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A circuit of evaluation and selection of the alternatives is considered a reliablemodel in neurobiology. The prominent contributions of the literature to this topic are reported. In this study, valuation and choice of a decisional process during Two-Alternative Forced- Choice (TAFC) task are represented as a two-layered network of computational cells, where information accrual and processing progress in nonlinear diffusion dynamics. The evolution of the response-to-stimulus map is thus modeled by two linked diffusive modules (2LDM) representing the neuronal populations involved in the valuation-and-decision circuit of decision making. Diffusion models are naturally appropriate for describing accumulation of evidence over the time. This allows the computation of the response times (RTs) in valuation and choice, under the hypothesis of ex-Wald distribution. A nonlinear transfer function integrates the activities of the two layers. The input-output map based on the infomax principle makes the 2LDM consistent with the reinforcement learning approach. Results from simulated likelihood time series indicate that 2LDM may account for the activity-dependent modulatory component of effective connectivity between the neuronal populations. Rhythmic fluctuations of the estimate gain functions in the delta-beta bands also support the compatibility of 2LDM with the neurobiology of DM. [ABSTRACT FROM AUTHOR]

Abstract: Eye movement is the simplest and repetitive movement that enables humans to interact with the environment. The common daily activities, such as reading a book or watching television, involve this natural activity, which consists of rapidly shifting our gaze from one region to another. In clinical application, the identification of the main components of eye movement during visual exploration, such as fixations and saccades, is the objective of the analysis of eye movements: however, in patients affected by motor control disorder the identification of fixation is not banal. This work presents a new fixation identification algorithm based on the analysis of variance and covariance: the main idea was to use bivariate statistical analysis to compare variance over x and y to identify fixation. We describe the new algorithm, and we compare it with the common fixations algorithm based on dispersion. To demonstrate the performance of our approach, we tested the algorithm in a group of healthy subjects and patients affected by motor control disorder. [Copyright &y& Elsevier]

Nontyphoidal Salmonella (NTS) is a leading cause of morbidity and mortality caused by enteric pathogens worldwide in both children and adults, and vaccines are not yet available. The measurement of antigen-specific antibodies in the sera of vaccinated or convalescent individuals is crucial to understand the incidence of disease and the immunogenicity of vaccine candidates. A solid and standardized assay used to determine the level of specific anti-antigens IgG is therefore of paramount importance. In this work, we presented the characterization of a customized enzyme-linked immunosorbent assay (ELISA) with continuous readouts and a standardized definition of EU/mL. We assessed various performance parameters: standard curve accuracy, dilutional linearity, intermediate precision, specificity, limits of blanks, and quantification. The simplicity of the assay, its high sensitivity and specificity coupled with its low cost and the use of basic consumables and instruments without the need of high automation makes it suitable for transfer and application to different laboratories, including resource-limiting settings where the disease is endemic. This ELISA is, therefore, fit for purpose to be used for quantification of antibodies against Salmonella Typhimurium and Salmonella Enteritidis O-antigens in human samples, both for vaccine clinical trials and large sero-epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: The recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees.Methods: Samples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant.Results: In patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant.Conclusions: Repeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: There is a need for individuating those post-stroke patients who may benefit from an optimal and customised rehabilitation plan aiming at early reintegration in community life participation. This study investigated whether the gain of independence in complex Activities of Daily Living (ADL) may be predicted before the discharge from the stroke unit using simple bedside determinants. METHODS: In 104 first-ever stroke patients with no previous disability, ten determinants at 10 days after stroke were selected. Multivariable logistic regression analysis was applied to identify the prognostic determinants able to predict independence in complex ADL, as measured by modified Rankin Scale grade ≤2. RESULTS: The model shows that having a Barthel Index ≥⃒9, a Motricity Index- Upper Limb ≥⃒75, an age ≤70 and being a male resulted in 100% probability of achieving independence in complex ADL. If three of the four determinants were present, the probability was more than 90%. With the presence of two of the four determinants, the probability ranged from 87% to 28%. With the presence of only one determinant, the probability was 13%. CONCLUSIONS: Accurate prediction of independence in complex ADL can be made before the discharge from the stroke unit. The strength of the paretic upper limb, age, gender, and the ability of performing basic ADL are the significant variables. The probability of favorable prognosis depends on the presence and on the robustness of each single determinant. [ABSTRACT FROM AUTHOR]

The Enzyme-Linked ImmunoSpot (ELISpot) assay detects cytokines secreted during T cell-specific immune responses against pathogens. As this assay has acquired importance in the clinical setting, standard bioanalytical evaluation of this method is required. Here, we describe a formal bioanalytical validation of a double-color ELISpot assay for the evaluation of IFN-γ and IL-4 released by T helper 1 and T helper 2 cells, respectively. As recommended by international guidelines, the parameters assessed were: range and detection limits (limit of detection, LOD; upper and lower limit of quantification, ULOQ and LLOQ), Linearity, Relative Accuracy, Repeatability, Intermediate Precision, Specificity and Robustness. The results obtained in this validation study demonstrate that this assay meets the established acceptability criteria. ELISpot is therefore a reliable technique for measuring T cell-specific immune responses against various antigens of interest. [ABSTRACT FROM AUTHOR]

The electrocardiographic (ECG) definition of Brugada syndrome (BS) can be challenging because benign ECG abnormalities, such as right bundle branch block (RBBB), may mimic pathological ECG characteristics of BrS. However, although myocardial delay and deformation can be quantified by advanced imaging, it has not yet been used to differentiate between BrS and RBBB. The aim of this study was to characterize the electro-mechanical behavior of the heart of patients with type-1 BrS and isolated complete RBBB in order to differentiate these conditions. In this two-center study, 66 subjects were analyzed by standard and speckle-tracking echocardiography (STE): 22 type-1 BrS, 24 isolated complete RBBB, and 20 healthy subjects. The participants were not treated by any drug potentially influencing myocardial conduction. Standard echocardiographic parameters did not differ among the groups. The greatest right ventricular (RV) mechanical dispersion was found in RBBB. Mean absolute deviations (MADs) of time-to-peak longitudinal strain calculated for each left ventricular (LV) region were greater in patients with RBBB as compared to BrS (p <.01). No differences were found between BrS and controls (p =.36). MADs in the basal segments in RBBB group were greater than MADs found in BrS group and controls (37.3 ms vs. 26.7 ms and 29.0 ms, respectively, p <.05). The greatest differences were found in the antero-septal, anterior, lateral, and infero-septal basal segments. Advanced echocardiographic techniques may help to differentiate between BrS and RBBB. Indeed, STE allows to identify an electro-mechanical conduction delay in RBBB patients that is not found in patients affected by type-1 BrS. • Standard echocardiography did not differ between RBBB and BrS. • In RBBB mechanical dispersion is greater than type1-BrS patients. • The greatest degree of dispersion is observed in LV basal segments. • Mechanical dispersion helps distinguishing between RBBB and type-1 BrS. [ABSTRACT FROM AUTHOR]

Background: Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods: We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results: The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P =.026). Conclusions: Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology. [ABSTRACT FROM AUTHOR]

