Hemispheric black carbon increase after the 13th-century Maori arrival in New Zealand.

New Zealand was among the last habitable places on earth to be colonized by humans1. Charcoal records indicate that wildfires were rare prior to colonization and widespread following the 13th- to 14th-century Maori settlement2, but the precise timing and magnitude of associated biomass-burning emissions are unknown1,3, as are effects on light-absorbing black carbon aerosol concentrations over the pristine Southern Ocean and Antarctica4. Here we used an array of well-dated Antarctic ice-core records to show that while black carbon deposition rates were stable over continental Antarctica during the past two millennia, they were approximately threefold higher over the northern Antarctic Peninsula during the past 700 years. Aerosol modelling5 demonstrates that the observed deposition could result only from increased emissions poleward of 40° S-implicating fires in Tasmania, New Zealand and Patagonia-but only New Zealand palaeofire records indicate coincident increases. Rapid deposition increases started in 1297 (±30 s.d.) in the northern Antarctic Peninsula, consistent with the late 13th-century Maori settlement and New Zealand black carbon emissions of 36 (±21 2 s.d.) Gg y-1 during peak deposition in the 16th century. While charcoal and pollen records suggest earlier, climate-modulated burning in Tasmania and southern Patagonia6,7, deposition in Antarctica shows that black carbon emissions from burning in New Zealand dwarfed other preindustrial emissions in these regions during the past 2,000 years, providing clear evidence of large-scale environmental effects associated with early human activities across the remote Southern Hemisphere.

Industrial-era decline in subarctic Atlantic productivity.

Marine phytoplankton have a crucial role in the modulation of marine-based food webs1, fishery yields2 and the global drawdown of atmospheric carbon dioxide3. However, owing to sparse measurements before satellite monitoring in the twenty-first century, the long-term response of planktonic stocks to climate forcing is unknown. Here, using a continuous, multi-century record of subarctic Atlantic marine productivity, we show that a marked 10 ± 7% decline in net primary productivity has occurred across this highly productive ocean basin over the past two centuries. We support this conclusion by the application of a marine-productivity proxy, established using the signal of the planktonic-derived aerosol methanesulfonic acid, which is commonly identified across an array of Greenlandic ice cores. Using contemporaneous satellite-era observations, we demonstrate the use of this signal as a robust and high-resolution proxy for past variations in spatially integrated marine productivity. We show that the initiation of declining subarctic Atlantic productivity broadly coincides with the onset of Arctic surface warming4, and that productivity strongly covaries with regional sea-surface temperatures and basin-wide gyre circulation strength over recent decades. Taken together, our results suggest that the decline in industrial-era productivity may be evidence of the predicted5 collapse of northern Atlantic planktonic stocks in response to a weakened Atlantic Meridional Overturning Circulation6-8. Continued weakening of this Atlantic Meridional Overturning Circulation, as projected for the twenty-first century9,10, may therefore result in further productivity declines across this globally relevant region.

Nonlinear rise in Greenland runoff in response to post-industrial Arctic warming.

The Greenland ice sheet (GrIS) is a growing contributor to global sea-level rise1, with recent ice mass loss dominated by surface meltwater runoff2,3. Satellite observations reveal positive trends in GrIS surface melt extent4, but melt variability, intensity and runoff remain uncertain before the satellite era. Here we present the first continuous, multi-century and observationally constrained record of GrIS surface melt intensity and runoff, revealing that the magnitude of recent GrIS melting is exceptional over at least the last 350 years. We develop this record through stratigraphic analysis of central west Greenland ice cores, and demonstrate that measurements of refrozen melt layers in percolation zone ice cores can be used to quantifiably, and reproducibly, reconstruct past melt rates. We show significant (P < 0.01) and spatially extensive correlations between these ice-core-derived melt records and modelled melt rates5,6 and satellite-derived melt duration4 across Greenland more broadly, enabling the reconstruction of past ice-sheet-scale surface melt intensity and runoff. We find that the initiation of increases in GrIS melting closely follow the onset of industrial-era Arctic warming in the mid-1800s, but that the magnitude of GrIS melting has only recently emerged beyond the range of natural variability. Owing to a nonlinear response of surface melting to increasing summer air temperatures, continued atmospheric warming will lead to rapid increases in GrIS runoff and sea-level contributions.

Abrupt ice-age shifts in southern westerly winds and Antarctic climate forced from the north.

The mid-latitude westerly winds of the Southern Hemisphere play a central role in the global climate system via Southern Ocean upwelling1, carbon exchange with the deep ocean2, Agulhas leakage (transport of Indian Ocean waters into the Atlantic)3 and possibly Antarctic ice-sheet stability4. Meridional shifts of the Southern Hemisphere westerly winds have been hypothesized to occur5,6 in parallel with the well-documented shifts of the intertropical convergence zone7 in response to Dansgaard-Oeschger (DO) events- abrupt North Atlantic climate change events of the last ice age. Shifting moisture pathways to West Antarctica8 are consistent with this view but may represent a Pacific teleconnection pattern forced from the tropics9. The full response of the Southern Hemisphere atmospheric circulation to the DO cycle and its impact on Antarctic temperature remain unclear10. Here we use five ice cores synchronized via volcanic markers to show that the Antarctic temperature response to the DO cycle can be understood as the superposition of two modes: a spatially homogeneous oceanic 'bipolar seesaw' mode that lags behind Northern Hemisphere climate by about 200 years, and a spatially heterogeneous atmospheric mode that is synchronous with abrupt events in the Northern Hemisphere. Temperature anomalies of the atmospheric mode are similar to those associated with present-day Southern Annular Mode variability, rather than the Pacific-South American pattern. Moreover, deuterium-excess records suggest a zonally coherent migration of the Southern Hemisphere westerly winds over all ocean basins in phase with Northern Hemisphere climate. Our work provides a simple conceptual framework for understanding circum-Antarctic temperature variations forced by abrupt Northern Hemisphere climate change. We provide observational evidence of abrupt shifts in the Southern Hemisphere westerly winds, which have previously documented1-3 ramifications for global ocean circulation and atmospheric carbon dioxide. These coupled changes highlight the necessity of a global, rather than a purely North Atlantic, perspective on the DO cycle.

North Atlantic jet stream projections in the context of the past 1,250 years.

Reconstruction of the North Atlantic jet stream (NAJ) presents a critical, albeit largely unconstrained, paleoclimatic target. Models suggest northward migration and changing variance of the NAJ under 21st-century warming scenarios, but assessing the significance of such projections is hindered by a lack of long-term observations. Here, we incorporate insights from an ensemble of last-millennium water isotope-enabled climate model simulations and a wide array of mean annual water isotope ([Formula: see text]O) and annually accumulated snowfall records from Greenland ice cores to reconstruct North Atlantic zonal-mean zonal winds back to the 8th century CE. Using this reconstruction we provide preobservational constraints on both annual mean NAJ position and intensity to show that late 20th- and early 21st-century NAJ variations were likely not unique relative to natural variability. Rather, insights from our 1,250 year reconstruction highlight the overwhelming role of natural variability in thus far masking the response of midlatitude atmospheric dynamics to anthropogenic forcing, consistent with recent large-ensemble transient modeling experiments. This masking is not projected to persist under high greenhouse gas emissions scenarios, however, with model projected annual mean NAJ position emerging as distinct from the range of reconstructed natural variability by as early as 2060 CE.

Chylous Ascites: Reassessment of Diagnostic Criteria in Patients With Portal Hypertension.

INTRODUCTION: The triglyceride (TG) threshold for diagnosis of chylous ascites in patients with portal hypertension remains uncertain. METHODS: Retrospective analysis of lipoprotein electrophoresis was conducted in 286 consecutive ascites samples. RESULTS: Ascitic TG ≥ 81 mg/dL is 95.4% sensitive and 94.6% specific for chylous ascites diagnosed by the presence of significant chylomicron population. DISCUSSION: The cutoff for chylous ascites diagnosis should be TG ≥ 81 mg/dL.

A mathematical model of the within-host kinetics of SARS-CoV-2 neutralizing antibodies following COVID-19 vaccination.

Compelling evidence continues to build to support the idea that SARS-CoV-2 Neutralizing Antibody (NAb) levels in an individual can serve as an important indicator of the strength of protective immunity against infection. It is not well understood why NAb levels in some individuals remain high over time, while in others levels decline rapidly. In this work, we present a two-state mathematical model of within-host NAb dynamics in response to vaccination. By fitting only four host-specific parameters, the model is able to capture individual-specific NAb levels over time as measured by the AditxtScore™ for NAbs. The model can serve as a foundation for predicting NAb levels in the long-term, understanding connections between NAb levels, protective immunity, and breakthrough infections, and potentially guiding decisions about whether and when a booster vaccination may be warranted.

The magnitude and impact of the 431 CE Tierra Blanca Joven eruption of Ilopango, El Salvador.

