functional model components via the posterior samples obtained. We propose central posterior envelopes (CPEs) for BFPCA based on functional depth as a descriptive visualization tool to summarize variation in the posterior samples of the estimated functional model components, contributing to uncertainty quantification in BFPCA. The proposed BFPCA relies on a latent factor model and targets model parameters within a mixed effects modeling framework using modified multiplicative gamma process shrinkage priors on the variance components. Functional depth provides a center-outward order to a sample of functions. We utilize modified band depth and modified volume depth for ordering of a sample of functions and surfaces, respectively, to derive at CPEs of the mean and eigenfunctions within the BFPCA framework. The proposed CPEs are showcased in extensive simulations. Finally, the proposed CPEs are applied to the analysis of a sample of power spectral densities (PSD) from resting state electroencephalography (EEG) where they lead to novel insights on diagnostic group differences among children diagnosed with autism spectrum disorder and their typically developing peers across age.

In oligo-metastatic renal cell carcinoma (RCC), neither computed tomography (CT) nor bone scan is sensitive enough to detect small tumor deposits hampering early treatment and potential cure. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the neo-vasculature of numerous malignant neoplasms, including RCC, that can be targeted by positron emission tomography (PET) using PSMA-targeting radioligands. Our aim was to investigate whether PSMA-expression patterns of renal cancer in the primary tumor or metastatic lesions on immunohistochemistry (IHC) are associated with PET/CT findings using [ 68 Ga]-PSMA-HBED-CC (PSMA-PET/CT). We then analyzed the predictive and prognostic role of the PSMA-PET/CT signal. In this retrospective single-center study we included patients with renal cancer submitted to PSMA-PET/CT for staging or restaging, with tumor specimens available for PSMA-IHC. Clinical information (age, tumor type, and grade) and IHC results from the primary tumor or metastases were collected. The intensity of PSMA expression at IHC was scored into four categories: 0: none; 1: weak; 2: moderate; 3: strong. PSMA expression was also graded according to the proportion of vessels involved (PSMA%) into four categories: 0: none; 1: 1-25%; 2: 25-50%; 3: >50%. The intensity of PSMA expression and PSMA% were combined in a three-grade score: 0-2 absent or mildly positive, 3-4 moderately positive, and 5-6 strongly positive. PSMA scores were used for correlation with PSMA-PET/CT results. Results: IHC and PET scans were available for the analysis in 26 patients (22 ccRCC, 2 papillary RCC, 1 chromophobe, 1 "not otherwise specified" RCC) . PSMA-PET/CT was positive in 17 (65%) and negative in 9 patients (35%). The mean and median SUVmax in the target lesion were 34.1 and 24.9, respectively. Reporter agreement was very high for both distant metastasis location and local recurrence (kappa 1, 100%). PSMA-PET detected more lesions than conventional imaging and revealed unknown metastases in 4 patients. Bone involvement, extension, and lesion number were greater than in the CT scan (median lesion number on PET/CT 3.5). The IHC PSMA score was concordant in primary tumors and metastases. All positive PSMA-PET/CT results (15/22 ccRCC, 1 papillary cancer type II, and 1 chromofobe type) were revealed in tumors with strong or moderate PSMA combined scores (3-4 and 5-6). In ccRCC tissue samples, PSMA expression was strong to moderate in 20/22 cases. The SUVmax values correlated to the intensity of PSMA expression which were assessed using IHC ( p = 0.01), especially in the ccRCC subgroup ( p = 0.009). Median survival was significantly higher in patients with negative PSMA-PET/CT (48 months) compared to patients with a positive scan (24 months, p = 0.001). SUVmax ≥ 7.4 provides discrimination of patients with a poor prognosis. Results of PSMA-PET/CT changed treatment planning. Conclusions: in renal cancer, positive PSMA-PET/CT is strongly correlated to the intensity of PSMA expression on immunohistochemistry in both ccRCC and chromophobe cancer. PSMA-PET/CT signal predicts a poor prognosis confirming its potential as an aggressiveness biomarker and providing paramount additional information influencing patient management.

Objective: The objective of this study was to identify baseline clinical and radiological characteristics of brain metastases (BMs) associated with a higher probability of lesion-specific progression-free survival (PFS-L) after laser interstitial thermal therapy (LITT)., Methods: A total of 47 lesions in 42 patients with BMs treated with LITT were retrospectively examined, including newly diagnosed BM, suspected recurrent BM, and suspected radiation necrosis. The association of baseline clinical and radiological features with PFS-L was assessed using survival analyses. Radiological features included lesion size measurements, diffusion and perfusion metrics, and sphericity, which is a radiomic feature ranging from 1 (perfect sphere) to 0., Results: The probability of PFS-L for the entire cohort was 88.0% at 3 months, 70.6% at 6 months, 67.4% at 1 and 2 years, and 62.2% at 3 years. For lesions progressing after LITT (n = 13), the median time to progression was 3.9 months, and most lesions (n = 11) progressed within 6 months after LITT. In lesions showing response to LITT (n = 17), the median time to response was 12.1 months. All 3 newly diagnosed BMs showed a long-term response. The mean (± SD) follow-up duration for all censored lesions (n = 34) was 20.7 ± 19.4 months (range 12 days to 6.1 years). The mean pretreatment enhancing volume was 2.68 cm3 and the mean sphericity was 0.70. Pretreatment small enhancing volume (p = 0.003) and high sphericity (p = 0.024) computed from lesion segmentation predicted a longer PFS-L after LITT. Lesions meeting optimal cutoffs of either enhancing volume < 2.5 cm3 (adjusted p = 0.004) or sphericity ≥ 0.705 (adjusted p = 0.019) had longer PFS-L, and their probability of PFS-L was 86.8% at 3 years. Lesions meeting both cutoffs showed a cumulative benefit (p < 0.0001), with a 100% probability of PFS-L at 3 years, which was unchanged at the end of follow-up (4.1 years). Manually computed estimates of lesion size (maximal axial diameter, p = 0.011) and sphericity (p = 0.043) were also predictors of PFS-L. Optimal cutoffs of diameter < 2 cm (adjusted p = 0.035) or manual sphericity ≥ 0.91 (adjusted p = 0.092) identified lesions with longer PFS-L, and lesions meeting both cutoffs showed a cumulative benefit (p = 0.0023). Baseline diffusion imaging did not predict PFS-L. A subset of lesions (n = 7) with highly perfused hotspots had worse PFS-L (adjusted p = 0.010), but perfusion signal contamination from vessels and cortex and underlying size differences were possible confounders., Conclusions: Small size and high sphericity are ideal baseline features for lesions considered for LITT treatment, with a cumulative PFS-L benefit when both features are present, that could aid patient selection.

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.

