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Purpose: During the third-year emergency medicine (EM) clerkship, medical students are immersed in traumatic incidents with their patients and clinical teams. Trauma-informed medical education (TIME) applies trauma-informed care (TIC) principles to help students manage trauma. We aimed to qualitatively describe the extent to which students perceived the six TIME domains as they navigated critical incidents during their EM clerkship.Methods: We employed a constructivist, modified grounded theory approach to explore medical students’ experiences. We used the critical incident technique to elicit narratives to better understand the six TIME domains as they naturally appear in the clerkship. Participants were asked to describe a traumatic incident they experienced during the clerkship, followed by the clerkship’s role in helping them manage the incident. Using the framework method, transcripts were analyzed 1) deductively by matching transcript excerpts to relevant TIME domains and 2) inductively by generating de novo themes to capture factors that affected students’ handling of trauma during critical incidents.Results: Twelve participants were enrolled and interviewed in July 2022. “Safety” was the most frequently described TIME domain, whereas “Gender, Cultural, and Historical issues” and “Peer Support” were discussed least. Inductive analysis revealed themes that hindered or supported their ability to manage traumatic experiences, which were grouped into three categories: 1) student interactions with the learning environment: complex social determinants of health, inequalities in care, and overt discrimination; 2) student interactions with patients: ethically ambiguous care, witnessing acute patient presentations, and reactivation of past trauma; and 3) student interactions with supervisors: power dynamics, invalidation of contributions, role-modeling, and student empowerment.Conclusion: The six TIME domains are represented in students’ perceptions of immediate, stressful critical incidents during their EM clerkship, with “Safety” being the most commonly described; however, the degree to which these domains are supported in students’ experiences of the EM clerkship differ, and instances of inadequately experienced domains may contribute to student distress. Understanding the EM clerkship through the specific lens of students’ experiences of trauma may be an effective strategy to guide curricular changes that promote a supportive learning environment for students in the emergency department.

In this paper, we argue that the consequences of democratic backsliding are not limited to the domestic sphere. Instead, we posit that democratic erosion generates strong incentives for leaders to engage in hostile foreign policy behavior toward other states. We estimate a series of models using event data from 2005–2018 to test our hypothesis. Our results consistently support our argument, even after using estimators that account for potential endogeneity issues. Leaders of backsliding democracies are more likely to behave in an aggressive way toward other countries. Our confidence in these results is strengthened by multiple robustness checks, all of which point to the same conclusion. This paper demonstrates that backsliding states are more likely than full democracies to engage in aggressive actions toward other states, which has important academic and policy implications for understanding the international ramifications of democratic erosion.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Educators are often on the frontline of supporting the well-being of their students. Thus, it is critical to ask teachers what they need in regard to implementing trauma-informed practices in schools (TIPS). This mixed-methods, community-initiated needs assessment explored educators' well-being and use of trauma-informed resources. A random selection of 450 certificated school staff from two school districts was invited to participate. Educators (n = 178; 39.5% response rate) completed a survey, and four focus groups were conducted (n = 14) to obtain feedback on factors affecting the use of TIPS. Descriptive statistics and logistic regression analyses were used to determine the factors most related to resource use. Teachers reported strong well-being and low levels of secondary traumatic stress, but high levels of burnout. Themes from the focus groups highlight administrator actions that can improve teacher well-being. Teachers rated their most used resources as a list of mental health resources, virtual-guided wellness activities, and opportunities to connect with others, whereas the most helpful were opportunities to connect with others, in-person-guided wellness activities, and training to identify students who may need support. Teacher well-being and school climate achieved traditional significance values for predicting teacher use of resources; however, they did not reach the Bonferroni-adjusted significance value. Results from this needs assessment indicate that teachers wanted resources to adequately respond to their own and their students' mental well-being. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

BACKGROUND: Early palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year. METHODS: This is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0-2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20-30 Gy of radiation in 2-10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha

This report presents a current snapshot of the state’s progress in implementing several of the strategies outlined in our 2020 report A Jobs and Climate Action Plan for 2030. Specifically, we review existing high road standard policies in California, and assess the reach of high road standards across the state’s proposed climate investments in California’s 2022-23 state budget.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

