French National Protocol for genetic of amyotrophic lateral sclerosis.

Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.

Primary Lateral Sclerosis: Clinical, radiological and molecular features.

Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category 'probable' PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.

Adaptive functional reorganization in amyotrophic lateral sclerosis: coexisting degenerative and compensatory changes.

BACKGROUND AND PURPOSE: Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction. METHODS: Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study-group-specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures. RESULTS: Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self-initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato-cerebellar connectivity. CONCLUSIONS: Our findings indicate that, despite the dysfunction of SMA-striatal and SMA-cerebellar networks, cerebello-striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.

Botulinum toxin therapy improves masseter spasticity in Amyotrophic Lateral Sclerosis.

Fifteen ALS patients, with troublesome symptoms linked to masseter spasticity, benefited from BoNT-A injections in each masseter. Based on the medical records of patients, the effect of the first injection was assessed one month later. We retrospectively collected information for 12 patients. Eight of them reported a beneficial effect after the injection for the following symptoms: trismus, tongue, lip and cheek biting, and jaw clonus. Five patients indicated that dental care was easier after injection. Our study showed that injections of BoNT-A unequivocally reduced masseter spasticity in ALS patients who subsequently enjoyed greater comfort in their daily living.

Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy.

Kennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by expansion of a CAG repeat sequence in exon 1 of the androgen receptor gene (AR) encoding a polyglutamine (polyQ) tract. The polyQ-expanded AR accumulates in nuclei, and initiates degeneration and loss of motor neurons and dorsal root ganglia. While the disease has long been considered a pure lower motor neuron disease, recently, the presence of major hyper-creatine-kinase (CK)-emia and myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide range of clinical manifestations. The disease, which affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs, and bulbar involvement. Sensory disturbances are associated with the motor phenotype, but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats taken as pathogenic. Despite several therapeutic attempts made in mouse models, no effective disease-modifying therapy is yet available, although symptomatic therapy is beneficial for the management of the weakness, fatigue and bulbar symptoms.

Biomarkers in amyotrophic lateral sclerosis: combining metabolomic and clinical parameters to define disease progression.

BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug's clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers. METHODS: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking. RESULTS: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected. CONCLUSION: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.

Comparative analysis of targeted metabolomics: dominance-based rough set approach versus orthogonal partial least square-discriminant analysis.

BACKGROUND: Metabolomics is an emerging field that includes ascertaining a metabolic profile from a combination of small molecules, and which has health applications. Metabolomic methods are currently applied to discover diagnostic biomarkers and to identify pathophysiological pathways involved in pathology. However, metabolomic data are complex and are usually analyzed by statistical methods. Although the methods have been widely described, most have not been either standardized or validated. Data analysis is the foundation of a robust methodology, so new mathematical methods need to be developed to assess and complement current methods. We therefore applied, for the first time, the dominance-based rough set approach (DRSA) to metabolomics data; we also assessed the complementarity of this method with standard statistical methods. Some attributes were transformed in a way allowing us to discover global and local monotonic relationships between condition and decision attributes. We used previously published metabolomics data (18 variables) for amyotrophic lateral sclerosis (ALS) and non-ALS patients. RESULTS: Principal Component Analysis (PCA) and Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA) allowed satisfactory discrimination (72.7%) between ALS and non-ALS patients. Some discriminant metabolites were identified: acetate, acetone, pyruvate and glutamine. The concentrations of acetate and pyruvate were also identified by univariate analysis as significantly different between ALS and non-ALS patients. DRSA correctly classified 68.7% of the cases and established rules involving some of the metabolites highlighted by OPLS-DA (acetate and acetone). Some rules identified potential biomarkers not revealed by OPLS-DA (beta-hydroxybutyrate). We also found a large number of common discriminating metabolites after Bayesian confirmation measures, particularly acetate, pyruvate, acetone and ascorbate, consistent with the pathophysiological pathways involved in ALS. CONCLUSION: DRSA provides a complementary method for improving the predictive performance of the multivariate data analysis usually used in metabolomics. This method could help in the identification of metabolites involved in disease pathogenesis. Interestingly, these different strategies mostly identified the same metabolites as being discriminant. The selection of strong decision rules with high value of Bayesian confirmation provides useful information about relevant condition-decision relationships not otherwise revealed in metabolomics data.

Framework for integrated MRI average of the spinal cord white and gray matter: the MNI-Poly-AMU template.

