Age-related changes in the primary auditory cortex of newborn, adults and aging bottlenose dolphins (Tursiops truncatus) are located in the upper cortical layers

Introduction: The auditory system of dolphins and whales allows them to dive in dark waters, hunt for prey well below the limit of solar light absorption, and to communicate with their conspecific. These complex behaviors require specific and sufficient functional circuitry in the neocortex, and vicarious learning capacities. Dolphins are also precocious animals that can hold their breath and swim within minutes after birth. However, diving and hunting behaviors are likely not innate and need to be learned. Our hypothesis is that the organization of the auditory cortex of dolphins grows and mature not only in the early phases of life, but also in adults and aging individuals. These changes may be subtle and involve sub-populations of cells specificall linked to some circuits. Methods: In the primary auditory cortex of 11 bottlenose dolphins belonging to three age groups (calves, adults, and old animals), neuronal cell shapes were analyzed separately and by cortical layer using custom computer vision and multivariate statistical analysis, to determine potential minute morphological differences across these age groups. Results: The results show definite changes in interneurons, characterized by round and ellipsoid shapes predominantly located in upper cortical layers. Notably, neonates interneurons exhibited a pattern of being closer together and smaller, developing into a more dispersed and diverse set of shapes in adulthood. Discussion: This trend persisted in older animals, suggesting a continuous development of connections throughout the life of these marine animals. Our findings further support the proposition that thalamic input reach upper layers in cetaceans, at least within a cortical area critical for their survival. Moreover, our results indicate the likelihood of changes in cell populations occurring in adult animals, prompting the need for characterization

Evaluation of qualitative and semi-quantitative cut offs for rapid diagnostic lateral flow test in relation to serology for the detection of SARS-CoV-2 antibodies: findings of a prospective study

Background:: There is limited information to compare the qualitative and semi-quantitative performance of rapid diagnostic tests (RDT) and serology for the assessment of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, the objective of the study was (a) to compare the efficacy of SARS-CoV-2 antibody detection between RDT and laboratory serology, trying to identify appropriate semi-quantitative cut-offs for RDT in relation with quantitative serology values and to (b) evaluate diagnostic accuracy of RDT compared to the NAAT gold standard in an unselected adult population. Methods:: SARS-CoV-2 antibodies were simultaneously measured with lateral flow immunochromatographic assays (LFA), the Cellex qSARS-CoV-2 IgG/IgM Rapid Test (by capillary blood), the iFlash-SARS-CoV-2 IgG/IgM chemiluminescent immunoassay (CLIA) (by venous blood) and the nucleic acid amplification test (NAAT) in samples from in- and out-patients with confirmed, suspected and negative diagnosis of coronavirus disease 2019 (COVID-19) attending Udine Hospital (Italy) (March-May 2020). Interpretation of RDT was qualitative (positive/negative) and semi-quantitative based on a chromatographic intensity scale (negative, weak positive, positive). Results:: Overall, 720 paired antibody measures were performed on 858 patients. The qualitative and semiquantitative agreement analysis performed in the whole sample between LFA and CLIA provided a Kendall’s tau of 0.578 (p < 0.001) and of 0.623 (p < 0.001), respectively, for IgM and IgG. In patients with a diagnosis of COVID-19, accordance between LFA and CLIA was maintained as a function of time from the onset of COVID-19 disease and the severity of disease both for qualitative and semi-quantitative assessments. RDT compared to the NAAT gold standard in 858 patients showed 78.5% sensitivity (95% CI 75.1%-81.7%) and 94.1% specificity (95% CI 90.4%-96.8%), with variable accordance depending on the timing from symptom onset. Conclusion:: The RDT used in our study can be a non-invasive and reliable alternative to serological tests and facilitate both qualitative and a semi-quantitative antibody detection in COVID-19

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Backgrounds & Aims Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC

Support of precision medicine through risk-stratification in autoimmune liver diseases – histology, scoring systems, and non-invasive markers

Autoimmune liver diseases (AILDs) are complex conditions, which arise from the interaction between a genetic susceptibility and unknown environmental triggers. They represent a relevant cause of liver failure and liver transplantation worldwide. As a testimony of our progress in understanding the biology of AILDs and the disease progression is the overall median survival which has increased over the last decade. However, there are still major challenges such as the lack of therapies and surveillance strategies in primary sclerosing cholangitis (PSC), the management and treatment of non-responders to first-line therapies in primary biliary cholangitis (PBC) and the need for tailoring immunosuppressive drugs in autoimmune hepatitis (AIH). The different disease course and treatment response in patients with AILDs might be related to a heterogeneous genetic background between individuals which translates in a heterogeneous clinical phenotype. Thus, it becomes essential to personalise management and treatment based on specific risk profiles, e.g. low-risk and high-risk, based on genetic and molecular signatures. It is now possible, thanks to the development of large-scale AILDs patient cohorts, that such diseases can be analysed using various high-throughput methods like gene expression profiling, next generation sequencing and other omics technologies to identify unique fingerprints based on which a personalised or tailor-made management and therapy can be developed. The final aim being to facilitate treatment decision-making that balances patient-specific risks and preferences. This is critical especially now with the current and forthcoming availability of more efficacious medications. To reach this point we need specific interventions such as creating bigger biobanks, sequencing more genomes and linking biological information to health-related data. We have already identified subsets of patients with different risk profiles among patients with PBC, PSC and AIH by using clinical tools such as liver histology, laboratory investigation and non-invasive methods. In this manuscript, we review the clinical features and investigations that already enable us to individualize the care of PBC patients and that might support the development of precision medicine (PM) in AILDs. © 2018 Elsevier B.V

Low risk of reinfections and relation with serological response after recovery from the first wave of COVID-19

