Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma.

Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Etude comparative des aspects cliniques et physiopathologiques des erreurs innées du métabolisme de la vitamine B12 en fonction de l’âge

Vitamin B12 metabolism is a complex process leading to the synthesis of two active forms: adenosylcobalamin, cofactor of methylmalonyl-CoA mutase, and methylcobalamin, cofactor of methionine synthase, which is essential for methylation reactions. Inborn errors of vitamin B12 metabolism are rare pathologies resulting from a deficiency of a protein or an enzyme in the transport, internalization, or intracellular utilization of vitamin B12. The clinical and metabolic manifestations presented by the patients offer a great diversity of presentations according to the age of onset of the first symptoms and the mutated gene. We performed a meta-analysis of 824 patients with a genetically documented deficiency of vitamin B12 metabolism. We were able to highlight the appearance of neurological manifestations (gait disorder, cerebral atrophy, peripheral neuropathy) with age, as well as cardiovascular manifestations (blood hypertension, thrombosis). These neurological and cardiovascular profiles underline the importance of evoking an inborn error of vitamin B12 metabolism, and the search for such a deficiency in case of a clinical evocative profile. The second part of this work aims to objectify the diagnostic yield of a clinical exome as a first level genetic test in a pediatric population of 128 consecutive children. 60% of CES were positive in case of suggestive biochemical abnormality, with a median delay of 5 months, offering a powerful diagnostic test for the identification of a IEM-B12. The third part of this work highlighted in patient fibroblasts an expression variation at the metabolomic, transcriptomic, proteomic and post-translational modification levels (such as the addition of propionaldehyde) of enzymes involved in metabolism, notably mitochondrial, associated with other pathologies whose clinical manifestations may explain the clinical variability observed in IEM-B12.Le métabolisme de la vitamine B12 est un processus complexe aboutissant à la synthèse des deux formes actives : l’adénosylcobalamine, cofacteur de la méthylmalonyl-CoA mutase, et la méthylcobalamine, cofacteur de la méthionine synthase, indispensable aux réactions de méthylation de l’organisme. Les erreurs innées du métabolisme de la vitamine B12 sont des pathologies rares consécutives à un déficit d’une protéine ou d’une enzyme sur le transport, l’internalisation ou l’utilisation intracellulaire de la vitamine B12. Les manifestations cliniques et métaboliques présentées par les patients offrent une grande diversité de présentation selon l’âge d’apparition des premiers symptômes et le gène muté. Nous avons réalisé une méta-analyse rassemblant l’ensemble des descriptions de 824 patients ayant un déficit génétiquement documenté du métabolisme de la vitamine B12. Nous avons pu souligner l’apparition de manifestations neurologiques (trouble de la marche, atrophie cérébrale, neuropathie périphérique) avec l’âge, tout comme celle de manifestations cardiovasculaires (hypertension artérielle, thrombose). Ces profils neurologiques et cardio-vasculaires soulignent l’importance d’évoquer une erreur innée du métabolisme de la vitamine B12, et la recherche génétique d’un tel déficit en cas de profil évocateur. La deuxième partie de ce travail a objectivé le rendement diagnostique d’un exome clinique comme test génétique de premier niveau au sein d’une population pédiatrique de 128 enfants consécutifs. 60% des CES étaient positifs en cas d’anomalie biochimique évocatrice, pour un délai médian de 5 mois, offrant un test diagnostique performant pour l’identification d’une IEM-B12. La troisième partie de ce travail a mis en évidence dans des fibroblastes de patient une variation d’expression aux niveaux métabolomique, transcriptomique, protéomique et de modification post-traductionnelle (tel que l’ajout de propionaldéhyde) d’enzymes impliqués dans le métabolisme, notamment mitochondriale, associés à d’autres pathologies dont les manifestations cliniques permettent d’expliquer la variabilité clinique observer dans les IEM-B12

Comparative study of the clinical and physiopathological aspects of inborn errors of vitamin B12 metabolism according to aging

Le métabolisme de la vitamine B12 est un processus complexe aboutissant à la synthèse des deux formes actives : l’adénosylcobalamine, cofacteur de la méthylmalonyl-CoA mutase, et la méthylcobalamine, cofacteur de la méthionine synthase, indispensable aux réactions de méthylation de l’organisme. Les erreurs innées du métabolisme de la vitamine B12 sont des pathologies rares consécutives à un déficit d’une protéine ou d’une enzyme sur le transport, l’internalisation ou l’utilisation intracellulaire de la vitamine B12. Les manifestations cliniques et métaboliques présentées par les patients offrent une grande diversité de présentation selon l’âge d’apparition des premiers symptômes et le gène muté. Nous avons réalisé une méta-analyse rassemblant l’ensemble des descriptions de 824 patients ayant un déficit génétiquement documenté du métabolisme de la vitamine B12. Nous avons pu souligner l’apparition de manifestations neurologiques (trouble de la marche, atrophie cérébrale, neuropathie périphérique) avec l’âge, tout comme celle de manifestations cardiovasculaires (hypertension artérielle, thrombose). Ces profils neurologiques et cardio-vasculaires soulignent l’importance d’évoquer une erreur innée du métabolisme de la vitamine B12, et la recherche génétique d’un tel déficit en cas de profil évocateur. La deuxième partie de ce travail a objectivé le rendement diagnostique d’un exome clinique comme test génétique de premier niveau au sein d’une population pédiatrique de 128 enfants consécutifs. 60% des CES étaient positifs en cas d’anomalie biochimique évocatrice, pour un délai médian de 5 mois, offrant un test diagnostique performant pour l’identification d’une IEM-B12. La troisième partie de ce travail a mis en évidence dans des fibroblastes de patient une variation d’expression aux niveaux métabolomique, transcriptomique, protéomique et de modification post-traductionnelle (tel que l’ajout de propionaldéhyde) d’enzymes impliqués dans le métabolisme, notamment mitochondriale, associés à d’autres pathologies dont les manifestations cliniques permettent d’expliquer la variabilité clinique observer dans les IEM-B12.Vitamin B12 metabolism is a complex process leading to the synthesis of two active forms: adenosylcobalamin, cofactor of methylmalonyl-CoA mutase, and methylcobalamin, cofactor of methionine synthase, which is essential for methylation reactions. Inborn errors of vitamin B12 metabolism are rare pathologies resulting from a deficiency of a protein or an enzyme in the transport, internalization, or intracellular utilization of vitamin B12. The clinical and metabolic manifestations presented by the patients offer a great diversity of presentations according to the age of onset of the first symptoms and the mutated gene. We performed a meta-analysis of 824 patients with a genetically documented deficiency of vitamin B12 metabolism. We were able to highlight the appearance of neurological manifestations (gait disorder, cerebral atrophy, peripheral neuropathy) with age, as well as cardiovascular manifestations (blood hypertension, thrombosis). These neurological and cardiovascular profiles underline the importance of evoking an inborn error of vitamin B12 metabolism, and the search for such a deficiency in case of a clinical evocative profile. The second part of this work aims to objectify the diagnostic yield of a clinical exome as a first level genetic test in a pediatric population of 128 consecutive children. 60% of CES were positive in case of suggestive biochemical abnormality, with a median delay of 5 months, offering a powerful diagnostic test for the identification of a IEM-B12. The third part of this work highlighted in patient fibroblasts an expression variation at the metabolomic, transcriptomic, proteomic and post-translational modification levels (such as the addition of propionaldehyde) of enzymes involved in metabolism, notably mitochondrial, associated with other pathologies whose clinical manifestations may explain the clinical variability observed in IEM-B12

La phénylcétonurie: De la diététique à la thérapie génique

International audienceLe pronostic de la phénylcétonurie (PCU) a été transformé par le dépistage néonatal et la prise en charge diététique via un apport contrôlé en phénylalanine. Ce traitement doit être suivi toute la vie durant, ce qui pose des problèmes de compliances importants. Un traitement médicamenteux par saproptérine (ou BH4) est venu apporter une aide à un pourcentage réduit de patients qui répondent à ce médicament. Une enzymothérapie par voie sous-cutanée est disponible aux États-Unis et a obtenue une AMM européenne, mais génère des effets secondaires importants, ce qui en limite l’efficacité. De nouvelles options thérapeutiques de la PCU sont actuellement en développement, en particulier par thérapie génique. Le but de cet article est de faire le point sur la physiopathologie et sur les différentes nouvelles modalités thérapeutiques actuellement en développement