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BACKGROUND: Despite the clinical importance of sepsis-associated acute kidney injury (SA-AKI), little is known about its epidemiology. We aimed to investigate the incidence and outcomes of SA-AKI, as well as the risk factors for mortality among patients with severe SA-AKI in critically ill patients. METHODS: This secondary multicenter, observational, prospective cohort analysis of sepsis in South Korea evaluated patients aged ≥ 19 years admitted to intensive care units with a diagnosis of sepsis. The primary outcome was the incidence of SA-AKI, defined using the new consensus definition of the Acute Disease Quality Initiative 28 Workgroup. Secondary outcomes were in-hospital mortality and risk factors for in-hospital mortality. RESULTS: Between September 2019 and December 2022, 5100 patients were admitted to intensive care units with a diagnosis of sepsis, and 3177 (62.3%) developed SA-AKI. A total of 613 (19.3%), 721 (22.7%), and 1843 (58.0%) patients had stage 1, 2, and 3 SA-AKI, respectively. Severe SA-AKI (stages 2 and 3 combined) was associated with an increased risk of in-hospital mortality. Adherence to the fluid resuscitation component of the one-hour sepsis bundle was associated with a decreased risk of in-hospital mortality in severe SA-AKI (adjusted odds ratio, 0.62; 95% confidence interval, 0.48-0.79; P

PURPOSE: The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients. METHODS: We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20 years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner. RESULTS: There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P

BackgroundThe association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established.ObjectivesThe aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults.MethodsA total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-β (Aβ) and tau] were considered as outcomes in regression models.ResultsLow ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aβ and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aβ accumulation (adjusted β = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted β = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted β = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers.ConclusionsLongitudinally, low ω-3 index was associated with greater Aβ accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.

BackgroundGalectin-3 (Gal-3) is a proinflammatory and profibrotic protein especially overexpressed after Acute Kidney Injury (AKI). The early renal prognostic value of Gal-3 after AKI in critically ill patients remains unexplored. The objective was to evaluate the prognostic value of plasma level of Gal-3 for Major Adverse Kidney Events (MAKE) and mortality 30 days after ICU admission across AKI stages.MethodsThis is an ancillary study of a prospective, observational, multicenter cohort (FROG-ICU). AKI was defined using KDIGO definition.ResultsTwo thousand and seventy-six patients had a Gal-3 plasma level measurement at ICU admission. Seven hundred and twenty-three (34.8%) were females and the median age was 63 [51, 74] years. Eight hundred and seven (38.9%) patients developed MAKE, 774 (37.3%) had AKI and mortality rate at 30 days was 22.4% (N = 465). Patients who developed MAKE had higher Gal-3 level at admission compared to patients without (30.2 [20.8, 49.2] ng/ml versus 16.9 [12.7, 24.3] ng/ml, p

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Intranasal oxytocin (IN OXT) administration has been proposed as a pharmacological treatment for a range of biomedical conditions including neurodevelopmental disorders. However, studies evaluating the potential long-lasting effects of chronic IN OXT during development are still scarce. Here we conducted a follow-up study of a cohort of adult titi monkeys that received intranasal oxytocin 0.8 IU/kg (n = 15) or saline (n = 14) daily for six months during their juvenile period (12 to 18 months of age), with the goal of evaluating the potential long-lasting behavioral and neural effects one year post-treatment. Subjects were paired with an opposite-sex mate at 30 months of age (one year post-treatment). We examined pair affiliative behavior in the home cage during the first four months and tested for behavioral components of pair bonding at one week and four months post-pairing. We assessed long-term changes in brain glucose uptake using 18FDG positron emission tomography (PET) scans. Our results showed that OXT-treated animals were more affiliative across a number of measures, including tail twining, compared to SAL treated subjects (tail twining is considered the "highest" type of affiliation in titi monkeys). Neuroimaging showed no treatment differences in glucose uptake between SAL and OXT-treated animals; however, females showed higher glucose uptake in whole brain at 23 months, and in both the whole brain and the social salience network at 33 months of age compared to males. Our results suggest that chronic IN OXT administration during development can have long-term effects on adult social behavior.

BackgroundDipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients.MethodsThe aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later.ResultsMedian [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p  40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality.ConclusionsAdmission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

PurposeTo evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.MethodsWe included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.ResultsFor BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

BackgroundThe potential relationship between a mild acute kidney injury (AKI) observed in the immediate postoperative period after major surgery and its effect on long term renal function remains poorly defined. According to the "Kidney Disease: Improving Global Outcomes" (KDIGO) classification, a mild injury corresponds to a KIDIGO stage 1, characterized by an increase in creatinine of at least 0.3 mg/dl within a 48-h window or 1.5 to 1.9 times the baseline level within the first week post-surgery. We tested the hypothesis that patients who underwent intermediate-to high-risk abdominal surgery and developed mild AKI in the following days would be at an increased risk of long-term renal injury compared to patients with no postoperative AKI.MethodsAll consecutive adult patients with a plasma creatinine value ≤1.5 mg/dl who underwent intermediate-to high-risk abdominal surgery between 2014 and 2019 and who had at least three recorded creatinine measurements (before surgery, during the first seven postoperative days, and at long-term follow up [6 months-2 years]) were included. AKI was defined using a "modified" (without urine output criteria) KDIGO classification as mild (stage 1 characterised by an increase in creatinine of > 0.3 mg/dl within 48-h or 1.5-1.9 times baseline) or moderate-to-severe (stage 2-3 characterised by increase in creatinine 2 to 3 times baseline or to ≥4.0 mg/dl). The exposure (postoperative kidney injury) and outcome (long-term renal injury) were defined and staged according to the same KDIGO initiative criteria. Development of long-term renal injury was compared in patients with and without postoperative AKI.ResultsAmong the 815 patients included, 109 (13%) had postoperative AKI (81 mild and 28 moderate-to-severe). The median long-term follow-up was 360, 354 and 353 days for the three groups respectively (P = 0.2). Patients who developed mild AKI had a higher risk of long-term renal injury than those who did not (odds ratio 3.1 [95%CI 1.7-5.5]; p

Introduction: Burn injury is associated with a high risk of death. Whether a pattern of immune and inflammatory responses after burn is associated with outcome is unknown. The aim of this study was to explore the association between systemic immune and inflammatory responses and outcome in severely-ill burn patients. Materials and Methods: Innate immunity, adaptive immunity, activation and stress and inflammation biomarkers were collected at admission and days 2, 7, 14, and 28 in severely-ill adult burn patients. Primary endpoint was mortality at day 90, secondary endpoint was secondary infections. Healthy donors (HD) served as controls. Multiple Factorial Analysis (MFA) was used to identify patterns of immune response. Results: 50 patients were included. Age was 49.2 (44.2-54.2) years, total burn body surface area was 38.0% (32.7-43.3). Burn injury showed an upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. High interleukin-10 (IL-10) at admission was associated with risk of death. However, no cluster of immune/inflammatory biomarkers at early timepoints was associated with mortality. HLA-DR molecules on monocytes at admission were associated with bacterial infections and septic shock. Later altered immune/inflammatory responses in patients who died may had been driven by the development of septic shock. Conclusion: Burn injury induced an early and profound upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. Immune and inflammatory responses were associated with bacterial infection and septic shock. Absence of immune recovery patterns was associated with poor prognosis.

