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Mutations in PCDH19gene, which encodes protocadherin-19 (PCDH19), cause Developmental and Epileptic Encephalopathy 9 (DEE9). Heterogeneous loss of PCDH19 expression in neurons is considered a key determinant of the disorder; however, how PCDH19 mosaic expression affects neuronal network activity and circuits is largely unclear. Here, we show that the hippocampus of Pcdh19mosaic mice is characterized by structural and functional synaptic defects and by the presence of PCDH19-negative hyperexcitable neurons. Furthermore, global reduction of network firing rate and increased neuronal synchronization have been observed in different limbic system areas. Finally, network activity analysis in freely behaving mice revealed a decrease in excitatory/inhibitory ratio and functional hyperconnectivity within the limbic system of Pcdh19mosaic mice. Altogether, these results indicate that altered PCDH19 expression profoundly affects circuit wiring and functioning, and provide new key to interpret DEE9 pathogenesis.

About 30–50% of Primary Care (PC) users in Spain suffer mental health problems, mostly mild to moderate anxious and depressive symptoms, which account for 2% of Spain's total Gross domestic product and 50% of the costs associated to all mental disorders. Mobile health tools have demonstrated to cost-effectively reduce anxious and depressive symptoms while machine learning (ML) techniques have shown to accurately detect severe cases. The main aim of this project is to develop a comprehensive ML digital support platform (PRESTO) to cost-effectively screen, assess, triage, and provide personalized treatments for anxious and depressive symptoms in PC.

Introduction: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. Methods: Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR(epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS(Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1(c-ros oncogene 1)-unknown gene fusion, and MET(MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. Results: Overall, a median DNA concentration of 3.3 ng/µL (range 0.1–10.0 ng/µL) and 13.4 ng/µL (range 2.0–45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2–11.9 ng/µL) and 9.3 ng/µL (range 0.5–18.0 ng/µL) were also detected. KRASexon 2 p.G12C, EGFRexon 19 p.E736_A750del hotspot mutations, and ROS1aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected METexon 14 skipping mutation. Conclusions: Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression.

AbstractContinued fractions can be introduced in the field of p-adic numbers Qp, however currently there is not a standard algorithm as in R. Indeed, it is not known how to construct p-adic continued fractions that give periodic representations for all quadratic irrationals and provide good p-adic approximations. In this article, we introduce a novel algorithm which terminates in a finite number of steps when processes rational numbers. Moreover, we study when it provides particular periodic representations of period 2 and pre-period 1 for quadratic irrationals. We also provide some numerical experiments regarding periodic representations and p-adic approximations of quadratic irrationals, comparing the performances with Browkin’s algorithm presented in [6], which is one of the most classical and interesting algorithm for continued fractions in Qp.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p< 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

The year 2021 witnessed the commemoration of the seven hundredth anniversary of Dante Alighieri’s passing. Across the globe, particularly in Italy, a plethora of undertakings were orchestrated to honor this significant milestone. This paper undertakes an examination of the primary events that transpired in homage to Dante. In particular, in juxtaposition to prior centenaries, the authors center their analysis on initiatives that highlighted the rekindling of interest in Dante within Italy as the progenitor of the Italian language, his pivotal role in the establishment of an Italian collective identity, and the broader proliferation of his literary oeuvre. Concurrently, the authors delve into the dissemination and reception of the Dante anniversary on the international stage.

ABSTRACT This work details the experimental and analytical procedures related to the quantification of dynamic modulus for Bitumen Stabilized Material (BSM). it is shown that the existing dynamic modulus test [...]

Several operations can be defined on the set of all linear recurrent sequences, such as the binomial convolution (Hurwitz product) or the multinomial convolution (Newton product). Using elementary techniques, we prove that this set equipped with the termwise sum and the aforementioned products is an R-algebra, given any commutative ring Rwith identity. Moreover, we provide explicitly a characteristic polynomial of the Hurwitz product and Newton product of any two linear recurrent sequences. Finally, we also investigate whether these R-algebras are isomorphic, considering also the R-algebras obtained using the Hadamard product and the convolution product.

A male excess in Sardinian type 1 diabetic cases has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype. In the present study, we have measured the male-to-female (M:F) ratio in a sample set of 542 newly collected, early-onset type 1 diabetic Sardinian patients. This data not only confirm the excess of male type 1 diabetic patients overall (M:F ratio = 1.3, P = 3.9 x [10.sup.-3]) but also that the bias in male incidence is largely confined to patients with the DR3/nonDR4 genotype (M:F ratio = 1.6, P = 2.0 x [10.sup.-4]). These sex effects could be due to a role for allelic variation of the Y chromosome in the susceptibility to type 1 diabetes, but to date this chromosome has not been evaluated in type 1 diabetes. We, therefore, established the frequencies of the various chromosome Y lineages and haplotypes in 325 Sardinian male patients, which included 180 cases with the DR3/nonDR4 genotype, and 366 Sardinian male control subjects. Our results do not support a significant involvement of the Y chromosome in DR3/nonDR4 type 1 diabetic cases nor in early-onset type 1 diabetes as a whole. Other explanations, such as X chromosome-linked inheritance, are thus required for the male bias in incidence in type 1 diabetes in Sardinia., Type 1 diabetes is the only common autoimmune trait that does not exhibit a strong female excess in the patients. A male excess has been reported in specific subgroups of [...]

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Lamotrigine (LTG) is an anticonvulsant drug used for the prevention of depressive episodes in bipolar disorder (BD) that might induce manic episodes in some cases. A 38-year-old man, stabilized with asenapine due to a brief psychotic episode, presented depressive symptoms and LTG was titrated up to 200 mg/day in 6 weeks. One week later he was diagnosed with a first manic episode with psychotic symptoms [Young Mania Rating Scale (YMRS = 31)] and type I BD (BD-I). LTG was withdrawn and he was treated with lithium and lurasidone. The episode remitted in 1 week. A 45-year-old woman with BD presented persistent depressive symptoms and received LTG 25 mg/day. After 3 weeks she was diagnosed with a manic episode with psychotic symptoms (YMRS = 35). LTG was suspended and aripiprazole increased. The episode remitted within 10 days. Both patients remained euthymic with no further episodes after 1-year follow-up. The propensity of LTG to induce manic episodes may be related to its lack of antimanic effects, along with its antidepressant properties, probably related to decreased glutamate release. Secondary analyses from LTG randomized clinical trials have excluded subjects with higher vulnerability to manic switches so that the risk of LTG-induced mania might have been underestimated. LTG-induced mania may be more likely to happen in patients with BD-I, manic predominant polarity, an index manic episode, or those with a history of the antidepressant manic switch. Therefore, in BD patients with the aforementioned risk factors, LTG use should be carefully managed: starting with low doses, extending tapering lengths, using adjunctive treatments and close monitoring manic symptoms.

Susac-syndrome is a rare autoimmune disease that manifests with mood alterations in up to 15% of cases and is usually treated with corticosteroids. We present the case of a 41-year-old woman with a first manic episode and history of Susac-syndrome, secondary Cushing’s syndrome after receiving high doses of corticosteroids and a previous depressive episode. Differentiating between primary and secondary mania is difficult, as people with bipolar disorder are prone to multiple psychiatric and nonpsychiatric comorbidities, in this case, the differential diagnosis included secondary mania, corticoid-induced manic episode and primary bipolar disorder. Upon admission, corticosteroid treatment was suspended, and the patient was started on lithium and risperidone. Secondary causes of mania were discarded and, assessing temporal and dosage criteria, it was deemed unlikely that the present episode was corticosteroid-induced. One-year outpatient follow-up pointed towards a primary bipolar type I disorder, as a separate entity from her Susac-syndrome. Corticosteroid use or abrupt withdrawal pose an underestimated risk of inducing depressive or manic symptoms, which may unmask affective disorders in susceptible individuals. Many medical conditions share CNS involvement and/or high-dose/prolonged corticosteroid treatment. In such cases, psychiatric manifestations such as mania or depression should be regarded as secondary and studied to determine the existence of medical complications before considering primary psychiatric conditions.

IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE: To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members. RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

To evaluate whether a peculiar plasma profile of fatty acids and endocannabinoidome (eCBome)-related mediators may be associated to longevity, we assessed them in octogenarians (Old; n=42) living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ), compared to sexagenarian (Young; n=21) subjects from the same area, and to Olds (n=22) from the Northern Sardinia indicated as Lower-Longevity Zone (LLZ). We found significant increases in conjugated linoleic acid (CLA) and heptadecanoic acid (17:0) levels in Old-HLZ with respect to younger subjects and Old-LLZ subjects. Young-HLZ subjects exhibited higher circulating levels of pentadecanoic acid (15:0) and retinol. Palmitoleic acid (POA) was elevated in both Young and Old subjects from the HLZ. eCBome profile showed a significantly increased plasma level of the two endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in Old-HLZ subjects compared to Young-HLZ and Old-LLZ respectively. In addition, we found increased N-oleoyl-ethanolamine (OEA), 2-linoleoyl-glycerol (2-LG) and 2-oleoyl-glycerol (2-OG) levels in Old-HLZ group with respect to Young-HLZ (as for OEA an d 2-LG) and both the Old-LLZ and Young-HLZ for 2-OG. The endogenous metabolite of docosahexaenoic acid (DHA), N-docosahexaenoyl-ethanolamine (DHEA) was significantly increased in Old-HLZ subjects. In conclusion, our results suggest that in the HLZ area, Young and Old subjects exhibited a favourable, albeit distinctive, fatty acids and eCBome profile that may be indicative of a metabolic pattern potentially protective from adverse chronic conditions. These factors could point to a suitable physiological metabolic pattern that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs—ibrutinib, idelalisib, and venetoclax—have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

AbstractWe discuss the use of matrices for providing sequences of rationals that approximate algebraic irrationalities. In particular, we study the regular representation of algebraic extensions, proving that ratios between two entries of the matrix of the regular representation converge to specific algebraic irrationalities. As an interesting special case, we focus on cubic irrationalities giving a generalization of the Khovanskii matrices for approximating cubic irrationalities. We discuss the quality of such approximations considering both rate of convergence and size of denominators. Moreover, we briefly perform a numerical comparison with well-known iterative methods (such as Newton and Halley ones), showing that the approximations provided by regular representations appear more accurate for the same size of the denominator.

Homeostatic and hedonic pathways distinctly interact to control food intake. Dysregulations of circuitries controlling hedonic feeding may disrupt homeostatic mechanisms and lead to eating disorders. The anorexigenic peptides nucleobindin-2 (NUCB2)/nesfatin-1 may be involved in the interaction of these pathways. The endogenous levels of this peptide are regulated by the feeding state, with reduced levels following fasting and normalized by refeeding. The fasting state is associated with biochemical and behavioral adaptations ultimately leading to enhanced sensitization of reward circuitries towards food reward. Although NUCB2/nesfatin-1 is expressed in reward-related brain areas, its role in regulating motivation and preference for nutrients has not yet been investigated. We here report that both dopamine and GABA neurons express NUCB2/nesfatin-1 in the VTA. Ex vivo electrophysiological recordings show that nesfatin-1 hyperpolarizes dopamine, but not GABA, neurons of the VTA by inducing an outward potassium current. In vivo, central administration of nesfatin-1 reduces motivation for food reward in a high-effort condition, sucrose intake and preference. We next adopted a 2-bottle choice procedure, whereby the reward value of sucrose was compared with that of a reference stimulus (sucralose + optogenetic stimulation of VTA dopamine neurons) and found that nesfatin-1 fully abolishes the fasting-induced increase in the reward value of sucrose. These findings indicate that nesfatin-1 reduces energy intake by negatively modulating dopaminergic neuron activity and, in turn, hedonic aspects of food intake. Since nesfatin-1´s actions are preserved in conditions of leptin resistance, the present findings render the NUCB2/nesfatin-1 system an appealing target for the development of novel therapeutical treatments towards obesity.

The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition introduced the specifier “with mixed features” including 3 or more nonoverlapping typical manic symptoms during a major depressive episode in bipolar disorder type I or II or unipolar major depressive disorder. Excluding overlapping excitatory symptoms, which are frequently observed in mixed depression, leaves many patients with mixed depression undiagnosed. As a consequence, alternative diagnostic criteria have been proposed, claiming for the inclusion in the rubric of mixed features the following symptoms: psychomotor agitation, mood lability, and aggressiveness. A deeper diagnostic reconsideration of mixed features in depression should be provided by the new nosologic classification systems.

With alcohol experiences increasingly shared on social media, this study investigated the construction and understanding of gender norms in alcohol posts: (a) whether stereotypical gender norms prevail across different platforms and message types (b) among adolescents. Focus group interviews with 47 adolescents (Mage= 16.21; SD = 1.22) indicated that social media are important outlets for reproducing stereotypical norms. While sharing alcohol depictions was deemed to be stereotypically female, there were gender differences in the acceptability of sharing certain types of alcohol depictions. As opposed to girls, it was more appropriate for males to depict extreme, negative alcohol behaviors. While girls acknowledged that ephemeral environments enabled them to feel comfortable sharing extreme alcohol behaviors, they carefully negotiated these references by limiting the number of these posts, highlighting female traits in them, and restricting this content to close friends only. Thus, alcohol-related social media posts are more stereotypical than actual drinking experiences, even in more deliberating message types including ephemeral ones.

ABSTRACTIntroduction: The peripartum period in bipolar disorder (BD) patients is associated with high risk of relapse. Relapse during this period may affect fetal and child development. The consequences of psychotropic medication during pregnancy are also a major concern. The extent to which mood stabilizers may potentially affect the embryogenesis or the child development varies from high (e.g. valproate) to less clear and more debated (e.g. lithium).Areas covered: This review describes the current state of evidence with respect to the impact of recommended pharmacological interventions for BD during the peripartum period. It compares recent international treatment guidelines for the management of BD during the peripartum period. Last, this review presents a summary of key recommendations for BD women of childbearing age, for BD women during pregnancy and postpartum period from the international guidelines.Expert opinion: Management of the pharmacological treatment for BD patients during the perinatal period is challenging. Although treatment guidelines may be of significant help, high heterogeneity exists across them. Shared decision-making represents a useful patient-centered approach during the perinatal period. Large cohort studies are needed to better identify risk associated to treatment discontinuation or treatment exposure.

Objectives:Conjugated linoleic acid (CLA) isomers have been shown to possess anti-inflammatory activity in the central nervous system. In this study, we aimed to evaluate whether modulation of the fatty acid profile by the CLA isomers c9,t11 or t10,c12CLA was associated with changes in the expression of pro-inflammatory molecules in human astrocytes.Methods:Cultured astrocytes were treated for 6 days with 100 µM fatty acids (c9,t11CLA or t10,c12CLA or oleic acid). Following the treatment, the fatty acid profile of the cell and pro-inflammatory molecule expression were assessed.Results:Only the t10,c12CLA isomer induced a significant decrease in arachidonic acid and increased the ratio of docosahexaenoic acid/eicosapentaenoic acid, which constitutes indirect evidence of peroxisome proliferator-activated receptor alpha activation. Inhibition of tumour necrosis factor-α, interleukin-1β, and RANTES expression was observed in astrocytes treated with c9,t11CLA and t10,c12CLA.Discussion:Current data demonstrate that CLA isomers, particularly t10,c12, may affect neuroinflammation by reducing the pro-inflammatory molecules in cultured astrocytes, suggesting a potential nutritional role of CLA isomers in modulating the astrocyte inflammatory response.

With the aim to investigate if the halophyte Halothamnus iraqensisBotsch. can be suitable for re-vegetation and remediation of salt-affected lands, this study evaluated (1) the effects of photoperiod, thermoperiod, storage period and wings' presence on its seed germination, and (2) the ability of its seeds to have successful germination recovery after salt stress. Germination tests in different photoperiods (12 h light/12 h darkness and total darkness) and thermoperiods (15°C/20°C and 20°C/25°C) were conducted for seeds collected in 2012, 2013, 2014, 2015 and 2016. The seeds collected in 2016 were sown under different salinity levels (0, 100, 200, 400 and 600 mM NaCl) to assess the salinity tolerance during the germination. Wings' presence highly inhibited seed germination of this species in both photoperiods and thermoperiods under all salinity level treatments. In addition, the germination recovery occurred well when seeds were deprived of their wings. The photoperiod of 12 h light/12 h darkness and the thermoperiod of 15°C/20°C were the best conditions for seed germination. Germination percentages of H. iraqensisseeds decreased with the increasing storage duration, especially after three years of the collection. In addition, H. iraqensisseeds were able to germinate under different salinity levels, and their germination percentages decreased with increasing salinity levels. H. iraqensisseeds have the ability to recover their germination after alleviating the salt stress, irrespective of photoperiod, highlighting the halophilous character of this species.

On-board comfort is one of the factors influencing bus users’ perceptions. Investigating on comfort levels can support transit agencies in monitoring service performance and implementing strategies to improve the service. The specific objective of this paper is to develop an innovative methodology that provides a measure of the quality level of a bus ride in terms of comfort on board, considering instantaneous values of lateral and longitudinal vehicle acceleration. This methodology is based on the matching of subjective and objective measures of comfort. More specifically, authors identify subjective thresholds from the perception of comfort on board and objective thresholds from kinematic parameters recorded along bus routes. The proposed methodology allows to identify a comfort domain and to recognise where passengers experiment comfort/discomfort conditions associated with the driving style of bus drivers.

In chronic lymphocytic leukemia (CLL) patients (pts) the first phase of treatment with covalent Bruton's tyrosine kinase inhibitors (cBTKi), Ibrutinib or Acalabrutinib, is characterized by an increased absolute lymphocyte count (ALC), regardless of previous lines of treatment. Ibrutinib, as first-line therapy, induces lymphocytosis in about 57% of pts, and it is more prominent in IGHV mutated CLL patients. This phenomenon, due to the spread of neoplastic lymphocytes from the nodal compartment into peripheral blood, is transient in most patients, resolving within 8 months, but can rarely persist over 12 months, without any impact on survival: the criterion of Partial Response with Lymphocytosis (PR-L) was introduced for this phenomenon. Despite lymphocytosis in Ibrutinib has been widely investigated, little is known about the effective presence, kinetics and duration of lymphocytosis in patients treated with Acalabrutinib.

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi.

In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch & wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.

Introduction. Expression of the CD49d integrin chain has prognostic impact on ibrutinib (IB)-treated CLL patients (Tissino et al, J Exp Med, 2018; Tissino et al, Blood 2020). In addition, a 4-factor (4-f) score, based on TP53 aberration, β2-microglobulin (β2M), lactate dehydrogenase (LDH) and previous therapy lines was proposed to identify patients at a higher risk of treatment failure or death during IB therapy (Ahn et al, J Clin Oncol, 2020; Morabito et al, Am J Hematol, 2021). The clinical impact of TP53 disruption was recently refined by demonstrating that only the co-presence of TP53 deletion and mutations, and not the single aberrations, has prognostic value in the IB setting (Bomben et al, Leukemia 2022). The aim here is to integrate these observations in a comprehensive scoring for the management of IB-treated patients.

Background:Although CLL primarily affects older adults (median age 71 years), limited data exist about the outcomes of adults who are ≥80 years old because they are under-enrolled in clinical trials.

Introduction:Based on the efficacy of the fixed-duration venetoclax and rituximab combination (VenR) in the setting of relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL), we investigated the efficacy and safety of the front-line VenR regimen in young (≤65 years) and fit patients with CLL and an unfavorable biologic profile in the GIMEMA LLC1518 VERITAS trial. Here, we report the 36-month updated results of this phase II, single-arm, multicenter, front-line study for young patients with CLL carrying an unmutated IGHV profile and/or a TP53 disruption.

Continued fractions have been introduced in the field of p-adic numbers Qpby several authors. However, a standard definition is still missing since all the proposed algorithms are not able to replicate all the properties of continued fractions in R. In particular, an analogue of the Lagrange’s Theorem is not yet proved for any attempt of generalizing continued fractions in Qp. Thus, it is worth to study the definition of new algorithms for p-adic continued fractions. The main condition that a new method needs to fulfill is the convergence in Qpof the continued fractions. In this paper we study some convergence conditions for continued fractions in Qp. These results allow to define many new families of continued fractions whose convergence is guaranteed. Then we provide some new algorithms exploiting the new convergence condition and we prove that one of them terminates in a finite number of steps when the input is rational, as it happens for real continued fractions.

Maternal leptin levels and their relationship with pre-pregnancy body mass index (BMI) and insulin levels were examined in 53 women, 19 normal pregnants (NP), 21 with impaired glucose tolerance during [...]

Rigolin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Coscia:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. 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Given a commutative ring with identity R, many different and interesting operations can be defined over the set $$H_R$$ HR of sequences of elements in R. These operations can also give $$H_R$$ HR the structure of a ring. We study some of these operations, focusing on the binomial convolution product and the operation induced by the composition of exponential generating functions. We provide new relations between these operations and their invertible elements. We also study automorphisms of the Hurwitz series ring, highlighting that some well-known transforms of sequences (such as the Stirling transform) are special cases of these automorphisms. Moreover, we introduce a novel isomorphism between $$H_R$$ HR equipped with the componentwise sum and the set of the sequences starting with 1 equipped with the binomial convolution product. Finally, thanks to this isomorphism, we find a new method for characterizing and generating all the binomial type sequences.

We study some properties and perspectives of the Hurwitz series ring $$H_R[[t]]$$ HR[[t]] , for an integral domain R, with multiplicative identity and zero characteristic. Specifically, we provide a closed form for the invertible elements by means of the complete ordinary Bell polynomials, we highlight some connections with well–known transforms of sequences, and we see that the Stirling transforms are automorphisms of $$H_R[[t]]$$ HR[[t]] . Moreover, we focus the attention on some special subgroups studying their properties. Finally, we introduce a new transform of sequences that allows to see one of this subgroup as an ultrametric dynamic space.

Given a commutative ring Rwith identity, let $$H_R$$ HR be the set of sequences of elements in R. We investigate a novel isomorphism between $$(H_R, +)$$ (HR,+) and $$(\tilde{H}_R,*)$$ (H~R,∗) , where $$+$$ + is the componentwise sum, $$*$$ ∗ is the convolution product (or Cauchy product) and $$\tilde{H}_R$$ H~R the set of sequences starting with $$1_R$$ 1R . We also define a recursive transform over $$H_R$$ HR that, together to the isomorphism, allows to highlight new relations among some well studied integer sequences. Moreover, these connections allow to introduce a family of polynomials connected to the D’Arcais numbers and the Ramanujan tau function. In this way, we also deduce relations involving the Bell polynomials, the divisor function and the Ramanujan tau function. Finally, we highlight a connection between Cauchy and Dirichlet products.

Communities and governments can learn from each other to provide access to education and meet the learning needs of their most vulnerable children. Education Diplomacy can be used to prioritize education challenges, build mutual understanding, and shape consensus toward solutions that are supported by empowered parents/guardians, teachers, school leaders, civil society, and local and central governments committed to inclusive learning for all children.

Background: Multiple Sclerosis (MS) is a chronic multifactorial disease of the central nervous system, specifically characterized by inflammatory demyelination and primary neurodegeneration. Recently, a possible role for the TARDBP Ala382Thr mutation in inducing neurodegeneration in MS has been hypothesized, considering its confirmed role in other neurodegenerative diseases. The aim of the present study was to explore if this mutation plays a role in inducing or enhancing the brain atrophy in MS. Methods: The study included a group of MS patients carrying the TARDBP Ala382Thr mutation, genetically tested at the MS Centre of the University of Cagliari. Mutated MS patients were age, sex, disease course and EDSS-matched with MS patients without mutation, randomly selected from the genetic database. Recruited patients underwent a brain MRI with a 1.5 Tesla Siemens scanner. Volumes of Whole Brain (WB),White Matter (WM) and Grey Matter (GM) were estimated with SIENAX. The difference in brain volumes was assessed with independent samples t-test. Results: Lower WM volumes resulted significantly associated to mutated group (688.68 ml ± 36.55 vs. 713,22 ml ± 27.34; p 0.03). No difference in WB and GM volumes was reported between the two groups. Discussion and Conclusion: Despite this mutation does not play a major role in MS pathogenesis, it may contribute in enhancing the brain atrophy, especially for WM. However, additional studies in other MS populations are needed to better know this issue.