Open Journal Systems

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Received: May 5^th 2014

Accepted: October 9^th 2014

Skin diseases and obesity

Carolina Guerra-Segovia,^a Jorge Ocampo-Candiani^b

^a,bServicio de Dermatología, Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, México

Communication with: Jorge Ocampo-Candiani
Telephone: (81) 8348 9846

Email: jocampo2000@yahoo.com.mx

Obesity is a public health problem worldwide. It predominates in industrialized countries; however, it is prevalent in all nations. It is defined as a condition of excess adipose tissue and is the result of changes in lifestyle, excessive consumption of energy-dense foods with poor nutritional value, physical inactivity and the reduction of open space where one can practice a sport. Although obesity is associated with multiple diseases, it is important to stress that the metabolic changes caused by it affect skin physiology and play a predisposing factor for the development of skin diseases. Very little has been studied on the impact of obesity on the skin. The purpose of this article is to review the most frequently skin diseases in obesity. Some skin pathologies in obesity are caused by changes in skin physiology, others are related to insulin resistance or constitute an exacerbating factor for dermatitis. This article covers the clinical features of obesity related skin disease and its management.

Keywords: Obesity; Skin diseases; Treatment; Dermatoses

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Obesity, defined as a pathological state of excess adipose tissue, is a public health problem worldwide and is one of the major challenges to face. It predominates in industrialized countries, however, it is prevalent in virtually all nations of the world. It is the result of changes in lifestyle, excessive consumption of foods with high caloric content and poor nutritional value, as well as sedentary lifestyles and reduction of outdoor spaces where athletics can be practiced.

Obesity involves environmental and genetic factors. Based on previous studies, approximately 60 to 70% of the variance in body mass index can be attributed to the environment and 30 to 40% to genetic factors.¹

Environmental factors include dietary habits, socioeconomic factors, and behavioral factors such as inactivity, which is often found in obese patients.

Obesity is the result of a chronic imbalance between caloric intake and energy expenditure. Three metabolic factors have been reported as predictors of weight gain: low energy expenditure, high respiratory quotient (carbohydrate-fat oxidation), and low spontaneous physical activity.¹

Recent studies have shown that the adipose cell is not only a repository of triglycerides, but represents an extraordinarily complex metabolic endocrine organ.

The World Health Organization (WHO) uses the body mass index (BMI or Quetelet index) as a criterion of universal classification of obesity. A normal BMI is considered between 18.5-24.9, while one over 30 is a diagnosis of obesity.

The group Consenso en Obesidad of the Fundación Mexicana para la Salud recommends (for the Mexican population) considering any person with BMI of 27 or higher as obese (NOM-174-SSA1-1998).²

Although obesity is associated with many diseases, it is important to emphasize that the metabolic changes that it causes affect skin physiology and are a predisposing factor for the development of some skin diseases.

Obesity, like other diseases, generates physiological changes in the skin that cause disorders not specific to it, such as sensitivity, temperature regulation, and the cutaneous vasculature; in addition, it presents factors that predispose other dermatoses, such as the presence of large and numerous skin folds, which favors the development of infections such as candidiasis.

Garcia-Hidalgo for their study divides dermatoses associated with obesity:²

• Associated with insulin resistance: acanthosis nigricans and pendulous or soft fibromas.
• Associated with hyperandrogenism in women: acne, hirsutism, and androgenetic alopecia pattern.
• Due to increasing folds: intertrigo candidal and bacterial complications.
• Mechanical causes: stretch marks from distension, benign lipodystrophy, plantar hyperkeratosis, and peripheral vascular insufficiency.
• Associated with the hospitalization of obese patients: pressure ulcers and abnormal scarring.

Molecular genetics of obesity

As mentioned above, environmental and genetic factors are involved in obesity, the latter of polygenic basis, in which environmental factors intervene. Other less common causes of obesity include monogenic forms, in which there is a mutation in the genes involved in the central lines of caloric intake. Endocrine factors also are involved in the physiology between the skin and obesity, such as the hormones leptin and proopiomelanocortin (POMC).

