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Clinical and molecular overlap between nucleotide excision repair (NER) disorders and DYRK1A haploinsufficiency syndrome
No full textInternational audienceNucleotide excision repair (NER) disorders are genetic conditions caused by defects in the pathway responsible for repairing DNA lesions due to UV radiation. These defects lead to a variety of heterogeneous disorders, including Cockayne syndrome (CS) and trichothiodystrophy (TTD). In this study, we report 11 patients initially suspected of having CS or TTD who were ultimately diagnosed with DYRK1A haploinsufficiency syndrome using high-throughput sequencing. Comparing clinical presentations, we observed that DYRK1A symptoms overlapped with CS, with shared features such as intellectual disability and microcephaly, systematically present in both disorders and other common symptoms including feeding difficulties, abnormal brain imaging, ataxic gait, hypertonia, and deep-set eyes. However, distinctive features of DYRK1A syndrome, such as severely impaired language, febrile seizures, and autistic behavior or anxiety, helped differentiate it from CS, which typically manifests with severe growth delay, bilateral cataracts, and pigmentary retinopathy. Among the cohort, three patients carried novel DYRK1A variants, including two truncating and one in-frame variant p.Val237_Leu241delinsGlu whose pathogenicity have been confirmed through functional analysis of DYRK1A protein. While previous research has implicated DYRK1A in DNA repair, with DYRK1A being one of the most downregulated genes in CS cells, our study found that DYRK1A patient-derived cell lines did not exhibit NER defects and did not share the CS transcriptomic signature. These findings suggest that if clinical symptoms overlap stems from common molecular disruptions, DYRK1A is involved downstream of the CS genes. This research highlights the importance of considering DYRK1A haploinsufficiency syndrome in the differential diagnoses for NER disorders
Transmural Healing Assessed by Combination of Fecal Calprotectin and Intestinal Ultrasonography Is Associated With Reduced Risk of Bowel Damage Progression in Patients With Crohn’s Disease
No full textInternational audienceFecal calprotectin (Fcal) and intestinal ultrasonography (IUS) could be used as noninvasive tools to monitor mucosal and transmural healing, respectively, in Crohn’s disease (CD). We assessed the agreement between Fcal and IUS to detect active CD and investigated their complementary to predict long-term CD outcomes. Methods In this prospective study, we consecutively included CD patients with concomitant IUS and Fcal testing within 7 days. Patients were divided into 4 groups: Transmural healing (TH; both normal), IUS healing (Fcal > 100 µg/g but normal IUS), biochemical remission reflecting mucosal healing (MH; Fcal < 100 µg/g but abnormal IUS), and no healing (abnormal Fcal and IUS). The primary endpoint was active CD. The secondary endpoints were time to bowel damage progression, time to relapse-related drug discontinuation, and patients’ acceptability (10-points acceptability numerical scale). Results Among the included 112 patients, 44.6% (50/112), 12.5% (14/112),16.1% (18/112), and 26.8% (30/122) achieved TH, IUS healing, biochemical remission, and no healing, respectively. The agreement between IUS and Fcal to detect an active CD was poor (71.4%, κ-coefficient = 0.41 ± 0.09). Transmural healing was associated with a reduced risk of bowel damage progression compared to no healing (P < .0001) contrary to IUS healing (P = .15) or biochemical remission (P = .84). Transmural healing was associated with a lower risk of relapse-related drug discontinuation than MH (hazard ratio [HR] = 0.09 [0.02-0.45], P = .003), IUS healing (HR = 0.10 [0.02-0.60], P = .001), or no healing (HR = 0.09 [0.018-0.04], P = .002). IUS was better accepted than Fcal testing (9.6 ± 0.8 vs 7.9 ± 2.3; P < .0001, 10-points range-acceptability numerical scale). Conclusions Transmural healing, evaluated by the combination of noninvasive and well-accepted tools such as Fcal and IUS, is associated with improved long-term outcomes and could be used to monitor patients with CD in daily practice
Revue de l’utilisation des dispositifs médicaux utilisés en chirurgie arthroscopique de l’épaule et des prothèses d’épaule.