The Tierra Blanca Joven (TBJ) eruption from Ilopango volcano deposited thick ash over much of El Salvador when it was inhabited by the Maya, and rendered all areas within at least 80 km of the volcano uninhabitable for years to decades after the eruption. Nonetheless, the more widespread environmental and climatic impacts of this large eruption are not well known because the eruption magnitude and date are not well constrained. In this multifaceted study we have resolved the date of the eruption to 431 ± 2 CE by identifying the ash layer in a well-dated, high-resolution Greenland ice-core record that is >7,000 km from Ilopango; and calculated that between 37 and 82 km3 of magma was dispersed from an eruption coignimbrite column that rose to ∼45 km by modeling the deposit thickness using state-of-the-art tephra dispersal methods. Sulfate records from an array of ice cores suggest stratospheric injection of 14 ± 2 Tg S associated with the TBJ eruption, exceeding those of the historic eruption of Pinatubo in 1991. Based on these estimates it is likely that the TBJ eruption produced a cooling of around 0.5 °C for a few years after the eruption. The modeled dispersal and higher sulfate concentrations recorded in Antarctic ice cores imply that the cooling would have been more pronounced in the Southern Hemisphere. The new date confirms the eruption occurred within the Early Classic phase when Maya expanded across Central America.

Extreme climate after massive eruption of Alaska's Okmok volcano in 43 BCE and effects on the late Roman Republic and Ptolemaic Kingdom.

The assassination of Julius Caesar in 44 BCE triggered a power struggle that ultimately ended the Roman Republic and, eventually, the Ptolemaic Kingdom, leading to the rise of the Roman Empire. Climate proxies and written documents indicate that this struggle occurred during a period of unusually inclement weather, famine, and disease in the Mediterranean region; historians have previously speculated that a large volcanic eruption of unknown origin was the most likely cause. Here we show using well-dated volcanic fallout records in six Arctic ice cores that one of the largest volcanic eruptions of the past 2,500 y occurred in early 43 BCE, with distinct geochemistry of tephra deposited during the event identifying the Okmok volcano in Alaska as the source. Climate proxy records show that 43 and 42 BCE were among the coldest years of recent millennia in the Northern Hemisphere at the start of one of the coldest decades. Earth system modeling suggests that radiative forcing from this massive, high-latitude eruption led to pronounced changes in hydroclimate, including seasonal temperatures in specific Mediterranean regions as much as 7 °C below normal during the 2 y period following the eruption and unusually wet conditions. While it is difficult to establish direct causal linkages to thinly documented historical events, the wet and very cold conditions from this massive eruption on the opposite side of Earth probably resulted in crop failures, famine, and disease, exacerbating social unrest and contributing to political realignments throughout the Mediterranean region at this critical juncture of Western civilization.

Pervasive Arctic lead pollution suggests substantial growth in medieval silver production modulated by plague, climate, and conflict.

Lead pollution in Arctic ice reflects large-scale historical changes in midlatitude industrial activities such as ancient lead/silver production and recent fossil fuel burning. Here we used measurements in a broad array of 13 accurately dated ice cores from Greenland and Severnaya Zemlya to document spatial and temporal changes in Arctic lead pollution from 200 BCE to 2010 CE, with interpretation focused on 500 to 2010 CE. Atmospheric transport modeling indicates that Arctic lead pollution was primarily from European emissions before the 19th-century Industrial Revolution. Temporal variability was surprisingly similar across the large swath of the Arctic represented by the array, with 250- to 300-fold increases in lead pollution observed from the Early Middle Ages to the 1970s industrial peak. Superimposed on these exponential changes were pronounced, multiannual to multidecadal variations, marked by increases coincident with exploitation of new mining regions, improved technologies, and periods of economic prosperity; and decreases coincident with climate disruptions, famines, major wars, and plagues. Results suggest substantial overall growth in lead/silver mining and smelting emissions-and so silver production-from the Early through High Middle Ages, particularly in northern Europe, with lower growth during the Late Middle Ages into the Early Modern Period. Near the end of the second plague pandemic (1348 to ∼1700 CE), lead pollution increased sharply through the Industrial Revolution. North American and European pollution abatement policies have reduced Arctic lead pollution by >80% since the 1970s, but recent levels remain ∼60-fold higher than at the start of the Middle Ages.

Alpine ice evidence of a three-fold increase in atmospheric iodine deposition since 1950 in Europe due to increasing oceanic emissions.

