From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations For Developing Precision Medicine in ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. In order to impact clinical care, identified subpopulations must do more than differentiate prognosis. They must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Corticosteroids for infectious critical illness: A multicenter target trial emulation stratified by predicted organ dysfunction trajectory.

Corticosteroids decrease the duration of organ dysfunction in a range of infectious critical illnesses, but their risk and benefit are not fully defined using this construct. This retrospective multicenter study aimed to evaluate the association between usage of corticosteroids and mortality of patients with infectious critical illness by emulating a target trial framework. The study employed a novel stratification method with predictive machine learning (ML) subphenotyping based on organ dysfunction trajectory. Our analysis revealed that corticosteroids' effectiveness varied depending on the stratification method. The ML-based approach identified four distinct subphenotypes, two of which had a large enough sample size in our patient cohorts for further evaluation: "Rapidly Improving" (RI) and "Rapidly Worsening," (RW) which showed divergent responses to corticosteroid treatment. Specifically, the RW group either benefited or were not harmed from corticosteroids, whereas the RI group appeared to derive harm. In the development cohort, which comprised of a combination of patients from the eICU and MIMIC-IV datasets, hazard ratio estimates for the primary outcome, 28-day mortality, in the RW group was 1.05 (95% CI: 0.96 - 1.04) whereas for the RW group, it was 1.40 (95% CI: 1.28 - 1.54). For the validation cohort, which comprised of patients from the Critical carE Database for Advanced Research, estimates for 28-day mortality for the RW and RI groups were 1.24 (95% CI: 1.05 - 1.46) and 1.34 (95% CI: 1.14 - 1.59), respectively. For secondary outcomes, the RW group had a shorter time to ICU discharge and time to cessation of mechanical ventilation with corticosteroid treatment, where the RI group again demonstrated harm. The findings support matching treatment strategies to empirically observed pathobiology and offer a more nuanced understanding of corticosteroid utility. Our results have implications for the design and interpretation of both observational studies and randomized controlled trials (RCTs), suggesting the need for stratification methods that account for the differential response to standard of care.

Sepsis subphenotyping based on organ dysfunction trajectory.

BACKGROUND: Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis. METHODS: We created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies. RESULTS: A total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers. CONCLUSIONS: Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.

Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells.

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence. Here, we evaluate the therapeutic effect of CO on metastatic cancer progression. We show that 250 ppm CO inhibits the migration of multiple types of cancer cell lines, including breast, pancreatic, colon, prostate, liver, and lung cancer and reduces the ability to adhere to fibronectin. We demonstrate that in mouse models, 250 ppm inhaled CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer. Moreover, low-dose CO suppresses recurrence and increases survival after surgical removal of primary pancreatic cancer in mice. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Taken together, low-dose CO therapy inhibits cell migration, reduces adhesion to fibronectin, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis.

Conditional deletion of myeloid-specific mitofusin 2 but not mitofusin 1 promotes kidney fibrosis.

Macrophages exert critical functions during kidney injury, inflammation, and tissue repair or fibrosis. Mitochondrial structural and functional aberrations due to an imbalance in mitochondrial fusion/fission processes are implicated in the pathogenesis of chronic kidney disease. Therefore, we investigated macrophage-specific functions of mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2, in modulating macrophage mitochondrial dynamics, biogenesis, oxidative stress, polarization, and fibrotic response. MFN1 and MFN2 were found to be suppressed in mice after adenine diet-induced chronic kidney disease, in transforming growth factor-beta 1-treated bone marrow-derived macrophages, and in THP-1-derived human macrophages (a human leukemic cell line). However, abrogating Mfn2 but not Mfn1 in myeloid-lineage cells resulted in greater macrophage recruitment into the kidney during fibrosis and the macrophage-derived fibrotic response associated with collagen deposition culminating in worsening kidney function. Myeloid-specific Mfn1 /Mfn2 double knockout mice also showed increased adenine-induced fibrosis. Mfn2-deficient bone marrow-derived macrophages displayed enhanced polarization towards the profibrotic/M2 phenotype and impaired mitochondrial biogenesis. Macrophages in the kidney of Mfn2-deficient and double knockout but not Mfn1-deficient mice exhibited greater mitochondrial mass, size, oxidative stress and lower mitophagy under fibrotic conditions than the macrophages in the kidney of wild-type mice. Thus, downregulation of MFN2 but not MFN1 lead to macrophage polarization towards a profibrotic phenotype to promote kidney fibrosis through a mechanism involving suppression of macrophage mitophagy and dysfunctional mitochondrial dynamics.

Sepsis-Induced Immunosuppression.

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy.

Early Aseptic Loosening with Increased Presence and Severity of Backside Burnishing in the Optetrak Logic Posterior-Stabilized Total Knee Arthroplasty Femoral Component.

Concerns persist that the Optetrak Logic posterior-stabilized (PS) total knee arthroplasty (TKA) femoral component might correlate with early failures due to aseptic loosening. The primary aim of this study was to examine if the use of the Optetrak Logic PS femoral component is associated with early (<5 years) and more extensive aseptic loosening compared with other PS femoral components. This is a single-institution retrieval analysis and revision registry study (based on prospectively collected data) of 27 failed primary PS TKA patients with loose femoral components that underwent revision TKAs between 2016 and 2019. Patients were stratified by components type: Group A (n = 16) received the Optetrak Logic PS femoral component, while Group B (n = 11) received other PS femoral components. Burnishing (macroscopic polishing of the component's backside) was observed and graded as a marker for relative motion at the cement-implant interface. No significant differences were found between the two groups regarding the baseline demographic, radiographic, and clinical characteristics. Mean length of implantation for Group A (3.8 ± 2.9 years) was significantly shorter (p < 0.001) than that of Group B (12.0 ± 6.7 years). A significant difference (p = 0.009) was found in presence of backside femoral burnishing between Group A (15 of 16 patients; 93.8%) and group B (5 of 11 patients; 45.6%). Furthermore, we found a significant difference (p < 0.001) in the severity of burnishing between Group A (13 of 16 patients with severe degree of burnishing; 81.3%) and Group B (1 of 11 patients with severe degree of burnishing; 9.1%). In contrast to Group B, a distinctive macroscopic pattern found in Logic retrieved femoral components (Group A) was the total absence of cement in the backside surface. The use of the Optetrak Logic PS TKA femoral component was associated with early aseptic loosening and increased presence and severity of backside burnishing with early cement-implant interface debonding compared with other commercially available types of PS TKA femoral components. The earlier failure rate with this implant is of concern.

Identifying organ dysfunction trajectory-based subphenotypes in critically ill patients with COVID-19.

COVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology. Sequential Organ Failure Assessment (SOFA) score is an objective and comprehensive measurement that measures dysfunction severity of six organ systems, i.e., cardiovascular, central nervous system, coagulation, liver, renal, and respiration. Our aim was to identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of SOFA score. Intubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Distinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p = 0.033; intermediate stratum, 29.3% vs. 8.0%, p = 0.002; severe stratum, 53.7% vs. 22.2%, p < 0.001). Pathophysiologic biomarkers associated with progression were distinct at each stratum, including findings suggestive of inflammation in low baseline severity of illness versus hemophagocytic lymphohistiocytosis in higher baseline severity of illness. The findings suggest that there are clear worsening and recovering subphenotypes of COVID-19 respiratory failure after intubation, which are more predictive of outcomes than baseline severity of illness. Distinct progression biomarkers at differential baseline severity of illness suggests a heterogeneous pathobiology in the progression of COVID-19 respiratory failure.

How Does Contact Length Impact Titanium Tapered Splined Stem Stability: A Biomechanical Matched Pair Cadaveric Study.

