Search

We investigate a quasi-2D suspension of Brownian particles in an optical speckle field produced by holographic manipulation of a laser wavefront. This system was developed to study, in a systematic and controllable way, a distinctive instance of diffusion, called Fickian yet Non Gaussian diffusion (FnGD), observed, during the last decade, for colloidal particles in a variety of complex and biological fluids. Our setup generates an optical speckle field that behaves like a disordered set of optical traps. First, we describe the experimental setup and the dynamics of the particles, focusing on mean square displacements, displacement distributions and kurtosis. Then, we present Brownian Dynamics simulations of point-like particles in a complex energy landscape, mimicking that generated by the optical speckle field. We show that our simulations can capture the salient features of the experimental results, including the emergence of FnGD, also covering times longer than the ones so far achieved in experiments. Some deviations are observed at long time only, with the Gaussian restoring being slower in simulations than in experiments. Overall, the introduced numerical model might be exploited to guide the design of upcoming experiments targeted, for example, to fully monitor the recovery of Gaussianity., (© 2023. The Author(s).)

Background: Specific autoantibodies and nailfold videocapillaroscopy (NVC) findings are serum and morphological diagnostic hallmarks of systemic sclerosis (SSc) as well as useful biomarkers which stratify the microvascular progression and prognosis of patients., Methods: The aim of our narrative review is to provide an update and overview of the link between SSc-related autoantibodies, used in clinical practice, and microvascular damage, evaluated by NVC, by exploring the interaction between these players in published studies. A narrative review was conducted by searching relevant keywords related to this field in Pubmed, Medline and EULAR/ACR conference abstracts with a focus on the findings published in the last 5 years., Results: Our search yielded 13 clinical studies and 10 pre-clinical studies. Most of the clinical studies (8/13, 61.5%) reported a significant association between SSc-related autoantibodies and NVC patterns: more specifically anti-centromere autoantibodies (ACA) were associated more often with an "Early" NVC pattern, whereas anti-topoisomerase autoantibodies (ATA) more frequently showed an "Active" or "Late" NVC pattern. Five studies, instead, did not find a significant association between specific autoantibodies and NVC findings. Among the pre-clinical studies, SSc-related autoantibodies showed different mechanisms of damage towards both endothelial cells, fibroblasts and smooth muscle vascular cells., Conclusions: The clinical and laboratory evidence on SSc-related autoantibodies and microvascular damage shows that these players are interconnected. Further clinical and demographic factors (e.g., age, sex, disease duration, treatment and comorbidities) might play an additional role in the SSc-related microvascular injury whose progression appears to be complex and multifactorial.

The Nipah and Hendra viruses (NiV and HeV) are biosafety level 4 human pathogens classified within the Henipavirus genus of the Paramyxoviridae family. In both NiV and HeV, the gene encoding the Phosphoprotein (P protein), an essential polymerase cofactor, also encodes the V and W proteins. These three proteins, which share an intrinsically disordered N-terminal domain (NTD) and have unique C-terminal domains (CTD), are all known to counteract the host innate immune response, with V and W acting by either counteracting or inhibiting Interferon (IFN) signaling. Recently, the ability of a short region within the shared NTD (i.e., PNT3) to form amyloid-like structures was reported. Here, we evaluated the relevance of each of three contiguous tyrosine residues located in a previously identified amyloidogenic motif (EYYY) within HeV PNT3 to the fibrillation process. Our results indicate that removal of a single tyrosine in this motif significantly decreases the ability to form fibrils independently of position, mainly affecting the elongation phase. In addition, we show that the C-terminal half of PNT3 has an inhibitory effect on fibril formation that may act as a molecular shield and could thus be a key domain in the regulation of PNT3 fibrillation. Finally, the kinetics of fibril formation for the two PNT3 variants with the highest and the lowest fibrillation propensity were studied by Taylor Dispersion Analysis (TDA). The results herein presented shed light onto the molecular mechanisms involved in fibril formation.

