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Purpose: Little 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). Methods: Men 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. Results: Women (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%. Conclusion: Although 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 registration: ClinicalTrials.gov NCT01816776; March 22, 2013. [ABSTRACT FROM AUTHOR]

Aims Sleep disorder breathing is an important non-cardiovascular comorbidity in patients with heart failure (HF). However, central sleep apnoea (CSA) remains poorly diagnosed and treated. This post hoc analysis examined symptoms and quality of life in patients with CSA and HF following 12 months of transvenous phrenic nerve stimulation (TPNS) therapy. Methods and results Patients enrolled in the remedē System Pivotal trial were invited to complete self-reported questionnaires. Symptoms and responses to three validated questionnaires were examined. Percentage of patients noting an impairment was calculated at baseline. At 12 months, % of patients experiencing improvement, no change, or worsening was calculated. Shifts from symptom presence at baseline to absence at 12 months were assessed for those symptoms experienced by ≥50% of patients at baseline. Seventy-five patients were included. Most frequently reported symptoms were fatigue and daytime sleepiness. Following 12 months of TPNS, a variety of subjective improvements were observed; 45% of patients indicating cessation of daytime sleepiness, 44% cessation of fatigue/weakness, and 52% no longer having difficulty falling/staying asleep. Specific questions related to tiredness/fatigue, motivation, and chance of dozing provided an insight into potential areas of improvement. Furthermore, at least 60% of patients reported resolution of insomnia/fragmented sleep and snoring on therapy. Conclusion Adult patients with CSA and HF experience distressing symptoms and limitations. Transvenous phrenic nerve stimulation was found to improve many of these. Awareness of key symptoms or limitations patients experience can be used to inform the development of a CSA-specific patient questionnaire to identify CSA sooner and aid treatment decisions. [ABSTRACT FROM AUTHOR]

Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE. [ABSTRACT FROM AUTHOR]

The adequacy of hemodialysis is now assessed by measuring the removal of the single-solute urea. The urea clearance provided by contemporary dialysis is a large fraction of the blood flow through the dialyzer and therefore cannot be increased much further. Other solutes however likely contribute more than urea to the residual uremic illness suffered by hemodialysis patients. We here review methods which could be employed to increase the clearance of nonurea solutes. We will separately consider the clearances of free low-molecular-mass solutes, free larger solutes, and protein-bound solutes. New clinical studies will be required to test the extent to which increasing the clearance on nonurea solutes with these various characteristics can improve patients' health. [ABSTRACT FROM AUTHOR]

Background: Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI‐PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. Methods: This was a global, multicenter, open‐label, single‐arm, phase 2 trial of ADI‐PEG 20 and modified 5‐fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child‐Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression‐free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI‐PEG‐20 intramuscularly weekly at 36 mg/m2. Results: In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30‐85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%‐15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression‐free survival was 3.8 months (95% CI, 1.8‐6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6‐20.9 months). The most common grade ≥3 treatment‐related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Conclusions: Concurrent mFOLFOX6 plus ADI‐PEG 20 exhibited limited antitumor activity in patients with treatment‐refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Lay Summary: Arginine is an important nutrient for hepatocellular carcinoma (HCC).The depletion of arginine with pegylated arginine deiminase (ADI‐PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial.To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI‐PEG 20 and FOLFOX in the treatment of patients with refractory HCC.The study showed limited activity of ADI‐PEG 20 and FOLFOX in advanced HCC and was stopped early. Despite high‐level preclinical and early phase clinical data suggesting a potentiating effect of arginine depletion on 5‐fluorouracil, leucovorin, and oxaliplatin (FOLFOX) anticancer activity in hepatocellular carcinoma, a global, single‐arm, phase 2 study of pegylated arginine deiminase (ADI‐PEG 20) plus FOLFOX in patients with hepatocellular carcinoma who progressed on 2 lines of systemic therapy failed to meet its primary end point. There is no role for the combination of AGI‐PEG 20 and FOLFOX in advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