BACKGROUND: Titanium tapered stems (TTS) achieve fixation in the femoral diaphysis and are commonly used in revision total hip arthroplasty. The initial stability of a TTS is critical, but the minimum contact length needed and impact of implant-specific taper angles on axial stability are unknown. This biomechanical study was performed to better guide operative decision-making by addressing these clinical questions. METHODS: Two TTS with varying conical taper angles (2° spline taper vs 3.5° spline taper) were implanted in 9 right and left matched fresh human femora. The proximal femur was removed, and the remaining femoral diaphysis was prepared to allow for either a 2 cm (n = 6), 3 cm (n = 6), or 4 cm (n = 6) cortical contact length with each implanted stem. Stepwise axial load was then applied to a maximum of 2600N or until the femur fractured. Failure was defined as either subsidence >5 mm or femur fracture. RESULTS: All 6 femora with 2 cm of stem-cortical contact length failed axial testing, a significantly higher failure rate (P < .02) than the 4 out of 6 femora and all 6 femora that passed testing at 3 cm and 4 cm, respectively, which were not statistically different from each other (P = .12). Taper angle did not influence success rates, as each matched pair either succeeded or failed at the tested contact length. CONCLUSION: 4 cm of cortical contact length with a TTS demonstrates reliable initial axial stability, while 2 cm is insufficient regardless of taper angle. For 3 cm of cortical contact, successful initial fixation can be achieved in most cases with both taper angle designs.

Attributable mortality of acute respiratory distress syndrome: a systematic review, meta-analysis and survival analysis using targeted minimum loss-based estimation.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS. OBJECTIVE: To estimate the attributable mortality, if any, of ARDS. DESIGN: First, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method. RESULTS: In the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; p<0.001) with a numerically stronger association between ARDS and mortality in trauma than sepsis. In the survival analysis of three ICU cohorts enrolling 1203 critically ill patients, 658 septic patients were included. After controlling for confounders, ARDS was found to increase the mortality rate by 15% (95% CI 3% to 26%; p=0.015). Significant increases in mortality were seen for severe (23%, 95% CI 3% to 44%; p=0.028) and moderate (16%, 95% CI 2% to 31%; p=0.031), but not for mild ARDS. CONCLUSIONS: ARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit. PROSPERO REGISTRATION NUMBER: CRD42017078313.

A Comparative Analysis of the Respiratory Subscore of the Sequential Organ Failure Assessment Scoring System.

Rationale: The Sequential Organ Failure Assessment (SOFA) tool is a commonly used measure of illness severity. Calculation of the respiratory subscore of SOFA is frequently limited by missing arterial oxygen pressure (PaO2) data. Although missing PaO2 data are commonly replaced with normal values, the performance of different methods of substituting PaO2 for SOFA calculation is unclear. Objectives: The study objective was to compare the performance of different substitution strategies for missing PaO2 data for SOFA score calculation. Methods: This retrospective cohort study was performed using the Weill Cornell Critical Care Database for Advanced Research from a tertiary care hospital in the United States. All adult patients admitted to an intensive care unit (ICU) from 2011 to 2019 with an available respiratory SOFA score were included. We analyzed the availability of the PaO2/fraction of inspired oxygen (FiO2) ratio on the first day of ICU admission. In those without a PaO2/FiO2 ratio available, the ratio of oxygen saturation as measured by pulse oximetry to FiO2 was used to calculate a respiratory SOFA subscore according to four methods (linear substitution [Rice], nonlinear substitution [Severinghaus], modified respiratory SOFA, and multiple imputation by chained equations [MICE]) as well as the missing-as-normal technique. We then compared how well the different total SOFA scores discriminated in-hospital mortality. We performed several subgroup and sensitivity analyses. Results: We identified 35,260 unique visits, of which 9,172 included predominant respiratory failure. PaO2 data were available for 14,939 (47%). The area under the receiver operating characteristic curve for each substitution technique for discriminating in-hospital mortality was higher than that for the missing-as-normal technique (0.78 [0.77-0.79]) in all analyses (modified, 0.80 [0.79-0.81]; Rice, 0.80 [0.79-0.81]; Severinghaus, 0.80 [0.79-0.81]; and MICE, 0.80 [0.79-0.81]) (P < 0.01). Each substitution method had a higher accuracy for discriminating in-hospital mortality (MICE, 0.67; Rice, 0.67; modified, 0.66; and Severinghaus, 0.66) than the missing-as-normal technique. Model calibration for in-hospital mortality was less precise for the missing-as-normal technique than for the other substitution techniques at the lower range of SOFA and among the subgroups. Conclusions: Using physiologic and statistical substitution methods improved the total SOFA score's ability to discriminate mortality compared with the missing-as-normal technique. Treating missing data as normal may result in underreporting the severity of illness compared with using substitution. The simplicity of a direct oxygen saturation as measured by pulse oximetry/FiO2 ratio-modified SOFA technique makes it an attractive choice for electronic health record-based research. This knowledge can inform comparisons of severity of illness across studies that used different techniques.

