Curr Hypertens Rep (2015)7:4
DOI 10.1007/s11906-015-0559-8
PREVENTION OF HYPERTENSION: PUBLIC HEALTH CHALLENGES (P MUNTNER, SECTION EDITOR)
Dietary Sodium and Cardiovascular Disease
Andrew Smyth 1,2 & Martin O’Donnell 1,2 & Andrew Mente 1 & Salim Yusuf 1
# Springer Science+Business Media New York 2015
Abstract Although an essential nutrient, higher sodium
intake is associated with increasing blood pressure (BP),
forming the basis for current population-wide sodium re-
striction guidelines. While short-term clinical trials have
achieved low intake (<2.0 g/day), this has not been
reproduced in long-term trials (>6 months). Guidelines
assume that low sodium intake will reduce BP and reduce
cardiovascular disease (CVD), compared to moderate in-
take. However, current observational evidence suggests a
J-shaped association between sodium intake and CVD;
the lowest risks observed with 3–5 g/day but higher risk
with <3 g/day. Importantly, these observational data also
confirm the association between higher intake (>5 g/day)
and increased risk of CVD. Although lower intake may
reduce BP, this may be offset by marked increases in
neurohormones and other adverse effects which may par-
adoxically be adverse. Large randomised clinical trials
with sufficient follow-up are required to provide robust
data on the long-term effects of sodium reduction on
CVD incidence. Until such trials are completed, current
This article is part of the Topical Collection on Prevention of
Hypertension: Public Health Challenges
* Andrew Smyth
andrew.smyth@phri.ca
Martin O’Donnell
odonnm@mcmaster.ca
Andrew Mente
andrew.mente@phri.ca
Salim Yusuf
salim.yusuf@phri.ca
1
Population Health Research Institute, Hamilton Health Sciences,
McMaster University, Hamilton, ON, Canada
2
HRB Clinical Research Facility Galway, NUI, Galway, Ireland
evidence suggests that moderate sodium intake for the
general population (3–5 g/day) is likely the optimum
range for CVD prevention.
Keywords Sodium . Salt intake . Cardiovascular disease .
Hypertension . Guidelines
Introduction
Sodium is required for normal physiological function, and
total body sodium is tightly regulated (via multiple mech-
anisms) to maintain extracellular sodium concentrations
within a narrow range [1]. The main dietary source of
sodium is salt (sodium chloride), which accounts for ap-
proximately 95 % of daily intake. The majority of the
world’s population (∼95 %) currently consume between
3 and 6 g/day of sodium [2, 3•].
Recently, there has been much debate about optimal sodi-
um intake and the evidence linking sodium intake and cardio-
vascular disease. Current guidelines are based on the follow-
ing assumptions: (i) any elevation in systolic blood pressure
(BP) above 115 mmHg is associated with increasing risk of
cardiovascular disease (CVD); (ii) measures of sodium intake
are positively associated with elevated BP; (iii) reducing so-
dium intake will reduce BP irrespective of the level of sodium
intake or BP level [4]; (iv) reducing sodium must therefore
reduce CVD. However, this chain of events has never been
fully demonstrated, and there are substantial data to question
these assumptions [5]. Small and short-term clinical trial data
show that sodium reduction reduces blood pressure, seen pre-
dominantly in those with elevated BP but not so in non-
hypertensives [6]. These data have prompted guidelines to
recommend that sodium intake should dramatically be re-
duced in the entire population [7] to less than 2 g/day (i.e. less
47 Page 2 of 8
than half current intake). These recommendations mean that
most people will require major dietary change to achieve
guideline targets. In this review, we discuss global sodium
intake (including measurement issues) and review the evi-
dence linking sodium intake to cardiovascular disease (includ-
ing blood pressure).
