Exploring the relationship between HCMV serostatus and outcomes in COVID-19 sepsis.

Background: Sepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19. Methods: A multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis. Results: The prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival. Discussion: These findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8+ T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management. Conclusion: This study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis.

No Sequestration of Commonly Used Anti-Infectives in the Extracorporeal Membrane Oxygenation (ECMO) Circuit-An Ex Vivo Study.

Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin-electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients.

Frequency of use and adequacy of Cochrane risk of bias tool 2 in non-Cochrane systematic reviews published in 2020: Meta-research study.

Risk of bias (RoB) assessment is essential to the systematic review methodology. The new version of the Cochrane RoB tool for randomized trials (RoB 2) was published in 2019 to address limitations identified since the first version of the tool was published in 2008 and to increase the reliability of assessments. This study analyzed the frequency of usage of the RoB 2 and the adequacy of reporting the RoB 2 assessments in non-Cochrane reviews published in 2020. This meta-research study included non-Cochrane systematic reviews of interventions published in 2020. For the reviews that used the RoB 2 tool, we analyzed the reporting of the RoB 2 assessment. Among 3880 included reviews, the Cochrane RoB 1 tool was the most frequently used (N = 2228; 57.4%), followed by the Cochrane RoB 2 tool (N = 267; 6.9%). From 267 reviews that reported using the RoB 2 tool, 213 (79.8%) actually used it. In 26 (12.2%) reviews, erroneous statements were used to indicate the RoB 2 assessment. Only 20 (9.4%) reviews presented a complete RoB 2 assessment with a detailed table of answers to all signaling questions. The judgment of risk of bias by the RoB 2 tool was not justified by a comment in 158 (74.2%) reviews. Only in 33 (14.5%) of reviews the judgment in all domains was justified in the accompanying comment. In most reviews (81.7%), the RoB was inadequately assessed at the study level. In conclusion, the majority of non-Cochrane reviews published in 2020 still used the Cochrane RoB 1 tool. Many reviews used the RoB 2 tool inadequately. Further studies about the uptake and the use of the RoB 2 tool are needed.

A Pilot Study of Renin-Guided Angiotensin-II Infusion to Reduce Kidney Stress After Cardiac Surgery.

BACKGROUND: Vasoplegia is common after cardiac surgery, is associated with hyperreninemia, and can lead to acute kidney stress. We aimed to conduct a pilot study to test the hypothesis that, in vasoplegic cardiac surgery patients, angiotensin-II (AT-II) may not increase kidney stress (measured by [TIMP-2]*[IGFBP7]). METHODS: We randomly assigned patients with vasoplegia (cardiac index [CI] > 2.1l/min, postoperative hypotension requiring vasopressors) and Δ-renin (4-hour postoperative-preoperative value) ≥3.7 µU/mL, to AT-II or placebo targeting a mean arterial pressure ≥65 mm Hg for 12 hours. The primary end point was the incidence of kidney stress defined as the difference between baseline and 12 hours [TIMP-2]*[IGFBP7] levels. Secondary end points included serious adverse events (SAEs). RESULTS: We randomized 64 patients. With 1 being excluded, 31 patients received AT-II, and 32 received placebo. No significant difference was observed between AT-II and placebo groups for kidney stress (Δ-[TIMP-2]*[IGFBP7] 0.06 [ng/mL]2/1000 [Q1-Q3, -0.24 to 0.28] vs -0.08 [ng/mL]2/1000 [Q1-Q3, -0.35 to 0.14]; P = .19; Hodges-Lehmann estimation of the location shift of 0.12 [ng/mL]2/1000 [95% confidence interval, CI, -0.1 to 0.36]). AT-II patients received less fluid during treatment than placebo patients (2946 vs 3341 mL, P = .03), and required lower doses of norepinephrine equivalent (0.19 mg vs 4.18mg, P < .001). SAEs were reported in 38.7% of patients in the AT-II group and in 46.9% of patients in the placebo group. CONCLUSIONS: The infusion of AT-II for 12 hours appears feasible and did not lead to an increase in kidney stress in a high-risk cohort of cardiac surgery patients. These findings support the cautious continued investigation of AT-II as a vasopressor in hyperreninemic cardiac surgery patients.

