News & Analysis
from choline and, in turn, reduce TMAO, pre- levels within as little as a month by eliminat-
venting heightened platelet reactivity and
thrombosis without increasing bleeding
risks. With the recent discovery of the intes-
tinal bacteria that convert L-carnitine into
TMA in a 2-step process, researchers can
now begin to develop an inhibitor for this
pathway, too. Meanwhile, scientists at the
Medical College of Wisconsin are also inves-
tigating probiotics to reduce TMAO levels in
patients with coronary artery disease.
But what about the most obvious ap-
proach, dietary modification? For Williams, a
self-described “plant-based cardiologist,” the
existing evidence solidly places TMAO among
what he says are the known animal-product
contributors to heart disease: saturated fat,
dietary cholesterol, heme iron, and ruminant
trans fat. Williams cited the mortality-
reducing effects of a “provegetarian” food
pattern, and said the research on TMAO is yet
another reason to stop eating animals in all
forms, or at the very least eliminate red meat.
Bolstering his argument, a recent meta-
analysis of randomized clinical trials found the
most favorable blood lipid changes when red
meat-heavy diets were substituted with high-
quality plant protein diets.
Researchers at Stanford University are
already studying the effects of plant-based
meat alternatives on TMAO levels in a clinical
trial. But short of going full-on herbivore,
people can substantially reduce TMAO
QUICK UPTAKES
For Fat Burning, Interval Training Beats Continuous Exercise
Jennifer Abbasi
E
xercisers can burn slightly more body
fat with interval training than mod-
erate-intensity continuous training,
according to a recent systematic review and
meta-analysis in the British Journal of Sports
Medicine. Although the differences in fat loss
weren’t huge, the interval workouts were
shorter, which could make it easier for people
to adhere to them.
The Problem
Weight-loss strategies usually include an in-
crease in energy expenditure (exercise) or a
decrease in energy intake (diet). But nei-
ther strategy seems to be effective for sus-
taining long-term weight changes in most
jama.com
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is only a part of the cardiovascular disease
ing or reducing red meat, according to the
European Heart Journal trial that compared
protein sources.
However, Cleveland Clinic cardiologist
W. H. Wilson Tang, MD, who coauthored
the study with Hazen, had reservations
about recommending that everyone do so.
In the trial, people eating red-meat heavy
diets had a range of responses, with some
participants’ TMAO levels shooting up far
less than others’.
As for animal products in general, white
meat, eggs, or dairy may not influence TMAO
levels to the same degree as red meat or
deep-sea fish. Before issuing blanket pre-
scriptions for patients to dramatically alter
their diets to reduce TMAO, Tang said more
studies are needed to determine who would
benefit the most. He’s currently leading a
pilot trial involving 90 people that will de-
termine the proportion of participants with
persistently elevated TMAO levels and their
response to a low-TMAO Mediterranean diet.
In Tang’s view, it could be a mistake to
focus too much on any single dietary com-
ponent, even red meat. It’s more important
to understand how the foods we eat influ-
ence and interact with our intestinal mi-
crobes and renal clearance system, both of
which are highly individualized. In fact, the
gut microbiome is increasingly being seen as
an important heart disease player. Red meat
people. Although lower-than-expected
weight loss is often blamed on poor follow-
through, other factors like metabolic down-
regulation likely also influence outcomes.
What We Already Knew
There’s no consensus on the best exercise
approach to burning fat, which is preferred
over losing muscle for shedding weight.
Some evidence suggests that interval train-
ing—including high-intensity interval train-
ing (HIIT) and sprint interval training (SIT)—
can help people reduce body fat and lose
weight more than sustained moderate ex-
ercise, even if the routine burns fewer calo-
ries. This could be because interval training
(Reprinted) JAMA June 11, 2019 Volume 321, Number 22
story, Tang argues—and one that may not
even matter for some people.
Hazen used to be avid red-meat eater,
but he said it’s now a “very, very rare item
on the plate.” Yet he, too, is wary of insisting
that others make the same drastic change.
“Diet is a personal choice,” he said. “We
beat up patients over their eating habits.
I don’t think that is productive.” Although
he believes that patients should be edu-
cated about the risks associated with eating
a red meat–heavy diet, which could nudge
them toward a plant-based one, he thinks
it’s unrealistic to expect everyone to act on
the information. “That’s why I want to
develop a drug: so that you can have your
steak and eat it, too,” he said.
In the meantime, Hazen and Tang’s dis-
coveries have kicked off an interest in di-
etary metabolites as marker-mediators of
disease, Manson said. Her team recently re-
ceived funding to expand their study in the
NHS and VITAL cohorts beyond TMAO.
They’re now looking at how dietary pat-
terns affect roughly 400 other plasma me-
tabolites. Ultimately, she wants to use the
findings to develop metabolomic risk scores
for future coronary heart disease develop-
ment. As she puts it, “this is really just the tip
of the iceberg.”
