Current situation is dangerous

An urgent clinical failure

With [humility] comes not only reverence for truth, but also proper estimation of the difficulties encountered in our search for it. …[T]his grace of humility is a precious gift.

William Osler, Aequanimitas: with other addresses to medical students, nurses and practitioners of medicine, 1849-1919

The stigma associated with sexual and mental dysfunctions, as well as a lack of medical support, are causing PFS to become a hidden epidemic. The scale and human cost of this failure cannot solely be attributed to pharmaceutical manufacturers. Rather, it is the result of a systemic clinical approach to ADRs that is not fit for purpose when considering a disease that manifests or progresses following withdrawal without a known biomarker. The staunch resistance patients continue to face in attempts to establish the very existence of the condition does not stem solely from the significant financial interest in antiandrogenic substances as first-line treatments in dermatology, but its ostensible implausibility given a remarkable reality and broad clinical endpoints. A perfect storm of novelty, rarity, and counter-intuitive clinical presentation compound clinical, pharmaceutical and regulatory failures to entrench a situation in which internet resources such as propeciahelp represent the only support for patients suffering profoundly following exposure to antiandrogenic endocrine disruptors. As symptoms vary between patients from moderate functional impairments to a life-threatening physiological and neuropsychological breakdown, this is an unsustainable situation that cannot continue.

Disturbingly, clinicians appear significantly more likely to report an ADR resulting from 5ari therapy in older men typically prescribed finasteride 5mg, despite the ADRs in this group being fewer and less frequently associated with lasting disability. Considering FAERS adverse event reports in the period April 2011 to October 2014, a significant majority of ADRs resulting from use of 1mg Finasteride by younger men were self-reported to the FDA despite a higher reported incidence of disability. Contrastingly, most side effects in older patients were reported by their doctors ​(Baas et al., 2018)​. With consideration to the alarming dissatisfaction amongst PFS patients with regards to clinical care reported by Ganzer et al. ​(Ganzer et al., 2014)​, this could indicate a widespread dismissal at the clinical level due to an erroneous assumption that patients’ symptoms are not possible and/or psychosomatic in nature. This would reflect the ubiquitous dissatisfaction of patients describing their experiences seeking help from primary care physicians and the ostensibly appropriate specialists in fields to which their symptomatology can generally be associated including urology and psychology. This deters patients with already stigmatising problems from professional engagement. This is extremely serious, as pharmacovigilant entities including the European Medicines Agency rely upon doctors to submit adverse event reports when reported by patients. Traish suggested that a misleading narrative that the condition does not exist has arisen from the current dearth of awareness and knowledge in the clinical community ​(Traish, 2018)​ despite the body of literature suggesting epigenetic susceptibility in a subset of consumers ​(Traish, 2020)​. He notes that patients are frustrated by the perception in the medical community that such condition does not exist and that they are labelled to suffer from psychological disorder, rather than an organic disorder, attributed to the inhibition of a key biochemical pathway in steroid biosynthesis and metabolism. Traish suggests this, along with the lack of attention to improve care for afflicted patients, has “translated into loss of credibility and confidence by patients in their doctors and huge loss of faith in the medical community at large” ​(Traish, 2018)​.

As of 2020, the status quo in frontline care is presenting a perilous circumstance to both existing PFS patients and the wider public. Awareness of PFS as a clinical entity is unacceptably poor amongst the medical profession and education is urgently needed ​(Garreton et al., 2016; Traish, 2020)​. Failure to acknowledge the novelty and clinical scope of the pathology continues to delay progress towards etiological understanding. The fact that Vice media have demonstrated a deeper understanding of the post-withdrawal “crash” than medical literature is a matter of concern ​(Morgans, 2018)​. The consequence of this void in clinical understanding has not only led to a lack of basic science, but the potential for PFS patients to be prescribed therapies that can result in additional and permanent harm, including SSRI medications. It is deeply concerning that, instead of psychological support being offered as adjunctive care alongside appropriate recognition of what is a serious physiological disorder, doctors are frequently issuing rapid and inappropriate psychosomatic diagnosis for what is nearly always a striking and clear description of health problems never before experienced by the patient following taking and ceasing Finasteride. Healy et al. note that this is similarly the experience for patients suffering persistently after SSRI antidepressant use, commenting that even though patients report normal sexual function prior to use and neither depression nor anxiety can account for symptomatic presentations, “physicians appear to default to attributing problems a patient has after treatment to manifestations of an underlying nervous diathesis” ​(David Healy et al., 2018)​. This is unacceptable and unjustifiable given how deeply complex the issue is and how much there is yet to know regarding the physiological consequences of endocrine disruption with 5aris ​(Traish et al., 2015)​.

