Vitamin
C supplements may raise cataract risk. (#09-52 December 24, 2009)
A study of women who were followed over an 8-year period has found
that vitamin C supplementation, particularly in high dose and
long duration, may increase the risk of age-related cataracts.
The study included 24,593 women aged 49-83 years from the Swedish
Mammography Cohort (follow-up from September 1997 to October 2005).
The researchers used a self-administered questionnaire to collect
information on dietary supplement use and lifestyle factors.
[Rautiainen S and others. Vitamin C supplements and the risk of
age-related cataract: a population-based prospective cohort study
in women. American Journal of Clinical Nutrition, Nov 18, 2009.
Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19923367.
The study does not prove cause-and-effect, but because high-dose
vitamin C provides no proven benefit for the general population,
the findings provide further reason to avoid vitamin C megadosage.
Many supplements
found ineffective for weight loss. (#10-28, July 15th, 2010)
At the International Congress on Obesity (ICO 2010) in Stockholm,
two research teams reported on studies that found that many popular
dietary supplement ingredients are not effective for weight control.
One study found that L-carnitine, polyglucosamine, cabbage powder,
guarana seed powder, bean extract, konjac extract, fiber, sodium
alginate, and selected plant extracts were no more effective than
placebos over an 8-week period. The other study was a literature
review that summarized the state of evidence from clinical trials
involving chromium picolinate, Ephedra, bitter orange, conjugated
linoleic acid (CLA), calcium, guar gum, glucomannan, chitosan
and green tea. [New research finds no evidence that popular
supplements facilitate weight loss. ICO news release, July 2010]
http://www.dietscam.org/reports/ico.shtml.
Dannon
Company settles FTC charges. (#11-01,
January 6th, 2011)
The Dannon Company, Inc. has agreed to stop making unsubstantiated
claims about its Activia yogurt and DanActive dairy drink, which
contain potentially beneficial bacteria known as probiotics. [Dannon
agrees to drop exaggerated health claims for Activia yogurt and
DanActive dairy drink. FTC news release, Dec 15, 2010] http://www.ftc.gov/opa/2010/12/dannon.shtm
Under the settlement:
**Dannon is prohibited from claiming that any yogurt, dairy drink,
or probiotic food or drink reduces the likelihood of getting a
cold or the flu, unless the claim is approved by the FDA.
**Dannon may not claim that any other yogurt, dairy drink, or
probiotic food or drink will relieve temporary irregularity or
help with slow intestinal transit time unless the claim is substantiated
by at least two well-designed human clinical studies.
**Dannon may not make any other claims about health benefits,
performance, or efficacy of any yogurt, dairy drink, or probiotic
food or drink, unless the claims are true and backed by competent
and reliable scientific evidence.
The FTC worked in close coordination with 39 state attorneys general,
who are simultaneously announcing the resolution of their own
inquiries into Dannon's advertising of DanActive and Activia.
Dannon has agreed to pay the states $21 million to resolve these
investigations. Dannon has also settled a class-action suit by
agreeing to create a $35 million fund to reimburse consumers for
up to $100 for products purchased. http://www.casewatch.org/civil/dannon/settlement.pdf.
Skin cream
manufacturer settles FTC charges. (#11-20 July 7, 2011)
Beiersdorf, Inc. has signed a consent agreement under which it
will pay $900,000 and stop claiming that using its Nivea My Silhouette!
skin cream can significantly reduce the user's body size. The
FTC's administrative complaint charged Beiersdorf with falsely
claiming that consumers could slim down by regularly applying
Nivea My Silhouette! cream to their skin. http://www.ftc.gov/os/caselist/0923194/110629beiersdorfcmpt.pdf
.
Beiersdorf touted the cream's "Bio-slim Complex," a
combination of ingredients that includes anise and white tea.
The proposed settlement (a) bars Beiersdorf from making unsubstantiated
claims that any product applied to the skin causes substantial
weight or fat loss or a substantial reduction in body size and
(b) requires that any claim about health benefits of any drug,
dietary supplement, or cosmetic be backed by competent and reliable
scientific evidence. The FTC advises consumers to be suspicious
of any claim that body size can be significantly reduced by applying
a cream. [FTC settlement prohibits marketer from claiming that
Nivea Skin Cream can help consumers slim down. FTC news release,
June 29, 2011] http://www.ftc.gov/opa/2011/06/beiersdorf.shtm.
Study
questions vitamin E safety. (#11-34
October 13, 2011)
A major clinical trial has found that dietary supplementation
with vitamin E appears to increase the risk of prostate cancer
among apparently healthy men. [Klein EA and others. Vitamin
E and the risk of prostate cancer: The Selenium and Vitamin E
Cancer Prevention Trial (SELECT). JAMA 306:1549-1556, 2011] http://www.ncbi.nlm.nih.gov/pubmed/21990298
The study, which spanned more than seven years, followed what
happened to more than 35,000 men who received either 400 IU of
vitamin E, vitamin E plus selenium, selenium, or a placebo. The
group that received vitamin E alone had a 17% higher incidence
of prostate cancer. The researchers warned:
"The observed . . . increase in prostate cancer incidence
demonstrates the potential for seemingly innocuous yet biologically
active substances such as vitamins to cause harm. The lack of
benefit from dietary supplementation with vitamin E or other agents
with respect to preventing common health conditions and cancers
or improving overall survival, and their potential harm, underscore
the need for consumers to be skeptical of health claims for unregulated
over-the-counter products in the absence of strong evidence of
benefit demonstrated in clinical trials."
Web site
warns of supplement risks. (#12-18
May 24, 2012)
The United States Anti-Doping Agency has launched the Supplement
411 Web site to warn about the danger of dietary supplements marketed
to athletes. http://www.usada.org/supplement411
The site features the stories of prominent athletes who were disqualified
from competition after illegal substances (originating from supplements)
were found in their urine. The site also reports news about supplement
hazards.
Study
finds little evidence that sports performance products are useful.
(#12-26 July
26, 2012)
Researchers who reviewed performance-enhancing claims for sports
drinks, supplements, clothing, footwear, and devices have concluded
that they were not adequately supported by scientific evidence.
The investigators viewed 1035 web pages, identified 431 performance-enhancing
claims for 104 different products, asked the marketers for additional
information, and evaluated 146 references that supposedly underpinned
the advertised claims. They found that half of the sites cited
no references and that among those that did, nearly all of the
studies were inadequately designed. [Heneghan C and others.
The evidence underpinning sports performance products: A systematic
assessment. BMJ Open 2:e001702, 2012] http://bmjopen.bmj.com/content/2/4/e001702.full.
Nobel
Prizewinner warns that antioxidants may cause cancer. (#13-3 January 17, 2013)
Geneticist James Watson, Ph.D., who won the Nobel Prize for discovering
the structure of DNA, has noted that clinical trials of antioxidant
supplements beta-carotene, vitamin A, vitamin C, vitamin E, and
selenium have shown no obvious effectiveness against common cancer
and may shorten the life of cancer patients who use them. In a
highly technical paper, he says that instead of doing more such
trials, future research should focus on innovative anti-metastatic
drug development, including drugs that inhibit antioxidant activity.
[Watson
J. Oxidants, antioxidants and the current incurability of
metastatic cancers. Open Biology 3:120144, 2013].
Vitamin
C supplements linked to kidney stones. (#13-7 February 14, 2013)
An 11 year study of more than 48,000 men has found that those
who took vitamin C (ascorbic acid) supplements were twice as likely
to develop kidney stones than those who did not. The dominant
component in these stones was calcium oxalate. The association
does not prove cause-and-effect, but the authors note: "Currently
there are no well-documented benefits of high-dose ascorbic acid
supplement use, and, therefore, it seems prudent to advise that
high-dose preparations be avoided, particularly by those with
a history of kidney stones." [Thomas
L and others. Ascorbic acid supplements and kidney stone
incidence among men: a prospective study. JAMA Internal Medicine,
Feb 4, 2013] An accompanying editorial notes that causation
is biologically plausible because ascorbic acid is partly metabolized
to oxalate and is excreted in the urine. [Fletcher
RH. The risk of taking ascorbic acid. JAMA Internal Medicine,
Feb 4, 2013] The full text of these articles is available
free online.