No full textInternational audienceLa chirurgie de l’épaule évolue fortement ces dernières années, du fait de l’essor de la chirurgie arthroscopique et du développement de dispositifs médicaux toujours plus adaptés. L’objectif de cette revue est de faire le lien entre les principales pathologies prises en charge et les dispositifs médicaux associés. Les principales indications à une arthroscopie d’épaule sont la réparation de la coiffe des rotateurs et la correction d’une instabilité d’épaule. L’intervention nécessite un ensemble d’équipements biomédicaux (arthroscope, arthropompe, arthroshaver, console à radiofréquence, portés par une colonne d’arthroscopie) associés à leurs instruments.Dans certains cas, des implants sont nécessaires, notamment les ancres pour les réparations de coiffe. Les principales indications des prothèses d’épaule sont les fractures de l’extrémité supérieure de l’humérus et l’omarthrose à coiffe fonctionnelle ou non. En fonction, ces prothèses se déclinent en prothèse humérale, prothèse totale anatomique ou prothèse totale inversée.Chacune est composée d’un ensemble d’implants qui remplacent tout ou partie de l’articulation gléno-humérale. Ces différents dispositifs médicaux permettent d’apporter des solutions évolutives à long terme à des patients de plus en plus nombreux
Development of an ophthalmic solution combining allogenic plasma with protective excipients for enhanced therapeutic role in the management of ocular surface diseases
No full textInternational audienceOcular surface diseases (OSDs) are characterised by an instability of the tear film. In severe cases, these disorders have been improved by using human serum or plasma formulated into eye drops. These blood-derived-products present a biological composition similar to that of tears and contain beneficial factors that modulate inflammation and tissue regeneration. However, the supply of blood derivatives remains a challenge due to the potential microbiological risk, the quality and inter-individual heterogeneity of the biological samples used, and logistical difficulties. Thus, the idea behind this work was to use a standardised blood-derived product produced and checked industrially from a pool of donors, and to combine it with protective excipients known for their lubricating, anti-inflammatory, and regenerative properties offering new treatment opportunities for OSDs. Attention was also given to the non-bioaccumulative nature of the excipients. In order to select the concentrations of different compounds of interest in the ophthalmic solution, a design of experiment was used to establish a formulation with physicochemical properties (pH, osmolality, turbidity, viscosity) compatible with good ocular tolerance. Once defined, a physicochemical stability study testing pH, osmolality and dosage of biological factors, was carried out using the storage conditions usually used in clinical practice. A comparator without the additional compounds was also tested. The final formulation consisted of 20 % allogenic plasma, 0.5 % sodium hyaluronate (HS), 3 % trehalose (TH), 0.2 % chondroitin sulfate (CS) and 0.5 % sodium chloride (NaCl) (m/v). Its physicochemical properties should allow for good ocular tolerance. The data from the preliminary stability study favours storage at −20 °C for some of the biological factors measured
Tumor sink effect on melanin-ligand [131I]ICF01012 in melanoma and its implications for targeted radionuclide therapy
No full textInternational audienceBackground: The tumor sink effect refers to the sequestration of a radiopharmaceutical compound by tumors, leading to a reduced bioavailability in non-target organs and potential alterations in radiopharmaceuticals distribution. This phenomenon has been widely studied in neuroendocrine, thyroid, and prostate cancers but remains unexplored for melanin-targeting radiopharmaceuticals in metastatic melanoma. [131I]ICF01012, an arylcarboxamide-derived radiopharmaceutical developed by our team, binds specifically to intra- and extracellular melanin. Given its high ocular uptake, we investigated whether tumor burden influences its biodistribution, particularly in organs at risk such as eyes.Results: We conducted an ex vivo biodistribution study using syngeneic murine melanoma models (B16-F10, B16-OVA, B16BL6) and correlated tumor volume with radiopharmaceutical uptake. In models, γ-counting revealed significant tumor uptake (18.8 ± 4.5 IA%/g at 24 h after injection of [131I]ICF01012), which was inversely correlated with ocular uptake (r = -0.7485, p < 0.0001). A significant reduction in ocular uptake was observed in mice with large tumor burdens (-41.8% at 24 h, -47.4% at 72 h, p = 0.022).Conclusion: These findings suggest that tumor burden impacts [131I]ICF01012 distribution in non-target organs, with potential clinical implications for dosimetry and toxicity mitigation in radiopharmaceutical therapy for metastatic melanoma. Further studies are needed to refine dosimetric models and assess the translational relevance of this effect in human subjects
