Volume 10 | Issue 10
Jonathan I. Silverberg MD PhD MPH,a,b,c Jared Jagdeo MD MS,a Mital Patel MD,a Daniel Siegel MD MS,a Neil Brody MD PhDa|
Oxidative damage by reactive oxygen species (ROS) plays a major role in skin aging, carcinogenesis and inflammation. Little is known about the protective effects of green tea extract (GTE) on toxic ROS-induced skin death. We use an in vitro model of normal human skin fibroblasts (AG13145) to study the effects of green tea extract (GTE) on hydrogen peroxide (H2O2) induced necrosis. Cell morphology, numbers, apoptosis, necrosis, and ROS were assessed by epifluorescence microscopy and flow cytometry. This study demonstrates that GTE protected from H2O2-induced necrosis in a dose-dependent manner, with highest dose GTE (100 ng/mL) resulting in the most protection from necrosis, as assessed by improved cell morphology, increased cell numbers, and decreased necrosis. The protective effects of GTE on H2O2-induced necrosis appear to be mediated directly by decreasing intracellular ROS. The present study suggests that pretreatment with high doses of GTE could protect from toxic ROS-induced injury of skin in the clinical setting. However, additional studies are necessary to determine the clinical utility of GTE for decreasing skin cell ROS, necrosis and inflammation.
J Drugs Dermatol. 2011;10(10):1096-1101.
Clinical Evidence for the Activity of Tetrahydroxypropyl Ethylenediamine (THPE), a New Anti-Aging Active Cosmetic
Background/ Objectives: The cellular surface modification of superficial epidermal keratinocytes can induce immediate skin tensioning effects and may improve signs of skin aging. Tetrahydroxypropyl ethylenediamine (THPE) is an active that has been described to induce keratinocytes' morphological changes in vitro. We conducted an in vivo study to assess anti-aging clinical benefits of a THPE-containing product.
Methods: An eight-week double-blind, randomized intra-individual placebo controlled clinical study was performed to evaluate the clinical benefits of a 2.5% THPE-containing cream. This study included 41 Caucasian women who received the THPE cream product on one side of the face and a placebo cream on the other side daily. Evaluations were performed at baseline, 45 minutes after first application, week 4 and week 8 and included clinical examination and digital photography.
Results: The study demonstrated the immediate lifting effect of a 2.5% THPE-containing cream. Forty-five minutes after a single application on the face, as the skin surface smoothed out, light reflection was modified: healthy glow and radiance of the skin were significantly improved (respectively 22.9% and 40% of improvement) and skin yellowishness was reduced (7.1%). Notably, the THPE-treated side was significantly lifted, both immediately after product application (8.1%) and after 8 weeks of application (14%), compared to the placebo-treated side.
Conclusion: This clinical study demonstrated that the effect of a 2.5% THPE-containing cream on the keratinocytes cells leads to an immediate and long-term clinical improvement of the skin appearance (radiance and skin firmness, skin lifting) and can therefore be considered as a new anti-aging cosmetic active.
J Drugs Dermatol. 2011;10(10):1102-1105.
A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial of a Novel Nutritional Supplement Product to Promote Healthy Skin
Steven H. Dayan MD,a,b John P. Arkins BS,c Vinny Sharma BS,d Elaine Paterson PhD,e David Barnes PhDf|
Background: Despite an abundance of nutritional supplements, very few well-controlled trials have assessed their beneficial effect on the skin, such as hydration, antioxidant levels, texture or appearance. The objective of the following placebo-controlled, double-blind study was to determine the effects of the Skin Health Experimental Product (SHEP) on skin health.
Methods: The study enrolled healthy men and women aged 30 years or older. Subjects were randomized to receive a twice-daily regimen of SHEP or placebo. The effects SHEP had on overall skin appearance and health were assessed by measuring improvements in: (1) skin hydration using a closed-aperture transepidermal water-loss moisture meter and a vapometer; (2) skin texture using silicon profilometry; (3) skin carotenoid concentration using Raman spectrometry; and (4) reported self-image assessments using the Global Aesthetic Improvement Scale (GAIS).
Results: SHEP-treated subjects demonstrated a significant reduction in fine lines compared to the placebo-treated group. Raman spectroscopy showed that SHEP increased carotenoids at some measurement sites. Based on the GAIS, SHEP-treated subjects were three times more likely to perceive an improvement in their appearance compared to placebo-treated subjects (P>0.049).
Conclusion: The orally-administered SHEP nutritional supplement improves skin texture, carotenoid levels in specific areas of the hand, and improves patients' perception of skin health.
J Drugs Dermatol. 2011;10(9):1106-1114.
Evaluation of Moisturizing Effect of Methanolic Extract of Five Medicinal Plants Incorporated Into Cream Bases Using Impedance and Extensiometry Methods
Background: Skin moisturizing is an important issue due to its impact on skin function. Adverse reactions to herbal extracts have been rarely reported and can be used in moisturizers. This study was conduct to evaluate moisturizing effect of a methanolic extract of five medicinal plants incorporated into cream bases.
Methods: Methanolic extract of five medicinal plants including olive, burdock, licorice, mallow and marsh horsetail was prepared. The extracts were dissolved in distilled water completely and freeze-dried to a dry powder. These extracts were added separately to the cream based formulation that has been suggested to be appropriate for adding herbal extracts. Moisturizing effects of these creams with herbal extracts were assessed using the impedance method on 12 rats equally divided into six groups (one control and five cases), as well as the extensiometry method on 25 mice divided into five groups (in each group one cream with herbal extract and control cream were tested concurrently). Obtained results were compared with the control cream based.
Results: The maximum moisturizing effect was observed with the marsh horsetail. Other creams with herbal extracts, except the one with the licorice, also exerted significantly higher moisturizing effect compared to the controls (P<0.05). Regarding the force for skin tearing, the differences were statistically significant in all groups when compared to the control group (P<0.05) and the highest difference was seen in the marsh horsetail group (2.0832 ± 0.6811 kgN).
Conclusions: The highest moisturizing activity was observed using marsh horsetail extract that can be explained by flavonoids content of marsh horsetail.
J Drugs Dermatol. 2011;10(10):1116-1121.
Effect of Retinoid Pretreatment on Outcomes of Patients Treated by Photodynamic Therapy for Actinic Keratosis of the Hand and Forearm
Barry I. Galitzer MD|
Background/Objective: Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) has been shown to be useful in both spot and field treatments of actinic keratoses (AK). This study evaluates the safety and efficacy of pretreatment of AK lesions on the dorsal hands and forearms with tazarotene gel (0.1%) twice a day for one week before broad-area ALA PDT.
Methods: Ten subjects aged 75.4 ± 11.6 years (mean ± SD) with at least four AK lesions on their dorsal forearm or hand were randomized so that one dorsal hand or forearm was pretreated with tazarotene gel (0.1%) twice daily for one week before ALA PDT with blue light. The other hand or forearm (control) was not pretreated. After seven days, ALA was applied to both sides and incubated 60 minutes before irradiation with blue light. ALA was applied first only to the AK lesions and then to the entire treatment area (defined as the extensor surface of the hand or forearm between the elbow and the base of the fingers) before 60-minute incubation. The ALA area on the control side was occluded during the 60-minute incubation. Efficacy and adverse effects were evaluated within 48 hours and eight weeks later.
Results: For both the pretreated and control group, lesion counts of the target areas decreased significantly from baseline to eight weeks after ALA PDT. Reduction percentages of the target area, however, did not differ significantly between the two groups. When reduction percentages of the entire treatment area for both groups were compared the difference between the two groups was of borderline significance (P=0.0547). When the entire treatment area was analyzed, lesion counts of the tazarotene group differed significantly from baseline at eight weeks (P=0.0002), but this was not the case with the control group (P=0.0365). Adverse events were limited to those expected after ALA PDT. Erythema was significantly more severe (P=0.0029) in the pretreated arm five minutes after ALA PDT.
Conclusion: Pretreatment of AK lesions on the dorsal hand and forearm with tazarotene gel (0.1%) may enhance the therapeutic effect of ALA PDT without serious side effects.