BACKGROUND:Obligate anaerobes usually account for less than 10% of bacteria recovered from blood cultures (BC). The relevance of routine use of the anaerobic bottle is under debate. The aim of this study was to evaluate the utility of anaerobic bottles for the diagnosis of bloodstream infections (BSI). METHODS:We conducted a 6-month, retrospective, monocentric study in a tertiary hospital. All positive BC were grouped into a single episode of bacteremia when drawn within 7 consecutive days. Bacteremia were classified into contaminants and BSI. Charts of patients with BSI due to obligate anaerobes were studied. RESULTS:A total of 19,739 blood cultures were collected, 2341 of which (11.9%) were positive. Anaerobic bottles were positive in 1528 (65.3%) of all positive BC but were positive alone (aerobic bottles negative) in 369 (15.8%). Overall 1081 episodes of bacteremia were identified, of which 209 (19.3%) had positive anaerobic bottles alone. The majority 126/209 (60.3%) were contaminants and 83 (39.7%) were BSI. BSI due to facultative anaerobes, obligate aerobes and obligate anaerobes were identified in 67 (80.7%), 3 (3.6%) and 13 (15.7%) of these 83 episodes, respectively. BSI due to obligate anaerobic bacteria were reported in 9 patients with gastro-intestinal disease, in 3 with febrile neutropenia and in 1 burned patient. CONCLUSIONS:Anaerobic bottles contributed to the diagnosis of a significant number of episodes of bacteremia. Isolated bacteria were mostly contaminants and non-obligate anaerobic pathogens. Rare BSI due to obligate anaerobes were reported mainly in patients with gastro-intestinal disorders and during febrile neutropenia.

BackgroundDipeptidyl peptidase-3 (DPP3) is a metallopeptidase which cleaves bioactive peptides, notably angiotensin II, and is involved in inflammation regulation. DPP3 has been proposed to be a myocardial depressant factor and to be involved in circulatory failure in acute illnesses, possibly due to angiotensin II cleavage. In this study, we evaluated the association between plasmatic DPP3 level and outcome (mortality and hemodynamic failure) in severely ill burn patients.MethodsIn this biomarker analysis of a prospective cohort study, we included severely ill adult burn patients in two tertiary burn intensive care units. DPP3 was measured at admission (DPP3admin) and 3 days after. The primary endpoint was 90-day mortality. Secondary endpoints were hemodynamic failure and acute kidney injury (AKI).ResultsOne hundred and eleven consecutive patients were enrolled. The median age was 48 (32.5-63) years, with a median total body surface area burned of 35% (25-53.5) and Abbreviated Burn Severity Index (ABSI) of 8 (7-11). Ninety-day mortality was 32%. The median DPP3admin was significantly higher in non-survivors versus survivors (53.3 ng/mL [IQR 28.8-103.5] versus 27.1 ng/mL [IQR 19.4-38.9]; p

The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV-2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.

Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions. Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury. We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10. These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.

BackgroundPotassium disturbances are associated with adverse prognosis in patients with chronic conditions. Its prognostic implications in stable patients attending the emergency department (ED) is poorly described.AimsThis study aimed to assess the prevalence of dyskalemia, describe its predisposing factors and prognostic associations in a population presenting the ED without unstable medical illness.MethodsPost-hoc analysis of a prospective, cross-sectional, multicenter study in the ED of 11 French academic hospitals over a period of 8 weeks. All adults presenting to the ED during this period were included, except instances of self-drug poisoning, inability to complete self-medication questionnaire, presence of an unstable medical illness and decline to participate in the study. All-cause hospitalization or deaths were assessed.ResultsA total of 1242 patients were included. The mean age was 57.2±22.3 years, 51% were female. The distribution according to potassium concentrations was: hypokalemia5mmol/L(n = 73, 0,6%). The proportion of patients with a kalemia

BackgroundPotassium disturbances are associated with adverse prognosis in patients with chronic conditions. Its prognostic implications in stable patients attending the emergency department (ED) is poorly described.AimsThis study aimed to assess the prevalence of dyskalemia, describe its predisposing factors and prognostic associations in a population presenting the ED without unstable medical illness.MethodsPost-hoc analysis of a prospective, cross-sectional, multicenter study in the ED of 11 French academic hospitals over a period of 8 weeks. All adults presenting to the ED during this period were included, except instances of self-drug poisoning, inability to complete self-medication questionnaire, presence of an unstable medical illness and decline to participate in the study. All-cause hospitalization or deaths were assessed.ResultsA total of 1242 patients were included. The mean age was 57.2±22.3 years, 51% were female. The distribution according to potassium concentrations was: hypokalemia5mmol/L(n = 73, 0,6%). The proportion of patients with a kalemia

