Abstract
Introduction
There is unmet need for male contraceptive options, but a recent injectable combination male contraceptive trial was terminated early due to adverse events (AEs).
Methods
We examined the frequency of reported AEs by male research participants compared to AEs reported in package inserts of approved female hormonal contraceptive methods. Published data from trials of the top five most-used female hormonal contraceptives, supplemented by contemporary contraceptive research, were compared to the frequency of AEs reported in a male injectable hormonal contraceptive trial.
Results
We observed similar frequencies of AEs reported by users of male contraceptives compared to those reported by female users. Among quantitatively comparable AEs, compared to men, women reported experiencing higher frequencies of headaches, pelvic pain, and weight gain and similar frequencies of decreased libido. Compared to women, men reported experiencing higher frequencies of acne and mood changes. Men discontinued participation due to AEs at a lower rate than women
Conclusion
Female hormonal methods generally have similar rates of AEs to those reported in a recent male hormonal contraceptive trial, and male users had lower rates of discontinuation due to AEs. There were fewer serious AEs of the male contraceptive than reported in contemporary female trials which resulted in FDA licensure. This suggests there may be implicit bias in the scientific community regarding the level of acceptable risk for users of male contraceptive methods.
INTRODUCTION
Men have unmet need for modern contraceptive options. Today, men have two contraceptive choices: condoms and vasectomy. Condoms have a high failure rate (13% with typical use[1]) while vasectomy is a permanent, surgical method and is not reliably reversible. In comparison, all female hormonal contraceptive options combined have a 6% to 8% failure rate, with long acting reversible female contraceptives at 99% efficacy[1]. No new methods of male contraception have come to market in almost a century.
Current hormonal research into male contraception has focused on the administration of an androgen, which results in markedly decreased sperm counts after 3–4 months; after hormone discontinuation, sperm counts return to pretreatment levels[2]. Weekly testosterone injections tested by the World Health Organization (WHO) in 1996 provided effective contraception for 98% of male participants, with no serious treatment-related adverse events (AEs)[3]. The low acceptability of weekly injections led to explorations into a daily pill; however, there has been difficulty in developing a daily dosage of an oral androgen that can completely suppress spermatogenesis while avoiding androgenic effects. Contemporary studies suggest that the combination of an androgen and a progestin to improve tolerability has potential to become a successful long-acting male contraceptive[4–7]. Despite 22 years elapsing since male hormonal contraception was shown to be effective in a clinical trial, there remains no male hormonal contraceptive in the market.
Recently, an injectable male contraceptive, 1000mg testosterone undecanoate and 200mg norethisterone enanthate, was studied in a phase II trial in 10 study sites between 2008 and 2012 [8]. Three hundred and twenty male participants received an injection every 8 weeks until sperm counts dropped to less than 1 million sperm per 1 milliliter of ejaculate. With a failure rate of 1.57 per 100 users (95% CI, 0.59–4.14), the contraceptive effectively and reversibly suppressed spermatogenesis in 95% of the participants; however, the study was terminated early following a recommendation by an external safety review by WHO. Though details were not disclosed, the committee said the termination of the study was due to their review of AEs, specifically mood changes, depression, pain at injection site, and increased libido [8].
As male contraceptive studies progress and regulatory agencies are faced with risk benefit assessments, there is need for a critical appraisal of how AE risk is determined for men using contraception. Adverse events experienced by female contraceptive users are assessed in terms of the physical risks of pregnancy and childbirth; because this risk-benefit equation cannot be applied to men, an unprecedented risk analysis for male users must be established in order to work towards regulatory approval. In light of this ethical dilemma, we gathered evidence to explore the differences in documented AEs in male compared to female contraceptives. Published data from injectable male contraceptive trials and representative female contraceptive methods were compared to assess reported AEs.
METHODS
We compiled data on AEs associated with the five most commonly used female, reversible, and hormonal contraceptive methods from 2006–2010: combined oral contraception (COC), levonorgestrel releasing intrauterine system (LNG-IUS), progestogen-only injectable, combined transdermal patch, and combined vaginal ring, as determined by a report using data from the National Survey of Family Growth, 2006–2010 [9]. We also examined AEs reported in the approval of the first female contraceptive pill in 1959, which set the precedent for risk-benefit analysis in approval of female hormonal contraceptives.