Global Sodium Intake
One of the most highly cited estimates of sodium intake comes
from the INTERSALT Study, which estimated sodium intake
from 24-h urine collections in 52 population samples in 32
countries (n = 10,079) [8]. In order to measure within-
individual variability, 8 % of the sample completed a second
24-h urine collection (3–6 weeks later). INTERSALT showed
wide global variations in 24-h sodium excretion ranging from
0.46 g/day (Yanomamo Indians, Brazil) to 6.0 g/day in men
and 5.4 g/day in women in Tianjin, northern China [9]. Subse-
quently, the INTERMAP study used two consecutive 24-h di-
etary recalls and one 24-h urine collection to estimate sodium
intake in Japan, China, UK and USA [10]. They confirmed that
the highest mean sodium excretion was found in northern Chi-
na, followed by Japan, USA and the UK [11, 12]. A recent
meta-analysis of cross-sectional studies (187 countries) esti-
mated mean global intake at 3.95 g/day, with significant region-
al variations [2]. The Prospective Urban Rural Epidemiological
Study (PURE Study) is the largest study (n>100,000) to report
global variations in sodium intake (628 communities in 18
countries) with a mean intake of 4.9 g/day [3•]. As sodium is
a nutrient rather than a food type, intake is embedded within the
overall diet pattern; sources include discretionary (added during
cooking or at the table) and non-discretionary (processed or
pre-prepared foods) [13]. The proportion of discretionary to
non-discretionary use varies between regions [14]. Importantly,
the regions of the world with the highest non-discretionary use
are not the regions with the highest overall intake.
Measurement
The method used to measure sodium intake is a key method-
ological issue, as differences between methods may affect the
absolute estimates of sodium intake and make comparisons
between studies challenging. Two main approaches can be
used to measure sodium intake—estimating sodium intake
from dietary questionnaires or measuring urinary sodium ex-
cretion. The current reference standard is repeated 24-h urine
collection for sodium, as 90–95 % of sodium ingested is
thought to be excreted in the urine. Multiple collections are
thought to be required to account for day-to-day variations in
sodium intake. However, recent data suggest that non-renal
mechanisms generate weekly and monthly infradian
Curr Hypertens Rep74: 1 )5 02(
rhythmicity of sodium storage (in the interstitium, especially
the skin), independent of daily sodium intake [15, 16•]. These
findings also suggest that variations in excretion, transfer of
sodium between different compartments in the body, accumu-
lation of sodium in the body and sodium intake itself may
influence the association between sodium and cardiovascular
disease. A key limitation of 24-h urine collection is the high
frequency of incomplete sample collection (due to under col-
lection) that may bias estimates (underestimate intake) or re-
sult in the exclusion of participants (e.g. those engaged in
manual labour or those who have to travel for work), limiting
generalizability. Based on these limitations, even single 24-h
urine collections are associated with high rates of incomplete
collection (as much as 30 %), and so repeat 24-h collection is
impractical in large international epidemiologic studies.
In order to address the limitations of 24-h urine collections
(single or multiple), various formula-derived estimates, in-
cluding the Kawasaki formula [17], Tanaka formula [18],
INTERSALT formula [19] and Mege formula, were devel-
oped and validated against 24-h urine collections [20]. The
timing and fasting status of urine samples and the population
included are important considerations when choosing a for-
mula. In North America, the Tanaka and INTERSALT formu-
lae applied to non-fasting, random urine samples are associat-
ed with the least biased estimates [20]. An international (11
countries) study validated Kawasaki formula-derived esti-
mates from fasting urine samples (ICC 0.71) [21], indicating
that this approach is a robust and reliable method of estimating
sodium intake in population-based studies.
While multiple urine collections (random, fasting or 24-h)
in the same individual is likely the best measure of usual
(habitual) sodium intake, this too is impractical in large stud-
ies. Instead, the approach is to measure the degree of variabil-
ity in the same individual at several time points in a subset of
individuals (e.g. a few percent) in larger studies, and using the
degree of correlation between two or measures in the same
group of individuals, the estimate of sodium intake is statisti-
cally adjusted. This method has been used by several investi-
gators including INTERSALT and PURE with regard to sodi-
um estimates and also for other risk factors such as cholesterol
or BP and is a widely accepted method to analyse epidemio-
logic associations [3•]. A key point is that if any estimate has
greater imprecision, the use of this measure tends to underes-
timate the slope of the association between sodium intake and
BP or CVD. However, it cannot change the shape of the as-
sociation, e.g., a direct association to an inverse association.
Further, if the variability between two measures is similar
across the entire range of exposures (e.g. sodium or cholester-
ol), then there is no reason to expect that a linear relationship
will be changed to one that is nonlinear or J-shaped.
Sodium consumption from the diet may also be estimated
using dietary questionnaires, such as food frequency question-
naires or 24-h dietary recall (ideally repeated multiple times).
