Impact of Diabetes and Glycemia on Cardiac Improvement and Adverse Events Following Mechanical Circulatory Support.

BACKGROUND: Type 2 diabetes is prevalent in cardiovascular disease and contributes to excess morbidity and mortality. We sought to investigate the effect of glycemia on functional cardiac improvement, morbidity, and mortality in durable left ventricular assist device (LVAD) recipients. METHODS AND RESULTS: Consecutive patients with an LVAD were prospectively evaluated (n=531). After excluding patients missing pre-LVAD glycated hemoglobin (HbA1c) measurements or having inadequate post-LVAD follow-up, 375 patients were studied. To assess functional cardiac improvement, we used absolute left ventricular ejection fraction change (ΔLVEF: LVEF post-LVAD-LVEF pre-LVAD). We quantified the association of pre-LVAD HbA1c with ΔLVEF as the primary outcome, and all-cause mortality and LVAD-related adverse event rates (ischemic stroke/transient ischemic attack, intracerebral hemorrhage, gastrointestinal bleeding, LVAD-related infection, device thrombosis) as secondary outcomes. Last, we assessed HbA1c differences pre- and post-LVAD. Patients with type 2 diabetes were older, more likely men suffering ischemic cardiomyopathy, and had longer heart failure duration. Pre-LVAD HbA1c was inversely associated with ΔLVEF in patients with nonischemic cardiomyopathy but not in those with ischemic cardiomyopathy, after adjusting for age, sex, heart failure duration, and left ventricular end-diastolic diameter. Pre-LVAD HbA1c was not associated with all-cause mortality, but higher pre-LVAD HbA1c was shown to increase the risk of intracerebral hemorrhage, LVAD-related infection, and device thrombosis by 3 years on LVAD support (P<0.05 for all). HbA1c decreased from 6.68±1.52% pre-LVAD to 6.11±1.33% post-LVAD (P<0.001). CONCLUSIONS: Type 2 diabetes and pre-LVAD glycemia modify the potential for functional cardiac improvement and the risk for adverse events on LVAD support. The degree and duration of pre-LVAD glycemic control optimization to favorably affect these outcomes warrants further investigation.

Comparison of Glomerular Filtration Rate Equations in a Rural New Mexico Cohort: Results from the COMPASS Study.

Rationale and Objective: The NKF-ASN Task Force recommends accurate kidney function estimation avoiding biases through racial adjustments. We explored the use of multiple kidney function biomarkers and hence estimated glomerular filtration rate (eGFR) equations to improve kidney function calculations in an ethnically diverse patient population. Study design: Prospective community cohort study. Setting and Participants: rural New Mexico clinic with patients > 18 yo. Methods: Markers of kidney function, IDMS-Creatinine (SCr), chemiluminescence Beta-2 Microglobulin (B2M), Nephelometry-calibrated ELISA Cystatin C (CysC), inflammation, glucose tolerance, demographics, BUN/UACR from the baseline visit of the COMPASS cohort, were analyzed by Kernel-based Virtual Machine learning methods. Results: Among 205 participants, the mean age was 50.1, 62% were female, 54.1% Hispanic American and 30.2% Native American. Average kidney function biomarkers were: SCr 0.9 mg/dl, B2M 1.8 mg/L, and CysC 0.7 mg/dl. The highest agreement was observed between SCr and B2M-based eGFR equations [mean difference in eGFRs: (4.48 ml/min/1.73m2], and the lowest agreement between B2M and CysC-based eGFR equations (-24.75 ml/min/1.73m2). There was no pattern of association between the differences in eGFR measures and gender. In the continuous analyses, the absolute eGFR value (p<2 x 10-16) and serum albumin (p =6.4 x 10-5) predicted the difference between B2M- and SCr-based e-GFR. The absolute eGFR value (p<2 x 10-16) and age (p =7.6 x 10-5) predicted the difference between CysC- and SCr-based e-GFR. Limitations: Relatively small sample size, elevated inflammatory state in majority of study participants and no inulin excretion rate measurements. Conclusion: B2M should be strongly considered as a kidney function biomarker fulfilling the criteria for the NKF-ASN. B2M's eGFR equation does not need adjustment for gender or race and showed the highest agreement with SCr-based eGFR equations.

Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.

INTRODUCTION: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. METHODS: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. RESULTS: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028. CONCLUSIONS: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support.

Hospital Readmissions in Patients Supported with Durable Centrifugal-Flow Left Ventricular Assist Devices.

Background: Centrifugal-flow left ventricular assist devices (CF-LVADs) have improved morbidity and mortality for their recipients. Hospital readmissions remain common, negatively impacting quality of life and survival. We sought to identify risk factors associated with hospital readmissions among patients with CF-LVADs. Methods: Consecutive patients receiving a CF-LVAD between February 2011 and March 2021 were retrospectively evaluated using prospectively maintained institutional databases. Hospital readmissions within three years post-LVAD implantation were dichotomized into heart failure (HF)/LVAD-related or non-HF/LVAD-related readmissions. Multivariable Cox regression models augmented using a machine learning algorithm, the least absolute shrinkage and selection operator (LASSO) method, for variable selection were used to estimate associations between HF/LVAD-related readmissions and pre-, intra- and post-operative clinical variables. Results: A total of 204 CF-LVAD recipients were included, of which 138 (67.7%) had at least one HF/LVAD-related readmission. HF/LVAD-related readmissions accounted for 74.4% (436/586) of total readmissions. The main reasons for HF/LVAD-related readmissions were major bleeding, major infection, HF exacerbation, and neurological dysfunction. Using pre-LVAD variables, HF/LVAD-related readmissions were associated with substance use, previous cardiac surgery, HF duration, pre-LVAD inotrope dependence, percutaneous LVAD/VA-ECMO support, LVAD type, and the left ventricular ejection fraction in multivariable analysis (Harrell's concordance c-statistic; 0.629). After adding intra- and post-operative variables in the multivariable model, LVAD implant hospitalization length of stay was an additional predictor of readmission. Conclusions: Using machine learning-based techniques, we generated models identifying pre-, intra-, and post-operative variables associated with a higher likelihood of rehospitalizations among patients on CF-LVAD support. These models could provide guidance in identifying patients with increased readmission risk for whom clinical strategies to mitigate this risk may further improve LVAD recipient outcomes.

Cardiac Reverse Remodeling Mediated by HeartMate 3 Left Ventricular Assist Device: Comparison to Older Generation Devices.

Currently, the fully magnetically levitated left ventricular assist device (LVAD) HeartMate 3 (HM3) is the only commercially available device for advanced heart failure (HF) patients. However, the left ventricular (LV) functional and structural changes following mechanical unloading and circulatory support (MCS) with the HM3 have not been investigated. We compared the reverse remodeling induced by the HM3 to older generation continuous-flow LVADs. Chronic HF patients (n = 405) undergoing MCS with HeartWare Ventricular Assist Device (HVAD, n = 115), HM3 (n = 186), and HeartMate II (HM2, n = 104) at four programs were included. Echocardiograms were obtained preimplant and at 1, 3, 6, and 12 months following LVAD implantation. There were no differences in the postimplant serial LV ejection fraction (LVEF) between the devices. The postimplant LV internal diastolic diameter (LVIDd) was significantly lower for HM2 at 3 and 6 months compared with HVAD and HM3. The proportion of patients achieving "cardiac reverse remodeling responder" status (defined as LVEF improvement to ≥40% and LVIDD ≤5.9 cm) was 11.9%, and was similar between devices. HeartMate 3 appears to result in similar cardiac reverse remodeling as older generation CF-LVADs, suggesting that the fully magnetically levitated device technology could provide an effective platform to further study and promote cardiac reverse remodeling.

White Cord Syndrome Following Cervical Surgery in a Patient With Klippel-Feil Syndrome: A Case Report.

White cord syndrome is a rare entity, as there are very few cases described in the current literature. Postoperative MRI examination reveals cord intrinsic changes, including edema and ischemia. It is also described as a reperfusion injury of the spinal cord. This report depicts a rare case of "white cord syndrome" with tetraplegia after posterior laminectomy and fusion of the cervical spine in a patient with Klippel-Feil syndrome. A 33-year-old male patient with Klippel-Feil syndrome presented to our department with cervical myelopathy, claudication, deteriorating neurological status, imbalance, and lower limb spasticity. Due to kyphotic malformation of the cervical spine, a two-stage surgical intervention was scheduled. The patient first underwent anterior spinal fusion of C4-C6 with corpectomy of C5, where many anatomical and visceral differentiations were signed, so the surgical team was enhanced by a vascular surgeon. The postoperative period was uneventful and the patient was discharged after a week of hospitalization without any neurological deterioration. A second surgical intervention was scheduled after two months where laminectomy of C5-C7 and posterior fusion of C5-T1 were carried out. However, due to intraoperative spinal instability and various anatomical spinal variations, a third surgery, which would be occipitocervical fusion, was decided as the final surgical solution. During the third surgical operation, after the laminectomy of C1 to C5 and the placement of the occipital plate, the screws, and the two rods in situ, complete nullification of the intraoperative neurophysiologic control was signed. The internal fixation was removed immediately, the wake-up test revealed tetraplegia below C5, and the patient was transferred to the ICU. Immediate MRI revealed no spinal cord hematoma; however, spinal cord edema was present. The patient underwent a tracheostomy and remained quadriplegic with a sensory level of T8 and motor level of C5 and was discharged to a rehabilitation center. The possibility of white cord syndrome should be explained by surgeons before any cervical decompression surgery, as well as a thorough neurological examination should be performed postoperatively. The early recognition and prompt management of white cord syndrome is recommended.

Hypernatremia in Hyperglycemia: Clinical Features and Relationship to Fractional Changes in Body Water and Monovalent Cations during Its Development.

In hyperglycemia, the serum sodium concentration ([Na]S) receives influences from (a) the fluid exit from the intracellular compartment and thirst, which cause [Na]S decreases; (b) osmotic diuresis with sums of the urinary sodium plus potassium concentration lower than the baseline euglycemic [Na]S, which results in a [Na]S increase; and (c), in some cases, gains or losses of fluid, sodium, and potassium through the gastrointestinal tract, the respiratory tract, and the skin. Hyperglycemic patients with hypernatremia have large deficits of body water and usually hypovolemia and develop severe clinical manifestations and significant mortality. To assist with the correction of both the severe dehydration and the hypovolemia, we developed formulas computing the fractional losses of the body water and monovalent cations in hyperglycemia. The formulas estimate varying losses between patients with the same serum glucose concentration ([Glu]S) and [Na]S but with different sums of monovalent cation concentrations in the lost fluids. Among subjects with the same [Glu]S and [Na]S, those with higher monovalent cation concentrations in the fluids lost have higher fractional losses of body water. The sum of the monovalent cation concentrations in the lost fluids should be considered when computing the volume and composition of the fluid replacement for hyperglycemic syndromes.

Integrating molecular and clinical variables to predict myocardial recovery.

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.

Invasive vs. conservative management of older patients with non-ST-elevation acute coronary syndrome: individual patient data meta-analysis.

BACKGROUND AND AIMS: Older patients with non-ST-elevation acute coronary syndrome (NSTEACS) are less likely to receive guideline-recommended care including coronary angiography and revascularization. Evidence-based recommendations regarding interventional management strategies in this patient cohort are scarce. This meta-analysis aimed to assess the impact of routine invasive vs. conservative management of NSTEACS by using individual patient data (IPD) from all available randomized controlled trials (RCTs) including older patients. METHODS: MEDLINE, Web of Science and Scopus were searched between 1 January 2010 and 11 September 2023. RCTs investigating routine invasive and conservative strategies in persons >70 years old with NSTEACS were included. Observational studies or trials involving populations outside the target range were excluded. The primary endpoint was a composite of all-cause mortality and myocardial infarction (MI) at 1 year. One-stage IPD meta-analyses were adopted by use of random-effects and fixed-effect Cox models. This meta-analysis is registered with PROSPERO (CRD42023379819). RESULTS: Six eligible studies were identified including 1479 participants. The primary endpoint occurred in 181 of 736 (24.5%) participants in the invasive management group compared with 215 of 743 (28.9%) participants in the conservative management group with a hazard ratio (HR) from random-effects model of 0.87 (95% CI 0.63-1.22; P = .43). The hazard for MI at 1 year was significantly lower in the invasive group compared with the conservative group (HR from random-effects model 0.62, 95% CI 0.44-0.87; P = .006). Similar results were seen for urgent revascularization (HR from random-effects model 0.41, 95% CI 0.18-0.95; P = .037). There was no significant difference in mortality. CONCLUSIONS: No evidence was found that routine invasive treatment for NSTEACS in older patients reduces the risk of a composite of all-cause mortality and MI within 1 year compared with conservative management. However, there is convincing evidence that invasive treatment significantly lowers the risk of repeat MI or urgent revascularisation. Further evidence is needed from ongoing larger clinical trials.

Trends in Digital Twin Framework Architectures for Smart Cities: A Case Study in Smart Mobility.

The main aim of this paper is to present an innovative approach to addressing the challenges of smart mobility exploiting digital twins within the METACITIES initiative. We have worked on this issue due to the increasing complexity of urban transportation systems, coupled with the urgent need to improve efficiency, safety, and sustainability in cities. The work presented in this paper is part of the project METACITIES, an Excellence Hub that spans a large geographical area, that of Southeastern Europe. The approach of the Greek innovation ecosystem of METACITIES involves leveraging digital twin technology to create intelligent replicas of urban mobility environments, enabling real-time monitoring, analysis, and decision making. Through use cases such as "Smart Parking", "Environmental Behavior Analysis on Traffic Incidents", and "Emergency Management", we demonstrate how digital twins can optimize traffic flow, mitigate environmental impact, and enhance emergency response; these use cases will be tested on a small scale, before deciding on implementation at a larger and more expensive scale. The final outcome is the METACITIES Architecture for smart mobility, which will be part of an Open Digital Twin Framework capable of evolving a smart city into a metacity.

AHoJ-DB: A PDB-wide Assignment of apo & holo Relationships Based on Individual Protein-Ligand Interactions.

A single protein structure is rarely sufficient to capture the conformational variability of a protein. Both bound and unbound (holo and apo) forms of a protein are essential for understanding its geometry and making meaningful comparisons. Nevertheless, docking or drug design studies often still consider only single protein structures in their holo form, which are for the most part rigid. With the recent explosion in the field of structural biology, large, curated datasets are urgently needed. Here, we use a previously developed application (AHoJ) to perform a comprehensive search for apo-holo pairs for 468,293 biologically relevant protein-ligand interactions across 27,983 proteins. In each search, the binding pocket is captured and mapped across existing structures within the same UniProt, and the mapped pockets are annotated as apo or holo, based on the presence or absence of ligands. We assemble the results into a database, AHoJ-DB (www.apoholo.cz/db), that captures the variability of proteins with identical sequences, thereby exposing the agents responsible for the observed differences in geometry. We report several metrics for each annotated pocket, and we also include binding pockets that form at the interface of multiple chains. Analysis of the database shows that about 24% of the binding sites occur at the interface of two or more chains and that less than 50% of the total binding sites processed have an apo form in the PDB. These results can be used to train and evaluate predictors, discover potentially druggable proteins, and reveal protein- and ligand-specific relationships that were previously obscured by intermittent or partial data. Availability: www.apoholo.cz/db.

Artificial intelligence predictive analytics in heart failure: results of the pilot phase of a pragmatic randomized clinical trial.

OBJECTIVES: We conducted an implementation planning process during the pilot phase of a pragmatic trial, which tests an intervention guided by artificial intelligence (AI) analytics sourced from noninvasive monitoring data in heart failure patients (LINK-HF2). MATERIALS AND METHODS: A mixed-method analysis was conducted at 2 pilot sites. Interviews were conducted with 12 of 27 enrolled patients and with 13 participating clinicians. iPARIHS constructs were used for interview construction to identify workflow, communication patterns, and clinician's beliefs. Interviews were transcribed and analyzed using inductive coding protocols to identify key themes. Behavioral response data from the AI-generated notifications were collected. RESULTS: Clinicians responded to notifications within 24 hours in 95% of instances, with 26.7% resulting in clinical action. Four implementation themes emerged: (1) High anticipatory expectations for reliable patient communications, reduced patient burden, and less proactive provider monitoring. (2) The AI notifications required a differential and tailored balance of trust and action advice related to role. (3) Clinic experience with other home-based programs influenced utilization. (4) Responding to notifications involved significant effort, including electronic health record (EHR) review, patient contact, and consultation with other clinicians. DISCUSSION: Clinician's use of AI data is a function of beliefs regarding the trustworthiness and usefulness of the data, the degree of autonomy in professional roles, and the cognitive effort involved. CONCLUSION: The implementation planning analysis guided development of strategies that addressed communication technology, patient education, and EHR integration to reduce clinician and patient burden in the subsequent main randomized phase of the trial. Our results provide important insights into the unique implications of implementing AI analytics into clinical workflow.

Machine Learning Multicenter Risk Model to Predict Right Ventricular Failure After Mechanical Circulatory Support: The STOP-RVF Score.

Importance: The existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support might be limited, partly due to lack of external validation, marginal predictive power, and absence of intraoperative characteristics. Objective: To derive and validate a risk model to predict RVF after LVAD implantation. Design, Setting, and Participants: This was a hybrid prospective-retrospective multicenter cohort study conducted from April 2008 to July 2019 of patients with advanced heart failure (HF) requiring continuous-flow LVAD. The derivation cohort included patients enrolled at 5 institutions. The external validation cohort included patients enrolled at a sixth institution within the same period. Study data were analyzed October 2022 to August 2023. Exposures: Study participants underwent chronic continuous-flow LVAD support. Main Outcome and Measures: The primary outcome was RVF incidence, defined as the need for RV assist device or intravenous inotropes for greater than 14 days. Bootstrap imputation and adaptive least absolute shrinkage and selection operator variable selection techniques were used to derive a predictive model. An RVF risk calculator (STOP-RVF) was then developed and subsequently externally validated, which can provide personalized quantification of the risk for LVAD candidates. Its predictive accuracy was compared with previously published RVF scores. Results: The derivation cohort included 798 patients (mean [SE] age, 56.1 [13.2] years; 668 male [83.7%]). The external validation cohort included 327 patients. RVF developed in 193 of 798 patients (24.2%) in the derivation cohort and 107 of 327 patients (32.7%) in the validation cohort. Preimplant variables associated with postoperative RVF included nonischemic cardiomyopathy, intra-aortic balloon pump, microaxial percutaneous left ventricular assist device/venoarterial extracorporeal membrane oxygenation, LVAD configuration, Interagency Registry for Mechanically Assisted Circulatory Support profiles 1 to 2, right atrial/pulmonary capillary wedge pressure ratio, use of angiotensin-converting enzyme inhibitors, platelet count, and serum sodium, albumin, and creatinine levels. Inclusion of intraoperative characteristics did not improve model performance. The calculator achieved a C statistic of 0.75 (95% CI, 0.71-0.79) in the derivation cohort and 0.73 (95% CI, 0.67-0.80) in the validation cohort. Cumulative survival was higher in patients composing the low-risk group (estimated <20% RVF risk) compared with those in the higher-risk groups. The STOP-RVF risk calculator exhibited a significantly better performance than commonly used risk scores proposed by Kormos et al (C statistic, 0.58; 95% CI, 0.53-0.63) and Drakos et al (C statistic, 0.62; 95% CI, 0.57-0.67). Conclusions and Relevance: Implementing routine clinical data, this multicenter cohort study derived and validated the STOP-RVF calculator as a personalized risk assessment tool for the prediction of RVF and RVF-associated all-cause mortality.

Effects of Extracorporeal Blood Flow Rates on Patient Tolerance for LIXELLE® Treatment during Outpatient Hemodialysis.

INTRODUCTION: Accumulation of ß2-microglobulin (B2M) in dialysis patients contributes to several comorbidities of end-stage kidney disease (ESKD). The LIXELLE® device adsorbs B2M from blood using sorbent bead technology. Studies in Japan showed that LIXELLE treatment during hemodialysis (HD) at blood flow rates up to 250 mL/min removes B2M above HD alone and is well tolerated. We investigated tolerance for LIXELLE treatment during HD at higher HD blood flow rates standard in the USA. METHODS: A prospective, open-label, non-randomized, single-arm, early-feasibility study (EFS) assessed tolerance and safety of LIXELLE treatment during HD at blood flow rates up to 450 mL/min. ESKD patients (40-75 years old) on thrice weekly outpatient HD were eligible. After a 1-week HD run-in, patients received LIXELLE plus HD at a blood flow rate of 250 mL/min (1 week), followed by LIXELLE plus HD at a blood flow rate up to 450 mL/min (1 week). These blood flow rates were tested with three LIXELLE column sizes in sequence (treatment = 6 weeks). B2M removal was assessed for each combination. RESULTS: Ten patients with a historic intradialytic hypotension (IDH) rate of 0.42 events/HD session/patient were enrolled. Nine patients completed all combinations without IDH events (treatment IDH rate: 0.56 events/HD session/patient). No treatment-emergent serious adverse events or significant changes in red blood cell, platelet, or complement indices except haptoglobin were reported. B2M reduction ratios and removal of select proteins (<40 kDa) increased with escalating column size and blood flow rate. CONCLUSION: LIXELLE plus HD across all column sizes was safe and well tolerated at blood flow rates up to 450 mL/min. Extent of B2M removal corresponded to column size-blood flow rate combinations. This EFS provides a risk profile to guide further studies of LIXELLE in ESKD patients at US-standard blood flow rates.

Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.

Mitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca2+, corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization.

The influence of continuous renal replacement therapy on 1,3-ß-d-glucan levels in critically ill patients: a single-center retrospective propensity score study.

1,3-ß-d-Glucan (BDG) is commonly used for diagnosing invasive fungal infections (IFIs). While exposure to cellulose-based hemodialyzers is known to cause false-positive BDG results, the impact of modern hemofilters used in continuous renal replacement therapy (CRRT) remains unclear. This retrospective, single-center cohort study aimed to evaluate the effect of CRRT on BDG levels in critically ill patients. We included adult intensive care unit (ICU) patients with ≥1 BDG measurement between December 2019 and December 2020. The primary outcome was the rate of false-positive BDG results in patients exposed to CRRT compared to unexposed patients. Propensity score analysis was performed to control for confounding factors. A total of 103 ICU patients with ≥1 BDG level were identified. Most (72.8%) were medical ICU patients. Forty patients underwent CRRT using hemofilter membranes composed of sodium methallyl sulfonate copolymer (AN 69 HF) (82.5%) and of polyarylethersulfone (PAES) (17.5%). Among the 91 patients without proven IFI, 31 (34.1%) had false-positive BDG results. Univariable analysis showed an association between CRRT exposure and false-positive BDG results. However, the association between CRRT exposure and false-positive BDG results was no longer significant across three propensity score models employed: 1:1 match (n = 32) (odds ratio (OR) 1.65, p = .48), model-adjusted (n = 91) (OR 1.75, p = .38), quintile-adjusted (n = 91) (OR 1.78, p = .36). In this single-center retrospective analysis, exposure to synthetic CRRT membranes did not independently increase the risk of false-positive BDG results. Larger prospective studies are needed to further evaluate the association between CRRT exposure and false-positive BDG results in critically ill patients with suspected IFI.