J Drugs Dermatol. 2011;10(10):1124-1132.
Jeffrey M. Weinberg MDa and Evelyn K. Koestenblatt MS MTa|
The treatment of cutaneous fungal infections has been shown to be directly affected by the extent of patients' adherence to therapy regimens that are often cumbersome and last for several weeks. One useful alternative approach is once-daily dosing of topical antifungal agents rather than the traditional twice-daily regimen, an example of what has been called a “forgiving” regimen, designed to promote patient adherence. Sertaconazole, an imidazole antifungal agent, is known to be safe and effective when used twice daily in the treatment of tinea pedis. This report discusses a small (n=32) clinical trial designed to determine whether sertaconazole nitrate 2% cream, used once daily, is as effective as the traditional regimen. Results demonstrated that sertaconazole is as effective when used once daily for four weeks. Patients showed rapid improvement in pruritus as early as week 2, and at six weeks' follow up, all patients were free of erythema while 93.8 percent were free of pruritus; no relapses had occurred. These encouraging findings suggest that sertaconazole nitrate may be useful in a once-daily regimen and also may result in better patient adherence to therapy.
J Drugs Dermatol. 2011;10(10):1135-1140.
A Double-Blind, Randomized, Vehicle-Controlled Study Evaluating the Efficacy and Safety of Naftifine 2% Cream in Tinea crurisObjective: Naftifine HCl 2% cream (NAFT-2%) is a topical allylamine antifungal preparation under development in the U.S. The objective of this randomized, double-blind, vehicle-controlled study was to evaluate the efficacy and safety of a two-week course of once-daily NAFT-2% vs. vehicle in the treatment of Tinea cruris ("jock itch"). Methods: A total of 334 subjects with T. cruris were enrolled and randomly assigned to NAFT-2% (n=166) or vehicle (n=168), which was applied once daily for 14 days. Efficacy and safety were evaluated at week 2 (end of treatment) and week 4. Efficacy measures included complete cure, treatment effectiveness, mycological cure, clinical cure, and clinical success and were analyzed only in subjects with a positive potassium hydroxide (KOH) and dermatophyte culture at baseline (n=75, naftifine; n=71, vehicle). Safety was assessed by adverse events and changes from baseline in clinical status and laboratory studies. Results: At week 4, 25 percent of naftifine-treated subjects achieved complete cure vs. three percent of vehicle subjects and 72 percent achieved mycological cure vs. 16 percent of vehicle treated subjects (one-sided, P<0.001). Treatment effectiveness was achieved in 60 percent of NAFT-2% subjects vs. 10 percent of vehicle subjects (one-sided, P<0.001). Clinical cure rate and clinical success rate were 33 percent and 84 percent in NAFT-2% subjects, respectively vs. 10 percent and 46 percent in vehicle subjects (both P<0.001, 2-sided). Week 2 efficacy response rates in NAFT-2% subjects were all lower than at week 4 but were significantly higher than week 2 vehicle-treated counterparts (P<0.025). Treatment-related AE occurred in 11 subjects (7 NAFT-2%, 4 vehicle) during the study. The most common AE in both groups were contact dermatitis (2 NAFT-2%), pruritus (2 vehicle), and application site reaction (1 per group). Conclusion: NAFT-2% applied once daily for two weeks (one-half the treatment duration for naftifine 1% cream) is efficacious and safe for the treatment of T. cruris. J Drugs Dermatol. 2011;10(10):1142-1147.
Comparing the Clinical Attributes of AbobotulinumtoxinA and OnabotulinumtoxinA Utilizing a Novel Contralateral Frontalis Model and the Frontalis Activity Measurement Standard
Mark S. Nestor MD PhDa and Glynis R. Ablon MDb|
Background: Studies on the pharmacodynamics of abobotulinumtoxinA (ABO) and onabotulinumtoxinA (ONA) have produced inconsistent results. This may be due to the lack of objective measurement methods.
Objective: To assess and compare pharmacodynamic attributes, including onset of action, spread and efficacy of ABO and ONA using a novel Frontalis Activity Measurement Standard (FMS) and 4-point Frontalis Rating Scale (FRS).
