Subclinical rejection after liver transplantation precludes immunosuppression withdrawal despite normal clinical function. To better understand the immunobiology of early subclinical rejection, we performed longitudinal, multimodal immune profiling and single-cell RNA sequencing (scRNA-seq) in adult living-donor recipients (n = 13) participating in an interventional immunosuppression withdrawal trial. Samples from patients with subclinical rejection (termed "nonpermissive") at 12 months posttransplant exhibited distinct immune trajectories from those with quiescent ("permissive") allografts despite comparable baseline profiles. Central to these distinct dynamics was biphasic Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-interferon signaling. Greater interferon-stimulated gene (ISG) expression and JAK-STAT activation occurred postreperfusion in permissive allograft recipients, which reversed at 12 months, when elevated ISG expression and JAK-STAT signaling were evident in nonpermissive recipients exhibiting subclinical rejection. We then leveraged our findings to ascertain whether a comparable signature existed in internal and external bulk RNA-seq and scRNA-seq liver transplant cohorts. Across cohorts, including a rodent model, there was a similar elevation in JAK-STAT signaling in instances of allograft rejection. We also detected distinct, portal-based phosphorylated STAT1 staining in a preliminary analysis of biopsies exhibiting histologic rejection compared with nonrejecting controls. Moreover, ruxolitinib-mediated JAK inhibition suppressed alloreactive CD8+ T cell proliferation and inflammatory-mediator production in vitro. Together, these exploratory findings suggest a temporal, biphasic role for JAK-STAT signaling in the regulation and occurrence of T cell-mediated rejection after liver transplant and highlight JAK inhibition as a potential therapeutic strategy.

Operational tolerance (OT) following complete immunosuppression withdrawal (ISW) is rare ( ~ 13%) in eligible adult liver transplant recipients when initiated 1-2-years post-transplant. Regulatory dendritic cells (DCregs) promote transplant tolerance in pre-clinical models and attenuate immune effector cells in humans. Here, we completed a first-in-human phase I/IIa trial (2-year recruitment; 5 ± 0.5 years follow-up) to evaluate the feasibility, safety and preliminary efficacy of pre-emptive donor-derived DCreg (ddDCreg) infusion 7-days pre-transplant in 15 prospective living-donor liver recipients. Two patients were excluded from analysis for reasons unrelated to the study. ISW began one year post-transplant in candidates with a quiescent/permissive protocol biopsy. ddDCreg infusions were safe, reproducible, and well-tolerated. One-year post-transplant, 8/13 patients were eligible for ISW, 4 achieved complete ISW, 3 remained off all immunosuppression for >1 year. These 3 remained drug-free for 3.0 ± 0.17-years, reflecting a 37.5% OT rate in ISW-eligible recipients. Given the exploratory nature of this trial, additional studies to evaluate efficacy are needed. ClinicalTrials.gov registration number NCT03164265.

Objective: To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Study Design: Term neonates with complex CHDs were recruited at Texas Children’s Hospital from 2005–2011. Ninety-five participants underwent three structural MRI scans and three neurodevelopmental assessments. Brain region volumes and white matter tract fractional anisotropy and radial diffusivity were used to calculate trajectories: perioperative, postsurgical, and overall. Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development and with the Wechsler Preschool and Primary Scale of Intelligence and Beery–Buktenica Developmental Test of Visual–Motor Integration. Multi-variable models incorporated risk factors. Results: Reduced overall period volumetric trajectories predicted poor language outcomes: brainstem ((β, 95% CI) 0.0977, 0.0382–0.1571; p = 0.0022) and white matter (0.0023, 0.0001–0.0046; p = 0.0397) at 5 years; brainstem (0.0711, 0.0157–0.1265; p = 0.0134) and deep grey matter (0.0085, 0.0011–0.0160; p = 0.0258) at 3 years. Maternal IQ was the strongest contributor to language variance, increasing from 37% at 1 year, 62% at 3 years, and 81% at 5 years. Genetic abnormality’s contribution to variance decreased from 41% at 1 year to 25% at 3 years and was insignificant at 5 years. Conclusion: Reduced postnatal subcortical–cerebral white matter trajectories predicted poor early childhood neurodevelopmental outcomes, despite high contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known cardiac and genetic factors in complex CHD, underscoring the importance of heritable and parent-based environmental factors.

