Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening.

Pro-inflammatory CD4+ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (TH17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in TH17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (TH1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover TH17 to TH1 cell plasticity in the human kidney in the context of renal autoimmunity.

Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

BACKGROUND: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. RESULTS: 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. CONCLUSIONS: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.

Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Species Diversity and Habitat Fragmentation Per Se: The Influence of Local Extinctions and Species Clustering.

AbstractAnthropogenic fragmentation of habitat is considered to be a critical factor contributing to the decline of species. However, a general consensus on the degree to which habitat loss and what has been called "habitat fragmentation per se" contribute to the loss of species diversity has not yet emerged. For empirical and theoretical reasons the topic has recently attracted renewed attention, thus reviving the "single large or several small" (SLOSS) debate. To study the effect of fragmentation per se, we use a spatially explicit and continuous, competitively neutral simulation model with immigration from a regional pool. The model accounts for the influence of ecological drift and intrafragment species clustering (due to limited dispersal) on local (plot) and global (landscape) diversity. We find that fragmentation increases global diversity but decreases local diversity, prominently so if fragments become more isolated. Cluster formation is a key mechanism reducing local diversity. By adding external disturbance events that lead to the occasional extinction of entire communities in habitat fragments, we show that the combined effect of such extinctions and cluster formation can create nonlinear interactive effects of fragmentation and fragment isolation on diversity patterns. We conclude that while in most cases fragmentation will decrease local and increase landscape diversity, universal predictions concerning the SLOSS debate should be taken with care.

Treatment of unstable forearm fractures at the metaphyseal-diaphyseal junction in children: antegrade ESIN vs. transepiphyseal intramedullary K-wire fixation.

BACKGROUND: Treatment of unstable forearm fractures in the metaphyseal-diaphyseal junction (MDJ) zone is still a matter of debate. Major drawbacks of all types of fixations include either invasiveness, technical impracticality, or lack of acceptance by patients. This study reports results after antegrade ESIN (a-ESIN) compared to transepiphyseal intramedullary K-wire (TIK) for unstable MDJ forearm fractures. METHODS: The MDJ of the forearm was defined as the square over the joints of both forearm bones subtracted with the square over the metaphysis of the radius alone. The data of 40 consecutive patients < 16 years of age who were treated either by a-ESIN (later treatment period) or TIK (early treatment period) for an unstable MDJ forearm fracture at a single high-volume pediatric trauma center were retrospectively analyzed. RESULTS: The average age was slightly lower in the first group (TIK = 7.42 years; a-ESIN = 10.5 years). An additional ulna fracture was found in 50% of cases and was treated with a classic antegrade ESIN in 10/20 (TIK) and 6/20 cases (a-ESIN). Additional plaster cast immobilization was performed in all cases with TIK and in three cases with a-ESIN. After TIK, no complication, malalignment, or functional limitation occurred. After a-ESIN, 19/20 patients had an event-free course with stable retention and healing without axial malalignment. In one case, a temporary sensor dysfunction occurred. The same patient suffered a refracture two months after the original trauma, which required a closed reduction. Metal removal was performed after 84 days (TIK) and 150 days (a-ESIN). The outcome in all patients was good. CONCLUSION: Both a-ESIN and TIK are minimally invasive procedures that are technically easy to perform. Both methods are safe and lead to a complete restoration of the forearm's range of motion. The decisive advantage of a-ESIN is the possibility of postoperative immobilization-free rehabilitation.

Bounds to electron spin qubit variability for scalable CMOS architectures.

Spins of electrons in silicon MOS quantum dots combine exquisite quantum properties and scalable fabrication. In the age of quantum technology, however, the metrics that crowned Si/SiO2 as the microelectronics standard need to be reassessed with respect to their impact upon qubit performance. We chart spin qubit variability due to the unavoidable atomic-scale roughness of the Si/SiO2 interface, compiling experiments across 12 devices, and develop theoretical tools to analyse these results. Atomistic tight binding and path integral Monte Carlo methods are adapted to describe fluctuations in devices with millions of atoms by directly analysing their wavefunctions and electron paths instead of their energy spectra. We correlate the effect of roughness with the variability in qubit position, deformation, valley splitting, valley phase, spin-orbit coupling and exchange coupling. These variabilities are found to be bounded, and they lie within the tolerances for scalable architectures for quantum computing as long as robust control methods are incorporated.

Differential roles of putative arginine fingers of AAA+ ATPases Rvb1 and Rvb2.

The evolutionarily conserved AAA+ ATPases Rvb1 and Rvb2 proteins form a heteromeric complex (Rvb1/2) required for assembly or remodeling of macromolecular complexes in essential cellular processes ranging from chromatin remodeling to ribosome biogenesis. Rvb1 and Rvb2 have a high degree of sequence and structural similarity, and both contain the classical features of ATPases of their clade, including an N-terminal AAA+ subdomain with the Walker A motif, an insertion domain that typically interacts with various binding partners, and a C-terminal AAA+ subdomain containing a Walker B motif, the Sensor I and II motifs, and an arginine finger. In this study, we find that despite the high degree of structural similarity, Rvb1 and Rvb2 have distinct active sites that impact their activities and regulation within the Rvb1/2 complex. Using a combination of biochemical and genetic approaches, we show that replacing the homologous arginine fingers of Rvb1 and Rvb2 with different amino acids not only has distinct effects on the catalytic activity of the complex, but also impacts cell growth, and the Rvb1/2 interactions with binding partners. Using molecular dynamics simulations, we find that changes near the active site of Rvb1 and Rvb2 cause long-range effects on the protein dynamics in the insertion domain, suggesting a molecular basis for how enzymatic activity within the catalytic site of ATP hydrolysis can be relayed to other domains of the Rvb1/2 complex to modulate its function. Further, we show the impact that the arginine finger variants have on snoRNP biogenesis and validate the findings from molecular dynamics simulations using a targeted genetic screen. Together, our results reveal new aspects of the regulation of the Rvb1/2 complex by identifying a relay of long-range molecular communication from the ATPase active site of the complex to the binding site of cofactors. Most importantly, our findings suggest that despite high similarity and cooperation within the same protein complex, the two proteins have evolved with unique properties critical for the regulation and function of the Rvb1/2 complex.

Correction: Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

[This corrects the article DOI: 10.1055/a-2238-3153.].

How dispersal rates depend on the prey capture strategy: A case study of Georgia's spiders.

Large-scale barcoding projects help to aggregate information on genetic variability of multiple species throughout their ranges. Comparing DNA sequences of both non-conspecific and conspecific individuals from distant parts of their ranges helps to compare level of genetic isolation-by-distance patterns in different species and adaptive types. We compared mitochondrial CO1 gene sequences of 223 spiders from Georgia (Caucasus), representing 124 species and eight families, with 3097 homological sequences from spiders mostly from Europe, but also from other parts of the World. In most families, a significant isolation-by distance pattern was observed on family level. On species level, a significant isolation-by-distance was observed in 40 species, although this low proportion is most likely related to a lack of data. Simultaneously, remarkable differences in spatial structure were shown for different species. Although the majority of the studied species have a broad western Palearctic range, web-building spiders from families Araneidae, Theridiidae, and Linyphiidae are less isolated spatially than flower spiders (Thomisidae), jumping spiders (Salticidae), wolf spiders (Lycosidae), sac spiders (Clubionidae), and ground spiders (Gnaphosidae). This pattern is related with more common ballooning in web building than in actively hunting spiders, which commonly remain isolated since preglacial time. Ground spiders build the most isolated populations in the Caucasus.

Cows with diverging haplotypes show differences in differential milk cell count, milk parameters and vaginal temperature after S. aureus challenge but not after E. coli challenge.

BACKGROUND: In dairy cattle, mastitis causes high financial losses and impairs animal well-being. Genetic selection is used to breed cows with reduced mastitis susceptibility. Techniques such as milk cell flow cytometry may improve early mastitis diagnosis. In a highly standardized in vivo infection model, 36 half-sib cows were selected for divergent paternal Bos taurus chromosome 18 haplotypes (Q vs. q) and challenged with Escherichia coli for 24 h or Staphylococcus aureus for 96 h, after which the samples were analyzed at 12 h intervals. Vaginal temperature (VT) was recorded every three minutes. The objective of this study was to compare the differential milk cell count (DMCC), milk parameters (fat %, protein %, lactose %, pH) and VT between favorable (Q) and unfavorable (q) haplotype cows using Bayesian models to evaluate their potential as improved early indicators of differential susceptibility to mastitis. RESULTS: After S. aureus challenge, compared to the Q half-sibship cows, the milk of the q cows exhibited higher PMN levels according to the DMCC (24 h, p < 0.001), a higher SCC (24 h, p < 0.01 and 36 h, p < 0.05), large cells (24 h, p < 0.05) and more dead (36 h, p < 0.001) and live cells (24 h, p < 0.01). The protein % was greater in Q milk than in q milk at 0 h (p = 0.025). In the S. aureus group, Q cows had a greater protein % (60 h, p = 0.048) and fat % (84 h, p = 0.022) than q cows. Initially, the greater VT of S. aureus-challenged q cows (0 and 12-24 h, p < 0.05) reversed to a lower VT in q cows than in Q cows (48-60 h, p < 0.05). Additionally, the following findings emphasized the validity of the model: in the S. aureus group all DMCC subpopulations (24 h-96 h, p < 0.001) and in the E. coli group nearly all DMCC subpopulations (12 h-24 h, p < 0.001) were higher in challenged quarters than in unchallenged quarters. The lactose % was lower in the milk samples of E. coli-challenged quarters than in those of S. aureus-challenged quarters (24 h, p < 0.001). Between 12 and 18 h, the VT was greater in cows challenged with E. coli than in those challenged with S. aureus (3-h interval approach, p < 0.001). CONCLUSION: This in vivo infection model confirmed specific differences between Q and q cows with respect to the DMCC, milk component analysis results and VT results after S. aureus inoculation but not after E. coli challenge. However, compared with conventional milk cell analysis monitoring, e.g., the global SCC, the DMCC analysis did not provide refined phenotyping of the pathogen response.

Precursor-Engineered Volatile Inks Enable Reliable Blade-Coating of Cesium-Formamidinium Perovskites Toward Fully Printed Solar Modules.

Reliable fabrication of large-area perovskite films with antisolvent-free printing techniques requires high-volatility solvents, such as 2-methoxyethanol (2ME), to formulate precursor inks. However, the fabrication of high-quality cesium-formamidinium (Cs-FA) perovskites has been hampered using volatile solvents due to their poor coordination with the perovskite precursors. Here, this issue is resolved by re-formulating a 2ME-based Cs0.05FA0.95PbI3 ink using pre-synthesized single crystals as the precursor instead of the conventional mixture of raw powders. The key to obtaining high-quality Cs-FA films lies in the removal of colloidal particles from the ink and hence the suppression of colloid-induced heterogeneous nucleation, which kinetically facilitates the growth of as-formed crystals toward larger grains and improved film crystallinity. Employing the precursor-engineered volatile ink in the vacuum-free, fully printing processing of solar cells (with carbon electrode), a power conversion efficiency (PCE) of 19.3%, a T80 (80% of initial PCE) of 1000 h in ISOS-L-2I (85 °C/1 Sun) aging test and a substantially reduced bill of materials are obtained. The reliable coating methodology ultimately enables the fabrication of carbon-electrode mini solar modules with a stabilized PCE of 16.2% (average 15.6%) representing the record value among the fully printed counterparts and a key milestone toward meeting the objectives for a scalable photovoltaic technology.

Erythrocytosis and CKD: A Review.

Erythrocytosis or polycythemia is defined as an increase in red blood cell concentration above the age- and sex-specific normal levels. Unlike anemia, which is very common in patients with chronic kidney disease (CKD), erythrocytosis is less frequent but requires specific understanding by health care professionals in order to provide the best care. Erythrocytosis, especially when undiagnosed and untreated, can lead to serious thrombotic events and higher mortality. Classic causes of erythrocytosis associated with CKD include cystic kidney diseases, kidney or other erythropoietin-secreting neoplasms, high-altitude renal syndrome, overdosage of erythropoietin-stimulating agents, androgen therapy, heavy smoking, chronic lung disease, obstructive sleep apnea, IgA nephropathy, post-kidney transplant erythrocytosis, renal artery stenosis, and congenital etiologies. After ruling out the common acquired causes of erythrocytosis and/or in the presence of suggestive parameters, primary erythrocytosis or polycythemia vera (PV) should be considered, and patients should be screened for JAK2V617F somatic mutation. The newest entity inducing erythrocytosis is linked to the use of sodium/glucose cotransporter 2 (SGLT2) inhibitors that hypothetically activate hypoxia-inducible factor 2α (HIF-2α) and in some cases unmask PV. This Review focuses on the pathogenesis, renal manifestations and management of PV, the pathophysiology of erythrocytosis induced by SGLT2 inhibitors and the relevance of timely JAK2 mutation screening in these patients.

[(Uro)genital developmental disorders]. / (Uro)genitale Entwicklungsstörungen.

CLINICAL ISSUE: Congenital anomalies of the urogenital tract are common, whereas isolated developmental disorders of the genital organs are rare and varied. The type and timing of imaging to characterize these developmental disorders and the planning of any treatment are the subject of discussion. The aim of this article is to provide a brief overview of embryology, diagnostic procedures, and examples of findings. STANDARD RADIOLOGICAL METHODS: The primary procedure for imaging the genitals is sonography, which must be performed with appropriate empathy. In addition to the genitals, the general situation of the kidneys and urinary tract should be examined, as urogenital malformations are often combined. Dedicated magnetic resonance imaging (MRI) is indicated as advanced imaging in interdisciplinary consultations. Invasive procedures, such as genitography combined with micturition cystourethrography (MCU) using X­rays or contrast-enhanced sonography, are rarely required. Computed tomography (CT) or excretory urography play no role. CONCLUSION: Imaging plays an important role in the assessment of genital anomalies. Knowledge of embryology facilitates anatomical understanding and the assessment of pathologies.

Contemporary Valvular Mechanisms of Aortic Regurgitation in Tricuspid Aortic Valves: Importance in Repair Versus Replacement Strategy.

BACKGROUND: This study was performed to determine cusp causes of aortic regurgitation in patients with tricuspid aortic valves without significant aortic dilatation and define cusp pathologies amenable to surgical repair (aortic valve repair [AVr]) versus aortic valve replacement. METHODS AND RESULTS: We retrospectively reviewed surgical reports of consecutive adults with tricuspid aortic valves undergoing surgery for clinically significant aortic regurgitation within a prospective registry from January 2005 to September 2019. Valvular mechanisms were determined by systematic in vivo intraoperative quantification methods. Of 516 patients, 287 (56%) underwent repair (AVr; mean±SD age, 59.9±12.4 years; 81% men) and 229 (44%) underwent replacement (aortic valve replacement; mean±SD age, 62.8±13.8 years [P=0.01 compared to AVr]; 67% men). A single valvular mechanism was present in 454 patients (88%), with cusp prolapse (46%), retraction (24%), and perforation (18%) being the most common. Prolapse involved the right cusp in 86% of cases and was more frequent in men (P<0.001). Two-dimensional transesophageal echocardiography accuracy for predicting mechanisms was 73% to 82% for the right cusp, 55% to 61% for the noncoronary cusp, and 0% for the left-coronary cusp. Cusp prolapse, younger age, and larger patient size were associated with successful AVr (all P<0.03), whereas retraction, perforation, older age, and concomitant mitral repair were associated with aortic valve replacement (all P<0.03). CONCLUSIONS: Right cusp prolapse is the most frequent single valvular mechanism in patients with tricuspid aortic valve aortic regurgitation, followed by cusp retraction and perforation. The accuracy of 2-dimensional transesophageal echocardiography is limited for left and noncoronary cusp mechanistic assessment. Prolapse is associated with successful AVr, whereas retraction and perforation are associated with aortic valve replacement. With systematic intraoperative quantification methods and current surgical techniques, more than half of tricuspid aortic valve aortic regurgitation cases may be successfully repaired.

The Mechanism of Rh(I)-Catalyzed Coupling of Benzotriazoles and Allenes Revisited: Substrate Inhibition, Proton Shuttling, and the Role of Cationic vs Neutral Species.

Direct coupling of benzotriazole to unsaturated substrates such as allenes represents an atom-efficient method for the construction of biologically and pharmaceutically interesting functional structures. In this work, the mechanism of the N2-selective Rh complex-catalyzed coupling of benzotriazoles to allenes was investigated in depth using a combination of experimental and theoretical techniques. Substrate coordination, inhibition, and catalyst deactivation was probed in reactions of the neutral and cationic catalyst precursors [Rh(µ-Cl)(DPEPhos)]2 and [Rh(DPEPhos)(MeOH)2]+ with benzotriazole and allene, giving coordination, or coupling of the substrates. Formation of a rhodacycle, formed by unprecedented 1,2-coupling of allenes, is responsible for catalyst deactivation. Experimental and computational data suggest that cationic species, formed either by abstraction of the chloride ligand or used directly, are relevant for catalysis. Isomerization of benzotriazole and cleavage of its N-H bond are suggested to occur by counteranion-assisted proton shuttling. This contrasts with a previously proposed scenario in which oxidative N-H addition at Rh is one of the key steps. Based on the mechanistic analysis, the catalytic coupling reaction could be optimized, leading to lower reaction temperature and shorter reaction times compared to the literature.

A new era in the science and care of kidney diseases.

Notable progress in basic, translational and clinical nephrology research has been made over the past five decades. Nonetheless, many challenges remain, including obstacles to the early detection of kidney disease, disparities in access to care and variability in responses to existing and emerging therapies. Innovations in drug development, research technologies, tissue engineering and regenerative medicine have the potential to improve patient outcomes. Exciting prospects include the availability of new drugs to slow or halt the progression of chronic kidney disease, the development of bioartificial kidneys that mimic healthy kidney functions, and tissue engineering techniques that could enable transplantable kidneys to be created from the cells of the recipient, removing the risk of rejection. Cell and gene therapies have the potential to be applied for kidney tissue regeneration and repair. In addition, about 30% of kidney disease cases are monogenic and could potentially be treated using these genetic medicine approaches. Systemic diseases that involve the kidney, such as diabetes mellitus and hypertension, might also be amenable to these treatments. Continued investment, communication, collaboration and translation of innovations are crucial to realize their full potential. In addition, increasing sophistication in exploring large datasets, implementation science, and qualitative methodologies will improve the ability to deliver transformational kidney health strategies.

Exposure to Polybrominated Diphenyl Ethers and Risk of All-Cause and Cause-Specific Mortality.

Importance: Polybrominated diphenyl ethers (PBDEs) are an important group of persistent organic pollutants with endocrine-disrupting properties. However, prospective cohort studies regarding the association of PBDE exposure with long-term health outcomes, particularly mortality, are lacking. Objective: To examine the association of environmental exposure to PBDEs with risk of all-cause and cause-specific mortality. Design, Setting, and Participants: This nationally representative cohort study used data from the National Health and Nutrition Examination Survey 2003 to 2004 and linked mortality information through December 31, 2019. Adults aged 20 years or older with available data on PBDE measurements and mortality were included. Statistical analysis was performed from February 2022 to April 2023. Exposures: PBDE analytes in serum samples were measured using solid phase extraction and isotope dilution gas chromatography high-resolution mass spectrometry. Main Outcomes and Measures: All-cause mortality, cancer mortality, and cardiovascular mortality. Results: This study included 1100 participants (mean [SE] age, 42.9 [0.6] years; proportion [SE] female, 51.8% [1.6%]; proportion [SE] Hispanic, 12.9% [2.7%]; proportion [SE] non-Hispanic Black, 10.5% [1.6%]; proportion [SE] non-Hispanic White, 70.8% [3.7%]; proportion [SE] other race and ethnicity, 5.8% [1.1%]). During 16 162 person-years of follow-up (median [IQR] follow-up, 15.8 [15.2-16.3] years; maximum follow-up, 17 years), 199 deaths occurred. Participants with higher serum PBDE levels were at higher risk for death. After adjustment for age, sex, and race and ethnicity, lifestyle and socioeconomic factors, and body mass index, participants with the highest tertile of serum PBDE levels had an approximately 300% increased risk of cancer mortality (HR, 4.09 [95% CI, 1.71-9.79]) compared with those with the lowest tertile of serum PBDE levels. No significant association of PBDE exposure with all-cause mortality (HR, 1.43 [95% CI, 0.98-2.07]) or cardiovascular mortality (HR, 0.92 [95% CI, 0.41-2.08]) was observed. Conclusions and Relevance: In this nationally representative cohort study, PBDE exposure was significantly associated with an increased risk of cancer mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.