The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To ...perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients' organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients' health and the mid- and long-term effects of the pandemic on their wellbeing.
Bronchoalveolar lavage (BAL) is a useful procedure for differential diagnosis of interstitial lung diseases (ILDs) and for identification of granulomatous lung diseases. We investigated a panel of ...biomarkers from BAL fluid of ILD patients to evaluate their utility in differentiating ILDs. Bronchoscopy with BAL was performed in 100 consecutive patients with suspected ILD (41 sarcoidosis, 11 cHP and 24 other ILDs); the 24 patients negative for ILD diagnosis were included as control group. BAL phenotypes and cell profiles (CD4
+
/CD8
+
ratio, NK and CD103
+
cell counts, chitotriosidase and KL-6 levels in BAL) were determined by flow cytometry. A decision-tree statistical algorithm was applied. Sarcoidosis was discriminated by a higher BAL CD4
+
/CD8
+
ratio (
p
= 5.8E−05), a lower BAL CD103
+
CD4
+
count (
p
= 5.0E−02) and lower BAL NK percentages (
p
= 8.8E−03) than the other groups. BAL KL-6 concentrations were higher in sarcoidosis than in other ILDs (
p
= 1.5E−02) and were directly correlated with CD4
+
/CD8
+
ratio. We used decision-tree statistical analysis to combine our biomarkers into two diagnostic algorithms for differential diagnosis of ILDs. A panel of BAL biomarkers for diagnosis of ILDs is proposed; CD4
+
/CD8
+
ratio, KL-6 concentrations, and NK and CD103
+
CD4
+
cell percentages in BAL could improve the identification and differential diagnosis of sarcoidosis.
Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD).
A panel of 8 serum cytokines ...interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1 was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15% from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD.
In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4-7.2, p = 0.007), but not in those with severe ILD.
In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.
Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup‐shaped low‐set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild ...intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described.
We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co‐occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID.
This report provides evidence that bi‐allelic null PAX1 mutations may lead to a multi‐system autosomal recessive disorders, where SCID might represent the main feature.
Segregation of a novel PAX1 mutation in a highly consanguineous family. The 2 homozygous children showed otofaciocervical syndrome and severe combined immunodeficiency, while heterozygous family member presented preauricular pits.
Abtract
Background
The pathogenetic and regulatory roles of natural killer (NK) and natural killer T-like cells in interstitial lung diseases (ILDs), fibrotic and granulomatous of unknown etiology ...are unclear.
Objectives
Here we investigated NK and NKT-like cells in peripheral blood (PB) and Bronchoalveolar lavage (BAL) from patients with ILDs.
Method
190 patients (94 male mean age 61 ± 14.3 years) and 8 controls undergoing bronchoscopy for ILD diagnostic work-up were enrolled consecutively; 115 patients sarcoidosis, 24 chronic fibrotic hypersensitivity pneumonitis and 43 patients other ILDs 32 idiopathic pulmonary fibrosis (IPF) and 11 non-specific interstitial pneumonia (NSIP). PB and BAL were processed by flow cytometry using monoclonal antibodies to differentiate NK and NKT-like cells.
Results
NK% in BAL was significantly different among ILDs (
p
= 0.02). Lower NK% was observed in BAL from sarcoidosis than other ILDs (
p
< 0.05). Similar findings were observed for NKT-like, whereas no differences were found for PB NK%. Difference of NK% was observed between BAL and PB in all groups (
p
< 0.001). Sarcoidosis patients reported the best area under the curve for NKT-like (AUC = 0.678,
p
= 0.0015) and NK cells (AUC = 0.61,
p
= 0.001). In the IPF-NSIP subgroup, NK% cell was inversely correlated with FVC% (
r
= − 0.34,
p
= 0.03) and DLCO% (
r
= − 0.47,
p
= 0.0044).
Conclusions
NK and NKT-like were expressed differently in BAL from patients with different ILD and were significantly depleted in sarcoidosis respect to other ILDs. This suggests that these cells may play a protective role in the pathogenesis of sarcoidosis.
