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Flanking policies – policies that aim to address potential negative effects of trade liberalization, and/or the concerns of domestic stakeholders regarding those negative effects, and that are either legally or factually linked to trade liberalization – have been a critical component of international trade policy since at least 1962. Over the years, however, flanking policies have changed. This Article argues that there is a heretofore unnoticed distinction between what I term first-generation flanking policies and second-generation flanking policies. Specifically, first-generation flanking policies target negative economic effects, or costs, of trade liberalization experienced within the enacting country. Trade adjustment assistance is the paradigmatic example. By contrast, second-generation flanking policies target non-economic costs that arise outside of the enacting country. Examples include the European Union's Carbon Border Adjustment Mechanism, Deforestation-free Products Regulation, and the United States' Uyghur Forced Labor Prevention Act. Because second-generation flanking policies directly target foreign activity, they often employ more trade-distorting policies – tariffs, imports bans, and associated administrative hurdles for imports – than first-generation flanking policies, which more often relied on domestic subsidies. Moreover, they reflect a significant reorientation of the limits of state authority in international trade law. Whereas authority to tax and regulate production in international economic law has historically been based primarily on a territorial link to productive activity, second-generation flanking policies target production but rely on a territorial nexus with consumption of goods and services.

This Essay argues that trade agreements may overly constrain the ability of states to regulate supply chains for critical products such as medical supplies. Free trade agreements (FTAs) may exacerbate supply chain concentration, especially through loose rules of origin. And WTO rules constrain preventative regulation of supply chain risks designed to prevent a crisis, while providing exceptions for aggressive action only in the face of a crisis. Thus, WTO members risk flouting WTO rules if they do not limit aggressive, preventative supply chain regulation.

The 2016 presidential election was one of the most divisive in recent memory, but it produced a surprising bipartisan consensus. Donald Trump, Hillary Clinton, and Bernie Sanders all agreed that U.S. trade agreements should be, but are not, “fair.” Although it achieved broad consensus only recently, the critique that U.S. trade agreements are unfair has been around for decades. Since 1992, much of this fairness critique has focused on ensuring that trade liberalization does not undermine noncommercial values, such as environmental protection and labor conditions. Beginning with the negotiation and ratification of the North American Free Trade Agreement (NAFTA) in the early 1990s, governments have responded by including in their trade agreements a prohibition on the selective enforcement of environmental and labor laws. This ban—a central component of efforts to make sure that free trade agreements are fair—aims to prevent a global race to the bottom in environmental and labor standards. These efforts have fallen wide of the mark. This Article makes two novel contributions. First, it demonstrates empirically that selective enforcement is considerably more pervasive than commonly thought. But contemporary selective enforcement is the reverse of the kind of selective enforcement that has traditionally concerned trade critics. Instead of selectively enforcing environmental and labor laws to gain a trade advantage, governments selectively enforce trade laws in ways that undermine environmental and labor interests. This Article presents data from trade enforcement actions in the energy and fisheries sectors to demonstrate this claim. In both sectors, trade laws are enforced exclusively against natural resource substitutes, such as renewable energy and farmed fish. The natural resources with which these products compete, fossil fuels and wild fish, benefit from the same allegedly unlawful conduct but are not targeted for enforcement. Second, this Article presents a theory of how selective enforcement of trade law distorts markets to the detriment of the environment. It argues that selective enforcement is an implicit subsidy for products that are not targeted for enforcement but benefit from the same allegedly unlawful conduct as targeted products. This Article presents evidence that selective enforcement in the energy and fisheries sectors has indeed caused these effects. This Article concludes by suggesting how governments can reform trade law enforcement to address the pernicious effects of selective enforcement. Governments have acted to address other kinds of selective enforcement in the past, so reform is politically feasible. Nevertheless, given the current political climate, reforms should concentrate on increasing trade law enforcement across the board.

The international trade regime has seen an explosion of challenges to government support for renewable energy in recent years, yet fossil fuel subsidies, which dwarf renewable energy subsidies, have remained unchallenged. Existing explanations for this puzzling discrepancy have focused on four rationales: major fossil fuel exporters have not historically been members of the General Agreement on Tariffs and Trade/World Trade Organization (WTO); WTO subsidies rules are inadequate to deal with the specifics of the fossil fuel trade; nations have developed separate institutions to govern energy; and all states have fossil fuel subsidies, so a challenge to one country’s subsidies will prompt a reciprocal challenge. This article makes two contributions. First, it uses a survey of existing renewable energy trade disputes to critique the existing explanations. Most importantly, the article shows that the threat of reciprocal litigation exists in the renewable energy sector, and that WTO subsidies rules are rarely used to challenge renewable energy subsidies. Hence, neither the threat of reciprocal litigation nor the relative ease of applying WTO subsidies rules explains the discrepancy in the number of disputes. Second, the article hypothesizes that the economic diversification of energy-producing countries is correlated with and may drive whether energy-producing countries face WTO challenges to their energy support policies. Most major fossil fuel producers lack significant non-fossil fuel exports that could be restricted in order to induce them to reform their fossil fuel policies, the usual mechanism for enforcing a WTO judgment. States may also be more likely to challenge new, rather than long-standing, trade restrictions. This suggests that trade challenges will arise more frequently where innovation leads to competition and a demand for new trade restrictions (as in renewable energy), as opposed to in mature sectors of the economy (i.e., the fossil fuel industry). Economic diversification, in turn, is a good predictor of innovation.

Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients. We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA. Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses. Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

Pruritus is a common debilitating symptom experienced by hemodialysis patients. Treatment is difficult because the cause of uremic pruritus is not known. This study addressed the hypothesis that pruritus is caused by solutes that accumulate in the plasma when the kidneys fail. We sought to identify solutes responsible for uremic pruritus using metabolomic analysis to compare the plasma of hemodialysis patients with severe pruritus versus mild/no pruritus. Pruritus severity in hemodialysis patients was assessed using a 100-mm visual analogue scale (VAS), with severe pruritus defined as >70 mm and mild/no pruritus defined as <10 mm. Twelve patients with severe pruritus (Itch) and 24 patients with mild/no pruritus (No Itch) were included. Pre-treatment plasma and plasma ultrafiltrate were analyzed using an established metabolomic platform (Metabolon, Inc.). To identify solutes associated with pruritus, we compared the average peak area of each solute in the Itch patients to that of the No Itch patients using the false discovery rate (q value) and principal component analysis. Dialysis vintage, Kt/V urea , and serum levels of calcium, phosphorus, PTH, albumin, ferritin, and hemoglobin were similar in the Itch and No Itch patients. Metabolomic analysis identified 1,548 solutes of which 609 were classified as uremic. No difference in the plasma or plasma ultrafiltrate levels of any solute or group of solutes was found between the Itch and No Itch patients. Metabolomic analysis of hemodialysis patients did not reveal any solutes associated with pruritus. A limitation of metabolomic analysis is that the solute of interest may not be included in the metabolomic platform’s chemical library. A role for uremic solutes in pruritus remains to be established.

Better knowledge of the uremic solutes that accumulate when the kidneys fail could lead to improved renal replacement therapy. This study employed the largest widely available metabolomic platform to identify such solutes. Plasma and plasma ultrafiltrate from 6 maintenance hemodialysis (HD) patients and 6 normal controls were first compared using a platform combining gas and liquid chromatography with mass spectrometry. Further studies compared plasma from 6 HD patients who had undergone total colectomy and 9 with intact colons. We identified 120 solutes as uremic including 48 that had not been previously reported to accumulate in renal failure. Combination of the 48 newly identified solutes with those identified in previous reports yielded an extended list of more than 270 uremic solutes. Among the solutes identified as uremic in the current study, 9 were shown to be colon-derived, including 6 not previously identified as such. Literature search revealed that many uremic phenyl and indole solutes, including most of those shown to be colon-derived, come from plant foods. Some of these compounds can be absorbed directly from plant foods and others are produced by colon microbial metabolism of plant polyphenols that escape digestion in the small intestine. A limitation of the metabolomic method was that it underestimated the elevation in concentration of uremic solutes which were measured using more quantitative assays.

PurposeLittle is known about sex differences in the treatment of central sleep apnea (CSA). Our post hoc analysis of the remedē System Pivotal Trial aimed to determine sex-specific differences in the safety and effectiveness of treating moderate to severe CSA in adults with transvenous phrenic nerve stimulation (TPNS).MethodsMen and women enrolled in the remedē System Pivotal Trial were included in this post hoc analysis of the effect of TPNS on polysomnographic measures, Epworth Sleepiness Scale, and patient global assessment for quality of life.ResultsWomen (n = 16) experienced improvement in CSA metrics that were comparable to the benefits experienced by men (n = 135), with central apneas being practically eliminated post TPNS. Women experienced improvement in sleep quality and architecture that was comparable to men post TPNS. While women had lower baseline apnea hypopnea index than men, their quality of life was worse at baseline. Additionally, women reported a 25-percentage point greater improvement in quality of life compared to men after 12 months of TPNS therapy. TPNS was found to be safe in women, with no related serious adverse events through 12 months post-implant, while men had a low rate of 10%.ConclusionAlthough women had less prevalent and less severe CSA than men, they were more likely to report reduced quality of life. Transvenous phrenic nerve stimulation may be a safe and effective tool in the treatment of moderate to severe CSA in women. Larger studies of women with CSA are needed to confirm our findings.Clinical trial registrationClinicalTrials.gov NCT01816776; March 22, 2013.

There is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis.