Diagnostic workup in children with arthrogryposis: description of practices from a single reference centre, comparison with literature and suggestion of recommendations

IntroductionArthrogryposis multiplex congenita (AMC) refers to a clinical presentation of congenital contractures involving two or more body areas. More than 400 distinct conditions may lead to AMC, making the aetiological diagnosis challenging. The objective of this work was to set up evidence-based recommendations for the diagnosis of AMC by taking advantage of both data from our nation-wide cohort of children with AMC and from the literature.Material and methodsWe conducted a retrospective single-centre observational study. Patients had been evaluated at least once at a paediatric age in the AMC clinic of Grenoble University Hospital between 2007 and 2019. After gathering data about their diagnostic procedure, a literature review was performed for each paraclinical investigation to discuss their relevance.ResultsOne hundred and twenty-five patients were included, 43% had Amyoplasia, 27% had distal arthrogryposis and 30% had other forms. A definitive aetiological diagnosis was available for 66% of cases. We recommend a two-time diagnostic process: first, non-invasive investigations that aim at classifying patients into one of the three groups, and second, selected investigations targeting a subset of patients.ConclusionThe aetiological management for patients with AMC remains arduous. This process will be facilitated by the increasing use of next-generation sequencing combined with detailed phenotyping. Invasive investigations should be avoided because of their limited yield.

Endocrine disorders in patients with Fabry disease: insights from a reference centre prospective study

Context Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. Objective To investigate the function of the endocrine system in patients with FD. Design We conducted an observational prospective study from 2017 to 2020. Setting and patients We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. Results 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD <20 μg/L) despite the fact that 19/36 (52.8%) were substituted with cholecalciferol. Only 21/77 (27.3%) patients had normal VitD levels without VitD substitution. 11/77 (14.3%) had significant hypophosphatemia (p < 0.80 mmol/L). Three new cases (3.9%) of subclinical, two (2.6%) of overt and six (7.8%) of known hypothyroidism were identified. Of note, men had significantly higher renin levels than women [61.4 (26.1–219.6) vs.25.4 (10.9–48.0) mU/L, p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. Conclusions VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

SARS-CoV-2 surveillance in Italy through phylogenomic inferences based on Hamming distances derived from pan-SNPs, -MNPs and -InDels

Background Faced with the ongoing global pandemic of coronavirus disease, the ‘National Reference Centre for Whole Genome Sequencing of microbial pathogens: database and bioinformatic analysis’ (GENPAT) formally established at the ‘Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise’ (IZSAM) in Teramo (Italy) is in charge of the SARS-CoV-2 surveillance at the genomic scale. In a context of SARS-CoV-2 surveillance requiring correct and fast assessment of epidemiological clusters from substantial amount of samples, the present study proposes an analytical workflow for identifying accurately the PANGO lineages of SARS-CoV-2 samples and building of discriminant minimum spanning trees (MST) bypassing the usual time consuming phylogenomic inferences based on multiple sequence alignment (MSA) and substitution model. Results GENPAT constituted two collections of SARS-CoV-2 samples. The first collection consisted of SARS-CoV-2 positive swabs collected by IZSAM from the Abruzzo region (Italy), then sequenced by next generation sequencing (NGS) and analyzed in GENPAT (n = 1592), while the second collection included samples from several Italian provinces and retrieved from the reference Global Initiative on Sharing All Influenza Data (GISAID) (n = 17,201). The main results of the present work showed that (i) GENPAT and GISAID detected the same PANGO lineages, (ii) the PANGO lineages B.1.177 (i.e. historical in Italy) and B.1.1.7 (i.e. ‘UK variant’) are major concerns today in several Italian provinces, and the new MST-based method (iii) clusters most of the PANGO lineages together, (iv) with a higher dicriminatory power than PANGO lineages, (v) and faster that the usual phylogenomic methods based on MSA and substitution model. Conclusions The genome sequencing efforts of Italian provinces, combined with a structured national system of NGS data management, provided support for surveillance SARS-CoV-2 in Italy. We propose to build phylogenomic trees of SARS-CoV-2 variants through an accurate, discriminant and fast MST-based method avoiding the typical time consuming steps related to MSA and substitution model-based phylogenomic inference.

Long-term Outcomes of Adult Pulmonary Langerhans Cell Histiocytosis: A Prospective Cohort

BackgroundThe long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience.MethodsTo address this issue, all newly diagnosed PLCH patients referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases, and extra-pulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan-Meier method.ResultsTwo hundred six patients (mean age: 39±13 years, 60% females, 95% current smokers) were prospectively followed for a median duration of 5.1 years (interquartile range [IQR], 3.2 to 7.6). Twelve (6%) patients died. The estimated rate of survival at 10 years was 93% (95% confidence interval [CI], 89–97). The cumulative incidences of CRF and/or PH were less than 5% at both 5 and 10 years, and 58% of these patients died. Twenty-seven malignancies were observed in 23 patients. The estimated standardized incidence ratio of lung carcinoma was 17.0 (95% CI, 7.45–38.7) compared to an age- and sex-matched French population. Eight (5.1%) of the 157 patients with isolated PLCH developed extra-pulmonary involvement.ConclusionsThe long-term prognosis of PLCH is significantly more favourable than was previously reported. Patients must be closely monitored after diagnosis to detect severe complications early.

Best Farming Practices for the Welfare of Dairy Cows, Heifers and Calves

The concept of animal welfare (AW) has many meanings. Traditionally, AW has been considered as freedom from disease and suffering. Nowadays, growing attention goes to the concept of “positive animal welfare” (PAW), which can be interpreted within the concept of quality of life (QoL), thinking about a “balance of positives over negatives” and a “life worth living”. In this vision, where the QoL represents a continuum between positives and negatives, the Italian National Reference Centre for Animal Welfare (CReNBA), within the Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IZSLER), has developed a welfare assessment protocol for dairy cows, heifers, and calves in loose housing systems, including both animal-based and non-animal-based indicators, in which not only hazards but also benefits are identified. This protocol is part of an integrated monitoring system called “ClassyFarm”, belonging to the Italian Ministry of Health and developed by IZSLER. The aim of this paper is to extrapolate from the mentioned protocol, a list of 38 best farming practices (on managerial and equipment factors) for ensuring a high level of welfare in dairy cattle. All stakeholders (veterinarians, farmers, competent authorities, consumers, etc.) can benefit of these best practices as a guide or toolbox to ensure a life worth living for these animals.

Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre

Background Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4–44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2–22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0–10) before treatment vs 0 (range 0–1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m2 respectively in the eculizumab group and in the control group. Conclusions These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.