In kidney transplantation, precision medicine has already entered clinical practice. Donor and recipient human leucocyte antigen (HLA) regions are genotyped in two class 1 and usually three class 2 loci, and the individual degree of sensitization against alloimmune antigens is evaluated by the detection of anti-HLA donor-specific antibodies. Recently, the contribution of non-HLA mismatches to outcomes such as acute T- and B-cell-mediated rejection and even long-term graft survival was described. Tracking of specific alloimmune T- and B-cell clones by next generation sequencing and refinement of the immunogenicity of allo-epitopes specifically in the interaction with HLA and T- and B-cell receptors may further support individualized therapy. Although the choices of maintenance immunosuppression are rather limited, individualization can be accomplished by adjustment of dosing based on these risk predictors. Finally, supplementing histopathology by a transcriptomics analysis allows for a biological interpretation of the histological findings and avoids interobserver variability of results. In contrast to transplantation, the prescription of hemodialysis therapy is far from precise. Guidelines do not consider modifications by age, diet or many comorbid conditions. Patients with residual kidney function routinely receive the same treatment as those without. A major barrier hitherto is the definition of 'adequate' treatment based on urea removal. Kt / V urea and related parameters neither reflect the severity of uremic symptoms nor predict long-term outcomes. Urea is poorly representative for numerous other compounds that accumulate in the body when the kidneys fail, yet clinicians prescribe treatment based on its measurement. Modern technology has provided the means to identify other solutes responsible for specific features of uremic illness and their measurement will be a necessary step in moving beyond the standardized prescription of hemodialysis. [ABSTRACT FROM AUTHOR]

Nocturnal hypoxemic burden is established as a robust prognostic metric of sleep-disordered breathing (SDB) to predict mortality and treating hypoxemic burden may improve prognosis. The aim of this study was to evaluate improvements in nocturnal hypoxemic burden using transvenous phrenic nerve stimulation (TPNS) to treat patients with central sleep apnea (CSA). The remedē System Pivotal Trial population was examined for nocturnal hypoxemic burden. The minutes of sleep with oxygen saturation < 90% significantly improved in Treatment compared with control (p <.001), with the median improving from 33 min at baseline to 14 min at 6 months. Statistically significant improvements were also observed for average oxygen saturation and lowest oxygen saturation. Hypoxemic burden has been demonstrated to be more predictive for mortality than apnea–hypopnea index (AHI) and should be considered a key metric for therapies used to treat CSA. Transvenous phrenic nerve stimulation is capable of delivering meaningful improvements in nocturnal hypoxemic burden. There is increasing interest in endpoints other than apnea–hypopnea index in sleep-disordered breathing. Nocturnal hypoxemia burden may be more predictive for mortality than apnea–hypopnea index in patients with poor cardiac function. Transvenous phrenic nerve stimulation is capable of improving nocturnal hypoxemic burden. [ABSTRACT FROM AUTHOR]

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/Vurea, 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. [ABSTRACT FROM AUTHOR]

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 (sp Kt/V urea 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 FROM AUTHOR]

Background: Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children. Methods: PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65–1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels. Results: The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69 ± 0.13, r2 0.84, p < 0.001). Production of PU rose in proportion with BSA (r2 0.57, p < 0.001). The pretreatment plasma level of PU was significantly higher in smaller children (r2 0.20, p = 0.051) while the pretreatment level of ureaN did not vary with size. Conclusions: Prescribing dialysis based on urea kinetics may leave uremic solutes at higher levels in small children. Measurement of a solute produced proportional to BSA may provide a better index of dialysis adequacy than measurement of urea. [ABSTRACT FROM AUTHOR]

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n + 10) or bilateral nephrectomy (n + 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSFto-plasma ultrafiltrate ratios of 0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 = 0.07 in control rats to 0.09 = 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail. [ABSTRACT FROM AUTHOR]

In this article, the authors expand upon their previously published findings (9) on the use of Spanish-language broadcasting. Discriminant analysis was used to produce a profile of Mexican-Americans who prefer Spanish-language television over English-language television. A comparison of this profile with that previously derived for Spanish-language radio listeners indicates that while there is some overlap between these audiences, they are far from identical. The implications of these results should be considered by those anticipating implementing an ethnic segmentation strategy utilizing Spanish-language radio or television. [ABSTRACT FROM AUTHOR]

The article reports a study measuring the cognitive responses and extra-product expectations fostered by U.S. television commercials for black and white children. The article addresses earlier research related to cognitive development and incidental learning of blacks and whites and develops two hypotheses: that regardless of age, white children would indicate a higher understanding of television commercials and that older children would indicate a higher understanding of the commercials. Details of the implementation of the study and the results as they relate to perceptions of specific commercials and the hypotheses are presented. The implications of the results are discussed relative to health and nutrition, alienation, distrust, awareness, and government regulation of commercials.

