Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy. METHODS: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed. FINDINGS: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups. INTERPRETATION: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm. FUNDING: Programme Hospitalier de Recherche Clinique.

Early prone positioning in acute respiratory distress syndrome related to COVID-19: a propensity score analysis from the multicentric cohort COVID-ICU network-the ProneCOVID study.

BACKGROUND: Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19. METHODS: All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. RESULTS: Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO2/FiO2 ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group (p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96-1.68], p = 0.09 and HR 1.19 [0.998-1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively). CONCLUSIONS: In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001). CONCLUSION: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Online information and support for carers of people with young-onset dementia: A multi-site randomised controlled pilot study.

OBJECTIVES: The European RHAPSODY project sought to develop and test an online information and support programme for caregivers of individuals diagnosed with young onset dementia. The objectives were to assess user acceptability and satisfaction with the programme and to test outcome measures for a larger effectiveness study. DESIGN: A pilot randomised controlled trial in England, France, and Germany was conducted with 61 caregivers for adults with young onset Alzheimer's disease or frontotemporal degeneration. Evaluations at baseline, week 6, and week 12 assessed user acceptability and satisfaction. Use of the programme was measured from online back-end data. Qualitative feedback on user experiences was collected via semi-structured interviews. Measures of caregiver well-being (self-efficacy, stress, burden, frequency of patient symptoms, and caregiver reactions) were explored for use in a subsequent trial. RESULTS: Participants logged in online on average once a week over a 6-week period, consulting approximately 31% of programme content. Seventy percent of participants described the programme as useful and easy to use. Eighty-five percent expressed intent to use the resource in the future. Reductions in reported levels of stress and caregivers' negative reactions to memory symptoms were observed following use of the programme. CONCLUSIONS: Results indicated that the RHAPSODY programme was acceptable and useful to caregivers. The programme may be complementary to existing services in responding to the specific needs of families affected by young onset dementia. Distribution of the programme is underway in England, France, Germany, and Portugal.

Emergency Abdominal Surgery Outcomes of Critically Ill Patients on Extracorporeal Membrane Oxygenation: A Case-Matched Study with a Propensity Score Analysis.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) induces coagulation disorders increasing the risk of bleeding during invasive procedures. We aimed to describe the outcomes of critically ill ECMO patients undergoing emergency abdominal surgery compared to non-ECMO patients. STUDY DESIGN: This is a retrospective case-matched single-center study with propensity score analysis in a tertiary ICU. All patients who underwent abdominal surgery were included. RESULTS: From 2006 to 2014, 77 patients admitted in our ICU underwent emergency abdominal surgery, 35 were on ECMO. Surgery indications were comparable for ECMO and non-ECMO patients: mostly intestinal ischemia (42%) and cholecystectomy (25%). Postoperative bleeding was significantly more frequent in ECMO group versus non-ECMO: 77% versus 40% transfused, with medians of 13 (6-22) versus 3 (0-5) packed red blood cell; 9 (3-17) versus 0 (0-4) fresh frozen plasma and 12 (3-22) versus 0 (0-8) platelet units (p < 0.001 for all items). Reintervention for hemorrhage was required in 20% versus 2%, respectively, p = 0.02. At multivariable analysis, ECMO was strongly associated with bleeding (OR, 5.6 [95% CI, 2.0-15.4]; p = 0.001). ICU mortality was higher for ECMO-treated patients (69% vs. 33%; p = 0.003), but perioperative mortality remained comparable between groups (11% vs. 12%, NS). Propensity score-matched analysis confirmed more frequent and severe bleeding in ECMO patients. CONCLUSIONS: Abdominal surgery procedures on ECMO-treated patients are associated with a higher risk of hemorrhage compared to non-ECMO ICU patients. Further studies are needed to optimize ECMO patient management during such interventions.

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease.

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.

Improving mutation screening in familial hematuric nephropathies through next generation sequencing.

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

Impact of intensive prone position therapy on outcomes in intubated patients with ARDS related to COVID-19.

BACKGROUND: Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less. METHODS: This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data. RESULTS: Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group (n = 79) had a median PP duration of 36 h, while standard PP group (n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group (p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52-1.74], p = 0.87 and HR 1.1 [0.77-1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively). CONCLUSIONS: This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.

Embolization of the middle meningeal artery for the prevention of chronic subdural hematoma recurrence in high-risk patients: a randomized controlled trial-the EMPROTECT study protocol.