BackgroundThe use of hydroxocobalamin has long been advocated for treating suspected cyanide poisoning after smoke inhalation. Intravenous hydroxocobalamin has however been shown to cause oxalate nephropathy in a single-center study. The impact of hydroxocobalamin on the risk of acute kidney injury (AKI) and survival after smoke inhalation in a multicenter setting remains unexplored.MethodsWe conducted a multicenter retrospective study in 21 intensive care units (ICUs) in France. We included patients admitted to an ICU for smoke inhalation between January 2011 and December 2017. We excluded patients discharged at home alive within 24 h of admission. We assessed the risk of AKI (primary endpoint), severe AKI, major adverse kidney (MAKE) events, and survival (secondary endpoints) after administration of hydroxocobalamin using logistic regression models.ResultsAmong 854 patients screened, 739 patients were included. Three hundred six and 386 (55.2%) patients received hydroxocobalamin. Mortality in ICU was 32.9% (n = 243). Two hundred eighty-eight (39%) patients developed AKI, including 186 (25.2%) who developed severe AKI during the first week. Patients who received hydroxocobalamin were more severe and had higher mortality (38.1% vs 27.2%, p = 0.0022). The adjusted odds ratio (95% confidence interval) of AKI after intravenous hydroxocobalamin was 1.597 (1.055, 2.419) and 1.772 (1.137, 2.762) for severe AKI; intravenous hydroxocobalamin was not associated with survival or MAKE with an adjusted odds ratio (95% confidence interval) of 1.114 (0.691, 1.797) and 0.784 (0.456, 1.349) respectively.ConclusionHydroxocobalamin was associated with an increased risk of AKI and severe AKI but was not associated with survival after smoke inhalation.Trial registrationClinicalTrials.gov, NCT03558646.

BackgroundAdrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial.MethodsAdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock.ResultsCirculating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8).ConclusionsAdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial.Trial registrationClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

BackgroundIntensive care unit (ICU) survivors have reduced long-term survival compared to the general population. Identifying parameters at ICU discharge that are associated with poor long-term outcomes may prove useful in targeting an at-risk population. The main objective of the study was to identify clinical and biological determinants of death in the year following ICU discharge.MethodsFROG-ICU was a prospective, observational, multicenter cohort study of ICU survivors followed 1 year after discharge, including 21 medical, surgical or mixed ICUs in France and Belgium. All consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following ICU admission and discharged from ICU were included. The main outcome measure was all-cause mortality at 1 year after ICU discharge. Clinical and biological parameters on ICU discharge were measured, including the circulating cardiovascular biomarkers N-terminal pro-B type natriuretic peptide, high-sensitive troponin I, bioactive-adrenomedullin and soluble-ST2. Socioeconomic status was assessed using a validated deprivation index (FDep).ResultsOf 1570 patients discharged alive from the ICU, 333 (21%) died over the following year. Multivariable analysis identified age, comorbidity, red blood cell transfusion, ICU length of stay and abnormalities in common clinical factors at the time of ICU discharge (low systolic blood pressure, temperature, total protein, platelet and white cell count) as independent factors associated with 1-year mortality. Elevated biomarkers of cardiac and vascular failure independently associated with 1-year death when they are added to multivariable model, with an almost 3-fold increase in the risk of death when combined (adjusted odds ratio 2.84 (95% confidence interval 1.73-4.65), p

