Renal replacement therapy initiation strategies in comatose patients with severe acute kidney injury: a secondary analysis of a multicenter randomized controlled trial.

PURPOSE: The effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in comatose patients with severe AKI. METHODS: We conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale [RASS] < - 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < - 3), incomplete awakening (RASS [- 3; - 2]), awakening (RASS [- 1; + 1] two consecutive days), and agitation (RASS > + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization. RESULTS: A total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio [HR] = 0.36 [0.17-0.78]; p = 0.010). Time spent awake was 10.11 days [8.11-12.15] and 7.63 days [5.57-9.64] in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results. CONCLUSION: In comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.

Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

Neutrophil activation in patients treated with endovascular therapy is associated with unfavorable outcomes and mitigated by intravenous thrombolysis.

BACKGROUND: Accumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT. METHODS: A single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3-6 at 3 months. RESULTS: Between 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR -2.1-150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline -0.8 ng/mL (IQR -7.6-6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes. CONCLUSIONS: A peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.

PupillOmetry for preDIction of DeliriUM in ICU (PODIUM): protocol for a prospective multicentre cohort study.

INTRODUCTION: Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU. METHODS AND ANALYSIS: The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥-3).The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days. ETHICS AND DISSEMINATION: The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV-NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05248035; clinicaltrials.gov.

Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish.

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Cerebrovascular complications and outcomes of critically ill adult patients with infective endocarditis.

BACKGROUND: Neurological complications are associated with poor outcome in patients with infective endocarditis (IE). Although guidelines recommend systematic brain imaging in the evaluation of IE patients, the association between early brain imaging findings and outcomes has never been evaluated in critically ill patients. We aimed to assess the association of CT-defined neurological complications with functional outcomes of critically ill IE patients. METHODS: This retrospective cohort study included consecutive patients with severe, left-sided IE hospitalized in the medical ICU of a tertiary care hospital. Patients with no baseline brain CT were excluded. Baseline CT-scans were classified in five mutually exclusive categories (normal, moderate-to-severe ischemic stroke, minor ischemic stroke, intracranial hemorrhage, other abnormal CT). The primary endpoint was 1-year favorable outcome, defined by a modified Rankin Scale score of 0-3. RESULTS: Between 06/01/2011 and 07/31/2018, 156 patients were included. Among them, 87/156 (56%) had a CT-defined neurological complication, including moderate-to-severe ischemic stroke (n = 33/156, 21%), intracranial hemorrhage (n = 24/156, 15%), minor ischemic stroke (n = 29/156, 19%), other (n = 3/156, 2%). At one year, 69 (45%) patients had a favorable outcome. Factors negatively associated with favorable outcome in multivariable analysis were moderate-to-severe ischemic stroke (OR 0.37, 95%CI 0.14 - 0.95) and age (OR 0.94, 95%CI 0.91-0.97). By contrast, the score on the Glasgow Coma Scale was positively associated with favorable outcome (per 1-point increment, OR 1.23, 95%CI 1.08-1.42). Sensitivity analyses conducted in operated patients revealed similar findings. Compared to normal CT, only moderate-to-severe ischemic stroke was associated with more frequent post-operative neurological complications (n = 8/23 (35%) vs n = 1/46 (2%), p < 0.01). CONCLUSION: Moderate-to-severe ischemic stroke had an independent negative impact on 1-year functional outcome in critically ill IE patients; whereas other complications, including intracranial hemorrhage, had no such impact.

Monoallelic CRMP1 gene variants cause neurodevelopmental disorder.

Collapsin response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the CRMP1 gene in three unrelated individuals with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. We further analyzed the effect of the variants on the protein structure/levels and cellular processes. We showed that the human CRMP1 variants impact the oligomerization of CRMP1 proteins. Moreover, overexpression of the CRMP1 variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic variants in CRMP1 gene have never been linked to human disease. We report for the first-time variants in the CRMP1 gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.

Acute ischemic stroke in adolescents.

OBJECTIVE: Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents. METHODS: This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation. RESULTS: A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40, p = 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases. CONCLUSIONS: Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe.

Sensitivities of a bulk-tank milk ELISA and composite fecal qPCR to detect various seroprevalence levels of paratuberculosis in cattle herds in Normandy, France.

