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Black patients face disparities in cancer outcomes. Additionally, Black patients are more likely to be undertreated and underrepresented in clinical trials. The recent recommendation to remove race from the estimated glomerular filtration rate (eGFR) results in lower eGFR values for Black patients. The ramifications of this decision, both intended and unintended, are still being elucidated in the medical community. Here, the authors analyze the removal of race from eGFR for Black patients with cancer, specifically with respect to clinical trial eligibility.In a cohort of self-identified Black patients who underwent nephrectomy at a tertiary referral center from 2009 to 2021 (n = 459), eGFR was calculated with and without race in commonly used equations (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease [MDRD]). The distribution of patients and changes within chronic kidney disease stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated on the basis of the utilization of the race coefficient.The median eGFR from CKD-EPI was significantly higher with race (76 ml/min/1.73 mRace-free renal function equations may inadvertently result in increased exclusion of Black patients from clinical trials. This is especially concerning because of the underrepresentation and undertreatment that Black patients already experience.Black patients experience worse oncologic outcomes and are underrepresented in clinical trials. Kidney function, as estimated by glomerular filtration rate equations, is a factor in who can and cannot be in a clinical trial. Race is a variable in some of these equations. For Black patients, removing race from these equations leads to the calculation of lower kidney function. Lower estimated kidney function may result in more black patients being excluded from clinical trials. The inclusion of all races in clinical trials is important for offering best care to everyone and for making results from clinical trials applicable to everyone.

NF-kB driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-kB tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic host phenotypic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate that TIGR4 both blunts and antagonizes NF-kB activation. We identified, through comparative mass spectrometry of the p65 interactome, that the 6B ST90 isolate drives a non-canonical NF-kB RelB cascade, whereas TIGR4 induces p65 degradation though aggrephagy. Mechanistically, we show that during TIGR4 challenge a novel interaction of COMMD2 with p65 and p62 is established to mediate degradation of p65. With these results, we establish a role for COMMD2 in negative NF-kB regulation, and present a paradigm for diverging NF-kB responses to pneumococcus. Thus, our studies reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 mediated turnover of p65.

Background In critically ill patients receiving kidney replacement therapy (KRT), high ultrafiltration rates and persistent fluid accumulation are associated with adverse outcomes. The purpose of this international survey was to evaluate current practices and evidence gaps related to fluid removal with KRT in critically ill patients. Methods This was a multinational, web-based survey distributed by 7 networks comprising nephrologists and intensivists. Physicians involved in the care of critically ill patients were invited to complete a 39 question survey about fluid-management practices on KRT. The survey was distributed from September 2021 to December 2021. Results There were 757 respondents from 96 countries (response rate of 65%). Most respondents practiced adult medicine (89%) and worked in an academic center (69%). The majority (91%) reported aiming for a 0.5 to 2 L negative fluid balance per day when fluid removal is indicated, although there was important variability in what respondents considered a safe maximal target. Intensivists were more likely than nephrologists to use adjunct volume status assessment methods (i.e. ultrasound, hemodynamic markers, intra-abdominal pressure) while nephrologists were more likely to deploy co-interventions aimed at improving tolerance to fluid removal (i.e. osmotic agents, low-temperature dialysate). There was a broad consensus that rapid decongestion should be prioritized when fluid accumulation is present, but the prevention of hypotension was also reported as a competing priority. A majority (77%) agreed that performing trials that compare fluid management strategies would be ethical and clinically relevant. Conclusions We have identified multiple areas of variability in current practice of fluid management for patients receiving KRT. The majority of nephrologists and intensivists agreed that several knowledge gaps related to fluid removal strategies should be investigated in future randomized controlled trials.