Psychosomatic misdiagnosis has, in extreme cases, caused patients to be deprived of their liberty through admission to psychiatric institutions. Patients have expressed feeling intense fear after being pressured into taking psychiatric drugs that have had a profound negative impact their condition. Routinely, additional stress, confusion and harm is caused to those suffering extreme symptoms by what is tantamount to “gaslighting” ​(Thomas, 2018)​ by clinicians and psychologists. The combination of clinical arrogance and ignorance is egregious and difficult to excuse at this stage. Maksym concluded that the lasting consequences of antiandrogen therapy on the organism remain obscure, and can be highly complex and multilateral, noting the extensive metabolism of steroid hormones in the central nervous system. They state that the presence of severe and persistent effects caused by the treatment of an aesthetic issue raises great concern for the clinician given the widespread use in young and healthy individuals, and that the low estimated prevalence of PFS cannot excuse nonvigilance ​(Maksym et al., 2019)​.

Those PFS patients who are most severely affected are those who are most vulnerable to these systemic failings. Many patients are very young, and young men left unable to function socially, work or continue their studies due to debilitating physiological and neurological symptoms can be left reliant on support from family and friends who cannot always understand or appreciate the etiology of their behavioural changes. Those around the patient will understandably defer to professional assessment, and simplistic misattribution is frequently the outcome. When physiological processes far beyond the patient’s control are responsible, this psychosomatic misattribution by those in positions of medical authority unfamiliar with PFS or literature regarding the condition can often have devastating interpersonal consequences for patients already in an unimaginably desperate situation. The potential etiological overlap between the recognised persistent syndrome occurring rarely with serotonergic treatment and PFS is an emergent consideration in medical literature ​(David Healy et al., 2018; Giatti et al., 2018)​. Importantly, recent research has identified profound interruption of the androgen steroid pathway by SSRI antidepressants ​(Griffin & Mellon, 1999; Hansen et al., 2017; Jacobsen et al., 2015; Munkboel et al., 2018)​. In context of anecdotal reports from PFS patients of significant worsening following exposure to serotonergic drugs, an extremely cautious approach should therefore be taken when considering prescription of serotonergic medications to patients reporting enduring health problems not experienced prior to finasteride use.

Recognising a consistent and concerning failure in the clinical care of our patients, we issued Post-Finasteride patients the Short Assessment of Patient Satisfaction, a robust measure of patient satisfaction with their experience in clinical practice ​(Hawthorne et al., 2014)​ as part of a wider survey. Patients were asked to complete the assessment once if they had seen only one professional with regards to PFS. If they had seen more than one clinical professional about PFS, we asked them to complete the questionnaire twice: Once considering their most positive experience with regards to an appointment, and once considering their most negative experience. After 170 submissions, the results were remarkable and alarming. The average score regarding even the most positive experiences PFS patients have had with a clinical appointment is on the verge between dissatisfaction and serious dissatisfaction, denoting that “severe and urgent failings” are the norm for PFS patients seeking healthcare support, and that the very best they can hope for is a dissatisfactory clinical outcome (Propeciahelp Post Drug Syndrome Survey: Data not provided). We will seek to publish this data in the future.