Although human endogenous retroviruses (HERVs) expression is a growing subject of interest, no study focused before on specific endogenous retroviruses loci activation in severely injured patients. Yet, HERV reactivation is observed in immunity compromised settings like some cancers and auto-immune diseases. Our objective was to assess the transcriptional modulation of HERVs in burn, trauma and septic shock patients. We analyzed HERV transcriptome with microarray data from whole blood samples of a burn cohort (n = 30), a trauma cohort (n = 105) and 2 septic shock cohorts (n = 28, n = 51), and healthy volunteers (HV, n = 60). We described expression of the 337 probesets targeting HERV from U133 plus 2.0 microarray in each dataset and then we compared HERVs transcriptional modulation of patients compared to healthy volunteers. Although all 4 cohorts contained critically ill patients, the majority of the 337 HERVs was not expressed (around 74% in mean). Each cohort had differentially expressed probesets in patients compared to HV (from 19 to 46). Strikingly, 5 HERVs were in common in all types of severely injured patients, with 4 being up-modulated in patients. We highlighted co-expressed profiles between HERV and nearby CD55 and CD300LF genes as well as autonomous HERV expression. We suggest an inflammatory-specific HERV transcriptional response, and importantly, we introduce that the HERVs close to immunity-related genes might have a role on its expression.

BackgroundIntravascular haemolysis has been associated with acute kidney injury (AKI) in different clinical settings (cardiac surgery, sickle cell disease). Haemolysis occurs frequently in critically ill burn patients. The aim of this study was to assess the predictive value of haptoglobin at admission to predict major adverse kidney events (MAKE) and AKI in critically ill burn patients.MethodsWe conducted a retrospective, single-centre cohort study in a burn critical care unit in a tertiary centre, including all consecutive severely burned patients (total burned body surface > 20% and/or shock and/or mechanical ventilation at admission) from January 2012 to April 2017 with a plasmatic haptoglobin dosage at admission.ResultsA total of 130 patients were included in the analysis. Their mean age was 49 (34-62) years, their median total body surface area burned was 29% (15-51%) and the intensive care unit (ICU) mortality was 25%. Early haemolysis was defined as an undetectable plasmatic haptoglobin at admission. We used logistic regression to identify MAKE and AKI risk factors. In multivariate analysis, undetectable haptoglobin was associated with MAKE and AKI (respectively, OR 6.33, 95% CI 2.34-16.45, p

AimsCardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.Methods and resultsThis multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.ConclusionThe primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

IntroductionPatients with cardiogenic shock (CS) are at a high risk of developing infectious complications; however, their early detection is difficult, mainly due to a frequently occurring noninfectious inflammatory response, which accompanies an extensive myocardial infarction (MI) or a postcardiac arrest syndrome. The goal of our prospective study was to describe infectious complications in CS and the immune/inflammatory response based on a serial measurement of several blood-based inflammatory biomarkers.MethodsEighty patients with CS were evaluated and their infections were monitored. Inflammatory markers (C-reactive protein, procalcitonin, pentraxin 3, presepsin) were measured seven times per week. The control groups consisted of 11 patients with ST segment elevation myocardial infarction without CS and without infection, and 22 patients in septic shock.ResultsInfection was diagnosed in 46.3% of patients with CS; 16 patients developed an infection within 48 h. Respiratory infection was most common, occurring in 33 out of 37 patients. Infection was a significant or even the main reason of death only in 3.8% of all patients with CS, and we did not find statistically significant difference in 3-month mortality between group of patients with CS with and without infection. There was no statistically significant prolongation of the duration of mechanical ventilation associated with infection. Strong inflammatory response is often in patients with CS due to MI, but we found no significant difference in the course of the inflammatory response expressed by evaluated biomarkers in patients with CS with and without infection. We found a strong relationship between the elevated inflammatory markers (sampled at 12 h) and the 3-month mortality: the area under the curve of receiver operating characteristic ranged between 0.683 and 0.875.ConclusionThe prevalence of infection in patients with CS was 46.3%, and respiratory tract infections were the most common type. Infections did not prolong statistically significantly the duration of mechanical ventilation and did not increase the prevalence of hospital mortality in this high-risk CS population. CS due to acute myocardial infarction was accompanied by a strong and highly variable inflammatory response, but it did not reach the intensity of the inflammatory response observed in patients with septic shock. An extensive immune/inflammatory response in patients with CS is linked to a poor prognosis.