Curr Hypertens Rep (2015)7:4
The main advantages of dietary methods over urinary methods
include convenience, the ability to carry out repeated measure-
ments easily and the ability to identify key dietary sources of
excess sodium. Dietary methods are limited by recall bias,
imprecision in estimating portion sizes, variations in the sodi-
um content of food items (e.g. sodium content of a slice of
bread may vary widely) and lack of information on sodium
added during cooking or at the table. In addition, dietary
methods need to be validated between regions due to signifi-
cant regional variations in common foods and in the sodium
content of food items. Because of these factors, the use of
dietary methods tends to add imprecision which in turn under-
estimates the association between sodium and BP or CVD
[22]. Therefore, any method of sodium estimation can under-
estimate the slope of the association with BP or with CVD, but
these methods are not expected to change the direction or
shape of the associations.
The purpose and design of a study will influence the choice
of method of measuring sodium. For example, for small stud-
ies that measure within-individual differences over time,
prolonged (24 h) urine collections on different days/weeks
will maximise individual-level precision. However, such an
approach is not necessary for improving the precision of pop-
ulation estimates of sodium consumption, as the largest
sources of variation in these are the marked interindividual
differences in sodium consumption. This variance can only
be reduced by including a large number of individuals and
little improvement in precision of group means can be
achieved by using prolonged collections (i.e. 24 h collections).
Studies exploring the association between sodium intake and
clinical outcomes (e.g. cardiovascular events) should focus on
enhancing group-level estimates of sodium intake (which is
mainly achieved by including a large number of individuals).
Further, large numbers of events are required to precisely re-
late an exposure (e.g. sodium intake) to an outcome (e.g. car-
diovascular disease); large studies which accrue several thou-
sands of events are required to be reliable. The methods used
in such studies need to be unbiased and practical. A single
fasting or non-fasting urine sample is ideally suited for such
studies. Moreover, by repeatedly obtaining such measures in a
subsample of the study population, statistical adjustments can
be made to calculate ‘usual or habitual’ levels of sodium con-
sumption. Finally, since there are fewer refusals and missing
data, the simple single measure of urine leads to less bias
compared to 24-h collections (as approximately 30 % of
approached individuals refuse to participate in research stud-
ies that require 24-h urine collections). These considerations
suggest that estimates of sodium derived from single fasting
urines (like BP or cholesterol) are reasonably reliable and
perhaps even superior to more involved measures such as
24-h urine collections for epidemiological studies. It is impor-
tant to note that to evaluate the impact of an intervention on
sodium intake, different approaches may be preferred.
Page 3 of 8 47
Sodium Intake and Cardiovascular Disease
Sodium is essential to produce osmotic pressure and maintain
water in the extracellular space [1]. This requires a balance
between sodium intake and excretion, maintained by the renal
response to renin and aldosterone, the sympathetic nervous
system and atrial natriuretic peptide production. Taken togeth-
er, these mechanisms adapt to variations in sodium intake
without significant increases in blood pressure. However,
some individuals have a significant blood pressure response
to moderate changes in sodium intake, known as salt sensitiv-
ity [23]. Low sodium intake may activate the renin-
angiotensin-aldosterone and sympathetic nervous systems
and has adverse effects on the lipid profile [24]. However,
most mechanistic studies of sodium reduction are small (n<
50) and had short durations of follow-up (median 28 days).
The long-term effects of low sodium intake on biomarkers
(such as CRP, IL-6, troponin, BNP/ProBNP and uromodulin
[25–28]) have not been adequately studied.