Note: Source references are available through
embedded hyperlinks in the article text online.
2151
 News & Analysis
increases resting energy expenditure and fat
burning right after exercise, countering
metabolic downregulation.
“Different types of exercise promote dif-
ferent metabolic responses,” said Paulo
Gentil, PhD, the study’s senior author and
a professor at the Federal University of Goiás
in Brazil. “In this regard, high-intensity exer-
cise might be particularly interesting for fat
loss, not because of the calories spent while
you exercise but because it makes your body
burn more fat after you exercise.”
The Design
Gentil’s team conducted a meta-analysis of
36 clinical trials comparing HIIT and SIT—
the 2 most common types of interval train-
ing—with moderate-intensity continuous
training for fat loss. The studies evaluated
changes in total body fat percentage and/or
total absolute fat mass. They included 1012
children through older adults, spanning a
range of baseline physical activity and rang-
ing from underweight to obese.
What We’ve Learned
• All of the exercise approaches signifi-
cantly reduced total body fat percentage
and total absolute fat mass.
The JAMA Forum
The “Conscience” Rule: How Will It Affect Patients’ Access
to Health Services?
Lawrence O. Gostin, JD
O
n May 2, 2019, the US Depart-
ment of Health and Human Ser-
vices (HHS) and Office of Civil
Rights (OCR) released a final rule that height-
ens the rights of hospitals and health work-
ers to refuse to participate in patients’ medi-
cal care based on religious or moral grounds.
The rule covers OCR’s authority to investi-
gate and enforce violations of 25 federal
“conscience protection” laws. Tied to the US
Constitution’s spending power, the rule ap-
plies to state and local governments, as well
as public and private health care profession-
als and entities if they receive federal funds
such as Medicare or Medicaid. The rule ap-
plies to a range of important health services
such as abortions, sterilizations, assisted sui-
2152 JAMA June 11, 2019 Volume 321, Number 22 (Reprinted)
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• None of the approaches outperformed
the others in terms of reducing total body
fat percentage.
• But interval training was more effective
for decreasing total absolute fat mass. On
average, the SIT and HIIT protocols re-
duced total absolute fat mass by 6.2% and
6%, respectively, compared with 3.4% for
moderate-intensity continuous training.
• The interval training workouts were
also shorter. The SIT, HIIT, and moderate-
intensity routines in studies evaluat-
ing total absolute fat mass lasted on
average 23 minutes, 25 minutes, and
41 minutes, respectively.
The Caveats
• The biggest reductions in total absolute
fat mass occurred when interval training
workouts were supervised, which likely in-
creases adherence.
• The study designs differed widely, and
many of them didn’t instruct participants
to stick to their normal diet, both of which
could make the findings less reliable.
How Intense Is Intense?
The terms “high intensity” and “sprint”
are relative. Keeping this in mind can
cide, and advance directives—extending to
sex reassignment and HIV treatment.
History and Purpose
In December 2008, OCR finalized a rule to
enforce the Church, Coates-Snow, and
Weldon amendments—all designed to pro-
tect health workers and entities who object
to assisting in abortion or sterilization for re-
ligious or moral reasons. In 2011, the Obama
administration substantially rescinded the
rule but maintained OCR’s authority to con-
duct investigations of alleged violations of
conscience protection laws.
On May 4, 2017, President Trump signed
an Executive Order, Promoting Free Speech
and Religious Liberty. Shortly thereafter, he
encourage exercising and help to avoid
injuries. “Interval training can be performed
by almost everyone; we just have to know
how to adapt it,” Gentil told JAMA. “If you
have knee problems and are not able to
run, you can cycle or even swim. If you have
heart disease, you can work at a controlled
intensity. For a healthy young person, a
sprint could involve running at high veloci-
ties, while for a frail elder, slow walking
might be enough.”
Gentil’s bottom line: “Interval training
seems to be a time-efficient approach for
promoting fat loss.”
What Is Interval Training?
• Interval training is an intermittent
period of physical effort interspersed
by recovery periods.
• High intensity interval training requires
“near-maximal” efforts performed
at or above 80% of maximal heart rate
or the equivalent of maximal oxygen
consumption.
• Sprint interval training requires
“all-out” efforts performed at or above
peak oxygen consumption.
Note: Source references are available through
embedded hyperlinks in the article text online.
created the Office of Conscience and
Religious Freedom within HHS to “more vig-
orously and effectively enforce existing laws
protecting the rights of conscience and re-
ligious freedom.”
The Conscience Rule
The final rule significantly expands OCR’s
authority to enforce federal conscience
protection laws. The earlier rule covered only
3 conscience statutes, while this final rule
extends to 25.
Thenewrulebroadlydefinesfederalcon-
science laws. Covered entities and protected
activities are equally broad, including those
performing services, paying for services
(private and employer-based insurance),
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