Circulating total and IgG4+ plasmablasts for the diagnosis of type 1 Autoimmune Pancreatitis

OBIETTIVI: La pancreatite autoimmune (AIP) di tipo 1 rappresenta una possibile manifestazione della malattia IgG4-relata (IgG4-RD), la cui diagnosi è a volte ancora difficile da formulare. I plasmablasti circolanti sono stati proposti come possibile marcatore sierico sensibile e specifico, anche se non è chiaro se possano differenziare tra AIP di tipo 1, di tipo 2 e altre condizioni pancreatiche. Obiettivo dello studio è stato valutare il valore diagnostico dei livelli di plasmablasti totali e di IgG4+ circolanti nell'AIP e in altre malattie del pancreas. METODI: Sono stati arruolati prospetticamente da Gennaio 2018 a Maggio 2020 pazienti con diagnosi di AIP di tipo 1 attiva (Gruppo AIP-1, n = 19) secondo i criteri diagnostici internazionali, insieme a pazienti affetti da AIP attiva di tipo 2 (AIP 2) o non altrimenti specificata (AIP NOS) (Gruppo AIP 2/NOS, n=10) adenocarcinoma pancreatico (Gruppo PDAC, n=17), pancreatite cronica (Gruppo CP, n=20), neoplasia mucinosa papillare intraduttale (IPMN) o iperenzimemia pancreatica cronica asintomatica (CAPH) (Gruppo IPMN-CAPH, n=21) come gruppi di controllo. La citometria a flusso è stata utilizzata per misurare la conta dei plasmablasti totali e dei plasmablasti IgG4+ nel sangue periferico utilizzando i seguenti anticorpi per le cellule CD45+CD19+CD38hiCD20-CD24-CD27+ e CD45+CD19+CD38hiCD20-CD24-CD27+ IgG4+. Inoltre, queste cellule sono state misurate nei pazienti con AIP dopo un mese di terapia, dopo 2-4 mesi dalla fine del trattamento e dopo un anno dall'arruolamento. RISULTATI: Il gruppo AIP-1 ha mostrato livelli significativamente più alti di plasmablasti totali (media 6365, SD 5522 cellule/mL) rispetto sia al gruppo PDAC (media 3216, SD 1228 cellule/mL) (p=0.0067) che al gruppo IPMN-CAPH (media 1065, SD 781 cellule/mL)(p<0.0001). Tuttavia, la conta dei plasmablasti totali non era significativamente differente nel gruppo AIP 1 rispetto a AIP 2/NOS. I plasmablasti IgG4+ hanno invece distinto il tipo 1 da tutti gli altri gruppi, incluso l'AIP di tipo 2, con una sensibilità dell'80% e una specificità del 97% utilizzando un cut-off di 210 cellule IgG4+/mL. Inoltre, i livelli di plasmablasti IgG4+ diminuiscono significativamente dopo la terapia. CONCLUSIONI: Solo i plasmablasti IgG4+ sembrano essere un biomarcatore potenzialmente utile per differenziare l'AIP di tipo 1 dall'AIP di tipo 2/NOS e da altre condizioni pancreatiche, in particolare il PDAC.OBJECTIVES: Type 1 autoimmune pancreatitis (AIP) is a manifestation of IgG4-related disease (IgG4-RD) whose diagnosis is still challenging. Circulating plasmablasts seem to be a useful tool in this setting. Whether they may differentiate type 1, type 2 AIP, and other pancreatic conditions is still unknown. The aim of the study was to investigate the diagnostic value of circulating total and IgG4+ plasmablasts levels in AIP and other pancreatic diseases. METHODS: Patients diagnosed with active type 1 AIP (Group AIP-1, n=19) according to International Consensus Diagnostic Criteria from January 2018 to May 2020, were prospectively enrolled together with patients suffering from active type 2 or not otherwise specified AIP (Group AIP 2/NOS, n=10) pancreatic adenocarcinoma (Group PDAC, n=17), chronic pancreatitis (Group CP, n=20), intraductal papillary mucinous neoplasia (IPMN) or chronic asymptomatic pancreatic hyperenzymemia (CAPH) (Group IPMN-CAPH, n=21) as control groups. Flow cytometry was used to measure total plasmablasts’ and IgG4+ plasmablasts’ counts by gating peripheral blood for CD45+CD19+CD38hiCD20-CD24-CD27+ cells and CD45+CD19+CD38hi CD20-CD24-CD27+IgG4+ cells. Moreover, these cells were measured after one month of therapy, after 2-4 months from the end of treatment, and after one year from the enrollment in AIP patients groups only. RESULTS: Group AIP-1 showed significantly higher levels of total plasmablasts (mean 6365, SD 5522 cells/mL) compared to both Group PDAC (mean 3216, SD 1228 cells/mL)(p=0.0067) and Group IPMN-CAPH (mean 1065, SD 781 cells/mL)(p<0.0001). However, plasmablasts count was not significantly higher in Group AIP 1 compared to AIP 2/NOS. IgG4+ plasmablasts distinguished type 1 AIP from all other pancreatic disorders with a sensitivity of 80% and a specificity of 97% using a cut-off of 210 IgG4+ cells/mL. IgG4+ plasmablasts significantly decrease after steroids. CONCLUSIONS: Only IgG4+ plasmablasts may be a potentially useful biomarker to differentiate type 1 AIP from type 2 or NOS AIP and other pancreatic conditions, especially PDAC