Current guidelines are primarily based on the association
between sodium intake and blood pressure [29•] with the as-
sumption that changing sodium has no other physiologic or
clinical effects. INTERSALT reported a weak but significant
positive association between mean sodium intake and blood
pressure (p=0.0446), but there were four outlier communities
(Brazilian tribes, Papua New Guinea and Kenya), which when
excluded, resulted in loss of statistical significance (p=0.33)
[8]. Subsequently, other studies reported a positive association
between sodium intake and blood pressure. Recently, the Pro-
spective Urban Rural Epidemiology (PURE) study, including
>100,000 individuals from 18 countries, reported a positive
but nonlinear association between sodium intake and blood
pressure, with modest effects in non-hypertensive and youn-
ger individuals [3•]. Several short-term clinical trials
(<6 months follow-up) reported an effect of sodium reduction
on blood pressure [30]. The Dietary Approaches to Stop Hy-
pertension (DASH) sodium trial (n=412) was a randomised
crossover feeding clinical trial (i.e. all foods were provided to
participants and their households for 1 month), comparing
moderate (mean 3.3 g/day), low (mean 2.5 g/day) and very
low sodium (mean 1.5 g/day) intake for 30 days [31]. Low and
very low sodium intake (compared to moderate intake) re-
duced systolic blood pressure. The Trials of Hypertension
Prevention (TOHP) II trial is the largest trial (n=2382) exam-
ining the effect of sodium reduction (target <1.8 g/day) on
blood pressure over a mean follow-up of 36 months [32].
The intervention group did not achieve the target level
(achieved level of 2.5 g/day at 6 months and 3.1 g/day at
36 months), and the difference in systolic blood pressure be-
tween the intervention and control groups was small and di-
minished over time (reduction in blood pressure of −1.6+/
−0.4 mmHg at 6 months and −0.5+/−0.4 mmHg at 36 months).
A recent meta-analysis showed no relation between sodium
47 Page 4 of 8
reduction and blood pressure reduction in normotensive pop-
ulations (change of 0.99 mmHg (95 % CI −2.12–4.10)), but a
significant dose-response relationship in pre-hypertensive and
hypertensive populations (change of 6.87 mmHg (95 % CI
5.61–8.12)) [6].
Guidelines also assume that reductions in blood pressure
will result in reductions in mortality and cardiovascular event
rates. However, as no large, long-term clinical trial has been
completed that demonstrates this clearly, large observational
studies are the next best source of evidence. The Trials of
Hypertension Prevention (TOHP) reported that sodium excre-
tion of <2.3 g/day (compared to excretion of 3.6–4.8 g/day)
was associated with a reduced risk of cardiovascular events or
cardiovascular disease deaths [33]. However, there were sev-
eral problems with these conclusions. First, 23 % of partici-
pants were lost to follow-up, and of those followed, records to
document CVD were unavailable in a further third. This sug-
gests that data on CVD may not have been available for more
than 40 % of the events. Second, individuals who were
randomised to reduced sodium intake were excluded from
the study, which resulted in the exclusion of half of the partic-
ipants in TOHP-2 and 15 % of TOHP-1. No tangible argument
was provided other than wanting to obtain ‘long-term usual
intake’, despite previously reporting that the sodium interven-
tion group expressed a meaningful preference for lower sodi-
um diet years after the study [34]. Third, the study also ex-
cluded cases that had a CVD outcome during the time of the
TOHP follow-up (i.e. before the final sodium reading), which
in TOHP-2 resulted in the exclusion of outcomes in the first 3
to 4 years, with no sensitivity analysis provided to show the
results with and without their exclusion. In total, only 193
cardiovascular events or cardiovascular disease deaths were
included. Fourth, the study assumes a linear relationship be-
tween sodium intake and cardiovascular disease. Finally, only
one of nine comparisons was statistically significant, which
was the spline test for linearity (p=0.046), although the spline
figure showed that the 95 % CI overlaps with null throughout
the range of sodium intake. Therefore, this study does not
inform us reliably as to whether or not reduction in sodium
intake affects CVD or mortality.
Few large studies of diverse populations explored the asso-
ciation between sodium intake and cardiovascular events and
mortality. In analyses of ONTARGET and TRANSCEND
(two clinical trials of a population at high cardiovascular risk)
(n=28,880), a J-shaped association was observed between
sodium intake and cardiovascular mortality, with an increased
risk in those consuming <3 or >6 g/day [35•]. In the PURE
study (a prospective cohort study of a population at average
cardiovascular risk), a similar association was observed with
higher risk of death or a major vascular event with low (<3 g/
day) or high (>7 g/day) intakes [36•]. It is possible that the
effects of sodium intake differ among populations. The Pre-
vention of Renal and Vascular End-Stage Disease
Curr Hypertens Rep74: 1 )5 02(
(PREVEND) study (n=7543) reported that the association
between high sodium intake and cardiovascular disease was
restricted to those with hypertension or elevated pro-BNP
levels at baseline [37•]. Although the absolute risk of cardio-
vascular events and mortality is higher in those with prior
cardiovascular disease, no study has reported a significant
interaction by pre-existing cardiovascular disease [36•, 38•,
39]. A prospective cohort study of French participants with
type 2 diabetes (n=1439) reported a J-shaped association be-
tween sodium excretion and cardiovascular mortality [40•].
