Sensitivity of Digital Thermal Monitoring Parameters to Reactive Hyperemia

2010 ◽  
Vol 132 (5) ◽  
Author(s):  
Mohammad W. Akhtar ◽  
Stanley J. Kleis ◽  
Ralph W. Metcalfe ◽  
Morteza Naghavi
Keyword(s):  
Blood Flow ◽  
Flow Rate ◽  
Vascular Reactivity ◽  
Early Stage ◽  
Reactive Hyperemia ◽  
Assessment Tools ◽  
Functional Evaluation ◽  
Thermal Monitoring ◽  
Essential Components ◽  
Baseline Flow

Both structural and functional evaluations of the endothelium exist in order to diagnose cardiovascular disease (CVD) in its asymptomatic stages. Vascular reactivity, a functional evaluation of the endothelium in response to factors such as occlusion, cold, and stress, in addition to plasma markers, is the most widely accepted test and has been found to be a better predictor of the health of the endothelium than structural assessment tools such as coronary calcium scores or carotid intima-media thickness. Among the vascular reactivity assessment techniques available, digital thermal monitoring (DTM) is a noninvasive technique that measures the recovery of fingertip temperature after 2–5 min of brachial occlusion. On release of occlusion, the finger temperature responds to the amount of blood flow rate overshoot referred to as reactive hyperemia (RH), which has been shown to correlate with vascular health. Recent clinical trials have confirmed the potential importance of DTM as an early stage predictor of CVD. Numerical simulations of a finger were carried out to establish the relationship between DTM and RH. The model finger consisted of essential components including bone, tissue, major blood vessels (macrovasculature), skin, and microvasculature. The macrovasculature was represented by a pair of arteries and veins, while the microvasculature was represented by a porous medium. The time-dependent Navier–Stokes and energy equations were numerically solved to describe the temperature distribution in and around the finger. The blood flow waveform postocclusion, an input to the numerical model, was modeled as an instantaneous overshoot in flow rate (RH) followed by an exponential decay back to baseline flow rate. Simulation results were similar to clinically measured fingertip temperature profiles in terms of basic shape, temperature variations, and time delays at time scales associated with both heat conduction and blood perfusion. The DTM parameters currently in clinical use were evaluated and their sensitivity to RH was established. Among the parameters presented, temperature rebound (TR) was shown to have the best correlation with the level of RH with good sensitivity for the range of flow rates studied. It was shown that both TR and the equilibrium start temperature (representing the baseline flow rate) are necessary to identify the amount of RH and, thus, to establish criteria for predicting the state of specific patient’s cardiovascular health.

Effect of sex difference and pregnancy on the normal reactive hyperemia curve

1977 ◽  
Vol 233 (4) ◽  
pp. H500-H504
Author(s):  
J. K. Vyden ◽  
T. Takano ◽  
K. Nagasawa ◽  
T. Ogawa ◽  
M. Groseth-Robertson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sex Difference ◽  
Vascular Reactivity ◽  
Forearm Blood Flow ◽  
Circulatory Arrest ◽  
Reactive Hyperemia ◽  
Normal Male ◽  
Normal Female ◽  
The Mean ◽  
Normal Males

The 10-min reactive hyperemia reaction was studied in a group of normal males, 10 normal females, 10 females in each trimester of pregnancy, and 10 females 6 wk postpartum. Sex difference had a marked effect on the hyperemic reaction, in that 5 and 15 s after release of circulatory arrest, the mean forearm blood flow in normal males was significantly reduced below that of normal females. During pregnancy there was a shift in the reaction of the pregnant female toward that in the normal male. In the 1st trimester of pregnancy, 5 s after circulatory arrest the mean forearm blood flow was diminished below that of the normal female; in the 2nd and 3rd trimesters at 5 s, the reaction was significantly diminished below that of the normal female. At 6wk postpartum, the reaction was essentially the same as in the nonpregnant female. Although these changes may be explained by a hormonal difference, they portray that there may be a marked difference in vascular reactivity due to sex difference only.