Measles, Nipah and Hendra viruses are severe human pathogens within the Paramyxoviridae family. Their non-segmented, single-stranded, negative-sense RNA genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid that is the substrate used by the viral RNA-dependent-RNA-polymerase (RpRd) for transcription and replication. The RpRd is a complex made of the large protein (L) and of the phosphoprotein (P), the latter serving as an obligate polymerase cofactor and as a chaperon for N. Both the N and P proteins are enriched in intrinsically disordered regions (IDRs), i.e. regions devoid of stable secondary and tertiary structure. N possesses a C-terminal IDR (NTAIL), while P consists of a large, intrinsically disordered N-terminal domain (NTD) and a C-terminal domain (CTD) encompassing alternating disordered and ordered regions. The V and W proteins, two non-structural proteins that are encoded by the P gene via a mechanism of co-transcriptional edition of the P mRNA, are prevalently disordered too, sharing with P the disordered NTD. They are key players in the evasion of the host antiviral response and were shown to phase separate and to form amyloid-like fibrils in vitro. In this review, we summarize the available information on IDRs within the N, P, V and W proteins from these three model paramyxoviruses and describe their molecular partnership. We discuss the functional benefit of disorder to virus replication in light of the critical role of IDRs in affording promiscuity, multifunctionality, fine regulation of interaction strength, scaffolding functions and in promoting liquid-liquid phase separation and fibrillation., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Anti-double-stranded DNA antibodies (anti-dsDNA) are considered a specific marker for systemic lupus erythematosus (SLE). Though the Farr technique was once the reference method for their detection, it has been almost entirely replaced by more recently developed assays. However, there is still no solid evidence of the commutability of these methods in terms of diagnostic accuracy and their correlation with the Crithidia luciliae immunofluorescence test (CLIFT). Anti-dsDNA antibody levels were measured in 80 subjects: 24 patients with SLE, 36 disease controls drawn from different autoimmune rheumatic diseases (14 systemic sclerosis, 10 Sjögren's syndrome, nine autoimmune myositis, three mixed connective tissue disease), 10 inflammatory arthritis and 10 apparently healthy blood donors by eight different methods: fluorescence enzyme immunoassay, microdot array, chemiluminescent immunoassay (two assays), multiplex flow immunoassay, particle multi-analyte technology immunoassay and two CLIFT. At the recommended manufacturer cut-off, the sensitivity varied from 67% to 92%, while the specificity ranged from 84% to 98%. Positive agreement among CLIFT and the other assays was higher than negative agreement. Mean agreement among methods assessed by the Cohen's kappa was 0.715, ranging from moderate (0.588) to almost perfect (0.888). Evaluation of the concordance among quantitative values by regression analysis showed a poor correlation index (mean r2, 0.66). The present study shows that current technologies for anti-dsDNA antibody detection are not fully comparable. In particular, their different correlation with CLIFT influences their positioning in the diagnostic algorithm for SLE (either in association or sequentially). Considering the high intermethod variability, harmonization and commutability of anti-dsDNA antibody testing remains an unachieved goal., (© 2022 The Scandinavian Foundation for Immunology.)

Purpose of Review: Paraneoplastic neurological syndromes (PNS) are caused by nervous system-targeting aberrant anti-tumoral immune responses. We review the updated criteria for PNS diagnosis, incorporating novel information on clinical phenotypes, neuronal autoantibodies (Nabs), and tumors. The impact of the oncologic use of immune checkpoint inhibitors (ICI) on PNS occurrence is also addressed., Recent Findings: Clinical phenotypes and Nabs are redefined as "high/intermediate/low" risk, following the frequency of cancer association. Nabs, the diagnostic hallmark of PNS, can target intracellular or surface neuronal proteins, with important prognostic and pathogenic implications. Many novel assays have been incorporated into laboratory diagnostics, that is becoming increasingly complex. ICI fight tumors, but favor autoimmunity, thus increasing the incidence of PNS-like disorders. Overcoming the old PNS criteria, the new ones are centered around the presence of tumor. Clinical presentation, Nabs, and tumor findings are translated in diagnostic scores, providing a useful tool for PNS diagnosis and management., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation., Competing Interests: Declaration of competing interest Authors declair Non competing interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID., Methods: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19., Results: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement., Conclusion: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Autoantibodies against extractable nuclear antigens (ENA) play a pivotal role in the diagnosis and classification of systemic autoimmune rheumatic diseases (SARD). In recent years, newly developed methods have enabled the simultaneous and quantitative detection of multiple anti-ENA reactivities. However, data regarding the comparability of results obtained using different technologies across different platforms are scarce. In this study we compared eight different immunoassays, commonly used in current laboratory practice for detection of anti-ENA antibodies., Methods: Sixty patients suffering from different SARD, 10 inflammatory arthritis patients (disease controls) and 10 healthy blood donors were included in this comparative study. Sera were collected in 15 centers belonging to the Study Group on Autoimmune Diseases of the Italian Society of Clinical Pathology and Laboratory Medicine. We evaluated the analytical sensitivity, specificity and diagnostic accuracy of each method for antibodies to Sm, RNP, Ro60, Ro52, Scl70, CENP-B and Jo1. Cohen's kappa was used to analyze the agreement among methods., Results: Average agreement among methods was 0.82, ranging from substantial (k = 0.72) to almost perfect (k = 0.92). However, while the specificity was very good for all methods, some differences emerged regarding the analytical sensitivity., Conclusions: Diagnostic performance of current technologies for anti-ENA antibody detection showed good comparability. However, as some differences exist among methods, laboratory scientists and clinicians must be aware of the diagnostic accuracy of the testing method in use., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children., Methods: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration., Results: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10 -8 ). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10 -8 , n = 577) and sleep onset latency (p = 8.8 × 10 -9 , n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539)., Conclusion: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available., (© 2022. The Author(s).)