RATIONALE & OBJECTIVE: Ultraprocessed foods are widely consumed in the United States and are associated with cardiovascular disease (CVD), mortality, and kidney function decline in the general population. We investigated associations between ultraprocessed food intake and chronic kidney disease (CKD) progression, all-cause mortality, and incident CVD in adults with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort Study participants who completed baseline dietary questionnaires. EXPOSURE: Ultraprocessed food intake (in servings per day) classified according to the NOVA system. OUTCOMES: CKD progression (≥50% decrease in estimated glomerular filtration rate [eGFR] or initiation of kidney replacement therapy), all-cause mortality, and incident CVD (myocardial infarction, congestive heart failure, or stroke). ANALYTICAL APPROACH: Cox proportional hazards models adjusted for demographic, lifestyle, and health covariates. RESULTS: There were 1,047 CKD progression events observed during a median follow-up of 7 years. Greater ultraprocessed food intake was associated with higher risk of CKD progression (tertile 3 vs tertile 1, HR, 1.22; 95% CI, 1.04-1.42; P=0.01 for trend). The association differed by baseline kidney function, such that greater intake was associated with higher risk among people with CKD stages 1/2 (eGFR≥60mL/min/1.73m2; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

What is a national economy? What does it measure, value, or represent? What does it do? This article argues for ethnographic attention to national economies as a serial global form, arguably the most privileged epistemological and political object of our unevenly shared modernity. In dialogue with feminist approaches to the study of capitalism, economic anthropology, and the social studies of finance, this article asks how national economies become both intelligible, possessing representational unity or naturalized authority, and compelling—the stuff of fantasy and desire, power and subjugation. Taking a series of national economic conferences in Equatorial Guinea as a point of departure, the article argues for the centrality of the state and questions of geopolitical scale in any approach to the national economy form. Juxtaposing the literature on economic performativity with Equatoguinean political history and the power of U.S. oil companies in the global South highlights the open-endedness of what Michel Callon has called economics “in the wild” and the as-if qualities generated at the crossroads of economic theory and postcolonial inequality. This article thus aims to open up ethnographic possibilities in the face of national economies far beyond Equatorial Guinea’s borders.

This article explores the making of an expansive and expanding economic imagination in disparate Occupy sites—the Alternative Banking working group of Occupy Wall Street, the daily life of lists in Liberty Square, née Zuccotti Park, and the work of Strike Debt. In particular, I focus on transformative possibility in unanticipated places. Where anthropology and critical theory have often sought out capitalism’s otherwises for inspiration and potential, the expansion of the economic imagination I trace here suggests that the centers constitute zones of possibility as well. I aim to show not only the conditions of possibility for a certain kind of imaginative work in the dense and seemingly definitive spaces of financial expertise but also a remarkable, and largely unrecognized, contemporary conversation around the future of banking, foreclosures, and democratized finance.

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.

We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5−2.0 cm in maximal diameter, treated with single-fraction SRS (22−24 Gy) during March 2019−February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan−Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases (p = 0.024), and a higher number of treated lesions per SRS course (median 7 vs. 3; p < 0.001). With a median follow up of 15 months, there was no difference in FFLF between the mask and frame immobilization groups on univariable (p = 0.29) or multivariable analysis (p = 0.518). Actuarial FFLF at 1 year was 90.5% for mask and 92% for frame immobilization (p = 0.272). Radiation necrosis rates at 1 year were 12.5% for mask and 4.1% for frame immobilization (p = 0.502). For BM 0.5−2.0 cm in maximal diameter treated with single-fraction SRS using 22−24 Gy, mask immobilization with zero SM produces comparable clinical outcomes to frame immobilization. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a Gamma Knife® Icon™.

BackgroundPolyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.MethodsIn this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.ResultsParticipants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.ConclusionsIn participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

The mass of the W boson, a mediator of the weak force between elementary particles, is tightly constrained by the symmetries of the standard model of particle physics. The Higgs boson was the last missing component of the model. After observation of the Higgs boson, a measurement of the W boson mass provides a stringent test of the model. We measure the W boson mass, MW, using data corresponding to 8.8 inverse femtobarns of integrated luminosity collected in proton-antiproton collisions at a 1.96 tera-electron volt center-of-mass energy with the CDF II detector at the Fermilab Tevatron collider. A sample of approximately 4 million W boson candidates is used to obtain [Formula: see text], the precision of which exceeds that of all previous measurements combined (stat, statistical uncertainty; syst, systematic uncertainty; MeV, mega-electron volts; c, speed of light in a vacuum). This measurement is in significant tension with the standard model expectation.

Recent far-reaching advances in synthetic biology have yielded exciting tools for the creation of new materials. Conversely, advances in the fundamental understanding of soft-condensed matter, polymers and biomaterials offer new avenues to extend the reach of synthetic biology. The broad and exciting range of possible applications have substantial implications to address grand challenges in health, biotechnology and sustainability. Despite the potentially transformative impact that lies at the interface of synthetic biology and biomaterials, the two fields have, so far, progressed mostly separately. This Perspective provides a review of recent key advances in these two fields, and a roadmap for collaboration at the interface between the two communities. We highlight the near-term applications of this interface to the development of hierarchically structured biomaterials, from bioinspired building blocks to 'living' materials that sense and respond based on the reciprocal interactions between materials and embedded cells.

Understanding the main factors contributing to individual differences in fluid intelligence is one of the main challenges of psychology. A vast body of research has evolved from the theoretical framework put forward by Cattell, who developed the Culture-Fair IQ Test (CFT 20-R) to assess fluid intelligence. In this work, we extend and complement the current state of research by analysing the differential and combined relationship between eye-movement patterns and socio-demographic information and the ability of a participant to correctly solve a CFT item. Our work shows that a participants eye movements while solving a CFT item contain discriminative information and can be used to predict whether the participant will succeed in solving the test item. Moreover, the information related to eye movements complements the information provided by socio-demographic data when it comes to success prediction. In combination, both types of information yield a significantly higher predictive performance than each information type individually. To better understand the contributions of features related to eye movements and socio-demographic information to predict a participants success in solving a CFT item, we employ state-of-the-art explainability techniques and show that, along with socio-demographic variables, eye-movement data. Especially the number of saccades and the mean pupil diameter, significantly increase the discriminating power. The eye-movement features are likely indicative of processing efficiency and invested mental effort. Beyond the specific contribution to research on how eye movements can serve as a means to uncover mechanisms underlying cognitive processes, the findings presented in this work pave the way for further in-depth investigations of factors predicting individual differences in fluid intelligence.

BackgroundTreatment paradigms for metastatic non-small cell lung cancer are increasingly based on biomarker-driven therapies, with the most common alteration being mutation in the epidermal growth factor receptor (EGFR). Change in expression of such biomarkers could have a profound impact on the choice and efficacy of a selected targeted therapeutic, and hence the objective of this study was to analyze discordance in EGFR status in patients with lung cancer brain metastasis (LCBM).MethodsUsing PRISMA guidelines, a systematic review was performed of series in the Medline database of biopsied or resected LCBM published before May, 2020. Key words included "lung cancer" and "brain metastasis" combined with "epidermal growth factor receptor/EGFR," and "receptor conversion/discordance or concordance." Weighted random effects models were used to calculate pooled estimates.ResultsWe identified 501 patients from 19 full-text articles for inclusion in this study. All patients underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. On primary/LCBM comparison, the weighted pooled estimate for overall EGFR receptor discordance was 10% (95% CI 5-17%). The weighted effects model estimated a gain of an EGFR mutation in a brain metastases in patients with negative primary tumors was 7% (95% CI 4-12%). Alternatively, the weighted effects model estimate of loss of an EGFR mutation in patients with detected mutations in the primary tumor was also 7% (95% CI 4-10%). KRAS testing was also performed on both primary tumors and LCBM in a subset of 148 patients. The weighted effects estimate of KRAS-mutation discordance among LCBM compared to primary tumors was 13% (95% CI 5-27%). The weighted effects estimated of KRAS gain and loss in LCBM was 10% (95% CI 6-18%) and 8% (95% CI 4-15%), respectively. Meta-regression analysis did not find any association with any factors that could be associated with discordances.ConclusionsEGFR and KRAS mutation status discordance between primary tumor and LCBM occurs in approximately 10% and 13% of patients, respectively. Evaluation of LCBM receptor status is key to biomarker-driven targeted therapy for intracranial disease and awareness of subtype switching is critical for those patients treated with systemic therapy alone for intracranial disease.