scholarly journals PO-087 4-weeks hypoxia (HHL) training improves rowers’ cutaneous microcirculation

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Zhijun Meng ◽  
Binghong Gao
Keyword(s):  
Blood Flow ◽  
Endothelial Function ◽  
Forearm Blood Flow ◽  
Early Stage ◽  
Reactive Hyperemia ◽  
Peripheral Circulation ◽  
Reserve Capacity ◽  
Hypoxic Training ◽  
Cutaneous Microcirculation ◽  
Traditional Research

Objective Sport scientists always pay attention to cardiorespiratory and hematologic system on benefit of hypoxic training, but peripheral circulation may be one of these benefit, which is one cause of improving performance. So, in order to know whether or not hypoxic training affect athletes’ cutaneous microcirculation, we test rowers’ microcirculation for 4 weeks’ High Live-High Train-Low exercise(HHL). Methods The subject is 21 male rowers of Shanghai rowing team.12 of them take part in 4 weeks HHL (train and live at 2500m, exercise at 100m), while 9 of them train in normoxia. Forearm and leg cutaneous blood flow(CBF) was measured using a laser doppler flowmeter (PeriFlux600, Perimed, Sweden) at room temperature (22℃) with subject lying position and after testing in that position for at least 10min. We tested the forearm and leg blood flow, and also the blood flow when localized heating to 44℃ for 3 mins. Microvascular reactivity(MVR) was evaluated form the maximal post occlusive reactive hyperemia(PORH) following 3-min forearm ischemia produced by cuff inflation (200mm Hg). Similar procedures have been used by other investigators. Blood pressure was measured by brachial auscultation. SPO2 and heart rate was measured by a hand hold pulse oximeter (NONIN, 9500, USA) .The blood flow was measured 4 times, baseline, 1stweek, 3rdweek and post. Results Blood flow and CMBC of forearm of HHL increased significantly at 1stweek(8.9,13.0;112.0,151.0,P<0.05), but thigh and NOM group did not increase. The lowest and highest blood flow of PORH both increase at 1stweek(2,9,3.2;46.0,53.0;0.05<P<0.1). At 3rdweek, HHL group’s resting blood flow and CMBC of forearm is lower than 1stweek(9.3,13.0;124.5,151.0), but higher than pretraining, but velocity of blood flow decreased(8.2,9.2).  These results suggest at early stage of HHL, vasoconstriction may be dominant. But when rowers suffer more and more hypoxia, vasodilation and angiogenesis may play a key role in their skin blood flow. At 3rdweek after training, the blood flow and CMBC are similar with baseline. Conclusions 4 weeks HHL training of rowers increase forearm blood flow, but no thigh. This is because thigh is main working muscle of rowers, which may be affected by training status and fatigue. And also, PORH reserve capacity is an indicator of endothelial function. In this study, we find HHL rowers increase their PORH reserve capacity, which means endothelial function is improved by hypoxia training. So, besides the traditional research of Hematologic System on hypoxia training, we find 4 weeks HHL training increase forearm blood flow and improve endothelial function. This may be one mechanism of improving performance, which need more studies to confirm.

Metabolic and functional consequences of blunted myocardial reactive hyperemia

1991 ◽  
Vol 261 (3) ◽  
pp. H892-H900 ◽  
Author(s):  
G. G. Schwartz ◽  
S. Schaefer ◽  
S. D. Trocha ◽  
S. Steinman ◽  
J. Gober ◽  
...  
Keyword(s):  
Blood Flow ◽  
Flow Rate ◽  
Coronary Flow ◽  
Coronary Occlusion ◽  
Reactive Hyperemia ◽  
Blood Flow Rate ◽  
Intracellular Acidosis ◽  
Ischemic Region ◽  
Phosphorus Metabolites ◽  
Contractile Recovery

This study determined whether the rapidity of myocardial metabolic and contractile recovery after brief coronary occlusion depends upon the intensity of reactive hyperemia. We also tested the hypothesis that coronary flow rate modulates contractility after brief myocardial ischemia, independent of changes in phosphorus metabolites. Eight open-chest pigs were studied with phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy with 14 s time resolution. After a 29-s anterior descending coronary occlusion, peak Doppler coronary flow velocity was alternately unrestricted (normal hyperemia, 443 +/- 40% of control) or limited to 159 +/- 9% of control. During 29 s coronary occlusion, phosphocreatine-to-inorganic phosphate ratio (PCr/Pi) and systolic segment shortening in the ischemic region fell to 28 +/- 4 and 7 +/- 7% of control, respectively. With normal hyperemia, PCr/Pi and segment shortening recovered within 29 s. With blunted hyperemia, recovery of both parameters was delayed an additional 29-43 s, associated with reduced subendocardial blood flow (measured with radioactive microspheres) and persistent intracellular acidosis. However, the relationship between segment shortening and PCr/Pi was unaffected by the intensity of reactive hyperemia. Thus blunted reactive hyperemia significantly delays metabolic and contractile recovery from brief ischemia, probably via transient maldistribution of transmural perfusion. However, coronary blood flow rate does not independently modulate contractility after brief reversible ischemia.

Advanced Thermal Measures of Vascular Reactivity

2017 ◽  
Author(s):  
M. Wasy Akhtar
Keyword(s):  
Flow Rate ◽  
Vascular Reactivity ◽  
Low Cost ◽  
Reactive Hyperemia ◽  
Reference Signal ◽  
Three Dimensional ◽  
External Environment ◽  
Temperature Response ◽  
Vascular Health ◽  
Finger Tip

New measures of Digital Thermal Monitoring (DTM), a low cost non-invasive tool to assess vascular health, are developed. Original measures of thermal vascular reactivity tend to be dependent upon the initial vascular state (such as temperature before occlusion). The objective of this study is to identify new measures that will provide a single independent predictor of vascular health. Full three dimensional simulations were carried out to simulate transient finger tip temperature response during brachial occlusion and reperfusion. These numerical results were validated with patient data and then used to simulate a variety of test cases and discern relationships between the thermal measure and the surge in flow rate (reactive hyperemia). Defining the zero-reactivity response as the response to a step change in flow rate from near zero back to the original steady state value before occlusion, a reference signal is constructed which accounts for the finger size, thermo-physical properties, external environment and the start temperature (initial vascular state). This reference is used to normalize the temperature reactivity, forming a new measure called adjusted temperature reactivity that is a function of reactive hyperemia only. It is independent of the initial vascular state and external environment, leading to a more robust and reliable measure of vascular health.

Visualizing and quantifying the impact of reactive hyperemia on cutaneous microvessels in humans

2020 ◽  
Vol 128 (1) ◽  
pp. 17-24
Author(s):  
Raden Argarini ◽  
Kurt J. Smith ◽  
Howard H. Carter ◽  
Louise H. Naylor ◽  
Robert A. McLaughlin ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Flow Rate ◽  
Reactive Hyperemia ◽  
Assessment Tools ◽  
Clinical Settings ◽  
Optical Coherence ◽  
Doppler Flowmetry ◽  
Microvascular Changes ◽  
And Function ◽  
The Impact

The mechanisms underlying reactive hyperemia (RH) responses in microvessels are poorly understood. Previous assessment tools have not been capable of directly visualizing microvessels during physiological stimulation in humans. Optical coherence tomography (OCT) is capable of imaging and quantifying subcutaneous microvessels as small as ~30 µm. In this study we use OCT to visualize and quantify skin microvascular changes in response to RH for the first time in humans. We also assessed the reproducibility of this technique. OCT and laser Doppler flowmetry (LDF) were used simultaneously to scan cutaneous microvessels in 10 young healthy subjects on 2 days. We applied a speckle decorrelation algorithm to assess OCT images and calculated flow rate, speed, diameter, and density parameters. Measures were obtained at rest (baseline) and 30-s following a 5-min cuff inflation (RH). All data were compared between days. The RH stimulus significantly increased ( P < 0.0001) OCT-derived microvascular diameter (37.6 ± 3.4 vs. 44.5 ± 5.2 µm), flow rate (82.4 ± 23.4 vs. 240.1 ± 58.6 pl/s), speed (48 ± 5.7 vs. 101.5 ± 17.1 µm/s), density (5.1 ± 1.7 vs. 14.6 ± 2.6%), and also LDF-derived flux (12.3 ± 5.7 vs. 31.6 ± 9.1 perfusion units). At baseline, OCT-derived diameter ( r = 0.55), flow rate ( r = 0.64), speed ( r = 0.55), and density ( r = 0.75) showed significant between-day correlations ( P < 0.05), as did LDF results ( r = 0.74). In response to RH, OCT-derived diameter ( r = 0.63) and density ( r = 0.64) showed significant correlations ( P < 0.05), whereas flow rate ( r = 0.45), speed ( r = 0.43), and LDF ( r = 0.26) were less reproducible. Our study is novel in that it establishes the feasibility of using OCT to visualize and quantify microvascular structure and function responses to RH in humans. NEW & NOTEWORTHY This study describes the first evidence in humans that optical coherence tomography provides direct visualization and comprehensive quantification of cutaneous microvascular hemodynamics as a response to reactive hyperemia. This imaging technique will greatly improve human cutaneous microvascular assessment in physiological and clinical settings.

scholarly journals Unilateral application of an external pneumatic compression therapy improves skin blood flow and vascular reactivity bilaterally

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4878 ◽  
Author(s):  
Jeffrey S. Martin ◽  
Allison M. Martin ◽  
Petey W. Mumford ◽  
Lorena P. Salom ◽  
Angelique N. Moore ◽  
...  
Keyword(s):  
Blood Flow ◽  
Skin Blood Flow ◽  
Lower Limb ◽  
Vascular Reactivity ◽  
Reactive Hyperemia ◽  
Lower Leg ◽  
Post Treatment ◽  
Time Points ◽  
Bilateral Lower Limb ◽  
External Pneumatic Compression

Background We sought to determine the effects of unilateral lower-limb external pneumatic compression (EPC) on bilateral lower-limb vascular reactivity and skin blood flow. Methods Thirty-two participants completed this two-aim study. In AIM1 (n = 18, age: 25.5 ± 4.7 years; BMI: 25.6 ± 3.5 kg/m2), bilateral femoral artery blood flow and reactivity (flow mediated dilation [FMD]) measurements were performed via ultrasonography at baseline (PRE) and immediately following 30-min of unilateral EPC treatment (POST). AIM2 (n = 14, age: 25.9 ± 4.5; BMI: 27.2 ± 2.7 kg/m2) involved 30-min unilateral EPC (n = 7) or sham (n = 7) treatment with thermographic bilateral lower-limb mean skin temperature (MST) measurements at baseline, 15-min of treatment (T15) and 0, 30 and 60-min (R0, R30, R60) following treatment. Results Comparative data herein are presented as mean ± 95% confidence interval. AIM1: No significant effects on total reactive hyperemia blood flow were observed for the treated (i.e., compressed) or untreated (i.e., non-compressed) leg. A significant effect of time, but no time*leg interaction, was observed for relative FMD indicating higher reactivity bilaterally with unilateral EPC treatment (FMD: +0.41 ± 0.09% across both legs; p < 0.05). AIM2: Unilateral EPC treatment was associated with significant increases in whole-leg MST from baseline during (T15: +0.63 ± 0.56 °C in the visible untreated/contralateral leg, p < 0.025) and immediately following treatment (i.e., R0) in both treated (+1.53 ± 0.59 °C) and untreated (+0.60 ± 0.45 °C) legs (p < 0.0125). Across both legs, MST remained elevated with EPC at 30-min post-treatment (+0.60 ± 0.45 °C; p < 0.0167) but not at 60-min post (+0.27 ± 0.46 °C; p = 0.165). Sham treatment was associated with a significant increase in the treated leg immediately post-treatment (+1.12 ± 0.31 °C; p < 0.0167), but not in the untreated leg (−0.27 ± 0.12 °C). MST in neither the treated or untreated leg were increased relative to baseline at R30 or R60 (p > 0.05). Finally, during treatment and at all post-treatment time points (i.e., R0, R30 and R60), independent of treatment group (EPC vs. sham), there was a significant effect of region. The maximum increase in MST was observed at the R0 time point and was significantly (p < 0.05) larger in the thigh region (+1.02 ± 0.31 °C) than the lower-leg (+0.47 ± 0.29 °C) region. However, similar rates of MST decline from R0 in the thigh and lower leg regions were observed at the R30 and R60 time points. Discussion Unilateral EPC may be an effective intervention for increasing skin blood flow and/or peripheral conduit vascular reactivity in the contralateral limb. While EPC was effective in increasing whole-leg MST bilaterally, there appeared to be a more robust response in the thigh compared to the lower-leg. Thus, proximity along the leg may be an important consideration in prospective treatment strategies.

Effects of neuropeptide Y on regulation of blood flow rate in canine myocardium

1990 ◽  
Vol 259 (6) ◽  
pp. H1709-H1717
Author(s):  
J. H. Svendsen ◽  
S. P. Sheikh ◽  
J. Jorgensen ◽  
J. D. Mikkelsen ◽  
W. P. Paaske ◽  
...  
Keyword(s):  
Blood Flow ◽  
Myocardial Blood Flow ◽  
Neuropeptide Y ◽  
Coronary Arteries ◽  
Flow Rate ◽  
Reactive Hyperemia ◽  
Blood Flow Rate ◽  
Nerve Fibers ◽  
Tension Development ◽  
Mean Values

The effect of neuropeptide Y (NPY) on tension development was examined in isolated canine coronary arteries, and the effects on local myocardial blood flow rate were studied in open-chest anesthetized dogs by the local 133Xe washout technique. By immunohistochemistry, numerous NPY-like immunoreactive nerve fibers were identified in the adventitia of canine coronary arteries. NPY (10(-9)-10(-6) M) supplied to isolated epicardial segments of the left anterior descending coronary artery induced a modest vasoconstriction, with a maximum tension of 0.95 mN, that was only 6.9% of the response to K+. In contrast, intracoronary NPY (0.01-10 micrograms) induced a considerable degree of vasoconstriction; the reduction of blood flow rate was dose related, with a maximum reduction to 52% of control values. The effect of intracoronary NPY (1 microgram) on maximally relaxed arterioles elicited by 30 s of ischemia was studied in separate experiments during reactive hyperemia. NPY induced a decrease in maximum blood flow during reactive hyperemia (166.6 vs. 214.6% of preocclusive blood flow rate, mean values; P = 0.05), an increase in the cumulative excess blood flow (61.0 vs. 35.3 ml/100 g; P = 0.02), and an increase in the duration of reactive hyperemia compared with control values (66 vs. 41 s; P = 0.02). Thus we conclude that in the heart NPY is a potent vasoconstrictor that seems to act preferentially on smaller intramyocardial arterioles. Furthermore, NPY inhibits vascular relaxation of myocardial resistance vessels after ischemia, suggesting that this peptide may participate in the regulation of myocardial blood flow not only during physiological conditions but also after ischemia.

scholarly journals Regional Cerebral Blood Flow and Arterial Blood Volume and Their Reactivity to Hypercapnia in Hypertensive and Normotensive Rats

2013 ◽  
Vol 34 (3) ◽  
pp. 408-414 ◽  
Author(s):  
Tae Kim ◽  
J Richard Jennings ◽  
Seong-Gi Kim
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Blood Volume ◽  
Vascular Reactivity ◽  
Early Stage ◽  
Blood Oxygenation ◽  
Chronic Hypertension ◽  
Arterial Blood ◽  
Wistar Kyoto ◽  
Arterial Blood Volume