Recent interest in male mate choice has prompted a re-examination of widely held beliefs regarding sex roles in animal mating systems. It is now known that males can be choosy based on female quality, but studies which directly compare the aspects of female quality and their influence on male mate choice are relatively rare. The brush-legged wolf spider Schizocosa ocreata (Hentz) has a well-studied male courtship display, which shows evidence of male mate choice based on female mating history and foraging history, as well as possible effects of experience and rearing environment. This makes it an excellent system to compare the importance of these 2 female states and examine how the choice patterns they give rise to may be influenced by the environment. By examining male courtship and female behavior under different circumstances and across environmental experience conditions, the relative effects of these factors can be inferred. Evidence collected in this study suggests that female mating status is the dominant predictor of mate choice, with males generally courting virgin females more vigorously regardless of context, as well as females showing higher levels of receptivity when unmated. An important exception to this trend is seen in field-reared males and their female partners, who show less behavioral differences based on female state, suggesting that this preference is not static and may be influenced by experience. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN. [ABSTRACT FROM AUTHOR]

All over the world, states are renegotiating international investment agreements at a rapid clip. Largely unnoticed, clauses in investment agreements that authorize or mandate renegotiation under specified conditions have facilitated these efforts. This article is the first to describe and analyze the variation in these renegotiation clauses. We develop a typology of renegotiation clauses in which such clauses vary along two dimensions. They range on a continuum from a full commitment to renegotiate to only a partial commitment. Renegotiation clauses can also call for full scope renegotiation or partial scope renegotiation. The literature on renegotiating international agreements has heretofore overlooked the existence and purposes of provisions requiring partial scope renegotiation. Partial scope renegotiation represents a departure from the 'single undertaking' model of negotiations common to international economic law. By altering both the scope of, and commitment to, renegotiation, parties can conclude agreements today while deferring resolution of difficult issues to the future. At the same time, they can also constrain the possibility of opportunism by limiting the subject matter under renegotiation. Most importantly, partial scope renegotiation offers a method to reduce the critical tension underlying the modern international economic order: the pace and degree to which non-Western style economies are required to liberalize their markets. [ABSTRACT FROM AUTHOR]

Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated. [ABSTRACT FROM AUTHOR]

The convention of prescribing hemodialysis on a thrice weekly schedule began empirically when it seemed that this frequency was convenient and likely to treat symptoms for a majority of patients. Later, when urea was identified as the main target and marker of clearance, studies supported the prevailing notion that thrice weekly dialysis provided appropriate clearance of urea. Today, national guidelines on hemodialysis from most countries recommend patients receive at least thrice weekly therapy. However, resource constraints in low- and middle-income countries (LMIC) have resulted in a substantial proportion of patients using less frequent hemodialysis in these settings. Observational studies of patients on twice weekly dialysis show that twice weekly therapy has noninferior survival rates compared with thrice weekly therapy. In fact, models of urea clearance also show that twice weekly therapy can meet urea clearance 'targets' if patients have significant residual function or if they follow a protein-restricted diet, as may be common in LMIC. Greater reliance on twice weekly therapy, at least at the start of hemodialysis, therefore has potential to reduce health care costs and increase access to renal replacement therapy in low-resource settings; however, randomized control trials are needed to better understand long-term outcomes of twice versus thrice weekly therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

On February 4, 2016, the United States and eleven other countries signed the Trans-Pacific Partnership (“TPP”)—the most far-reaching free trade agreement since the World Trade Organization’s founding in 1995. Unlike most prior trade agreements, the TPP’s purported benefits do not come primarily from reductions in tariffs paid on goods at the border. Instead, they flow from assumptions that so-called non-tariff barriers— such as discrimination against foreign investors or service providers—will fall significantly under the TPP. [ABSTRACT FROM AUTHOR]

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1 year ( n = 410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D ( p = 0.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10 % increase in sST2 1.11 (1.04-1.20), p = 0.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification. [ABSTRACT FROM AUTHOR]

Patients maintained on standard three times weekly hemodialysis have a high mortality rate and a limited quality of life. Some of this illness is due to systemic diseases that have caused kidney failure, and thus may be irreversible. But we presume that imperfect replacement of normal kidney function by dialysis contributes importantly. Patients on hemodialysis are subject to fluctuations in extracellular fluid volume and inorganic ion concentrations and their plasma levels of many organic waste solutes remain very high. It is thus natural to suppose that their health could be improved by increasing the intensity of dialysis treatment. But despite a great deal of work over the past 20 years, evidence that such improvement can be obtained is generally lacking. Specific benefits can indeed be achieved. Patients who cannot control their intradialytic weight gains or plasma phosphate levels with standard therapy can benefit from extending treatment time. But we cannot promise the average patient that longer or more frequent treatment will reduce mortality or improve the quality of life. [ABSTRACT FROM AUTHOR]

