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Introduction: Although familial Mediterranean fever (FMF) is a relevant disease in countries surrounding the Mediterranean Sea, there are still few reports from Italy. Methods: We retrospectively evaluated patients with FMF diagnosed according to the EuroFever/PRINTO classification criteria in three pediatric rheumatology referral centers in central-southern Italy. Logistic regression analysis assessed the associations between age at disease onset and symptoms. Results: Overall, 48 patients were enrolled (28 females, 20 males), with a median age at onset of 3.3 [3.1] years, and a median follow-up period of 5.1 [10.8] years. The most common MEFV genotype was M694V/- (11 patients, 22.9%), followed by M694V/M694V (6 patients, 12.5%). At onset, recurrent fever was observed in 47 patients (97.9%), with a median time between attacks of 18 [11] days. Overall, recurrent fever was observed in all patients, abdominal pain in 44 (91.7%), and chest pain in 18 (37.5%). At the last follow-up visit, 24 patients were on colchicine (50%), 2 on biologic (4.2%), and 6 on both (12.5%). Canakinumab was the most used biologic drug, in 6 (12.5%) patients. MEFV genotype was associated with disease severity (p = 0.007) and the use of a biological drug (p = 0.01). FMF prevalence in the Abruzzo region was found highly than expected (at least 1:45,000). Differently, we found a relevant gap among FMF patients expected and observed in the Apulia and Sicily regions. Conclusions: FMF is a relevant issue in central-southern Italy. A large epidemiologic study should be performed to better define its prevalence in the country. Key Points • Italian children with familial Mediterranean fever tend to have an early age of onset, primarily manifesting with recurrent fever and characteristic associated symptoms. • Many MEFV gene variants are present in Italian children with familial Mediterranean fever, and these patients are most often heterozygous, exhibiting a mild to moderate phenotype. • The prevalence of familial Mediterranean fever in Italy is still unknown but recently estimated to be around 1:60,000, probably higher in central and southern Italy. • According to our cohort, the prevalence of FMF in the Abruzzo region is at least 1:45,000, higher than expected. Differently, we found lower prevalence rates of the disease in Apulia and Sicily. [ABSTRACT FROM AUTHOR]

Consider a large labeled graph (network), denoted the target. Subgraph matching is the problem of finding all instances of a small subgraph, denoted the query, in the target graph. Unlike the majority of existing methods that are restricted to graphs with labels solely on vertices, our proposed approach, named can effectively handle graphs with labels on both vertices and edges. ntroduces an efficient new vertex/edge domain data structure filtering procedure to speed up subgraph queries. The procedure, called path-based reduction, filters initial domains by scanning them for paths up to a specified length that appear in the query graph. Additionally, ncorporates existing techniques like variable ordering and parent selection, as well as adapting the core search process, to take advantage of the information within edge domains. Experiments in real scenarios such as protein–protein interaction graphs, co-authorship networks, and email networks, show that s faster than state-of-the-art systems varying the number of distinct vertex labels over the whole target graph and query sizes. [ABSTRACT FROM AUTHOR]

Introduction: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL). Aims: In this case–control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features. Methods: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP. Results: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r. Conclusion: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment. [ABSTRACT FROM AUTHOR]

Background and purpose: Glucose transporter‐1 (GLUT1) deficiency syndrome (GLUT1‐DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1‐DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant. Methods: We present clinical and genetic features of a five‐generation family with GLUT1‐DS. Results: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8‐year‐old proband, who also had drug‐responsive absences associated with attention‐deficit/hyperactivity disorder. His 52‐year‐old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core. Conclusions: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1‐DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1‐DS. [ABSTRACT FROM AUTHOR]

Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core–shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin–chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration. [ABSTRACT FROM AUTHOR]

Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix and in mice fed with EAA-rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable antiproliferative properties. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM10 and PM2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population's average exposure to annual mean total PM10 and PM2.5 lag 1–5 years was 9.50 µg/m3 and 5.61 µg/m3, respectively. Increased risks were identified for PM10-Traffic (35% [95% CI 0–82%]) and PM2.5-Exhaust (33% [95% CI − 2 to 79%]) in the second exposure tertile for lag 1–5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM2.5-Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM10-Traffic and PM2.5-Exhaust, and conversely, a negative association for PM2.5-Wood burning, no clear exposure–response relationships were evident. [ABSTRACT FROM AUTHOR]

Objective: Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. Methods: Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid β 1‐42, hyperphosphorylated tau, and total tau [t‐tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. Results: CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aβ42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR‐SOB (r = −0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t‐tau levels in all patients (r = −0.144, p = 0.082) and in the female subgroup (r = −0.189, p = 0.084). Interpretation: The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61–73 [ABSTRACT FROM AUTHOR]

