Evidence that cranberry juice may improve augmentation index in overweight men

Evidence that cranberry juice may improve augmentationindex in overweight men Guillaume Ruel, Annie Lapointe, Sonia Pomerleau, Patrick Couture, Simone Lemieux,Benoît Lamarche, Charles Couillard Institute of Nutraceuticals and Functional Foods, Université Laval, Québec (Canada), G1V 0A6 The stiffening of arteries is a key step in atherogenesis leading to cardiovascular disease. It Received 13 April 2012 has been suggested that dietary polyphenols may be cardioprotective through possible Revised 10 October 2012 favorable effects on oxidative stress and vascular function. The present study was Accepted 2 November 2012 undertaken in order to examine the effect of consuming low-calorie cranberry juicecocktail (CJC), a source of polyphenols, on arterial stiffness in abdominally obese men. We hypothesize that regular CJC consumption will reduce circulating oxidized low-density Arterial stiffness lipoproteins concentrations and have a beneficial impact on endothelial function. Thirty- five men (mean age ± SD: 45 ± 10 years) were randomly assigned to drink 500 mL CJC/day (27% juice) or 500 mL placebo juice (PJ)/day for 4 weeks in a double-blind crossover design.
Abdominal obesity Augmentation index (AIx), an index of arterial stiffness, was measured by applanation tonometry of the radial artery and the cardiometabolic profile was assessed in eachparticipant before and after each phase of the study. We found no significant difference inAIx changes between men who consumed CJC or PJ for 4 weeks (P = .5820). Furthermore,there was no between-treatment difference in changes in AIx responses to salbutamol (P =.6303) and glyceryl trinitrate (P = .4224). No significant difference was noted in othercardiometabolic variables between men consuming PJ or CJC. However, a significant withingroup decrease in AIx (mean decrease ± SE; -14.0 ± 5.8%, P = .019) was noted following theconsumption of 500 mL CJC/day for 4 weeks. Our results indicate that the effect of chronicconsumption of CJC on AIx was not significantly different from changes associated with theconsumption of PJ. However, the significant within-group decrease in AIx following CJCconsumption in abdominally obese men may deserve further investigation.
2013 Elsevier Inc. All rights reserved.
gulant and proinflammatory conditions prevail . ED isassociated with cardiovascular disease (CVD) risk factors Endothelial dysfunction (ED), ie, the impairment of the normal that can also affect the mechanical properties of arteries functions of the vascular endothelium, develops in an leading to arterial stiffness Peripheral pulse wave individual when vasoconstrictive, growth-promoting, procoa- analysis is frequently used to measure augmentation index Abbreviations: AIx, augmentation index; BMI, body-mass index; CJC, cranberry-juice cocktail; CVD, cardiovascular disease; ED, endothelial dysfunction; FAV, fruits and vegetables; GTN, glyceryl trinitrate; HDL, high-density lipoprotein; LDL, low-density lipoprotein;MAP, mean arterial pressure; MetS, metabolic syndrome; NO, nitric oxide; NOS, nitric oxide synthase; NOx, total nitrates/nitrites; PJ,placebo juice; Salb, salbutamol; TG, triglycerides.
⁎ Corresponding author. Tel.: +1 418 656 2131x12855; fax: +1 418 656 3423.
E-mail address: (C. Couillard).
0271-5317/$ – see front matter 2013 Elsevier Inc. All rights reserved.
(AIx), an index of arterial stiffness which depends largely Subjects gave their written consent to participate in the on the proportion of collagen and elastin present in the artery study which was approved by the Medical Ethics Committee wall AIx can be reduced by β2-adrenoceptor agonists (eg, of Université Laval.
salbutamol) through the stimulation of endothelial nitricoxide (NO) production and is used as an index of endotheli- um-dependent function. On the other hand, endothelium-independent function can be assessed by the administration Upon their entry into the study, subjects were instructed by a of glyceryl trinitrate (GTN), an NO donor which is also known dietician to maintain their usual nutritional habits, limit their to reduce AIx by relaxing arterial smooth muscle cells alcohol consumption to a maximum of 1 drink per day Adoption of healthy nutritional habits is now considered (equivalent to 15 g alcohol/day) as well as restrain themselves an important and relevant way to help prevent and treat CVD from consuming any vitamin, antioxidant or mineral supple- through improvements in circulating lipoprotein-lipid and ments. Following a run-in period of 4 weeks during which inflammatory profiles as well as in endothelial function participants were asked to drink 500 mL of water a day in order Whereas a lot of emphasis has been put over the to get the subjects acquainted with the introduction of such years on the reduction of dietary fat intake and a shift from an amount of liquid into their usual diet, subjects were then saturated towards mono and polyunsaturated fatty acid randomly assigned to drink 500 mL/d of either low-calorie CJC consumption recent epidemiological observations also (27% juice) or placebo juice (PJ) for 4 weeks. After a 4 week suggest that increasing fruits and vegetables (FAV) consump- washout period (500 mL water a day), treatments were crossed tion may be helpful in lowering CVD risk .
over for another 4 weeks. All subjects had to complete the A commonly proposed explanation for the cardioprotective entire protocol to be considered for the statistical analyses.
potential of FAV is their high content in polyphenolic The CJC and PJ used in the present study (Ocean Spray compounds like flavonoids which have been identified as Cranberries Inc, Lakeville-Middleboro, MA, USA) had similar mediators of beneficial effects against inflammation and organoleptic properties (taste, color and texture) and vitamin oxidative stress . Furthermore, in support of the favorable C contents but no cranberries entered in the preparation of the vascular effects of dietary polyphenols, consumption of PJ. Both juices were packaged at Université Laval in 125 mL flavonoid-rich foods such as dark chocolate, red wine or tea ready-to-drink TetraBrik boxes (Tetra-Pak, Richmond Hill, has been shown to acutely and chronically reduce Ontario, Canada) under the close monitoring of Ocean Spray arterial stiffness likely through the regulation of the synthesis to ensure adequate reconstitution and quality of the juices.
of NO and endothelin-1 .
Subjects had to drink 4 (4) 125 mL boxes a day of either PJ or Cranberries are also a potent source of different poly- CJC and were instructed to consume 2 boxes of juice in the phenols such as phenolic acids, flavonols, anthocyanins, morning and 2 in the evening in order to maximize exposition proanthocyanidins . Low-calorie cranberry juice cocktail to the potentially bioactive compounds of CJC. Each daily (CJC) consumption has been associated with favorable cardi- serving of CJC (500 mL) provided 87 kcal of energy and ometabolic adaptations such as an increase in circulating contained 400 mg total polyphenols, 20.8 mg anthocyanins, high-density lipoprotein (HDL) cholesterol concentrations and 21.84 g carbohydrates. A more detailed description of the and decreases in plasma oxidized low-density lipoproteins PJ and CJC has been previously published In an effort to (OxLDL) levels as well as in circulating adhesion keep the subjects' sugar consumption to a minimum and molecule and matrix metalloproteinase-9 concentra- limit possible detrimental health effects, we provided sub- tions, the latter observations suggesting some beneficial jects with CJC and PJ sweetened with sucralose. All CJC used effects of cranberries on vascular health.
in the present study was reconstituted from concentrate of The present short-term placebo-controlled double-blind the same processed batch of cranberries, in order to avoid crossover study examines the effect of consuming low-calorie any variations in the composition of the juice throughout CJC on a daily basis for a period of 4 consecutive weeks on AIx the intervention.
and cardiometabolic profile of overweight men. We hypoth-esize that regular CJC consumption will reduce AIx and improve the cardiometabolic profile.
Body weight and height as well as waist and hip circumfer-ences were measured following standardized procedures Methods and materials upon each visit of the subjects to the investigation unit. BMIand waist-to-hip ratio values were calculated.
Plasma measurements Thirty-five sedentary and healthy overweight men wererecruited through the media to participate in the present Blood samples were collected in the morning after a 12-hour intervention. To be eligible, subjects had to have a body-mass fast. Upon collection, cholesterol and triglyceride (TG) con- index (BMI) ≥25 kg/m2 and a waist circumference ≥90 cm.
centrations were determined in plasma by enzymatic Participants also had to be free from diabetes and CVD as well methods using a Technicon RA-1000 analyzer (Bayer Corpo- as renal, hepatic and endocrine disorders. Furthermore, they ration Inc, Tarrytown, NY, USA), as previously described .
had to be nonsmokers and not be using medications known Plasma very low-density lipoproteins (d<1.006 g/mL) were to affect lipid and insulin metabolism or blood pressure.
isolated by ultracentrifugation and the HDL fraction was obtained after precipitation of LDL from the infranatant and the Canadian Nutrient File (CNF, version 2007b, Ottawa, (d>1.006 g/mL) with heparin and MnCl2 . The cholesterol ON, Canada) .
and TG contents of the infranatant fraction were measuredbefore and after the precipitation step. Apolipoproteins (apo) Statistical analyses AI and B concentrations were measured by nephelometry(Dade Behring, Mississauga, ON, Canada). The lyophilized Data are presented as means ± SD unless stated otherwise.
serum standards for apo measurements were prepared at the Men were separated in those with (MetS+, n = 13) and without Lipid Research Center of Laval University Medical Center and (MetS−, n = 22) the metabolic syndrome (MetS) according to calibrated with reference standards obtained from the Centers the definition of the National Cholesterol Education Program for Disease Control (Atlanta, GA, USA). Plasma glucose , ie, the presence of at least three of the following criteria: concentration was determined with a glucose oxidase assay waist circumference ≥102 cm; fasting triglycerides ≥1.7 mmol/ (Sigma, St-Louis, MO, USA) as previously described while L; fasting HDL cholesterol ≤1.03 mmol/L; fasting glucose ≥5.6 insulin level was measured in plasma using a commercial mmol/L and blood pressure ≥130/85 mm Hg. In MetS+ men, double-antibody radio immunoassay (LINCO Research, St- 46% had a waist circumference ≥ 102 cm, 85% had TG ≥1.70 Louis, MO, USA) that shows little cross-reactivity (<0.02%) with mmol/L, 77% had HDL cholesterol ≤1.03 mmol/L, 46% had TG pro-insulin. Plasma uric acid (BioAssay Systems, Hayward, ≥1.70 mmol/L and all of them had hyperglycemia (>5.6 mmol/ CA, USA) as well as total nitrate/nitrite (NOx, Cayman L). Furthermore, the most common combination of features in Chemical, Ann Arbor, MI, USA) concentrations were measured the 13 men with the MetS of the present study was high TG/ by colorimetry.
low HDL cholesterol/hyperglycemia (n = 9). The MIXED modelprocedure was used to test the difference between treatments Blood pressure and arterial stiffness (PJ vs CJC) as well as within-group differences with anadjustment for sequence of treatments. Adjustment for Blood pressure was measured using a sphygmomanometer baseline value was also used when comparing changes in with the subject in a supine position after a 5 minute rest.
the variables of interest. Plasma triglycerides levels were log10 Mean arterial pressure (MAP) was calculated as the sum of transformed for the analysis but raw data are presented in diastolic blood pressure and one-third of the difference Tables. All analyses were performed with the SAS statistical between systolic and diastolic blood pressure as previously package (version 9.2; SAS Institute, Cary, NC, USA) and P ≤ .05 reported Arterial stiffness (expressed as the augmenta- was considered significant.
tion index, AIx) was obtained by applanation tonometry usingthe SphygmoCor System (AtCor Medical, Sydney, Australia) aspreviously described Briefly, after a 30-minute resting period, peripheral artery waveforms were recorded on thesubjects' radial artery. Pulse waveforms were also recorded at Baseline physical and metabolic characteristics of study 5, 10, 15, and 20 minutes after inhalation of 400 μg of participants are presented in As a group, subjects salbutamol (a short-acting β2-adrenergic receptor agonist) were overweight and abdominally obese with plasma which elicits the synthesis of nitric oxide (NO) and a vascular lipoprotein lipid levels within recommended guidelines response that can be used as a proxy measure of endothelium- Although at the high-end for total fat and low-end for dependent vasodilation. The same tonometry technique was carbohydrate intakes, daily energy and nutrient intakes of used to assess arterial stiffness during endothelium-indepen- the subjects at baseline also corresponded to nutritional dent radial artery vasodilation by performing measurements recommendations for the Canadian adult population, ie, at 3, 5, 10, 15, 20, and 30 minutes following sublingual 45% to 65% carbohydrates, 10% to 35% protein and 20% to administration of 400 μg of GTN, an NO donor . Global 35% total fat Furthermore, men with the MetS endothelial function was calculated as the ratio of the changes (MetS+) had a higher BMI as well as higher circulating TG in AIx in response to salbutamol relative to GTN as previously and lower HDL cholesterol concentrations compared to those without the MetS (MetS−). No difference was foundin daily energy and nutrient intakes between MetS+ vs.
