Thermal Interferometry of Anyons in Spin Liquids.

Aharonov-Bohm interferometry is the most direct probe of anyonic statistics in the quantum Hall effect. The technique involves oscillations of the electric current as a function of the magnetic field and is not applicable to Kitaev spin liquids and other systems without charged quasiparticles. Here, we establish a novel protocol, involving heat transport, for revealing fractional statistics even in the absence of charged excitations, as is the case in quantum spin liquids. Specifically, we demonstrate that heat transport in Kitaev spin liquids through two distinct interferometer's geometries, Fabry-Perot and Mach-Zehnder, exhibit drastically different behaviors. Therefore, we propose the use of heat transport interferometry as a probe of anyonic statistics in charge insulators.

Cryogenic probe for low-noise, high-frequency electronic measurements.

The design and performance of a low-noise, modular cryogenic probe, which is applicable to a wide range of measurements over a broad range of working frequencies, temperatures, and magnetic fields, is presented. The design of the probe facilitates the exchange of sample holders and sample-stage amplifiers, which, combined with its characteristic low transmission and reflection loss, make this design suitable for high precision or low sensitivity measurements. The specific example of measuring the shot noise of magnetic tunnel junctions is discussed. We highlight various design characteristics chosen specifically to expand the applicability of the probe to measurement techniques such as nuclear magnetic resonance.

Field evolution of coexisting superconducting and magnetic orders in CeCoIn5.

We present nuclear magnetic resonance (NMR) measurements on the three distinct In sites of CeCoIn5 with a magnetic field applied in the [100] direction. We identify the microscopic nature of the long range magnetic order (LRO) stabilized at low temperatures in fields above 10.2 T while still in the superconducting (SC) state. We infer that the ordered moment is oriented along the c axis and map its field evolution. The study of the field dependence of the NMR shift for the different In sites indicates that the LRO likely coexists with a modulated SC phase, possibly that predicted by Fulde, Ferrell, Larkin, and Ovchinnikov. Furthermore, we discern a field region dominated by strong spin fluctuations where static LRO is absent and propose a revised phase diagram.

A Reusable, Low-profile, Cryogenic Wire Seal.

We describe the design of a reusable Indium wire seal which has a small profile and is leak tight to better than 1x10(-10) std. cc/sec. from room temperature down to approximately mK. The pressure necessary to deform the Indium wire o-ring is provided by a screw-cap mating to threads on the outside of the cylindrical volume to be sealed.

First principles calculations of the electric field gradient tensors of Ba2NaOsO6, a Mott insulator with strong spin orbit coupling.

We present first principles calculations of the electrostatic properties of Ba2NaOsO6 (BNOO), a 5d1 Mott insulator with strong spin orbit coupling (SOC) in its low temperature quantum phases. In light of recent NMR experiments showing that BNOO develops a local octahedral distortion that is accompanied by the emergence of an electric field gradient (EFG) and precedes the formation of long range magnetic order (Lu et al 2017 Nat. Commun. 8 14407, Liu et al 2018 Phys. Rev. B 97 224103; Liu et al 2018 Physica B 536 863), we calculated BNOO's EFG tensor for several different model distortions. The local orthorhombic distortion that we identified as most strongly agreeing with experiment corresponds to a Q2 distortion mode of the Na-O octahedra, in agreement with conclusions given in (Liu et al 2018 Phys. Rev. B 97 224103). Furthermore, we found that the EFG is insensitive to the type of underlying magnetic order. By combining NMR results with first principles modeling, we have thus forged a more complete understanding of BNOO's structural and magnetic properties, which could not be achieved based upon experiment or theory alone.

Application of surface coil in nuclear magnetic resonance studies of physical properties of quasi-2D materials.

We conduct a comprehensive set of tests of performance of surface coils used for nuclear magnetic resonance (NMR) study of quasi-2-dimensional samples. We report 115In and 31P NMR measurements on InP, semi-conducting thin substrate samples. Surface coils of both zig-zag meander-line and concentric spiral geometries were used. We compare reception sensitivity and signal-to-noise ratio of the NMR signal obtained by using surface-type coils to that obtained by standard solenoid-type coils. As expected, we find that surface-type coils provide better sensitivity for NMR study of thin film samples. Moreover, we compare the reception sensitivity of different types of the surface coils. We identify the optimal geometry of the surface coils for a given application and/or direction of the applied magnetic field.