In this paper, we describe a general-purpose dialogue management framework used to design SOPHIE (Standardized Online Patient for Healthcare Interaction Education). SOPHIE simulates a virtual standardized cancer patient that allows physicians to practice skills such as empathy and patient empowerment in end-of-life communication. To provide the user with an opportunity to practice these skills, SOPHIE must produce a natural, emotionally appropriate conversation, yet handle topic shifts and open-ended questions from the user. To accomplish this, our approach to dialogue management loosely follows schemas – explicit representations of the typical flows of dialogue in end-of-life communication – while also using flexible pattern-driven methods for interpretation and generation. We conduct a crowdsourced evaluation of conversations between medical students and SOPHIE. Our agent is judged to produce responses that are natural, emotionally appropriate, and consistent with her role as a cancer patient. Furthermore, it significantly outperforms an end-to-end neural model fine-tuned on a human standardized patient corpus, attesting to the advantages of a schema-guided approach in this domain. However, the system is currently limited in its ability to generate responses that are judged to demonstrate deep understanding of the user, suggesting that future work should place focus on integrating this framework with robust natural language understanding and commonsense reasoning methods. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients, substantial morphological alterations have been observed in the hippocampus, which represents an important region for the development of social skills. Melatonin, commonly found in many foods and plants, is also produced by the pineal gland. This indolamine, known to regulate the circadian rhythm, shows antioxidant and anti-inflammatory properties. We therefore hypothesized that melatonin may reduce oxidative stress and inflammation in the hippocampus of ASD patients. We explored our hypothesis using the BTBR mouse, a well-regarded murine transgenic model for ASD. Immediately after weaning, male BTBR and C57BL/6 mice underwent an 8-week treatment with melatonin or vehicle. Later, through immunohistochemistry and the immunoblotting analysis of the hippocampus, we evaluated the overall expression and cellular localization of Nrf2 and SOD1, two enzymes involved in the oxidative stress response. Similarly, we evaluated NLRP3 and NFkB, two mediators of inflammation, and GAD67, an enzyme responsible for the synthesis of GABA. Ultimately, we addressed melatonin's potential to regulate iron metabolism through a DAB-enhanced Perls reaction assay. Results showed melatonin's potential for modulating the analyzed markers in BTBR mice, suggesting a potential neuroprotective effect in ASD patients. [ABSTRACT FROM AUTHOR]

Mild mesial temporal lobe epilepsy (MTLE) patients may remain untreated for a considerable time after disease onset or achieve seizure control with a single anti‐seizures medication (ASM). Thus, they represent an optimal population to investigate whether ASMs might have influence on brain structure. We consecutively enrolled 56 mild MTLE patients (22/56 untreated, 34/56 on‐monotherapy) and 58 healthy controls, matched for age and gender. All subjects underwent 3T‐brain MRI, using FreeSurfer for automated morphometry. Differences in gray matter were assessed using one‐way Analysis of Covariance (ANCOVA), adjusting for age, disease duration and intracranial volume. No significant change was observed between treated and untreated patients. We observed a significant reduction in cortical thickness of left inferior parietal, inferior temporal, middle temporal gyri, and right inferior parietal gyrus, temporal pole in monotherapy patients compared to healthy controls, as well as an increase in left isthmus of cingulate gyrus in untreated MTLE subjects compared to controls. Surface and subcortical volumes analysis revealed no differences among groups. Our study demonstrated no substantial morphological abnormalities between untreated mild MTLE patients and those undergoing monotherapy. Although exploratory, these results may reassure about safety of commonly used drugs and their marginal role in influencing neuroimaging results. Plain Language Summary: This study investigated the following question: can medications against epileptic seizures have an effect on brain structure in mild mesial temporal lobe? Preliminary results from our analyses suggest not, as we did not find any difference in brain gray matter between untreated patients and those treated with a single anti‐seizures medication. On the other hand, epilepsy patients presented cortical thinning compared to healthy controls in several regions of the temporal and parietal lobes, in line with previous studies investigating the disease. [ABSTRACT FROM AUTHOR]

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both "active" and "passive" immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology. [ABSTRACT FROM AUTHOR]

Motivation Cytometry comprises powerful techniques for analyzing the cell heterogeneity of a biological sample by examining the expression of protein markers. These technologies impact especially the field of oncoimmunology, where cell identification is essential to analyze the tumor microenvironment. Several classification tools have been developed for the annotation of cytometry datasets, which include supervised tools that require a training set as a reference (i.e. reference-based) and semisupervised tools based on the manual definition of a marker table. The latter is closer to the traditional annotation of cytometry data based on manual gating. However, they require the manual definition of a marker table that cannot be extracted automatically in a reference-based fashion. Therefore, we are lacking methods that allow both classification approaches while maintaining the high biological interpretability given by the marker table. Results We present a new tool called GateMeClass (Gate Mining and Classification) which overcomes the limitation of the current methods of classification of cytometry data allowing both semisupervised and supervised annotation based on a marker table that can be defined manually or extracted from an external annotated dataset. We measured the accuracy of GateMeClass for annotating three well-established benchmark mass cytometry datasets and one flow cytometry dataset. The performance of GateMeClass is comparable to reference-based methods and marker table-based techniques, offering greater flexibility and rapid execution times. Availability and implementation GateMeClass is implemented in R language and is publicly available at https://github.com/simo1c/GateMeClass [ABSTRACT FROM AUTHOR]