Acute kidney injury after cardiac surgery.

PURPOSE OF REVIEW: Patients undergoing cardiac surgery are at high risk to develop cardiac surgery-associated acute kidney injury (CS-AKI) postoperatively. CS-AKI is associated with an increased risk for persistent renal dysfunction, morbidity and mortality. This review summarizes the epidemiology and pathophysiology of CS-AKI, as well as current treatment and prevention strategies. RECENT FINDINGS: As AKI is a syndrome with complex pathophysiology, no causative treatment strategies exist. Recent advances in the field of AKI biomarkers offer new perspectives on the issue and the implementation of biomarker-guided preventive strategies may reduce rates of CS-AKI. Finally, nephroprotective treatments and angiotensin II as a novel vasopressor may offer new opportunities for high-risk patients undergoing cardiac surgery. SUMMARY: Based on the described novel approaches for early detection, prevention and management of CS-AKI, a precision-medicine approach should be implemented in order to prevent the development of AKI in patients undergoing cardiac surgery.

Renin-angiotensin-aldosterone system dynamics after targeted blood pressure control using angiotensin II or norepinephrine in cardiac surgery: mechanistic randomised controlled trial.

BACKGROUND: The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels. METHODS: In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70-80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery. RESULTS: In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3-88] µU ml-1; P<0.001) but angiotensin II did not (MD -3 [IQR -62 to 35] µU ml-1; P=0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD -0.01 [IQR -0.14 to 0.03] µU ml-1 per ng dl-1, P=0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004-0.26] µU ml-1 per ng dl-1, P<0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points. CONCLUSIONS: Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry-ACTRN12621000195853 23/02/2021.

Evaluation of Proenkephalin A 119-159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury.

INTRODUCTION: Recent evidence suggests an association of plasma Proenkephalin A 119-159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort. METHODS: Data and plasma samples from the "Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury-A Randomized Clinical Trial" (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output. RESULTS: Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73-1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45-3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26-0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80-4.73, p < 0.001) compared to penKid. DISCUSSION: This study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial. Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.

Recombinant Alpha-1-Microglobulin (RMC-035) to Prevent Acute Kidney Injury in Cardiac Surgery Patients: Phase 1b Evaluation of Safety and Pharmacokinetics.

Introduction: Acute kidney injury (AKI) is a common complication in cardiac surgery patients and prevention is needed to improve clinical outcomes. Alpha-1-microglobulin (A1M) is a physiological antioxidant with strong tissue-protective and cell-protective properties that has demonstrated renoprotective effects. RMC-035, a recombinant variant of endogenous human A1M, is being developed for the prevention of AKI in cardiac surgery patients. Methods: In this phase 1b, randomized, double-blind, and parallel group clinical study, 12 cardiac surgery patients undergoing elective, open-chest, on-pump coronary artery bypass graft and/or valve surgery with additional predisposing AKI risk factors were enrolled to receive in total 5 intravenous doses of either RMC-035 or placebo. The primary objective was to evaluate the safety and tolerability of RMC-035. The secondary objective was to evaluate its pharmacokinetic properties. Results: RMC-035 was well tolerated. The nature and frequency of adverse events (AEs) were consistent with the expected background rates in the underlying patient population with no AEs reported as related to study drug. No clinically relevant changes were observed for vital signs or laboratory parameters except for renal biomarkers. Several established AKI urine biomarkers were reduced at 4 hours after first dose administration in the treatment group, indicating a reduced perioperative tubular cell injury following RMC-035 treatment. Conclusion: Multiple intravenous doses of RMC-035 were well tolerated in patients undergoing cardiac surgery. Observed RMC-035 plasma exposures were safe and in the range of expected pharmacological activity. Furthermore, urine biomarkers suggest reduced perioperative kidney cell injury, warranting further investigation of RMC-035 as a potential renoprotective treatment.