Introduction: Differentiation between normal solid (non-cystic) pineal glands and pineal pathologies on brain MRI is difficult. The aim of this study was to assess the size of the solid pineal gland in children (0-5 years) and compare the findings with published pineoblastoma cases. Methods: We retrospectively analyzed the size (width, height, planimetric area) of solid pineal glands in 184 non-retinoblastoma patients (73 female, 111 male) aged 0-5 years on MRI. The effect of age and gender on gland size was evaluated. Linear regression analysis was performed to analyze the relation between size and age. Ninety-nine percent prediction intervals around the mean were added to construct a normal size range per age, with the upper bound of the predictive interval as the parameter of interest as a cutoff for normalcy. Results: There was no significant interaction of gender and age for all the three pineal gland parameters (width, height, and area). Linear regression analysis gave 99 % upper prediction bounds of 7.9, 4.8, and 25.4 mm, respectively, for width, height, and area. The slopes (size increase per month) of each parameter were 0.046, 0.023, and 0.202, respectively. Ninety-three percent (95 % CI 66-100 %) of asymptomatic solid pineoblastomas were larger in size than the 99 % upper bound. Conclusion: This study establishes norms for solid pineal gland size in non-retinoblastoma children aged 0-5 years. Knowledge of the size of the normal pineal gland is helpful for detection of pineal gland abnormalities, particularly pineoblastoma. [ABSTRACT FROM AUTHOR]

In about 50% of sporadic cases of retinoblastoma, no constitutive RB1 mutations are detected by conventional methods. However, recent research suggests that, at least in some of these cases, there is somatic mosaicism with respect to RB1 normal and mutant alleles. The increased availability of next generation sequencing improves our ability to detect the exact percentage of patients with mosaicism. Using this technology, we re-tested a series of 40 patients with sporadic retinoblastoma: 10 of them had been previously classified as constitutional heterozygotes, whereas in 30 no RB1 mutations had been found in lymphocytes. In 3 of these 30 patients, we have now identified low-level mosaic variants, varying in frequency between 8 and 24%. In 7 out of the 10 cases previously classified as heterozygous from testing blood cells, we were able to test additional tissues (ocular tissues, urine and/or oral mucosa): in three of them, next generation sequencing has revealed mosaicism. Present results thus confirm that a significant fraction (6/40; 15%) of sporadic retinoblastoma cases are due to postzygotic events and that deep sequencing is an efficient method to unambiguously distinguish mosaics. Re-testing of retinoblastoma patients through next generation sequencing can thus provide new information that may have important implications with respect to genetic counseling and family care. [ABSTRACT FROM AUTHOR]

Literature has suggested that changes in brain flow circulation occur in patients with multiple sclerosis. In this study, digital subtraction angiography (DSA) was used to measure the absolute CCT value in MS patients and to correlate its value to age at disease onset and duration, and to expand disability status scale (EDSS). DSA assessment was performed on eighty MS patients and on a control group of forty-four age-matched patients. CCT in MS and control groups was calculated by analyzing the angiographic images. Lesion and brain volumes were calculated in a representative group of MS patients. Statistical correlations among CCT and disease duration, age at disease onset, lesion load, brain volumes and EDSS were considered. A significant difference between CCT in MS patients (mean = 4.9s; sd = 1.27s) and control group (mean = 2.8s; sd = 0.51s) was demonstrated. No significant statistical correlation was found between CCT and the other parameters in all MS patients. Significantly increased CCT value in MS patients suggests the presence of microvascular dysfunctions, which do not depend on clinical and MRI findings. Hemodynamic changes may not be exclusively the result of a late chronic inflammatory process. [ABSTRACT FROM AUTHOR]

Objectives A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible. Materials and methods In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years. Results On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other human cancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311). Conclusions This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor. [ABSTRACT FROM AUTHOR]

Since the first detection of a novel Coronavirus (SARS-CoV-2) in December 2019 in Wuhan (China), it has become crucial to assess and quantize the human humoral immune response after SARS-CoV-2 natural infection and/or vaccination. Having well standardized and reliable serological assays able to accurately measure the total IgG antibodies response as well as the neutralization dynamics, play a pivotal role for the evaluation of "second" and "third" vaccines generation and in monitoring the effect in case of reinfection in the human population caused by the original strains or new SARS-CoV-2 variants. In the present study we reported that both symptomatic convalescent and vaccinated donors showed the presence of different levels of neutralizing antibodies. In addition, vaccinated subjects presented high levels of anti-S antibodies, whereas the complete absence of anti-N antibodies, whereas convalescent patients presented high levels of both anti-S and anti-N antibodies. The evaluation of the correlation between SARS-CoV-2 neutralizing and binding antibodies in convalescent and vaccinated subjects revealed that the IgG anti-S log-values were significantly higher in the vaccinated group respect to convalescent subjects. In addition, the level of binding antibodies recognizing the S protein shows a positive linear regression when compared to neutralizing titres in both the two groups evaluated. [ABSTRACT FROM AUTHOR]

Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°–18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich’s, in which saccadic intrusions are prominent. [ABSTRACT FROM AUTHOR]

Background: Internal Jugular Veins (IJVs) are the principle outflow pathway for intracranial blood in clinostatism condition. In the seated position, IJVs collapse, while Vertebral Veins (VVs) increase the venous outflow and partially compensate the venous drainage. Spinal Epidural Veins are an additional drainage pathway in the seated position. Colour- Doppler- Sonography (CDS) examination is able to demonstrate IJVs and VVs outflow in different postural and respiratory conditions. The purpose of this study was to evaluate CDS quantification of the cerebral venous outflow (CVF) in healthy subjects and patients with multiple sclerosis (MS). Methodology/Principal Findings: In a group of 27 healthy adults (13 females and 14 males; mean age 37.8±11.2 years), and 52 patients with MS (32 females and 20 males; mean age 42.6±12.1 years), CVF has been measured in clinostatism and in the seated position as the sum of the flow in IJVs and VVs. The difference between CVF in clinostatism and CVF in the seated position (ΔCVF) has been correlated with patients' status (healthy or MS), and a number of clinical variables in MS patients. Statistical analysis was performed by Fisher's exact test, non-parametric Mann-Whitney U test, ANOVA Kruskal- Wallis test, and correntropy coefficient. The value of ΔCVF was negative in 59.6% of patients with MS and positive in 96.3% of healthy subjects. Negative ΔCVF values were significantly associated with MS (p<0.0001). There was no significant correlation with clinical variables. Conclusions/Significance: Negative ΔCVF has a hemodynamic significance, since it reflects an increased venous return in the seated position. This seems to be a pathologic condition. In MS patients, a vascular dysregulation resulting from involvement of the autonomous nervous system may be supposed. ΔCVF value should be included in the quantitative CDS evaluation of the cerebral venous drainage, in order to identify cerebral venous return abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: In this experiment, the changes in excitability of motor axons produced after natural activity were measured in nine healthy subjects using 1 min of maximal voluntary contractions (MVC) of the abductor digiti minimi (ADM) by studying the relationship between stimulus intensity applied to the ulnar nerve and the size of the ADM compound muscle action potential (CMAP). On cessation of the contraction, there was a prominent right-shift of the input–output curve: the intensity required to produce a control CMAP ∼60% of maximum, generated a post-contraction response ∼25% of maximum. Similar changes occurred in the input–output curves obtained by recording the ulnar nerve volley evoked by same test stimulus for CMAP. Motor-evoked potential (MEP) and F-waves (and H-reflex in one subject) were recorded from ADM before and after 1 min of MVC. On cessation of contraction, the MEP input–output curves exhibited a significant right-shift: the stimulus required to evoke a pre-contraction maximum MEP (∼60% of maximum CMAP) generated a post-contraction response ∼65% of initial values. One minute of MVC produced similar decreases of F (∼35%)- and H (∼30%)-ADM responses. All responses recovered their control value in 15–20 min after the end of contraction. The almost identical depressive effect produced by 1 min of MVC on peripherally and centrally generated muscle responses suggests a common conditioning factor. These findings are discussed within the context of activity-induced motor axonal hyperpolarizion. [Copyright &y& Elsevier]