Multivitamin
use blasted. (#13-48
- December 19, 2013)
The Annals of Internal Medicine has published the results
of three studies which found no benefit from taking multivitamins:
The U.S. Preventive Services Task Force updated its evaluation
of vitamin supplements for primary prevention in community-dwelling
adults with no nutritional deficiencies. After reviewing 3 trials
of multivitamin supplements and 24 trials of single or paired
vitamins that randomly assigned more than 400,000 participants,
the authors concluded that there was no clear evidence of a beneficial
effect on all-cause mortality, cardiovascular disease, or cancer.
[Fortmann SF and others. Vitamin and mineral supplements
in the primary prevention of cardiovascular disease and cancer:
An updated systematic evidence review for the U.S. Preventive
Services Task Force. Annals of Internal Medicine 159:824-834,
2013 (link)]
Another team evaluated the use of a daily multivitamin to prevent
cognitive decline among 5947 men physicians aged 65 years or older
participating in the Physicians' Health Study II. After 12 years
of follow-up, there were no differences between the multivitamin
and placebo groups in overall cognitive performance or verbal
memory. [Grodstein F and others. Long-term multivitamin
supplementation and cognitive function in men: A randomized trial.
Annals of Internal Medicine 159:806-814, 2013 (link)]
The full text is available online free-of-charge.
Another team assessed the potential benefits of a high-dose, 28-component
multivitamin supplement in 1708 men and women with a previous
heart attack who participated in the Trial to Assess Chelation
Therapy. After a median follow-up of 4.6 years, there was no significant
difference in recurrent cardiovascular events with multivitamins
compared with placebo, although, as the authors noted, the significance
of this study was limited by high rates of nonadherence and dropouts.
[Lamas GA and others. Oral high-dose multivitamins and
minerals after myocardial infarction: A randomized trial. Annals
of Internal Medicine 159:717-804, 2013 (link)]
An accompanying editorial, which considered the gamut of previously
published studies drew a very harsh conclusion that generated
headline news throughout the United States:
Beta-carotene, vitamin E, and possibly high doses of vitamin A
supplements are harmful. Other antioxidants, folic acid and B
vitamins, and multivitamin and mineral supplements are ineffective
for preventing mortality or morbidity due to major chronic diseases.
Although available evidence does not rule out small benefits or
harms or large benefits or harms in a small subgroup of the population,
we believe that the case is closed supplementing the diet
of well-nourished adults with (most) mineral or vitamin supplements
has no clear benefit and might even be harmful. These vitamins
should not be used for chronic disease prevention. Enough is enough.
[Gualler E and others. Enough Is enough: Stop wasting
money on vitamin and mineral supplements. Annals of Internal Medicine
159:850-851, 2013 link]
Quackwatch has suggestions about the rational use of dietary supplements
(link).
Among other things, it recommends that people who wish to take
multivitamins should do so only every 2 or 3 days and spend no
more than $1 per month.
Toxic
supplement product triggers call for greater regulation (#14-14 April 20, 2014)
Nearly 100 cases of hepatitis (liver inflammation) and liver failure
have been linked to the use of OxyElite Pro, a dietary supplement
intended for muscle-building or weight loss. In response, Pieter
A. Cohen, M.D., has pointed out:
- Americans spend more than $32 billion a year on more than 85,000
different combinations of vitamins, minerals, botanicals, amino
acids, probiotics, and other supplement ingredients. Unlike prescription
medications, supplements do not require premarketing approval
before they reach store shelves.
- Under the Dietary Supplement Health and Education Act of 1994,
anything labeled as a dietary supplement is assumed to be safe
until proven otherwise. The FDA is charged with the unenviable
task of identifying and removing dangerous supplements only after
they have caused harm.
- Although OxyElite Pro was recalled, nothing has been done to
prevent another supplement from causing organ failure or death.
Nor have any changes been made to improve the FDA's ability to
detect dangerous supplements.
- More than 500 supplements have already been found to be adulterated
with pharmaceuticals or pharmaceutical analogues, including new
stimulants, novel anabolic steroids, unapproved antidepressants,
banned weight-loss medications, and untested analogues of sildenafil
(the active ingredient in Viagra).
- If consumers and physicians are to have confidence that all
supplements are safe, the laws regulating supplements must be
reformed so that every ingredient is required to undergo rigorous
safety testing before marketing.
[Cohen P. Hazards
of hindsight: Monitoring the safety of nutritional supplements.
