Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Form-function relationships underlie rapid dietary changes in a lizard.

Macroevolutionary changes such as variation in habitat use or diet are often associated with convergent, adaptive changes in morphology. However, it is still unclear how small-scale morphological variation at the population level can drive shifts in ecology such as observed at a macroevolutionary scale. Here, we address this question by investigating how variation in cranial form and feeding mechanics relate to rapid changes in diet in an insular lizard (Podarcis siculus) after experimental introduction into a new environment. We first quantified differences in the skull shape and jaw muscle architecture between the source and introduced population using three-dimensional geometric morphometrics and dissections. Next, we tested the impact of the observed variation in morphology on the mechanical performance of the masticatory system using computer-based biomechanical simulation techniques. Our results show that small differences in shape, combined with variation in muscle architecture, can result in significant differences in performance allowing access to novel trophic resources. The confrontation of these data with the already described macroevolutionary relationships between cranial form and function in these insular lizards provides insights into how selection can, over relatively short time scales, drive major changes in ecology through its impact on mechanical performance.

Estimating the prevalence of congenital disaccharidase deficiencies using allele frequencies from gnomAD.

BACKGROUND: There are currently three known congenital disaccharidase deficiencies: congenital lactase deficiency (CLD), congenital sucrase-isomaltase deficiency (CSD), and congenital trehalase deficiency (CTD). No congenital deficiency has been described for maltase-glucoamylase (MGAM). METHODS: A literature search was performed in PubMed for the pathogenic variants CLD, CSD, and CTD and the articles retrieved were analyzed to estimate the prevalence of congenital disaccharidase deficiencies. RESULTS: Based on reported variants, the estimated prevalence was 1.3 per 106 births (95% CI: 1.1-1.7) for CLD, and 31.4 per 106 births (95% CI: 28.3-34.8) for CSD. Using data on previously reported variants and variants predicted to be loss-of-function in gnomAD, the overall estimated prevalence was 2.3 per 106 births (95% CI: 1.9-2.9) for CLD, 57.6 per 106 births (95% CI:52.5-63.2) for CSD, and 9.2 per 106 births (95% CI: 2.5-3.7) for CTD. CONCLUSION: The prevalence of CSD was found to be relatively high, while for other congenital disaccharidase deficiencies, the estimated prevalence was very low.

A reply to "Relevant factors in the eutrophication of the Uruguay River and the Río Negro".

A recent paper by Beretta-Blanco and Carrasco-Letelier (2021) claims that agricultural eutrophication is not one of the main causes for cyanobacterial blooms in rivers and artificial reservoirs. By combining rivers of markedly different hydrological characteristics e.g., presence/absence and number of dams, river discharge and geological setting, the study speculates about the role of nutrients for modulating phytoplankton chlorophyll-a. Here, we identified serious flaws, from erratic and inaccurate data manipulation. The study did not define how erroneous original dataset values were treated, how the variables below the detection/quantification limit were numerically introduced, lack of mandatory variables for river studies such as flow and rainfall, arbitrary removal of pH > 7.5 values (which were not outliers), and finally how extreme values of other environmental variables were included. In addition, we identified conceptual and procedural mistakes such as biased construction/evaluation of model prediction capability. The study trained the model using pooled data from a short restricted lotic section of the (large) Uruguay River and from both lotic and reservoir domains of the Negro River, but then tested predictability within the (small) Cuareim River. Besides these methodological considerations, the article shows misinterpretations of the statistical correlation of cause and effect neglecting basic limnological knowledge of the ecology of harmful algal blooms (HABs) and international research on land use effects on freshwater quality. The argument that pH is a predictor variable for HABs neglects overwhelming basic paradigms of carbon fluxes and change in pH because of primary productivity. As a result, the article introduces the notion that HABs formation are not related to agricultural land use and water residence time and generate a great risk for the management of surface waterbodies. This reply also emphasizes the need for good practices of open data management, especially for public databases in view of external reproducibility.

Publishing in pandemic times: A bibliometric analysis of early medical publications on Kawasaki-like disease (MIS-C, PIMS-TS) related to SARS-CoV-2.