Disappointingly, PFS represents a neglected opportunity to broaden scientific understanding of biological mechanisms critical to human health and will undoubtedly bridge identified knowledge gaps in the understanding of endocrine disruption ​(Solecki et al., 2016)​. As well as a virtue, professional humility is important to being a good doctor ​(Chou et al., 2014; DuBois et al., 2013; Mahant et al., 2012; Wear, 2008)​, and the vast anecdotal experience of our patients attests to a widespread shortcoming in this regard. That physicians commonly deem what has happened to those suffering PFS as implausible or impossible is telling as to the biological significance of this disease. In his commentary stressing the importance of humility in medical professionals and scientists to avoid future harms, Ritterman notes that the “problem of mistaken ideas persisting despite scientific evidence to the contrary has been present since the onset of the scientific method…This problem is of particular concern in medical science, where outmoded ideas translate into excess morbidity and mortality” ​(Ritterman, 2017)​. What differentiates our remarkable situation from examples of historic medical ignorance such as this is that, in 2020, there exists compelling objective evidence which can be contextualised, as we have attempted to the best of our ability, in a broader framework of biological understanding. It is now abundantly clear that the androgen pathway has critical roles across the entire organism, and that understanding of the implications of this on health has expanded rapidly. With so much yet to be elucidated, and such profound effects described by a subpopulation of consumers for years, the arrogance faced by our patients when reporting their drug-induced symptoms is impossible to justify. “If the toxin is professional arrogance,” Ritterman wrote, “the antidote is professional humility”.

In the absence of the acknowledgement of the true scope of the condition, informed consent to the risk of PFS is never obtained from AGA patients commencing Finasteride therapy. Demand for – and marketing of – antiandrogenic hair loss remedies such as Finasteride is expanding, and an inevitable consequence will be more cases of PFS. As of 2020, emergent subscription services are engaging in social media advertising campaigns with modern production values. Hims present a video of young woman in a lab coat visibly laughing while saying that “anything (sic) can write anything on google”. Another woman, also wearing a lab coat, assures consumers that “fewer than 1% of men actually experience side effects, but don’t be scared; this happens to very few men, and we’re here to help you if it does” ​(Hims, 2018)​. What that help consists of is difficult to infer, considering we nor professors engaged with the issue in the fields of neuroendocrinology, urology, andrology, steroid biology and psychology seeking an explanation as to this breakdown of expected function in the androgen pathway are aware of any effective and safe treatment. Manual are an internet-based prescription company who at time of writing advertise on social networks including the image sharing service Snapchat. They state on a web page intending to answer frequent questions about Finasteride that “Animal studies did not show negative effects on fertility.” ​(Manual, 2019)​. As we have previously discussed, animal studies have entailed a deficiency in fertility parameters that is transgenerational ​(Garcia et al., 2012; Kolasa-Wołosiuk et al., 2019)​. We are already receiving new PFS patients citing having taken finasteride after receiving the marketing of the companies mentioned. Considering increasing primary objective evidence in study of PFS patients, the multitude of deleterious molecular level effects in animal research and the numerous reviews stating that this is a rare and distinct clinical entity, those promoting Finasteride as a safe product for young men without warning of PFS can easily be likened to the tobacco executives of the 1980s. As public appreciation grew of the dangers associated with smoking, advertisement campaigns designed to obfuscate reality, including a smoker depicted to be saying “Please don’t tell me my cigarette smoke is harmful to you. There’s just no convincing proof that it is” (​United States v. Philip Morris USA Inc.​, 2006).

Certain dermatologists remain opposed to acknowledgement of what is physiologically happening to a subset of consumers after taking finasteride. In a report of a single AGA patient without a depressive history who presented with sexual dysfunction following Finasteride withdrawal, Trüeb et al. presented a hypotheses that PFS is a “delusional disorder” ​(Trüeb et al., 2019)​. Trüeb suggests that the airing of a documentary on Swiss television may have had a psychosomatic influence on this patient and hypothesise the condition to be one of a “mass hysteria”. The authors define mass hysteria as many people believing “obviously false and potentially distressing things based purely on hearsay”. By their own definition, this does not apply to PFS considering basic science and animal research, as well as the outcomes of several case-controlled studies of PFS patients, which are not addressed. ADR data additionally refutes this suggestion: Ali et al. had previously considered the potential for bias due to stimulated reporting of persistent sexual dysfunction. Analysing FAERS adverse event data, Ali et al. acknowledged an increase in ADRs, but noted that significant signals with a 95% confidence interval lower limit of 2.0 or greater exists before and after 2011, irrespective of the public’s knowledge of sexual dysfunction as a safety concern associated with finasteride. Ali et al. considered underreporting likely and the actual incidences of persistent sexual dysfunction to be potentially underestimated ​(Ali et al., 2015)​. Based upon their hypothesis and without any reported success in remediating the symptoms of their single patient, Trüeb et al. encourage the prescription of psychiatric medicines for an “underlying psychopathological disorder”. First line treatments for depression ordinarily fail and have commonly worsened PFS patients as we have discussed. SSRIs are frequently antiandrogenic ​(Hansen et al., 2017; Jacobsen et al., 2015; Munkboel et al., 2018)​ and are associated with a remarkably similar persistent cognitive, physiological and sexual dysfunction with the potential to represent a single syndrome ​(David Healy et al., 2018)​. As such, this baseless and irresponsible recommendation is not without the potential to result in harm to profoundly vulnerable patients should it influence clinical practitioners. It is interesting, however, that even in a commentary seeking to cast doubt on the existence of PFS as an organic condition, there is some awareness of a key novelty of the syndrome common to self-reports: The subsequential nature of onset or intensification frequently featured in patient reports ​(Trüeb et al., 2019)​. The author declares no conflict of interest despite stating that his private hair clinic continues to prescribe the drug after two decades of doing so.

Patient driven platforms cannot compensate for clinical disregard

While propeciahelp continues to provide as much support to patients as is feasible, this is a serious medical problem and patient-operated support platforms cannot possibly compensate for the entrenched failures in clinical practice that both patients and medical literature continue to highlight. Maksym et al. recognise the variable reporting in different healthcare settings is making the problem hard to evaluate ​(Maksym et al., 2019)​. Patients who have suddenly stopped visiting the propeciahelp forum are impossible to account for due to anonymity. Failure to achieve diagnosis of this syndrome and improper clinical inquiry means valuable medical records and investigation are usually non-existent or cannot be pursued in context. This is especially serious in the cases of those experiencing extremely severe and degenerative health problems, who can disappear suddenly and untraceably after expressing suicidality due to the extent of their symptoms. Clinical appreciation of PFS must be improved to provide patients accurate diagnosis and ensure the proper contextual documenting of patients with appropriate follow-up. As severely affected patients are regularly left unable to work due to resultant disabilities, the lack of professional recognition is hampering their ability to receive much-needed financial support from welfare systems. Post-mortem study will likely be extremely beneficial to a mechanistic understanding of the induced epigenetic changes in PFS, and this is dependent on appropriate diagnosis and clinical profiling.

Clinical disregard and a dire need for hope compounds the potential for the exploitation of a vulnerable and often desperate cohort by individuals or businesses offering simplistic explanations and suggesting treatments. The risk of additional harms resulting from self-medication in attempts to relieve debilitating symptoms is significant, particularly amongst the worst affected. The inability of specialist doctors to provide answers or symptomatic relief drives some patients to embark upon self-experimentation. Patients will commonly express belief that supradietary doses of concentrated “natural” extracts, vitamins or minerals have a preferential safety profile as compared with that of pharmaceutical drugs in the attempted alleviation of PFS symptoms. In patients that can exhibit a novel fragility to any further disruption of the androgen pathway, therapeutic attempts with both clinically prescribed pharmaceuticals and self-sought nutraceuticals have led to permanent worsening and directly preceded completed suicide. It is urgent and imperative that clinicians presented with PFS patients inform the patient of a physiological vulnerability to substances with endocrine disruptive properties. This is particularly important for severely affected cases of PFS who present following a short exposure to Finasteride or other causative antiandrogenic substance.

A desperate need for improvement often results in a significant selection bias on the part of patients when considering other patient reports. This can often involve a rejection of the complex situation in favour of alternative health or pseudoscientific concepts. Strong views and poorly defined etiological conclusions can be rapidly formed. Significant heterogeneity in clinical endpoints results in many patients having a poor appreciation of the situation for other patients, or as indicative of a vast array of etiologically distinct disease states. A well-known parable describes a group of blind men touching an elephant. Grasping the tusk, one believes it to be a spear. Another touching its leg is sure it is a tree. A third man near the trunk asserts it is a snake, while the man touching its ear believes it to be a fan, and the tale concludes with vehement arguments based on a selective perception ​(Snyder & Ford, 1987)​. This analogy is appropriate and can be well observed. Mild to moderately affected patients can find reading the experiences and clinical condition of severely affected patients to be psychologically difficult, potentially owing to uncertainty surrounding their own prognoses. This contributes to an incohesive community and increases the difficulty of representing the true scale of the issue.