New England Journal of Medicine 370:1277-1280, 2014]
Cosmetic
company settles FTC charges. (#14-24
- July 6, 2014)
L'Oréal USA, Inc. has agreed to settle Federal Trade Commission
charges of deceptive advertising about its Lancôme Génifique
and L'Oréal Paris Youth Code skin-care products. According
to the FTC's complaint, L'Oréal made false and unsubstantiated
claims that its Génifique and Youth Code products provided
anti-aging benefits by targeting users' genes. Under the proposed
administrative settlement, the company is prohibited from making
unsubstantiated claims that any Lancôme or L'Oréal
Paris facial skin-care product targets or boosts the activity
of genes to make skin look or act younger, or respond five times
faster to aggressors like stress, fatigue, and aging. [L'Oréal
settles FTC charges alleging deceptive advertising for anti-aging
cosmetics. FTC news release, June 20, 2014]
Anti-Doping
Agency warns athletes about dietary supplements (#14-29 - August 10, 2014)
The United States
Anti-Doping Agency (USADA) maintains a Web site that challenges
myths about dietary supplements and discourages their use. Among
other things, the site warns:
Navigating the supplement marketplace and supplement issues is
difficult. No one person or organization can provide all the answers.
Many people have hastily jumped to the conclusion that supplements
are safe, effective, and a necessary part of being an elite athlete.
It is very unlikely that healthy people will be unable to get
the nutrients they need from diet alone. There is simply no substitution
for eating a proper diet.
The majority of supplements have not been proven to improve performance.
Certain dietary supplements contain exorbitant amounts of nutrients
that are unnecessary, unusable by the body, or even potentially
harmful.
The best option may be to not take dietary supplements.
The site also contains the Supplement
411 High Risk List of products that have been found to
contain substances that are banned in high-level athletic competition.
The list is accessible free of charge but requires viewers to
register.
Supplement
products associated with liver toxicity (#14-38 - October 12, 2014)
The Drug-Induced Liver Injury Network has reported that about
15% of the cases that it studied involved herbal and dietary supplement
products. The organization was established in 2003 to identify
and study cases of drug-induced liver injury attributable to medications
(excluding acetaminophen [APAP]) and supplements. The 130 patients
with liver injury from supplements consisted of 45 (35%) who had
taken bodybuilding products and 85 (65%) who had taken non-bodybuilding
products. The report noted the problems attributable to bodybuilding
products were relatively mild but severe outcomes (deaths and
liver transplants) were more frequent among users non-bodybuilding
products than among medication users. [Navarro VJ and others. Liver injury
from herbals and dietary supplements in the U.S. Drug-Induced
Liver Injury Network. Hepatology 60:1399-1408, 2014]
Many herbs and dietary supplements fail ingredient tests (#15-28 - July 19, 2015)
ConsumerLab.com,
which has tested over 4,500 products since November 1999, has
found that, through July 2015, 20% of the vitamins and minerals,
43 percent of the herbals, 21% of other supplements, and 24% of
nutritional powders and drinks failed their evaluations. The most
common problem was too little or none of the main ingredient.
The other problems included too much active ingredient; the wrong
ingredient; potentially dangerous or illegal ingredients; contamination
with heavy metals; "spiking" with unexpected ingredients;
poor disintegration (which affects absorption); and misleading
or incomplete product information.
Herbal products blasted (#15-45
- November 15, 2015)
Donald M. Marcus,
Professor of Medicine and Immunology Emeritus at Baylor College
of Medicine in Houston, has severely criticized the use of herbal
products and the loose way in which they are regulated. [Marcus
DM. Dietary supplements: What's in a name? What's in the bottle?
Drug Testing and Analysis, Nov 2, 2015] He concludes:
The Dietary Supplement Health and Education Act of 1994 (DSHEA),
which arbitrarily classified herbals and other medicinal products
as dietary supplements, obscured fundamental differences between
two classes of products. Authentic supplements to the diet, such
as multivitamins or calcium, have nutritional value and are safe.
Herbals are used worldwide as medicines, they do not supplement
the diet, they may cause severe adverse events, and they should
be regulated as medicines. DSHEA also prevented the FDA from effectively
regulating herbal supplements as medicines. One consequence of
weak FDA regulatory oversight is the poor quality of herbals.
FDA inspections of manufacturing facilities have revealed violations
of good manufacturing practices in over half of facilities inspected,
including unsanitary conditions and lack of product specifications.