Leptin, product of the Ob gene, is a hormone secreted by adipocytes that regulates homeostasis and energy consumption through hypothalamic routes.³ Congenital leptin deficiency has been identified in humans and is associated with a rare and severe form of early-onset obesity;⁴ in such patients, treatment with leptin is successful.⁵ However, most obese patients have high levels of circulating leptin associated with resistance to it, so leptin treatment in these cases is ineffective.⁶

Leptin receptors are located in tissues such as keratinocytes, fibroblasts, endothelial cells, and adipose tissue.^7-9 In wound repair it is secreted in damaged tissue and in vitro it promotes fibroblast proliferation and collagen synthesis.⁸ It also promotes the growth of endothelial cells and angiogenesis, but in high concentrations it can cause avascular necrosis. Low levels of it have been shown in forms of lipodystrophy. In mouse models with generalized lipodystrophy, leptin administration increases glucose metabolism and restores insulin sensitivity.¹⁰

The second gene involved is proopiomelanocortin. POMC is expressed in several tissues, including the pituitary gland, immune system, the hypothalamus, and the skin.^11,12

It is divided into several small peptides including beta-endorphin, adrenocorticotropin, and alpha, beta, and gamma melanocyte stimulating hormone, which exert a role in the control of analgesia, inflammation, skin pigmentation, and steroidogenesis.^11,13

The peptides derived from POMC have different affinity and specificity to five melanocortin counterpart receptors.¹⁴ The MC1 receptor is associated with human pigmentation, mutations in which cause reddish hair and white skin.¹⁵ MC4R deficiency is the leading cause of monogenic obesity and its mutation is observed in 3% of extremely obese individuals.^14,16 This receptor plays a role in dietary intake control behavior.¹⁷ A syndromic variant of POMC deficiency consists of severe early-onset obesity, adrenal insufficiency, and reduced skin pigmentation as well as reddish hair.

Skin physiology in obesity

Obesity is linked to a number of effects on skin physiology, such as: skin barrier, the production of sebaceous and sweat glands, the lymphatic system, the structure and function of collagen, wound repair, micro- and macro-circulation, and subcutaneous cellular tissue.

Loffler, Aramaki, and Effendy used bioengineering methods to investigate the correlation between BMI and epidermal function. Obese individuals showed a significant increase in transepidermal water loss and erythema compared to control subjects.¹⁴ It has been shown that obese patients have dry skin and disorders in skin repair.

Sebaceous glands

Diet can directly or indirectly influence the development of acne, including proliferation of basal keratinocytes within the pilosebaceous duct and incomplete separation of corneocytes from the pilosebaceous duct, which causes clogging thereof and increased production of androgen-mediated sebum.

Acne is clearly exacerbated by disorders associated with obesity, such as hyperandrogenism and hirsutism. Androgens, insulin, growth hormone, and other growth factors like insulin are frequently elevated in obese individuals.^18,19

Apocrine and eccrine sweat glands

Obese individuals have large skin folds and show profuse sweating when overheating occurs, due to the increased thickness of subcutaneous fat, which exacerbates the components of friction and moisture. In diabetic patients a higher pH was found the skin folds of women with a BMI greater than 25 compared to those patients with a BMI under 25, which predisposes to infections.²⁰

Lymph nodes

Obesity prevents lymphatic flow, leading to collections of protein-rich lymph fluid in the subcutaneous tissue. This results in lymphedema, which is associated with dilation of dermal channels and decreased tissue oxygenation.2 Greater accumulation of fluid decreases oxygen tension and leads to fibrosis and to a chronic inflammatory state.

Collagen structure and function

Enser and Avery showed that the skin of obese mice was mechanically weaker and generated less isometric force compared with the skin of a lean mouse.²¹ The authors suggest that loss of cutaneous mechanical strength is due to faulty collagen deposition, since it has to cover a greater surface area.²² These authors suggest a decrease in collagen repair due to changes in adipose tissue. Another study showed an increase of type III collagen replacement in obesity, particularly in abdominal obesity.²³

Microcirculation and macrocirculation

Obesity appears to be a primary cause of microvascular dysfunction, which contributes to the development of microangiopathy and hypertension.

Obese women show impaired capillary recruitment and acetylcholine-mediated vasodilatation compared to thin women.²⁴ Impaired vagosympathetic cardiac activity has been suggested. In obese nondiabetic patients there is a significant reduction in vasoconstrictor response to sympathetic activation.²⁵

Subcutaneous fat

Subcutaneous fat is mainly composed of white adipose tissue and serves as an energy reserve. This plays an important role in the metabolism of lipids and glucose. Among the peptides secreted by adipocytes are the tumor necrosis factor alpha and leptin.