Propeciahelp’s volunteer staff, who are suffering ourselves, are placed in a deeply difficult situation in which we must constantly advise patients to be wary of theoretical proclamations and treatment suggestions online, while being aware that clinicians cannot currently provide practical help and often present an equal risk to PFS patients. It is our opinion that there will be serious questions to be answered in the future as to why such obstacles were faced in the clinical acknowledgement of a disease as deeply serious and biologically significant as Post-Finasteride Syndrome.

Regulatory activity is overdue

Reappraisal of the use cases for these substances is necessitated at the regulatory level, ensuring adequate warning and mandating informed consent as to the potential of developing this condition. PFS has no known predictive factors, unpredictable severity between patients, a complete absence of dose-dependence, and no available therapeutic options for any of the affected symptomatic domains. PFS does not conform to the presentation of known disease state and consumers are not placed to imagine the potential implications on their physiology, minds, and lives; an impact which cannot be overstated and is not currently widely appreciated at the clinical level. PFS patients almost invariably express shock and disbelief at what is happening to them. In this regard we support the conclusion of Motofei et al. insofar as the patient must be informed and consent to the full potential health risk. Motofei notes that this is especially important in aesthetic treatment, as therapy of AGA with dutasteride places treatment of an aesthetic condition on the same level as a life-threatening disease ​(Motofei et al., 2019)​. In the rare instance a consumer were so psychologically distraught by hair loss they would countenance the risk of irreparable physical damage and the permanent loss of sexual, neurological and physiological function, there is simply no excuse for the current situation in which consumers are not informed that this disease even exists as novel clinical entity with all it entails per se. Measures to address this must begin now. In particular, the dermatology profession should at a minimum address failure in assessing patient’s pre-treatment conditions, pursue a fully informed consent, and begin effective reporting of adverse events according to national and supranational guidelines. As we are discussing frontline drugs of the dermatology profession that represent a significant worldwide revenue, at this late stage we pragmatically recognise that regulatory action will have to precede any widespread self-initiated clinical responsibility. A simple truth can be represented by the words of Upton Sinclair: “It is difficult to get a man to understand something, when his salary depends upon his not understanding it” ​(Sinclair, 1994)​.

A good therapy should have tissue selectivity to the pathogenesis and not broadly interfere with other important processes in humans ​(Zheng et al., 2006)​. Finasteride interferes with fundamental and ubiquitous physiological processes ​(Traish, 2020)​, with PFS manifesting in some consumers as a disastrous and permanent result of this. Many scientific insights into the critical role of androgens across the body and brain were not appreciated at the time of its approval. While there is now significant post-marketing evidence and animal research illustrating the systemic influence and thus potential danger of finasteride, the evidentiary basis for its continued presentation as safe product is not robust ​(Belknap et al., 2015)​. Adverse reaction warnings in the product leaflet of Finasteride remain direly inadequate and do not include PFS as a distinct entity, do not mention the post-withdrawal development seen in the majority of PFS cases, nor most of the multi-systemic symptoms PFS entails. These are well recognised in publications centring on patient reports, as we have discussed, and it is noted that despite this evidence the leaflet continues to make little mention of the broad symptom profile ​(Walf et al., 2018)​. It is therefore unacceptable that consumers are still presented with a wolf in sheep’s clothing. PFS is not imaginable by those thankfully able to take what it can strip away for granted: The emotional, physical and intellectual joys of human experience, and, often, even the ability earn a subsistence income. Patisaul and Belcher suggest that, when considering risk from EDCs, the human brain performs a risk assessment as it would in anything else: “Using an imperfect calculus incorporating intuition, experience, a mix of facts (and more often fiction) combined with something like raw gut instinct”, generally favouring short term benefit over the possibility of long term harm ​(Patisaul & Belcher, 2017)​. This “common sense” risk calculus is not adequate in the absence of accurate information, as it is novel amongst adverse drug reactions and astonishingly counter-intuitive. It is wholly unreasonable to presume consumers are placed to consider such an outcome as even the remotest possibility, particularly in absence of their doctors nor the product labelling making it abundantly clear that men are experiencing horrendous and progressive changes to the physiological structure and function of their bodies and minds as a result of taking as little as one tablet.