The data on female hormonal contraceptives were collected from published prescribing information from each method’s leading brands, as determined by reports using data from the National Survey of Family Growth, 2006–2010 [9,10]. For COCs, we reported data from Ortho Tri-Cyclen Lo: norgestimate/ethinyl estradiol [11], Yasmin: drospirenone/ethinyl estradiol [12], Yaz: drospirenone/ethinyl [13], and Ortho Tri-Cyclen: norgestimate/ethinyl estradiol [14]- the top four most-used COC brands in the United States from 2006–2010 [10]. For the IUS, we used data from Mirena: levonorgestrel-releasing [15]. For the injection, we used data from Depo-Provera: medroxyprogesterone acetate [16]. For the vaginal ring, we used data from NuvaRing®: etonogestrel/ethinyl estradiol [17]. Finally, for the contraceptive patch, we used data from Ortho Evra: norelgestromin / ethinyl estradiol [18]. For each of these contraceptives, we report AEs as reported by FDA approved prescribing information, found under subsection 6.1: Clinical Trial Experience. The most contemporary prescribing information for each method was used, each being most recently revised in 2019 except for Ortho Evra, for which the most recently revised data available is from 2010. We assumed that these clinical trials were conducted appropriately, since they led to FDA approval of their respective contraceptives.
Data on the first female contraceptive approved by the FDA, the COC Enovid, was collected from a 1959 report of efficacy [19]. Adverse events of the injectable combination male contraceptive were collected directly from clinical trial data [8].
The goal of this analysis is to understand the AEs of female hormonal contraceptives as reported in studies that lead to FDA approval, not to review all AEs for contraceptives. Through understanding AE reporting for female contraceptives in trials leading to licensure, we can start to compare how this process is working for male contraceptives.
We grouped the AEs as described by each study. Some AEs were similar between men and women, such as weight gain or mood changes. Some AEs were reported differently for men and women. We aggregated the following AEs under the category of pelvic pain: abdominal pain/tenderness discomfort, pelvic pain/tenderness/discomfort and testicular pain/discomfort. Based on the definition used in the FDA approved package inserts, the following AEs are included under the category of mood changes for female users: mood swings, depression, depressed mood, and affect lability. Of the mood-related AEs reported in the male clinical trials, depression, emotional disorders, hostility, aggression, affective disorder and mood swings are included in ‘mood changes’.
To evaluate the scope of discontinuation of female methods, we collected additional data on discontinuation due to AEs, reported by a population-based study that provided a larger scope and sample size than data available from the package inserts [9].
In this review, the terms women/female refer to any person born with female sex organs and man/male refer to any person born with male sex organs.
Patient and Public Involvement
No patients were involved in this research.
RESULTS
We reviewed 12 reports, detailing 7 AEs quantifiably comparable between sexes. There were 320 men evaluated in the single 2016 WHO study [8], while a range of 830 to 45021 women were evaluated in the trials from which we compiled data.
Acne:
Male participants reported acne more frequently than users of female contraceptives (Table 1). This is as expected, as estrogen-containing contraceptives reduce acne and are prescribed for acne treatment, while acne is a known AE of exogenous androgens. A range of 1% to 8% of users (dose-dependent) of testosterone gel 1% (AndroGel) experience acne as an AE [20].
Table 1.
The percentage of people who reported different adverse events on the male injectable combination contraceptive, the female combination contraceptive (COC), the female intrauterine system (IUS), the female vaginal ring, the female injection, the female patch, and the COC during the 1956 trials.