The aim of the study was to assess reinfection rates in relation to long-term antibody dynamics against SARS-CoV-2 after the first wave. A prospective longitudinal study with monthly serological follow-up during the first 4\ua0months, and then at 6, 8, and 10\ua0months after the disease onset of all recovered adult in- and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. During the follow-up, reinfections were collected. A total of 546 unselected individuals with COVID-19 acquired from March to May 2020 were included (292 female, mean age 53\ua0years). After a median follow-up of 10\ua0months (IQR 6.2\u201310.4), reinfection occurred in 6 (1.1%) patients, median age of 44.5\ua0years (IQR 33\u201249). All had a previous history of mild COVID-19 (all were healthcare workers) and reinfection occurred a median of 9\ua0months (IQR 8.2\u201210.2) after the onset of the first episode. Patients with reinfection were either seronegative (2/56, n = 3.6%), seroreverted (2/137, 1.5%), or seropositive (2/353, 0.6%) (p = 0.085). All reinfections were mild (n = 5) or asymptomatic (n = 1). After reinfection, none of patients developed IgM response and only two had a transitory boosted IgG immunization response. In an unselected population after the first wave of COVID-19, after a prolonged observation period (mean 10\ua0months), reinfection was very uncommon; occurred in patients with a previous history of mild infection, mostly with weak or absent serological response; and manifested with mild or asymptomatic clinical presentation

Glycopatterns of the foregut in the striped dolphin Stenella coeruleoalba, Meyen 1833 from the Mediterranean Sea

The glycopatterns of the glycans secreted by the mucosa of stomach and duodenal ampulla of the striped dolphin, Stenella coeruleoalba were studied by histochemical (Periodic acid-Schiff, Alcian Blue pH 2.5, High Iron Diamine) and lectin-binding (SBA, DBA, PNA, WGA, MAA-II, SNA, ConA, UEA-I, AAA, LTA) techniques. The stomach can be divided into four compartments: main stomach, two connecting chambers and pylorus. The pylorus is followed by the duodenal ampulla. Mucins are secreted by surface cells and intramucosal glands specific for each compartment. In the main stomach glands, neck cells were weakly sulphated, with prevailing glycosaminylated, glycosylated/mannosylated, and fucosylated residuals. Parietal and chief cells in general were scarcely reactive. In the connecting chambers glands, there were high levels of sulphation, glycosaminylation, glycosylation/mannosylation, and fucosylation, the latter with more complex patterns than those observed in the main stomach glands. In the pyloric glands sulphated, glycosaminylated and fucosylated residuals decreased, whereas the opposite was observed for galactosyl/galactosaminylated residuals. Glycosylation patterns in the glands of the duodenal ampulla differed from those of the pyloric ones, with similar levels of sulphation, lower levels of galactosyl/galactosaminylation and glycosaminylation, and higher level of fucosylation. The results are compared with those available in literature

Cytoarchitectureal changes in hippocampal subregions of the NZB/W F1 mouse model of lupus

Over 50% of clinical patients affected by the systemic lupus erythematosus disease display impaired neurological cognitive functions and psychiatric disorders, a form called neuropsychiatric systemic lupus erythematosus. Hippocampus is one of the brain structures most sensitive to the cognitive deficits and psychiatric disorders related to neuropsychiatric lupus. The purpose of this study was to compare, layer by layer, neuron morphology in lupus mice model NZB/W F1 versus Wild Type mice. By a morphometric of cells identified on Nissl-stained sections, we evaluated structural alterations between NZB/W F1 and Wild Type mice in seven hippocampal subregions: Molecular dentate gyrus, Granular dentate gyrus, Polymorph dentate gyrus, Oriens layer, Pyramidal layer, Radiatum layer and Lacunosum molecular layer. By principal component analysis we distinguished healthy Wild Type from NZB/W F1 mice. In NZB/W F1 mice hippocampal cytoarchitecture, the neuronal cells resulted larger in size and more regular than those of Wild Type. In NZB/W F1, neurons were usually denser than in WT. The Pyramidal layer neurons were much denser in Wild Type than in NZB/W F1. Application of principal component analysis, allowed to distinguish NZB/W F1 lupus mice from healthy, showing as NZBW subjects presented a scattered distribution and intrasubject variability. Our results show a hypertrophy of the NZB/W F1 hippocampal neurons associated with an increase in perikaryal size within the CA1, CA2, CA3 region and the DG. These results help advance our understanding on hippocampal organization and structure in the NZB/W F1 lupus model, suggesting the hypothesis that the different subregions could be differentially affected in neuropsychiatric systemic lupus erythematosus disease. Leveraging an in-depth analysis of the morphology of neural cells in the hippocampal subregions and applying dimensionality reduction using PCA, we propose an efficient methodology to distinguish pathological NZBW mice from WT mice.

Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients

Objectives: To assess the prevalence of and factors associated with post-coronavirus disease 2019 (COVID-19) syndrome 6 months after the onset. Methods: A bidirectional prospective study. Interviews investigated symptoms potentially associated with COVID-19 6 months after the disease onset of all consecutive adult inpatients and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated 6 months after the onset of symptoms, at the time of the interview. Results: A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48\u20134.38, p 0.001) and median SARS-CoV-2 IgG titres were significantly higher in patients with post-COVID-19 syndrome than in patients without symptoms (42.1, IQR 17.1\u201378.4 vs. 29.1, IQR 12.1\u201354.2 kAU/L, p 0.004). Female gender (OR 1.55, 95% CI 1.05\u20132.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59\u20132.05) and ICU admission OR 3.10, 95% CI 1.18\u20138.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00\u20131.02, p 0.04). Discussion: Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titres as a means of early detection of post-COVID-19 long-term sequelae