Methods: Twenty subjects with severe frontalis lines at maximum elevation received equal volumes of ABO or ONA using a dose ratio of 2.5:1 in five injection points on contralateral sides of the frontalis (statistical n=40). Subjects were evaluated using the FMS and FRS for 30 days using pre-defined endpoints for onset and effectiveness. Other assessments included areas of effectiveness and injection pain.
Results: For ABO vs. ONA, the FMS revealed a median Initial Onset of 12 vs. 48 hours (P<0.001), Full Onset of 24 vs. 72 hours (P<0.001) and Complete Onset of three vs. five days (P=0.01). The FRS indicated an Initial Onset for ABO and ONA of 18 hours vs. two days (P=0.002), Full Onset of two vs. three days (P=0.001) and Complete Onset of four days vs. eight days (P=0.01). The FMS showed 90 percent of ABO treatment achieved Complete Efficacy vs. 75 percent for ONO, while 90 percent of ABO treatments reached Complete Efficacy using the FRS vs. 65 percent for ONO. No differences in area of effectiveness or spread were observed. Most subjects (80%) reported ABO injections were less painful than ONA injections (P<0.05).
Conclusion: The FMS appears to be a sensitive, objective tool for measuring ABO and ONA pharmacodynamics. Using a dose ratio of 2.5:1, ABO displayed significantly earlier onset of effect and less injection pain than ONA but similar areas of effectiveness.
J Drugs Dermatol. 2011;10(10):1148-1157.
We retrospectively reviewed the records of 195 patients with suspected cutaneous reactions from NSAIDs. Two hundred and six different non-steroidal anti-inflammatory drugs (NSAIDs) were suspected of causing cutaneous reactions, and the most frequent suspected causative NSAID was ibuprofen (25.7%). Angioedema and/or urticaria were the most frequent cutaneous reactions (54.4%), and the foremost suspected causative drug for these reactions was ibuprofen. The second most frequently found cutaneous reaction was maculopapular eruption (26.2%), and celecoxib was the most commonly suspected causative NSAID for it. The primary suspected NSAIDs causing fixed drug eruption were in enolic acid group. Furthermore, drug hypersensitivity syndrome was diagnosed in five patients, and Stevens-Johnson syndrome and toxic epidermal necrolysis were detected in five patients. J Drugs Dermatol. 2011;10(10):1160-1167.
Oregano Extract Ointment for Wound Healing: A Randomized, Double-Blind, Petrolatum-Controlled Study Evaluating Efficacy
Jennifer Ragi MD,a Amy Pappert MD,a Babar Rao MD,a Daphna Havkin-Frenkel PhD,b Sandy Milgraum MDa|
Background: Wound healing is a dynamic and complex process affected by tissue hydration, the presence of bacteria, inflammation, and other variables. Oregano has potent antibacterial, antifungal, antioxidant, and anti-inflammatory properties. Studies of oregano ointment on wound healing are lacking.
Objective: To determine the efficacy of 3% oregano extract ointment on wound healing.
Methods: An investigator initiated, randomized, double-blind, petrolatum-controlled study was performed to determine the effects of oregano ointment on wound healing. Forty patients who underwent surgical excision were enrolled and randomized. Cultures were obtained on day 12 and scars were evaluated using the Patient and Observer Scar Assessment tool on day 12, 45, and 90.
Results: The oregano ointment group had 19 percent of cultures test positive for Staphlococcus aureus compared to 41 percent in the petrolatum group. One patient in the oregano ointment group developed a cellulitis compared to three patients in the petrolatum group. The oregano group had a statistically significant improvement over petrolatum in scar color, pigmentation, and pliability.
Conclusion: Oregano extract ointment decreased bacterial contamination and subsequent infection on post-surgical wounds and had equivalent overall scar appearance compared to petrolatum.
J Drugs Dermatol. 2011;10(10):1168-1172.