Manifestations of obesity with skin effects

Pseudoacantosis nigricans

This is the most common dermatologic manifestation. Its appearance is symmetric, characterized by hyperpigmented and rough plates that can be in any location (Figure 1). It is most commonly seen in the armpits, groin, and at the back of the neck, but it can occur on the elbows, knuckles, and face, especially in people of African ancestry. Hyperpigmentation is secondary to acanthosis and papillomatosis of the epidermis. Dermal proliferation is associated with hyperinsulinemia and resistance to this.²⁶ Hud et al. found that the obese population presents acanthosis nigricans and elevated plasma insulin levels.²⁷ Obese children shown resistance to this. Hyperinsulinemia increases ovarian androgen production, which is associated with hirsutism and acne vulgaris. The triad of polycystic ovaries, hirsutism, and acanthosis nigricans is commonly observed.²⁸ The pathophysiology of this dermatosis is caused by high insulin levels, which leads to a downregulation of the number of functional insulin receptors.^29,30 These receptors have the function of regulating glucose intake, cell growth, DNA synthesis, lipid metabolism, and protein metabolism via tyrosine kinase. It is important to remember that the fibroblasts and keratinocytes express insulin-like growth factor receptors, which can bind to insulin and have growth-promoting effects. Due to the decrease in the number of insulin receptors, IGF receptors bind to circulating insulin and exert the effects previously mentioned.²⁹

Acrochordons or soft fibroids

Acrochordons are tumors of a soft consistency, fibrous, smooth, and pedicled, of varying size (0.3 to 0.5 cm in diameter) (Figure 2). Soft fibroids or pendula are elongated, measuring 5 mm in diameter or more, can be single or multiple and large, the color of the skin or a little darker; also they appear as superficial tumors or with papillomatous appearance in healthy skin. These two varieties of tumors may or may not accompany acanthosis nigricans and diabetes mellitus type 2, so it is advisable to study these patients for both diseases. They are located mainly on the eyelids, neck, armpits, the gluteal fold, and the groin, although they can be in any skin fold; they are usually asymptomatic and occasionally there is inflammation and necrosis.³¹ In a study of 156 obese patients, the percentage of acrochordons increased with the severity of obesity. Kanhana et al. found no increase in the incidence of obesity, but reported that patients had a metabolic disorder in carbohydrates.³² Treatment consists of surgical resection.

Keratosis pilaris

This appears as small perifollicular papules on the extensor surface of the extremities. It is associated with atopic diathesis,³³ and has increased incidence in people with high BMI.^2,34 It has been suggested that insulin resistance plays an important role in pathogenesis.^35,36 Treatment consists of topical keratolytics, retinoids, and corticosteroids.

Hyperandrogenism and hirsutism

These are the result of increased ovarian production of endogenous androgen due to increased adipose tissue which synthesizes testosterone, and hiperisulinemia which also increases due to ovarian androgen production. Cutaneous virilism includes hirsutism, acne vulgaris, hidradenitis suppurativa, and androgenic alopecia (Figure 3).

Ruutiainen et al. found that facial hirsutism is significantly correlated with BMI, regardless of age and testosterone level.³⁷

Hyperandrogenism in obese women is due to the ovarian production stimulated by increased blood insulin and the peripheral transformation of estrogens into androgens by adipose tissue. The hair follicle is stimulated by alpha-reductase activity, which is higher from androgen stimulation, which causes hirsutism; however, this activity in the scalp decreases and generates alopecia. Sebum production in the sebaceous glands also increases, which causes the appearance of acne lesions.³⁸

The treatment is based on controlling insulin levels, weight loss, contraception, and antiandrogens.2 In obese women with polycystic ovary syndrome (PCOS), thiazolidinediones improve insulin resistance and hyperandrogenism.^39,40

Distension stretch marks

These are atrophic linear plates distributed perpendicular to tensile forces. They are located mainly in the breasts, buttocks, abdomen, and thighs. They begin with an erythematous phase that changes to violet and then to whitish plaques. Their pathogenesis has not been well elucidated, but it involves mechanical, hormonal, and genetic factors, which are found in obese patients, in pregnancy, Cushing's syndrome, and the use of steroids.⁴¹ Hsu et al. diagnosed stretch marks in 40% of children with moderate obesity, and its incidence was greater according to the duration of the obesity.⁴²

Simkin and Arce observed greater increase in urinary adrenocorticosteroids in obese patients with stretch marks than in obese patients without stretch marks.⁴³

Treatment includes isotretinoin 0.1% and tretinoin 0.05% combined with glycolic acid 20%. Concentrations of tretinoin lower than 0.25% did not seem effective.^44,45

Pulsed light improves stretch marks clinically and with minimal histological effects.⁴⁶ Laser therapy is effective depending on the state of the stretch mark. The 585 nm laser decreases erythema in early lesions and the 308 nm excimer laser improves the hypopigmentation associated with late stretch marks.^47,48 Red and white stretch marks have been treated with pulsed dye laser with little success. Laser therapy should be avoided in patients with skin types IV-VI due to resulting hyperpigmentation.⁴⁹

Adiposis dolorosa or Dercum’s disease

Its incidence is rare and is characterized by multiple subcutaneous, painful lipomas, usually in obese post-menopausal women.⁵⁰ They are symmetrically distributed and may be localized or diffuse. The sites most often affected are the trunk and lower extremities, particularly the knees. The pain is out of proportion with the physical examination.^51,52 The pain increases with BMI when patients are 50% above normal weight for their age. Other signs include hyperalgesia to mild pressure, edema of acral parts, bruising, and telangiectasia. The syndrome is associated with severe fatigue, weakness, depression, confusion, and dementia, for which a metabolic or autoimmune mechanism is suspected.⁵³ Diagnosis is by ultrasound and magnetic resonance.⁵⁴ Treatment is ineffective. The goal of treatment is to relieve pain and restore normal appearance. The pain may improve with corticosteroids, intravenous lidocaine, methylxanthines, or analgesics.^54-56

Surgical excision or liposuction is sometimes effective.^51,52

Lymphedema

This is caused by lymphatic flow resistance. Its clinical presentation is characterized by mild pitting edema that often begins in the lower extremities and progresses proximally over time; the accumulation of fluid decreases oxygen tension and macrophage function, which leads to fibrosis and a state of chronic inflammation. In this context there is a reduction of tissue oxygenation and development of bacterial growth.² In patients with recurrent bacterial infections, the affected tissue causes perilymphatic hardening and increased lymphatic flow impedance. Chronic lymphedema can lead to a final state known as elephantiasis nostra verrucosa, characterized by hyperkeratosis and papillomatosis of the epidermis in the dermal and hardened subcutaneous tissue.⁵⁷ One complication of lymphedema is the development of angiosarcoma, which is a malignant vascular tumor. Treatment for lymphedema is to decrease the circumference and weight of the limb and to prevent infections.² Weight reduction, meticulous skin care, and elevation and compression with elastic bandages and compressive pneumatic devices are instituted. Non-invasive therapies involve physical therapy, manual lymphatic drainage, and compressive bands.⁵⁹

Chronic venous insufficiency

Obesity is a risk factor for the development of this.⁶⁰ Padberg et al.⁶¹ showed no venous valvular disease in obese patients, suggesting that obesity itself is a risk factor for its development, as it brings increased intraabdominal pressure, which produces opposition to lower extremity venous outflow and consequent valvular insufficiency and subsequent venous dilatation and the formation of varicose veins.²

Another dermatological disease frequently found in patients with varicose veins is stasis dermatitis, which is the result of increased hydrostatic pressure and intravascular fluid outlet, besides erythrocytes, which deposit hemoglobin in the dermis and incite an inflammatory reaction with erythema and warmth. It is clinically characterized by pitting edema, and hyperpigmented, brownish, scaly macules.² It is accompanied by burning, which is the result of irritation of the superficial nerve fibers by increased pressure and reduced metabolic products that increase the local pH.⁶²