Constraining the Nordtvedt parameter with the BepiColombo Radioscience experiment

BepiColombo is a joint ESA/JAXA mission to Mercury with challenging objectives regarding geophysics, geodesy and fundamental physics. The Mercury Orbiter Radioscience Experiment (MORE) is one of the on-board experiments, including three different but linked experiments: gravimetry, rotation and relativity. The aim of the relativity experiment is the measurement of the post-Newtonian parameters. Thanks to accurate tracking between Earth and spacecraft, the results are expected to be very precise. However, the outcomes of the experiment strictly depends on our "knowledge" about solar system: ephemerides, number of bodies (planets, satellites and asteroids) and their masses. In this paper we describe a semi-analytic model used to perform a covariance analysis to quantify the effects, on the relativity experiment, due to the uncertainties of solar system bodies parameters. In particular, our attention is focused on the Nordtvedt parameter $\eta$ used to parametrize the strong equivalence principle violation. After our analysis we estimated $\sigma[\eta]\lessapprox 4.5\times 10^{-5}$ which is about 1~order of magnitude larger than the "ideal" case where masses of planets and asteroids have no errors. The current value, obtained from ground based experiments and lunar laser ranging measurements, is $\sigma[\eta]\approx 4.4\times 10^{-4}$. Therefore, we conclude that, even in presence of uncertainties on solar system parameters, the measurement of $\eta$ by MORE can improve the current precision of about 1~order of magnitude

Genetic Diversity of Old Chicken Breeds Kept in Poland

The aim of this study was to compare the genetic variation of five local chicken breeds reared in Poland. Twenty-seven microsatellite markers were investigated in 138 birds belonging to five breeds: Miniature Cochin (MCO), Gold Italian (GI), Green Legged Partridge (GLP), Silver Italian (SI) and White Leghorn (WL). One hundred eighty five alleles were detected in the overall population, with a mean number of 6.85 ± 3.32 alleles per locus. For the local breeds, the observed and expected heterozygosity ranged from a minimum of 0.287 to a maximum of 0.458 and from 0.397 to 0.499 for the GI and SI breeds, respectively. The overall population heterozygote deficiency was 0.430, the average Wright’s inbreeding coefficient (FIS) was 0.061 and the heterozygote deficiency due to breed subdivision was 0.393. Wright’s fixation index was slightly positive for all breeds excluding MCO (FIS = -0.476) and the estimated molecular inbreeding (fij) within breed ranged from 0.296 (GLP and SI) to 0.361 (WL) evidencing limited coancestry. Mean allelic richness, obtained with rarefaction method based on sixteen observations, was 2.12 being the WL the less variable (1.79). Tomiuk and Loeschcke’s DTL genetic distance values were used to draw a neighbornet network which separated the cluster made of MCO and GLP from the cluster of GI, WL and SI. The results arising from our microsatellites analysis represent a starting point for the valorization of these local Polish chicken breeds for monitoring and preserving their genetic variability

Epidemiologia ambientale ben temperata: etica, sociologia e storia in un progetto di citizen science

The article presents the research performed by an Italian multi-disciplinary team jointly with a group of citizen scientists. The research was part of the project CitieS-Health (Citizen Science for Urban Environment and Health) funded by the EU under the Horizon2020 Programme. Aria di Ricerca in Valle del Serchio , one of the project five pilot studies, was performed in eight municipalities of Valle del Serchio (Lucca, Tuscany) and addressed the prevalence of chronic kidney diseases in the context of potential industrial pollution on health and, in particular, the presence of heavy metals in the environment. Since long, health and environmental issues have been of concern for the local residents who over the years promoted many initiatives to ensure adequate monitoring and appropriate policy interventions. Inspired by the PNS (Post-Normal Science) approach, and in particular the idea of Extended Peer Community, the study addressed local concerns and expectations integrating a multiplicity of competences, knowledges and perspectives. Researchers from Social Sciences and Humanities – namely history, sociology and ethics – collaborated with others from the health sector – epidemiology in particular – and with citizens in all the phases of the work: from the definition of the research objective to the collection, analysis and dissemination of the research results, and the suggestion of policy recommendations

Risk of Covid-19 severe outcomes and mortality in migrants and ethnic minorities compared to the general population in the european WHO region. A systematic review

The Covid-19 pandemic has had a major impact on migrants and ethnic minorities (MEMs). Socio-economic factors and legal, administrative and language barriers are among the reasons for this increased susceptibility. The aim of the study is to investigate the impact of Covid-19 on MEMs compared to the general population in terms of serious outcomes. We conducted a systematic review collecting studies on the impact of Covid-19 on MEMs compared to the general population in the WHO European Region regarding hospitalisation, intensive care unit (ICU) admission and mortality, published between 01/01/2020 and 19/03/2021. Nine researchers were involved in selection, study quality assessment and data extraction. Of the 82 studies included, 15 of the 16 regarding hospitalisation for Covid-19 reported an increased risk for MEMs compared to the white and/or native population and 22 out of the 28 studies focusing on the ICU admission rates found an increased risk for MEMs. Among the 65 studies on mortality, 43 report a higher risk for MEMs. An increased risk of adverse outcomes was reported for MEMs. Social determinants of health are among the main factors involved in the genesis of health inequalities: a disadvantaged socio-economic status, a framework of structural racism and asymmetric access to healthcare are linked to increased susceptibility to the consequences of Covid-19. These findings underline the need for policymakers to consider the socio-economic barriers when designing prevention plans

"It's All COVID's Fault!": Symptoms of Distress among Workers in an Italian General Hospital during the Pandemic

Background: Since the outbreak of the COVID-19 pandemic, healthcare workers (HCWs) have been faced with specific stressors endangering their physical and mental health and their functioning. This study aimed to assess the short-term psychological health of a sample of Italian HCWs and the related influencing factors. In particular, the study focused on the differences related to HCWs' gender and to having been directly in charge of COVID-19 patients or not. Methods: An online survey was administered to the whole staff of the Modena General University Hospital three months after the onset of the pandemic, in 2020. Demographic data and changes in working and living conditions related to COVID-19 were collected; mental health status was assessed by the Depression, Anxiety and Stress Scale (DASS-21) and the Impact of Event Scale-Revised (IES-R). Results: 1172 out of 4788 members returned the survey (response rate = 24.5%), the male/female ratio was 30/70%. Clinically significant symptoms assessed according to the DASS-21 emerged among 21.0% of the respondents for depression, 22.5% for anxiety and 27.0% for stress. Symptoms suggestive of a traumatic reaction were reported by 19.0% of the sample. Symptoms of psychological distress were statistically associated with female gender, job role, ward, changes in lifestyle, whereas first-line work with COVID-19 patients was statistically associated with more stress symptoms. HCWs reported a significant level of psychological distress that could reach severe clinical significance and impact dramatically their quality of life and functioning. Conclusions: Considering the persistence of the international emergency, effective strategies to anticipate, recognize and address distress in HCWs are essential, also because they may impact the organization and effectiveness of healthcare systems

CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants

Background: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants. Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI). Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function. Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators.</p

CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants

Background: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants. Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in&nbsp;vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI). Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function. Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators

Risk of SARS-CoV-2 infection in migrants and ethnic minorities compared with the general population in the European WHO region during the first year of the pandemic. A systematic review

Background: Migrants and ethnic minorities have suffered a disproportionate impact of the COVID-19 pandemic compared to the general population from different perspectives. Our aim was to assess specifically their risk of infection in the 53 countries belonging to the World Health Organization European Region, during the first year of the pandemic. Methods: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD42021247326). We searched multiple databases for peer-reviewed literature, published on Medline, Embase, Scisearch, Biosis and Esbiobase in 2020 and preprints from PubMed up to 29/03/2021. We included cross-sectional, case-control, cohort, intervention, case-series, prevalence or ecological studies, reporting the risk of SARS-CoV-2 infection among migrants, refugees, and ethnic minorities. Results: Among the 1905 records screened, 25 met our inclusion criteria and were included in the final analysis. We found that migrants and ethnic minorities during the first wave of the pandemic were at increased exposure and risk of infection and were disproportionately represented among COVID-19 cases. However, the impact of COVID-19 on minorities does not seem homogeneous, since some ethnic groups seem to be more at risk than others. Risk factors include high-risk occupations, overcrowded accommodations, geographic distribution, social deprivation, barriers to access to information concerning preventive measures (due to the language barrier or to their marginality), together with biological and genetic susceptibilities. Conclusions: Although mixed methods studies will be required to fully understand the complex interplay between the various biological, social, and cultural factors underlying these findings, the impact of structural determinants of health is evident. Our findings corroborate the need to collect migration and ethnicity-disaggregated data and contribute to advocacy for inclusive policies and programmatic actions tailored to reach migrants and ethnic minorities