The field of spinal cord MRI is lacking a common template, as existing for the brain, which would allow extraction of multi-parametric data (diffusion-weighted, magnetization transfer, etc.) without user bias, thereby facilitating group analysis and multi-center studies. This paper describes a framework to produce an unbiased average anatomical template of the human spinal cord. The template was created by co-registering T2-weighted images (N = 16 healthy volunteers) using a series of pre-processing steps followed by non-linear registration. A white and gray matter probabilistic template was then merged to the average anatomical template, yielding the MNI-Poly-AMU template, which currently covers vertebral levels C1 to T6. New subjects can be registered to the template using a dedicated image processing pipeline. Validation was conducted on 16 additional subjects by comparing an automatic template-based segmentation and manual segmentation, yielding a median Dice coefficient of 0.89. The registration pipeline is rapid (~15 min), automatic after one C2/C3 landmark manual identification, and robust, thereby reducing subjective variability and bias associated with manual segmentation. The template can notably be used for measurements of spinal cord cross-sectional area, voxel-based morphometry, identification of anatomical features (e.g., vertebral levels, white and gray matter location) and unbiased extraction of multi-parametric data.

Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end-stage liver disease score.

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

Revisiting the spectrum of lower motor neuron diseases with snake eyes appearance on magnetic resonance imaging.

BACKGROUND AND PURPOSE: The 'snake eyes' sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors. METHODS: A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling. RESULTS: Twenty-nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow-up. CONCLUSION: The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.

271st ENMC international workshop: Towards a unifying effort to fight Kennedy's disease. 20-22 October 2023, Hoofddorp, Netherlands.

The workshop held in the Netherlands from October 20-22, 2023, united 27 scientists from academia, healthcare, and industry representing 11 countries, alongside four patient and charity representatives. Focused on Kennedy's Disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), the workshop aimed to consolidate knowledge, align on clinical trial designs, and promote participative medicine for effective treatments. Discussions emphasized KD's molecular mechanisms, highlighting its status as a neuromuscular disorder with motor neuron degeneration. Strategies for therapeutic intervention, including AR activity modulation and targeting post-translational modifications, were proposed. The need for diagnostic, prognostic, and target engagement biomarkers was stressed. Challenges in patient stratification and clinical trial recruitment were acknowledged, with the International KD/SBMA Registry praised for its role. The workshop concluded with a patient-focused session, underscoring challenges in KD diagnosis and the vital support provided by patient associations.

A new perfusion system to reduce the burden of central-venous-line-associated bloodstream infections in neonates.

BACKGROUND: Central-venous-line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in preterm infants. As there is large variation in the reported effect of multi-modal preventive strategies, it could be relevant to propose new additional strategies. AIM: To assess the impact of a new perfusion system on CLABSI rate. METHODS: A before-and-after study was performed in infants born at <32 weeks of gestation or with birth weight <1500 g who required a multi-perfusion system connected to a central venous line. In the first 12-month period ('before'), the pre-existing perfusion system (multiple stopcocks) was used. An intervention period then occurred with implementation of a new perfusion closed system, without change in 'bundles' related to various aspects of central line care. During the second 12-month period ('after'), the CLABSI rate was assessed and compared with the pre-intervention period. FINDINGS: In total, 313 infants were included in this study (before: N=163; after: N=150), and 46% had birth weight <1000 g. The change in perfusion system resulted in a significant decrease in CLABSI rate from 11.3 to 2.2 per 1000 catheter-days (P<0.001). The period was independently associated with an 88% reduction in the risk of CLABSI after implementation of the new perfusion system [odds ratio (OR) 0.12, 95% confidence interval (CI) 0.03-0.39; P<0.001]. The duration of central line use was also associated with CLABSIs (for each additional day: OR 1.05, 95% CI 1.02-1.07; P<0.001). CONCLUSIONS: Implementation of the new perfusion system was feasible in a large neonatal unit, and reduced the CLABSI rate soon after implementation.

Cost-effectiveness of a new multi-lumen infusion device to reduce central venous line-associated bloodstream infections in neonates.

BACKGROUND: A new medical device was developed for multi-infusion in neonatal intensive care units (NICUs) with the aim to address issues related to drug incompatibilities and central line-associated bloodstream infections (CLABSI). AIM: To assess the cost-effectiveness of implementing this new perfusion system in a NICU setting. METHODS: We conducted a single-centre, observational study in all infants admitted to the NICU within the first 3 days after birth and who required central-venous line, to evaluate the cost and effectiveness before (Year 2019) and after (Year 2020) the implementation of the new perfusion system. We calculated the costs from the hospital perspective, and we examined the incidence of CLABSI, over a time horizon spanning from admission to NICU discharge. We measured the resource utilisation (infusion medical device, infection treating drugs and biological analyses), and valued corresponding costs using tariffs for year 2019. We calculated incremental cost-effectiveness ratio (ICER) expressed as euros per CLABSI avoided, and conducted one-way and multivariate sensitivity analyses. FINDINGS: Among 609 infants selected, clinical characteristics were similar across both periods. The CLABSI rate significantly decreased (rate ratio: 0.22; IC95% [0.07-0.56]), and total costs were reduced (from €65,666 to €63,932 per 1000 catheter days respectively; p<0.001), yielding to an ICER of €251 saved per CLABSI avoided. The majority of sensitivity analyses showed the new intervention remaining economically dominant. CONCLUSION: This single-centre study showed a significant decrease in the incidence of CLABSI without incurring additional costs. Further prospective multicentre randomised studies are needed to confirm these results in other NICU.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