TOTUM-854 Human Circulating Bioactives Preserve Endothelial Cell Function
No full textInternational audienceBackground: TOTUM-854 is a patented plant extract blend characterized by its components that have previously been described for their potential health benefits in limiting hypertension onset. However, most of the literature data remain descriptive regarding the mode of action at the cellular level, especially in humans, and further investigations are required for optimized therapeutic strategies. Methods: We first demonstrated in an L-NAME mouse model that TOTUM-854 supports the prevention of hypertension in vitro and in vivo. Then, we designed an ex vivo clinical innovative approach considering the circulating metabolites produced by the digestive tract upon TOTUM-854 ingestion in humans. Human serum was collected in healthy volunteers before and after the acute intake of 3.71 g of TOTUM-854. The bioavailability of circulating metabolites was confirmed and characterized by UPLC-MS. Human serum containing TOTUM-854-derived metabolites was further processed for incubation with human endothelial cells (HUVECs), in the absence or presence of palmitate (200 µM). Results: HUVEC protection against lipotoxicity was characterized by (1) decreased ACE-1 activity (−32% p < 0.0001); (2) the inhibition of oxidative stress with decreased ROS (−12% observed by DCFDA and DHE fluorescent microscopy) and decreased Nox2 gene expression (−6.7 fold change vs. palmitate, p < 0.01); and (3) the inhibition of an inflammatory response, with a decrease in IL-1β release (−37% compared to palmitate, p < 0.001) and decreased MCP-1 and VCAM-1 gene expression (−93% p < 0.001 and −77% p < 0.001, respectively). Conclusions: Overall, this study provides insightful data regarding the protective role of TOTUM-854 in human endothelial cells. Using an innovative clinical ex vivo approach, our data support the role of TOTUM-854 circulating metabolites in vascular protection in humans
Predicting Deep Brain Stimulation Outcomes Using Intra-Operative Stimulation Test Data
No full textInternational audienceAbstract Deep Brain Stimulation (DBS) is an effective treatment for movement disorders. Optimizing stimulation parameters remains, however, a trial-and-error process. Datadriven models leveraging Probabilistic Mapping have shown promise in predicting DBS outcomes, yet current studies rely on chronic stimulation data. This study explores the feasibility of using intra-operative stimulation test data for DBS effect prediction. Probabilistic volumes of beneficial and adverse effects were computed from intra-operative stimulation test data of 65 patients (23 with Essential Tremor + 42 with Parkinson’s Disease). A prediction dataset was generated including clinical, morphological, stimulation features along with features derived from probabilistic maps and simulated Volumes of Tissue Activated. Three machine learning models (Adaboost, Support Vector Classifier and Naïve Bayes) were implemented to predict stimulation effects in a classification task. The models were validated in a leave-one-out crossvalidation and their performances were compared. All the developed models were able to predict DBS outcome classes. The best predictive performance was achieved by the Adaboost model with a maximum balanced accuracy of 0.71 on 3 classes. These results show that intra-operative stimulation test data can predict DBS effects with a similar approach and comparable accuracy to post-operative monopolar review data
Prognostic Impact of Early Appropriate Antimicrobial Therapy in Critically Ill Patients With Nosocomial Pneumonia Due to Gram-Negative Pathogens: A Multicenter Cohort Study
No full textInternational audienceOBJECTIVES: To evaluate whether early appropriate antimicrobial therapy (EAAT) is associated with improved outcomes in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP), or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria (GNB). DESIGN: Retrospective cohort study based on prospectively collected data. SETTING: Thirty-two French ICUs (OutcomeRéa network). PATIENTS: All patients with a first HAP, vHAP, or VAP due to GNB during their ICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The relationship between EAAT and day 28 all-cause mortality (primary endpoint) was explored through Cox proportional-hazard models, with subgroup analyses according to pneumonia types, causative GNB, features of EAAT, and the occurrence of septic shock at pneumonia diagnosis. The course of Sequential Organ Failure Assessment (SOFA) score values, the clinical cure rate at day 14, and the time to mechanical ventilation (MV) weaning and ICU discharge after pneumonia diagnosis were investigated as secondary endpoints. Among the 804 included patients, 495 (61.6%) received EAAT (single-drug, 25.4%; combination, 36.2%). Day 28 mortality was 32.6%. EAAT was not independently associated with this outcome (adjusted hazard ratio, 0.87; 95% CI, 0.67–1.12). This result was confirmed in subgroup analyses as in a second model considering all episodes of pneumonia occurring during the ICU stay. EAAT was not associated with a faster decrease in SOFA score values ( p = 0.11), a higher day 14 clinical cure rate (overall, 43.7%), or a shorter MV duration (cause-specific hazard ratio [HR] for extubation, 0.84; 95% CI, 0.69–1.01) or ICU stay (cause-specific HR for discharge alive, 0.85; 95% CI, 0.72–1.00). CONCLUSIONS: In this study, EAAT was not associated with a reduced day 28 mortality, a faster resolution of organ failure, a higher day 14 clinical cure rate, or a shorter time to MV weaning or ICU discharge in critically ill patients with HAP, vHAP, or VAP due to GNB. However, a prognostic benefit from EAAT cannot be ruled out due to lack of statistical power