INTRODUCTION: At the end of April 2020, three European pediatric societies published an alert on a new hyperinflammatory disorder linked to SARS-CoV-2. This disease has alternatively been called Kawasaki-like disease, pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), and multisystem inflammatory syndrome in children (MIS-C). These alerts provide a clear starting point from which to study the early response of the medical and scientific community to a new disease in terms of scientific publications, and to compare the timeline of this response with levels of general public interest. To this aim, we conducted a bibliometric analysis of articles on this disease published between 1 April and 5 July 2020. METHOD: A literature search was performed using PubMed and in three preprint repositories. For each article, the name used for the disease in the title, the number of authors, the number of patients, the citations according to Google Scholar, the journal impact factor, and the Altmetric score were retrieved. Google search trends for the terms "Kawasaki" and "COVID," "COVID-19," and "coronavirus" were also retrieved, as was the number of Reuters news articles published on the topic. These data were compared longitudinally on a weekly basis. The quality of the reporting of the study was evaluated using the STROBE guidelines for observational studies with more than three patients and using the CARE guidelines for case reports of three or fewer patients. RESULTS: Eighty-six articles were included, among which ten were preprints (three of which were subsequently published) and 49 were clinical articles (57%). A total of 857 patients were described. The median number of authors per article was five (range, 1-45), the median number of patients was four (1-186), the median number of citations was one (0-170), the median Altmetric score was 12 (0-7242), and the median journal impact factor was 3.7 (1-74.7). For the clinical articles, the median percentage of STROBE or CARE checklist items satisfied was 70% (IQR, 56.75-79.25; range, 40-90). Guideline adherence was significantly higher for observational studies than for case reports (median percentage of checklist items satisfied, 78.5% vs 61.5%; P<0.001); however, guideline adherence did not differ significantly between peer-reviewed and preprint articles (median percentage of checklist items satisfied, 57% vs 72%; P=0.205). The only statistically significant difference between clinical articles and other types of articles was the number of authors (median, 7 vs 2; P=2.53E-9). Fifty-seven of the 86 articles were authored by researchers from just three countries (the USA, 31; France, 14; and the UK, 12). The names most frequently used in the title were Kawasaki-like disease (n=37), followed by MIS-C (n=27), PIM-TS (n=14), and other names involving the term "inflammatory" (n=12). Google searches for related terms peaked between weeks 18 and 21, following the initial alerts and decreased rapidly thereafter. The number of Reuters articles on the subject was correlated with Google search trends (ρ: 0.86, 95% CI [0.59; 0.96]; P=0.00016), but the number of medical articles published was not (ρ: -0.54, 95% CI [-0.87; 0.14]; P=0.11). The first small case series was published less than 2 weeks after the initial alert; however, if all articles had been deposited as preprints when they were submitted to journals, the cumulative number of reported cases would have been 300% higher in week 18 (3 vs 1), 400% higher in week 19 (44 vs 11), 70% higher in week 20 (124 vs 73), and 54% higher in week 21 (129 vs 84). CONCLUSION: In a period of 9 weeks after the initial alerts from European pediatric societies, 85 medical articles were published, involving 856 patients (one case report was published before the alerts), allowing rapid dissemination of research information. However, general public interest followed the news cycle rather than scientific releases. The quality of the reporting, as assessed by adherence to STROBE or CARE guidelines, was adequate with more than two-thirds of checklist items satisfied. Learned societies play an important role in the early dissemination of up-to-date peer-reviewed information. Preprint deposition should be encouraged to accelerate the dissemination of research information.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Medical thesis publication and academic productivity of pediatric residents at the Medical University of Marseille: Associated factors and evolution over 20 years.