BackgroundThe objective of this study was to evaluate the impact of the time interval between planning imaging and stereotactic radiosurgery (SRS) delivery on tumor volumes and spatial anatomic displacements of brain metastases (BM).MethodsConsecutive patients diagnosed with BM treated with SRS over a 3-year period were evaluated. Only patients who underwent an institutionally standardized diagnostic MRI (MRI-1) and a treatment planning MRI (MRI-2) were included. The impact of histology, inter-scan time interval, lesion location, tumor volume, and diameter were evaluated on final lesion diameter, volume, anatomic displacement, and ultimate need for change in management (ie, expanding margins, rescanning).Results101 patients (531 lesions) with a median inter-scan time interval of 8 days (range: 1-42 days) met the inclusion criteria. The median percentage increase in BM diameter and volume were 9.5% (IQR: 2.25%-24.0%) and 20% (IQR: 0.7%-66.7%). Overall, 147 lesions (27.7%) in 57 patients (56.4%) required a change in management. There was a statistically significant relationship between initial tumor diameter (cm) and change in management (OR: 2.69, 95% CI: 1.93-3.75; P < .001). Each day between MRI-1 and MRI-2 was associated with a change in management with an OR of 1.05 (95% CI: 1.03-1.07; P < .001).ConclusionsChanges in tumor diameter, volume, and spatial position occur as a function of time. Planning imaging for SRS is recommended to occur in close temporal proximity to treatment; for those with delays, a larger setup margin may need to be used to ensure tumor coverage and account for positional changes.

At the Fermilab Tevatron proton-antiproton (pp¯) collider, high-mass electron-neutrino (eν) pairs are produced predominantly in the process pp¯→W(→eν)+X. The asymmetry of the electron and positron yield as a function of their pseudorapidity constrain the slope of the ratio of the u- to d-quark parton distributions versus the fraction of the proton momentum carried by the quarks. This paper reports on the measurement of the electron-charge asymmetry using the full data set recorded by the Collider Detector at Fermilab in 2001-2011 and corresponding to 9.1 fb-1 of integrated luminosity. The measurement significantly improves the precision of the Tevatron constraints on the parton-distribution functions of the proton. Numerical tables of the measurement are provided.

BackgroundPatients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome.MethodsAmong 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage.ResultsThe mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death.ConclusionsMore advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time.

Rationale & objectiveThe clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.Study designA multicenter, prospective, cohort study.Setting & participantsWe evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.ExposuresBaseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).OutcomesIncident heart failure, myocardial infarction, and stroke events.Analytical approachWe used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.ResultsParticipants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR.LimitationsExclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.ConclusionsIn a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

IntroductionManagement of chronic kidney disease (CKD) entails high medical complexity and often results in high hospitalization burden. There are limited data on the associations of longitudinal hospital utilization patterns with adverse clinical outcomes in individuals with CKD.MethodsWe derived cumulative all-cause hospitalization trajectory groups using latent class trajectory analysis in 3012 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study who were alive and did not reach end-stage kidney disease (ESKD) within 4 years of study entry. Cox proportional hazards models tested the associations between hospitalization trajectory groups and risks of ESKD and death prior to the onset of ESKD (ESKD-censored death).ResultsWithin 4 years of study entry, there were 5658 hospitalizations among 3012 participants. We identified 3 distinct subgroups of individuals with CKD based on cumulative all-cause hospitalization trajectories over 4 years: low-utilizer (n = 1066), intermediate-utilizer (n = 1802), and high-utilizer (n = 144). High-utilizers represented a patient population of lower socioeconomic status who had a greater prevalence of comorbid conditions and lower kidney function compared with intermediate- and low-utilizers. After the 4-year ascertainment period to form the trajectory subgroups, there were 544 ESKD events and 437 ESKD-censored deaths during a median follow-up time of 5.1 years. Compared with low-utilizers, intermediate-utilizers and high-utilizers were at 1.49-fold (95% confidence interval [CI] 1.22-1.84) and 1.75-fold (95% CI 1.20-2.56) higher risk of ESKD in adjusted analyses, respectively. Compared with low-utilizers, intermediate-utilizers and high-utilizers were at 1.48-fold (95% CI 1.17-1.87) and 2.58-fold (95% CI 1.74-3.83) higher risk of ESKD-censored death in adjusted analyses, respectively.ConclusionsTrajectories of cumulative all-cause hospitalization identify subgroups of individuals with CKD who are at high risk of ESKD and death.

The high-precision X-ray diffraction setup for work with diamond anvil cells (DACs) in interaction chamber 2 (IC2) of the High Energy Density instrument of the European X-ray Free-Electron Laser is described. This includes beamline optics, sample positioning and detector systems located in the multipurpose vacuum chamber. Concepts for pump-probe X-ray diffraction experiments in the DAC are described and their implementation demonstrated during the First User Community Assisted Commissioning experiment. X-ray heating and diffraction of Bi under pressure, obtained using 20 fs X-ray pulses at 17.8 keV and 2.2 MHz repetition, is illustrated through splitting of diffraction peaks, and interpreted employing finite element modeling of the sample chamber in the DAC.

The high-precision X-ray diffraction setup for work with diamond anvil cells (DACs) in interaction chamber 2 (IC2) of the High Energy Density instrument of the European X-ray Free-Electron Laser is described. This includes beamline optics, sample positioning and detector systems located in the multipurpose vacuum chamber. Concepts for pump-probe X-ray diffraction experiments in the DAC are described and their implementation demonstrated during the First User Community Assisted Commissioning experiment. X-ray heating and diffraction of Bi under pressure, obtained using 20 fs X-ray pulses at 17.8 keV and 2.2 MHz repetition, is illustrated through splitting of diffraction peaks, and interpreted employing finite element modeling of the sample chamber in the DAC.

BackgroundUromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels.MethodsWe used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression.ResultsBaseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42).ConclusionsIn a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

BackgroundStudies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population.Methods and resultsWe studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF (n = 3158), those with incident AF (n = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score.ConclusionIn this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.

BackgroundChange in hormone receptor (estrogen [ER] and progesterone [PR]) and/or human epidermal growth factor receptor type 2 (HER2) status during the evolutionary course of metastatic breast cancer and the effect of tumor classification subtype switching remain understudied and underappreciated in brain metastasis patients.MethodsUsing preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a systematic review of series published prior to April 2020 obtained from the Medline database of biopsied or resected breast cancer brain metastasis (BCBM) was performed. Weighted random effects models were used to calculate pooled estimates.Results15 full-text articles were included with receptor expression analyses on 1373 patients who underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. Primary tumor receptor expression immunophenotypes were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding BCBM immunophenotypes were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. On primary/BCBM comparison, 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordant on ER, 23.0% (95% CI: 18.0%-30.0%) discordant on PR, and 12.0% (95% CI: 8.0%-16.0%) discordant on HER2 status. The most common receptor conversions found in BCBM were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%).ConclusionsBCBM exhibits significant receptor expression discordance in comparison to primary tumors in approximately 40% of patients. Classification patterns need to be analyzed to determine factors predictive of BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.

Biosensors that continuously measure circulating biomolecules in real time could provide insights into the health status of patients and their response to therapeutics. But biosensors for the continuous real-time monitoring of analytes in vivo have only reached nanomolar sensitivity and can measure only a handful of molecules, such as glucose and blood oxygen. Here we show that multiple analytes can be continuously and simultaneously measured with picomolar sensitivity and sub-second resolution via the integration of aptamers and antibodies into a bead-based fluorescence sandwich immunoassay implemented in a custom microfluidic chip. After an incubation time of 30 s, bead fluorescence is measured using a high-speed camera under spatially multiplexed two-colour laser illumination. We used the assay for continuous quantification of glucose and insulin concentrations in the blood of live diabetic rats to resolve inter-animal differences in the pharmacokinetic response to insulin as well as discriminate pharmacokinetic profiles from different insulin formulations. The assay can be readily modified to continuously and simultaneously measure other blood analytes in vivo.

We present the case of a 72-year-old man with a one-week history of a red rash on the palms of both hands. A 4mm punch biopsy revealed interstitial granulomatous inflammation within the dermis and a colloidal iron stain showed increased dermal acid mucin. Immunohistochemical staining for CD68 confirmed the presence of abundant histiocytes within the dermis. The clinical and pathological correlation was consistent with the diagnosis of interstitial granuloma annulare. Exclusive involvement of the palms is a rare presentation and serves as a reminder for practitioners to keep granuloma annulare in their differential diagnosis when observing palmar plaques.

BackgroundNovel immunotherapeutic strategies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are often administered when metastatic tumors show PD-L1 positivity, even in the setting of lung cancer brain metastasis (LCBM). However, biological differences exist between primary tumors and metastatic sites. The objective of this study was to analyze rates of PD-L1 receptor discordance between primary tumors and LCBM.MethodsA systematic review of studies of biopsied or resected LCBM evaluating PD-L1 discordance published in the Medline database was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates.ResultsSix full-text articles (n = 230 patients) with a median of 32 patients in each study (range: 24-73) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases and met inclusion criteria. The pooled estimate for tumor cell (TC) PD-L1 receptor discordance between primary tumors and LCBM was 19% (95% confidence interval [CI]: 10-27%). For PD-L1 receptor expression in tumor-infiltrating lymphocytes (TIL), the weighted pooled estimate for discordance was 21% (95% CI: 8-44%). For primary versus LCBM, the positive rates by expression levels of 50% were 52% (95% CI: 30-73%) versus 56% (95% CI: 34-76%), 30% (95% CI: 22-40%) versus 20% (95% CI: 10-35%), and 15% (95% CI: 6-36%) versus 22% (95% CI: 15-31%) (P = .425), respectively.ConclusionsPD-L1 discordance occurs in ~20% of LCBM, with the greatest discordance in the 1-50% expression category. Although controversial, confirming discordance might be important for selection of immune checkpoint inhibitor therapy and in the analysis of patterns of failure after treatment.

BackgroundChange in hormone receptor (estrogen [ER] and progesterone [PR]) and/or human epidermal growth factor receptor type 2 (HER2) status during the evolutionary course of metastatic breast cancer and the effect of tumor classification subtype switching remain understudied and underappreciated in brain metastasis patients.MethodsUsing preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a systematic review of series published prior to April 2020 obtained from the Medline database of biopsied or resected breast cancer brain metastasis (BCBM) was performed. Weighted random effects models were used to calculate pooled estimates.Results15 full-text articles were included with receptor expression analyses on 1373 patients who underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. Primary tumor receptor expression immunophenotypes were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding BCBM immunophenotypes were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. On primary/BCBM comparison, 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordant on ER, 23.0% (95% CI: 18.0%-30.0%) discordant on PR, and 12.0% (95% CI: 8.0%-16.0%) discordant on HER2 status. The most common receptor conversions found in BCBM were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%).ConclusionsBCBM exhibits significant receptor expression discordance in comparison to primary tumors in approximately 40% of patients. Classification patterns need to be analyzed to determine factors predictive of BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.

Turbulence is a key process in many fields of astrophysics. Advances in numerical simulations of fluids over the last several decades have revolutionized our understanding of turbulence and related processes such as star formation and cosmic ray propagation. However, data from numerical simulations of astrophysical turbulence are often not made public. We introduce a new simulation-oriented database for the astronomical community: The Catalogue for Astrophysical Turbulence Simulations (CATS), located at www.mhdturbulence.com. CATS includes magnetohydrodynamic (MHD) turbulent box simulation data products generated by the public codes athena++, arepo, enzo, and flash. CATS also includes several synthetic observational data sets, such as turbulent HI data cubes. We also include measured power spectra and three-point correlation functions from some of these data. We discuss the importance of open-source statistical and visualization tools for the analysis of turbulence simulations such as those found in CATS.

Turbulence is a key process in many fields of astrophysics. Advances in numerical simulations of fluids over the last several decades have revolutionized our understanding of turbulence and related processes such as star formation and cosmic ray propagation. However, data from numerical simulations of astrophysical turbulence are often not made public. We introduce a new simulation-oriented database for the astronomical community: The Catalogue for Astrophysical Turbulence Simulations (CATS), located at www.mhdturbulence.com. CATS includes magnetohydrodynamic (MHD) turbulent box simulation data products generated by the public codes athena++, arepo, enzo, and flash. CATS also includes several synthetic observational data sets, such as turbulent HI data cubes. We also include measured power spectra and three-point correlation functions from some of these data. We discuss the importance of open-source statistical and visualization tools for the analysis of turbulence simulations such as those found in CATS.

Implementation of prevention policies has often been impeded or delayed due to the lack of randomized controlled trials (RCTs) with hard clinical outcomes (eg, incident disease, mortality). Despite the prominent role of RCTs in health care, it may not always be feasible to conduct RCTs of public health interventions with hard outcomes due to logistical and ethical considerations. RCTs may also lack external validity and have limited generalizability. Currently, there is insufficient guidance for policymakers charged with establishing evidence-based policy to determine whether an RCT with hard outcomes is needed before policy recommendations. In this context, the purpose of this article is to assess, in a case study, the feasibility of conducting an RCT of the oft-cited issue of sodium reduction on cardiovascular outcomes and then propose a framework for decision-making, which includes an assessment of the feasibility of conducting an RCT with hard clinical outcomes when such trials are unavailable. We designed and assessed the feasibility of potential individual- and cluster-randomized trials of sodium reduction on cardiovascular outcomes. Based on our assumptions, a trial using any of the designs considered would require tens of thousands of participants and cost hundreds of millions of dollars, which is prohibitively expensive. Our estimates may be conservative given several key challenges, such as the unknown costs of sustaining a long-term difference in sodium intake, the effect of differential cotreatment with antihypertensive medications, and long lag time to clinical outcomes. Thus, it would be extraordinarily difficult to conduct such a trial, and despite the high costs, would still be at substantial risk for a spuriously null result. A robust framework, such as the one we developed, should be used to guide policymakers when establishing evidence-based public health interventions in the absence of trials with hard clinical outcomes.

Los Angeles Countys Office of Diversion and Reentry (ODR) has removed over 3800 people from the largest jail system in the country. Across various diversion programs, ODRs fundamental goal is to provide permanent, lifetime care for each diverted person. This article describes ODRs various diversion programs, and elucidates the types of elaborate clinical and court-related interventions that are necessary to remove persons with serious mental disorders from jail custody. As Los Angeles continues to build the necessary community-based continuum of mental health care, ODRs model proves that thoughtfully removing persons with serious mental disorders from jail is possible and necessary for the health of both patients and community.

Rationale & objectiveAmong individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list.Study designProspective cohort study.Setting & population1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m2 at study entry or during follow-up.ExposuresHRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory.OutcomesTime to kidney transplant wait-listing and time to pre-emptive wait-listing.Analytic approachTime-to-event analysis using Cox proportional hazards regression.ResultsDuring a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85; P

Rationale & objectiveStudies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levels are associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changes in FGF-23 levels as kidney disease progresses.Study designCase-cohort study.Setting & participantsTo evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort.ExposureSerial FGF-23 measurements and FGF-23 trajectory group membership.OutcomesIncident KRT.Analytical approachTo handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure.ResultsIn our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group.LimitationsResidual confounding and lack of intact FGF-23 values.ConclusionsIncreasing FGF-23 levels are independently associated with increased risk for incident KRT.