Rapid Transition of a PICU Space and Staff to Adult Coronavirus Disease 2019 ICU Care.

OBJECTIVES: We describe the process by which a PICU and a PICU care team were incorporated into a hospital-wide ICU care model during the coronavirus disease 2019 pandemic. DESIGN: A descriptive, retrospective report from a single-center PICU. SETTING: Twenty-three bed, quaternary PICU, within an 862-bed hospital. PATIENTS: Critically ill adults, with coronavirus disease 2019-related disease. INTERVENTIONS: ICU care provided by pediatric intensivists with training and support from medical intensivists. MEASUREMENTS AND MAIN RESULTS: Within the context of the institution's comprehensive effort to centralize and systematize care for adults with severe coronavirus disease 2019 disease, the PICU was transitioned to an adult coronavirus disease 2019 critical care unit. Nurses and physicians underwent just-in-time training over 3 days and 2 weeks, respectively. Medical ICU physicians and nurses provided oversight for care and designated hospital-based teams were available for procedures and common adult emergencies. Over a 7-week period, the PICU cared for 60 adults with coronavirus disease 2019-related critical illness. Fifty-three required intubation and mechanical ventilation for a median of 18 days. Eighteen required renal replacement therapy and 17 died. CONCLUSIONS: During the current and potentially in future pandemics, where critical care resources are limited, pediatric intensivists and staff can be readily utilized to meaningfully contribute to the care of critically ill adults.

Patient Rights at the End of Life: The Ethics of Aid-in-Dying.

PURPOSE/OBJECTIVES: The end-of-life needs and desires of patients, whether it is related to a terminal illness or age-related end-of-life physiological function, can vary from patient to patient. Each dying patient's case should be approached in an individual and patient-centered fashion while supporting the dying patient's desired preferences related to end-of-life treatment. This serves to recognize the dying patient's individual rights related to self-determination of preserving his or her dignity during the end-of-life process. As the U.S. population continues to age at the fastest pace in history, it is vital for end-of-life patients and their family members, health care providers, and lawmakers to consider how health policy can drive legislation that supports the dying patient's right to express his or her dignity and own end-of-life desires related to aid-in-dying by allowing health care providers to legally provide physician-assisted health (PAD) and death with dignity (DD) the end-of-life care dying patients prefer. PRIMARY PRACTICE SETTING(S): Palliative, hospice, and long-term care. FINDINGS/CONCLUSIONS: When state laws do not support a terminally ill person's ability to make his or her own end-of-life decisions based on his or her own preferences and desires related to PAD and dignity in dying, there can be moral conflictions with the existing ethical principles that can contribute to additional distress and anxiety in the terminally ill patient. Not allowing the terminally ill patient the legal right to choose his or her preferences and desires at the end of life goes against the freedom of the patient to choose. The aging population is growing quickly, and people are living longer, which means the frail elderly in their final stages of death due to multisystem organ failure might also desire to have the option of PAD that supports dignity in dying. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Case managers are an instrumental and integral part of the end-of-life care team. They are held to the same standard of practice as clinical care providers when it comes to promoting the biomedical ethical points autonomy, beneficence, nonmaleficence, justice, and fidelity. Following these ethical principles is critical for case managers to consider when supporting the desires and preferences of terminally ill patients. Case managers should be involved in all the patient-centered decision making for a terminally ill patient's desire for DD and PAD. It is critical for case managers to follow their organization's defined code of professional conduct as well their specific professional organization and professional certifying body's defined code of ethics and conduct despite their personal convictions.