Background: The protein-bound solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) accumulate to high plasma levels in renal failure and have been associated with adverse events. The clearance of these bound solutes can be altered independently of the urea clearance by changing the dialysate flow and dialyzer size. This study tested whether a sustained difference in clearance would change the plasma levels of PCS and IS. Methods: Fourteen patients on thrice-weekly nocturnal hemodialysis completed a crossover study of two periods designed to achieve widely different bound solute clearances. We compared the changes in pre-dialysis plasma PCS and IS levels from baseline over the course of the two periods. Results: The high-clearance period provided much higher PCS and IS clearances than the low-clearance period (PCS: 23 ± 4 mL/min versus 12 ± 3 mL/min, P < 0.001; IS: 30 ± 5 mL/min versus 17 ± 4 mL/min, P < 0.001). Despite the large difference in clearance, the high-clearance period did not have a different effect on PCS levels than the low-clearance period [from baseline, high: +11% (−5, +37) versus low: −8% (−18, +32), (median, 25th, 75th percentile), P = 0.50]. In contrast, the high-clearance period significantly lowered IS levels compared with the low-clearance period [from baseline, high: −4% (−17, +1) versus low: +22% (+14, +31), P < 0.001). The amount of PCS removed in the dialysate was significantly greater at the end of the high-clearance period [269 (206, 312) versus 199 (111, 232) mg per treatment, P < 0.001], while the amount of IS removed was not different [140 (87, 196) versus 116 (89, 170) mg per treatment, P = 0.15]. Conclusions: These findings suggest that an increase in PCS generation prevents plasma levels from falling when the dialytic clearance is increased. Suppression of solute generation may be required to reduce plasma PCS levels in dialysis patients. [ABSTRACT FROM AUTHOR]

This article argues that the form of international agreements - binding hard law agreements versus non-binding soft law agreements - can be partially explained by states' interests in promoting renegotiation in the presence of uncertainty and shifting power. I make this argument in three steps. First, I explain that states regularly use unilateral non-compliance as a renegotiation strategy. Second, I argue that making an agreement soft facilitates this use of unilateral non-compliance. Third, I analyse the conditions - uncertainty characterized by common interests (but not uncertainty characterized by distributive concerns) and shifting power - under which facilitating renegotiation through soft law will appeal to states. In particular, I argue that in the presence of these conditions preventing renegotiation creates longterm costs for states that can inhibit short-term cooperation. In effect, under these conditions the shadow of the future can inhibit cooperation rather than support it, as is conventionally thought. These conditions are common to many major contemporary subjects of international cooperation in a way they were not during the latter half of the 20th century, partially explaining the increased importance of soft law to contemporary international governance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

International negotiations struggle to keep pace with global problems like climate change. To fill this gap, local governments increasingly take matters into their own hands. For example, to promote the benefits of clean energy, a local government might give subsidies to renewable energy companies. Since 2001, California has given $2 billion in such subsidies, while states ranging from Minnesota to Kansas and Mississippi have doled out hundreds of millions OF dollars each. Cities, such as Austin and Los Angeles, have also gotten into the act, contributing millions to renewable energy firms. To build support for these measures, the local government might condition the subsidy on the recipient's use OF components manufactured in the locality. In 2013, the World Trade Organization (WTO) said these kinds of subsidies are unlawful because they discriminate against foreign products. This Article argues that the decision fails to account for the public goods generated by such programs, and suggests a new way for the WTO to review local subsidy programs that would balance the WTO's impulse to protect international trade with the valuable global public goods such programs promise. To make the case, I report on the results OF an original fifty-state survey. I identify forty-four state renewable energy programs in twenty-three states within the United States that violate the WTO's 2013 decision. I argue that these programs can increase global welfare in the aggregate, notwithstanding their discriminatory nature. They can do so by creating political support at the local level for renewable energy programs that might not pass otherwise. Local governments internalize few of the benefits from providing global public goods, such as reducing greenhouse gas emissions through costly investments in renewable energy technology. Local efforts to address global public goods problems thus have to be linked to a concentrated benefit within the enacting jurisdiction. Protectionist measures that discriminate against foreign products provide this link, mobilizing local economic interests to pass global public goods programs that create benefits in other jurisdictions. Reforming international trade law to allow these linkages is imperative if local governments are to continue to play a role in solving global problems. [ABSTRACT FROM AUTHOR]

