Post Genome-Wide Association Studies of Novel Genes Associated with Type 2 Diabetes Show Gene-Gene Interaction and High Predictive Value

Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. rs7903146 SNP, were combined (8.68-fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. strongly associate with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests

Pertinence des examens complémentaires au cours du bilan étiologique des uvéites : étude rétrospective de 300 patients

Objective: the diagnostic workup of uveitis is a challenge due to the wide range of diagnoses and the lack of a well-codified diagnostic procedure. We aimed to evaluate the relevance of diagnostic investigations for the etiological diagnosis of uveitis. Methods: retrospective cohort study of patients referred for etiological diagnosis of uveitis. Uveitis related to ophthalmological diseases or occurring during the course of previously diagnosed diseases were not included. Results: three hundred patients were included. Chest CT-scan was suggestive of sarcoidosis in 29%. Features associated with abnormal CT-scan were: snowballs and/or peripheral multifocal choroiditis (PMC) upon ocular examination, blood lymphopenia, angiotensin converting enzyme (ACE) level > 1.5 ULN. Bronchoscopy showed granuloma in 11% while alveolar lymphocytosis suggestive of sarcoidosis was reported in 27%. Presence of granuloma on bronchial biopsies was always associated with chest CT-scan abnormalities, whereas 31% of patients with alveolar lymphocytosis had normal CT-scan. Features associated with contributive bronchoscopy were: snowballs and/or PMC, ACE>1.5 ULN, abnormal chest-CT scan. Salivary gland biopsy revealed granuloma in 5%. Cerebral MRI was abnormal in 9% who mostly presented with snowballs and/or retinal vasculitis. Finally, the main causes of uveitis were latent tuberculosis (25%) and sarcoidosis (22%), but 34% remained of undetermined origin. Conclusion: identification of factors associated with abnormal investigations might improve the optimal diagnostic workup adapted to each patient.Introduction : le bilan étiologique des uvéites représente un challenge diagnostic. L’objectif de cette étude est d’évaluer la pertinence des méthodes d’investigations réalisées. Patients et méthode : étude rétrospective monocentrique de patients référés pour le bilan étiologique d’une uvéite. Résultats : trois cents patients ont été inclus. Le scanner (TDM) thoracique a montré des anomalies évocatrices de sarcoïdose chez 29%. Les facteurs associés à un TDM anormal étaient : la présence d’œufs de fourmi dans le vitré et/ou d’une choroïdite multifocale périphérique (CMP), une lymphopénie sanguine, et une augmentation de l'enzyme de conversion de l’angiotensine (ECA) supérieure à 1,5 fois la normale (1.5N). La fibroscopie bronchique a montré du granulome chez 11%, tandis qu’une lymphocytose alvéolaire suggestive de sarcoïdose a été reportée chez 27%. La présence de granulome était toujours associée à des anomalies au TDM, tandis que 31% des patients avec une lymphocytose alvéolaire avaient un TDM normal. Les facteurs associés avec une fibroscopie contributive étaient : présence d’œufs de fourmi et/ou d’une CMP, ECA >1,5N, et TDM thoracique anormal. La biopsie des glandes salivaires accessoires a révélé un granulome chez 5%. L'IRM cérébrale a été considérée anormale chez 9%, surtout chez ceux présentant des œufs de fourmi et/ou une vascularite rétinienne. Les principales causes identifiées étaient l’uvéite associée à une tuberculose latente (25%) et la sarcoïdose (22%), mais 33% restaient d'origine indéterminée. Conclusion : l’identification de facteurs associés à la rentabilité des examens complémentaires pourrait améliorer la pertinence du bilan étiologique des uvéites