Background: The prevalence of obstructive sleep apnea is higher in women after menopause. This is suggested to be a result of an altered sex hormone balance but has so far not been confirmed in a population-based study., Objective: To investigate whether serum concentration of estrogens and progesterone are associated with the prevalence of sleep apnea symptoms in middle-aged women of the general population., Methods: We analyzed data from 774 women (40-67 years) from 15 study centers in seven countries participating in the second follow-up of the European Community Respiratory Health Survey (2010-2012). Multiple logistic regression models were fitted with self-reported symptoms of sleep apnea as outcomes and serum concentrations of various estrogens and progesterone as predictors. All analyses were adjusted for relevant covariates including age, BMI, education, study center, smoking habits, and reproductive age., Results: Among all included women, a doubling of serum concentrations of estrone and progesterone was associated with 19% respectively 9% decreased odds of snoring. Among snorers, a doubling of the concentrations of 17β-estradiol, estrone and estrone 3-sulfate was associated with 18%, 23% and 17% decreased odds of breathing irregularly, and a doubling of the progesterone concentration was further associated with 12% decreased odds of waking up suddenly with a chocking sensation. Other evaluated associations were not statistically significant., Conclusions: Middle-aged women with low serum estrogen and progesterone levels are more likely to snore and report symptoms of obstructive sleep apnea., Competing Interests: The authors have declared that no competing interests exist.

Parkinson's disease (PD) is an uncommon disease with a long prodromal period and higher incidence in men than women. Large cohort studies of women with a long follow-up are needed. Within the E3N French cohort study (98,995 women, 40-65 years at baseline), we identified 3,584 participants who self-reported PD or used anti-parkinsonian drugs over 27 years (1992-2018). We obtained medical records to validate PD diagnosis (definite, probable, possible, no). When medical records were not available, we used a validated algorithm based on drug claims to predict PD status. We retained a PD diagnosis for 1,294 women (medical records, 62%; algorithm, 38%). After exclusion of prevalent/possible cases, cases without age at diagnosis, and women lost to follow-up, our analyses included 98,069 women, of whom 1,200 had incident PD (mean age at diagnosis = 71.8 years; incidence rate = 0.494/1,000 person-years). Age-adjusted incidence rates increased over the six first years of follow-up, possibly due to healthy volunteer bias, and remained stable thereafter, similar to incidence rates in women from Western Europe. Forty three percent of PD cases occurred after 20 years of follow-up (2012-2018). The cumulative incidence of PD from 50 to 90 years was 2.41% (95% confidence interval [CI] = 2.27-2.65). PD incidence was lower in ever than never smokers (hazard ratio = 0.86, 95% CI = 0.76-0.96). In conclusion, we estimated PD incidence rates in French women over a 27-year follow-up, and showed stable incidence between 2002 and 2018. The long follow-up and large sample size make this study a valuable resource to improve our knowledge on PD etiology in women., (© 2022. Springer Nature B.V.)

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22., (© 2022. The Author(s).)

Objective: Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations., Research Design and Methods: To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression., Results: Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] -0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm., Conclusions: Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses., (© 2022 by the American Diabetes Association.)

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10 -4 , p-value = 5.87 × 10 -5 ) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10 -5 ), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10 -7 ) in GRK1 and cg02212000 (β = -0.001, p-value = 8.13 × 10 -7 ) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins.