BACKGROUND: Middle meningeal artery (MMA) embolization has been proposed as a treatment of chronic subdural hematoma (CSDH). The benefit of the procedure has yet to be demonstrated in a randomized controlled trial. We aim to assess the efficacy of MMA embolization in reducing the risk of CSDH recurrence 6 months after burr-hole surgery compared with standard medical treatment in patients at high risk of postoperative recurrence. METHODS: The EMPROTECT trial is a multicenter open label randomized controlled trial (RCT) involving 12 French centers. Adult patients (≥18 years) operated for CSDH recurrence or for a first episode with a predefined recurrence risk factor are randomized 1:1 to receive either MMA embolization within 7 days of the burr-hole surgery (experimental group) or standard medical care (control group). The number of patients to be included is 342. RESULTS: The primary outcome is the rate of CSDH recurrence at 6 months. Secondary outcomes include the rate of repeated surgery for a homolateral CSDH recurrence during the 6-month follow-up period, the rate of disability and dependency at 1 and 6 months, defined by a modified Rankin Scale (mRS) score ≥4, mortality at 1 and 6 months, total cumulative duration of hospital stay during the 6-month follow-up period, directly or indirectly related to the CSDH and embolization procedure-related complication rates. CONCLUSIONS: The EMPROTECT trial is the first RCT evaluating the benefit of MMA embolization as a surgical adjunct for the prevention of CSDH recurrence. If positive, this trial will have a significant impact on patient care. TRIAL REGISTRATION NUMBER: NCT04372147.

Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life.

BACKGROUND: The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. METHODS: A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS-CoV-2-related early (< 96 h) mild-to-severe acute respiratory distress syndrome. RESULTS: Between April 2020 and October 2020, 47 patients were enrolled, of whom 19 completed a 1-year follow-up. There were no significant differences in any endpoints or adverse effects between the UC-MSCs and placebo groups at the 6- and 12-month assessments. Ground-glass opacities persisted at 1 year in 5 patients (26.3%). Furthermore, diffusing capacity for carbon monoxide remained altered over 1 year, although no patient required oxygen or non-invasive ventilatory support. Quality of life revealed declines in mental, emotional and physical health throughout the follow-up period, and the six-minute walking distance remained slightly impaired at the 1-year patient assessment. CONCLUSIONS: This study suggests a favorable safety profile for the use of intravenous UC-MSCs in the context of the first French wave of SARS-CoV-2-related moderate-to-severe acute respiratory distress syndrome, with no adverse effects observed at 1 year.

Serum and Salivary IgG and IgA Response After COVID-19 Messenger RNA Vaccination.

Importance: There is still considerable controversy in the literature regarding the capacity of intramuscular messenger RNA (mRNA) vaccination to induce a mucosal immune response. Objective: To compare serum and salivary IgG and IgA levels among mRNA-vaccinated individuals with or without previous SARS-CoV-2 infection. Design, Setting, and Participants: In this cohort study, SARS-CoV-2-naive participants and those with previous infection were consecutively included in the CoviCompare P and CoviCompare M mRNA vaccination trials and followed up to day 180 after vaccination with either the BNT162b2 (Pfizer-BioNTech) vaccine or the mRNA-1273 (Moderna) vaccine at the beginning of the COVID-19 vaccination campaign (from February 19 to June 8, 2021) in France. Data were analyzed from October 25, 2022, to July 13, 2023. Main Outcomes and Measures: An ultrasensitive digital enzyme-linked immunosorbent assay was used for the comparison of SARS-CoV-2 spike-specific serum and salivary IgG and IgA levels. Spike-specific secretory IgA level was also quantified at selected times. Results: A total of 427 individuals were included in 3 groups: participants with SARS-CoV-2 prior to vaccination who received 1 single dose of BNT162b2 (Pfizer-BioNTech) (n = 120) and SARS-CoV-2-naive individuals who received 2 doses of mRNA-1273 (Moderna) (n = 172) or 2 doses of BNT162b2 (Pfizer-BioNTech) (n = 135). The median age was 68 (IQR, 39-75) years, and 228 (53.4%) were men. SARS-CoV-2 spike-specific IgG saliva levels increased after 1 or 2 vaccine injections in individuals with previous infection and SARS-CoV-2-naive individuals. After vaccination, SARS-CoV-2-specific saliva IgA levels, normalized with respect to total IgA levels, were significantly higher in participants with previous infection, as compared with the most responsive mRNA-1273 (Moderna) recipients (median normalized levels, 155 × 10-5 vs 37 × 10-5 at day 29; 107 × 10-5 vs 54 × 10-5 at day 57; and 104 × 10-5 vs 70 × 10-5 at day 180 [P < .001]). In contrast, compared with day 1, spike-specific IgA levels in the BNT162b2-vaccinated SARS-CoV-2-naive group increased only at day 57 (36 × 10-5 vs 49 × 10-5 [P = .01]). Bona fide multimeric secretory IgA levels were significantly higher in individuals with previous infection compared with SARS-CoV-2-naive individuals after 2 antigenic stimulations (median optical density, 0.36 [IQR, 0.16-0.63] vs 0.16 [IQR, 0.10-0.22]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that mRNA vaccination was associated with mucosal immunity in individuals without prior SARS-CoV-2 infection, but at much lower levels than in previously infected individuals. Further studies are needed to determine the association between specific saliva IgA levels and prevention of infection or transmission.

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.

VNtyper enables accurate alignment-free genotyping of MUC1 coding VNTR using short-read sequencing data in autosomal dominant tubulointerstitial kidney disease.

The human genome comprises approximately 3% of tandem repeats with variable length (VNTR), a few of which have been linked to human rare diseases. Autosomal dominant tubulointerstitial kidney disease-MUC1 (ADTKD-MUC1) is caused by specific frameshift variants in the coding VNTR of the MUC1 gene. Calling variants from VNTR using short-read sequencing (SRS) is challenging due to poor read mappability. We developed a computational pipeline, VNtyper, for reliable detection of MUC1 VNTR pathogenic variants and demonstrated its clinical utility in two distinct cohorts: (1) a historical cohort including 108 families with ADTKD and (2) a replication naive cohort comprising 2,910 patients previously tested on a panel of genes involved in monogenic renal diseases. In the historical cohort all cases known to carry pathogenic MUC1 variants were re-identified, and a new 25bp-frameshift insertion in an additional mislaid family was detected. In the replication cohort, we discovered and validated 30 new patients.

Surgery for glioblastomas in the elderly: an Association des Neuro-oncologues d'Expression Française (ANOCEF) trial.

OBJECTIVE: The role of surgery in the treatment of malignant gliomas in the elderly is not settled. The authors conducted a randomized trial that compared tumor resection with biopsy only-both followed by standard therapy-in such patients. METHODS: Patients ≥ 70 years of age with a Karnofsky Performance Scale (KPS) score ≥ 50 and presenting with a radiological suspicion of operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy groups. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008-2017), with the addition of adjunct therapy with temozolomide when this regimen became standard (2017-2019). The primary endpoint was survival, and secondary endpoints were progression-free survival (PFS), cognitive status (Mini-Mental State Examination), autonomy (KPS), quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-BN20), and perioperative morbidity and mortality. RESULTS: Between 2008 and 2019, 107 patients from 9 centers were enrolled in the study; 101 were evaluable for analysis because a GBM was histologically confirmed (50 in the surgery arm and 51 in the biopsy arm). There was no statistically significant difference in median survival between the surgery (9.37 months) and the biopsy (8.96 months, p = 0.36) arms (adjusted HR 0.79, 95% CI 0.52-1.21, p = 0.28). However, the surgery group had an increased PFS (5.06 vs 4.02 months; p = 0.034) (adjusted HR 0.50, 95% CI 0.32-0.78, p = 0.002). Less deterioration of quality of life and KPS score evolution than in the biopsy group was observed. Surgery was not associated with increased mortality or morbidity. CONCLUSIONS: This study suggests that debulking surgery is safe, and-compared to biopsy-is associated with a less severe deterioration of quality of life and autonomy, as well as a significant although modest improvement of PFS in elderly patients suffering from newly diagnosed malignant glioma. Although resection does not provide a significant survival benefit in the elderly, the authors believe that the risk/benefit analysis favors an attempt at optimal tumor resection in this population, provided there is careful preoperative geriatric evaluation. Clinical trial registration no.: NCT02892708 (ClinicalTrials.gov).

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Low dose of morphine to relieve dyspnea in acute respiratory failure (OpiDys): protocol for a double-blind randomized controlled study.

BACKGROUND: Dyspnea is common and severe in intensive care unit (ICU) patients managed for acute respiratory failure. Dyspnea appears to be associated with impaired prognosis and neuropsychological sequels. Pain and dyspnea share many similarities and previous studies have shown the benefit of morphine on dyspnea in patients with end-stage onco-hematological disease and severe heart or respiratory disease. In these populations, morphine administration was safe. Here, we hypothesize that low-dose opioids may help to reduce dyspnea in patients admitted to the ICU for acute respiratory failure. The primary objective of the trial is to determine whether the administration of low-dose titrated opioids, compared to placebo, in patients admitted to the ICU for acute respiratory failure with severe dyspnea decreases the mean 24-h intensity of dyspnea score. METHODS: In this single-center double-blind randomized controlled trial with 2 parallel arms, we plan to include 22 patients (aged 18-75 years) on spontaneous ventilation with either non-invasive ventilation, high flow oxygen therapy or standard oxygen therapy admitted to the ICU for acute respiratory failure with severe dyspnea. They will be assigned after randomization with a 1:1 allocation ratio to receive in experimental arm administration of low-dose titrated morphine hydrochloride for 24 h consisting in an intravenous titration relayed subcutaneously according to a predefined protocol, or a placebo (0.9% NaCl) administered according to the same protocol in the control arm. The primary endpoint is the mean 24-h dyspnea score assessed by a visual analog scale of dyspnea. DISCUSSION: To our knowledge, this study is the first to evaluate the benefit of opioids on dyspnea in ICU patients admitted for acute respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT04358133 . Registered on 24 April 2020.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Neutralizing antibodies against SARS-CoV-2 variants following mRNA booster vaccination in adults older than 65 years.

Immune response induced by COVID-19 vaccine booster against delta and omicron variants was assessed in 65 adults (65-84 years old) early aftesr a first booster dose. An increase in SARS-CoV-2 neutralizing antibodies was shown in individuals not previously infected without evidence of an age-related effect, with lower increase in those infected before a single dose of primary vaccination. Of note, humoral response was observed only starting from the 5th day after the boost.