Purpose of the study: The usefulness of sentinel lymph node biopsy in thick melanomas is debated. The aim of this study was to evaluate the possible prognostic significance of sentinel lymph node ...biopsy in T4 melanoma patients and to verify whether this was a homogeneous group of patients with similar poor behavior.
Materials and Methods: A retrospective observational study was performed. Data were extracted from the Tuscan Regional Referral Center database. The outcome of sentinel lymph node-negative and sentinel lymph node-positive T4 melanomas were compared. A systematic review of published series on this issue and a meta-analysis were performed.
Results: Among 125 T4 melanoma patients, 53 patients (42.4%) were sentinel lymph node-positive and 72 (57.6%) patients were sentinel lymph node-negative. The 5-year and the 10-year melanoma specific survival were 81.9% and 72.3% for sentinel lymph node-negative patients and 42.4% and 17.9% (P < 0.001) for sentinel lymph node-positive patients. A positive sentinel lymph node showed an HR of 3.08. The meta-analysis confirmed that there was a significantly greater risk of death for patients with thick melanoma and positive sentinel lymph node (RR 1.75).
Conclusions: The results of the study point out that the sentinel lymph node biopsy is required for the correct staging of patients with melanoma thicker than 4 mm and that the status of sentinel lymph node is a significant predictor of melanoma specific survival. This knowledge allows early surgical and adjuvant treatment as well as appropriate trial enrollment and tailored follow-up.
T regulatory cells (Tregs), involved in tumour tolerance, can generate Adenosine by CD39/CD73 surface enzymes, which identify four Tregs subsets: CD39+CD73− nTregs, CD39+CD73+ iTregs, CD39−CD73+ ...oTregs and CD39−CD73− xTregs. In melanoma patients, increased Tregs levels are detected in peripheral blood (PB), sentinel lymph node (SLN) and tumour infiltrating lymphocytes (TILs), but Adenosine role was not investigated yet. We examined total Tregs and Adenosine subsets in PB, SLN and TILs from melanoma patients (n = 32) and PB from healthy donors (HD; n = 10) by flow cytometry. Total Tregs significantly increased in stage III-IV patients PB, in SLN and TILs, as compared to HD/stage I-II patients. Tregs subsets analyses showed that: 1) PB nTregs significantly increased in SLN and decreased in TILs; 2) iTregs significantly increased in stage III-IV patients PB and further significantly increased in SLN and TILs; 3) PB oTregs and xTregs significantly decreased in SLN and TILs. Patients clinical features did not significantly influence total Tregs, except SLN excision order. Results confirmed Tregs role in melanoma progression and indicate Adenosine generation as a novel escape mechanism, being nTregs and iTregs increased in PB/SLN/TILs.
•Total and Adenosine-producing Tregs were investigated in melanoma patients (MP).•Total Tregs significantly increased in MP blood, sentinel lymph node (SLN) and TILs.•Adenosine pathway identified four Tregs subsets by CD39/CD73 enzyme expression.•Natural CD39+CD73− Tregs significantly increased in MP SLN as compared to blood.•Inducible CD39+CD73+ Tregs significantly increased in MP blood, SLN and TILs.
The application of the Isogeometric Analysis (IgA) paradigm to Symmetric Galerkin Boundary Element Method (SGBEM) is investigated. In order to obtain a very flexible approach, the study is here ...developed by using non-polynomial spline functions to represent both the domain boundary and the approximate solution. The numerical comparison between IGA-SGBEM and both curvilinear and standard SGBEM approaches shows the general capability of the presented method to produce accurate approximate solutions with less degrees of freedom.
•Non-polynomial spline alternatives are analyzed and tested for the IGA-SGBEM.•The new approach is compared to both standard and curvilinear SGBEM, showing its superiority.•Simulations cover exterior and interior problems, admitting both smooth and not regular solutions.•Mixed BVP on trimmed domains are also taken into account.
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