Magnetism and local symmetry breaking in a Mott insulator with strong spin orbit interactions.

Study of the combined effects of strong electronic correlations with spin-orbit coupling (SOC) represents a central issue in quantum materials research. Predicting emergent properties represents a huge theoretical problem since the presence of SOC implies that the spin is not a good quantum number. Existing theories propose the emergence of a multitude of exotic quantum phases, distinguishable by either local point symmetry breaking or local spin expectation values, even in materials with simple cubic crystal structure such as Ba2NaOsO6. Experimental tests of these theories by local probes are highly sought for. Our local measurements designed to concurrently probe spin and orbital/lattice degrees of freedom of Ba2NaOsO6 provide such tests. Here we show that a canted ferromagnetic phase which is preceded by local point symmetry breaking is stabilized at low temperatures, as predicted by quantum theories involving multipolar spin interactions.

Nickel release, a possible indicator for the duration of antiplatelet treatment, from a nickel cardiac device in vivo: a study in patients with atrial septal defects implanted with an Amplatzer occluder.

UNLABELLED: The present study was undertaken to evaluate the safety and release of nickel after implantation of a nickel device (Amplatzer occluder) in patients with an atrial septal defect (ASD) receiving antiplatelet therapy. METHODS: Blood and urine samples were obtained from 24 patients with ASD before occluder implantation (baseline) and during a 12-month post closure period. Antiplatelet drugs were administered for the initial 6-month period post implantation. The nickel content in the specimens was determined using electrothermal atomic absorption spectroscopy. The clinical, sonographic and magnetic resonance imaging follow-ups were carried out 1 week, 1 month, 6 months and 12 months post implantation. RESULTS: Mean baseline concentrations of nickel in serum and urine were within normal range with values of 0.6 +/- 0.2 microg/l and 3.1 +/- 1.2 microg/l, respectively. During the 6-week post closure period, the time needed for the formation of neointima on the surface of the graft, nickel levels in serum increased up to 5-fold (p < 0.01 versus baseline). Mean concentrations in serum and urine returned to baseline levels within 4-6 months post implantation. All patients showed satisfactory clinical improvements and there was no sonographic evidence of complications. CONCLUSIONS: The initial dissolution of nickel from the Amplatzer occluder is not a specific cardiovascular risk and is temporarily linked to the formation of the non-thrombogenic neointima on the surface of the graft. The antiplatelet drug regimen used (300 mg aspirin + 75 mg clopidogrel daily for 3 months in the initial phase and 100 mg aspirin daily for a further 3 months) appears to cover the period of neointima formation on the nickel device when nickel levels are significantly elevated. However, further studies in a larger number of patients and over a period greater than 12 months are needed to confirm the validity of these conclusions and to formulate definitive recommendations on the duration of the antiplatelet treatment.

[Pulmonary hypertension associated with left heart disease: recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Linksherzerkrankungen: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more common forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern because of limited ressources and the need to base treatments on scientific evidence. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, representing an unmet need of targeted PH therapies. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, several working groups were initiated, one of which was specifically dedicated to PH associated with left heart disease. This article summarizes the results and recommendations of this working group.

Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators.

OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF). BACKGROUND: Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest. METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%. RESULTS: Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant. CONCLUSIONS: In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure.

OBJECTIVES: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements. RESULTS: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.

OBJECTIVES: We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components. BACKGROUND: In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available. METHODS: In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay. RESULTS: Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF). CONCLUSIONS: In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

Hemodynamic and hormonal effects of quinaprilat in patients with congestive heart failure.