Iodine is an important nutrient and a significant sink of tropospheric ozone, a climate-forcing gas and air pollutant. Ozone interacts with seawater iodide, leading to volatile inorganic iodine release that likely represents the largest source of atmospheric iodine. Increasing ozone concentrations since the preindustrial period imply that iodine chemistry and its associated ozone destruction is now substantially more active. However, the lack of historical observations of ozone and iodine means that such estimates rely primarily on model calculations. Here we use seasonally resolved records from an Alpine ice core to investigate 20th century changes in atmospheric iodine. After carefully considering possible postdepositional changes in the ice core record, we conclude that iodine deposition over the Alps increased by at least a factor of 3 from 1950 to the 1990s in the summer months, with smaller increases during the winter months. We reproduce these general trends using a chemical transport model and show that they are due to increased oceanic iodine emissions, coupled to a change in iodine speciation over Europe from enhanced nitrogen oxide emissions. The model underestimates the increase in iodine deposition by a factor of 2, however, which may be due to an underestimate in the 20th century ozone increase. Our results suggest that iodine's impact on the Northern Hemisphere atmosphere accelerated over the 20th century and show a coupling between anthropogenic pollution and the availability of iodine as an essential nutrient to the terrestrial biosphere.

Lead pollution recorded in Greenland ice indicates European emissions tracked plagues, wars, and imperial expansion during antiquity.

Lead pollution in Arctic ice reflects midlatitude emissions from ancient lead-silver mining and smelting. The few reported measurements have been extrapolated to infer the performance of ancient economies, including comparisons of economic productivity and growth during the Roman Republican and Imperial periods. These studies were based on sparse sampling and inaccurate dating, limiting understanding of trends and specific linkages. Here we show, using a precisely dated record of estimated lead emissions between 1100 BCE and 800 CE derived from subannually resolved measurements in Greenland ice and detailed atmospheric transport modeling, that annual European lead emissions closely varied with historical events, including imperial expansion, wars, and major plagues. Emissions rose coeval with Phoenician expansion, accelerated during expanded Carthaginian and Roman mining primarily in the Iberian Peninsula, and reached a maximum under the Roman Empire. Emissions fluctuated synchronously with wars and political instability particularly during the Roman Republic, and plunged coincident with two major plagues in the second and third centuries, remaining low for >500 years. Bullion in silver coinage declined in parallel, reflecting the importance of lead-silver mining in ancient economies. Our results indicate sustained economic growth during the first two centuries of the Roman Empire, terminated by the second-century Antonine plague.

Centennial-scale changes in the global carbon cycle during the last deglaciation.

Global climate and the concentration of atmospheric carbon dioxide (CO2) are correlated over recent glacial cycles. The combination of processes responsible for a rise in atmospheric CO2 at the last glacial termination (23,000 to 9,000 years ago), however, remains uncertain. Establishing the timing and rate of CO2 changes in the past provides critical insight into the mechanisms that influence the carbon cycle and helps put present and future anthropogenic emissions in context. Here we present CO2 and methane (CH4) records of the last deglaciation from a new high-accumulation West Antarctic ice core with unprecedented temporal resolution and precise chronology. We show that although low-frequency CO2 variations parallel changes in Antarctic temperature, abrupt CO2 changes occur that have a clear relationship with abrupt climate changes in the Northern Hemisphere. A significant proportion of the direct radiative forcing associated with the rise in atmospheric CO2 occurred in three sudden steps, each of 10 to 15 parts per million. Every step took place in less than two centuries and was followed by no notable change in atmospheric CO2 for about 1,000 to 1,500 years. Slow, millennial-scale ventilation of Southern Ocean CO2-rich, deep-ocean water masses is thought to have been fundamental to the rise in atmospheric CO2 associated with the glacial termination, given the strong covariance of CO2 levels and Antarctic temperatures. Our data establish a contribution from an abrupt, centennial-scale mode of CO2 variability that is not directly related to Antarctic temperature. We suggest that processes operating on centennial timescales, probably involving the Atlantic meridional overturning circulation, seem to be influencing global carbon-cycle dynamics and are at present not widely considered in Earth system models.

Synchronous volcanic eruptions and abrupt climate change ∼17.7 ka plausibly linked by stratospheric ozone depletion.

Glacial-state greenhouse gas concentrations and Southern Hemisphere climate conditions persisted until ∼17.7 ka, when a nearly synchronous acceleration in deglaciation was recorded in paleoclimate proxies in large parts of the Southern Hemisphere, with many changes ascribed to a sudden poleward shift in the Southern Hemisphere westerlies and subsequent climate impacts. We used high-resolution chemical measurements in the West Antarctic Ice Sheet Divide, Byrd, and other ice cores to document a unique, ∼192-y series of halogen-rich volcanic eruptions exactly at the start of accelerated deglaciation, with tephra identifying the nearby Mount Takahe volcano as the source. Extensive fallout from these massive eruptions has been found >2,800 km from Mount Takahe. Sulfur isotope anomalies and marked decreases in ice core bromine consistent with increased surface UV radiation indicate that the eruptions led to stratospheric ozone depletion. Rather than a highly improbable coincidence, circulation and climate changes extending from the Antarctic Peninsula to the subtropics-similar to those associated with modern stratospheric ozone depletion over Antarctica-plausibly link the Mount Takahe eruptions to the onset of accelerated Southern Hemisphere deglaciation ∼17.7 ka.