It cannot be emphasised strongly enough that we are primarily discussing finasteride prescribed as a cosmetic product. It is our strong contention that members of the public will rightly consider such an indication to be held to a considerably higher bar of safety than drugs for serious medical conditions, yet the de facto reality speaks to the opposite. Review after review now acknowledges evidential support for the existence of PFS and therefore the need for adequate consent to the potential risk to health and quality of life upon prescription of finasteride ​(Irwig, 2015; Maksym et al., 2019; Motofei et al., 2019; Said & Mehta, 2018; Than et al., 2018; Traish, 2020)​. In the absence of accurate clinical communication of the full risk to the patient, informed consent can never currently be obtained. Multidisciplinary scientific conclusion is not reflected in pharmacovigilant activity. The status quo begs the question: What precisely will it take to achieve the most basic of protections for the public? Discussing regulatory action in regards to endocrine disruptors for the protection of human health in their 2012 guidance to decision makers, the WHO describe that the 1973 United States ban on tetraethyl lead in gasoline followed “decades of inaction” during which children were continually exposed to a serious health risk. They suggest that “perhaps the answer is in making more use of the precautionary principle to ban or restrict chemicals in order to reduce exposure early, even when there are significant but incomplete data and before there is significant and long-lasting harm” ​(Bergman et al., 2012)​. Significant data exists with which conclude Finasteride is inestimably dangerous in a subpopulation, causes permanent harm, and that this is not positively correlated to duration of use. This justifies its withdrawal from sale as a cosmetic. Rosario and Bourke, discussing underappreciated cardiovascular risk associated with modern antiandrogen treatments in prostate cancer, suggest that in an era of media soundbytes and “wonder drugs” that men will insist on, the scientific community must respond and remain circumspect, with regulatory bodies, trial oversight committees, reviewers and editors having a duty of care “to ensure the correct health warnings go out alongside the positive messages” ​(Rosario & Bourke, 2020)​. If this is deemed the necessary response in the treatment of life threatening cancer, it is unfathomable that this vigilance should not be all the more appropriate to the prescription of antiandrogens to young healthy men for conditions like AGA and acne – conditions which are very mild in terms of androgen-mediated pathologies ​(Heemers & Tindall, 2007)​. Wolfgang Becker-Brüser, editor in chief of the German medical journal Arznei-Telegramm, recently stated that the “very serious side effects caused by finasteride [are] absolutely unacceptable for a lifestyle drug. Rationally, one cannot advocate for this medicine or justify the fact that it’s still on the market. Actually, it should be banned” ​(Südwestrundfunk, 2019)​.

Some authors continue to call for repeated placebo-controlled trials to determine the existence of persistent effects from finasteride, considering little else to be of sufficient evidential quality ​(Basaria et al., 2016; Diviccaro et al., 2020; Gray & Semla, 2019)​. Further study of this kind will not be enlightening nor practically useful to the scientific community, the PFS patient or consumer in the medium term, if ever. It is urgently necessary to acknowledge both the novel nature of the condition and the rarity of the syndrome ​(Traish, 2018)​ for a pragmatic approach. Considering the medical history of 6 PFS patients who committed suicide, Irwig noted that a prospective study that may determine causality would likely require at least 10,000 participants in each arm and a duration of at least 5 years, making it practically and financially unfeasible ​(Irwig, 2020)​. It is very possible that even in such a trial, occurrence of PFS would not reach signal. Rarity, however, cannot and should not be construed to justify dismissal of the gravity of this condition ​(Maksym et al., 2019)​. This is particularly relevant with consideration to the unpredictability and dose-independence of PFS, and its atypical progression following withdrawal. Dismissal of retrospective studies is often attempted owing to a perceived lack of credibility in normal instances of ADR. This disease is not a normal ADR, to the point that existing drug reaction algorithms are unable to accommodate it ​(David Healy et al., 2018)​. As well as statistical rarity, objective differences at the molecular level in control study of patients are increasingly established in PFS. A pragmatic approach to any progress must take the reality of this issue into account, not defer to an arbitrary standard of perceived evidential quality appropriate to a more ordinary adverse drug reaction while patients continue to be driven to suicide by profound and unresolvable suffering. Insistence on the application of a formula that is not fit for purpose in this circumstance manifests as a dereliction of duty. This will be at the expense of lives that could be saved by the most basic of warnings. It is astonishing to consider that mechanistic elucidation may now plausibly precede acknowledgement of a syndrome that has been clinically reported by patients for two decades. Patients cannot continue to shoulder this global problem in lieu of clinicians.

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