OBJECTIVE: To assess the pharmacodynamic activity and safety of rising single and multiple doses of intravenous quinaprilat compared with placebo in patients with New York Heart Association (NYHA) class III and IV congestive heart failure who were receiving digitalis or diuretic therapy or both. METHODS: Patients were randomly assigned to three treatment groups to receive low (0.5 to 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) single intravenous doses of quinaprilat or placebo on day 1. On the basis of responses observed on day 1, the three treatment groups received stable multiple intravenous doses of either quinaprilat or placebo every 6 hours on days 2 and 3. Hemodynamic measurements, hormonal assessments, and safety were evaluated before and at specified intervals during the study. RESULTS: Compared with placebo, single and multiple doses of quinaprilat increased cardiac index and reduced pulmonary capillary wedge pressure, mean arterial pressure, systemic vascular resistance, and right atrial pressure in a dose-related manner. No clinically important change in heart rate was observed. Hemodynamic changes after multiple-dose quinaprilat administration were similar to those observed after single doses and were generally sustained during the 6-hour dosing interval. Relative to placebo, quinaprilat reduced plasma angiotensin converting enzyme (ACE) activity, angiotensin II concentration, and aldosterone concentration and increased plasma renin activity; no prominent changes in plasma catecholamine and atrial natriuretic peptide concentrations were observed. There were no clinically important drug-related changes in the safety parameters. CONCLUSIONS: Single and multiple intravenous doses of 0.5 to 10 mg quinaprilat are well-tolerated and produce favorable dose-dependent hemodynamic effects and hormonal changes consistent with those expected of an ACE inhibitor in patients with NYHA class III and IV congestive heart failure.

Acute and 3-month treatment effects of candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure.

BACKGROUND: This study evaluated the short-term and long-term effects of the angiotensin II type 1 receptor antagonist candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure (CHF). METHODS: In this multicenter, double-blind, parallel-group study, 218 patients with CHF (New York Heart Association class II or III) with impaired left ventricular function (ejection fraction < or =40%) and pulmonary capillary wedge pressure > or =13 mm Hg were randomly assigned to 12 weeks of treatment with placebo (n = 44) or candesartan cilexetil (2 mg [n = 45], 4 mg [n = 46], 8 mg [n = 39], or 16 mg [n = 44]) once daily after a 2-week placebo run-in period. Hemodynamic measurements were performed by right heart catheterization over a 24-hour period after single (day 1) and repeated (3-month) treatment with the study drug. RESULTS: On regression analysis of the time-response curves, single and multiple doses of candesartan cilexetil produced sustained, significant, and dose-dependent reductions in pulmonary capillary wedge pressure (short-term effect P =.036, long-term effect P =.035) and mean pulmonary arterial pressure (short-term effect P =.031, long-term effect P =.042). Systemic vascular resistance showed a trend toward decreasing with dose on short-term and long-term treatments. No consistent changes were seen in cardiac index. Compensatory increases in plasma renin activity and angiotensin II levels with decreases in aldosterone and atrial natriuretic peptide were dose-dependent and significant. Candesartan cilexetil improved clinical symptoms, stabilized patient New York Heart Association status compared with placebo, and was judged to be an efficacious treatment by the investigators. More patients receiving placebo stopped the trial prematurely because of an adverse event than in any candesartan cilexetil group, and there was no excess of deaths in any treatment group. Candesartan was safe and well tolerated at all dosages. CONCLUSIONS: Candesartan cilexetil demonstrated significant short-term and long-term improvements in hemodynamic, neurohormonal, and symptomatic status and was well tolerated in patients with CHF.

Effects of clonidine on sinus node function in man.

Drugs interfering with sympathetic tone may result in depression of the function of the sinus node, especially in patients with disease of the sinus node. In 11 patients presenting with palpitations, vertigo, or syncope, the heart rate, the recovery time of the sinus node, the carotid sinus pressure slowing, and the atrioventricular conduction capacity were assessed before and every five minutes up to 30 minutes after intravenous administration of 0.15 mg of clonidine. The following significant maximal mean effects were noted at about 15 minutes after the administration of clonidine: the heart rate decreased 12 percent (59 vs 52 beats per minute); and the atrioventricular conduction capacity (ie, paced heart rate at second-degree atrioventricular block) decreased by 9 percent (132 vs 121 beats per minute), while the maximal recovery time of the sinus node increased by a factor of two (1,704 vs 3,562 msec) when atrial overdrives of 120, 150, and 200 beats per minute were used for each five minute period. In analyzing maximal carotid sinus pressure slowing after administration of clonidine, three of 11 patients developed hypersensitive carotid sinus reflex de novo, and two patients showed a decrease and three patients an increase of carotid sinus pressure slowing, while three patients had no carotid sinus pressure slowing both before and after administration of clonidine. We conclude that caution should be taken in administering clonidine to patients with signs indicative of dysfunction of the sinus node.

Interactions of clonidine and nifedipine in moderately severe hypertensive patients.