A newly identified coronavirus, named SARS-CoV-2, emerged in December 2019 in Hubei Province, China, and quickly spread throughout the world; so far, it has caused more than 49.7 million cases of disease and 1,2 million deaths. The diagnosis of SARS-CoV-2 infection is currently based on the detection of viral RNA in nasopharyngeal swabs by means of molecular-based assays, such as real-time RT-PCR. Furthermore, serological assays detecting different classes of antibodies constitute an excellent surveillance strategy for gathering information on the humoral immune response to infection and the spread of the virus through the population. In addition, it can contribute to evaluate the immunogenicity of novel future vaccines and medicines for the treatment and prevention of COVID-19 disease. The aim of this study was to determine SARS-CoV-2-specific antibodies in human serum samples by means of different commercial and in-house ELISA kits, in order to evaluate and compare their results first with one another and then with those yielded by functional assays using wild-type virus. It is important to identify the level of SARS-CoV-2-specific IgM, IgG and IgA antibodies in order to predict human population immunity, possible cross-reactivity with other coronaviruses and to identify potentially infectious subjects. In addition, in a small sub-group of samples, a subtyping IgG ELISA has been performed. Our findings showed a notable statistical correlation between the neutralization titers and the IgG, IgM and IgA ELISA responses against the receptor-binding domain of the spike protein. Thus confirming that antibodies against this portion of the virus spike protein are highly neutralizing and that the ELISA Receptor-Binding Domain-based assay can be used as a valid surrogate for the neutralization assay in laboratories that do not have biosecurity level-3 facilities. [ABSTRACT FROM AUTHOR]

Recently, this journal published a paper from Marr et al concerning multi-drug intra-arterial chemotherapy (IAC) for intraocular retinoblastoma. In many centres IAC has quickly garnered exciting interest, emerging as a promising, highly effective alternative for globe conserving treatment.–4 In our institution, IAC with melphalan (IACM) has been performed since June 2008, and topotecan was added in June 2011. Fifty-nine patients have at least 1 year follow-up. Here we report our results obtained with IACM. [ABSTRACT FROM AUTHOR]

The recent outbreak of a novel Coronavirus (SARS-CoV-2) and its rapid spread across the continents has generated an urgent need for assays to detect the neutralising activity of human sera or human monoclonal antibodies against SARS-CoV-2 spike protein and to evaluate the serological immunity in humans. Since the accessibility of live virus microneutralisation (MN) assays with SARS-CoV-2 is limited and requires enhanced bio-containment, the approach based on "pseudotyping" can be considered a useful complement to other serological assays. After fully characterising lentiviral pseudotypes bearing the SARS-CoV-2 spike protein, we employed them in pseudotype-based neutralisation assays in order to profile the neutralising activity of human serum samples from an Italian sero-epidemiological study. The results obtained with pseudotype-based neutralisation assays mirrored those obtained when the same panel of sera was tested against the wild type virus, showing an evident convergence of the pseudotype-based neutralisation and MN results. The overall results lead to the conclusion that the pseudotype-based neutralisation assay is a valid alternative to using the wild-type strain, and although this system needs to be optimised and standardised, it can not only complement the classical serological methods, but also allows serological assessments to be made when other methods cannot be employed, especially in a human pandemic context. [ABSTRACT FROM AUTHOR]

Influenza D virus is a novel influenza virus, which was first isolated from an ailing swine in 2011 and later detected in cattle, suggesting that these animals may be a primary natural reservoir. To date, few studies have been performed on human samples and there is no conclusive evidence on the ability of the virus to infect humans. The aim of this serological study was to assess the prevalence of antibodies against influenza D virus in human serum samples collected in Italy from 2005 to 2017. Serum samples were analysed by haemagglutination inhibition and virus neutralization assays. The results showed that the prevalence of antibodies against the virus increased in the human population in Italy from 2005 to 2017, with a trend characterized by a sharp increase in some years, followed by a decline in subsequent years. The virus showed the ability to infect and elicit an immune response in humans. However, prevalence peaks in humans appear to follow epidemics in animals and not to persist in the human population. [ABSTRACT FROM AUTHOR]