No Difference in Force Required for Intraprosthetic Dislocation of Mixed Manufacturer vs Same Manufacturer Dual Mobility Articulations.

BACKGROUND: To avoid the morbidity of removing well-fixed implants during revision surgery, the off-label practice of mixing femoral heads with dual mobility (DM) polyethylene liners from different manufacturers is commonly performed. The resistance to intraprosthetic dislocation, when the inner prosthetic head disengages from the polyethylene bearing, between mixed and same manufacturer constructs remains unknown. METHODS: Between January 2010 and July 2018, 168 DM liners were retrieved. Specimens were excluded for catastrophic wear (n = 14), previously levered-out (n = 17), and cases in legal proceedings (n = 8). Using a validated setup, 129 specimens were uniaxially loaded 100 mm from the femoral head until lever-out failure of the head from the liner. The difference in maximum lever-out force (LOF) was compared for same and mixed manufacturer retrievals (Student t-test). Multivariable regression analysis evaluated the influence of potential confounders (length of implantation, head size, head material, presence of skirt) on LOF. RESULTS: Ninety-seven same and 32 mixed manufacturer DM constructs were tested. The average LOF for same (272.6 ± 68.7 N) and mixed (299.2 ± 89.0 N) manufacturer specimens was not significantly different (P = .08). An inner head size of 22.2 mm was associated with 184.4-N increase in LOF (P < .001), the presence of a skirt was associated with 63.8-N increase in maximum LOF, and head material (ceramic vs metal) did not influence LOF. CONCLUSION: We found no difference in the force required to lever-out same and mixed manufacturer inner heads from DM liners, suggesting that mixing manufacturers when placing DM articulations on well-fixed femoral stems should not increase the risk of intraprosthetic instability.

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis.

Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-ß1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-ß1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity.

The prevalence of obesity is rising worldwide and obese patients comprise a specific population in the intensive care unit. Acute respiratory distress syndrome (ARDS) incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the features of ARDS. In this report, we demonstrate that high fat diet induced obesity increases the severity of hyperoxic acute lung injury in mice in part by altering fatty acid synthase (FASN) levels in the lung. Obese mice exposed to hyperoxia had significantly reduced survival and increased lung damage. Transcriptomic analysis of lung homogenates identified Fasn as one of the most significantly altered mitochondrial associated genes in mice receiving 60% compared to 10% fat diet. FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. Depletion of FASN in type II alveolar epithelial cells resulted in altered mitochondrial bioenergetics and more severe lung injury with hyperoxic exposure, even upon the administration of a 60% fat diet. This is the first study to show that a high fat diet leads to altered FASN expression in the lung and that both a high fat diet and reduced FASN expression in alveolar epithelial cells promote lung injury.

Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials.

BACKGROUND: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it. METHODS: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao2 to Fio2 ratio (Pao2:Fio2) > 300 on the first study day following enrollment. RESULTS: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao2:Fio2 at screening, change in Pao2:Fio2 from screening to enrollment, use of vasopressor agents, Fio2 at enrollment, and serum bilirubin levels were useful predictive variables. CONCLUSIONS: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials.