JOURNAL OF WOMEN’S HEALTH

Volume 19, Number 2, 2010 Editorial

ª Mary Ann Liebert, Inc.
DOI: 10.1089=jwh.2009.1632

Sex-Gender Research Sensitivity

and Healthcare Disparities

Michael Gochfeld, M.D., Ph.D.

Abstract

Authors Nieuwenhoven and Klinge (Journal of Women’s Health 2010;19:1–6) argue that despite advances, sex
and gender are not well treated in the biomedical literature. Many studies in which males and females are
represented do not address the similarities or differences between sexes, sometimes adjusting for (thereby
obscuring) sex differences and sometimes ignoring sex altogether. Women continue to be underrepresented in
randomized drug trials, excluded from some by potential reproductive effects, and perhaps frightened from
others by IRB-required warnings. Although recognized, sex disparities in treatment, for example, for acute
cardiac syndrome, persist. As electronic abstracts become a prime means of communicating research results,
they must adequately and accurately represent a study’s findings.

Introduction to the XX and XY chromosomal determination (with very few

deviations), whereas gender is determined by complex and

‘‘B eing male or female is an important fundamental

variable that should be considered when designing
and analyzing basic and clinical research.’’1 It is obvious that
there are profound differences in health and disease related to
the reproductive and endocrine systems,2 but there are many
more subtle differences where sex and gender and age and
work and social factors and education and income and be-
havior interact. Large population-based studies can offer
important clues even when there are many potential con-
founders or effect modifiers, but only if researchers address
sex and gender head on. Is that happening? Linda Nieu-
wenhoven and Ineke Klinge examined this in ‘‘Scientific Ex-
cellence in Applying Sex- and Gender-Sensitive methods in
Biomedical and Health Research’’3 and concluded that despite
advances, the answer is still No, and they elaborate on the
importance of sex-gender sensitivity in biomedical research.
I have long been puzzled by the realization that despite half
the world being female and the other half having females as
mothers, wives, and daughters, there remains a gender gap in
biomedical research related to causation, diagnosis, risk fac-
tors, prevention, and treatment. It is not always possible or
relevant to include males and females in a study, whether
it is rodent toxicology or human epidemiology, but even if
females are represented, Nieuwenhoven and Klinge aver that
is no guarantee of sex-gender sensitivity in interpretation.3
Krieger4 provides a comprehensive discussion and defini-
tion of the terms ‘‘sex’’ and ‘‘gender.’’ The common distinction
is that sex refers to biologically determined differences related
continuing interactions among biological sex, personality, life
experience, and culture(s)—the interaction of environment
and biology. Nieuwenhoven and Klinge3 indicate that the
terms are often used interchangeably or wrongly, and as the
editor of a special journal issue (16 articles) on sex and toxi-
cology, I plead guilty, for on the vote of the authors, we used
the term gender throughout, as if it were not quite tasteful for
grownups to speak of sex in mixed company. Sex is a crucial
variable, however, and for environmental toxicologists like
me, it offers a fertile and challenging, if frustrating, field. A
growing number of articles find differences between men and
women in a variety of toxicological responses,5 but are these
caused by differential exposures (gender), differential bio-
chemistry (sex), or a combination of the two (most likely).6
Animal research can only go so far in addressing sex and
gender differences.
It is generally assumed that gender is a uniquely human
trait; Nieuwenhoven and Klinge say ‘‘almost exclusively,’’3
but this is certainly not true. Depending on how they are
raised, male and female animals experience different social
groups and dominance relationships and develop different
suites of behavior appropriate to different social interactions.
We should not ignore gender just because animals do not
dress up or play with dolls or trucks. Roles certainly analo-
gous to gender are obvious at least in carnivores, primates,
ungulates, and elephants, with effects apparent, for example,
when a senior or dominant male or female is removed from or
introduced into an animal society, reflecting the ‘‘evolutionary

Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey.

189
190
continuity of mental experience.’’7 Toxicology researchers are
well aware of the importance of the social combinations of
rodents being tested, although unfortunately they often resort
to testing only males ‘‘to keep things simple.’’ A good example
of the weakness of single-sex studies is the discovery of the
unique enzyme in the kidney cortex of male rats, an alpha-
globulin, that is not expressed in females or in mice and
renders the male rats vulnerable to kidney diseases caused by
hydrocarbons.
Sex Insensitivity
One of my first impressions in reviewing Nieuwenhoven
and Klinge3 was that these authors correctly appreciate the
importance of sex and gender in both health and disease but
that they underestimated the tremendous progress in study-
ing sex differences in morbidity, mortality, or management,
not to mention toxicology and epidemiology, and overstated
the lack of sensitivity in the literature. Donning gender-
sensitivity goggles, however, reveals the underlying truth in
their thesis. A great deal of studies include men and women
(now mandated by regulations), without adequately inter-
preting or explaining differences or similarities.
In preparation for this editorial, I read a sample of recent
medical and epidemiological studies. Searching PubMed with
terms, such as gender disparities in healthcare or medical care,
yielded only two pages of references. Searching on sex dis-
parities in medical care returned 214 entries, the most recent of
which were mainly about race or social class bias, revealing
lack of attention to sex rather than the converse Although
most of these studies included data on men and women, I was
surprised at how often the data on sex differences were
downplayed or even ignored or obscured by adjustment even
in otherwise excellent papers.
For example, Macinko and Elo8 have just published a
valuable analysis of racial disparity in avoidable mortality.
They compare black and white mortality for several diseases,
separately for males and for females. Not surprisingly, their
data show dramatic (and expected) racial differences in ab-
solute mortality, as well a gratifying reduction in the dis-
crepancy over a 25-year period. However, data for men and
women are presented in separate parts of the table, preclud-
ing easy comparison, and there is little mention of some of the
surprising sex differences, for instance, between white men
and white women. Deaths avoidable by ‘‘improved medical
care’’ showed a 6.1% improvement in white men compared
with 13.4% improvement in white women, and mortality
‘‘averted by public health policy’’ improved 32.1% in men but
only 4.7% in women. The latter gender gap was even greater
for blacks 71.9% vs 9.1%. Why? This latter category includes
‘‘public health interventions and policies directed at changing
behaviors (e.g., smoking, drunk driving, and excessive
drinking; seatbelt use; access to firearms).’’8 It may simply be
that men were so much more likely to die from these in the
first place that they had much more room for improvement.
Burge et al.9 studied age differences in the use of palliative
care among 7500 cancer decedents in Nova Scotia. Old (>65
years) people were less likely to get such care, but in this age
group, men were significantly less likely than women to
register for care, perhaps because they are more likely to have
a younger, surviving spouse as caretaker. Hanchate et al.10
compared ethnic=racial groups with respect to cost of end of
GOCHFELD
life care and found significant differences overall, which
persisted within sexes, but they do not discuss any difference
between sexes. Why, for example, do younger women (aged
65–75) cost more and older women cost less than men of the
same age. Why is the black=white discrepancy much greater
in women than men? Sex was one of the three independent
variables studied by Koller and Mielck,11 investigating obe-
sity, inadequate checkups, and inadequate vaccinations
among children in Germany. The Abstract makes no mention
of the sex outcome, perhaps because girls and boys were
equally likely to miss vaccinations (55%) or be obese (10%),
whereas girls were slightly more likely to miss examinations
(24% vs. 22%, p ¼ 0.08). Similarities must be uninteresting.
For the period 1996–2000, blacks and women on a national
liver transplant list were more likely to die or become sick
prior to transplant and less likely to receive a transplant
within 3 years than white males. After introduction of the
Model for End-Stage Liver Disease (MELD) objective score in
2002, the racial disparity declined to nonsignificant, but the
sex disparity widened to a relative risk of 1.3 ( p < 0.05).12
There is no clear explanation for the sex difference. The au-
thors suggest that the score itself, which includes creatinine
level as a component, discriminates against women who,
because of smaller muscle mass, tend to have lower creatinine
levels, hence, lower scores and lower priorities.12 This is
presumably an unintended consequence of failing to pay at-
tention to sex and gender.
The cited articles either adjust for sex (obscuring differ-
ences) or do not mention sex differences in the Abstract;
sometimes, the results from men and women are combined. It
is safe to say that there are probably no circumstances in
which results from men and women should be lumped a priori
without testing for differences, and the contribution of sex
differences as confounders or effect modifiers should be elu-
cidated in papers and referred to in the Abstract, which is
what most readers see.
Nieuwenhoven and Klinge emphasize that sex differences
translate into health differences and disparities in the diag-
nosis and treatment of diseases.3 This has been established on
numerous occasions for racial=ethnic differences but on fewer
occasions for male=female differences. Ignoring, for today, the
extensive literature on different incidences of various diseases
among men and women, there are some pervasive treatment
disparities.
Women’s Health and Treatment
An oft-mentioned gender difference is that men and women
differ in health-seeking behavior and in their attentiveness
to symptoms. Women are more likely to seek treatment ear-
lier than men for similar symptoms; indeed, adult women
are more likely to have a physician than men. There is also a
health perception difference; for example, in a study of over
22,000 men and women in Britain, women were significantly
less likely to rate their health as excellent regardless of social
class.13 The differences, 16.1% vs. 18.4%, seem small at first
but translate to a 12% difference. Even the same disease, de-
pression, can be defined differently and carry different stig-
mas in males and females.14
Nieuwenhoven and Klinge wrote ‘‘sex and gender can help
explain the differences in etiology and prognosis of diseases’’
and can ‘‘modify the outcomes of diagnostic procedures and
SEX-GENDER RESEARCH SENSITIVITY 191

of preventive and treatment interventions.’’3 There is a further Toxicology and Sex

factor to consider, however, Physicians, regardless of their
In 2005, I was an organizer of a weeklong workshop on
own sex and gender, treat men and women differently.
‘‘Gender in Toxicology and Risk Assessment’’ for the Scientific
Women who suffer acute myocardial infarction (AMI) are
Group on Methodologies for the Safety Evaluation of Che-
less likely to receive prompt aggressive treatment, are more
micals (an affiliate of the Paris-based, international Scientific
likely to have symptoms labeled as psychologic or atypical,3
Group on Problems of the Environment24). Aside from con-
and are more likely to have back pain than chest pain.15
fusing gender and sex, the toxicologists recognized ‘‘three
Discrepancies in medical treatment, now widely recognized
major themes surrounding biologic sex differences: genetic,
for racial disparities as elucidated in the Institute of Medicine
human health, and ecologic.’’25 ‘‘From embryonic life onward
report on ‘‘Unequal Treatment,’’16 persist for gender. In 1991,
males and females have very different internal milieus me-
Ayanian and Epstein,17 noting prior reports of treatment dis-
diated by the powerful influence of sex hormones and their
parity, examined 82,782 heart diseases cases including 18,759
receptors’’ (sex) and have different external environments
diagnosed with AMI, and found that women in Massachusetts
influenced by roles in relationships, recreation, reproduction,
were 28% and 45% less likely to be referred than men for an-
and employment (gender).25
giography and revascularization, respectively. Maryland re-
Ironically, much of our knowledge of human toxicology
sults (15% and 27%) were less extreme, but all were statistically
stems from relatively highly exposed people working in
significant. Their report, published in the New England Journal
chemical and other factories. Women and minority workers
of Medicine,17 garnered attention, but over the ensuing years,
were almost universally excluded from such jobs and, hence,
some treatment has not changed much. ‘‘Women receive less
are absent in most occupational epidemiology studies or, if
evidence-based medical care than men and have higher rates
included in the data, were usually ignored in the analysis
of death after AMI.’’18 Why? Women were less likely than men
because of small sample sizes.6 The workshop offered a
to have ST-elevation myocardial infarction (STEMI), but
framework for examining sex and gender differences by
women who were admitted with STEMI were half as likely
focusing on (1) exposure opportunity, (2) toxicokinetics
to leave the hospital alive. Women were less likely to receive
(what the body does to chemicals), (3) toxicodynamics (what
aspirin or beta-blockers or reperfusion (angioplasty), and
chemicals do to the body), and (4) modifiers (particularly
when the latter occurred, the lag time was longer. When all MIs
sex hormones).6 There are sex differences as early as germ
were considered, the sex difference was not significant, but for
cell division and mutagenesis, including differences in mu-
STEMI, the most common type of AMI in men, the results were
tation rates at specific loci26 and in the induction of chro-
striking and scary. The way the authors worded their conclu-
mosomal aberrations.27 A broad range of sex differences in
sion is puzzling, however. They begin their conclusion with
toxicokinetics and toxicodynamics occurs throughout the life
‘‘Overall, no sex differences in in-hospital mortality rates after
span.5
AMI were observed after multivariable adjustment. However,
The basic paradigm for studying sex differences has cen-
women with STEMI had higher adjusted mortality rates than
tered around the sex hormones, including treatment with
men.’’18 Surely, they would vigorously deny that their work or
agonists or antagonists or castration, followed by adminis-
views are insensitive to sex, yet the emphasis in the conclusion
tering the same or opposite hormones. Much has been learned
suggests otherwise, that the sex discrepancy for STEMI is just a
from complex variations on this theme about the reproductive
sidelight, barely worth mentioning. Enriquez et al.19 reported
system, development, and effects in other organs. However,
even stronger discrepancy in drug treatment rates for statins,
the study of the role of sex hormones and receptors modu-
aspirin, and beta-blockers. Nguyen et al.15 noted in their Ab-
lating metabolism is in its infancy. For example, males and
stract no sex difference in drug treatment for AMI. However,
females exposed to arsenic in drinking water metabolize and
even though not statistically significant at the 0.05 level,
distribute arsenic compounds differently because of different
women were still 5%–10% less likely to receive the three classes
methylation rates, which become faster in older women.28 The
of drugs. Significantly, they found a 46% lower likelihood of
overall workshop conclusion was: ‘‘Wherever possible, stud-
women being referred for invasive diagnostic procedures.15
ies should use balanced gender and gender
age designs and
Perhaps the most gender-sensitive feature of their article was
should analyze data by sex and interactions, rather than
the conclusion that women might be undertreated or men
simply adjusting for (discarding) gender.’’6
overtreated with invasive procedures.
The American College of Cardiology and American Heart
Drugs and Women
Association (ACCA-AHA) published detailed guidelines for
various management approaches to different cardiac syn- From toxicology, it is a short step to pharmacology. An-
dromes.20 Management of patients with acute coronary syn- other point articulated by Nieuwenhoven and Klinge3 is the
drome (unstable angina or MI) continues to be suboptimal.21 lack of data on drug efficacy and side effects in women.
Evaluating adherence to the guidelines as metrics for acute Medicine has recently emphasized the importance of indi-
coronary care, the CRUSADE study shows that the gender vidual variability in pharmacokinetics (what the body does to
gap for some treatments (aspirin and clopidogrel) has nar- a drug in terms of absorption, metabolism, distribution, and
rowed to a few percentage points, but a broad gender gap elimination) and less so in pharmacodynamic variability
remains for some treatments. Women were less likely to be (what a drug does to the body in terms of entering cells,
treated according to the ACCA-AHA guidelines and were less binding to receptors, affecting membranes, organelles, macro-
likely to receive early glycoprotein IIb=IIIa inhibitor therapy molecules, cell signaling, carcinogenesis). There is a grow-
(29% vs. 39%).22 It is scant consolation that men also are ing interest in individualizing drug treatments, tailoring
undertreated according to the new guidelines with glyco- prescribing practices to take into account genetic variation
protein IIb=IIIa inhibitors.23 that may influence the metabolism of one or more drugs,
192
requiring an adjustment in dosage or timing. Sex is likely to be
a contributing factor, if only because of the commonality of
metabolic pathways between xenobiotics and sex hormones,
for example, the affinity of estrogen and some anti-epilepsy
drugs for P450 3A4, such that coadministration results in
enzyme induction and reduced efficacy of both, causing more
seizures and more pregnancies.29
Calabrese,30 in 1985, assembled a long list of drugs that
affect men and women differently. The list has grown since
then, of course, but the mechanisms for these differences are
not all apparent. Individual tailoring of drug treatment based
on variations in metabolizing hormone patterns, receptor
biology, circadian cycles, and monthly cycles may elucidate
some of the mechanisms of male-female differences. It is an
exciting challenge for biologists, pharmacologists, and toxi-
cologists. To date, we have crude estimates that metabolic
differences between sexes can be on the order of 2-fold and
that xenobiotic distribution can differ greatly among indi-
viduals based on body composition, with the tendency to-
ward women being more susceptible to drug interactions.5
Some of the differences in how men and women handle and
respond to drugs depend on their physical variability. Aver-
age relative organ sizes tell only a small part of the sex story
but can be instructive. The International Commission on Ra-
diation Protection (ICRP) assembled a monograph describing
in detail sex differences to support health physicist calcula-
tions.31 It may come as no surprise that women have (on av-
erage) a third more adipose tissue and a third less muscle
mass, but other significant differences include women having
10%–15% less bone, blood, and skin, and an 8%–14% larger
gastrointestinal tract, kidneys, and brain. Cartilage, skin, and
liver vary <5%.
Drug Trials
A major impediment to individual tailoring is that women
have always been underrepresented in drug development
trials, forbidden to participate in phase I trials, and discour-
aged or reluctant to participate in phase II trials. The U.S. Food
and Drug Administration (FDA) is sensitive to this, requir-
ing enrollment of women,32 and the situation has gradually
improved. However, the FDA’s Office of Women’s Health
identifies persistent obstacles while suggesting that new
technologies and techniques may improve the representation
of women in drug trials.33
The exclusion of women of childbearing age from most
drug studies continued into the 1990s, and many trial proto-
cols require women to prove they are sterile or are using
effective birth control. Observational studies (rather than
randomized trials) have revealed striking sex differences. For
example, Gan et al.34 found that women recover from general
anesthesia significantly more quickly (7 minutes) than men
(11 minutes), and this persists when corrected for dose.35 The
difference in the hypnotic effects of the drug propofol was
partly the result of pharmacokinetics (a consistently more
rapid decline in blood concentration of the drug in women)34
and partly the result of pharmacodynamics (men awoke at a
higher blood concentration).37 This sex difference is more
pronounced in premenopausal women,37 opening a new
avenue for investigation.
Drug development studies now include more females than
previously, but for many drugs that carry a potential for fetal
GOCHFELD
effects or teratogenicity (almost any new drug), pregnant
women are still excluded, and women of childbearing age can
participate only if they adhere to a strict birth control regimen.
Thus, equality in drug trials may never be achieved if a large
portion of women’s life cycle is excluded from studies. For
example, a review of 221 trials of anti-HIV drugs averaged
only 11.6% female participation. Of 24 trials that had no
women, there were no outright exclusions, and nonpregnant
women would have been allowed to participate (with some
form of birth prevention). The reviewers concluded that other
factors (not specified) precluded women from participating.38
One can infer that the trial investigators were insensitive? But
how? Did information on the trials fail to reach women, or did
they find the information unappealing or scary? One can
image that marketing approaches advertising the availability
of trials might reach one sex more than another or might
appeal differently to men and women or that the warnings
about reproductive consequences might discourage most
women from participating. One can easily imagine that the
requisite warnings on Institutional Review Board-approved
informed consent forms would scare all but the most intrepid
female participant.
Hormone Replacement
In my view a dramatic example of sex-gender insensitiv-
ity was the sudden, probably premature termination39 of
the Women’s Health Initiative (WHI) randomized, placebo-
controlled, study of hormone replacement therapy (HRT) in
postmenopausal women. One of the major health decisions
women face is whether to start or continue HRT, and the
trade-off of benefits and risks remains controversial. This ar-
guably valuable treatment included some significant risks but
was seriously compromised when the trial was terminated
because of mounting adverse effects. Although the investi-
gators reported the stopping criteria and explained that the
trial involved older women and might not be applica-
ble to perimenopausal women, there was a widespread im-
pression that the adverse effects overwhelmed any benefits for
anyone, causing confusion. Although HRT continued to be
approved for menopausal symptoms, many doctors stopped
prescribing HRT entirely, and many women feared to con-
tinue its use. The termination left a void. A gender-sensitive
approach would have been to reconfigure the study with new
warnings. Termination of the WHI study also brought about
termination of other trials just getting underway, including a
New York study of hormones and Alzheimer’s disease40 and
an international study (United Kingdom, Australia, New
Zealand).41 That study also found adverse cardiovascular and
thromboembolic risks early in use but also found a non-
statistically significant decrease in stroke and fractures,
not to mention breast cancer.41 Moreover, in lieu of doctor-
prescribed HRT, women seeking to alleviate menopausal
symptoms have turned to a hodgepodge of untested, uncon-
trolled herbal and alternative treatments largely outside the
scope of medicine and FDA control.42
Epidemiology
With so much evidence of sex-gender insensitivity, I turned
to the epidemiology literature. Surely, epidemiologists ap-
preciate sex, and consideration of sex in research studies is
alive and well, or so I thought. As I was preparing this edi-
SEX-GENDER RESEARCH SENSITIVITY
torial, the latest issue of the American Journal of Epidemiology
arrived in my email-box. I turned to it for relief from insen-