Moreover, many "all natural" herbals marketed for weight
loss, enhancement of sexual health and improving sports performance
are adulterated with prescription and over-the-counter medications
that have caused adverse cardiovascular events. New procedures
to authenticate the identity of plants used in herbals will neither
detect adulteration by medications nor provide assurance of appropriate
pharmacological activity or safety. Nonvitamin, nonmineral "supplements"
should be regulated as medicines, but revision or repeal of DSHEA
faces strong opposition in Congress. The marketing of botanical
supplements is based on unfounded claims that they are safe and
effective. Health professionals need to inform patients and the
public that there is no reason to take herbal medicines whose
composition and benefits are unknown, and whose risks are evident.
The full
text of the article is accessible free of charge.
Frontline report blasts dietary supplement industry (#16-05 - January 31, 2016)
Frontline, The New
York Times and the Canadian Broadcasting Corporation have co-produced
a 55-minute video report that examines problems in the marketing
and regulation of vitamins, herbals, and other supplement products.
The report spotlights (a) contaminated products that have caused
severe harm, (b) irresponsible promotion, (c) regulatory weaknesses,
and (d) industry denialists. [Supplements
and Safety. Frontline, Jan 19, 2016]
FTC attacks "natural" claims (#16-14 - April 17, 2016)
Four companies that
market skin care products, shampoos, and sunscreens online have
agreed to settle FTC charges that they falsely claimed that their
products were "all natural" or "100% natural,"
despite the fact that they contain synthetic ingredients. [Four
companies agree to stop falsely promoting their personal-care
products as "all natural" or "100% natural";
fifth is charged in Commission complaint. FTC news release,
April 12, 2016] Under the proposed settlements, each of the
four companies is barred from making similar misrepresentations
in the future and must have competent and reliable evidence to
substantiate any ingredient-related, environmental, or health
claims it makes. The Commission has issued a complaint against
a fifth company for making similar claims. Jessica Rich, Director
of the FTC's Bureau of Consumer Protection, said that "all
natural" and "100% natural" mean that the product
must not contain artificial ingredients. In response to a citizen
petition, the
FDA is reviewing the use of "natural" claims in labeling.
Tanning bed use declining but still of concern (#17-10 - March 5, 2017)
USA Today has published
an excellent review of the status of tanning bed use in the United
States today. [Painter K. Home
tanning beds: convenient but dangerous, health experts say.
USA Today, Feb 26, 2017] The article notes that more than
10,000 of the 18,000 tanning salons operating in 2010 have closed,
but unknown numbers of people continue to use tanning beds in
private homes. Behavioral psychologist Sherry Pagoto, PhD, is
taking part in a campaign to encourage colleges to reduce easy
access to tanning beds on or near college campuses. In 2014, she
authored a study
which found that 48% of U.S. News and World Report's 125 top colleges
had indoor tanning facilities either on campus or in off-campus
housing surrounding the schools and that 14% allowed campus cash
cards to be used to pay for tanning. In a 2015 interview,
she said that these circumstances create a perception among students
that colleges endorse tanning despite its association with a greatly
elevated cancer risk. An estimated 450,000+ cases of nonmelanoma
skin cancer and 10,000+ cases of melanoma each year have been
attributed to indoor tanning in the United States, Europe, and
Australia. [Weiner MR and others. International
prevalence of indoor tanning A systematic review and meta-analysis.
JAMA Dermatology 150:390-400, 2014].
Kidney failure after high-dose vitamin D reported (#19-15 - April 4, 2019)
A 54-year-old man
developed kidney failure after: (a) being advised by a naturopath
to take 8 drops daily of a brand of vitamin D that contained 500
international units (IU) per drop and, (b) unknowingly obtaining
another vitamin D preparation containing 1,000 IU per drop. The
resultant total 8,000 to 12,000 IU daily for 2.5-years, during
which he was not counseled about toxicity risks. A year after
his kidney failure was diagnosed and treatment was initiated for
his elevated blood levels of vitamin D and calcium, he was left
with stage 3B chronic kidney disease. [Auguste BL and others.