In ten patients (age: 47-59 yr) with moderately severe essential hypertension, the humoral and hemodynamic effects of a 4-day therapy with 2 x 75 micrograms clonidine, 2 x 20 mg nifedipine (slow-release), and their combination were investigated and compared with baseline values. The following measurements were observed under clonidine (C), nifedipine (N), and on combination (C/N), respectively: heart rate fell significantly under C from a mean of 79 to 67/min (P less than .05), increased to 73/min after N (P greater than .05) and fell again to 68/min under combination (P less than .05). Systolic blood pressure (Riva-Rocci method) decreased from a mean of 184 to 171 (C), 168 (N) and 161 mm Hg (C/N), respectively (P less than .01). Diastolic blood pressure was also significantly altered (113 vs. 104 (C), 107 (N), and 100 mm Hg (C/N); P less than .05). Stroke volume (ECHO) was not altered significantly (77 vs. 71 (C), 79 (N), and 80 mL (C/N), respectively), whereas cardiac output dropped from 5.9 to 4.9 L/min (C; P less than .05), increased to 5.7 (N; P greater than .05), and dropped again to 5.3 L/min (C/N; P greater than .05). Peripheral vascular resistance increased from a mean of 2091 to 2297 (C), fell to 1933 (N), and increased again to 2138 dyn/sec/cm-5 (C/N). Plasma norepinephrine levels fell from 440 to 281 (C; P less than .01), increased to 391 (N; P greater than .05), and fell again to 404 pg/mL (C/N; P greater than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

NMR phase noise in bitter magnets.

We have studied the temporal instability of a high field resistive Bitter magnet through nuclear magnetic resonance (NMR). This instability leads to transverse spin decoherence in repeated and accumulated NMR experiments as is normally performed during signal averaging. We demonstrate this effect via Hahn echo and Carr--Purcell--Meiboom--Gill (CPMG) transverse relaxation experiments in a 23-T resistive magnet. Quantitative analysis was found to be consistent with separate measurements of the magnetic field frequency fluctuation spectrum, as well as with independent NMR experiments performed in a magnetic field with a controlled instability. Finally, the CPMG sequence with short pulse delays is shown to be successful in recovering the intrinsic spin--spin relaxation even in the presence of magnetic field temporal instability.

Thrombotic complications with pacemakers.

To analyze thrombotic complications, we performed brachial phlebographies in 100 consecutive patients (group 1), about 44 months after permanent pacemakers had been installed. Thirty-nine patients showed thrombotic lesions in the veins used to pass the stimulation electrode into the right ventricle. In 10 patients the medical history and in 12 patients clinical symptoms and signs indicated an impairment of venous flow. Fifteen of the 39 patients showed complete occlusion of one venous segment; collateral vessel formation was found dependent on the site and the extent of the occlusion. In the remaining 24 patients only partial occlusion without collateralization was demonstrated. Group 2 comprised 12 patients in whom the pacing lead originally inserted via right-sided veins had been severed and the free distal end left unsecured intraluminally when the second electrode was inserted via the left-sided cephalic vein. In all these patients phlebography about 19 months later revealed thrombotic complications, while 11 presented with clinical symptoms and signs. The incidence of thrombotic complications including segmental occlusion after the application of permanent pacer leads is only one-third of patients with segmental occlusion symptoms. However, since severed leads produce severe symptomatic complications in almost all cases their removal is mandatory.

Neurohumoral blockade in CHF management.

Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.

Steady-state plasma concentrations of propafenone--chirality and metabolism.

In a selected group of 86 patients (60 males, 26 females) with symptomatic ventricular arrhythmias, possible interactions between metabolic and chiral effects at steady-state were investigated by comparing the plasma levels of propafenone, its major metabolites and the 2 structural isomers. The antiarrhythmic drug propafenone is metabolized--besides a minor dealkylation pathway--mainly via 5-hydroxylation. It is a well-known phenomenon that this oxidative pathway is not shared by all individuals to the same extent. We were able to verify among our subjects the portion of so-called poor metabolizers reported in the literature for the total population. Propafenone was administered as a slow release formulation at 3 different dose regimens (2 x 225 mg, 2 x 325 mg and 2 x 425 mg). The crude drug is a racemic mixture of equal amounts of R- and S-forms. During treatment, the plasma S and R ratio was shifted towards the S-isomer due to preferential clearance of the R-form. It was further found that neither a genetic disposition (gender, metabolic phenotype) nor age or the dose applied had any influence on the measured plasma isomer ratio.