BACKGROUND: In many countries, as in France, medical training is not complete until the defense of a thesis, based on a research project; however, the publication of research work is not mandatory. This study investigated the evolution of the publication pattern of pediatric residents and identified the possible factors associated with an increased productivity, by investigating both thesis and non-thesis-related publications. MATERIALS AND METHODS: We conducted a retrospective cohort study of pediatric residents who graduated from the Medical University of Marseille in France over a 20-year period (1996-2015). Their theses were retrieved from the French database of university theses (SUDOC). Their publications were collated by scanning the PubMed and Google Scholar databases. Non-thesis-related publications were included up to 1 year after the medical thesis defense and medical thesis publications were included without date limits. For each thesis or publication, the resident's characteristics, the supervisor's characteristics, the thesis characteristics, and bibliometric features were retrieved. RESULTS: Out of the 148 graduated residents, 110 (74%) published articles (thesis-related article with no publication deadline and non-thesis-related articles with a publication deadline of up to 1 year postgraduation): 76 residents (51%) published their medical thesis and 88 residents (60%) published at least one non-thesis-related article. In multivariate analysis, publishing the thesis was significantly associated with a shorter dissertation length (43 vs. 84 pages [median]; p=0.009**) and with a thesis supervisor more experienced in supervising theses (P=0.01**). The thesis publication rate increased significantly over the years (P=0.005**), with the number of theses published tripling. Dissertation length significantly decreased over the years (linear slope=-4.13 pages/year; P<0.0001***). In multivariate analysis, the number of publications per resident was significantly higher when the resident had also completed a scientific thesis (ß=1.62; P=0.007**), when he or she had published more papers during the post-residency period (ß=0.40; P<0.0001***) and when he or she graduated at an older age (ß=0.24; P=0.04*). CONCLUSION: The thesis publication rate of pediatric residents has improved significantly in 20 years; however, these results are from a single-center study. Publishing the thesis was significantly associated with shorter dissertation length and a more experienced thesis supervisor.

Mutations in NBAS and SCYL1, genetic causes of recurrent liver failure in children: Three case reports and a literature review.

Acute liver failure (ALF) in childhood is a life-threatening emergency. ALF is often caused by drug toxicity, autoimmune hepatitis, inherited metabolic diseases, and infections. However, despite thorough investigations, a cause cannot be determined in approximately 50% of cases. Here, we report three cases with recurrent ALF caused by NBAS and SCYL1 pathogenic variants. These patients did not present with any other phenotypic sign usually associated with NBAS and SCYL1 pathogenic variants. Two of them underwent liver transplantation and are healthy without recurrence of ALF. We propose NBAS and SCYL1 genetic analysis in children with unexplained fever-triggered recurrent ALF even without a typical phenotype.

MICI-MINOTS: Linguistic and metric validation of a pediatric questionnaire on knowledge about inflammatory bowel disease.

BACKGROUND: Therapeutic education is an essential part of the treatment of chronic diseases, such as inflammatory bowel disease (IBD). The IBD-KID, developed in Canada in English, assesses children's and adolescents' acquired knowledge about their condition and has been validated in Canadian and Australian populations. However, there is no pediatric questionnaire in French to assess patients' knowledge about IBD. OBJECTIVE: To report the linguistic validation process and metric validity of the MICI-MINOTS, the French version of the IBD-KID. METHOD: The translation process consisted of three consecutive steps: forward-backward translation, acceptability testing, and cognitive interviews. The IBD-KID consists of 23 questions, but a 24th question about immunomodulatory therapy was added in the MICI-MINOTS. Psychometric testing was conducted with five groups: children with IBD, their parents, children in a control group, their parents, and health workers recruited from the Timone Pediatric Hospital and the Saint-Sébastien Maternal and Child Protection Center, Marseille, France. A total of 15 individuals completed the tool twice, with a 15-day interval. Internal consistency, reliability, external validity, reproducibility, and sensitivity to change were tested. RESULTS: A total of 38 children with IBD (sex: 20 boys, 18 girls; age: 13.90 [±2.88] years; 25 with Crohn's disease), 20 children in the control group, 58 parents (every child was included with one parent), and 62 health workers were included in the analysis. Intraclass correlation was 0.94 (95% confidence interval 0.83-0.98) for test-retest assessment. Readability using the Scolarius score corresponded to elementary school level. Among the children with IBD, 89.5% answered all 24 questions. For 23 questions, the mean score of children with IBD was higher than among children in the control group: 9.58 (±3.01) versus 5.47 (±3.56), respectively (P<0.01). Parents of children with IBD scored higher than parents of children in the control group: 10.63 (±3.16) versus 8.4 (±3.07), respectively (P=0.012). In the health workers' group, pediatric residents (17.82±3.46) scored higher than nurses 11.75 (±3.4) and ward clerks (8.67±2.40; P<0.01). Patients' knowledge score was significantly related to their parents' knowledge score (r=0.402, P=0.012) for 23 questions. CONCLUSION: The French version of the IBD-KID showed satisfactory psychometric properties to assess knowledge about the disease in French-speaking children.

A Practical Guide to Sliding and Surface Semilandmarks in Morphometric Analyses.

Advances in imaging technologies, such as computed tomography (CT) and surface scanning, have facilitated the rapid generation of large datasets of high-resolution three-dimensional (3D) specimen reconstructions in recent years. The wealth of phenotypic information available from these datasets has the potential to inform our understanding of morphological variation and evolution. However, the ever-increasing ease of compiling 3D datasets has created an urgent need for sophisticated methods of capturing high-density shape data that reflect the biological complexity in form. Landmarks often do not take full advantage of the rich shape information available from high-resolution 3D specimen reconstructions, as they are typically restricted to sutures or processes that can be reliably identified across specimens and exclude most of the surface morphology. The development of sliding and surface semilandmark techniques has greatly enhanced the quantification of shape, but their application to diverse datasets can be challenging, especially when dealing with the variable absence of some regions within a structure. Using comprehensive 3D datasets of crania that span the entire clades of birds, squamates and caecilians, we demonstrate methods for capturing morphology across incredibly diverse shapes. We detail many of the difficulties associated with applying semilandmarks to comparable regions across highly disparate structures, and provide solutions to some of these challenges, while considering the consequences of decisions one makes in applying these approaches. Finally, we analyze the benefits of high-density sliding semilandmark approaches over landmark-only studies for capturing shape across diverse organisms and discuss the promise of these approaches for the study of organismal form.

Um guia prático para demarcação de semi pontos de referência de superfície e de deslizamento em análises morfométricas Os avanços nas tecnologias de imagem, como a tomografia computadorizada (CT) e a varredura de superfície, facilitaram a rápida geração de grandes conjuntos de dados de reconstruções de espécimes 3D de alta resolução nos últimos anos. A riqueza de informações fenotípicas disponíveis nesses conjuntos de dados tem o potencial de informar nossa compreensão da variação e evolução morfológica. No entanto, a facilidade cada vez maior de compilar conjuntos de dados 3D criou uma necessidade urgente de métodos sofisticados para a captura de dados de alta densidade que reflitam a complexidade biológica na forma. Os pontos de referência morfológicos geralmente não capturam o máximo das informações sobre a morfologia disponíveis nas reconstruções de espécimes 3D em alta resolução, pois normalmente são restritas a suturas ou processos que podem ser identificados de forma confiável em diferentes espécimes, excluindo a maior parte da morfologia de superfície. O desenvolvimento de técnicas de deslizamento e de semi pontos de referência de superfíce melhorou muito a quantificação da forma, mas sua aplicação a diversos conjuntos de dados pode ser um desafio, especialmente quando algumas regiões dentro de uma estrutura são ausentes. Usando conjuntos de dados tridimensionais abrangentes do crânio, abrangendo todos os clados de pássaros, lagartos Squamata e cecílias, nós demonstramos métodos para captura da morfologia em formas incrivelmente diversas. Nós detalhamos muitas das dificuldades associadas à aplicação de semi pontos de referência em regiões comparáveis de estruturas altamente díspares, e fornecemos soluções para alguns desses desafios, enquanto consideramos as consequências das decisões tomadas na aplicação dessas abordagens. Finalmente, analisamos os benefícios das abordagens de deslizamento do semi pontos de referência em alta densidade para capturar a forma em diversos organismos e discutir a promessa dessas abordagens para o estudo da forma do organismo. Translated to Portuguese by Diego Vaz (dbistonvaz@vims.edu).

[NISCH syndrome, a rare cause of neonatal cholestasis: A case report]. / Le syndrome NISCH, une cause rare de cholestase néonatale : à propos d'un cas.

NISCH syndrome is a rare autosomal recessive disease. It is characterized by scalp hypotrichosis, scarring alopecia, ichthyosis, and neonatal sclerosing cholangitis. It is caused by mutations in the CLDN1 gene encoding the claudin-1 protein, which is located at tight junctions. Fifteen cases have been reported to date and three different mutations have been identified. We report on the case of a 2-year-old boy from a consanguineous Moroccan family, presenting with NISCH syndrome and carrying the so-called Moroccan homozygous mutation (c.200-201delTT). The patient presented with the characteristic symptoms of the syndrome and a favorable progression with normalization of hepatic analyses under symptomatic treatment (vitamin supplementation and ursodeoxycholic acid). The currently limited availability of clinical and therapeutic data does not allow accurate prediction of the course of the disease and short- and long-term prognosis. Moreover, substantial interindividual variability has been reported. Description of new cases will provide new insights into the understanding and the overall management of this syndrome, the course of which remains elusive.