Use of vitamin
D drops leading to kidney failure in a 54-year-old man. CMAJ
191:E390-E394, 2019]
A 2014 review of hundreds of studies concluded that highly convincing
evidence of a clear role of vitamin D does not exist for any health
outcome. [Theodoratou E. and others. Vitamin
D and multiple health outcomes: umbrella review of systematic
reviews and meta-analyses of observational studies and randomised
trials. BMJ 348:g2035, 2014]
Last year, the U.S. Preventive Services Task Force recommended
against daily supplementation of 400 IU or less of vitamin
D and 1000 milligrams or less of calcium for the primary prevention
of fractures in community-dwelling, postmenopausal women. It
also concluded that current evidence is insufficient to assess
the balance of the benefit and harms of:
- daily supplementation with doses greater than 400 IU of vitamin
D and greater than 1000 mg of calcium for the primary prevention
of fractures in community-dwelling, postmenopausal women
- vitamin D and calcium supplementation, alone or combined, for
the primary prevention of fractures in men and premenopausal women.
Collagen hype scrutinized (#20-45
- November 17, 2020)
Consumer Reports has spotlighted the lack of scientific
support for claims that consuming collagen powders, pills, and
foods can result in smoother skin, shinier hair, stronger nails,
healthier joints, and more lean muscle mass. [Wadyka S. The
real deal on collagen. Consumer Reports, Oct 13, 2020]
The article notes that Nutrition Business Journal projects
collagen supplement sales in the U.S. to reach $298 million this
yearup from $73 million in 2015. Collagen is a protein that
holds skin, tendons, ligaments, bones, and cartilage together.
But that doesn't mean that consumers benefit from collagen in
supplements or added to foods, such as energy bars, oatmeal, smoothies,
coffee creamers, and popcorn. The human body makes collagen from
glycine, proline, hydroxyproline, and other amino acids when proteins
(not limited to collagen) are digested. The bottom line in the
article is that "until there's more conclusive evidence in
favor of supplements or collagen-enhanced foods, the best solution
may be to focus on eating a healthy diet that supplies adequate
amounts of protein and limiting sun exposure."
Collagen hype scrutinized (#21-12
- March 28, 2021)
Stem cell biologist
Paul Knoepfler, Ph.D., has provided an illuminating guide to the
stem cell face cream marketplace, which he sees as a particularly
frustrating example of consumers losing money related to stem
cells. With a simple search for stem cell face cream
on Amazon.com, he found 183 products, many of which cost over
$100 and some that cost more than $200 for a tiny vial. He believes
that most of these products dont appear to actually contain
stem cells. [Knoepfler P. Fact-checking
stem cell face cream: Less than face value. The Niche, March
25, 2021] He concluded:
Stem cell creams have many of the same ingredients as other face
creams.
The stem cell part seems to be a marketing gimmick involving big
claims.
Products that contain actual human or animal cell materials can
pose risks and should be considered unapproved drugs.
Supplements discouraged for preventing cardiovascular disease
and cancer (#22-26
- June 26, 2022)
A U.S. Preventive
Services Task Force (USPSTF) report is skeptical about using certain
dietary supplements to prevent cancer or cardiovascular disease.
[Vitamin,
mineral, and multivitamin supplementation to prevent cardiovascular
disease and cancer: Preventive medication. USPSTF website,
June 21, 2022]
The report concludes:
with moderate certainty: (a) the harms of beta carotene supplementation
outweigh the benefits, and (b) there is no net benefit of supplementation
with vitamin E
current evidence is insufficient to assess the balance of benefits
and harms of the use of multivitamin supplements
current evidence is insufficient to assess the balance of benefits
and harms of the use of other single- or paired-nutrient supplements
The recommendations are applicable to community-dwelling adults
who are not pregnant or trying to become pregnant. An editorial
commenting on the USPSTF report notes that people find vitamin
and mineral supplementation appealing when they: (a) think in
terms of good/bad dichotomies and lump supplementation in the
good category, (b) dont consider that whats beneficial
in small doses isnt necessarily beneficial in larger doses,
(c) are biased toward what they perceive as natural, and (d) prefer
risking action over inaction. The editorial concludes: If
we want people to stop taking unnecessary vitamins and start receiving
lifesaving vaccines, we need to address the psychological (and
political) factors that cause people to embrace evidence-incongruent
beliefs. [Ubel PA. Why
too many vitamins feels just about right. JAMA Internal Medicine,
June 21, 2022]