DeepTSE: A Time-Sensitive Deep Embedding of ICU Data for Patient Modeling and Missing Data Imputation.

Missing data is a common problem in the intensive care unit as a variety of factors contribute to incomplete data collection in this clinical setting. This missing data has a significant impact on the accuracy and validity of statistical analyses and prognostic models. Several imputation methods can be used to estimate the missing values based on the available data. Although simple imputations with mean or median generate reasonable results in terms of mean absolute error, they do not account for the currentness of the data. Furthermore, heterogeneous time span of data records adds to this complexity, especially in high-frequency intensive care unit datasets. Therefore, we present DeepTSE, a deep model that is able to cope with both, missing data and heterogeneous time spans. We achieved promising results on the MIMIC-IV dataset that can compete with and even outperform established imputation methods.

Implementation of Nephroprotective Measures to Prevent Acute Kidney Injury in Septic Patients: A Retrospective Cohort Study.

BACKGROUND: Sepsis remains the leading cause of mortality in critically ill patients, and mortality is increased when acute kidney injury (AKI) occurs. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends the implementation of supportive measures in patients at high risk for AKI. However, it remains unclear to what extent these nephroprotective measures are implemented in daily clinical practice in critically ill patients, especially those with high-risk exposures such as sepsis. METHODS: We analyzed the Medical Information Mart for Intensive Care IV (MIMIC-IV) database to identify septic patients with and without AKI. The primary outcome of interest was the adherence to the KDIGO bundle consisting of avoidance of nephrotoxic agents, implementation of a functional hemodynamic monitoring, optimization of perfusion pressure and volume status, close monitoring of renal function, avoidance of hyperglycemia, and avoidance of radiocontrast agents. Secondary outcomes included the development of AKI, progression of AKI, the use of renal replacement therapy (RRT), mortality, and a composite end point consisting of progression of AKI and mortality within 7 days. RESULTS: Our analysis included 34,679 patients with sepsis with 1.6% receiving the complete bundle (10% received 5, 42.3% 4, 35.4% 3, and 9.8% 2 bundle components). In 56.4%, nephrotoxic agents were avoided, and hemodynamic optimization was reached in 86.5%. Secondary end points were improved in patients with bundle adherence. Avoidance of nephrotoxic drugs and optimization of hemodynamics were significantly associated with lower rates of AKI and improved patient outcomes, including 30-day mortality. CONCLUSIONS: Implementation of the KDIGO bundle is poor in patients with sepsis but may be associated with improved outcomes.

Study protocol of a phase 2, randomised, placebo-controlled, double-blind, adaptive, parallel group clinical study to evaluate the efficacy and safety of recombinant alpha-1-microglobulin in subjects at high risk for acute kidney injury following open-chest cardiac surgery (AKITA trial).

INTRODUCTION: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites. ETHICS AND DISSEMINATION: The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code '2021-778 f-A') and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT05126303.

The Role of Cell Cycle Arrest Biomarkers for Predicting Acute Kidney Injury in Critically Ill COVID-19 Patients: A Multicenter, Observational Study.

OBJECTIVES: Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) have a high risk for developing acute kidney injury (AKI) which is associated with an increased risk of death and persistent renal failure. Early prediction of AKI is crucial in order to implement preventive strategies. The purpose of this study was to investigate the predictive performance of tissue inhibitor of metalloproteinases 2 and insulin like growth factor binding protein 7 (TIMP-2) × (IGFBP7) in critically ill patients with COVID-19-associated ARDS. DESIGN: Multicenter, prospective, observational study. SETTING: Twelve centers across Europe and United Kingdom. PATIENTS: Patients with moderate or severe COVID-19-associated ARDS were included and serial measurements of (TIMP-2) × (IGFBP7) were performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the development of moderate or severe AKI according to the Kidney Disease: Improving Global Outcomes definition. Three hundred patients were available for the primary analysis, and 39 met the primary endpoint. At enrollment, urinary (TIMP-2) × (IGFBP7) had high predictive value for the primary endpoint with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.84-0.93). (TIMP-2) × (IGFBP7) was significantly higher in endpoint-positive patients at enrollment and at 12 hours. CONCLUSIONS: Urinary (TIMP-2) × (IGFBP7) predicts the occurrence of AKI in critically ill patients with COVID-19-associated ARDS.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

Predicting the Development of Renal Replacement Therapy Indications by Combining the Furosemide Stress Test and Chemokine (C-C Motif) Ligand 14 in a Cohort of Postsurgical Patients.

OBJECTIVES: Optimal timing of renal replacement therapy (RRT) initiation in severe acute kidney injury (AKI) remains controversial. Initiation of treatment early in the course of AKI may lead to some patients undergoing unnecessary RRT, whereas delayed treatment is associated with increased mortality. This study aims to investigate whether the combination of the furosemide stress test (FST) and AKI-associated biomarkers can predict the development of indications for RRT. DESIGN: Single-center, prospective, observational study. SETTING: University Hospital of Muenster, Germany. PATIENTS: Critically ill, postoperative patients with moderate AKI (Kidney Disease: Improving Global Outcomes stage 2) and risk factors for further progression (vasopressors and/or mechanical ventilation) receiving an FST. INTERVENTIONS: Sample collection and measurement of different biomarkers (chemokine [C-C motif] ligand 14 [CCL14], neutrophil gelatinase-associated lipocalin, dipeptidyl peptidase 3). MEASUREMENT AND MAIN RESULTS: The primary endpoint was the development of greater than or equal to one predefined RRT indications (hyperkalemia [≥ 6 mmol/L], diuretic-resistant hypervolemia, high urea serum levels [≥ 150 mg/dL], severe metabolic acidosis [pH ≤ 7.15], oliguria [urinary output < 200 mL/12 hr], or anuria). Two hundred eight patients were available for the primary analysis with 108 having a negative FST (urine output < 200 mL in 2 hr following FST). Ninety-eight patients (47%) met the primary endpoint, 82% in the FST negative cohort. At the time of inclusion, the combination of a negative FST test and high urinary CCL14 levels had a significantly higher predictive value for the primary endpoint with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.82-0.92) compared with FST or CCL14 alone (AUC, 0.79; 95% CI, 0.74-0.85 and AUC, 0.83; 95% CI, 0.77-0.89; p < 0.001, respectively). Other biomarkers showed lower AUCs. CONCLUSIONS: The combination of the FST with the renal biomarker CCL14 predicts the development of indications for RRT.

Proenkephalin A 119-159 predicts early and successful liberation from renal replacement therapy in critically ill patients with acute kidney injury: a post hoc analysis of the ELAIN trial.

BACKGROUND: Renal replacement therapy (RRT) remains the key rescue therapy for critically ill patients with severe acute kidney injury (AKI). However, there are currently no tools available to predict successful liberation from RRT. Biomarkers may allow for risk stratification and individualization of treatment strategies. Proenkephalin A 119-159 (penKid) has been suggested as a promising marker of kidney function in the context of AKI, but has not yet been evaluated for RRT liberation in critically ill patients with AKI. METHODS: This post hoc analysis included 210 patients from the randomized clinical ELAIN trial and penKid levels were measured in the blood of these patients. Competing risk time-to-event analyses were performed for pre-RRT penKid at initiation of RRT and in a landmark analysis at day 3 after initiation of RRT. Competing risk endpoints were successful liberation from RRT or death without prior liberation from RRT. RESULTS: Low pre-RRT penKid levels (penKid ≤ 89 pmol/l) at RRT initiation were associated with early and successful liberation from RRT compared to patients with high pre-RRT penKid levels (subdistribution hazard ratio (sHR) 1.83, 95%CI 1.26-2.67, p = 0.002, estimated 28d-cumulative incidence function (28d-CIF) of successful liberation from RRT 61% vs. 45%, p = 0.022). This association persisted in the landmark analysis on day 3 of RRT (sHR 1.78, 95%CI 1.17-2.71, p = 0.007, 28d-CIF of successful liberation from RRT 67% vs. 47%, p = 0.018). For both time points, no difference in the competing event of death was detected. CONCLUSIONS: In critically ill patients with RRT-dependent AKI, plasma penKid appears to be a useful biomarker for the prediction of shorter duration and successful liberation from RRT and may allow an individualized approach to guide strategies of RRT liberation in critically ill patients with RRT-dependent AKI. TRIAL REGISTRATION: The ELAIN trial was prospectively registered at the German Clinical Trial Registry (Identifier: DRKS00004367) on 28th of May 2013.

Biomarkers for the Prediction and Judgement of Sepsis and Sepsis Complications: A Step towards precision medicine?

Sepsis and septic shock are a major public health concern and are still associated with high rates of morbidity and mortality. Whilst there is growing understanding of different phenotypes and endotypes of sepsis, all too often treatment strategies still only employ a "one-size-fits-all" approach. Biomarkers offer a unique opportunity to close this gap to more precise treatment approaches by providing insight into clinically hidden, yet complex, pathophysiology, or by individualizing treatment pathways. Predicting and evaluating systemic inflammation, sepsis or septic shock are essential to improve outcomes for these patients. Besides opportunities to improve patient care, employing biomarkers offers a unique opportunity to improve clinical research in patients with sepsis. The high rate of negative clinical trials in this field may partly be explained by a high degree of heterogeneity in patient cohorts and a lack of understanding of specific endotypes or phenotypes. Moving forward, biomarkers can support the selection of more homogeneous cohorts, thereby potentially improving study conditions of clinical trials. This may finally pave the way to a precision medicine approach to sepsis, septic shock and complication of sepsis in the future.

Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19.

Clonal hematopoiesis of indeterminate potential (CHIP) leads to higher mortality, carries a cardiovascular risk and alters inflammation. All three aspects harbor overlaps with the clinical manifestation of COVID-19. This study aimed to identify the impact of CHIP on COVID-19 pathophysiology. 90 hospitalized patients were analyzed for CHIP. In addition, their disease course and outcome were evaluated. With a prevalence of 37.8%, the frequency of a CHIP-driver mutation was significantly higher than the prevalence expected based on median age (17%). CHIP increases the risk of hospitalization in the course of the disease but has no age-independent impact on the outcome within the group of hospitalized patients. Especially in younger patients (45 - 65 years), CHIP was associated with persistent lymphopenia. In older patients (> 65 years), on the other hand, CHIP-positive patients developed neutrophilia in the long run. To what extent increased values of cardiac biomarkers are caused by CHIP independent of age could not be elaborated solely based on this study. In conclusion, our results indicate an increased susceptibility to a severe course of COVID-19 requiring hospitalization associated with CHIP. Secondly, they link it to a differentially regulated cellular immune response under the pressure of SARS-CoV-2 infection. Hence, a patient's CHIP-status bears the potential to serve as biomarker for risk stratification and to early guide treatment of COVID-19 patients.

Exponential growth of systematic reviews assessing artificial intelligence studies in medicine: challenges and opportunities.

The evidence-based medicine (EBM) movement is stepping up its efforts to assess medical artificial intelligence (AI) and data science studies. Since 2017, there has been a marked increase in the number of published systematic reviews that assess medical AI studies. Increasingly, data from observational studies are used in systematic reviews of medical AI studies. Assessment of risk of bias is especially important in medical AI studies to detect possible "AI bias".

Prediction of Acute Kidney Injury in the Intensive Care Unit: Preliminary Findings in a European Open Access Database.

Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with long-term complications and an increased mortality. This work presents preliminary findings from the first freely available European intensive care database released by Amsterdam UMC. A machine learning (ML) model was developed to predict AKI in the intensive care unit 12 hours before the actual event. Main features of the model included medications and hemodynamic parameters. Our models perform with an accuracy of 81.8% on moderate to severe AKI and 79.8% on all AKI patients. Those results can compete with models reported in the literature and introduce an ML model for AKI based on European patient data.