Fickian yet non-Gaussian Diffusion (FnGD), widely observed for colloidal particles in a variety of complex and biological fluids, emerges as a most intriguing open issue in Soft Matter. To fully monitor FnGD and advance its understanding, recording many trajectories over a large time range is crucial, which makes experiments challenging. Here we exploit a recently introduced experimental model of finely tunable FnGD: a quasi-2d system of Brownian beads in water moving in a heterogeneous energy landscape generated by a static and spatially random optical force field (speckle pattern). By performing experiments at different optical power, we succeed in monitoring the evolution as well as the precursors of FnGD. Fickian scaling of the mean square displacement is always attained after a subdiffusive regime while the displacement distributions keep on being non-Gaussian, which allows for measuring a characteristic length- and time-scale for the onset of FnGD, ξ f and t f . We find that ξ f stays constant, whereas t f grows as the inverse of the long-time diffusion coefficient t f ∝ D -1 for increasing the optical power. Deviations from the standard Gaussian shape of the displacement distribution are neatly characterized on a broad range of times, focusing on the excess probability at small displacements and on the decay-length of the distinctive exponential tails. Such deviations are fully built in the subdiffusive regime and, at the FnGD onset, grow with the optical power. As time goes on, the small-displacement probability narrows and the exponential tails progressively break up, with a tendency to recover the Gaussian behaviour. Overall, both subdiffusion and FnGD become more marked and persistent on increasing the optical power, suggesting a strict relation between these two regimes. As clearly demonstrated by our results, the adopted model-system represents a privileged stage for in-depth study of FnGD and opens the way to unveil the nature of this phenomenon through finely tuned and well-controlled experiments.

In the last two decades it has become increasingly evident that a large number of proteins adopt either a fully or a partially disordered conformation. Intrinsically disordered proteins are ubiquitous proteins that fulfill essential biological functions while lacking a stable 3D structure. Their conformational heterogeneity is encoded by the amino acid sequence, thereby allowing intrinsically disordered proteins or regions to be recognized based on their sequence properties. The identification of disordered regions facilitates the functional annotation of proteins and is instrumental for delineating boundaries of protein domains amenable to crystallization. This chapter focuses on the methods currently employed for predicting protein disorder and identifying intrinsically disordered binding sites., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.

Objectives: We aimed to evaluate joint and vessel uptake in patients with polymyalgia rheumatica (PMR) by FDG-PET and correlate it with clinical findings., Methods: Consecutive PMR patients, without clinical signs of giant cell arteritis, underwent a standardised clinical examination and FDG-PET/CT. Controls were consecutive subjects undergoing FDG-PET for the suspicion of neoplasm not confirmed by the examination. Uptake was evaluated by a qualitative visual score, using the liver uptake as reference and by the semi-quantitative mean standardised uptake value (SUV) and target-to-background ratio (TBR) methods., Results: Eighty-four patients and 84 controls (55 women, median age 73 years, range 50-92 years in both groups) were studied. Sixteen patients were taking glucocorticoids (GC). PMR patients showed a higher articular uptake than controls. GC-treated patients showed uptake lower than GC-naïve patients, but still higher than controls. PMR patients showed a higher vascular uptake than controls in all districts except in the carotid arteries, when evaluated by the visual score. Conversely, the semi-quantitative approach yielded no significant differences. Forty-two patients (50%) showed PET evidence of large-vessel vasculitis (LVV), defined as uptake ≥ than that of the liver, and 11.9% showed LVV with vascular uptake higher than that of the liver. The correlation between clinical findings and uptake was scarce. Neither clinical nor laboratory findings could predict the presence of LVV., Conclusions: Patients with PMR show a typical joint pattern at FDG-PET. There are no clinical or laboratory predictors of LVV. Imaging appears to be the only tool to assess LVV in these patients.

Although, the association between celiac disease (CD) and selective immunoglobulin A deficiency (SIgAD) has been known for more than fifty years, the procedures for diagnosing and monitoring patients with both conditions are still far from definitive. When serological markers were introduced as pre-bioptic investigations, it was immediately clear that searching for specific IgA antibodies without checking total serum IgA could lead to a failure in diagnosing IgA-deficient CD patients, while specific IgG antibodies could be useful as additional tests, because they are frequently found in the serum of affected patients. Nonetheless, until recently the diagnosis of CD in IgA-deficient patients was based on the few, fragmentary and often contradictory data available in literature. The introduction of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines in 2012 provided the current criteria for diagnosing CD in IgA-deficient patients, although some issues remained open, such as the selection of patients who should undergo specific IgG antibody testing and the choice of the most reliable IgG-based test for both diagnosis and follow-up. A real-life study recently assessed the impact of the 2012 ESPGHAN guidelines in diagnosing and monitoring CD in SIgAD patients, highlighting several pitfalls that can lead to operational uncertainties and difficulties in patient management. In the present report, the evolution of diagnostic tools and criteria for CD in SIgAD patients has been critically assessed, both strengths and open issues have been highlighted, and future perspectives for improving the current diagnostic protocols have been suggested., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Henipaviruses are BSL-4 zoonotic pathogens responsible in humans for severe encephalitis. Their V protein is a key player in the evasion of the host innate immune response. We previously showed that the Henipavirus V proteins consist of a long intrinsically disordered N-terminal domain (NTD) and a β-enriched C-terminal domain (CTD). These terminals are critical for V binding to DDB1, which is a cellular protein that is a component of the ubiquitin ligase E3 complex, as well as binding to MDA5 and LGP2, which are two host sensors of viral RNA. Here, we serendipitously discovered that the Hendra virus V protein undergoes a liquid-to-hydrogel phase transition and identified the V region responsible for this phenomenon. This region, referred to as PNT3 and encompassing residues 200-310, was further investigated using a combination of biophysical and structural approaches. Congo red binding assays, together with negative-staining transmisison electron microscopy (TEM) studies, show that PNT3 forms amyloid-like fibrils. Fibrillation abilities are dramatically reduced in a rationally designed PNT3 variant in which a stretch of three contiguous tyrosines, falling within an amyloidogenic motif, were replaced by three alanines. Worthy to note, Congo red staining experiments provided hints that these amyloid-like fibrils form not only in vitro but also in cellula after transfection or infection. The present results set the stage for further investigations aimed at assessing the functional role of phase separation and fibrillation by the Henipavirus V proteins.