| Adverse Event Frequency (%) | |||||
|---|---|---|---|---|---|
| Adverse Event | Contraceptive | Men | Women | Sample size | Publication |
| ACNE | Injectable Combination Male Contraceptive | 45.9 | 320 | Behre et al 2016 | |
| COC | 5.1 | 1723 | Ortho Tri-Cyclen Lo (2019) | ||
| IUS | 6.8* | 5091 | Mirena (2017) | ||
| Vaginal Ring | 2.4 | 2501 | NuvaRing® (2017) | ||
| Patch | 2.9 | 3322 | Ortho Evra (2010) | ||
| Injection | 1.2 | >3900 | Depo-Provera (2019) | ||
| LIBIDO DECREASE | Injectable Combination Male Contraceptive | 4.1 | 320 | Behre et al 2016 | |
| COC (1959) | 22 | 830 | Pincus et al 1959 | ||
| Vaginal Ring | 2 | 2501 | NuvaRing® (2017) | ||
| Injection | 5.5 | >3900 | Depo-Provera (2019) | ||
| LIBIDO INCREASE | Injectable Combination Male Contraceptive | 38.1 | 320 | Behre et al 2016 | |
| COC (1959) | 20 | 830 | Pincus et al 1959 | ||
| PELVIC PAIN | Injectable Combination Male Contraceptive | 1.9 | 320 | Behre et al 2016 | |
| COC | 5.6 | 4826 | Ortho Tri-Cyclen (2019) | ||
| COC | 9.2 | 1723 | Ortho Tri-Cyclen Lo (2019) | ||
| IUS | 22.6† | 5091 | Mirena (2017) | ||
| Vaginal Ring | 7.2 | 2501 | NuvaRing® (2017) | ||
| Patch | 8.1 | 3322 | Ortho Evra (2010) | ||
| Injection | 11.2 | >3900 | Depo-Provera (2019) | ||
| WEIGHT GAIN | Injectable Combination Male Contraceptive | 3.8 | 320 | Behre et al 2016 | |
| COC (1959) | 55 | 830 | Pincus et al 1959 | ||
| COC | 2.4 | 1723 | Ortho Tri-Cyclen Lo ) | ||
| Vaginal Ring | 4.9 | 2501 | NuvaRing® (2017) | ||
| Patch | 2.7 | 3322 | Ortho Evra (2010) | ||
| Injection | 37.7 | >3900 | Depo-Provera (2019) | ||
| MOOD CHANGES | Injectable Combination Male Contraceptive | 31.7 | 320 | Behre et al 2016 | |
| COC | 2.2 | 1056 | Yaz (2017) | ||
| COC | 2.3 | 2837 | Yasmin (2017) | ||
| COC | 3.8 | 4826 | Ortho Tri-Cyclen (2019) | ||
| COC | 7.6 | 1723 | Ortho Tri-Cyclen Lo (2019) | ||
| IUS | 6.4† | 5091 | Mirena (2017) | ||
| Injection | 1.5 | >3900 | Depo-Provera (2019) | ||
| Vaginal Ring | 6.4 | 2501 | NuvaRing® (2017) | ||
| Patch | 6.3 | 3322 | Ortho Evra (2010) | ||
| HEADACHE | Injectable Combination Male Contraceptive | 5.3 | 320 | Behre et al 2016 | |
| COC | 6.7 | 1056 | Yaz (2017) | ||
| COC | 10.7 | 2837 | Yasmin (2017) | ||
| COC | 33.6 | 4826 | Ortho Tri-Cyclen (2019) | ||
| COC | 30.5 | 1723 | Ortho Tri-Cyclen Lo (2019) | ||
| IUS | 16.3† | 5091 | Mirena (2017) | ||
| Vaginal Ring | 11.2 | 2501 | NuvaRing® (2017) | ||
| Patch | 21.0 | 3322 | Ortho Evra (2010) | ||
Crude incidence per person-years
Changes in Libido:
Men reported a decrease in libido at a similar frequency to users of female contraceptives today, while women from the 1959 trials reported decreases in libido at about half the frequency (Table 1).
Men reported an increase in libido at a higher frequency than women in the 1959 trials (Table 1). There were no reports of libido increase among modern female hormonal contraceptive users.
Pelvic Pain:
The frequency of pelvic pain experienced by men was less frequent than users of female contraceptives (Table 1).
Weight Gain:
The frequency of men experiencing weight gain was less frequent than women today. Women in the 1959 trials reported more weight gain by over 14 fold. This is likely attributable to the greater concentration of estrogen in the 1959 COC than in today’s COCs (Table 1).
Mood Changes:
Male participants reported mood changes at a greater frequency to users of female contraceptives using data from package inserts (Table 1).
While depression, hostility, aggression, affective disorder and mood swings were reported in fewer than 5% of men, respectively, 16.9% of men reported emotional disorders; however, the lack of differentiation between mood swings, emotional disorders, and affective disorders renders them difficult to compare to previously reported AEs by women.
Headache:
Male participants reported experiencing headaches at less than one third of the frequency that female users of hormone contraception did (Table 1).