Characteristics and outcomes of ICU patients with sepsis transmitted by cats and dogs: the PETSEPSIS multicentre retrospective observational cohort study
No full textInternational audienceBackgroundMillions of households have cats or dogs as pets, and infections due to bites or scratches are increasing, with the most common pathogens being Pasteurella spp., Bartonella spp., Capnocytophaga spp, and Francisella tularensis. The objective of this study was to describe patients admitted to the intensive care unit (ICU) for infection transmitted by cats or dogs, as well as their outcomes.MethodsThe retrospective multicentre observational cohort study PETSEPSIS included consecutive adults admitted to 46 ICUs in France between 2009 and 2019 for sepsis due to cat or dog bites and/or caused by any of the four above-listed bacteria. We described their features and outcomes and performed univariate and multivariate analyses to identify factors associated with death.ResultsWe included 174 patients with a median age of 64 [50–74] years; 58.1% were male. The median SAPS II score was 42 [28–58]. Mechanical ventilation was required in 51.2% of patients, for a median duration of 7 [4–13] days. Vasopressor support was used in 53.5%, renal replacement therapy in 19%, and limb amputation in 3.6% of the patients. The median ICU length of stay was 7 [4–16] days. Hospital mortality was 24.1%. The clinical presentation and severity of sepsis were similar across bacteria, although patients with Pasteurella spp. were older and had more comorbidities. Contact with cats were more often reported for Pasteurella spp. and Bartonella spp. infections and contact with dogs for Capnocytophaga spp. infections. Risk factors for hospital mortality present on ICU admission were older age, smoking, preexisting liver disease, high serum creatinine, and anaemia. Neither the type of micro-organism nor the initial antimicrobial treatment was associated with mortality.ConclusionsThis large multicentre study shows that infections transmitted by cats and dogs are infrequent reasons for ICU admission but are associated with substantial morbidity and mortality. Mortality was associated with older age and comorbidities but not with the type of microorganism or initial antibiotic treatment
Dexmedetomidine for treatment of hyperactive delirium in non-intubated ICU patients: the 4D randomized clinical trial
No full textInternational audiencePurposeWhether dexmedetomidine improves the control of hyperactive delirium in non-intubated intensive care unit (ICU) patients as compared with placebo remains uncertain.MethodsIn a multicenter, double-blind, placebo-controlled, two-arm, investigator-initiated, randomized trial conducted in 9 ICUs, we randomly assigned non-intubated critically ill adults with hyperactive delirium to receive continuous intravenous infusion of dexmedetomidine or placebo for at least 36 h. The primary outcome was a joint modelling of multiple outcomes of agitation duration (score of + 1 or higher on the Richmond agitation-sedation scale), delirium duration, or the need for intubation and deep sedation. Key secondary outcomes included the occurrence of complications (such as bradycardia or hypotension), length of stay in ICU, or death.ResultsEnrollment occurred from December 2017 to February 2022. Final follow-up was in February 2023. The study was stopped for efficacy at the time of the preplanned interim analysis. Among the 151 patients who were included in the final analysis, the between-group difference in the primary outcome was statistically significant (median difference, -30 points; 95% CI, − 49 to − 12, p = 0.001). Agitation duration was shorter in the dexmedetomidine group (1.0 (1.0–2.0) vs 2.0 (1.0–7.0) hours, absolute difference 95% CI − 1.0 (− 2.0 to − 0.1); ES, − 0.60; 95% CI, -0.92 to -0.27, p = 0.001). Other key secondary outcomes were similar between groups.ConclusionIn non-intubated adult ICU patients with hyperactive delirium, the use of dexmedetomidine was associated with a greater clinical benefit than placebo for the joint modelling of multiple endpoints of agitation control, delirium resolution, and intubation with mechanical ventilation. Dexmedetomidine appears to be a valuable alternative that significantly reduced the median duration of agitation by approximately 1 h compared to placebo in hyperactive delirious non-intubated intensive care unit patients