Integrating skin color assessments into clinical practice and research: A review of current approaches.

Skin color classification can have importance in skin health, pigmentary disorders, and oncologic condition assessments. It is also critical for evaluating disease course and response to a variety of therapeutic interventions and aids in accurate classification of participants in clinical research studies. A panel of dermatologists conducted a literature review to assess the strengths and limitations of existing classification scales, as well as to compare their preferences and utilities. We identified 17 skin classification systems utilized in dermatologic settings. These systems include a range of parameters such as UV light reactivity, race, ethnicity, and degree of pigmentation. The Fitzpatrick skin type classification is most widely used and validated. However it has numerous limitations including its conflation with race, ethnicity, and skin color. There is a lack of validation data available for the remaining scales. There are significant deficiencies in current skin classification instruments. Consensus-based initiatives to drive the development of validated and reliable tools are critically needed.

Efficacy and Safety of a New Resilient Hyaluronic Acid Filler in the Correction of Moderate-to-Severe Dynamic Perioral Rhytides: A 52-Week Prospective, Multicenter, Controlled, Randomized, Evaluator-Blinded Study.

BACKGROUND: The perioral region is highly mobile and subject to multifactorial changes during aging. Resilient Hyaluronic Acid Redensity (RHAR), an RHA filler, was developed with the aim of optimizing outcomes in dynamic facial areas. OBJECTIVE: This randomized, blinded, multicenter clinical study aimed to demonstrate superiority of RHAR over no-treatment control for correction of moderate-to-severe dynamic perioral rhytides. MATERIALS AND METHODS: Blinded live evaluator assessments of efficacy included improvement in perioral rhytides severity using a proprietary scale (Perioral Rhytids Severity Rating Scale [PR-SRS]) and the Global Aesthetic Improvement Scale. Subjects self-assessed their results with FACE-Q, a validated patient-reported outcome measure, and satisfaction scales. Safety was monitored throughout the study based on common treatment responses (CTRs) and adverse events (AEs). RESULTS: The primary efficacy end point was achieved, with the treatment group showing statistically significant superiority over the control group at Week 8 (80.7% vs 7.8% responder rate by PR-SRS, p < .0001). Most patients (66%) were still responders at Week 52 (study completion). Most AEs were CTRs after perioral injection of a dermal filler, and none was a clinically significant treatment-related AE. CONCLUSION: Resilient Hyaluronic Acid Redensity is effective and safe for the correction of dynamic perioral rhytides in all Fitzpatrick phototypes, with marked durability.

The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as assessed by the investigator on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment of 20 U prabotulinumtoxinA (4 U/0.1 mL freeze-dried formulation injected into 5 target glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety was evaluated throughout the study. RESULTS: The 352 study patients received a median total dose of 60 U, that is, 3 treatments per year. Fifty-one patients (14.5%) experienced adverse events (AEs) assessed as possibly study drug related; 11.1% experienced study drug-related AEs after the initial treatment. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Six patients (1.7%) experienced study drug-related AEs of special interest: 3 eyelid ptosis (0.9%), 2 speech disorder (0.6%), and 1 blepharospasm (0.3%). Seven patients (2.0%) experienced serious AEs; none were study drug related. Of the 2393 samples tested, 2 patients (0.6%) tested positive for antibotulinum toxin antibodies at a single postbaseline visit. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was first established in this early phase II study based on a broad range of outcomes.

Aspiration Revisited: Prospective Evaluation of a Physiologically Pressurized Model With Animal Correlation and Broader Applicability to Filler Complications.

BACKGROUND: Aspiration testing before filler injection is controversial. Some believe that aspiration can help prevent inadvertent intravascular injection, whereas others cite false-negative results and question its value given that the needle position always changes somewhat during injection procedures. OBJECTIVES: The authors sought to test the relation of false-negative results to the viscosity of the material within the needle lumen and determine whether a less viscous material within the needle lumen could decrease the incidence of false-negative results. METHODS: In vitro aspiration tests were performed utilizing 30-G and 27-G needle gauges, 2 cross-linked hyaluronic acid fillers, normal saline bags pressurized at 140 and 10 mmHg to mimic human arterial and venous pressures, and 3 needle lumen conditions (normal saline, air, and filler). Testing was repeated 3 times under each study condition (72 tests in total). For in vivo correlation, aspiration tests were performed on femoral arteries and central auricular veins in 3 rabbits (4-5 aspirations per site, 48 tests in total). RESULTS: In vitro and in vivo testing utilizing 30-G needles containing filler both showed false-negative results on aspiration testing. In vitro and in vivo testing utilizing needles containing saline or air showed positive findings. CONCLUSIONS: False-negative results from aspiration testing may be reduced by pre-filling the needle lumen with saline rather than a filler. The pressurized system may help overcome challenges of animal models with intravascular pressures significantly different from those of humans. The adaptability of this system to mimic various vessel pressures may facilitate physiologically relevant studies of vascular complications.