sitivity. The Table of Contents started off balanced enough:
three articles on prostate disease and three on pregnant
women, but then a study of whether nitrogen dioxide expo-
sure in early childhood affects cognitive function at age 4,
which enrolled about 50% girls, makes no mention of any
outcome similarity or difference by sex—it was ignored en-
tirely.43 The next article on asthma and birth weight in same-
sex twins does not tell us if male-male and female-female
twins were similar or different.44 That sample seemed enough
to demonstrate at least a lack of sensitivity.
It is not enough to include both sexes in a study. The sample
size of each should be large enough to provide sufficient
power for subset analyses. Power is the ability to avoid a type
II error, the ability to confirm a difference that is really there,
and to say that a difference has reached statistical significance.
Science has been much more attentive to avoiding type I
errors than type II errors, so when a difference does not reach
the sacred (but entirely arbitrary) 0.05 level, it is reported as
not significant or, worse, not mentioned at all. Readers should
have the opportunity to judge for themselves if a difference is
important and if ‘‘no difference’’ is real or, as is so often the
case, due to lack of power.
Changes on Horizon
Gender differences evolve. Clothing changes; bare skin
appears (healthful tans) then disappears (sun and cancer).
Ambiguous or ambivalent gender identity is much more ac-
ceptable now than a generation ago. Expectations for life and
livelihood, health and longevity have changed. Women make
up about half the workforce, although they still hold some-
what different jobs (and get paid less), and by 2004, women
made up half of the U.S. entering medical school class.45 Re-
lationships between men and women and between patients
and physicians have changed as well. As a medical house
officer in the 1960s, the idea that patients might be allowed to
see their medical record was anathema. Patients had to be
guarded from their ignorance or innocence. Do women have
different expectations from men from their doctor-patient re-
lationships? And most importantly, will the influx of women
into all these related fields mean that more female-relevant,
sex-gender-sensitive research will be done? And applied? I do
not think it is risky or presumptuous to answer Yes.
Conclusions
There are varying ways in which researchers are not sen-
sitive to sex, even when data have been gathered appropri-
ately. Doing studies that include men and women need not be
difficult, although disparities in clinical trials of new drugs
will be hard to overcome. Communicating results is a weak
link. Like it or not, Abstracts are now among the predominant
ways of communicating biomedical information. Many
readers cannot or will not pay for whole articles. Therefore,
Abstracts had better be right and inclusive. One of the in-
sensitive ways of dealing with sex is to leave it out of the
Abstract, for example, in studies of other risk factors, or to
report data that are adjusted for sex without providing or
discussing the sex differences themselves. Sex is not alone in
this: age and sex interact in important ways from birth to
193
death, through puberty, reproduction, menopause and an-
dropause, and aging.
The bottom line
1. Unless there is a good reason not to, clinical trials or
population studies should recruit or observe both men
and women in sufficient numbers to achieve statistical
power for testing differences (adequate power in each
subgroup).
2. Unless there is a good reason not to, demographic data
(e.g., age, education, income, occupation) should allow
analysis of factors related to sex, including interactions.
3. Abstracts will become (have become) a major tool for
reading the literature; hence, where sex contributes to
an outcome (even where sex is not the primary variable
of interest), its impact should be mentioned. Merely
adjusting for sex should not be sufficient reason to
ignore it.
4. Public funding of research carries the responsibility for
making research data available in a usable fashion.
Thus, if authors do not plan on analyzing the sex-
gender contribution, the availability of their data should
allow others to do so.
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Address correspondence to:
Michael Gochfeld, M.D., Ph.D.
Professor of Environmental and Occupational Medicine
Robert Wood Johnson Medical School
Environmental and Occupational Health Sciences Institute
170 Frelinghuysen Road
Piscataway, NJ 08854
E-mail: gochfeld@eohsi.rutgers.edu
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