Method for Correcting Continuous Ice-Core Elemental Measurements for Under-Recovery.

Measurement of elemental concentrations in ice cores are critical for determining atmospheric aerosol variations. For such measurements, acidified ice-core meltwater typically is analyzed continuously (<5 min after acidification) or discretely (∼3 months after acidification). The reduced acidification time during continuous analysis may result in a measured elemental concentration that is lower than the concentration of discrete analysis if particulates are not fully dissolved. To evaluate this, sections of three ice cores from Greenland and Antarctica were measured both continuously (4.5 min after acidification) and discretely (repeatedly from 1 to 151 days after continuous measurements), with discrete samples collected from the meltwater sample stream prior to continuous measurement. We show that elements such as Na, Sr, and S dissolved readily and therefore were fully recovered during continuous measurements. Average recovery for other elements was between 70 to 100% for Cd, Gd, Mg, Mn, U, and Yb, 50 to 90% for Ca, Ce, Sm, and V, and less than 50% for Al, Fe, and La. Given the advantages of continuous measurements, we conclude that the preferred method for ice-core measurements is continuous analysis with simultaneous discrete sample collection, followed by adjustment of the continuous measurements based on discrete sample analysis at least 3 months after acidification.

Prokaryotes in the WAIS Divide ice core reflect source and transport changes between Last Glacial Maximum and the early Holocene.

We present the first long-term, highly resolved prokaryotic cell concentration record obtained from a polar ice core. This record, obtained from the West Antarctic Ice Sheet (WAIS) Divide (WD) ice core, spanned from the Last Glacial Maximum (LGM) to the early Holocene (EH) and showed distinct fluctuations in prokaryotic cell concentration coincident with major climatic states. The time series also revealed a ~1,500-year periodicity with greater amplitude during the Last Deglaciation (LDG). Higher prokaryotic cell concentration and lower variability occurred during the LGM and EH than during the LDG. A sevenfold decrease in prokaryotic cell concentration coincided with the LGM/LDG transition and the global 19 ka meltwater pulse. Statistical models revealed significant relationships between the prokaryotic cell record and tracers of both marine (sea-salt sodium [ssNa]) and burning emissions (black carbon [BC]). Collectively, these models, together with visual observations and methanosulfidic acid (MSA) measurements, indicated that the temporal variability in concentration of airborne prokaryotic cells reflected changes in marine/sea-ice regional environments of the WAIS. Our data revealed that variations in source and transport were the most likely processes producing the significant temporal variations in WD prokaryotic cell concentrations. This record provided strong evidence that airborne prokaryotic cell deposition differed during the LGM, LDG, and EH, and that these changes in cell densities could be explained by different environmental conditions during each of these climatic periods. Our observations provide the first ice-core time series evidence for a prokaryotic response to long-term climatic and environmental processes.

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431 239 Patients.

OBJECTIVE: Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. APOE genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. APPROACH AND RESULTS: APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), Lp(a) mass, directly measured Lp(a)-cholesterol levels, and a variety of apoB-related lipoproteins were measured in 431 239 patients. The prevalence of APOE traits were ε2: 7.35%, ε3: 77.56%, and ε4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared with ε2/ε2 genotypes and increased significantly according to APOE genotype: ε2/ε2: 23.4 (29.2), ε2/ε3: 31.3 (38.0), ε2/ε4: 32.8 (38.5), ε3/ε3: 33.2 (39.1), ε3/ε4: 35.5 (41.6), and ε4/ε4: 38.5 (44.1) mg/dL (P<0.0001). LDL-cholesterol, apoB, Lp(a)-cholesterol, LDL-cholesterol corrected for Lp(a)-cholesterol content, LDL-particle number, and small, dense LDL also had similar patterns. Patients with LDL-cholesterol ≥250 mg/dL, who are more likely to have LDL receptor mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ε2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 isoforms and lowest LDL-cholesterol. CONCLUSIONS: APOE genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.

Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial.

BACKGROUND: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. CONCLUSIONS: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.