Background: Alterations in tumor growth rate (TGR) in recurrent glioblastoma (rGBM) after treatment may be useful for identifying therapeutic activity. The aim of this study was to assess the impact of volumetric TGR alterations on overall survival (OS) in rGBM treated with chemotherapy with or without radiation therapy (RT)., Methods: Sixty-one rGBM patients treated with chemotherapy with or without concomitant radiation therapy (RT) at 1st or 2nd recurrence were retrospectively examined. Pre- and post-treatment contrast enhancing volumes were computed. Patients were considered "responders" if they reached progression-free survival at 6 months (PFS6) and showed a decrease in TGR after treatment and "non-responders" if they didn't reach PFS6 or if TGR increased., Results: Stratification by PFS6 and based on TGR resulted in significant differences in OS both for all patients and for patients without RT ( P < 0.05). A decrease of TGR ( P = 0.009), smaller baseline tumor volume ( P = 0.02), O 6 -methylguanine-DNA methyltransferase promoter methylation ( P = 0.048) and fewer number of recurrences ( P = 0.048) were significantly associated with longer OS after controlling for age, sex and concomitant RT., Conclusion: A decrease in TGR in patients with PFS6, along with smaller baseline tumor volume, were associated with a significantly longer OS in rGBM treated with chemotherapy with or without radiation. Importantly, all patients that exhibited PFS6 also showed a measurable decrease in TGR., Competing Interests: BME is a Paid Consultant and Advisor for Siemens;Medicenna;MedQIA;Imaging Endpoints;Agios Pharmaceuticals;Neosoma;Janssen;Kazia;VBL;Oncoceutics;Boston Biomedical Inc;ImmunoGenesis;and Ellipses Pharma. BME has received grant funding from Siemens, Agios, and Janssen. TFC is cofounder, major stock holder, consultant and board member of Katmai Pharmaceuticals, member of the board for the 501c3 Global Coalition for Adaptive Research, holds stock option of Notable Labs, holds stock in Chimerix and receives milestone payments and possible future royalties, member of the scientific advisory board for Break Through Cancer, member of the scientific advisory board for Cure Brain Cancer Foundation, has provided paid consulting services to GCAR;Gan & Lee;BrainStorm;Katmai;Sapience;Inovio;Vigeo Therapeutics;DNATrix;Tyme;SDP;Novartis;Roche; Kintara;Bayer;Merck;Boehinger Ingelheim;VBL;Amgen;Kiyatec;Odonate Therapeutics QED;Medefield;Pascal Biosciences;Bayer;Tocagen;Karyopharm;GW Pharma;Abbvie;VBI;Deciphera;VBL;Agios;;Genocea;Celgene;Puma;Lilly;BMS;Cortice;Wellcome Trust;Novocure;Novogen;Boston Biomedical;Sunovion;Human Longevity;Insys;ProNai;Pfizer;Notable labs;Medqia Trizel;Medscape and has contracts with UCLA for the Brain Tumor Program with Oncovir;Merck;Oncoceutics;Novartis;Amgen;Abbvie;DNAtrix;Beigene;BMS;AstraZeneca;Kazia;Agios;Boston Biomedical;Deciphera;Tocagen;Orbus;AstraZenica;Karyopharm., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread use of aluminum adjuvants is due to their excellent safety profile, which has been established through the use of hundreds of millions of doses in humans over many years. In addition, they are inexpensive, readily available, and are well known and generally accepted by regulatory agencies. Moreover, they offer a very flexible platform, to which many vaccine components can be adsorbed, enabling the preparation of liquid formulations, which typically have a long shelf life under refrigerated conditions. Nevertheless, despite their extensive use, they are perceived as relatively 'weak' vaccine adjuvants. Hence, there have been many attempts to improve their performance, which typically involves co-delivery of immune potentiators, including Toll-like receptor (TLR) agonists. This approach has allowed for the development of improved aluminum adjuvants for inclusion in licensed vaccines against HPV, HBV, and COVID-19, with others likely to follow. This review summarizes the various aluminum salts that are used in vaccines and highlights how they are prepared. We focus on the analytical challenges that remain to allowing the creation of well-characterized formulations, particularly those involving multiple antigens. In addition, we highlight how aluminum is being used to create the next generation of improved adjuvants through the adsorption and delivery of various TLR agonists.

Background: Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice., Materials and Methods: In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes., Results: The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) ( p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T ( p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) ( p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) ( p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies., Conclusions: The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is coming up as a superior imaging tool for prostate cancer (PCa). However, its use in primary staging is still debated. The aim of this study was to assess accuracy of 68Ga-PSMA PET/CT in staging patients with intermediate and high risk PCa candidates to radical prostatectomy managed in the Prostate Cancer Unit of our institution., Methods: We retrospectively evaluated patients with biopsy-proven PCa staged through PSMA PET/CT before undergoing radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND). PET findings were categorized with respect to primary tumor (T), nodal (N) and distant metastasis (M). We analyzed the correspondence between PSMA PET/CT and final histopathological examination., Results: We evaluated 42 men with high and intermediate risk PCa submitted to RP with ePLND. Mean age was 65.5 years (range, 49-76 years) and median preoperative prostate-specific antigen (PSA) was 13 ng/mL (IQR, 8.1-20 ng/mL). Patients in the high-risk group were 23 (54.7%), and the remainders were in the intermediate risk group. The mean risk of lymph node involvement (LNI) using the Memorial Sloan Kettering Cancer Center (MSKCC)-nomogram was 20%. The most common International Society of Urological Pathology (ISUP) grade was 3 (26.19%) after prostate biopsy. PSMA PET/CT showed focal prostatic uptake in 28 patients [mean value of maximum standardized uptake value (SUVmax) 18.5] and detected pelvic lymph node metastases in 6 cases (14.3%) with a median value of SUVmax 4.5 (IQR, 2-6.9). Histopathological examination detected lymph node metastases in seven patients (16.6%). In the only patient with negative PSMA PET/CT pathology revealed the presence of micrometastasis. After histopathological confirmation, sensitivity, specificity, positive and negative predictive values of pre-operative 68Ga-PSMA PET/CT were 85.7%, 100%, 100% and 97%, respectively., Conclusions: In our series, 68Ga-PSMA PET/CT holds high overall diagnostic value for lymph node staging in patients with intermediate and high risk PCa. Accuracy may depend on lymph node size.