Cryosurgical Treatment of Warts: Dimethyl Ether and Propane Versus Liquid Nitrogen -- Case Report and Review of the LiteratureFor years, dermatologists have relied on cryotherapy with liquid nitrogen as a safe and effective treatment for warts. More recently, several over-the-counter (OTC) wart-freezing therapies have become available. Manufacturers have substituted liquid nitrogen with dimethyl ether and propane (DMEP), and marketed these new preparations to be safe and effective alternatives to in-office cryotherapy with liquid nitrogen. However, data from in vitro studies and comparative studies in humans refute manufacturers' claims that these products reproduce in-office cryotherapy. J Drugs Dermatol. 2011;10(10):1174-1176.
Efficacy of a Novel Rosacea Treatment System: An Investigator-Blind, Randomized, Parallel-Group Study
James J. Leyden MD|
Introduction: A rosacea treatment system (cleanser, metronidazole 0.75% gel, hydrating complexion corrector, and sunscreen SPF30) has been developed to treat rosacea.
Methods: Thirty women with mild or moderate erythema of rosacea on their facial cheeks were randomly assigned to use one of the following for 28 days: the rosacea treatment system (RTS); RTS minus metronidazole (RTS-M); or metronidazole 0.75% gel plus standard skin care (standard cleanser and standard moisturizer/sunscreen) (M+SSC).
Results: At day 28, global improvement was evident in 90 percent of patients using RTS, 60 percent using RTS-M, and 67 percent using M+SSC. Erythema was significantly lower with RTS from day 14 onward, and unchanged with M+SSC. The proportion of patients reporting their skin was easily irritated at least sometimes was 40 percent with RTS, 70 percent with RTS-M, and 89 percent with M+SSC.
Conclusion: The rosacea treatment system may offer superior efficacy and tolerability to metronidazole plus the standard skin care used in this study.
J Drugs Dermatol. 2011;10(10):1179-1185.
Objective: This clinical study assessed the safety and efficacy of an investigational topical product for the treatment of onychomycosis (nail fungus). Method: A prospective, multi-center, single-arm, self-controlled clinical investigation was done with adult subjects that met the inclusion criteria, primarily culture-confirmed dermatophyte infection of at least one great toe. Subjects self-treated in a weekly regimen of topical application for six months, with clinical assessment at one, three, and six months. Primary efficacy endpoint was clearance of fungal nail infection after six months of weekly treatment. Primary safety endpoint was freedom from product-related adverse events for the duration of the treatment term. Results: Fifty males and 13 females, ages 24 to 65, infected with Trichophyton (n=62) or Epidermophyton (n=1) were enrolled; 53 completed six months of assessment. Sixty percent showed improvement in clinical parameters (nail color, nail plate involvement, onycholysis, thickness, and hyperkeratosis) at six months. Cumulative rates of dermatophyte-negative culture results (test of cure) were 28, 36, and 62 percent of subjects after one, three, and six months of treatment, respectively. Three minor adverse events were device-related, with no unanticipated or serious adverse events. Limitations: This study was single-arm and self-controlled; 53 of 63 enrolled subjects completed the study. Conclusion: This study describes a new topical medical device with safety and efficacy profiles that compare favorably to results reported for topically applied onychomycosis drug treatments. J Drugs Dermatol. 2011;10(10):1186-1191.
David S. Lee MD,a* Nicholas Gulati BA,b* Frank Martiniuk PhD,c William R. Levis MDd|CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm.
J Drugs Dermatol. 2011;10(10):1192-1194.
Samantha F. Smith BSa and Steven R. Feldman MD PhDa,b,c|
The Koebner phenomenon refers to the development of lesions in response to injury of previously uninvolved skin. It occurs in psoriasis and a number of other inflammatory diseases. We present a patient who developed a Koebner reaction at the site of a tattoo. Treatment with ustekinumab resulted in striking clearance of the psoriasis changes at the tattoo site.
J Drugs Dermatol. 2011;10(10:1199-1200.