Discontinuation and Acceptability
Women discontinued trials of hormonal contraceptives due to AEs at a higher rate than men discontinued the 2016 trial due to AEs (Table 2).
Table 2.
The percentage of total users who discontinued their contraceptive method either during clinical trials or everyday use, specifically due to adverse events or worries about possible adverse events. The data on discontinuation from everyday use was measured over a four-year period in the United States.
| DISCONTINUATION | Discontinuation due to adverse events (%) | |||
|---|---|---|---|---|
| Contraceptive | Men | Women | Sample size | Publication |
| Injectable Combination Male Contraceptive | 6.25 | 320 | Behre et al 2016 | |
| Depo-provera Injection | 36.6 | 12529 | Daniels et al 2013 | |
| Patch | 25.8 | 5631 | Daniels et al 2013 | |
| COC | 22.71 | 45021 | Daniels et al 2013 | |
| COC | 6.0 | 1056 | Yaz (2017) | |
| COC | 6.7 | 2837 | Yasmin (2017) | |
| COC | 4.0 | 1723 | Ortho Tri Cyclen-Lo (2019) | |
| Vaginal Ring | 13 | 2501 | NuvaRing® (2017) | |
Additionally, 81.7% of male participants reported they would use a contraceptive similar to the male injectable combination method, were it available on the market [8].
Adverse Events Exclusive to Men
Gynaecomastia (5.6%) was reported by men and is not experienced by women, due to biological differences. Additionally, the following AEs reported by men are not events that women on hormonal contraceptives have significantly reported: injection site pain (23.1%), increased libido (38.1%); night sweats (2.8%); irritability (2.8%); increased appetite (5.0%); hyperhidrosis (5.3%); and musculoskeletal pain and myalgia (20.7%).
Adverse Events Exclusive to Women
Commonly reported AEs by women but not men include abdominal pain, sore breasts, nausea/vomiting, changes in premenstrual syndrome, vaginal discharge, alternation of menstrual bleeding patterns, vulvovaginitis, back pain, dysmenorrhea, and (Table 3).
Table 3.
The percentage of women who reported specific adverse events during clinical trials of hormonal contraceptive methods.
| Adverse Event | Contraceptive | Adverse Event Frequency (%) | Sample size | Publication |
|---|---|---|---|---|
| SORE BREASTS | COC | 8.3 | 2837 | Yasmin (2017) |
| COC | 3.8 | 2501 | NuvaRing® (2017) | |
| IUS | 8.5† | 5091 | Mirena (2017) | |
| Injection | 2.8 | >3900 | Depo-Provera (2019) | |
| NAUSEA/ VOMITING | COC | 4.5 | 2837 | Yasmin (2017) |
| COC | 16.3 | 1723 | Ortho Tri-Cyclen Lo (2019) | |
| Injection | 3.3 | >3900 | Depo-Provera (2019) | |
| Patch | 16.6 | 3322 | ||
| Vaginal Ring | 5.9 | 2501 | NuvaRing® (2017) | |
| CHANGES IN PREMENSTRUAL SYNDROME | COC | 13.2 | 2837 | Yasmin (2017) |
| VAGINAL DISCHARGE | IUS | 14.9* | 5091 | Mirena (2017) |
| Vaginal Ring | 5.7 | 2501 | NuvaRing® (2017) | |
| ALTERATION OF MENSTRUAL BLEEDING PATTERNS | IUS | 31.9* | 5091 | Mirena (2017) |
| VULVOVAGINITIS | IUS | 10.5* | 5091 | Mirena (2017) |
| BACK PAIN | IUS | 7.9* | 5091 | Mirena (2017) |
| DYSMENORRHEA | Vaginal Ring | 3.5 | 2501 | NuvaRing® (2017) |
| COC | 6.4* | 5091 | Mirena (2017) | |
| Injection | 1.7 | >3900 | Depo-Provera (2019) | |
| Patch | 7.8 | 3322 | Ortho Evra (2010) |
When Enovid was first approved in 1960, the most common problems encountered by users were irregular menstruation, scanty or absent menses, weight change, headaches, nausea and other gastrointestinal disturbances [19]. Self-reported changes in libido were reported by 42% of the participants [19]. Across four separate trials, 28.2 – 41.8% of participants using Enovid dropped out due to AEs [19].