Objective: Risk for memory decline is a common concern for individuals with temporal lobe epilepsy (TLE) undergoing surgery. Global and local network abnormalities are well documented in TLE. However, it is less known whether network abnormalities predict postsurgical memory decline. The authors examined the role of preoperative global and local white matter network organization and risk of postoperative memory decline in TLE., Methods: One hundred one individuals with TLE (n = 51 with left TLE and 50 with right TLE) underwent preoperative T1-weighted MRI, diffusion MRI, and neuropsychological memory testing in a prospective longitudinal study. Fifty-six age- and sex-matched controls completed the same protocol. Forty-four patients (22 with left TLE and 22 with right TLE) subsequently underwent temporal lobe surgery and postoperative memory testing. Preoperative structural connectomes were generated via diffusion tractography and analyzed using measures of global and local (i.e., medial temporal lobe [MTL]) network organization. Global metrics measured network integration and specialization. The local metric was calculated as an asymmetry of the mean local efficiency between the ipsilateral and contralateral MTLs (i.e., MTL network asymmetry)., Results: Higher preoperative global network integration and specialization were associated with higher preoperative verbal memory function in patients with left TLE. Higher preoperative global network integration and specialization, as well as greater leftward MTL network asymmetry, predicted greater postoperative verbal memory decline for patients with left TLE. No significant effects were observed in right TLE. Accounting for preoperative memory score and hippocampal volume asymmetry, MTL network asymmetry uniquely explained 25%-33% of the variance in verbal memory decline for left TLE and outperformed hippocampal volume asymmetry and global network metrics. MTL network asymmetry alone produced good diagnostic classification of memory decline in left TLE (i.e., an area under the receiver operating characteristic curve of 0.80-0.84 and correct classification of 65%-76% of cases with cross-validation)., Conclusions: These preliminary data suggest that global white matter network disruption contributes to verbal memory impairment preoperatively and predicts postsurgical verbal memory outcomes in left TLE. However, a leftward asymmetry of MTL white matter network organization may confer the highest risk for verbal memory decline. Although this requires replication in a larger sample, the authors demonstrate the importance of characterizing preoperative local white matter network properties within the to-be-operated hemisphere and the reserve capacity of the contralateral MTL network, which may eventually be useful in presurgical planning.

Background and Objectives: There is growing evidence that bilingualism can induce neuroplasticity and modulate neural efficiency, resulting in greater resistance to neurologic disease. However, whether bilingualism is beneficial to neural health in the presence of epilepsy is unknown. We tested whether bilingual individuals with temporal lobe epilepsy (TLE) have improved whole-brain structural white matter network organization., Methods: Healthy controls and individuals with TLE recruited from 2 specialized epilepsy centers completed diffusion-weighted MRI and neuropsychological testing as part of an observational cohort study. Whole-brain connectomes were generated via diffusion tractography and analyzed using graph theory. Global analyses compared network integration (path length) and specialization (transitivity) in TLE vs controls and in a 2 (left vs right TLE) × 2 (bilingual vs monolingual) model. Local analyses compared mean local efficiency of predefined frontal-executive and language (i.e., perisylvian) subnetworks. Exploratory correlations examined associations between network organization and neuropsychological performance., Results: A total of 29 bilingual and 88 monolingual individuals with TLE matched on several demographic and clinical variables and 81 age-matched healthy controls were included. Globally, a significant interaction between language status and side of seizure onset revealed higher network organization in bilinguals compared with monolinguals but only in left TLE (LTLE). Locally, bilinguals with LTLE showed higher efficiency in frontal-executive but not in perisylvian networks compared with LTLE monolinguals. Improved whole-brain network organization was associated with better executive function performance in bilingual but not monolingual LTLE., Discussion: Higher white matter network organization in bilingual individuals with LTLE suggests a neuromodulatory effect of bilingualism on whole-brain connectivity in epilepsy, providing evidence for neural reserve. This may reflect attenuation of or compensation for epilepsy-related dysfunction of the left hemisphere, potentially driven by increased efficiency of frontal-executive networks that mediate dual-language control. This highlights a potential role of bilingualism as a protective factor in epilepsy, motivating further research across neurologic disorders to define mechanisms and develop interventions., (© 2023 American Academy of Neurology.)