Bases génétiques et mécanismes moléculaires du syndrome d'Evans pédiatrique

Evans syndrome is a rare and severe autoimmune disorder defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In the majority of cases, the underlying cause is unknown. We hypothesized that in children, mutations of genes involved in pathways regulating the function, survival, and proliferation of immune cells could be responsible for this pathology. The goal of this project was to identify new molecular defects in this pathology using 3 complementary approaches: genetic, functional and phenotypic. In a prospective national cohort of 80 patients with pediatric Evans syndrome, we identified potentially damaging variants in immune genes in 65% of cases (including mutations known to be associated with autoimmunity and new variants). Patients with a genetic diagnosis displayed more severe disease than those without identified genetic abnormality, with a greater frequency of additional immunopathologic manifestations, a greater number of lines of treatment, and a trend toward higher mortality. Furthermore, by whole exome sequencing, we identified germline, heterozygous autosomal-dominant loss of function mutations in the SOCS1 gene in ten patients from five unrelated families with early-onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patients-derived lymphocytes showed exhibited increased STAT activation in vitro in response to interferon-gamma as well as to interleukin 2 and 4. This was associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Finally, we observed an improvement in vitro, ex vivo and in vivo of these abnormalities using a JAK1 / 2 inhibitor.Le syndrome d'Evans est une maladie auto-immune rare et sévère définie par l'apparition concomitante ou séquentielle d'une anémie hémolytique auto-immune et d'une thrombopénie immunologique. Dans la majorité des cas, la cause sous-jacente est inconnue. Nous avons fait l'hypothèse que chez l'enfant, des mutations de gènes impliqués dans des voies régulant la fonction, la survie, et la prolifération des cellules immunes pourraient être responsable de cette pathologie. L'objectif de ce projet était d'identifier de nouveaux défauts moléculaires dans cette pathologie à l'aide de 3 approches complémentaires : génétique, fonctionnelles et phénotypiques. Dans une cohorte nationale prospective de 80 patients avec syndrome d'Evans pédiatrique, nous avons identifié des variants possiblement pathogènes dans 65% des cas (incluant des mutations connues comme étant associées à des maladies auto-immunes et de nouveaux variants). Les patients avec un diagnostic génétique présentaient une maladie plus sévère que ceux sans anomalie génétique identifiée, avec une plus grande fréquence de manifestations immunopathologiques additionnelles, un plus grand nombre de ligne de traitements, et une tendance vers une mortalité plus importante. Par ailleurs, par séquençage de l'exome entier, nous avons identifié des mutations germinales, hétérozygotes, de transmission autosomique dominante et pertes de fonction dans le gène SOCS1 chez dix patients de cinq familles avec manifestations auto-immunes à début précoce. La protéine intracellulaire SOCS1 est connue pour être un régulateur négatif de l'action des cytokines par inhibition de la voie JAK/STAT. Ainsi, les lymphocytes de ces patients présentaient une hyperactivité des protéines STATs en réponse à l'interféron-gamma ainsi qu'aux interleukine 2 et 4. Ceci était associé à des anomalies in vivo and in vitro suggestives d'hyperactivité des lymphocytes. Finalement, nous avons observé une amélioration in vitro, ex vivo et in vivo de ces anomalies en utilisant un inhibiteur des JAK1/2

Fatty liver index is a strong predictor of changes in glycemic status in people with prediabetes: The IT-DIAB study

International audienceBACKGROUND & AIMS:In patients at metabolic risk, nonalcoholic fatty liver disease is a strong and highly prevalent predictor for type 2 diabetes. Its assessment in clinical practice is not easy but the fatty liver index (FLI) could be used as a surrogate. Here, we studied the association between the FLI and the conversion to new-onset diabetes (NOD) or prediabetes reversion in patients with prediabetes.METHODS:The IT-DIAB observational study included 389 individuals with prediabetes, defined as fasting plasma glucose (FPG) between 110 and 125 mg/dL. NOD conversion was defined as a first FPG value ≥ 126 mg/dL and prediabetes reversion as a first FPG value < 110 mg/dL. The associations of both events with baseline FLI were studied separately using multivariate Cox models.RESULTS:After a median follow-up of 3.9 years (range 0.1-6.1), 138 individuals (35.5%) converted to NOD. FLI was associated with a higher risk of NOD conversion (unadjusted HR per SD = 1.54, 95%CI 1.27-1.86, p<0.0001), even after multiple adjustment on FPG, HbA1c and diabetes risk score (adjusted HR per SD 1.31, 95%CI 1.07-1.61, p = 0.008). FLI was also associated with prediabetes reversion: adjusted HR per SD = 0.85, 95%CI 0.75-0.96, p = 0.0077. Changes in FLI were significantly associated with changes in FPG during follow-up (p<0.0001). When compared to a full model including the diabetes risk score, FPG, HbA1C and FLI, only HbA1C added a significant prediction information (AUROC: 72.8% for full model vs 69.4% for the model without HbA1C; p = 0.028), while the removal of FLI to the full model did not alter its predictive value (AUROC 72.2%). The predictive value for NOD conversion was not significantly better for HOMA-IR compared to FLI (AUROC: 69.3 vs 63.7%, p = 0.067).CONCLUSIONS:FLI is a simple, practical score to further stratify the risk of conversion to NOD or the possibility of prediabetes reversion in clinical practice, independently of classical glucose parameters.TRIAL REGISTRATION:ClincialTrials.gov number NCT01218061 and NCT01432509

Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value

International audienceBackground. Coronavirus disease 2019 (COVID-19) is a global public health problem that has already caused more than 662,000 deaths worldwide. Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients present other severe damage such as cardiovascular, renal and liver injury or/and multiple organ failure, suggesting a spread of the SARS-CoV-2 in blood. Recent ultrasensitive polymerase chain reaction (PCR) technology now allows absolute quantification of nucleic acids in plasma. We herein intended to use the droplet-based digital PCR technology to obtain sensitive detection and precise quantification of plasma SARS-CoV-2 viral load (SARSCoV-2 RNAaemia) in hospitalized COVID-19 patients.Methods. Fifty-eight consecutive COVID-19 patients with pneumonia 8 to 12 days after onset of symptoms and 12 healthy controls were analyzed. Disease severity was categorized as mild-to-moderate in 17 patients, severe in 16 patients and critical in 26 patients. Plasma SARS-CoV-2 RNAaemia was quantified by droplet digital Crystal Digital PCR™ nextgeneration technology (Stilla Technologies, Villejuif, France).Results. Overall, SARS-CoV-2 RNAaemia was detected in 43 (74.1%) patients. Prevalence of positive SARS-CoV-2 RNAaemia correlated with disease severity, ranging from 53% in mild-to-moderate patients to 88% in critically ill patients (p=0.036). Levels of SARS-CoV-2 RNAaemia were associated with severity (p=0.035). Among nine patients who experienced clinical deterioration during follow-up, eight had positive SARS-CoV-2 RNAaemia at baseline while only one critical patient with undetectable SARS-CoV-2 RNAaemia at thetime of analysis died at day 27.Conclusion. SARS-CoV-2 RNAaemia measured by droplet-based digital PCR constitutes a promising prognosis biomarker in COVID-19 patients

Anti-CD38 therapy impairs SARS-CoV-2 vaccine response against alpha and delta variants in patients with multiple myeloma

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Neutralizing antibody levels as a correlate of protection against SARS‐CoV‐2 infection: a modeling analysis

International audienceWhile anti‐SARS‐CoV‐2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half‐life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half‐life of both infected cells and circulating virus by a 6‐fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre‐existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by ED 50 >10 3 , could reduce by 46% the risk of having viral load detectable by standard PCR assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission

Prospective evaluation of a dynamic insulin infusion algorithm for non critically-ill diabetic patients: A before-after study

International audienceIntroduction: Insulin infusion is recommended during management of diabetic patients in critical care units to rapidly achieve glycaemic stability and reduce the mortality. The application of an easy-to-use standardized protocol, compatible with the workload is preferred. Glycaemic target must quickly be reached, therefore static algorithms should be replaced by dynamic ones. The dynamic algorithm seems closer to the physiological situation and appreciates insulin sensitivity. However, the protocol must meet both safety and efficiency requirements. Indeed, apprehension from hypoglycaemia is the main deadlock with the dynamic algorithms, thus their application remains limited. In contrary to the critical care units, to date, no prospective study evaluated a dynamic algorithm of insulin infusion in non-critically ill patients.Aim: This study primarily aimed to evaluate the efficacy of a dynamic algorithm of intravenous insulin therapy in non-critically-ill patients, and addressed its safety and feasibility in different departments of our university hospital.Methods: A "before-after" study was conducted in five hospital departments (endocrinology and four “non-expert” units) comparing a dynamic algorithm (during the "after" period-P2) to the static protocol (the “before” period-P1). Static protocol is based on determining insulin infusion according to an instant blood glycaemia (BG) level at a given time. In the dynamic algorithm, insulin infusion rate is determined according to the rate of change of the BG (the previous and actual BG under a specific insulin infusion rate). Additionally, two distinct glycaemic targets were defined according to the patients’ profile: 100–180 mg/dl (5.5–10 mmol/l) for vigorous patients and 140–220 mg/dl (7.8–12.2 mmol/l) for frail ones. Different BG measurements for each patient were collected and recorded in a specific database (e-CRF) in order to analyse the rates of hypo- and hyperglycaemia. A satisfaction survey was also performed. A study approval was obtained from the institutional revision board before starting the study.Results: Over 8 months, 72 and 66 patients during P1 and P2 were respectively included. The dynamic algorithm was more efficient, with reduced time to control hyperglycaemia (P1 vs P2:8.3 vs 5.3 hours; HR: 2.02 [1.27; 3.21]; p<0.01), increased the number of in-target BG measurements (P1 vs P2: 37.0% vs 41.8%; p<0.05), and reduced the glycaemic variability related to each patient (P1 vs P2, %CV: 40.9 vs 38.2;p<0.05, Index Correlation Class:0.30 vs 0.14; p<0.05). In patients after the first event of hypoglycemia after having started the infusion, new events were lower (P1 vs P2: 19.4 vs 11.4; p<0.001) thanks to an earlier reaction to hypoglycaemia (8.3% during P1 vs 44.3% during P2; p = 0.004). With the dynamic algorithm, the percentage of recurrence of mild hypoglycaemia was significantly lower in frail patients (20.5% vs 10.2%; p<0.001), and in patients managed in the non-expert units (18 vs 7.1%, p<0.001). The %CV was significantly improved in frail patients (36.9%). Mean BG measurements for each patient/day were 5.5±1.1 during P1 and 6.0±1.6 during P2 (p = 0.6). The threat from hypoglycaemia and the difficulty in using dynamic algorithm are barriers for nurses’ adherence.Conclusions: This dynamic algorithm for non-critically-ill patients is more efficient and safe than the static protocol, and adapted for frail patients and non-expert units