Topical fluorouracil is widely used for the treatment of precancerous and cancerous lesions of the skin. The most common side effect of this medication is localized irritant dermatitis. The authors report a case of dysgeusia with metallic taste as a side effect of this medication. While not previously seen with topical use, this is not an uncommon side effect seen with systemic administration of 5-fluorouracil. The etiology of dysgeusia from chemotherapeutic agents and systemic absorption of fluorouracil is discussed. J Drugs Dermatol. 2011;10(10:1201-1203
Levamisole Induced Necrosis of the Skin and Neutropenia Following Intranasal Cocaine Use: A Newly Recognized Syndrome
John Mouzakis MD,a Charurut Somboonwit MD,b Seetha Lakshmi MBBS,c Mark Rumbak MDd John Sinnott MD,e Basil Cherpelis MD,f Jonathan Keshishian MDg|
Levamisole is a veterinary anti-helminthic used to treat several autoimmune conditions but also commonly utilized as an additive in cocaine distribution. Toxicity resulting in agranulocytosis and cutaneous necrosis in association with cocaine use is an infrequently described phenomenon of an emerging problem. Although levamisole is found extensively in the cocaine supply of the United States, relatively few cases of necrotic skin lesions associated with intranasal use have been reported. The skin necrosis secondary to levamisole toxicity is characterized by variable findings on biopsy, ranging from leukocytoclastic vasculitis to occlusive vasculopathy. The following case describes a 54-year-old male who developed fever, agranulocytosis, p-ANCA autoantibodies and extensive skin necrosis following heavy intranasal cocaine use. Necrosis of greater than 50% of the patient's total body surface area resulted and was followed by thorough wound debridement.
J Drugs Dermatol. 2011;10(10:1204-1207.
Program Spotlight: The Unified Division of Dermatology Residency Program of Albert Einstein College of Medicine
Adam Friedman MDa and Steven Cohen MD MPHa|
Resident Rounds is a section of the JDD dedicated to highlighting various dermatology departments with residency training programs. Resident Rounds includes three sections: (1) a program spotlight, highlighting pertinent information about the department and residency training program; (2) a section presenting study materials used by residents at the program; and (3) a section designed to highlight recent interesting cases seen at the institution. This issue of Resident Rounds features The Unified Division of Dermatology Residency Program of Albert Einstein College of Medicine. The editor of Resident Rounds is Omar A. Ibrahimi, MD, PhD. He is currently the Director of Cutaneous Laser and Cosmetic Surgery and a Mohs surgeon at the University of Connecticut. Dr. Ibrahimi is also a Visiting Scientist at the Wellman Center for Photomedicine at Massachusetts General Hospital/Harvard Medical School. If you are interested in highlighting your training program in a future issue, please contact Dr. Ibrahimi at email@example.com
Sound-Alike and Look-Alike Terms in Dermatology: The Unified Division of Dermatology of the Albert Einstein College of MedicineNo abstract details for the moment.
No abstract details for the moment.
Sarit Itenberg DO,a Ryan Turner MD,a Bijal Amin MD,a Mark Jacobson MD,a Karthik Krishnamurthy DOa|No abstract details for the moment.
David Schairer BA and Adam Friedman MD|No abstract details for the moment.
Pipeline Previews brings to you information on the newest drugs and medical products as they become available to the dermatologic community. This department may include additional information from the manufacturers, plus reports from physicians who wish to share their clinical experience with these new products. In addition, we will inform our readers about the latest drugs receiving Food and Drug Administration (FDA) approval.
Clinical Trial Review is a JDD department designed to provide physicians with information on drugs and devices undergoing clinical testing. It is our goal to inform the reader of the status of select drug and device studies relevant to the practice of dermatology before this information is available through standard channels. To participate in or learn more about these and additional trials, visit www.clinicaltrials.gov.
Brian Berman MD PhD, James Q. Del Rosso DO, Jacquelyn Levin DO, Paul C. Contard MD PhD|This supplement to the Journal of Drugs in Dermatology seeks to advance our knowledge of the structure and function of the stratum corneum. Previously considered a "static" or unremarkable barrier, it has now attained new clinical importance in regards to its role in conditions such as atopic dermatitis and other cutaneous abnormalities. Dr. Brian Berman provides an insightful introduction to articles by Dr. James Q. Del Rosso and Dr. Jacquelyn Levin, as well as by Dr. Paul C. Contard, that discuss the role and relevance of the stratum corneum in today's dermatologic world.