Prospective, Randomized, Investigator-Blinded, Split-Face Evaluation of a Topical Crosslinked Hyaluronic Acid Serum for Post-Procedural Improvement of Skin Quality and Biomechanical Attributes.

BACKGROUND: This split-face, controlled study investigated the ability of a topical crosslinked hyaluronic acid formulation (RHA serum) to enhance clinical results from fillers, microneedling, or chemical peeling of aging skin. Previous comparative skin explant studies demonstrated greater efficacy of RHA serum than topical non-crosslinked high or low molecular weight hyaluronic acid in decreasing trans-epidermal water loss, increasing epidermal hydration, and improving corneocyte microstructure. METHODS: 24 female subjects aged 35 to 55 were enrolled. 8 received intradermal hyaluronic acid filler injection, 8 received microneedling, and 8 received superficial mandelic acid chemical peeling. Subjects initiated twice-daily, standardized application of RHA serum to one side of the face 2 days after the procedure. Topographical imaging, bioinstrumental, and blinded clinical evaluations were performed at days 0, 14, and 28. RESULTS: Areas treated with RHA serum showed statistically significant improvements in skin surface topography and hydration compared to untreated areas. Blinded investigator scoring showed greater improvement of RHA serum-treated skin in moisture, tone/complexion, radiance, texture, uniformity, and global appearance. Subjects' questionnaire responses correlated with these findings. Subjects expressed greater satisfaction with appearance of the treated hemiface. No adverse events were observed during the study. CONCLUSIONS: When initiated post-procedurally, topical RHA serum was well-tolerated and enhanced biomechanical properties, quality, and clinical appearance of the skin. Based on these data, RHA serum may be of value in improving patient outcomes and satisfaction following minimally invasive aesthetic procedures. The availability of the same hyaluronic acid technology also as a cohesive, tissue-integrating injectable filler enables synergistic, multi-level treatment plans to be devised.

J Drugs Dermatol. 2018;17(4):442-450.

The Mechanisms and Potential Impact of Stem Cell Activation in Skin Rejuvenation: An Evidence-Based Analysis.

Stem cells can propagate indefinitely in an undifferentiated state; or, with appropriate signals, differentiate into various types of mature cells. Strong interest in stem cell therapies for degenerative diseases has extended to skin aging, itself a degenerative process. This article reviews mechanisms of skin aging, and enables an evidence-based approach to topical skin rejuvenation - specifically, to formulations labeled as stem cell products.

J Drugs Dermatol. 2017;16(4):378-384.

Global Aesthetics Consensus: Avoidance and Management of Complications from Hyaluronic Acid Fillers-Evidence- and Opinion-Based Review and Consensus Recommendations.

BACKGROUND: Although the safety profile of hyaluronic acid fillers is favorable, adverse reactions can occur. Clinicians and patients can benefit from ongoing guidance on adverse reactions to hyaluronic acid fillers and their management. METHODS: A multinational, multidisciplinary group of experts in cosmetic medicine convened the Global Aesthetics Consensus Group to review the properties and clinical uses of Hylacross and Vycross hyaluronic acid products and develop updated consensus recommendations for early and late complications associated with hyaluronic acid fillers. RESULTS: The consensus panel provided specific recommendations focusing on early and late complications of hyaluronic acid fillers and their management. The impact of patient-, product-, and technique-related factors on such reactions was described. Most of these were noted to be mild and transient. Serious adverse events are rare. Early adverse reactions to hyaluronic acid fillers include vascular infarction and compromise; inflammatory reactions; injection-related events; and inappropriate placement of filler material. Among late reactions are nodules, granulomas, and skin discoloration. Most adverse events can be avoided with proper planning and technique. Detailed understanding of facial anatomy, proper patient and product selection, and appropriate technique can further reduce the risks. Should adverse reactions occur, the clinician must be prepared and have tools available for effective treatment. CONCLUSIONS: Adverse reactions with hyaluronic acid fillers are uncommon. Clinicians should take steps to further reduce the risk and be prepared to treat any complications that arise.