Background : Over the past few decades, there has been much debate and research into the link between alcohol consumption and the development and progression of pancreatic ductal adenocarcinoma (PDAC). Objectives : To contribute to the ongoing discussion and gain further insights into this topic, our study analysed the gene expression differences in PDAC patients based on their alcohol consumption history. Methods : To this end, we interrogated a large publicly available dataset. We next validated our findings in vitro. Results : Our findings revealed that patients with a history of alcohol consumption showed significant enrichment in the TGFβ-pathway: a signaling pathway implicated in cancer development and tumor progression. Specifically, our bioinformatic dissection of gene expression differences in 171 patients with PDAC showed that those who had consumed alcohol had higher levels of TGFβ-related genes. Moreover, we validated the role of the TGFβ pathway as one of the molecular drivers in producing massive stroma, a hallmark feature of PDAC, in patients with a history of alcohol consumption. This suggests that inhibition of the TGFβ pathway could serve as a novel therapeutic target for PDAC patients with a history of alcohol consumption and lead to increased sensitivity to chemotherapy. Our study provides valuable insights into the molecular mechanisms underlying the link between alcohol consumption and PDAC progression. Conclusions : Our findings highlight the potential significance of the TGFβ pathway as a therapeutic target. The development of TGFβ-inhibitors may pave the way for developing more effective treatment strategies for PDAC patients with a history of alcohol consumption.

Introduction: Predicting the success of smoking cessation might be crucial to guide towards the treatment of smoking dependence in a clinical setting. We analyzed the potential determinants of successful smoking cessation with a specific focus on self-efficacy in predicting quitting smoking., Methods: All consecutive smokers (n=478; 224 men and 254 women) attending the Careggi University Hospital Smoking Cessation Service in Florence (Italy) in 2018-2019 provided information on self-efficacy in predicting smoking cessation, using a 1-10 rating scale during their first visit. Patients were followed up for success in quitting smoking at 3, 6 and 12 months, validated through CO exhaled measurement. To evaluate the association between self-efficacy and the probability of success, we estimated multivariable relative risks (RRs) and corresponding 95% confidence intervals (CIs) through log-binomial models for longitudinal data., Results: Overall, 47.9% of smokers succeeded in their attempt to quit at 3 months, 40.2% at 6 months, and 33.9% at 12 months. Compared to low self-efficacy (rating scale 1-5), the RR of success in quitting smoking was 1.40 (95% CI: 1.06-1.85) for intermediate self-efficacy (scale 6-7) and 1.64 (95% CI: 1.28-2.12) for high self-efficacy (scale 8-10)., Conclusions: Self-efficacy is an independent determinant of smoking cessation. We recommend to systematically collect self-efficacy, together with other relevant variables, to predict successful smoking cessation. Moreover, strategies to develop and maintain high levels of self-efficacy are essential to increase quit success and improve treatment., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2023 Gallus S. et al.)

Eye tracking (ET) experiments commonly record the continuous trajectory of a subject's gaze on a two-dimensional screen throughout repeated presentations of stimuli (referred to as trials). Even though the continuous path of gaze is recorded during each trial, commonly derived outcomes for analysis collapse the data into simple summaries, such as looking times in regions of interest, latency to looking at stimuli, number of stimuli viewed, number of fixations or fixation length. In order to retain information in trial time, we utilize functional data analysis (FDA) for the first time in literature in the analysis of ET data. More specifically, novel functional outcomes for ET data, referred to as viewing profiles, are introduced that capture the common gazing trends across trial time which are lost in traditional data summaries. Mean and variation of the proposed functional outcomes across subjects are then modeled using functional principal components analysis. Applications to data from a visual exploration paradigm conducted by the Autism Biomarkers Consortium for Clinical Trials showcase the novel insights gained from the proposed FDA approach, including significant group differences between children diagnosed with autism and their typically developing peers in their consistency of looking at faces early on in trial time., Competing Interests: McPartland consults with Customer Value Partners, Bridgebio, Determined Health, and BlackThorn Therapeutics, has received research funding from Janssen Research and Development, serves on the Scientific Advisory Boards of Pastorus and Modern Clinics, and receives royalties from Guilford Press, Lambert, and Springer. Dawson is on the Scientific Advisory Boards of Janssen Research and Development, Akili Interactive, Inc, LabCorp, Inc, Roche Pharmaceutical Company, and Tris Pharma, and is a consultant to Apple, Gerson Lehrman Group, Guidepoint Global, Inc, and is CEO of DASIO, LLC. Dawson has stock interests in Neuvana, Inc. Dawson has the following patent No. 10,912,801 and patent applications: 62,757,234, 25,628,402, and 62,757,226. Dawson has developed technology, data, and/or products that have been licensed to Apple, Inc. and Cryocell, Inc. and Dawson and Duke University have benefited financially. Shic consults for Roche Pharmaceutical Company, Janssen Research and Development, BlackThorn Therapeutics, and BioStream Technologies.