This study evaluated an ELISA on bulk tank milk (BTM) samples and a qPCR on a single composite fecal sample to detect paratuberculosis seropositive cattle dairy herds. Individual serum (n = 15 372), BTM and composite fecal samples were obtained from 192 herds. The within-herd apparent seroprevalence was categorized and compared with BTM ELISA and fecal qPCR results. The BTM ELISA had poor overall sensitivity (16%) to detect seropositive herds but higher sensitivity (53%) in the higher apparent seroprevalence group of > 9%. Using an optimized cut-off point (5.0% S/P), sensitivities overall and in the high apparent seroprevalence group were 53% and 88%, respectively. The BTM ELISA gave 5% positive results in seronegative herds and 25% using the optimized cut-off. Fecal qPCR had 72% sensitivity to detect seropositive herds and 88% in the higher apparent seroprevalence group, but gave 25% positive results in fully seronegative herds. The combination of BTM ELISA and composite fecal qPCR improved the sensitivity to detect seropositive herds.

Sensibilités d'un test ELISA sur lait de réservoir et d'une qPCR sur prélèvement composite de fèces pour le dépistage de cheptels bovins à différents niveaux de séroprévalence en paratuberculose en Normandie, France. L'étude a été entreprise pour évaluer les performances diagnostiques d'un test ELISA, effectué sur un échantillon de lait de réservoir (BTM), et d'une qPCR, réalisée sur un échantillon composite de fèces (CF), pour détecter les troupeaux de bovins séropositifs pour la paratuberculose. Les sérums individuels (n = 15 372), les échantillons de BTM et de CF ont été collectés dans 192 troupeaux. La séroprévalence apparente intra-troupeau a été calculée puis catégorisée avant d'être comparée aux résultats de l'ELISA sur BTM et de la qPCR sur CF. Le test ELISA sur BTM a montré une faible sensibilité globale (16 %) mais celle-ci était plus élevée dans les élevages les plus fortement séropositifs > 9 % (53 %). En utilisant un seuil optimisé (E/P 5,0 %), les sensibilités étaient de 53 % et 88 %, respectivement. Le test ELISA sur BTM a donné 5 % de résultats positifs sur des troupeaux entièrement séronégatifs et 25 % en utilisant le seuil optimisé. La qPCR sur CF avait une bonne sensibilité (72 %), en particulier dans les élevages fortement séropositifs (88 %), et a donné 25 % de résultats positifs sur des cheptels entièrement séronégatifs. L'utilisation combinée de BTM ELISA et CF qPCR a permis d'améliorer la sensibilité à dépister des cheptels séropositifs.(Traduit par Docteur Serge Messier).

DIAGNOSIS OF PREGNANCY IN BARBARY SHEEP (AMMOTRAGUS LERVIA) USING A BOVINE ASSAY FOR PREGNANCY-ASSOCIATED GLYCOPROTEINS.

Pregnancy diagnosis is an important part in reproduction management of wild ruminants involved in free-ranging and captive programs. Pregnancy-associated glycoproteins (PAGs) are placenta-expressed proteins released into maternal blood circulation. Tests with high specificity have been developed and validated in domestic species and have been used in some wild ungulate species. One hundred and seventeen serum samples collected from 72 mature female Barbary sheep ( Ammotragus lervia ) were tested using a commercial enzyme-linked immunosorbent assay (ELISA) test. Pregnancy was determined either postmortem (n = 5) or by visualization of parturition (n = 33). The other sera were controls from known nonpregnant females (n = 71). The following values were obtained: sensitivity = 100.0%, specificity = 95.8%. Using a commercial ELISA for the detection of PAGs appears to be a rapid, inexpensive, and accurate test for pregnancy diagnosis in the endangered Barbary sheep. The number of offspring cannot be determined with this method.

vanA in Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus detected in French cattle.

The goal of this study was to assess the presence of enterococci species presenting van-mediated glycopeptide resistance in French cattle. Fecal samples were collected from healthy and sick animals, and enterococci were screened for vancomycin resistance. Vancomycin resistance was principally encountered in Enterococcus gallinarum and Enterococcus casseliflavus strains. However, glycopeptide resistance was detected in three different species of enterococci (E. faecalis, E. faecium, and E. casseliflavus). Molecular characterization of the genetic support proved that they all presented the prototypic VanA element. Interestingly, the E. casseliflavus strain displayed a remarkable VanB phenotype/vanA-vanC genotype. Transferability, associated resistances, and factors of vanA cotransfer were sought. This study proved that acquired vanA genes can still be detected in food-producing animals more than a decade after the avoparcin ban. Indeed, calves, which are recurrently exposed to antibiotics in France, may allow the re-emergence of glycopeptide resistance through coselection factors, and this might potentially be concerning for human health.