Nutritional habits assessment MetS− individuals ).
illustrates AIx in the 35 participants prior to the start A 91-item validated food frequency questionnaire was of the intervention. Administration of salbutamol significant- administered by a nutritionist during each of the subjects' ly reduced AIx compared to resting values by −10.8% ± 6.4% (P visit to the investigation unit. During the interview, partici- < .0001). GTN further decreased AIx values compared to pants were questioned about frequency of intake for different salbutamol (−2.1% ± 6.0%, P < .05).
foods during the last month and were asked to report the As shown in there was no significant difference frequency of daily, weekly, and monthly consumption. The between changes in AIx following the consumption of CJC or nutritionist used food models for a better estimation of the PJ. Furthermore, changes in AIx responses to salbutamol and real portion consumed by the subjects. Analysis of data GTN did not significantly differ between men who consumed derived from the food frequency questionnaire was per- CJC or PJ for 4 weeks. However, we noted a statistically formed using the following food composition databases: significant within-group decrease in AIx (P < .05 vs Week 0) in Nutrition Data System for Research (software version 4.03, subjects that consumed 500 mL CJC per day for 4 weeks.
Food and Nutrient Database 31, Minneapolis, MN, USA) Furthermore, there were apparent deteriorations of the AIx Table 1 – Baseline physical and metabolic characteristics of men Body mass index (kg/m2) Waist circumference (cm) Waist-to-hip ratio Visceral AT (cm2) Subcutaneous AT (cm2) Systolic BP (mm Hg) Diastolic BP (mm Hg) Cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Total/HDL cholesterol Triglycerides (mmol/L) Apolipoprotein AI (g/L) Apolipoprotein B (g/L) Results are presented as means ± SD.
BP, blood pressureProc MIXED with adjustment for treatment sequence.
response to salbutamol and global endothelial function within MetS Prior to the intervention, responses to salbutamol those who consumed CJC (P < .05 vs. Week 0). also and GTN were comparable when MetS− vs. MetS+ men were shows the changes in different metabolic markers following compared (data not shown). After the intervention, we found the consumption of PJ and CJC for 4 weeks. We found no that there was no significant between-treatment (PJ vs. CJC) significant between-treatment differences in plasma NOx, differences in changes in AIx measured at rest or following uric acid, oxidized LDL and sE-selectin concentrations. There salbutamol and GTN administration in men with or without was a tendency (P = .10) for a difference between PJ and CJC for the MetS ). However, we noted a significant within-group changes in plasma sVCAM-1 levels which was mostly due to a decrease in resting AIx values in MetS+ men who consumed significant within-group decrease in sVCAM-1 when men CJC for 4 weeks (P < .05 vs Week 0). Surprisingly, within MetS+ consumed PJ for 4 weeks (P < .005 vs Week 0). Furthermore, individuals who consumed CJC, there were also significant despite the fact that the changes in circulating sICAM-1 increases in AIx responses to salbutamol and GTN (P < .05 vs concentrations did not significantly differ between both treatments, we noted a tendency for a decrease in plasma Finally, significant decreases in global endothelial function sICAM-1 levels within CJC treatment (P = .09 vs Week 0).
and circulating sICAM-1 concentrations in MetS− individuals In an effort to further explore the vascular impact of CJC who consumed CJC () whereas MetS− individuals supplementation, we compared AIx values in men separated supplemented with PJ for 4 weeks showed a significant on the basis of the presence (n = 13) or absence (n = 22) of the reduction in plasma sVCAM-1 levels. We found no other Table 2 – Baseline daily nutritional profiles of men Carbohydrates (% of energy) Proteins (% of energy) Fat (% of energy) Alcohol (% of energy) Saturated fat (% of energy) Monounsaturated fat (% of energy) Polyunsaturated fat (% of energy) Vitamin A (retinol equivalents, μg) Results are presented as means ± SD.
Proc MIXED with adjustment for treatment sequence.

decrease in AIx was not found to significantly differ from theplacebo group. Therefore, we rejected our original studyhypothesis that, compared to a placebo, regular CJC consump-tion reduces AIx. However, we feel that the significant within-group decrease in AIx following CJC consumption cannot beoverlooked and may need to be further investigated.
Our results are in apparent contradiction with recent observations in coronary patients showing that chronic CJCconsumption reduced carotid-femoral pulse wave velocitywhich is recognized as a clinically relevant measure of arterialstiffness . Daily consumption of 400 mL of polyphenol-richdealcoholized red wine for a period of 6 weeks has also beenassociated with a decrease in AIx in postmenopausal women. Differences in the populations under study as well as in Fig. 1 – Baseline augmentation index (AIx) of the 35 men the design of these previous studies and the one we describe measured at rest as well as following oral administration of herein may account for these apparent discrepancies. For Salb and glyceryl trinitrate (GTN). Data are presented as instance, Dohadwala et al used a CJC containing 54% juice means ± SEM. 1 Significantly different from resting values while we provided our subjects with CJC containing 27% juice.
(P < .0001) 2 Significantly different from salbutamol values Our choice to use the 27% juice was based on the fact that (P < .05).
when the study was conducted, the 54% CJC was not marketedin Canada. Further, Naissides et al tested the effects ofdealcoholized red wine over a period of 6 weeks compared to significant differences in the effects of the intervention (PJ vs.
our study which lasted only 4 weeks.
CJC) on the metabolic markers of MetS− or MetS+ individuals.
Studies have suggested a cause/effect relationship between endothelial NO production and arterial stiffness . Salb, aα-adrenoceptor agonist, has been shown to reduce AIx through the stimulation of NO release by endothelial cellsand thus, the vascular response to salbutamol is considered as Dietary FAV intake is negatively associated with the risk of a marker of endothelium-dependent vasodilation. In addition, CVD , an observation that is explained, at least partly, endothelium-independent vasodilation can be measured by the polyphenolic compounds present in FAV that are through the vasodilatory response to NO donors like GTN, known to regulate antioxidant and anti-inflammatory mech- leading to relaxation of smooth muscle cells As presented anisms improving the vascular function. Cran- above, although chronic consumption of CJC has been reported berries are rich in polyphenols and results from the to beneficially impact carotid-femoral pulse wave velocity present 4-week placebo-controlled double-blind crossover no chronic effect of CJC on flow-mediated dilation measures trial in healthy overweight men indicate that although CJC was reported in the same study suggesting no improvement of consumption did reduce resting AIx in overweight men, this arterial vasodilatory function. Furthermore, a 4-month daily Table 3 – Changes in hemodynamic variables and AIx values in the 35 men effect Placebo vs. CJC Heart rate (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) Δ AIx salbutamol (%) Global endothelial Uric acid (mg/dL) Oxidized LDL (U/L) sE-selectin (ng/mL) Results are presented as means ± SD.
BP, blood pressure.
Proc MIXED with adjustments for treatment sequence and baseline value.

Fig. 2 – Changes in arterial stiffness following the consumption of 500 mL PJ/day (white bars) and 500 mL CJC/day (black bars) for4 weeks in men characterized with (right panel) or without (left panel) the metabolic syndrome (MS) Augmentation index(AIx) was measured at rest as well as after oral administration of Salb and glyceryl trinitrate (GTN). Data are presented as means± SEM. p values for between-treatment effects are shown above the square brackets * Significant within-group difference (P < .05vs. Week 0) Proc MIXED with adjustment for treatment sequence and baseline value.
supplementation with 54% CJC had a neutral effect on adhesion molecule levels we report herein are in line with endothelial function assessed by digital peripheral arterial previous reports showing that CJC consumption for 2 weeks tonometry These observations are in accordance with had no effect on oxidative stress markers while supple- results of the present study as we found no significant menting men and women with 54% CJC for 4 consecutive difference between the effects of consuming CJC or PJ for 4 weeks failed reduce circulating sICAM-1 concentrations weeks on AIx responses to salbutamol. Within-group analyses When men were separated on the basis of the presence or rather suggest a less important AIx response to salbutamol absence of the MetS, differences between the effects of CJC after consuming CJC for 4 weeks.
and PJ on AIx also failed to reach statistical significance.
