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The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0–12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1–47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4–7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0). [ABSTRACT FROM AUTHOR]

Purpose: Blood culture contamination is still a frequently observed event and may lead to unnecessary antibiotic prescriptions and additional hazards and costs. However, in patients hospitalized in tertiary care, true bacteremias for pathogens that are classically considered as contaminants can be observed. We assessed the diagnostic accuracy of procalcitonin for differentiating blood culture contamination from bacteremia in patients with positive blood cultures for potential contaminants. Methods: We carried out a retrospective, cross-sectional, observational study on consecutive patients hospitalized between January 2016 and May 2019 at the University Hospital of Nancy and who had a positive peripheral blood culture for a pathogen classically considered as a potential contaminant. Results: During the study period, 156 patients were screened, and 154 were retained in the analysis. Among the variables that were significantly associated with a diagnosis of blood culture contamination in univariate analyses, four were maintained in multivariate logistic regression analysis: a number of positive blood culture bottles ≤ 2 (OR 23.76; 95% CI 1.94–291.12; P = 0.01), procalcitonin < 0.1 ng/mL (OR 14.88; 95% CI 1.62–136.47; P = 0.02), non-infection-related admission (OR 13.00; 95% CI 2.17–77.73; P = 0.005), and a percentage of positive blood culture bottles ≤ 25% (OR 12.15; 95% CI 2.02–73.15; P = 0.006). Conclusions: These data provide new evidence on the usefulness of plasma procalcitonin as a reliable diagnostic biomarker in the diagnostic algorithm of peripheral blood culture contamination among patients hospitalized in tertiary care. Clinical trial: ClinicalTrials.gov #NCT04573894. [ABSTRACT FROM AUTHOR]

Abstract: Background: Ocular manifestations are frequent in patients with inflammatory bowel disease. Aim: To evaluate for the first time the value of ocular symptoms in predicting ophthalmologic inflammation in inflammatory bowel disease. Methods: All consecutive inflammatory bowel disease patients seen in the Department of Gastroenterology (Nancy, University Hospital, France) between April 2009 and July 2011 were interviewed for this cross-sectional study using a pre-established questionnaire. If the patient had at least one ocular symptom, he systematically underwent an ophthalmologic examination (visual acuity, Break-Up Time test, Schirmer Test, slit-lamp exam with fundus examination). Results: This cross-sectional survey was completed by 305 patients: 169 were women (55.2%), 228 had Crohn''s disease (74.5%). Ninety-eight patients (32%) reported at least one ocular symptom: ocular irritation (56.8%), red eye (40.5%), blurred vision (37.8%), progressive visual loss (34.4%), ocular pain (31.1%), myodesopsia (23.3%), eyelid secretion (12.2%), dry eye (9.5%), watering (6.8%), diplopia (5.4%), metamorphopsia (4%), and sudden visual loss (4%). Following ophthalmologic examination (n =74), 41.9% patients had evidence of dry eye (n =31), 14.9% blepharitis (n =11) and 1.4% scleritis (n =1). No uveitis was reported. Conclusion: Ocular symptoms are frequent in inflammatory bowel disease, but are non-specific and rarely associated with ocular inflammation. Systematic ocular symptoms assessment is of poor value for diagnosing ocular inflammation in inflammatory bowel disease. [Copyright &y& Elsevier]

Background: To face the Covid19 pandemic, many European countries have developed a public health strategy with digital contact tracing (DCT) applications improving timely tracking and contact tracing. The France's independent COVID-19 Control and Society Connection Council (CCL) has been established by law in May 2020 to issue advice and recommendations on the national epidemic digital systems.Objective: We are presenting here the CCL's recommendations, the objective being to increase French DCT's uptake and utility.Methods: As the country's most vulnerable population has been subjected to greater virus exposure, stronger lockdown impact and less access to prevention and health care services, the CCL is particularly aware of health inequalities.Results: French apps "TousAntiCovid" had been downloaded by 13.6 million (20%) of the French population in March, 2021. To promote the use of the apps, the CCL had recommended to introduce increased communication about the app's individual and collective objectives. The CCL has also recommended the introduction of clear, simple, accessible, incentivising, non-coercive information inside the tool. In addition, the CCL recommended improving public health policies to address the needs of underprivileged.Conclusions: The CCL calls for developing population empowerment with digital tools, public health culture for decision-makers dealing with health determinants, taking social considerations into account, and incorporating community participation. [ABSTRACT FROM AUTHOR]

Neuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis. ALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. Overall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions. Patients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis. NCT02250729. [ABSTRACT FROM AUTHOR]

To combat the COVID-19 pandemic, many European countries have developed a public health strategy involving the use of digital contact tracing (DCT) applications to improve timely tracking and contact tracing of COVID-19 cases. France's independent COVID-19 Control and Society Connection Council (CCL) was established by law in May 2020 to issue advice and recommendations on the national epidemic digital systems. In this paper, we present the recommendations by the CCL, with the objective to increase the uptake and utility of French DCT applications. As the country's most vulnerable population has been subjected to greater virus exposure, a stronger impact of the lockdown, and less access to preventive and health care services, the CCL is particularly aware of health inequalities. The French DCT app TousAntiCovid had been downloaded by 13.6 million users (ie, 20% of the French population) in March 2021. To promote the use of DCT apps, the CCL has recommended that communication about the app's individual and collective objectives be increased. The CCL has also recommended the introduction of clear, simple, accessible, incentivizing, noncoercive information within the digital tools. In addition, the CCL has recommended improving public health policies to address the needs of the underprivileged. The CCL calls for promoting population empowerment with the use of digital tools, improving public health culture for decision-makers dealing with health determinants, taking social considerations into account, and incorporating community participation., (©Marion Albouy-Llaty, Caroline Martin, Daniel Benamouzig, Eric Bothorel, Gilles Munier, Catherine Simonin, Jean-Louis Guéant, Emmanuel Rusch. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.10.2021.)