The European Prospective Investigation of Cancer (EPIC)
Norfolk prospective cohort study of healthy men and women
aged 39–79 years (n=19,857) reported a J-shaped association
between estimated 24-h urinary sodium excretion and risk of
heart failure [41•]. The Health, Aging and Body Composition
(Health ABC) study of adults aged 71–80 years (n=2642)
reported that food frequency questionnaire-assessed sodium
intake was not associated with mortality, cardiovascular dis-
ease or heart failure [42•]. Thus, at least five independent
prospective cohort studies have indicated a J-shaped associa-
tion between sodium intake and CVD, with the lowest event
rates occurring in the 3–5 g/day range of sodium intake
(Fig. 1). A systematic review of prospective cohort studies
also reported a J-shaped association, when all prospective
studies are meta-analysed [6].
The absolute level of sodium intake in individual studies
may modify the association between sodium intake and cardio-
vascular disease. Among studies that include high sodium in-
take (>5 g/day), most report an increased risk of cardiovascular
events [43] and meta-analyses report that compared to the low-
est quantile of intake, the highest quantile of sodium intake was
associated with an increased risk of stroke (RR 1.24; 95 % CI
1.08–1.43) and fatal coronary events (RR 1.32; 1.13–1.53), but
not all-cause mortality (RR 1.06; 0.94–1.20) or all CVD (1.12;
0.93–1.34) [30]. A different meta-analysis, of the same studies,
compared high (>5 g/day) to moderate (2.7–5 g/day) intakes
and reported an association between increased risk of all-cause
mortality (HR 1.16; 1.03–1.30), CVD (HR 1.12; 1.02–1.24),
stroke (HR 1.18; 1.05–1.33) and heart disease (HR 1.17; 1.08–
1.27) and high sodium intake [44]. When comparing low
(<2.7 g/day) to moderate (2.7–5 g/day) intakes, this meta-
analysis reported that moderate intake was associated with low-
er risks of all-cause mortality (0.91; 0.82–0.99) and all CVD
(HR 0.90; 0.82–0.99) [44].
Factors Modifying the Association Between Sodium
Intake and Cardiovascular Disease
As dietary components are not consumed in isolation, other
dietary factors (e.g. fruit and vegetable intake) or diet patterns
(e.g. Mediterranean diet) may modify the association between
sodium intake and cardiovascular disease [45, 46]. A key
Curr Hypertens Rep (2015)7:4
(a) Thomas et al Diabetes Care 2011 (b) Saulnier et al NEJM 2014
(d) O’Donnell et al JAMA 2011 (e) Pfister al EHJ 2014
Fig. 1 Association between sodium and cardiovascular disease. This
figure shows the association between sodium and cardiovascular
outcomes in a number of prospective cohort studies. Panel a shows the
association between measured 24-h urine sodium and all-cause mortality
in a cohort of patients with type 1 diabetes (n=638) [38•]. Panel b shows
the association between estimated 24-h urine sodium and cardiovascular
mortality in a cohort of patients with type 2 diabetes (n=1439) [40•].
Panel c shows the association between estimated 24-h urine sodium and
death or cardiovascular events in a large international cohort (n=101,945)
[36•]. Panel d shows the association between estimated 24-h urine sodi-
um and death or cardiovascular events in an international cohort at high
measure of other dietary components is potassium intake [47,
48]. Higher potassium intake is associated with reduced risk
of cardiovascular disease, particularly stroke [7]. A small clus-
ter randomised controlled trial (n=1981) carried out in Taiwan
reported that reduced sodium (5.2 to 3.8 g/day) and increased
potassium consumption (use of potassium-enriched salt) was
associated with a reduction in cardiovascular mortality (HR
0.59; 95 % CI 0.37–0.95) [49]. The sources of dietary sodium
may also confound the associations with health outcomes. For
example, in some regions, high sodium intake may come from
processed foods (which may independently be associated with
cardiovascular disease), but in other regions, high sodium in-
take may come from salted fish and vegetables (which are not
independently associated with cardiovascular disease) [13].
Further, some individuals respond differently to dietary so-
dium, as those who are ‘salt sensitive’ have a greater blood
pressure response to increased sodium intake than others [50].
Page 5 of 8 47
(c) O’Donnell et al NEJM 2014
(f) Kalogeropoulos et al JAMA-Int Med 2015
cardiovascular risk (n=28,880) [35•]. Panel e shows the association be-
tween estimated 24-h urine sodium and heart failure in an apparently
healthy cohort (n=19,857) [41•]. Panel f shows the association between
sodium intake (food frequency questionnaire) and mortality in a cohort of
older adults (age range 71–80 years) (n=2642) [42•]. Part a reproduced
with permission from the American Diabetes Association. Parts b and c
reproduced with permission from the Massachusetts Medical Society.
Parts d and f reproduced with permission from the American Medical
Association. Part e reproduced with permission from the European Heart
Journal
However, there is no consensus definition of salt sensitivity in
clinical practice, although up to one-half of patients with hy-
pertension are thought to be salt sensitive [50]. Genetic poly-
morphisms have been associated with salt sensitivity, hyper-
tension and cardiovascular disease [26]. Although genome
wide association studies (GWAS) have not been conducted
for salt sensitivity, possible candidates include (i) genes that
express proteins that increase renal sodium transport (e.g. an-
giotensin I converting enzyme); (ii) genes that express pro-
teins to decrease renal sodium transport; (iii) G protein-
coupled receptor 4 [GRK4]; and (iv) activators of the renal
sodium co-transporter NKCC2 (e.g. uromodulin) [50].
Uromodulin (Tamm-Horsfall protein) may be a key determi-
nant of salt sensitivity, as common variants in the promoter of
the UMOD gene increase susceptibility to hypertension and
uromodulin overexpression in transgenic mice leads to salt
sensitivity hypertension [26].
47 Page 6 of 8
Optimal Sodium Intake
The optimal range of sodium intake, both for the general pop-
ulation and for specific subpopulations, requires definition
using a range of physiologic and epidemiologic investiga-
tions. External toxins (e.g. tobacco, alcohol, artificial sweet-
eners, artificial transfats or pollutants) usually exhibit a linear
association with disease and the ideal level of exposure for
most is likely zero or very low. However, many nutrients are
essential to human function and normal physiology [51];
therefore, there is a need to establish what range of intake is
associated with the most benefit and least harm. This would be
considered to follow a ‘homeostatic model’ whereby levels
that are too low or too high are adverse. Sodium is clearly
involved in several normal human physiologic functions
(e.g. the action potential depends on the movement of sodium
and potassium across cell membranes), and so it would be
naïve to assume that extremely low levels of sodium are in
the homeostatic range. The preponderance of the available
epidemiologic data is consistent with the ‘homeostasis model’
as sodium and potassium are key to maintaining physiologic
function. Therefore, sodium intake that is either too high or
too low should be avoided.
Future Goals
In order to test the effectiveness of sodium reduction (to low
intake levels) on reducing clinically important cardiovascular
outcomes and mortality, large randomised controlled trials are
required to address the current uncertainty about risks and ben-
efits. Although clinical trials of nutrition intervention are chal-
lenging, they are essential before we recommend large changes
in public health policy and population nutrition, especially
when there are concerns about safety. Relying solely on the
relationship between sodium and blood pressure ignores that
nutrient intake is not changed in isolation, that extreme sodium
reduction may have ‘off-target’ adverse effects and that a large
body of epidemiologic data relating sodium to cardiovascular
disease, challenge conventional dogma and indicate that sodi-
um intake below approximately 3.0 g/day may be harmful.
Conclusion
Based on current data, a range of 3–5 g/day of sodium is
associated with the lowest risk of cardiovascular disease in
multiple studies.
Acknowledgments No funding was received for the current article.
Authors received funding from the Heart and Stroke Foundation of On-
tario for PURE Salt Study of association of sodium intake and cardiovas-
cular events and mortality.
Curr Hypertens Rep74: 1 )5 02(
Compliance with Ethics Guidelines
Conflict of Interest Andrew Smyth, Martin O’Donnell, Andrew Mente
and Salim Yusuf declare no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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