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INTRODUCTION: Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. METHODS: We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. RESULTS: The mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma. CONCLUSION: Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.

INTRODUCTION 1956 I. THE DELEGATIONS AND THEIR ELABORATIONS 1959 A. Early Statutes and Institutional Foundations 1960 B. The Statutory Free-Trade and Security Dichotomy 1964 II. CONSTITUTIONALIZING PRESIDENTIAL CONTROL OF 1968 [...], The U.S. Constitution grants Congress the power "[t]o regulate Commerce with foreign Nations," but today the exercise of the foreign commerce power resides primarily with the executive branch. That transfer of control is partly the result of significant delegations of responsibility for managingforeign commerce from Congress to the executive. It is also, however, the result of the securitization of foreign commerce. The executive branch asserts that foreign commerce issues fall under its constitutional powers over foreign affairs, and, thus, that it enjoys authority over foreign commerce that exceeds the scope of congressional delegations. This Article makes three contributions. First, we analyze the development of a trade administrative state charged with managing two sets of broad delegations: to liberalize trade, on the one hand, and to restrict it in the name of "economic security" when the executive deems necessary. Second, we document the way in which the executive branch in recent presidential administrations of both parties has defended those administrations&apos; trade policies in court by arguing that the president&apos;s independent constitutional powers over (noncommercial) foreign affairs give him license to exercise power over commerce beyond that delegated by Congress, or that congressional delegations should be construed in his favor. The courts, for their part, have often accepted these claims either directly or indirectly. Third, we propose three statutory reforms that Congress could pass to restore balance to the branches&apos; regulation of foreign commerce: (1) Congress should sunset the president&apos;s imposition of tariffs or other trade restrictions pursuant to economic security statutes after 90 or 180 days without the possibility of renewal unless Congress acts; (2) Congress should prohibit the executive branch from relying on any international agreement as the legal basis under which any good or service is imported into the United States, exported from the United States, or regulated while in the United States, unless Congress has either explicitly authorized the agreement in advance or approved it after its conclusion; and (3) Congress should eliminate the Federal Circuit&apos;s exclusive jurisdiction over appeals in most trade cases.

TABLE OF CONTENTS I. INTRODUCTION 983 II. THE COURT OF INTERNATIONAL TRADE 984 III. A CHANGING DOCKET 986 IV. THE ARTICLES 989 V. CONCLUSION 994 I. INTRODUCTION Judicial conferences offer [...]

TABLE OF CONTENTS INTRODUCTION I. THE RISE OF ECONOMIC WARFARE AS A NATIONAL SECURITY STRATEGY II. ECONOMIC WARFARE AS A MAJOR QUESTION A. The Major Questions Doctrine B. Why Economic [...], The rise of the major questions doctrine--the rule that says that in order to delegate to the executive branch the power to resolve a "question of &apos;deep economic and political significance&apos; that is central to [a] statutory scheme," Congress must do so expressly--threatens to unmake the modern executive&apos;s authority over foreign affairs, especially in matters of national security and interstate conflict. In the twenty-first century, global conflicts increasingly involve economic warfare, rather than (or in addition to) the force of arms. In the United States, the executive power to levy economic sanctions and engage in other forms of economic warfare are generally based on extremely broad delegations of authority from Congress. The major questions doctrine (MQD) threatens the ability to fight modern conflicts for two reasons. First, classic national-security-related conflicts--wars of territorial conquest, terrorism, or nuclear proliferation--increasingly are met with economic measures. But the statutes that authorize economic warfare actions are incredibly broad and recent administrations have interpreted these statutes in ways that risk running afoul of an expansive and free-form MQD. Second, "foreign affairs exceptionalism," in which the Court decides not to apply the MQD to statutes involving foreign affairs, is not likely to work well as a response because what is "foreign" and "domestic" cannot be easily distinguished and attempts to do so will have perverse consequences. The MQD raises serious problems for foreign affairs and national security. If the MQD is applied to domestic, but not foreign, delegations, then the executive branch will have an incentive to use broad foreign affairs delegations to accomplish domestic policy objectives in order to evade the safeguards and limits that attend domestic administrative action. At the same time, judges will have to police the porous boundary between "foreign" and "domestic," with especially high error costs because wrong decisions will affect national security. If the MQD is applied to economic delegations that touch foreign commerce, the most likely consequence is that judges--particularly lower court judges--will be put in the position of second-guessing executive branch decisionmaking on precisely those questions--economic foreign policy questions of deep economic and political significance--on which the political branches enjoy both constitutional primacy and institutional expertise. This result is troubling; judges lack the knowledge and training to make effective decisions bearing on foreign policy, and putting them in the position to do so contravenes the norms of our legal system.