Guillain-Barré syndrome (GBS) is an immune-mediated peripheral neuropathy characterized by a typical post-infectious profile. Some post-Zika virus and post-severe acute respiratory syndrome-related coronavirus-2 GBS cases have been reported to occur with very short intervals between the infection and GBS onset. Evaluating 161 GBS patients consecutively admitted to two Italian Regional Hospitals between 2003 and 2019, we found that the only three with an antecedent influenza A (H1N1) virus infection developed GBS within an interval of less than 10 days from the influenza illness. The two of them with a demyelinating subtype promptly recovered without therapy. Overall, the parainfectious cases add heterogeneity to the GBS category, warranting pathogenetic insights., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF., Methods: Patients were selected from the French national prospective cohort COFI. Patients' income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis., Results: 200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM 2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI 95% : 1.24-2.62, p = 0.001) and overall survival (HR: 1.49; CI 95% : 1.0006-2.23, p = 0.049)., Conclusions: Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes., Methods: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques., Results: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months., Conclusions: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN., Trial Registration: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Results regarding the association between hormonal exposure and risk of Parkinson's disease (PD) are heterogeneous., Objectives: To investigate the association of reproductive life characteristics with PD among postmenopausal women., Methods: The PARTAGE case-control included 130 female cases and 255 age-matched female controls. Information on gynecological history was obtained from a standardized questionnaire and PD was validated by neurological examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression., Results: After adjustment for education level, smoking status, professional exposure to pesticides, and coffee and alcohol drinking, bilateral oophorectomy (OR = 3.55, 95%CI = 1.75-7.20), but neither menopause before age 50 years (OR = 1.24, 95%CI = 0.74-2.09) nor hormone therapy (HT; OR = 1.07, 95%CI = 0.62-1.86), was associated with PD., Conclusion: Our findings suggest that bilateral oophorectomy is associated with increased risk of PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objectives: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis., Methods: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques., Results: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions., Conclusion: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients., Trial Registration: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by specific vascular and obstetric manifestations and by antiphospholipid antibodies (aPL) positivity. Microvascular damage in the course of APS and "aPL carrier" patients without symptoms is poorly investigated., Objectives: This study aims to compare nailfold videocapillaroscopy (NVC) microvascular parameters in APS patients and non-symptomatic "aPL carriers" and to investigate their possible correlations with different aPL subtypes., Methods: NVC was performed during standard evaluations in 18 APS patients (mean age 50 ± 13.8 years), 24 "aPL carriers" without symptoms (mean age 46.4 ± 16.4 years), and 18 control patients (CTR) (mean age 74 ± 12.5 years) taking oral anticoagulants for non-immunological indications (i.e., cardiovascular accidents). All patients were investigated for the presence of dilated capillaries, giant capillaries, microhemorrhages, capillary loss, and further non-specific/specific abnormalities (i.e., branched "bushy" capillaries, sign of neoangiogenesis) by NVC. Every alteration was also classified according to a semi-quantitative score. Lupus anticoagulant, anticardiolipin antibodies, and antibeta2 glycoprotein I antibodies were tested in each patient., Results: APS patients showed at NVC increased frequency of microhemorrhages (p = 0.039)-particularly a "comb-like" pattern (parallel hemorrhages) (p = 0.002)-than "aPL carriers". Of note, there were no significant differences concerning the isolated number of microhemorrhages between APS and the CTR group (p = 0.314), but "comb-like" hemorrhages were significantly more frequent in the APS group (p = 0.034). Not any significant correlation was found between the aPL subtypes and NVC parameters., Conclusions: APS patients showed significantly a greater number of non-specific NVC abnormalities than "aPL carriers", particularly the "comb-like" NVC pattern. Oral anticoagulants may represent a confounding factor for isolated microhemorrhages. Not any correlation was found between aPL subtypes and NVC parameters. Further investigations are needed to better characterize the microvascular endothelium damage induced by aPL.