International audience; The obligate intracellular bacteria Chlamydia trachomatis obtain all nutrients from the cytoplasm of their epithelial host cells and stimulate glucose uptake by these cells. They even hijack host ATP, exerting a strong metabolic pressure on their host at the peak of the proliferative stage of their developmental cycle. However, it is largely unknown whether infection modulates the metabolism of the host cell. Also, the reliance of the bacteria on host metabolism might change during their progression through their biphasic developmental cycle. Herein, using primary epithelial cells and two cell lines of non-tumoral origin, we showed that between the two main ATP-producing pathways of the host, oxidative phosphorylation (OxPhos) remained stable and glycolysis was slightly increased. Inhibition of either pathway strongly reduced bacterial proliferation, implicating that optimal bacterial growth required both pathways to function at full capacity. While we found C. trachomatis displayed some degree of energetic autonomy in the synthesis of proteins expressed at the onset of infection, functional host glycolysis was necessary for the establishment of early inclusions, whereas OxPhos contributed less. These observations correlated with the relative contributions of the pathways in maintaining ATP levels in epithelial cells, with glycolysis contributing the most. Altogether, this work highlights the dependence of C. trachomatis on both host glycolysis and OxPhos for efficient bacterial replication. However, ATP consumption appears at equilibrium with the normal production capacity of the host and the bacteria, so that no major shift between these pathways is required to meet bacterial needs.

Critically ill patients who develop severe acute kidney injury in the intensive care unit often require treatment with renal replacement therapies (RRTs). This complication is associated with severe morbidity and mortality and high costs, both during hospitalization and postdischarge. This article discusses the operational requirements to develop and conduct a RRT program, as well as the financial implications of this complex form of patient care. The management of these programs must occur in a context where a clear organizational and educational framework and a multidisciplinary team ensures safety, effectiveness, cost-control, and a clear quality control framework.

Amidst the pandemic, geographical boundaries presented challenges to those in need of higher levels of care from referral centers. Authors sought to evaluate potential predictors of treatment success; assess our transport and remote cannulation process; and identify transport associated complications. Retrospective series of critically ill adults with COVID-19 transferred by our Extracorporeal Membrane Oxygenation (ECMO) team 24 March 2020 through 8 June 2021. Descriptive statistics and associated interquartile ranges (IQR) were used to summarize the data. Sixty-three patients with COVID associated acute respiratory distress syndrome (ARDS) requiring ECMO support were admitted to our ECMO center. Mean age was 44 years old (SD 12; IQR 36–56). 59% ( n = 37) of patients were male. Average body mass index was 39.7 (SD 11.3; IQR 31–48.5). Majority of patients (77.8%; n = 35) had severe ARDS. Predictors of treatment success were not observed. Transport distances ranged from 2.2 to 236 miles (median 22.5 miles; IQR 8.3–79); round trip times from 18 to 476 min (median 83 min; IQR 44–194) . No transport associated complications occurred. Median duration of ECMO support was 17 days (IQR 9.5–34.5). Length of stay in the Intensive Care Unit (median 36 days; IQR 17–49) and hospital (median 39 days; IQR 25–57) varied. Amongst those discharged, 60% survived.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional ‘surges’ in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI., COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and is an independent risk factor for all-cause in-hospital death in patients with COVID-19. This Consensus Statement from the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI and for areas of future research, with the aim of improving understanding of the underlying processes and outcomes for patients with COVID-19 AKI.

Summary: Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show that a natural colonizer, Streptococcus pneumoniae, induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10 (H3S10), during infection of respiratory epithelial cells. The bacterial pore-forming toxin pneumolysin (PLY), along with the pyruvate oxidase SpxB responsible for H2O2 production, play important roles in the induction of this modification. The combined effects of PLY and H2O2 trigger host signaling that culminates in H3S10 dephosphorylation, which is mediated by the host cell phosphatase PP1. Strikingly, S. pneumoniae infection induces dephosphorylation and subsequent activation of PP1 catalytic activity. Colonization of PP1 catalytically deficient cells results in impaired intracellular S. pneumoniae survival and infection. Interestingly, PP1 activation and H3S10 dephosphorylation are not restricted to S. pneumoniae and appear to be general epigenomic mechanisms favoring intracellular survival of pathogenic bacteria. : Dong et al. show that Streptococcus pneumoniae infection induces histone H3 dephosphorylation in lung epithelial cells, through two bacterial factors, PLY and SpxB. Infection-triggered activation of the host phosphatase PP1 is required for this histone modification and efficient intracellular infection. Keywords: histone modification, Streptococcus pneumoniae, H3S10 dephosphorylation, protein phosphatase 1, bacterial infection, pneumolysin, SpxB