Serious Adverse Events
A variety of serious adverse events (SAEs), such as deep vein thrombosis, pulmonary embolism, and cervical dysplasia, were reported for contemporary female contraceptives (Table 4); these SAEs are consistent with clinical use of female hormonal contraception over the years, especially COCs [21]. In the 2016 male injectable contraceptive clinical trials, out of a total of 320 participants, there were 14 SAEs, ten of which were assessed as not related to the study regimen. There was one death from suicide, assessed as not related to the study. There was one case of depression, assessed to be probably related, and there was one case of intentional paracetamol overdose and one case of tachycardia with paroxysmal atrial fibrillation, both assessed to be possibly related.
Table 4.
The serious AEs reported by FDA-approved package inserts of contemporary hormonal female contraceptives and the serious AEs assessed to be possibly or probably related to the male injectable contraceptive. The number of female participants that reported each AE was not reported.
| SERIOUS ADVERSE EVENTS | ||
|---|---|---|
| Contraceptive | Reported Serious AEs | Publication |
| COC | Depression, pulmonary embolism, toxic skin eruption, uterine leiomyoma. | Yasmin (2017) |
| COC | Migraine, cervical dysplasia. | Yaz (2017) |
| COC | Carcinoma of the cervix in situ, and cervical dysplasia. | Ortho Tri-Cyclen Lo (2019) |
| COC | Breast cancer, carcinoma of the cervix in situ, Hypertension, and migraine. |
Ortho Tri-Cyclen (2019) |
| IUS | Group A streptococcal sepsis. | Mirena (2017) |
| Vaginal Ring | Deep vein thrombosis, anxiety, cholelithiasis, vomiting. | NuvaRing® (2017) |
| Injectable Combination Male Contraceptive | Depression, Intentional paracetamol overdose, tachycardia with paroxysmal atrial fibrillation. | Behre et al 2016 |
DISCUSSION
This critical appraisal of adverse events in contraceptive trials reveals what appears to be similar AE frequency in most categories for female contraceptive trial participants and male contraceptive trial participants. With the exceptions of increased acne, mood changes, and increased libido, all comparable AEs reported on the male injectable contraceptive were either similar to or less frequent than the same events experienced by women on a broad array of hormonal contraceptives.
AE Analysis
Emotional disorders were the main reported AE in the male contraceptive. Mood changes, an area of concern for all hormonal treatments, were experienced by a greater frequency of men; however, not represented in Table 1, recent population-level data from Denmark show that female hormonal contraceptive use can result in up to an 80% relative increase in risk of depression [22].
Notably, 95% of emotional disorders in the male contraceptive trial were rated ‘mild,’ and few led to discontinuation [8]. Other adverse events commonly reported in the male clinical trial, such as myalgia and injection site pain, are difficult to compare to female effects seen in contraceptive trials. However, while quantifiable data on insertion/injection site pain of applicable female contraceptives were not found, it is understood that pain, bleeding, and dizziness are common side effects of IUS insertion [15].
Serious AEs
With regard to serious AEs, death, typically from thrombotic events, is the most severe AE reported in association with female contraception. A 2019 systematic review suggests at least 300–400 women die annually from venous thrombosis due to hormonal contraception [23]. Death has not been reported as a correlated event in any male contraceptive efficacy studies. Notably, however, there was one death by suicide, classified as unrelated, and one suicide attempt (paracetamol overdose), classified as possibly related, in the 2016 injectable male contraceptive study [8].
Limitations
Due to heterogeneity of the studies, we cannot be certain that trial populations were similar prior to entering the trial. This prevents us from comparing any of the AEs; however; these heterogeneous trial populations were each used to achieve FDA approval. This provides valuable context in understanding how AEs are interpreted and ultimately deemed safe enough to receive FDA approval.
Additionally, the disproportionally smaller sample size of male contraceptive users compared to female users widens the confidence interval for all data on male contraception and hinders our ability to understand potential risk of adverse events at the population level. However, reviewing data on AEs side-by-side provides a tool to understanding the reality of AE frequency, and its regulatory assessment, across different contraceptive methods.
An improved framework for evaluation of male contraception that assesses AEs in conjunction with a placebo group could produce a better understanding of AE correlation, avoiding potential ecological fallacies, and resulting in a more equal application of patient safety.