We previously reported that CJC supplementation was However, a significant within-group decrease in AIx measured associated with reductions in circulating OxLDL and at rest was noted in men with the MetS consuming CJC while adhesion molecule concentrations in men. In the present significant increases in AIx responses to salbutamol and GTN study, we found no significant variation in plasma OxLDL or were observed suggesting a probable deterioration of the adhesion molecule concentrations in response to CJC supple- endothelium-dependent and independent vasodilation pro- mentation for 4 weeks. Differences in the design of our studies cesses. These results may appear contradictory but it has been (duration and dose of CJC) are likely to explain the discrepan- shown that vascular tone is positively correlated with flow- cies between the present study and our previous observations.
mediated dilation in healthy individuals and thus, a more However, the lack of effect of CJC on plasma OxLDL and relaxed (and possibly wider) artery at rest has a lower Table 4 – Changes in hemodynamic variables in the men with and without the metabolic syndrome Heart rate (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) Global endothelial function Uric acid (mg/dL) Oxidized LDL (U/L) −45.1 ± 119.2 sE-selectin (ng/mL) Results are presented as means ± SD.
BP, blood pressure.
Proc MIXED with adjustments for treatment sequence and baseline value1 P value for between-treatment comparisons ⁎ P < .05 for within-group comparisons.
endothelium-dependent vasodilation response as previously significant variation in circulating uric acid concentrations reported This suggestion of abnormal dilation in following either CJC or PJ.
individuals with larger arteries that in reality have a normal In summary, results of the present study indicate no endothelial function has already been suggested statistically significant difference between the effects of a 4- The significant within-group improvement in AIx in men week low-calorie CJC and PJ supplementation on arterial consuming CJC could result from different physiological stiffness. However, the significant within-group decrease in mechanisms. Arterial stiffness has been shown to decrease AIx following CJC consumption in overweight men as well as after angiotensin-converting enzyme inhibitor therapy in those with the MetS remains intriguing and surely deserves and consumption of flavonoid-rich foods has been shown to to be further investigated with regards to its clinical and inhibit angiotensin-converting enzyme activity in rodents . Interestingly, a cranberry water-soluble phytochemicalextract has also been associated with angiotensin-convertingenzyme activity inhibition Cyanidin-3-glucoside, a poly- phenol found in cranberries, has been also shown to increaseendothelial nitric oxide synthase (eNOS) expression and This study was supported by the Canadian Institutes of Health decrease inducible nitric oxide synthase (iNOS) expression Research (CIHR, MOP-64438). Guillaume Ruel was supported by . Such changes in the balance between eNOS and iNOS the Fonds de la recherche en santé du Québec (FRSQ). Benoît expression/abundance/activity would favor the bioavailability Lamarche holds a Canada Research Chair in Nutrition, Func- of the vasoactive NO. However, as we did not measure enzyme tional Foods and Cardiovascular Disease. The authors would like activities/expressions in the present study, we were not able to thank Marge Leahy and Robin Roderick from Ocean Spray to establish whether our intervention was able to modulate Cranberries Inc. for kindly assessing the composition of CJC and these parameters. On the other hand, we did measure total PJ as well as supervising the packaging sessions at Laval plasma nitrate/nitrite concentration (NOx), which is often University. We also acknowledge the contributions of Danielle used as a marker of eNOS activity , and found that the Aubin, Mélanie Martineau, Jocelyne Giasson, Raoul Géra, Pascal intervention had no effect on the plasma NOx. It must be Cliche, Bernard Béliveau, Valérie Carnovale and Johanne Marin.
stressed that other more sensible techniques that the one we Finally, we would like to thank the subjects who participated in used to determine NOx are available and may have provided this study without whom, no clinical research would be possible.
more insights on the modulation of NO bioavailability in Charles Couillard received honoraria and reimbursement of response to CJC supplementation.
expenses from Ocean Spray Cranberries Inc as an invited Some factors may also have contributed to limit the extent of speaker in 2007 as well as research funding from the Canadian the change in AIx following CJC supplementation. Although we Cranberry Growers Coalition in 2003. These organizations were recruited overweight men with slightly elevated waist circum- not involved in the design and conduct of the present study. All ference, they were still healthy individuals which may have other authors have no conflict of interest to disclose.
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