BACKGROUND:Residual kidney function (RKF) is thought to exert beneficial effects through clearance of uremic toxins. However, the level of native kidney function where clearance becomes negligible is not known. METHODS:We aimed to assess whether levels of nonurea solutes differed among patients with 'clinically negligible' RKF compared with those with no RKF. The hemodialysis study excluded patients with urinary urea clearance >1.5 mL/min, below which RKF was considered to be 'clinically negligible'. We measured eight nonurea solutes from 1280 patients participating in this study and calculated the relative difference in solute levels among patients with and without RKF based on measured urinary urea clearance. RESULTS:The mean age of the participants was 57 years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7 ± 0.4 mL/min) and 66% had no RKF. Seven of the eight nonurea solute levels measured were significantly lower in patients with RKF than in those without RKF, ranging from -24% [95% confidence interval (CI) -31 to -16] for hippurate, -7% (-14 to -1) for trimethylamine-N-oxide and -4% (-6 to -1) for asymmetric dimethylarginine. The effect of RKF on plasma levels was comparable or more pronounced than that achieved with a 31% higher dialysis dose (spKt/Vurea 1.7 versus 1.3). Preserved RKF at 1-year follow-up was associated with a lower risk of cardiac death and first cardiovascular event. CONCLUSIONS:Even at very low levels, RKF is not 'negligible', as it continues to provide nonurea solute clearance. Management of patients with RKF should consider these differences.

ABSTRACT In a bid to save the planet from rising temperatures, the European Union is introducing a carbon border adjustment mechanism--essentially a levy on imports from countries with weak climate [...]

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

BackgroundAsymmetric (ADMA) and symmetric dimethylarginine (SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms, including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients.Study designPost hoc analysis of the Hemodialysis (HEMO) Study.Setting & participants1,276 prevalent hemodialysis patients with available samples 3 to 6 months after randomization.PredictorADMA and SDMA measured in stored specimens.OutcomesCardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbid conditions, albumin level, and residual kidney function).ResultsMean age of patients was 57±14 (SD) years, 63% were black, and 57% were women. Mean ADMA (0.9±0.2μmol/L) and SDMA levels (4.3±1.4μmol/L) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis ADMA or SDMA concentrations. In fully adjusted models, each doubling of ADMA level was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29-2.58), sudden cardiac death (1.79; 1.19-2.69), first cardiovascular event (1.50; 1.20-1.87), and any-cause death (1.44; 1.13-1.83). Compared to the lowest ADMA quintile (

Table of Contents I. Introduction 588 II. The Appellate Body and Precedent 590 A. How the AB Used Precedent 592 B. The Implications of the AB's Use of Precedenl III. [...], This Article argues that the World Trade Organization&apos;s Appellate Body (AB), or a successor body, must become more transparent in justifying its decision to rely (or not) on prior decisions. The AB&apos;s practice of precedent--which the United States cited as a cause of its decision to paralyze the AB by blocking new appointments--is similar to how it has approached "likeness" in nondiscrimination cases. It placed a lot of weight on whether two cases (or products) are sufficiently similar to be compared, and it spent relatively less time substantively justifying its treatment of prior cases. Because the WTO does not have a system of stare decisis, the AB and WTO panels generally must explain why they find prior decisions persuasive, rather than simply relying on similarity to justify carrying prior interpretations forward. The Article begins by examining and evaluating the results of a new study from Jeffrey Kucik and Sergio Puig, the first study to use a large dataset to study the AB&apos;s use of precedent. The Article then advances a framework for how WTO dispute panels should evaluate the relevance of prior cases in future disputes. The proposed approach would treat the comparison of cases as merely a threshold inquiry. If two cases are sufficiently alike and one party contests the applicability of the prior decision, then a tribunal must substantively justify its treatment of the prior decision in light of a variety of factors. In some instances, the result may be that the AB or a panel acknowledges that a prior interpretation was wrong and should not be followed. Openly analyzing the persuasive value of prior cases, and acknowledging when those cases should not be followed, would better promote the goals of relying on prior decisions--promoting predictability, transparency, and coherence in the law&apos;s application--as compared to deference to prior decisions based only on the similarity of two disputes.