Background: Colon microbes produce a large number of organic compounds that are foreign to mammalian cell metabolism. Summary: Some of the compounds made by microbes are absorbed in the colon and then normally excreted by the kidneys. Accumulation of these compounds in the plasma as uremic solutes may contribute to illness in patients whose kidneys have failed. Mass spectrometry is expanding our knowledge of the chemical identity of the colon-derived uremic solutes, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other uremic solutes. Key Messages: 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. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Objectives: 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. Design, Setting, Participants and Measurements: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

The future of international lawmaking is in peril. Both trade and climate negotiations have failed to produce a multilateral agreement since the mid-1990s, while the U.N. Security Council has been unable to comprehensively respond to the humanitarian crisis in Syria. In response to multilateralism's retreat, many prominent commentators have called for international institutions to be given the power to bind holdout states--often rising or reluctant powers such as China and the United States--without their consent. In short, these proposals envision international law traveling the road taken by federal systems such as the United States and the European Union: from contractual lawmaking in which states are free to make commitments to each other and free to decline commitments to which they object, to legislative lawmaking in which states--through international institutions--make collective decisions about what legal obligations to undertake. In this Article, I argue that international legislatures--institutions such as the Ministerial Conference of the World Trade Organisation (WTO) and the Conference of the Parties to the United Nations Framework Convention on Climate Change (UNFCCC) that make collective decisions about the legal obligations that members may make to each other-- are already numerous. But international legislatures of the kind envisioned by global government's proponents are unlikely to emerge because the rise of international legislatures is not driven by the desire to reduce the role of holdouts. To the contrary, I contend that legislatures exist to magnify the ability of holdouts to stall and even paralyse lawmaking. Further, I argue that the increased importance of holdouts is, within limits, beneficial for international lawmaking. In contractual lawmaking states are free to expel holdouts from negotiations and make commitments among a smaller group of the willing. Moving from contract to legislation removes this freedom. In the U.S. Congress, the minority's holdup power is created through procedures such as the filibuster in the Senate and the committee system, under which a proposal with majority support can nevertheless fail to obtain a floor vote due to the opposition of a few key committee members. In international legislatures, this holdup poiver is created chiefly through a process known as "adoption," which requires that an institution as a whole, usually by consensus, approve an agreement before any individual member state can sign and ratify it. Adoption does not imply that member states will ratify or be bound by the agreement; as with agreements like the Kyoto Protocol, some states that vote for adoption will not ratify the agreement. Instead, one of the adoption procedure's main effects is to empower states with no intention of joining a treaty to nevertheless veto its enactment by cooperation-minded The increased holdup power created by legislatures is a feature, not a bug. This holdup power is beneficial because it allows states to enforce legislative bargains: deals in which a state makes concessions in one negotiation in exchange for another state's concessions in a later related negotiation. Such iterative negotiations--found in free trade talks, environmental regimes, and efforts to establish a robust international criminal law--are a hallmark of modern international lawmaking. Absent some enforcement mechanism, though, states would be unwilling to "trade votes" across negotiations out offear that other parties would not uphold their end of the bargain. International legislatures thus do not lubricate international lawmaking by allowing states to be bound against their will. Quite the opposite, international legislatures facilitate lawmaking by allowing states to stall lawmaking in the event that a legislative bargain is violated. This rationale for holdup power explains a number of pules in international law. In particular, it explains why international legislatures have not adopted robust majoritarian voting and further clarifies how international institutions enforce international law, which critics often claim is unenforceable [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time- and frequency-domain analyses compared 24-h HRV in 22 CR individuals aged 35-82 years and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group ( P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in heart rate (HR) and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs. [ABSTRACT FROM AUTHOR]

Background. The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis.Methods. Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min.Results. Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27 ± 9 versus 14 ± 6 mL/min) and indoxyl sulfate (IS: 26 ± 8 versus 14 ± 5 mL/min) without altering the clearance of urea (204 ± 20 versus 193 ± 16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375 ± 200 versus 207 ± 86 mg/session; IS: 201 ± 137 versus 153 ± 74 mg/session), while urea removal was not different.Conclusions. The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/Vurea during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity. [ABSTRACT FROM PUBLISHER]

Aims The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial. Methods and results This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58–6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis. Conclusion Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement. [ABSTRACT FROM PUBLISHER]