Phenylketonuria is the most common inborn error of metabolism and causes irreversible mental retardation if left untreated. Its newborn screening was made possible by the technique of blood collection on filter paper developed by Robert Guthrie. Neonatal PKU screening began in France in the early 1970s. It was initially carried out by a bacteriological method, then by fluorometry, and finally, since 2020, by tandem mass spectrometry. More than 35 million newborns have been screened to date. This resulted in the diagnosis of more than 3,500 children with PKU or mild hyperphenylalaninemia. The management of these children has improved over time, in particular thanks to the techniques of biochemistry and molecular genetics which lead to an accurate diagnosis and the arrival of drug treatment by sapropterin. Thanks to this screening, which allows for early management, the prognosis of PKU has been transformed and, although neurological or behavioral problems may arise, these patients are living normally today., (© 2021 médecine/sciences – Inserm.)

Background: In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes., Methods: We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures., Results: On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% confidence interval [CI], 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05-11.96)., Conclusions: Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus., Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH., Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin&#95;H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively., Interpretation: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH., Funding: French National Institute of Health and Medical Research (INSERM) UMR&#95;S 1256., Competing Interests: Declaration of Competing Interest The authors who have taken part in this study declare that they do not have anything to disclose regarding conflicts of interest concerning this manuscript., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations., Methods: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification., Results: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response., Conclusions: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.

Background: Few data are available on the incidence, characteristics, treatment, and prognosis of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) in population-based cohorts., Methods: Among the 19,451 new cases of CRC recorded in the Burgundy digestive cancer registry between 1976 and 2008, all cases of IBD-associated CRC were identified. Incidence rates were age-standardized according to the world standard population. Prognosis was determined using univariate and multivariate relative survival., Results: Thirty-eight IBD-associated CRC were identified (ulcerative colitis, n = 29; Crohn's disease, n = 9). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (70.9 vs. 56.9 years, respectively; P < 0.001). Distributions of gender, stage at presentation, location, and histological type of CRC did not differ from those of sporadic cases. The overall world age-standardized incidence of IBD-associated CRC per 100,000 was 0.11 (standard deviation [SD]: 0.03) for men and 0.06 (SD: 0.02) for women. Only age was independently associated with IBD-associated CRC (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.12-0.43; P < 0.001). Treatment modalities did not differ between IBD and non-IBD patients. Five-year relative survival was 51.9% (95% CI: 51.1-52.8%) in non-IBD patients and 41.3% (95% CI: 24.6-57.2%) in IBD patients (P = 0.201). After adjustment for age, gender, and stage at diagnosis, the excess hazard of death was 1.46 times higher in IBD than in non-IBD patients (95% CI: 0.94-2.27; P = 0.070)., Conclusions: Apart from age, the characteristics of IBD-associated CRC were similar to those of non-IBD CRC. The prognosis of CRC may be poorer in patients with IBD than in those without IBD., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Background: Occupational exposures are thought to be responsible for 10-15% of new-onset asthma cases in adults, with disparities across sectors. Because most of the data are derived from registries and cross-sectional studies, little is known about incidence of occupational asthma (OA) during the first years after inception of exposure. This paper describes the design of a study that focuses on this early asthma onset period among young workers in the bakery, pastry making and hairdressing sectors in order to assess early incidence of OA in these "at risk" occupations according to exposure duration, and to identify risk factors of OA incidence., Methods/design: The study population is composed of subjects who graduated between 2001 and 2006 in these sectors where they experience exposure to organic or inorganic allergenic or irritant compounds (with an objective of 150 subjects by year) and 250 young workers with no specific occupational exposure. A phone interview focusing on respiratory and 'Ear-Nose-Throat' (ENT) work-related symptoms screen subjects considered as "possibly OA cases". Subjects are invited to participate in a medical visit to complete clinical and lung function investigations, including fractional exhaled nitric oxide (FENO) and carbon monoxide (CO) measurements, and to collect blood samples for IgE (Immunoglobulin E) measurements (total IgE and IgE for work-related and common allergens). Markers of oxidative stress and genetic polymorphisms exploration are also assessed. A random sample of 200 "non-cases" (controls) is also visited, following a nested case-control design., Discussion: This study may allow to describ a latent period between inception of exposure and the rise of the prevalence of asthma symptoms, an information that would be useful for the prevention of OA. Such a time frame would be suited for conducting screening campaigns of this emergent asthma at a stage when occupational hygiene measures and adapted therapeutic interventions might be effective., Trial Registration: Clinical trial registration number is NCT01096537.

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6., ((c) 2008 Wiley-Liss, Inc.)