The uremic syndrome is attributed to progressive retention of compounds that, under normal conditions, are excreted by the healthy kidneys. p-cresol sulfate (PCS), a prototype protein-bound uremic retention solute, has been shown to exert toxic effects in vitro. Recent studies have identified relations between increased levels of PCS and indoxyl sulfate (IS) and adverse clinical outcomes in hemodialysis patients. We explored the relationship between free and total PCS and IS with infection-related hospitalizations (IH) and septicemia in 2 cohorts, Choices for Healthy Outcomes in Caring for end-stage renal disease (ESRD) Study (CHOICE) and Hemodialysis Study (HEMO).We measured free and total levels of PCS and IS in stored specimens in CHOICE, a cohort of 464 incident hemodialysis patients enrolled in 1995 to 1998 and followed for an average of 3.4 years and in a prevalent dialysis cohort of 495 patients enrolled in HEMO from 1995 to 2000 and followed for an average of 4.4 years. We measured free PCS and IS using mass spectroscopy. The 2 cohorts were linked to United States Renal Data System (USRDS) Medicare billing records to ascertain IH over follow-up. We examined the association of free and total levels of PCS and IS with IH and septicemia using multilevel Poisson regression models adjusted for demographics, comorbidities, clinical factors, and laboratory tests including residual kidney function. We stratified patients a priori based on gastrointestinal (GI) disease as PCS and IS are produced in colon.In CHOICE, highest tertile of free PCS in multivariable model was associated with 50% higher risk of IH [95% CI = 1.01-2.23] compared with lowest tertile in patients with no-GI disease. A significant trend was noted between greater levels of free PCS and septicemia in no-GI disease group in both cohorts, while no association was noted in GI disease group. Total PCS concentrations were not associated with either IH or septicemia in either cohort. No significant risk of IH or septicemia was noted with higher levels of free or total IS in either GI or no-GI disease group.These results suggest an association between higher concentrations of free PCS and infection-related and sepsis-related hospitalizations in hemodialysis patients. Better methods of dialysis should be developed to evaluate the utility of removing PCS and its effect on the outcome and also therapies to decrease gastrointestinal tract production of uremic solutes.

One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.

INTRODUCTION 153 I. DECOUPLING TRADE REGULATION AND LABOR SUBSIDIZATION 161 A. The Costs and Benefits of Trade Liberalization 162 B. Decoupling Market Access from Government Support for Domestic Industries and [...], Since 1962, when Congress passed the Trade Expansion Act, every new U.S. trade deal has had the same essential bargain at its core. Congress agrees to give the president the power to lower trade barriers, while at the same time providing adjustment assistance for those workers displaced by competition with new imports. This bargain illustrates what I refer to as the Misalignment Thesis: when a legislative bargain is struck over two or more interdependent policies, the policy subject to more frequent or costlier renegotiation and implementation will be disfavored in the long run. In the trade context, the misalignment occurs because trade liberalization commitments are indefinite, enshrined in international agreements, and implemented by the executive branch; the adjustment assistance provisions are temporary, purely domestic, and require renegotiation and reauthorization in Congress. As a consequence, proponents of policies to help displaced workers must constantly renegotiate and defend laws to help their constituents. Moreover, they must do so within an institution, Congress, in which the transaction costs of securing favorable policy outcomes are very high. The result is that policies aimed at helping workers displaced by trade liberalization are chronically under supplied. Proponents of trade liberalization, on the other hand, never have to renegotiate their gains. Each trade agreement goes into the pocket of trade proponents, and then they move on to securing the next trade agreement. Nor does Congress maintain a meaningful role in the implementation of trade agreements. Once an agreement is in effect, implementation is left to the executive branch, where the transaction costs of enacting a trade-liberalizing agenda are quite low. This Article makes three contributions. First, it introduces the Misalignment Thesis in the context of U.S. trade policy. The Misalignment Thesis is a descriptive claim about how the structure of a legislative bargain influences the long-term stability and effectiveness of that bargain. Second, the Article introduces the normative corollary to the Misalignment Thesis: if political stability hinges on respecting the legislative bargain, interdependent policies should be subject to renegotiation on the same timeline and implementation on the same terms. In light of this prescription, I offer three concrete proposals for aligning trade liberalization and trade adjustment assistance in order to protect and promote the goals of both policies. Most importantly, I argue--contrary to most commentary--that the Trump Administration&apos;s proposal to limit the duration of trade agreements like NAFTA would better align trade liberalization and trade adjustment assistance. Third, the Article discusses the Misalignment Thesis&apos;s broader application to deregulatory bargains struck in a wide variety of fields, including transportation, telecommunications, and healthcare. The Misalignment Thesis suggests that deregulation often has unintended consequences because the structure of deregulatory bargains undermines their long-term effectiveness.

Abstract Background Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality. Methods We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index. Results Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043). Conclusions In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.