Introduction : Myasthenia gravis (MG) is a prototypical autoimmune disease, characterized by pathogenic autoantibodies targeting structures of the neuromuscular junction. Radioimmunoprecipitation assays (RIPAs) represent the gold standard for their detection. However, new methods are emerging to complement, or overcome RIPAs, also with the perspective of eliminating the use of radioactive reagents. Areas covered : We discuss advances in laboratory methods, prompted especially by cell-based assays (CBAs), for the detection of the autoantibodies of MG diagnostics, above all those to the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low molecular-weight receptor-related low-density lipoprotein-4 (LRP4). Expert opinion : CBA technology makes AChRs aggregate on cell membranes, thus allowing to detect autoantibodies to clustered AChRs, with reduction of seronegative MG cases. The diagnostic relevance of RIPA/CBA-measurable LRP4 antibodies is still unclear, in Caucasian patients at least. Live CBAs for the detection of AChR, MuSK, and LRP4 antibodies might represent an alternative to RIPAs, but first require full validation. CBAs could be used as screening tests, limiting RIPAs for antibody quantification. To this end, ELISAs might be an alternative.Fixation procedures preserving enough degree of antigen conformationality could yield AChR and MuSK CBAs suitable for a wide use in clinical-chemistry laboratories.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The management of brain tumour patients who would like to resume driving is complex, and needs multidisciplinary input and a consensus among treating physicians. The Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM) aim to provide guidance on how to assess “fitness-to-drive” of glioblastoma patients and to harmonise the relevant procedures in Switzerland., Methods: At several meetings, Swiss neuro-oncologists discussed common practices on how to advise patients with a stable, i.e., non-progressive, glioblastoma, who wish to resume driving after the initial standard tumour treatment. All participants of the SwissNOS meetings were invited twice to return a questionnaire (modified Delphi process) on specific tools/procedures they commonly use to assess “fitness-to-drive” of their patients. Answers were analysed to formulate a tentative consensus for a structured and reasonable approach., Results: Consensus on minimum requirements for a “fitness-to-drive” programme for glioblastoma patients could be reached among Swiss neuro-oncologists. The recommendations were based on existing guidelines and expert opinions regarding patients with seizures, visual disturbances, cognitive impairment or focal deficits for safe driving. At this point in time, the Swiss neuro-oncologists agreed on the following requirements for glioblastoma patients after the initial standard therapy and without a seizure for at least 12 months: (1) stable cranial magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria, to be repeated every 3 months; (2) thorough medical history, including current or new medication, a comprehensive neurological examination at baseline (T0) and every 3 months thereafter, optionally an electrocencephalogram (EEG) at baseline; (3) ophthalmological examination including visual acuity and intact visual fields; and (4) optional neuropsychological assessment with a focus on safe driving. Test results have to be compatible with safe driving at any time-point. Patients should be informed about test results and optionally sign a document., Conclusions: We propose regular thorough clinical neurological examination and brain MRI, optional EEG, neuropsychological and visual assessments to confirm “fitness-to-drive” for glioblastoma patients after initial tumour-directed therapy. The proposed “fitness-to-drive” assessments for glioblastoma patients serves as the basis for a prospective Swiss Pilot Project GLIODRIVE (BASEC ProjectID 2020-00365) to test feasibility, adherence and safety in a structured manner for patients who wish to resume driving. Research will focus on confirming the usefulness of the proposed tools in predicting “fitness-to-drive” and match results with events obtained from the road traffic registry (Strassenverkehrsamt).