Background: Split phenomena (SP) are characterized by patterns of differential muscle wasting and atrophy, which are highly prevalent in amyotrophic lateral sclerosis (ALS) patients. Several neurophysiological indicators, including the split-hand index (SHI), split-leg index (SLI), and split-elbow index (SEI), have been proposed to assess SP. Nevertheless, their cutoff values and the impact of age and sex on these measures remain unclear. Methods: We prospectively collected neurophysiological data from 300 healthy adult subjects. The following indices were measured from compound muscle action potentials (CMAPs): SHI [abductor pollicis brevis (APBcmap) x first dorsal interosseous (FDI)cmap/adductor digiti minimi (ADMcmap)], SEI (BICEPScmap/TRICEPScmap), SLI (extensor digit brevis (EDB)cmap/abductor Hallucis (AH)cmap), and the neurophysiological ratios APBcmap/ADMcmap and FDIcmap/ADMcmap. Multiple linear regression analysis was used to investigate the association between age, sex, CMAPs, and neurophysiological indicators. Results: The median SHI was 10.4, with a median APBcmap/ADMcmap ratio of 0.9 and a median FDIcmap/ADMcmap ratio of 1.2. The median SEI was 1.6 (IQR:1.1-2.4) and the median SLI was 0.7 (IQR:0.5-1.0). Negative associations were observed between age, most of the CMAPs, and all the neurophysiological indices, except for SLI. The male subjects exhibited significantly higher CMAP values for the first dorsal interosseous (FDI), biceps, and SHI compared to the female participants. Conclusion: Our findings highlight the importance of age- and sex-adjusted normative data for SP indices, which could enhance their diagnostic accuracy and clinical utility in patients with ALS. The SL index appears to be the most reliable indicator, as it showed no significant association with age or sex. [ABSTRACT FROM AUTHOR]

Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults. [ABSTRACT FROM AUTHOR]

Background and Aims Transcatheter pulmonary valve implantation (TPVI) is indicated to treat right-ventricular outflow tract (RVOT) dysfunction related to congenital heart disease (CHD). Outcomes of TPVI with the SAPIEN 3 valve that are insufficiently documented were investigated in the EUROPULMS3 registry of SAPIEN 3-TPVI. Methods Patient-related, procedural, and follow-up outcome data were retrospectively assessed in this observational cohort from 35 centres in 15 countries. Results Data for 840 consecutive patients treated in 2014–2021 at a median age of 29.2 (19.0–41.6) years were obtained. The most common diagnosis was conotruncal defect (70.5%), with a native or patched RVOT in 50.7% of all patients. Valve sizes were 20, 23, 26, and 29 mm in 0.4%, 25.5%, 32.1%, and 42.0% of patients, respectively. Valve implantation was successful in 98.5% [95% confidence interval (CI), 97.4%–99.2%] of patients. Median follow-up was 20.3 (7.1–38.4) months. Eight patients experienced infective endocarditis; 11 required pulmonary valve replacement, with a lower incidence for larger valves (P =.009), and four experienced pulmonary valve thrombosis, including one who died and three who recovered with anticoagulation. Cumulative incidences (95%CI) 1, 3, and 6 years after TPVI were as follows: infective endocarditis, 0.5% (0.0%–1.0%), 0.9% (0.2%–1.6%), and 3.8% (0.0%–8.4%); pulmonary valve replacement, 0.4% (0.0%–0.8%), 1.3% (0.2%–2.4%), and 8.0% (1.2%–14.8%); and pulmonary valve thrombosis, 0.4% (0.0%–0.9%), 0.7% (0.0%–1.3%), and 0.7% (0.0%–1.3%), respectively. Conclusions Outcomes of SAPIEN 3 TPVI were favourable in patients with CHD, half of whom had native or patched RVOTs. [ABSTRACT FROM AUTHOR]

Background: Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies. Aims: This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters. Methods: Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0–1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters. Results: Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1–35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1–9.1; p = 0.03) were associated with shorter survival than those in "cluster-2". Conclusions: Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both motor and non-motor functions, including sleep regulation. Emerging evidence suggests that the hypothalamus, a brain region that plays a critical role in sleep-wake regulation, may be involved in the pathogenesis of ALS-related sleep disturbances. In this review, we have summarized results of studies on sleep disorders in ALS published between 2000 and 2023. Thereafter, we examined possible mechanisms by which hypothalamic dysfunctions may contribute to ALS-related sleep disturbances. Achieving a deeper understanding of the relationship between hypothalamic dysfunction and sleep disturbances in ALS can help improve the overall management of ALS and reduce the burden on patients and their families. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper (UMN) and lower motor neurons (LMN) in four different body regions (bulbar, cervical, thoracic, and lumbosacral). Over the past decades, several clinical scoring systems have been developed to assess the UMN and LMN burden in ALS. However, concerning the bulbar LMN burden, the available scoring systems solely assess the presence/absence of bulbar LMN signs without providing a degree of impairment. Therefore, in this study, we proposed a novel scale to stratify subjects with ALS according to the bulbar LMN involvement and assessed its prognostic value. Methods: We developed a four-item scale based on the LMN signs according to the El Escorial criteria. Ten raters, specializing in ALS or neurocognitive disorders, retrospectively applied the scale to the first evaluation of 195 patients with ALS. Cohen's kappa (Cohen's k) and an intra-class correlation coefficient (ICC) were used to assess the inter-rater reliability. The Kaplan–Mayer estimator was used to estimate survival distribution according to the bulbar scale scores. Results: The raters showed a substantial to excellent agreement with Cohen's k, ranging from 0.834 to 0.975, with an overall ICC of 0.922 (95% CI = 0.906–0.936). The survival distribution was statistically different across the three bulbar scale scores (χ2(2) = 9.50, p < 0.01). Conclusions: Our bulbar LMN scale represents a reliable measure of the bulbar LMN signs in ALS. This easy-to-administer clinical scale could provide unique information in phenotyping and predicting survival in ALS. [ABSTRACT FROM AUTHOR]

Chronic neuroinflammation plays a crucial role in the progression of several neurodegenerative diseases (NDDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, in the last decade, leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic PD, was revealed as a key mediator of neuroinflammation. Therefore, the anti-inflammatory properties of LRRK2 inhibitors have started to be considered as a disease-modifying treatment for PD; however, to date, there is little evidence on the beneficial effects of targeting LRRK2-related neuroinflammation in preclinical models. In this study, we further validated LRRK2 kinase modulation as a pharmacological intervention in preclinical models of AD- and PD-related neuroinflammation. Specifically, we reported that LRRK2 kinase inhibition with MLi2 and PF-06447475 (PF) molecules attenuated neuroinflammation, gliosis and cytotoxicity in mice with intracerebral injection of Aβ1-42 fibrils or α-syn preformed fibrils (pffs). Moreover, for the first time in vivo, we showed that LRRK2 kinase activity participates in AD-related neuroinflammation and therefore might contribute to AD pathogenesis. Overall, our findings added evidence on the anti-inflammatory effects of LRRK2 kinase inhibition in preclinical models and indicate that targeting LRRK2 activity could be a disease-modifying treatment for NDDs with an inflammatory component. [ABSTRACT FROM AUTHOR]

Introduction: Split phenomena in ALS refers to the preferential dysfunction of some groups of muscles over others. The split-elbow sign (SE) is characterized by the predominant weakness of the biceps compared to the triceps, but available results are conflicting. Objectives: To evaluate the prevalence of the SE in two independent cohorts: the randomized controlled trial-based PRO-ACT cohort (n = 500) and a monocentric cohort of patients with ALS from Southern Italy (n = 144); to investigate the demographic and clinical variables associated with the SE sign. Methods: Wilcoxon signed-rank test was used to compare biceps with triceps power in the same limb measured by hand-held dynamometry in the PRO-ACT cohort and Medical Research Council (MRC) in our cohort. Each limb was considered independently and not paired within the same individual. The arm where the triceps was stronger than the biceps was defined SE + , whereas the arm where the biceps was stronger than the triceps was considered SE-. A backward stepwise multivariate logistic regression was used to analyze the relationship between clinical and demographic variables and SE. PENN Upper Motor Neuron and Devine scales were used to evaluate the different upper (UMN) and lower (LMN) motor neuron impairments between the SE + and SE- arms. Results: In both cohorts, the biceps were on average stronger than the triceps, and the SE sign was present in 41% of the PRO-ACT cohort and just 30% of the Southern Italy cohort. The multivariate logistic regression revealed that older age (OR: 1.45; p = 0.01), male gender (OR: 1.55; p = 0.002), spinal onset (OR: 1.59; p = 0.007), and higher disease severity (OR: 1.70; p = 0.001) were significant predictors of the SE sign in the PRO-ACT cohort. Conversely, in Southern Italy patients, only a lower ALSFRS-R score was a significant determinant of the SE (OR: 8.47; p = 0.008). Finally, SE + arms exhibited a significantly higher median Devine sub-score compared to SE- [1 vs 0, p = < 0.05], while arms SE- showed a significantly higher median PUMNS sub-score [2 vs 0; p = < 0.05)]. Conclusion: In our study, most patients with ALS do not show SE. Patients with SE are more likely older, males, with spinal onset, a higher degree of disease severity, and predominant and wider LMN impairment. [ABSTRACT FROM AUTHOR]

Global neuropsychological impairments with intellectual disability (ID) seem to play a major role in the occurrence of psychogenic non‐epileptic seizures (PNES) in epilepsy. Conversely, the pathophysiology underlying PNES combined with epilepsy without ID remains elusive. We investigated the neuropsychiatric profile in 26 average intelligent subjects (15 women, mean age: 40.04 ± 13.53 years) with temporal lobe epilepsy (TLE) plus PNES (TLE + PNES), compared with 28 with TLE and 22 with PNES alone, matched for age and sex. All subjects underwent neuropsychiatric assessment, including Beck Depression Inventory‐2 (BDI‐2), State‐Trait Anxiety Inventory (STAI), Dissociative Experiences Scale (DES), Toronto Alexithymia Scale (TAS‐20), Traumatic Experience Checklist (TEC), and cognitive evaluation. TLE + PNES and PNES groups shared a similar psychiatric profile with higher levels of depression (BDI‐2, P < 0.001), anxiety (STAI‐S, P < 0.001; STAI‐T, P < 0.001), dissociation (DES, P < 0.001), and alexithymia (TAS, P = 0.005) scales than the TLE group. Nonetheless, like individuals with TLE, patients with TLE + PNES had a lower rate of a potentially traumatizing event than PNES. The very low rate of potentially traumatizing event in subjects with TLE + PNES leads us to hypothesize that epilepsy itself may be the psychophysiological distress that contributed to PNES. A psychopathological assessment in subjects with epilepsy is crucial to identify those more likely to develop PNES. [ABSTRACT FROM AUTHOR]

Background: To evaluate the rates of lumbar puncture (LP) in infants with culture-proven sepsis. Study design: We prospectively enrolled 400 infants with early- or late-onset sepsis due to Group B streptococcus (GBS) or Eschericha coli, diagnosed within 90 days of life. Rates of LP and potential variables associated with LP performance were evaluated. Moreover, cerebrospinal fluid (CSF) characteristics and results of the molecular analysis were investigated. Results: LP was performed in 228/400 (57.0%) infants; 123/228 LPs (53.9%) were performed after antibiotic initiation, hampering the ability to identify the pathogen in the CSF culture. However, polymerase chain reaction increased the probability of positive results of CSF analysis compared to microbiological culture (28/79, 35.4% vs. 14/79, 17.7%, p = 0.001). Severe clinical presentation and GBS infection were associated with higher LP rates. The rate of meningitis was 28.5% (65/228). Conclusions: Rates of LP are low in culture-proven neonatal sepsis and antibiotics are frequently given before LP is carried out. Thus meningitis may be underestimated, and the chances of giving an effective therapy to the newborn are reduced. LP should be performed before the start of antibiotics when there is a clinical suspicion of infection. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) are key regulatory proteins that control the transcriptional rate of cells by binding short DNA sequences called transcription factor binding sites (TFBS) or motifs. Identifying and characterizing TFBS is fundamental to understanding the regulatory mechanisms governing the transcriptional state of cells. During the last decades, several experimental methods have been developed to recover DNA sequences containing TFBS. In parallel, computational methods have been proposed to discover and identify TFBS motifs based on these DNA sequences. This is one of the most widely investigated problems in bioinformatics and is referred to as the motif discovery problem. In this manuscript, we review classical and novel experimental and computational methods developed to discover and characterize TFBS motifs in DNA sequences, highlighting their advantages and drawbacks. We also discuss open challenges and future perspectives that could fill the remaining gaps in the field. [ABSTRACT FROM AUTHOR]

The effectiveness of "inadequate" intrapartum antibiotic prophylaxis (IAP administered < 4 h prior to delivery) in preventing early-onset sepsis (EOS) is debated. Italian prospective surveillance cohort data (2003–2022) were used to study the type and duration of IAP according to the timing of symptoms onset of group B streptococcus (GBS) and E. coli culture-confirmed EOS cases. IAP was defined "active" when the pathogen yielded in cultures was susceptible. We identified 263 EOS cases (GBS = 191; E. coli = 72). Among GBS EOS, 25% had received IAP (always active when beta-lactams were administered). Most IAP-exposed neonates with GBS were symptomatic at birth (67%) or remained asymptomatic (25%), regardless of IAP duration. Among E. coli EOS, 60% were IAP-exposed. However, IAP was active in only 8% of cases, and these newborns remained asymptomatic or presented with symptoms prior to 6 h of life. In contrast, most newborns exposed to an "inactive" IAP (52%) developed symptoms from 1 to >48 h of life. The key element to define IAP "adequate" seems the pathogen's antimicrobial susceptibility rather than its duration. Newborns exposed to an active antimicrobial (as frequently occurs with GBS infections), who remain asymptomatic in the first 6 h of life, are likely uninfected. Because E. coli isolates are often unsusceptible to beta-lactam antibiotics, IAP-exposed neonates frequently develop symptoms of EOS after birth, up to 48 h of life and beyond. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and has emerged among the disorders with the largest increasing incidence in Western countries. Although the diagnosis is based on clinical grounds, electromyography (EMG), and nerve conduction studies (NCS) play a crucial role to exclude other potential etiologies of lower motor neuron (LMN) dysfunction. Based on clinical grounds, a peculiar pattern of dissociated atrophy of the intrinsic hand and foot muscles, termed the "split-hand" (SH) and "split-leg" (SL) signs, has been described in a significant proportion of subjects with ALS, even at the early stages of the disease, when symptoms are focal. These signs are rare in neurological and non-neurological diseases other than ALS. In this review, we discussed current evidences concerning SH and SL signs, their pathogenetic hypotheses and neurophysiological findings. We also analyze whether SH and SL signs can be reliable markers in the differential diagnosis and in the prognosis of ALS. [ABSTRACT FROM AUTHOR]

Background: Guillain-Barrè syndrome (GBS) is an acute immune-mediated disorder affecting peripheral nerves and nerve roots with a variable clinical course and outcome. Epidemiologic analyses have revealed that the incidence of the syndrome increases linearly among the age. The clinical diagnosis of GBS is based on the family history, physical and neurological examination, electrodiagnostic exams, and cerebrospinal fluid analysis with the classical presence of albumin-cytologic dissociation. Prognosis is associated with the severity of clinical signs and the type of peripheral nerves involved. Methods: This study aims to clarify which clinical features can be used for prognostic purposes. We evaluated the correlation between (1) brain MRI lesions and grade of disability; (2) brain MRI lesions and elevated cerebrospinal fluid (CSF) protein; and (3) increased levels of CSF protein and grade of disability. Statistical analysis extracted from these data indicated a good correlation to be a prognostic indicator in children affected by GBS. We found little evidence regarding laboratory tests, imaging, and prognosis. We enrolled 12 continuous patients who met the Brighton criteria for GBS in this retrospective study. Each patient was clinically evaluated at the time of disease onset to assess the GBS disability score and after 2 weeks. Results: We estimated Pearson's correlation index to evaluate the possible correlation between MRI and disability and CSF protein levels and disability. The correlation coefficient was 0.92 and 0.85, respectively. In addition, we developed a graph to see the trend of the disability values, proteins in the CSF, and damage assessed with MRI in the 12 patients. It seems that these parameters have a parallel trend and a good correlation in each patient. Finally, we calculated the correlation betweenMRI and CSF protein values, with an r-value of 0.87. The values suggest a correlation among the MRI score, CSF protein, and prognosis. Conclusion: The MRI and CSF laboratory parameters can be important tools for the clinician not only for diagnosis but also to evaluate the possible worsening of general conditions or the need to prepare measures to support life parameters. Patients who need ventilatory support could be established early from patients who have less severe GBS and can begin rehabilitation earlier. We suggest MRI should be performed routinely in children with GBS to be able to estimate the evolution of the clinical condition. [ABSTRACT FROM AUTHOR]

Purpose: Internal thoracic veins are increasingly used as recipient's vessels in chest wall reconstructive surgery due to their predictable anatomy and to the possibility to make a double venous anastomosis, exploiting the retrograde flow within them. Over the years, retrograde flow had been explained by the absence of valves in internal thoracic veins, which have been found recently instead. Therefore, our aim is to analyze the retrograde flow and its relationship with valves in the internal thoracic veins. Methods: We evaluated 32 internal thoracic veins of 16 fresh-frozen specimens with undamaged thoracic cages by dynamic analysis focused on retrograde flow assessment through a partial external circulation system obtained cannulating the subclavian veins. Gross anatomical and morphological evaluations about the presence of valves and their pattern were then made. Results: Efficient, partial, and absent retrograde flow was, respectively, found in 17/30, 8/30 and ITVs and 5/30 internal thoracic veins. Following Arnez's classification, 20/32 Type I and 12/32 Type II internal thoracic veins were identified. Valves were observed in 10/16 specimens (62.50%) corresponding to 36.67% of examined veins (11/30). Three valves were found between the 2nd intercostal space and 12 valves in the 3rd intercostal space. 13/15 valves were bicuspid, 2/15 tricuspid. A significant correlation (p < 0.001) between the retrograde flow and the presence of valves in internal thoracic veins was observed. Conclusion: Our study suggests a possible influence of the presence and the number of valves in the efficient retrograde flow of the internal thoracic veins, suggesting that, especially for more complex cases, a preoperative or intraoperative evaluation of the chest wall drainage should be recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: In this manuscript, we offer an integrated molecular analysis of 44 combined large cell neuroendocrine carcinomas (CoLCNECs) in order to deepen the knowledge about these rare histotypes and to clarify their relationship with lung cancers. In the present state of research, molecular studies are still scant, consisting of small and heterogeneous cohorts, and the genomic landscape is poorly characterized. This study shows that CoLCNECs constitute a standalone group of neuroendocrine neoplasm, with three different molecular profiles, two of which overlap with pure LCNEC or adenocarcinoma. CoLCNECs can be considered an independent histologic category with specific genomic and transcriptomic features, different and therefore not comparable to other lung cancers. Indeed, in addition to a histological re-evaluation of lung cancer classification, our study may help to develop a new diagnostic approach for novel and personalized treatments in CoLCNECs. Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. Results: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. Conclusions: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC. [ABSTRACT FROM AUTHOR]

Transfer learning techniques use information from pre-trained machine learning models (e.g., information on the feature relevance or feature effects with respect to a clinical outcome of interest) to apply it to a new but similar data analysis task, in order to exploit the prior information to build more robust and accurate models (see [[150]] for a review of methodologies). Tailored software solutions have been made available to preprocess clinical data [[21]], NGS data [[49]], microarray data [[50]], different types of metabolomics and proteomics data [[18]], and cellular and brain imaging data [[51]-[54]]. Relevant quality controls typically include statistical outlier checks and computing data type-specific quality metrics, as implemented in established software packages, e.g., the I fastQC/FQC i package for next-generation sequencing (NGS) data [[14]], I arrayQualityMetrics i for microarray data [[15]], I pseudoQC i , I MeTaQuaC i , and I Normalyzer i for proteomics and metabolomics data [[16]-[18]]. [Extracted from the article]

Background: Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.Methods: Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.Results: We show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.Conclusion: These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD. [ABSTRACT FROM AUTHOR]

Purpose: The COVID-19 pandemic has affected the mental and physical health of the world population. This study aims to investigate incidence of sleep-related difficulties and post-traumatic stress disorder in the school-aged children after 1 year of the pandemic. Methods: A sample of Italian children (6-12 years) was queried about their sleep behaviors after 1 year of the pandemic, answering the Children's Sleep Habits Questionnaire (CSHQ). We also evaluated trauma symptoms with the Children's Impact of Event Scale (CRIES-8). Results: Among 205 participants, 184 (89.8%) presented sleep-related difficulties. Out of all, 99 (48.3%) had a high risk to develop post-traumatic stress disorder. Ninety-five (51.6%) children with sleep-related difficulties also presented an abnormal CRIES-8 total score. A correlation was found between the CSHQ total score and the CRIES-8 total score (r = 0.354, P <.01). Conclusions: The sleep-related difficulties occurring during COVID-19 outbreak may compound to increase the risk to develop post-traumatic stress disorder among Italian children. [ABSTRACT FROM AUTHOR]

Although rare, ischemic lesions in neonates may occur in Neonatal Intensive Care Units (NICUs) secondary to routine procedures and/or medicaments. We present double‐center case series, reporting three preterm neonates with ischemic lesions following cardiac arrest and radial blood sampling. The overall outcome after treatment with 2% nitroglycerine (NTG) ointment showed optimal results with no adverse events. The most frequent causes responsible for the onset of such lesions are peripheral arterial catheterization procedures and dopamine extravasation. Our series describe the cardiac arrest as an underestimated cause of onset. Despite the optimal results emerging from the treatment of such lesions with NTG ointment, both in our experience and in the scientific literature, a defined protocol for its use in NICUs is not currently available, hence the need for further studies. [ABSTRACT FROM AUTHOR]

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients. [ABSTRACT FROM AUTHOR]

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Background and purpose: Real‐world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease‐modifying therapies (DMTs). Our aim was to provide real‐world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab. Methods: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation. Results: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow‐up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first‐line oral agents (56), first‐line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty‐five patients were treatment‐naïve. The pre‐alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous‐year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression‐free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re‐baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years. Conclusions: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab. [ABSTRACT FROM AUTHOR]

Background Spatial transcriptomics (ST) combines stained tissue images with spatially resolved high-throughput RNA sequencing. The spatial transcriptomic analysis includes challenging tasks like clustering, where a partition among data points (spots) is defined by means of a similarity measure. Improving clustering results is a key factor as clustering affects subsequent downstream analysis. State-of-the-art approaches group data by taking into account transcriptional similarity and some by exploiting spatial information as well. However, it is not yet clear how much the spatial information combined with transcriptomics improves the clustering result. Results We propose a new clustering method, Stardust , that easily exploits the combination of space and transcriptomic information in the clustering procedure through a manual or fully automatic tuning of algorithm parameters. Moreover, a parameter-free version of the method is also provided where the spatial contribution depends dynamically on the expression distances distribution in the space. We evaluated the proposed methods results by analyzing ST data sets available on the 10x Genomics website and comparing clustering performances with state-of-the-art approaches by measuring the spots' stability in the clusters and their biological coherence. Stability is defined by the tendency of each point to remain clustered with the same neighbors when perturbations are applied. Conclusions Stardust is an easy-to-use methodology allowing to define how much spatial information should influence clustering on different tissues and achieving more stable results than state-of-the-art approaches. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) are proteins that promote or reduce the expression of genes by binding short genomic DNA sequences known as transcription factor binding sites (TFBS). While several tools have been developed to scan for potential occurrences of TFBS in linear DNA sequences or reference genomes, no tool exists to find them in pangenome variation graphs (VGs). VGs are sequence-labelled graphs that can efficiently encode collections of genomes and their variants in a single, compact data structure. Because VGs can losslessly compress large pangenomes, TFBS scanning in VGs can efficiently capture how genomic variation affects the potential binding landscape of TFs in a population of individuals. Here we present GRAFIMO (GRAph-based Finding of Individual Motif Occurrences), a command-line tool for the scanning of known TF DNA motifs represented as Position Weight Matrices (PWMs) in VGs. GRAFIMO extends the standard PWM scanning procedure by considering variations and alternative haplotypes encoded in a VG. Using GRAFIMO on a VG based on individuals from the 1000 Genomes project we recover several potential binding sites that are enhanced, weakened or missed when scanning only the reference genome, and which could constitute individual-specific binding events. GRAFIMO is available as an open-source tool, under the MIT license, at https://github.com/pinellolab/GRAFIMO and https://github.com/InfOmics/GRAFIMO. Author summary: Transcription factors (TFs) are key regulatory proteins and mutations occurring in their binding sites can alter the normal transcriptional landscape of a cell and lead to disease states. Pangenome variation graphs (VGs) efficiently encode genomes from a population of individuals and their genetic variations. GRAFIMO is an open-source tool that extends the traditional PWM scanning procedure to VGs. By scanning for potential TBFS in VGs, GRAFIMO can simultaneously search thousands of genomes while accounting for SNPs, indels, and structural variants. GRAFIMO reports motif occurrences, their statistical significance, frequency, and location within the reference or alternative haplotypes in a given VG. GRAFIMO makes it possible to study how genetic variation affects the binding landscape of known TFs within a population of individuals. [ABSTRACT FROM AUTHOR]

Model development and simulation of biological networks is recognized as a key task in Systems Biology. Integrated with in vitro and in vivo experimental data, network simulation allows for the discovery of the dynamics that regulate biological systems. Stochastic Petri Nets (SPNs) have become a widespread and reference formalism to model metabolic networks thanks to their natural expressiveness to represent metabolites, reactions, molecule interactions, and simulation randomness due to system fluctuations and environmental noise. In the literature, starting from the network model and the complete set of system parameters, there exist frameworks that allow for dynamic system simulation. Nevertheless, they do not allow for automatic model parameterization, which is a crucial task to identify, in silico, the network configurations that lead the model to satisfy specific temporal properties. To cover such a gap, this work first presents a framework to implement SPN models into SystemC code. Then, it shows how the framework allows for automatic parameterization of the networks. The user formally defines the network properties to be observed and the framework automatically extrapolates, through Assertion-based Verification (ABV), the parameter configurations that satisfy such properties. We present the results obtained by applying the proposed framework to model the complex metabolic network of the purine metabolism. We show how the automatic extrapolation of the system parameters allowed us to simulate the model under different conditions, which led to the understanding of behavioral differences in the regulation of the entire purine network. We also show the scalability of the approach through the modeling and simulation of four biological networks, each one with different structural characteristics. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "A systematic review of immunotherapy in high-grade glioma: learning from the past to shape future perspectives" published in the journal Neurological Sciences. The correction addresses a spelling error in one of the author's names, stating that "Eleonara Rollo" should be corrected to "Eleonora Rollo." The correction has been made to the original article. The publisher, Springer Nature, maintains a neutral stance on jurisdictional claims and institutional affiliations. The authors of the article are Giacomo Sferruzza, Stefano Consoli, Fedele Dono, Giacomo Evangelista, Alessia Giugno, Edoardo Pronello, Eleonora Rollo, Marina Romozzi, Lucrezia Rossi, and Umberto Pensato. [Extracted from the article]

Stressful conditions induce the cell to save energy and activate a rescue program modulated by mammalian target of rapamycin (mTOR). Along with transcriptional and translational regulation, the cell relies also on post-transcriptional modulation to quickly adapt the translation of essential proteins. MicroRNAs play an important role in the regulation of protein translation, and their availability is tightly regulated by RNA competing mechanisms often mediated by long noncoding RNAs (lncRNAs). In our paper, we simulated the response to growth adverse condition by bimiralisib, a dual PI3K/mTOR inhibitor, in diffuse large B cell lymphoma cell lines, and we studied post-transcriptional regulation by the differential analysis of exonic and intronic RNA expression. In particular, we observed the upregulation of a lncRNA, lncTNK2-2:1, which correlated with the stabilization of transcripts involved in the regulation of translation and DNA damage after bimiralisib treatment. We identified miR-21-3p as miRNA likely sponged by lncTNK2-2:1, with consequent stabilization of the mRNA of p53, which is a master regulator of cell growth in response to DNA damage. [ABSTRACT FROM AUTHOR]

Given a group of genomes, represented as the sets of genes that belong to them, the discovery of the pangenomic content is based on the search of genetic homology among the genes for clustering them into families. Thus, pangenomic analyses investigate the membership of the families to the given genomes. This approach is referred to as the gene-oriented approach in contrast to other definitions of the problem that takes into account different genomic features. In the past years, several tools have been developed to discover and analyse pangenomic contents. Because of the hardness of the problem, each tool applies a different strategy for discovering the pangenomic content. This results in a differentiation of the performance of each tool that depends on the composition of the input genomes. This review reports the main analysis instruments provided by the current state of the art tools for the discovery of pangenomic contents. Moreover, unlike previous works, the presented study compares pangenomic tools from a methodological perspective, analysing the causes that lead a given methodology to outperform other tools. The analysis is performed by taking into account different bacterial populations, which are synthetically generated by changing evolutionary parameters. The benchmarks used to compare the pangenomic tools, in addition to the computational pipeline developed for this purpose, are available at https://github.com/InfOmics/pangenes-review. Contact: V. Bonnici, R. Giugno Supplementary information: Supplementary data are available at Briefings in Bioinformatics online. [ABSTRACT FROM AUTHOR]

The Enhanced Recovery After Surgery (ERAS) protocol affected traditional cardiac surgery processes and COVID-19 is expected to accelerate its scalability. The aim of this study was to assess the impact of an ERAS-based protocol on the length of hospital stay after cardiac surgery. From January 2019 to June 2020, 664 patients underwent consecutive cardiac surgery at a Latin American center. Here, 46 patients were prepared for a rapid recovery through a multidisciplinary institutional protocol based on the ERAS concept, the "TotalCor protocol". After the propensity score matching, 46 patients from the entire population were adjusted for 12 variables. Patients operated on the TotalCor protocol had reduced intensive care unit time (P < 0.025), postoperative stay (P ≤ 0.001) and length of hospital stay (P ≤ 0.001). In addition, there were no significant differences in the occurrence of complications and death between the two groups. Of the 10-central metrics of TotalCor protocol, 6 had > 70% adherences. In conclusion, the TotalCor protocol was safe and effective for a 3-day discharge after cardiac surgery. Postoperative atrial fibrillation and renal failure were predictors of postoperative stay > 5 days. [ABSTRACT FROM AUTHOR]

Background: Graphs are mathematical structures widely used for expressing relationships among elements when representing biomedical and biological information. On top of these representations, several analyses are performed. A common task is the search of one substructure within one graph, called target. The problem is referred to as one-to-one subgraph search, and it is known to be NP-complete. Heuristics and indexing techniques can be applied to facilitate the search. Indexing techniques are also exploited in the context of searching in a collection of target graphs, referred to as one-to-many subgraph problem. Filter-and-verification methods that use indexing approaches provide a fast pruning of target graphs or parts of them that do not contain the query. The expensive verification phase is then performed only on the subset of promising targets. Indexing strategies extract graph features at a sufficient granularity level for performing a powerful filtering step. Features are memorized in data structures allowing an efficient access. Indexing size, querying time and filtering power are key points for the development of efficient subgraph searching solutions. Results: An existing approach, GRAPES, has been shown to have good performance in terms of speed-up for both one-to-one and one-to-many cases. However, it suffers in the size of the built index. For this reason, we propose GRAPES-DD, a modified version of GRAPES in which the indexing structure has been replaced with a Decision Diagram. Decision Diagrams are a broad class of data structures widely used to encode and manipulate functions efficiently. Experiments on biomedical structures and synthetic graphs have confirmed our expectation showing that GRAPES-DD has substantially reduced the memory utilization compared to GRAPES without worsening the searching time. Conclusion: The use of Decision Diagrams for searching in biochemical and biological graphs is completely new and potentially promising thanks to their ability to encode compactly sets by exploiting their structure and regularity, and to manipulate entire sets of elements at once, instead of exploring each single element explicitly. Search strategies based on Decision Diagram makes the indexing for biochemical graphs, and not only, more affordable allowing us to potentially deal with huge and ever growing collections of biochemical and biological structures. [ABSTRACT FROM AUTHOR]