In vivo infectivity of liver extracts after resolution of hepadnaviral infection following therapy associating DNA vaccine and cytokine genes.

DNA-based vaccination appears of promise for chronic hepatitis B immunotherapy, although there is an urgent need to increase its efficacy. In this preclinical study, we evaluated the therapeutic benefit of cytokine (IL-2, IFN-γ) genes co-delivery with DNA vaccine targeting hepadnaviral proteins in the chronic duck hepatitis B virus (DHBV) infection model. Then, we investigated the persistence of replication-competent virus in the livers of apparently resolved animals. DHBV carriers received four injections of plasmids encoding DHBV envelope and core alone or co-delivered with duck IL-2 (DuIL-2) or duck IFN-γ (DuIFN-γ) plasmids. After long-term (8 months) follow-up, viral covalently closed circular (ccc) DNA was analysed in duck necropsy liver samples. Liver homogenates were also tested for in vivo infectivity in neonatal ducklings. Co-delivery of DuIFN-γ resulted in significantly lower mean viremia starting from week 21. Viral cccDNA was undetectable by conventional methods in the livers of 25% and 57% of animals co-immunized with DuIL-2 and DuIFN-γ, respectively. Interestingly, inoculation of liver homogenates from 7 such apparently resolved animals, exhibiting cccDNA undetectable in Southern blotting and DHBV expression undetectable or restricted to few hepatocytes, revealed that three liver homogenates transmitted high-titre viremia (3-5×10(10) vge/mL) to naïve animals. In conclusion, our results indicate that IFN-γ gene co-delivery considerably enhances immunotherapeutic efficacy of DNA vaccine targeting hepadnaviral proteins. Importantly, we also showed that livers exhibiting only minute amounts of hepadnaviral cccDNA could induce extremely high-titre infection, highlighting the caution that should be taken in occult hepatitis B patients to prevent HBV transmission in liver transplantation context.

Evolution of glomerular filtration rate in HIV-infected, HIV-HBV-coinfected and HBV-infected patients receiving tenofovir disoproxil fumarate.

We aimed to compare the evolution of estimated glomerular filtration rate (eGFR) in HIV-, HIV-HBV- and HBV-infected patients treated with tenofovir disoproxil fumarate (TDF). Three groups of patients receiving TDF > 12 months were recruited: 194 HIV-infected patients, 85 HIV-HBV-coinfected patients and 50 HBV-infected patients. eGFR was estimated using the Modification of the Diet in Renal Disease (MDRD) equation. Multivariate regression models were constructed to estimate factors associated with eGFR decrease from baseline. A total of 329 patients were studied. Median follow-up was 2.7 years. Median eGFR decrease was -4.9 (-16.6 to +7.2) mL/min/1.73 m(2) . After multivariate stepwise regression analysis, age (P = 0.0002), non-African origin (P < 0.0001), baseline eGFR (P < 0.0001) and TDF duration (P = 0.02) were associated with eGFR decrease in the whole population, while hypertension, diabetes and type of infection were not. Age (P < 0.0001), non-African origin (P = 0.0004), baseline eGFR (P < 0.0001) and TDF duration (P = 0.007) remained associated with eGFR decline in HIV and HIV-HBV-infected patients, while other variables including HIV risk factor, CDC stage, CD4 and HIV-RNA levels were not. Age (P = 0.03), non-African origin (P = 0.004), baseline eGFR (P < 0.0001) and baseline HBV-DNA > 2000 IU/mL (P = 0.04) were associated with eGFR decline in HBV and HIV-HBV-infected patients, while other variables including HBV risk factor and fibrosis stage were not. Estimated glomerular filtration rate decline under TDF therapy appears mainly associated with older age, non-African origin, higher baseline eGFR and longer TDF administration but not with the type of viral infection. Regular follow-up of renal function, especially tubular function is recommended during TDF therapy.

Suboptimal exposure to fluconazole in critically ill patients: Pharmacokinetic analysis and determinants.

OBJECTIVES: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter. PATIENTS AND METHODS: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included. RESULTS: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy. CONCLUSIONS: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L.