Objectives and Methods: the current understanding of the interplay between cardiovascular (CV) risk and Covid-19 is grossly inadequate. CV risk-prediction models are used to identify and treat high risk populations and to communicate risk effectively. These tools are unexplored in Covid-19. The main objective is to evaluate the association between CV scoring systems and chest X ray (CXR) examination (in terms of severity of lung involvement) in 50 Italian Covid-19 patients. Results only the Framingham Risk Score (FRS) was applicable to all patients. The Atherosclerotic Cardiovascular Disease Score (ASCVD) was applicable to half. 62% of patients were classified as high risk according to FRS and 41% according to ASCVD. Patients who died had all a higher FRS compared to survivors. They were all hypertensive. FRS≥30 patients had a 9.7 higher probability of dying compared to patients with a lower FRS. We found a strong correlation between CXR severity and FRS and ASCVD (P < 0.001). High CV risk patients had consolidations more frequently. CXR severity was significantly associated with hypertension and diabetes. 71% of hypertensive patients' CXR and 88% of diabetic patients' CXR had consolidations. Patients with diabetes or hypertension had 8 times greater risk of having consolidations., Conclusions: High CV risk correlates with more severe CXR pattern and death. Diabetes and hypertension are associated with more severe CXR. FRS offers more predictive utility and fits best to our cohort. These findings may have implications for clinical practice and for the identification of high-risk groups to be targeted for the vaccine precedence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The recently discovered Fickian yet non-Gaussian diffusion (FnGD) is here finely tuned and investigated over a wide range of probabilities and timescales using a quasi-2D suspension of colloidal beads under the action of a static and spatially random optical force field. This experimental model allows one to demonstrate that a "rapid" FnGD regime with a diffusivity close to that of free suspension can originate from earlier subdiffusion. We show that these two regimes are strictly tangled: as subdiffusion deepens upon increasing the optical force, deviations from Gaussianity in the FnGD regime become larger and more persistent in time. In addition, the distinctive exponential tails of FnGD are quickly built up in the subdiffusive regime. Our results shed new light on previous experimental observations and suggest that FnGD may generally be a memory effect of earlier subdiffusive processes.

Introduction: In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi., Case Reports: The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. DISCUSSION AND CONCLUSION: We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.

Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.

The aim of this study is the creation of a 5-step ultrasound examination to evaluate and monitor Heart Failure (HF) patients during hospitalization and follow-up. "ABCDE" is the acronym of an Italian multicentre study composed of a consecutive sample of HF patients admitted from the Emergency to the Internal Medicine/Geriatric Departments of several Italian hospitals. The "ABCDE" score includes the evaluations of A, the Ankle-brachial index (ABI), B, the B-lines, C, the Carotid intima media thickness (CIMT), D, the Diameter of the abdominal aorta and of the inferior cave vein and E, the echocardiographic assessment of the ejection fraction. This paper reports the preliminary results. Up to now, the "ABCDE" multicenter study seems an exciting opportunity to create an integrative ultrasound approach in HF. The definitive confirmation of these preliminary results and the effective usefulness of the "ABCDE" will be available in 2022, at the end of the study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

During coronavirus disease 2019 (COVID-19) pandemic, the early diagnosis of patients is a priority. Serological assays, in particular immunoglobulin (Ig)M and IgG anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have today several applications but the interpretation of their results remains an open challenge. Given the emerging role of the IgA isotype in the COVID-19 diagnostics, we aimed to identify the SARS-CoV-2 IgA antibodies in a COVID-19 population seronegative for IgM. A total of 30 patients hospitalized in San Giovanni di Dio Hospital (Florence, Italy) for COVID-19, seronegative for IgM antibodies, have been studied for anti-SARS-CoV-2 antibodies. They all had a positive oro/nasopharyngeal swab reverse transcription-polymerase chain reaction result. Assays used were a chemiluminescent assay measuring SARS-CoV-2 specific IgM and IgG (S + N) and an ELISA, measuring specific IgG (S1) and IgA antibodies against SARS-CoV-2. Among the 30 patients, eight were positive for IgA, seven were positive for IgG (N + S), and two for IgG (S1), at the first point (5-7 days from the onset of symptoms). The IgA antibodies mean values at the second (9-13 days) and third (21-25 days) time points were even more than twice as high as IgG assays. The agreement between the two IgG assays was moderate (Cohen's K = 0.59; SE = 0.13). The inclusion of the IgA antibodies determination among serological tests of the COVID-19 diagnostic is recommended. IgA antibodies may help to close the serological gap of the COVID-19. Variations among anti-SARS-CoV-2 IgG assays should be considered in the interpretation of results., (© 2020 Wiley Periodicals LLC.)

Background: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema., Objective: We sought to identify DNA methylation profiles associated with childhood allergy., Methods: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses., Results: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium., Conclusion: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The recent availability of automated computer-assisted diagnosis (CAD) systems for the reading and interpretation of the anti-nuclear antibody (ANA) test performed with the indirect immunofluorescence (IIF) method on HEp-2 cells, has improved the reproducibility of the results and initiated a process of harmonization of this test. Furthermore, CAD systems provide quantitative expression of fluorescence intensity, allowing the introduction of objective quality control procedures to the monitoring of the entire process. The calibration of the reading systems and the automated image interpretation are essential prerequisites for obtaining reproducible and harmonized IIF test results and form the basis for standardization, regardless of the computer algorithms used in the different systems. The use of automated CAD systems, facilitating control procedures, represents a step forward for the quality certification of the laboratory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cinquanta, Bizzaro and Pesce.)

Background: Accumulating evidence suggests that in utero exposures can influence the development of the immune system and thus contribute to disease development. Studies investigating the association between prenatal exposures to heavy metals and atopic diseases, however, are scarce., Methods: Children from the EDEN birth cohort were prospectively followed up using parental questionnaires with validated questions on asthma, allergic rhinitis, eczema, and food allergy symptoms. The questionnaires were administered every 4 months during the children's first year, and then every year until the age of 5, with a final survey at the age of 8. Serum concentrations of lead (Pb), cadmium (Cd), and manganese (Mn) were assessed in maternal blood samples collected during mid-pregnancy and in cord blood of 651 mother-children pairs. Hazard ratios (HR) for the incidence of each atopic disease in relation to the exposure to metals were calculated using Cox proportional hazard models., Results: Levels of Cd in cord blood were associated with greater risk of asthma (hazard ratio [95% confidence interval] for upper vs lower quartile: 1.81 [1.00-3.29]), eczema (1.60 [1.09-2.35]), and food allergy (3.17 [1.36-7.38]), while Mn levels in maternal serum were associated with eczema (1.55 [1.05-2.28]). These associations were similar in males and females and were confirmed using log concentrations of metals as exposures., Conclusions: Our results support the hypothesis that fetal exposure to heavy metals may affect the development of asthma, eczema, and food allergy in childhood and suggest that timing of exposure in utero may have a role in these associations., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Raising tobacco prices effectively reduces smoking, the main risk factor for chronic obstructive pulmonary disease (COPD). Using the Health Impact Assessment tool "DYNAMO-HIA", this study quantified the reduction in COPD burden that would occur in Italy, England and Sweden over 40 years if tobacco prices were increased by 5%, 10% and 20% over current local prices, with larger increases considered in secondary analyses. A dynamic Markov-based multi-state simulation modelling approach estimated the effect of changes in smoking prevalence states and probabilities of transitioning between smoking states on future smoking prevalence, COPD burden and life expectancy in each country. Data inputs included demographics, smoking prevalences and behaviour and COPD burden from national data resources, large observational cohorts and datasets within DYNAMO-HIA. In the 20% price increase scenario, the cumulative number of COPD incident cases saved over 40 years was 479,059 and 479,302 in Italy and England (populous countries with higher smoking prevalences) and 83,694 in Sweden (smaller country with lower smoking prevalence). Gains in overall life expectancy ranged from 0.25 to 0.45 years for a 20 year-old. Increasing tobacco prices would reduce COPD burden and increase life expectancy through smoking behavior changes, with modest but important public health benefits observed in all three countries.

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barré Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale ≥4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS., (Copyright © 2020. Published by Elsevier B.V.)

Photoperiodic light quality affects flowering of long day plants, by influencing the phytochrome photoequilibria (PPE) at plant level; however, the most effective light spectrum to promote flowering is still unknown for most of the flower crops. We evaluated the influence of light spectrum of three light sources, with different induced PPE, on photosynthesis, metabolic profiling, plant growth and flowering in two hybrids of Ranunculus asiaticus L., MBO (early flowering) and MDR (medium earliness). Three photoperiodic treatments were compared to natural day length (NL): white fluorescent light (PPE 0.84), light emitting diodes (LEDs) with red:far red (R:FR) light at 3:1 ratio (PPE, 0.84) and LEDs with R:FR light at 1:3 ratio (PPE 0.63). Under natural light, net photosynthesis was higher in MDR than in MBO, while photochemistry was similar in the hybrids. Compared to NL, photoperiodic treatments did not affect net photosynthesis, while they promoted the quantum yield of PSII and reduced the non-photochemical quenching. Under NL, plant growth was greater in MBO, while flowering started earlier in MDR and flowers characteristics were similar in the hybrids. Despite the greater sensitivity of MDR plants in terms of metabolism, photoperiodic lighting improved plant growth and reduced the flowering time only in MBO, with a stronger effect under R:FR 3:1 light. MDR plants were characterized by higher soluble sugars, polyphenols, photosynthetic pigments and proteins, while MBO plants by higher starch and amino acid content. The morphological effects of photoperiodic light quality and the hybrid-specific response should be taken into account to optimize lighting protocols in commercial farms., (© 2020 Scandinavian Plant Physiology Society.)