Objective: Although seizures are a relatively common phenomenon in the setting of brain metastases (BMs), there are no discrete recommendations regarding the use of antiepileptic drugs (AEDs) in this population, either in general or in the context of treatment. The authors' aim was to better understand the underlying pathological factors as well as the therapeutic techniques that may lead to seizures following the radiosurgical treatment of BMs with the goal of guiding appropriate AED prophylaxis., Methods: Adult patients with BMs diagnosed from 2013 to 2020 at a single academic institution and treated with radiation therapy were included in this study. The authors evaluated factors associated with the incidence of seizures throughout the disease course, with a focus on seizures in the 90-day period following stereotactic radiosurgery (SRS)., Results: Four hundred forty-four patients with newly diagnosed BMs were identified, 10% of whom had seizures at the time of presentation and 28% of whom had a seizure at any point during the study period. Tumor histology was significantly associated with initial seizure risk. AED use was highly variable. In the 90-day post-SRS period, the summed total planning target volume (PTV) was independently predictive of post-SRS seizures, regardless of the fractionation scheme (single fraction vs hypofractionated) and other clinical factors. The number of supratentorial BMs was not predictive of post-SRS seizures., Conclusions: PTV is a superior predictor of post-SRS seizures relative to the number of supratentorial BMs, as it serves as a volumetric proxy for intracranial disease burden. A larger PTV, alongside tumor histology and prior seizure history, should be considered in the decision-making process for AED use following radiosurgery.

Predictors of genitourinary toxicity after post-prostatectomy radiotherapy remain elusive. A previously defined germline DNA signature (PROSTOX) has shown predictive ability for late grade ≥ 2 GU toxicity after intact prostate stereotactic body radiotherapy. We explore whether PROSTOX would predict toxicity among patients receiving post-prostatectomy SBRT on a phase II clinical trial., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Weidhaas is a co-founder of MiraDx, which holds intellectual property related to germline microRNA mutations as discussed in this manuscript. The other authors have no relevant conflicts of interest., (© 2023 The Authors.)

COVID-19 has threatened the capability of receiving and allocating patients in emergency departments (EDs) all over the world. This is a retrospective cohort study to explore the role of a simple procedure like an ECG to screen for the severity of COVID-19 on admission to the ED. For this study, 548 consecutive patients were enrolled in a multicenter international registry and stratified upon ECG on admission with a simple distinction between normal vs. abnormal rhythm. Among patients in the abnormal ECG group were those with heart rates higher than 100 beats per minute and/or atrial fibrillation. Survival in patients with normal ECG rhythm was deemed below 75% after 58 days and then stabilized, while survival in patients with abnormal ECG rhythm was deemed below 75% after 11 days and below 50% after 21 days. A multivariate analysis including abnormal rhythm, gender, age, diabetes, obesity, respiratory failure during hospitalization, heart failure during hospitalization, and abnormal rhythm was an independent predictor of death (HR 7.20 95% CI 3.63-14.28, p < 0.01). This finding, if confirmed in large prospective studies, is promising for identifying a cheap and simple procedure for patients in need of a closer look.

Although aluminium-based vaccines have been used for almost over a century, their mechanism of action remains unclear. It is established that antigen adsorption to the adjuvant facilitates delivery of the antigen to immune cells at the injection site. To further increase our understanding of aluminium-based vaccines, it is important to gain additional insights on the interactions between the aluminium and antigens, including antigen distribution over the adjuvant particles. Immuno-assays can further help in this regard. In this paper, we evaluated how established formulation strategies (i.e., sequential, competitive, and separate antigen addition) applied to four different antigens and aluminium oxyhydroxide, lead to formulation changes over time. Results showed that all formulation samples were stable, and that no significant changes were observed in terms of physical-chemical properties. Antigen distribution across the bulk aluminium population, however, did show a maturation effect, with some initial dependence on the formulation approach and the antigen adsorption strength. Sequential and competitive approaches displayed similar results in terms of the homogeneity of antigen distribution across aluminium particles, while separately adsorbed antigens were initially more highly poly-dispersed. Nevertheless, the formulation sample prepared via separate adsorption also reached homogeneity according to each antigen adsorption strength. This study indicated that antigen distribution across aluminium particles is a dynamic feature that evolves over time, which is initially influenced by the formulation approach and the specific adsorption strength, but ultimately leads to homogeneous formulations.