Risk Analysis
Discussion of female methods has always occurred within a shared understanding that unsought pregnancy can harm and even kill women. In the approval of the first COC, regulators considered the risks of abortion and childbirth as factors in their approval decision for the contraceptive [24]. Additionally, psychological harms can be accounted for and used in risk determination. For example, while 5.4% of female users report mood changes, including depression, as an AE of their hormonal contraception (Table 1), that is still lower than the 20–22% of women who may experience maternal or postpartum depression [25]. The risk of the contraceptive can thus be deemed less severe than the risk that would exist if the contraceptive were not approved. We report that current male contraceptives under study would be more effective than any methods already available to men (condoms), and further have been shown to be highly acceptable to participants. Therefore, it may be premature to conclude that risk of AEs outweigh any potential benefits. The same risk analysis that is applied to women cannot be extended to men, who cannot physically get pregnant; however, a framework for evaluating the risks and benefits of male partners is an approaching ethical dilemma that regulators must contend with. Male contraceptives are often evaluated at an individual level, which does not account for benefits seen at the family level. For example, a common scenario of male contraceptive demand comes from male partners of women with health problems for whom hormonal contraception is medically contraindicated [26]. In that scenario, the contraceptive benefit is for the family as well as for the man. When viewed through this lens, it is rational to understand why men would be willing to accept some risk of AEs for contraception that benefits their family situation.
Further, safety assessments of male contraceptive methods limited to AEs neglect the counterfactual, namely that, similarly to women, unintended pregnancy can cause harm to men. Various studies have demonstrated the presence of postpartum depression in men [27]. It is possible that the effects of paternal postpardum depression, particularly when a pregnancy is unintended or unwanted, will outweigh the risks of contraceptive use. Understood in this framework, the possible benefits of a male contraception might outweigh the possible risks. Unfortunately, there is a critical lack of research specifically on the mental and other health adverse effects of unintended pregnancies on fathers. A 2018 study demonstrated that prenatal motivation to have a child significantly predicted postpartum depression symptoms, both maternally and paternally, however, the frequency at which symptoms occur in fathers remains unstudied [28]. At present, we are unable to quantify the negative consequences of a woman’s pregnancy on their male partners. Better data on paternal postpartum depression and paternal consequences of undesired pregnancy would enable a more equitable analysis of AEs, and would allow us to also describe potential male health benefits of male contraception.
Conclusion
Our data show that although there were concerning AEs of the injectable male contraceptive, placed in context of other current contraceptive technology, it appears that this method is promising and could have a place in the method mix even if there are AEs to be managed. AEs are expected and managed for women using hormonal contraception; however, the same basis of acceptability has not been applied to men. The acceptability of AEs for approved female contraceptive methods, compared to a very low tolerance of AEs for male methods, does show gender bias. This bias assigns contraceptive responsibility to women, normalizes female discomfort and pain associated with reproductive health, and fails to consider mental health consequences of ill-timed pregnancy for men as well as women. Despite a long history of AEs, female contraceptives are widely demanded, used and supported. Regulatory bodies have granted women the right to choose whether the risks associated with contraception outweigh the risks of unplanned pregnancy. A disturbing paradigm seems to be developing where male contraceptive methods are perceived, even before creation, to be unlikely to achieve regulatory approval and unlikely to attract pharmaceutical investment if the method has even minimal safety concerns [29,30]. As numerous male contraceptive methods are under development, the data reviewed here reminds us that female contraception has been acceptable to regulators and consumers despite a nuanced balance of risks and benefits. Regulatory, pharmaceutical and research actors should work to extend to men the same choice to assess risks and benefits of contraception.
Key Message Points.
A 2016 study on an injectable combination male hormonal contraceptive was terminated early due to adverse events.
Adverse events reported during a male contraceptive research trial are reported at seemingly similar frequencies to those reported for women during hormonal contraceptive trials.
We observed different standards for acceptable side effects for male and female contraceptives, which may lead to slower product development for male contraception
ACKNOWLEDGMENTS
We would like to thank Valerie Tarico and Dr. Emily Wiley for their editorial contributions.
Contributor Information
Carmen R. Abbe, University of Washington, Department of Medicine, Seattle, WA.
Alison C. Roxby, University of Washington, Department of Medicine and Global Health, Seattle, WA.
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