IMPORTANCE:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has evolved through multiple phases in the United States, with significant differences in patient centered outcomes with improvements in hospital strain, medical countermeasures, and overall understanding of the disease. We describe how patient characteristics changed and care progressed over the various pandemic phases; we also emphasize the need for an ongoing clinical network to improve the understanding of known and novel respiratory viral diseases. OBJECTIVES:To describe how patient characteristics and care evolved across the various COVID-19 pandemic periods in those hospitalized with viral severe acute respiratory infection (SARI). DESIGN:Severe Acute Respiratory Infection-Preparedness (SARI-PREP) is a Centers for Disease Control and Prevention Foundation-funded, Society of Critical Care Medicine Discovery-housed, longitudinal multicenter cohort study of viral pneumonia. We defined SARI patients as those hospitalized with laboratory-confirmed respiratory viral infection and an acute syndrome of fever, cough, and radiographic infiltrates or hypoxemia. We collected patient-level data including demographic characteristics, comorbidities, acute physiologic measures, serum and respiratory specimens, therapeutics, and outcomes. Outcomes were described across four pandemic variant periods based on a SARS-CoV-2 sequenced subsample: pre-Delta, Delta, Omicron BA.1, and Omicron post-BA.1. SETTING:Multicenter cohort of adult patients admitted to an acute care ward or ICU from seven hospitals representing diverse geographic regions across the United States. PARTICIPANTS:Patients with SARI caused by infection with respiratory viruses. MAIN OUTCOMES AND RESULTS:Eight hundred seventy-four adult patients with SARI were enrolled at seven study hospitals between March 2020 and April 2023. Most patients (780, 89%) had SARS-CoV-2 infection. Across the COVID-19 cohort, median age was 60 years (interquartile range, 48.0-71.0 yr) and 66% were male. Almost half (430, 49%) of the study population belonged to underserved communities. Most patients (76.5%) were admitted to the ICU, 52.5% received mechanical ventilation, and observed hospital mortality was 25.5%. As the pandemic progressed, we observed decreases in ICU utilization (94% to 58%), hospital length of stay (median, 26.0 to 8.5 d), and hospital mortality (32% to 12%), while the number of comorbid conditions increased. CONCLUSIONS AND RELEVANCE:We describe increasing comorbidities but improved outcomes across pandemic variant periods, in the setting of multiple factors, including evolving care delivery, countermeasures, and viral variants. An understanding of patient-level factors may inform treatment options for subsequent variants and future novel pathogens.

Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined. Here, we assessed the phenotypic, functional, and transcriptomic profiles of peripheral blood CD8(+)/CD4(+) T cells, including EBV-specific T cells, in 77 pediatric heart, kidney, and liver Tx recipients and established the relationship between memory differentiation and progression toward exhaustion. Unlike kidney and liver HVL carriers, heart HVL carriers displayed distinct CD8(+) T cells with (1) up-regulation of interleukin-21R, (2) decreased naive phenotype and altered memory differentiation, (3) accumulation of terminally exhausted (TEX PD-1(+)T-bet-Eomes(+)) and decrease of functional precursors of exhausted (TPEX PD-1(int)T-bet(+)) effector subsets, and (4) transcriptomic signatures supporting the phenotypic changes. In addition, CD4(+) T cells from heart HVL carriers displayed similar changes in naive and memory subsets, elevated Th1 follicular helper cells, and plasma interleukin-21, suggesting an alternative inflammatory mechanism that governs T cell responses in heart Tx recipients. These results may explain the different incidences of EBV complications and may help improve the risk stratification and clinical management of different types of Tx recipients.

OBJECTIVES: The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN: Prospective weekly hospital stress survey, November 2020–June 2022. SETTING: Society of Critical Care Medicine’s Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS: Thirteen hospitals across seven U.S. health systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% (sd, 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5–12%), 7% (3–10%), and 4% (2–6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9–14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6–14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5–6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS: During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.

Background: Malignant mesothelioma is associated with environmental and occupational exposure to certain mineral fibers, especially asbestos. This study aims to examine work histories of mesothelioma patients and their survival time. Method: Using the NIOSH Industry and Occupation Computerized Coding System, we mapped occupations and industries recorded for 748 of 1444 patients in the U.S. National Mesothelioma Virtual Bank (NMVB) during the period 2006-2022. Descriptive and survival analyses were conducted. Results: Among the 1023 industries recorded for those having mesothelioma, the most frequent cases were found for those in manufacturing (n = 225, 22.0%), construction (138, 13.5%), and education services (66, 6.5%); among the 924 occupation records, the most frequent cases were found for those in construction and extraction (174, 18.8%), production (145, 15.7%), and management (84, 9.1%). Males (583) or persons aged >40 years (658) at the time of diagnosis tended to have worked in industries traditionally associated with mesothelioma (e. g., construction), while females (163) or persons aged 20-40 years (27) tended to have worked in industries not traditionally associated with mesothelioma (e.g., health care). Asbestos, unknown substances, and chemical solvents were the most frequently reported exposure, with females most often reporting an unknown substance. A multi-variable Cox Hazard Regression analysis showed that significant prognostic factors associated with decreased survival in mesothelioma cases are sex (male) and work experience in utility-related industry, while factor associated with increased survival are epithelial or epithelioid histological type, prior history of surgery and immunotherapy, and industry experience in accommodation and food services. Conclusion: The NMVB has the potential of serving as a sentinel surveillance mechanism for identifying industries and occupations not traditionally associated with mesothelioma. Results indicate the importance of considering all potential sources of asbestos exposures including occupational, environmental, and extra-occupational ex-posures when evaluating mesothelioma patients and advising family members.

CCR Translation for This Article from Serum Biomarker Panels for the Detection of Pancreatic Cancer

Importance Congenital heart disease (CHD), especially the complex forms – such as hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA) – have been linked to neurodevelopmental deficits including impairments in gross cognitive functions, language abilities, and visuo-motor skills. The prognostic value of early infant brain trajectories and cumulative impact of demographic factors in relation to childhood neurodevelopmental outcomes is unknown. Objective To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Design, Setting, and Participants We studied a prospective cohort study of term neonates with complex CHD (TGA and HLHS) were recruited at Texas Children’s Hospital between 2005-2011. Participants underwent structural MRI scans at three time points (one preoperative scan, one postoperative scan within 7 days of surgery, and one follow-up postoperative scan at 4 months). Participants also received three neurodevelopmental assessments at 1, 3, and 5 years of age. Main Outcomes and Measures Brain region volumes (macrostructure) and white matter tract (microstructure) fractional anisotropy (FA) and radial diffusivity (RD) were measured from the MRI scans acquired in the three neonatal time points. Three imaging trajectories – changes in volume, FA and RD, over time – corresponding to periods of brain changes were determined: perioperative (preoperative to postoperative #1), post-surgical (postoperative #1 to postoperative #2), and overall (preoperative #1 to postoperative #2). Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 1 and 3 years, and with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III Full-Scale IQ and Verbal IQ, and Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI)., 6th Edition at 5 years. The analysis included development of predictive multi-variable models incorporating other known risk factors (i.e., heart lesion type, microdeletion-related genetic abnormality, and maternal IQ) of poor neurodevelopmental outcomes in CHD. Results A total of 95 term (38.5±1.3 weeks gestational age) neonates with complex CHD (49 [51.6%] HLHS, 46 [48.4%] TGA; 42 [44.2%] girls) were analyzed. Reduced overall period trajectories predicted poor language outcomes: brainstem (p=0.0022) and white matter (p=0.0397) predicted poor 5-year verbal IQ; brainstem (p=0.0134), deep grey (p=0.0258), and FA of superior longitudinal fasciculus (SLF) (p=0.0256) predicted poor 3-year language; whole brain volume predicted poor performance on measures of language at 1 year. Maternal IQ was the strongest contributor to language outcome variance that increased from 37% at 1-year, up to 62% at 3-year, and up to 81% at 5-year testing. Genetic abnormality contribution to variance in these same models decreased from 41% in 1-year to about 25% at 3-year, and then to not significant in the 5-year assessments. Heart lesion type was found to be not significant in predicting outcomes in these models. Conclusion and Relevance A dysmaturation pattern of reduced postnatal trajectories of subcortical-cerebral white matter MRI metrics predicted poor early childhood neurodevelopmental outcomes, despite the high relative contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of both heritable factors and parent-based environmental factors. Question Do early infant brain trajectories in congenital heart disease (CHD) patients predict early childhood neurodevelopmental (ND) outcomes adjusted for known genetic abnormalities and maternal intelligence (IQ)? Findings Among infants with, reduced brainstem and white matter volumetric trajectories in children with CHD predicted language outcomes at five years, adjusting for maternal IQ and known genetic abnormalities. At the same time, known genetic abnormalities exerted a maximum effect at 1-year relative to 5-year neurodevelopmental testing. Maternal IQ was the most substantial contributor to ND outcome variance, nearly doubling from 1-year relative to 5-year time points. Meaning Postnatal infant brain trajectories may aid in the prognostication of early childhood neurodevelopment outcomes in complex CHD. The influence of maternal IQ is cumulative and can exceed the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of not only heritable factors but also parent-based environmental factors. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding was provided by the National Heart, Lung, and Blood Institute (R01 HL152740-1, R01 HL128818-05). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol, including all clinical data collection, acquisition of MRI data under sedation, and neurodevelopmental outcomes testing of subjects and maternal IQ testing was approved by the Baylor College of Medicine Institutional Review Board, and written informed parental consent was obtained. Written informed consent was obtained from a parent under Baylor College of Medicine IRB Protocols H-18531 and H-17115. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