Other complications include the presence of lipodermatosclerosis and venous ulcers. Lipodermatosclerosis is a fibrosing panniculitis with depressed skin on a hardened subcutaneous dermis and cellular tissue. The legs are most commonly affected, but the abdomen may also be affected in obese individuals.⁶³ Venous ulcers are most often found between mid-calf and the inner ankle, along the great saphenous vein, approximately 70% having that location.⁶⁴ It has been shown that overweight individuals have a higher risk compared to individuals of normal weight. Treatment includes compression and elevation of the limb; in case of ulceration, surgical debridement of devitalized tissue with occlusive dressings. Applying bandages impregnated with zinc with gradient sequential compression is recommended, because they strengthen healing while promoting fibrinolytic activity.⁶⁵ Adjuvants are included such as pentoxifylline 800 mg every 8 hours, along with the use of compressive bands.⁶⁶

Plantar hyperkeratosis

This was first described by Garcia Hidalgo in 1999. The horseshoe-shaped hyperkeratosis in the rear portion of the plantar is the most common symptom in patients weighing more than 176% of their body weight. It is caused by increased pressure when standing and walking, as well as the increased breadth of the forefoot.⁶⁷ There is also greater mechanical stress on the bony prominences due to abnormal weight transfer while walking.⁶⁸

Treatment is focused on weight reduction and use of protective soles.²

Cellulitis

This is more prevalent in women, predominantly affecting the abdomen, thighs, buttocks, and pelvis. It is characterized by dimpling and "orange peel".⁶⁹ It is the result of changes in the epidermis and dermis. It is found in non-obese and obese patients, however, in the latter it is exacerbated. Treatment is unsatisfactory, it is based on the use of topical retinoids, physical mechanical massage, and aminophylline. Weight reduction is not always effective.

Intertrigo

This is characterized by the presence of erythematous macerated plaques in dermal folds such as those submammary, genitocrural, axillary, and abdominal (Figure 4). It is frequently associated with infections by fungi and bacteria. Obesity is a predisposing factor for its development, since obese patients have large skin folds, increasing the frictional component, which along with moisture encourages their development.2 A study with diabetic patients found that pH was higher in the inguinal folds in women with a BMI greater than 25 compared to women with a BMI under 25.⁷⁰ This last factor predisposes the growth of saprophytic flora (e.g. yeast), since their growth is favored by alkaline pH, which modifies its morphology, allows adherence in the form of yeasts, and originates infection.⁷¹ The typical lesion is satellite papules and pustules in the intertriginous region. Treatment consists of low to medium strength steroids with Silvadene for a short time, and soaps that lower the pH. The application of tacrolimus 0.1% has proven effective in healing, in addition to having the advantage of not causing atrophy or stretch marks.⁷² Yeast superinfections can be treated with topical antifungal agents; in case of resistance to topical medications, systemic antifungals can be used such as fluconazole and itraconazole.

It has been shown that obesity is a risk factor for tinea pedis and onicomicosis.^73,74 Its handling is with oral antifungals such as terbinafine, which has proven to be more effective than itraconazole and fluconazol.⁷⁵ Topical antifungals are frontline therapy for skin infections not involving the nails.

Erysipelas and necrotizing fasciitis

The first is mainly caused by some species of Streptococcus and can be a potential complication for individuals with lymphedema.⁷⁶ Obesity has been associated as an independent risk factor for its development.⁷⁷ Penicillin G remains the treatment of first choice.^78,79

Necrotizing fasciitis is a deep subcutaneous tissue gangrenous infection that progresses to destruction of the fascia and fats.⁸⁰ It presents extensive tissue destruction, systemic toxicity, and high mortality. Pathophysiologically thrombosis of blood vessels is found, presence of bacteria at deep levels, and infiltration of acute inflammatory cells. One study found that 88% of women hospitalized with necrotizing fasciitis were obese. It has been associated with the presence of three or more risk factors, including obesity, as well as hypertension, diabetes, and advanced age, which predict a 50% mortality.⁸¹ The diagnosis is based on fever, signs of systemic toxicity, and skin involvement, accompanied by pain out of proportion to the physical findings, and the presence of elevated levels of creatine phosphokinase (CPK). The diagnosis can be confirmed by surgical exploration and cultures of it, or by punch biopsy.