BackgroundThe Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality.MethodsArticles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; >50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index.ResultsStandardized data were obtained for 17 studies (n = 16,534, mean age 76 ± 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95%CI 2.86-3.79), 4-6 (OR 2.14, 95%CI 1.92-2.39), and 7-9 (OR 1.50, 95%CI 1.32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men.ConclusionsAn SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. The study protocol was published on PROSPERO (CRD42015024916).

BackgroundOliguria is one of the leading triggers of fluid loading in patients in the intensive care unit (ICU). The purpose of this study was to assess the predictive value of urine Na(+) (uNa(+)) and other routine urine biomarkers for cardiac fluid responsiveness in oliguric ICU patients.MethodsWe conducted a prospective multicenter observational study in five university ICUs. Patients with urine output (UO) 65 mmHg received a fluid challenge. Cardiac fluid responsiveness was defined by an increase in stroke volume >15 % after fluid challenge. Urine and plasma biochemistry samples were examined before fluid challenge. We examined renal fluid responsiveness (defined as UO > 0.5 ml/kg/h for 3 consecutive hours) after fluid challenge as a secondary endpoint.ResultsFifty-four patients (age 51 ± 37 years, Simplified Acute Physiology Score II score 40 ± 20) were included. Most patients (72 %) were not cardiac responders (CRs), and 50 % were renal responders (RRs) to fluid challenge. Patient characteristics were similar between CRs and cardiac nonresponders. uNa(+) (37 ± 38 mmol/L vs 25 ± 75 mmol/L, p = 0.44) and fractional excretion of sodium (FENa(+)) (2.27 ± 2.5 % vs 2.15 ± 5.0 %, p = 0.94) were not statistically different between those who did and those who did not respond to the fluid challenge. Areas under the receiver operating characteristic (AUROC) curves were 0.51 (95 % CI 0.35-0.68) and 0.56 (95 % CI 0.39-0.73) for uNa(+) and FENa(+), respectively. Fractional excretion of urea had an AUROC curve of 0.70 (95 % CI 0.54-0.86, p = 0.03) for CRs. Baseline UO was higher in RRs than in renal nonresponders (1.07 ± 0.78 ml/kg/3 h vs 0.65 ± 0.53 ml/kg/3 h, p = 0.01). The AUROC curve for RRs was 0.65 (95 % CI 0.53-0.78) for uNa(+).ConclusionsIn the present study, most oliguric patients were not CRs and half were not renal responders to fluid challenge. Routine urinary biomarkers were not predictive of fluid responsiveness in oliguric normotensive ICU patients.

ObjectiveThe objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF).MethodsIn a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF.Results26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF.ConclusionsIn ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153).

IntroductionThe role of systemic hemodynamics in the pathogenesis of septic acute kidney injury (AKI) has received little attention. The purpose of this study was to investigate the association between systemic hemodynamics and new or persistent of AKI in severe sepsis.MethodsA retrospective study between 2006 and 2010 was performed in a surgical ICU in a teaching hospital. AKI was defined as development (new AKI) or persistent AKI during the five days following admission based on the Acute Kidney Injury Network (AKIN) criteria. We studied the association between the following hemodynamic targets within 24 hours of admission and AKI: central venous pressure (CVP), cardiac output (CO), mean arterial pressure (MAP), diastolic arterial pressure (DAP), central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2).ResultsThis study included 137 ICU septic patients. Of these, 69 had new or persistent AKI. AKI patients had a higher Simplified Acute Physiology Score (SAPS II) (57 (46 to 67) vs. 45 (33 to 52), P

Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising candidate biomarkers of renal injury, with expression in renal tissue increasing dramatically after ischemia-reperfusion injury but not in the case of pure pre-renal failure. In a recent issue of Critical Care, Di Somma and colleagues reported that NGAL could improve the classification of acute kidney injury compared with clinical assessment and showed that NGAL was associated with poor prognosis. NGAL may therefore carry different information than biomarkers of renal function. This study finally provides additional evidence for the highly complex relationship between renal function and renal injury.