BACKGROUND: Multifocal hepatocellular carcinoma (HCC) differs biologically and immunologically from single-nodule HCC. Asian and European guidelines consider liver transplantation (LT) and partial hepatectomy (PH) as effective for T2 multifocal HCC, with preference toward LT, but few US studies compare these treatments directly. This propensity score–based observational study uses an established national cancer outcomes registry to compare overall survival in patients undergoing PH and LT for multifocal HCC. STUDY DESIGN: Data from the 2020 National Cancer Database were obtained on patients who underwent LT or PH for multifocal stage 2 HCC within Milan criteria and without vascular invasion. Propensity score matching and Cox regression analysis was applied to evaluate overall survival in an observational cohort balanced by age, sex, treatment facility type, treatment year, prothrombin time, α-fetoprotein, comorbidity burden, liver fibrosis severity, and pretreatment creatinine and bilirubin levels. RESULTS: Of 21,248 T2 HCC patients identified, 6,744 had multifocal tumors with largest tumor diameter <3 cm without major vascular invasion, with 1,267 and 181 having undergone LT and PH, respectively. Propensity score–matched Cox regression analysis associated LT with a hazard ratio of 0.39 (95% CI 0.30 to 0.50) relative to PH. Landmark analyses to account for a longer interval to LT demonstrated survival benefits of similar magnitude. CONCLUSIONS: Although early-stage HCC can be effectively treated with either LT or PH, propensity score–matched analysis comparatively shows a survival benefit for LT in patients with multifocal HCC who are within the Milan criteria.

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Immune cell–based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet + Eomes + CD8 + T cells and CD16 bright natural killer (NK) cells and an increase in putative tolerogenic CD141 + CD163 + DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ + (IFN-γ + ) CD4 + and CD8 + T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8 + T cells, as well as attenuation of cytolytic T H 1 effector genes and pathways among intragraft CD8 + T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.

This article describes the use of prognostic, predictive, and response biomarkers that have been developed for autosomal dominant polycystic kidney disease and their use in clinical care or drug development. We focus on biochemical markers that can be assayed in patients' blood and urine and their association with the outcome of decreased glomerular filtration rate. There have been several studies on prognostic biomarkers. The most promising ones have been markers of tubular injury, inflammation, metabolism, or the vasopressin-urinary concentration axis. So far, none have been shown to be superior to kidney volume-based biomarkers. Several biomarkers are additive to kidney volume and genotype in prognostic models, but there have been few direct comparisons between the biochemical markers to identify the best ones. Moreover, there is a lack of uniformity in the statistical tools used to assess and compare biomarkers. There have been few reports of predictive and response biomarkers, and none are suitable surrogate endpoints. The U.S. Food and Drug Administration's Biomarker Qualification Program provides a regulatory pathway to approve biomarkers for use across multiple drug-development programs.

Journal Article Use of kidney injury molecule-1 for sepsis-associated acute kidney injury staging Get access Luca Molinari, Luca Molinari Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Translational Medicine, Università del Piemonte Orientale, Novara, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Douglas P Landsittel, Douglas P Landsittel Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar John A Kellum, John A Kellum Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Correspondence to: John A. Kellum; E-mail: kellum@pitt.edu Search for other works by this author on: Oxford Academic PubMed Google Scholar for the ProCESS and ProGReSS-AKI Investigators* for the ProCESS and ProGReSS-AKI Investigators* Search for other works by this author on: Oxford Academic PubMed Google Scholar Nephrology Dialysis Transplantation, Volume 38, Issue 6, June 2023, Pages 1560–1563, https://doi.org/10.1093/ndt/gfad004 Published: 16 January 2023 Article history Received: 30 August 2022 Published: 16 January 2023 Corrected and typeset: 22 March 2023

It is increasingly assumed that there is no one-size-fits-all approach to dietary recommendations for the management and treatment of chronic diseases such as obesity. This phenomenon that not all individuals respond uniformly to a given treatment has become an area of research interest given the rise of personalized and precision medicine. To conduct, interpret, and disseminate this research rigorously and with scientific accuracy, however, requires an understanding of treatment response heterogeneity. Here, we define treatment response heterogeneity as it relates to clinical trials, provide statistical guidance for measuring treatment response heterogeneity, and highlight study designs that can quantify treatment response heterogeneity in nutrition and obesity research. Our goal is to educate nutrition and obesity researchers in how to correctly identify and consider treatment response heterogeneity when analyzing data and interpreting results, leading to rigorous and accurate advancements in the field of personalized medicine.

IMPORTANCE:. Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES:. To assess the role of ANGPTL4 in COVID-19–related outcomes. DESIGN, SETTING, AND PARTICIPANTS:. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES:. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS:. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17–2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10–5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE:. ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.