611 Background: Race is no longer recommended in estimated glomerular filtration rate (eGFR) equations. The resulting lower eGFR may positively impact black patients, such as with earlier nephrology referral. However, the impact of race-free equations on black oncology patients–a cohort more likely to experience inferior cancer outcomes and underrepresentation in clinical trials–has not been fully examined. Here, we analyze removal of race from eGFR in black patients with cancer, specifically with regards to clinical trial eligibility. Methods: Self-identified black patients undergoing nephrectomy at a referral center from 2009-2021 were identified. Patients with end-stage renal disease were excluded. Using preoperative creatinine, height, and weight, eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation with and without race (CKD-EPI-WithRace; CKD-EPI-WithoutRace, respectively), and the Modification of Diet in Renal Disease equation with and without race (MDRD-WithRace; MDRD-WithoutRace, respectively). Distribution of patients and changes within CKD stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated based on utilization of the race coefficient. Subgroup analysis was completed on patients with stage III-IV disease only. Results: 459 self-identified black patients that underwent nephrectomy at our institution were identified, 135 of which had stage III-IV disease. On average, eGFR decreased around 10-13ml/min/1.73m2 with removal of the race coefficient (Table). 13-22%, 6-12%, and 2-3% more black patients would fall under common clinical trial cutoffs of 60, 45, or 30ml/min cutoffs, respectively, depending on the equation used (Table). Subanalysis of stage III-IV patients only were similar. Conclusions: Race free renal function equations may inadvertently result in increased exclusion of black patients from clinical trials. [Table: see text]

Background COVID-19 associated hyperviscosity is a potential driver for the increased rates of thrombotic complications and multi-organ failure associated with severe COVID-19. Limited experience suggests a promising role for Therapeutic Plasma Exchange (TPE) in COVID-19 management based on the hypothesis that clinical benefit is derived from reduction in plasma viscosity. However, systematic study evaluating the safety and efficacy of TPE in these patients has not been done. Objective To evaluate the safety and efficacy of TPE in a subset of critically ill patients with COVID-19 and elevated blood viscosity in a randomized controlled trial (RCT). Study Design and Methods This study was conducted in the intensive care units (ICUs) of 3 hospitals in our health system, with a limited initial enrollment target of 20 patients. Participants included adult COVID-19 patients with moderate elevation in plasma viscosity (2.3-3.5 centipoise) or significant hyperfibrinogenemia (>800 mg/dL) that were not improving despite standard supportive care. Patients with bacterial or fungal coinfection or moribund patients were specifically excluded. Upon enrollment, patients were randomized 1:1 to the treatment group (1 plasma volume TPE with frozen plasma (FP) replacement on 2 consecutive days) or control group (continued standard of care (SOC)). Primary measures included the safety/tolerability of TPE and change in plasma viscosity levels after TPE versus SOC. Secondary measures included evaluation of various clinical and laboratory parameters, including fibrinogen and other coagulation-related markers, mortality, bleeding and thromboembolic complications, ICU length of stay and time to discharge after enrollment. Results Preliminary analysis of collected data demonstrates that TPE is safe and well-tolerated in these patients, with adverse events limited to one mild occurrence of tachycardia that improved upon decreasing the flow rate. There was significant decrease in plasma viscosity in the TPE treatment group, compared to the SOC control group. Secondary measures of select laboratory parameters also show a significant decrease in fibrinogen, von Willebrand factor (vWF), Factor VIII, and erythrocyte sedimentation rate in the TPE treatment group. No significant differences were seen in levels of fibrin monomer, total IgG, total IgM, total protein, or total albumin between the two groups. Data collection and analysis for clinical parameters are ongoing. Conclusions and Relevance Here we report preliminary results suggesting that TPE is safe and effective for normalizing plasma viscosity in critically ill COVID-19 patients. Concomitant removal of large plasma proteins (fibrinogen, vWF) hints at their role in driving the increased viscosity associated with severe disease, which may contribute to clotting and end-organ damage in COVID-19. Based on lack of change in total IgG/IgM levels, TPE is not anticipated to hinder the patient’s humoral immunity by removing existing anti-SARS-CoV-2 specific antibodies. These results warrant further studies on the utility of TPE to mitigate critical illness in COVID-19 patients.

Mutations in mitochondrial genes impairing energy production lead to mitochondrial diseases (MD) and clinical studies have shown that MD patients are prone to bacterial infections. However, the relationship between mitochondrial (dys)function and infection remains largely unexplored, especially in epithelial cells, the first barrier to pathogens. We generated an epithelial cell model for one of the most common MD, Leigh syndrome by deleting SURF1, an assembly factor for the respiratory chain complex IV. We employed this genetic model and a complementary, nutrient-based approach to modulate mitochondrial respiration rates and show that impaired mitochondrial respiration favors entry of the human pathogen Listeria monocytogenes, a well-established bacterial infection model. Reversely, enhanced mitochondrial energy metabolism decreases infection efficiency. We further demonstrate that endocytic recycling is reduced in mitochondrial respiration-dependent cells, dampening L. monocytogenes infection by slowing down recycling of its host cell receptor c-Met, highlighting a previously undescribed role of mitochondrial respiration during infection.

Streptococcus pneumoniae is a natural colonizer of the human respiratory tract and an opportunistic pathogen. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show that a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive-disease-causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 and requires a histone demethylase KDM6B. We show, molecularly, that the interaction of the 6B strain with epithelial cells leads to chromatin remodelling within the IL-11 promoter in a KDM6B-dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 dimethyl. Remodelling of the IL-11 locus facilitates p65 access to three NF-κB sites that are otherwise inaccessible when stimulated by IL-1β or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B with GSK-J4 inhibitor and through exogenous addition of IL-11 that the host responses to the 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies therefore reveal how a chromatin modifier governs cellular responses during infection. A non-invasive Streptococcus pneumoniae strain induces a unique NF-κB signature response in epithelial cells that requires the histone demethylase KDM6B. Modulation of KDM6B can interchange the host response to non-invasive and invasive pneumococcal strains, demonstrating the biological role of KDM6B in cellular responses during infection.

Background Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID‐19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID‐19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID‐19‐associated hyperviscosity. Study Design and Methods Six critically ill COVID‐19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4‐1.8 cP) underwent daily TPE for 2‐3 treatments. Results TPE decreased plasma viscosity in all six patients (Pre‐TPE median 3.75 cP, range 2.6‐4.2 cP; Post‐TPE median 1.6 cP, range 1.5‐1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre‐TPE median 739 mg/dL, range 601‐1188 mg/dL; Post‐TPE median 359 mg/dL, range 235‐461 mg/dL); D‐dimer levels in all six patients (Pre‐TPE median 5921 ng/mL, range 1134‐60 000 ng/mL; Post‐TPE median 4893 ng/mL, range 620‐7518 ng/mL); and CRP levels in five of six patients (Pre‐TPE median 292 mg/L, range 136‐329 mg/L; Post‐TPE median 84 mg/L, range 31‐211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. Conclusions This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID‐19‐associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID‐19.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.

Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables a priori. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts.

As advances in Critical Care Medicine continue, critically ill patients are surviving despite the severity of their illness. The incidence of acute kidney injury (AKI) has increased, and its impact on clinical outcomes as well as medical expenditures has been established. The role, indications and technological advancements of renal replacement therapy (RRT) have evolved, allowing more effective therapies with less complications. With these changes, Critical Care Nephrology has become an established specialty, and ongoing collaborations between critical care physicians and nephrologist have improved education of multi-disciplinary team members and patient care in the ICU. Multidisciplinary programs to support these changes have been stablished in some hospitals to maximize the delivery of care, while other programs have continue to struggle in their ability to acquire the necessary resources to maximize outcomes, educate their staff, and develop quality initiatives to evaluate and drive improvements. Clearly, the role of the nephrologist in the ICU has evolved, and varies widely among institutions. This special article will provide insights that will hopefully optimize the role of the nephrologist as the leader of the acute care nephrology program, as clinician for critically ill patients, and as teacher for all members of the health care team.

For most American Society of Nephrology (ASN) Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire (NQ&Q) is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. This year

Fatty acid stress can have divergent effects in various cancers. We explored how metabolic and redox flexibility in HepG2 hepatocarcinoma cells mediates protection from palmitoylcarnitine. HepG2 cells, along with HCT 116 and HT29 colorectal cancer cells were incubated with 100 μM palmitoylcarnitine for up to 48 h. Mitochondrial H2O2 emission, glutathione, and cell survival were assessed in HT29 and HepG2 cells. 100 μM palmitoylcarnitine promoted early growth in HepG2 cells by ~8% after 48 h versus decreased cell survival observed in HT29 and HCT 116 cells. Palmitoylcarnitine increased mitochondrial respiration at physiological and maximal concentrations of ADP, while lowering cellular lactate content in HepG2 cells, suggesting a switch to mitochondrial metabolism. HepG2 cell growth was associated with an early increase in H2O2 emission by 10 min, followed by a decrease in H2O2 at 24 h that corresponded with increased glutathione content, suggesting a redox-based compensatory mechanism. In contrast, abrogation of HT29 cell proliferation was related to decreased mitochondrial respiration (likely due to cell death) and decreased glutathione. Concurrent glutathione depletion with BSO prevented palmitoylcarnitine-induced growth in HepG2 cells, indicating that glutathione was critical for promoting growth following palmitoylcarnitine. Inhibiting UCP2 with genipin sensitized HepG2 cells to palmitoylcarnitine, suggesting that activation of UCP2 may be a 2nd redox-based mechanism conferring protection. These findings suggest that HepG2 cells possess inherent metabolic and redox flexibility relative to HT29 cells that confers protection from palmitoylcarnitine-induced stress via adaptive increases in mitochondrial respiratory control, glutathione buffering, and induction of UCP2.

Streptococcus pneumoniaeis a natural colonizer of the human upper respiratory tract and an opportunistic pathogen. After colonization, bacteria either remain in the human upper respiratory tract, or may progress to cause pneumococcal disease. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show aS. pneumoniaeserotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive disease causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 (RelA) and requires a histone demethylase, KDM6B. At the molecular level, we show that interaction of the 6B strain with epithelial cells leads to chromatin remodeling within the IL-11 promoter in a KDM6B dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 di-methyl. Chromatin remodeling of the IL-11 locus facilitates p65 access to three NF-κB sites, which are otherwise inaccessible when stimulated by IL-1β or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B, with GSK-J4 inhibitor, and through exogenous addition of IL-11 that the host responses to 6B ST90 and TIGR4 strains can be interchanged bothin vitroand in a murine model of infectionin vivo. Our studies hereby reveal how a chromatin modifier governs cellular responses during infection.

Successful bacterial colonizers and pathogens have evolved with their hosts and have acquired mechanisms to customize essential processes that benefit their lifestyle. In large part, bacterial survival hinges on shaping the transcriptional signature of the host, a process regulated at the chromatin level. Modifications of chromatin, either on histone proteins or on DNA itself, are common targets during bacterium-host cross talk and are the focus of this article.

INTRODUCTION: Amongst COVID19 patients in the intensive care unit (ICU), acute kidney injury (AKI) occurs in 40-60% with 10-30% requiring renal replacement therapy (RRT) During any ICU surge situation, an increase in the total number of patients that will require RRT should be expected as the number of ICU patients increases This surge in RRT needs can quickly exhaust RRT machine availability During the pandemic, hospitals developed RRT surge contingency plans to maximize the number of patients who can receive RRT on a given day This may involve mixing modalities of therapy to include using CRRT machines to provide prolonged intermittent RRT (PIRRT) in a shift-based model However, implementing a machine allocation system to deploy RRT machines in the most efficient manner is a vexing challenge Automated strategies for machine allocation could aid staff in quickly developing daily RRT operational plans METHODS: Efficient routing of CRRT machines is analogous to an optimization routing problem, traditionally formulated with multiple vehicles picking up varying loads at each stop We reformulate the problem with CRRT machines as vehicles and patient needs as varying loads, with a maximum load of 24 patient-hours per day per machine, including transition time between patients RESULTS: Our solution, designed to be run daily, was written in Python 3 6 In conjunction with the primary team, nephrologists determine RRT durations based on patient need (6-12 hours vs 24 hours), generating a list of needs in the upcoming 24h period on a shared server If there is more RRT demand than capacity, nephrologists will be asked to reallocate required hours Next, we process CRRT machine locations with patient needs and locations The distance matrix preferentially routes machines between patients within units, then between closeby units, with preference given towards patients and units of similar COVID status to support cohorting The system then generates a sequence of patients that each machine should serve within minutes CONCLUSIONS: We report this as the first known implementation of automated scheduling for optimizing CRRT machine utilization given scarcity constraints from COVIDrelated surges Further characterization is necessary to quantify workload benefit and machine utilization

Background and objectives Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of β -lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT. Design, setting, participants, & measurements We conducted an institutional review board–approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one– and two–compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 μ g/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate. Results Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion. Conclusions Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

The molecular mechanisms behind the obesity-breast cancer association may be regulated via adipokine secretion by white adipose tissue. Specifically, adiponectin and leptin are altered with adiposity and exert antagonistic effects on cancer cell proliferation. We set out to determine whether altering adiposity in vivo via high fat diet (HFD) feeding changed the tumor growth supporting nature of adipose tissue and whether voluntary physical activity (PA) could ameliorate these HFD-dependent effects. We show that conditioned media (CM) created from the adipose tissue of HFD fed animals caused an increase in the proliferation of MCF7 cells compared with cells exposed to CM prepared from the adipose of lean chow diet fed counterparts. This increased proliferation was driven within the MCF7 cells by an HFD-dependent antagonism between AMP-activated protein kinase (AMPK) and protein kinase B (Akt) signaling pathways, decreasing p27 protein levels via reduced phosphorylation at T198 and downregulation of adiponectin receptor 1 (AdipoR1). PA can ameliorate these proliferative effects of HFD-CM on MCF7 cells, increasing p27(T198) by AMPK, reducing pAkt(T308), and increasing AdipoR1, resulting in cell cycle withdrawal in a manner that depends on the PA intensity. High physical activity (3 km/day) completely abolished the effects of HFD feeding. In addition, AdipoR1 overexpression mimics the effects of exercise, abolishing the proliferative effects of the HFD-CM on MCF7 cells and further enhancing the antiproliferative effects of PA on the HFD-CM. Thus voluntary PA represents a means to counteract the proliferative effects of adipose tissue on breast cancers in obese patients.

The substantial burden of acute kidney injury and end-stage kidney disease among patients with critical illness highlights the importance and need for a specialized nephrologist in the intensive care unit. The last decade has seen a growing interest in a career focused on critical care nephrology. However, the scope of practice and job satisfaction of those who completed dual training in nephrology and critical care are largely unknown. This article discusses the current practice landscape of critical care nephrology and describes the educational tracks available to pursue this pathway and considerations to enhance the future of this field.

The use of extracorporeal membrane oxygenation (ECMO) is increasing rapidly. Patients on ECMO have a high risk of developing acute kidney injury (AKI) and needing renal replacement therapy (RRT). The aim of this review is to describe different strategies of combining RRT and ECMO and to outline their advantages and drawbacks.Fluid overload is the most common indication for RRT during ECMO, and continuous renal replacement therapy (CRRT) is the most commonly used modality. The optimal timing for initiation of CRRT should be individualized based on degree of fluid overload and severity of AKI-related metabolic derangements. In ECMO patients, CRRT can be provided via an integrated approach (i.e. in-line haemofilter or a fully integrated CRRT device) or a parallel system with separate ECMO and RRT circuits. In-depth knowledge of the resulting intra-circuit pressure changes, risks of air entrapment and haemolysis, and implications for ultrafiltration and solute clearance are essential. There is no evidence that the different methods of combining ECMO and CRRT impact mortality.In patients on ECMO, CRRT can be provided via an integrated approach or independently via parallel systems. An in-depth understanding of the advantages and drawbacks of the different techniques is required.