Treatment includes surgical debridement, antibiotics, and broad-spectrum nutritional support.^81,82

Hidradenitis suppurativa

This is a chronic disease characterized by recurrent abscesses, fistulas, and scars on the apocrine glands (Figure 5). It affects 2% of the population.⁸³ Its etiology appears to be caused by follicular occlusion with secondary involvement of apocrine glands.⁸⁴ Obesity exacerbates this by increasing shear and androgenic effect. Management of these includes topical antiseptics, antibiotics, and corticosteroid antibiotics.⁸⁵ Among the antibiotics topical clindamycin, tetracycline and systemic dapsona are included.^86-88 Infliximab appears to be a promising therapy.^89-92 Oral retinoids and steroids in the injury have shown variable results.⁸⁴ The only effective treatment is surgical excision of the apocrine glands.^84,92

Psoriasis

Recent data show a significant prevalence of obesity in patients with psoriasis (Figure 6). Inverse psoriasis appears to be most often associated with obesity, with a study reporting its presence in 13% of patients with morbid obesity, 11% of those obese, and 5% of those not obese.⁹³

Obesity is a chronic inflammatory state. It has been observed that the expansion of adipose tissue during weight gain is associated with macrophage recruitment by chemokines such as CCL2. Adipocytes and macrophages produce cytokines such as TNF and IL-6, and adipokines such as adiponectin, resistin, and leptin, which are associated with obesity, insulin resistance, and inflammatory disorders.⁹⁴

Adiponectin is anti-inflammatory, whereas leptin and resistin are proinflammatory. The effect of leptin in natural and acquired immunity may be responsible for the worsening of psoriasis, as it acts on native T cells and increases the production and secretion of IL-2, plus IFN production by memory T cells, and inhibits proliferation of regulatory T cells, the latter being defective in psoriasis.

Leptin levels show a direct correlation with psoriasis area and severity index (PASI).

In vitro, leptin and resistin induce the production of CXCL8 Y and TFN by monocytes, which is involved in the pathogenesis of psoriasis. In addition, leptin induces the secretion of IL-1, IL-1R antagonist, and amphiregulin secretion, which stimulates epidermal proliferation. Adiponectin levels are lower in patients with psoriasis than in controls, and correlate inversely with PASI score.

Studies of the Utah Psoriasis Initiative in the United States suggest that obesity is a consequence of psoriasis.⁹⁵ Herron et al. presented retrospective data of 557 patients with psoriasis suggesting that this precedes the development of obesity.⁹³

There are several mechanisms by which psoriasis can lead to obesity, including social isolation, depression, increased alcohol consumption, and decreased physical activity, the latter being associated with psoriatic arthritis. A case-control study reports that patients with psoriasis typically consume a greater amount of total fat, saturated fat, and alcohol than a control group of healthy patients.

The first report of improvement in psoriasis was during World War II in malnourished prisoners. One case was described of full resolution of severe psoriasis without medication in a patient who underwent Roux-en-Y gastric bypass.⁹⁶

A randomized trial of 82 hospitalized patients with psoriasis shows that those who had a diet low in calories and fat for four weeks showed an improvement in psoriatic lesions. Another prospective study of 78,626 women reported that weight gain is associated with an increased risk of developing psoriasis.

Diet seems to have a significant influence on psoriasis. Medications used for diabetes are undergoing clinical trials in psoriasis therapy, one example of which is the thiazolidinediones, insulin-sensitizing drugs whose mechanism of action is based on the activation of peroxisome proliferator-activated receptor PPRX, which is a type of nuclear receptor expressed in human keratinocytes. In culture, PPRX ligands inhibit the proliferation of normal keratinocytes in patients with psoriasis.⁹⁷ New drugs like rosiglitazone and pioglitazone are effective in treating psoriasis.⁹⁸

Based on the above, it is possible to identify a well-established association between obesity and psoriasis which involves genetic, metabolic, and environmental factors; nonetheless, the question remains whether psoriasis precedes obesity or vice versa.

Conclusion

Obesity is currently the largest epidemic in Mexico, representing a serious public health problem. This disease causes metabolic changes that favor the development or exacerbation of skin diseases. It is important to recognize these diseases in obese patients and their proper treatment; skin can also be an external marker of the metabolic state of the patient. The cornerstone is the treatment of obesity, either through change in dietary habits, promoting physical activity, or through changes in lifestyle that holistically lead to a better state of health and quality of life for the patient.

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