Chronic hypertension induces cerebrovascular remodeling, changing the inner diameter and elasticity of arterial vessels. To examine cerebrovascular morphologic changes and vasodilatory impairment in early-stage hypertension, we measured baseline (normocapnic) cerebral arterial blood volume ( CBVa) and cerebral blood flow ( CBF) as well as hypercapnia-induced dynamic vascular responses in animal models. All experiments were performed with young (3 to 4 month old) spontaneously hypertensive rats (SHR) and control Wistar–Kyoto rats (WKY) under ∼1% isoflurane anesthesia at 9.4 Tesla. Baseline regional CBF values were similar in both animal groups, whereas SHR had significantly lower CBVa values, especially in the hippocampus area. As CBF is maintained by adjusting arterial diameters within the autoregulatory blood pressure range, CBVa is likely more sensitive than CBF for detecting hypertensive-mediated alterations. Unexpectedly, hypercapnia-induced CBF and blood-oxygenation-level-dependent (BOLD) response were significantly higher in SHR as compared with WKY, and the CBF reactivity was highly correlated with the BOLD reactivity in both groups. The higher reactivity in early-stage hypertensive animals indicates no significant vascular remodeling occurred. At later stages of hypertension, the reduced vascular reactivity is expected. Thus, CBF and CBVa mapping may provide novel insights into regional cerebrovascular impairment in hypertension and its progression as hypertension advances.

scholarly journals High Frequency of Microvascular Dysfunction in US Outpatient Clinics: A Sign of High Residual Risk? Data from 7,105 Patients

2022 ◽  
Vol 2022 ◽  
pp. 1-9
Author(s):  
Morteza Naghavi ◽  
Stanley Kleis ◽  
Hirofumi Tanaka ◽  
Albert A. Yen ◽  
Ruoyu Zhuang ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Reactive Hyperemia ◽  
Microvascular Dysfunction ◽  
Microvascular Function ◽  
Residual Risk ◽  
Outpatient Clinics ◽  
Reactivity Index ◽  
Maximum Temperature ◽  
Thermal Monitoring ◽  
Arterial Tonometry

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men ( 1.62 ± 0.56 vs. 1.54 ± 0.47 , p < 0.001 ). VRI was inversely but mildly correlated with age ( r = − 0.19 , p < 0.001 ). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Ventilatory threshold is related to walking tolerance in patients with intermittent claudication

VASA ◽  
2012 ◽  
Vol 41 (4) ◽  
pp. 275-281 ◽  
Author(s):  
da Rocha Chehuen ◽  
G. Cucato ◽  
P. dos Anjos Souza Barbosa ◽  
A. R. Costa ◽  
M. Ritti-Dias ◽  
...  
Keyword(s):  
Blood Flow ◽  
Oxygen Uptake ◽  
Intermittent Claudication ◽  
Lower Limb ◽  
Ventilatory Threshold ◽  
Reactive Hyperemia ◽  
Ankle Brachial Index ◽  
Metabolic Parameters ◽  
Walking Distance ◽  
The Relationship

Background: This study assessed the relationship between lower limb hemodynamics and metabolic parameters with walking tolerance in patients with intermittent claudication (IC). Patients and methods: Resting ankle-brachial index (ABI), baseline blood flow (BF), BF response to reactive hyperemia (BFRH), oxygen uptake (VO2), initial claudication distance (ICD) and total walking distance (TWD) were measured in 28 IC patients. Pearson and Spearman correlations were calculated. Results: ABI, baseline BF and BF response to RH did not correlate with ICD or TWD. VO2 at first ventilatory threshold and VO2peak were significantly and positively correlated with ICD (r = 0.41 and 0.54, respectively) and TWD (r = 0.65 and 0.71, respectively). Conclusions: VO2peak and VO2 at first ventilatory threshold, but not ABI, baseline BF and BFHR were associated with walking tolerance in IC patients. These results suggest that VO2 at first ventilatory threshold may be useful to evaluate walking tolerance and improvements in IC patients.

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