Global Aesthetics Consensus: Hyaluronic Acid Fillers and Botulinum Toxin Type A-Recommendations for Combined Treatment and Optimizing Outcomes in Diverse Patient Populations.

BACKGROUND: Combination of fillers and botulinum toxin for aesthetic applications is increasingly popular. Patient demographics continue to diversify, and include an expanding population receiving maintenance treatments over decades. METHODS: A multinational panel of plastic surgeons and dermatologists convened the Global Aesthetics Consensus Group to develop updated guidelines with a worldwide perspective for hyaluronic acid fillers and botulinum toxin. This publication considers strategies for combined treatments, and how patient diversity influences treatment planning and outcomes. RESULTS: Global Aesthetics Consensus Group recommendations reflect increased use of combined treatments in the lower and upper face, and some midface regions. A fully patient-tailored approach considers physiologic and chronologic age, ethnically associated facial morphotypes, and aesthetic ideals based on sex and culture. Lower toxin dosing, to modulate rather than paralyze muscles, is indicated where volume deficits influence muscular activity. Combination of toxin with fillers is appropriate for several indications addressed previously with toxin alone. New scientific data regarding hyaluronic acid fillers foster an evidence-based approach to selection of products and injection techniques. Focus on aesthetic units, rather than isolated rhytides, optimizes results from toxin and fillers. It also informs longitudinal treatment planning, and analysis of toxin nonresponders. CONCLUSIONS: The emerging objective of injectable treatment is facial harmonization rather than rejuvenation. Combined treatment is now a standard of care. Its use will increase further as we refine the concept that aspects of aging are intimately related, and that successful treatment entails identifying and addressing the primary causes of each. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Pilot Comparative Study of the Topical Action of a Novel, Crosslinked Resilient Hyaluronic Acid on Skin Hydration and Barrier Function in a Dynamic, Three-Dimensional Human Explant Model.

BACKGROUND: Hyaluronic acid (HA) is a popular ingredient in topical formulations for cosmetic improvement of the skin. Most formulations contain linear, non-crosslinked HA oligomers, low molecular weight (LMW) HA, and/or high molecular weight (HMW) HA. Crosslinking of HA enhances its clinical longevity and mechanical characteristics. The objective of this study was to characterize the topical effects of a new, crosslinked resilient HA (RHA) that is also available as a cohesive, tissue-integrating injectable filler, compared with non-crosslinked HMW HA and LMW HA. Living human skin explants that preserve the 3-dimensional structure of in vivo skin were used to maximize clinical relevance. METHODS: Standardized doses of each HA product were applied daily for 9 days to human skin explant surfaces. Untreated explants served as controls. Water content of the stratum corneum and entire epidermis was analyzed by Raman spectroscopy. Transepidermal water loss (TEWL) was measured to assess skin barrier function. Explant morphology and microrelief were evaluated by optical and scanning electron microscopy. RESULTS: Crosslinked RHA achieved a significant increase in epidermal water content (7.6%) over the control. Spectral cartography confirmed a higher epidermal water content with RHA than with HMW HA or LMW HA. TEWL was reduced by 27.8% with RHA, and by 15.6% with HMW HA, but increased by 55.5% with LMW HA. Cutaneous microrelief improved with RHA. Corneocyte cohesion improved with RHA and HMW HA. CONCLUSIONS: This comparative, multimodal study demonstrated greater benefits of topical crosslinked RHA over linear HMW HA or LMW HA in reducing TEWL, retaining and redistributing water within the epidermis, maintaining skin integrity, and improving skin barrier structure and function. RHA was a more efficacious humectant than LMW HA, and a more efficacious occlusive moisturizer than HMW HA. These integrative epidermal repair activities are of significant value for addressing primary deficits of aging skin, improving tolerance to retinoids and other topical agents, and optimizing procedural outcomes. A combination of topical and injectable HA provides an elegant model of synergistic, multi-level skin restoration.

Global Aesthetics Consensus: Botulinum Toxin Type A--Evidence-Based Review, Emerging Concepts, and Consensus Recommendations for Aesthetic Use, Including Updates on Complications.

BACKGROUND: Botulinum toxin type A injection remains the leading nonsurgical cosmetic procedure worldwide, with a high rate of efficacy and patient satisfaction. METHODS: A multinational, multidisciplinary group of plastic surgeons and dermatologists convened the Global Aesthetics Consensus Group to develop updated consensus recommendations with a worldwide perspective for botulinum toxin and hyaluronic acid fillers. This publication on botulinum toxin type A considers advances in facial analysis, injection techniques, and avoidance and management of complications. RESULTS: Use of botulinum toxin has evolved from the upper face to also encompass the lower face, neck, and midface. The Global Aesthetics Consensus Group emphasizes an integrative, diagnostic approach. Injection dosage and placement are based on analysis of target muscles in the context of adjacent ones and associated soft and hard tissues. The indication for selection of botulinum toxin as a primary intervention is that excessive muscular contraction is the primary etiology of the facial disharmony to be addressed. Global Aesthetics Consensus Group recommendations demonstrate a paradigm shift toward neuromodulation rather than paralysis, including lower dosing of the upper face, more frequent combination treatment with hyaluronic acid fillers, and intracutaneous injection where indicated to limit depth and degree of action. CONCLUSIONS: The accumulation of clinical evidence and experience with botulinum toxin has led to refinements in treatment planning and implementation. The Global Aesthetics Consensus Group advocates an etiology-driven, patient-tailored approach, to enable achievement of optimal efficacy and safety in patient populations that are rapidly diversifying with respect to ethnicity, gender, and age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Aesthetic Applications of Botulinum Toxin A in Asians: An International, Multidisciplinary, Pan-Asian Consensus.

BACKGROUND: Botulinum toxin type A remains the most popular nonsurgical aesthetic treatment worldwide. Previous consensus statements have focused on Caucasians and on Koreans as generally representative of Asians. However, indications and dosages vary among different ethnic groups. This publication reports the results of a multidisciplinary, pan-Asian consensus focusing on incobotulinumtoxinA. METHODS: A consensus group of plastic surgeons and dermatologists from Asia, Europe, and the United States convened for a live meeting in Asia, followed by a questionnaire-based Delphi procedure. Treatment of Asians in both their native countries and countries of migration was discussed. RESULTS: For most items, the group achieved a majority consensus. A number of treatment indications, strategies, and dosages were identified in Asians, which are distinct to those previously described for Caucasians due to differences in facial morphotypes, anatomy, and cultural expectations. The group also formulated position statements for intradermal botulinum toxin type A ("mesotoxin"), body shaping with the calves as a paradigm, and reduction of parotid glands. While Asians have previously been considered a homogeneous group for the purposes of aesthetic treatment, this publication considers regional variations. A new classification of Asian facial morphotypes is proposed to aid treatment planning and implementation. CONCLUSIONS: This is the first pan-Asian consensus for aesthetic use of botulinum toxin type A. Its unique objective is to optimize treatment safety and efficacy for patients of complete or part-Asian ancestry in all regions. The recommendations for incobotulinumtoxinA may be extended with care to other botulinum toxin formulations.

Pilot, Multicenter, Open-Label Evaluation of Safety, Tolerability and Efficacy of a Novel, Topical Multipotent Growth Factor Formulation for the Periorbital Region.

BACKGROUND: This multicenter, open-label pilot study evaluated safety, efficacy and tolerability of a topical formulation containing a multipotent growth factor resignaling complex (MRCx), when applied to infraorbital and lateral canthal skin. METHODS: Thirty-nine female subjects with mean age of 56.8 years who had periorbital lines and wrinkles, uneven skin texture, puffiness, and lack of skin firmness were enrolled, and 38 completed the study. All subjects applied the multipotent growth factor formulation bilaterally to the periorbital area, twice daily for 60 days. Efficacy and treatment-related adverse events were evaluated at Baseline and days 14, 30, and 60. Investigators rated the periorbital areas based on 10-point scales. RESULTS: Subjects' self-reported compliance with treatment was greater than 99% throughout the study. At day 60, all subjects had improvement in infraorbital brightness (≥ 2 points), moistness (≥ 2 points), wrinkles (≥ 1 point), sallowness (≥ 1 point), crepiness (≥ 1 point), smooth texture (≥ 1 point), skin tightness (≥ 1 point), and skin tone (≥ 1 point). Investigator-rated assessments showed ≥ 1-point improvement for lateral canthal wrinkles, dyschromia/mottled pigmentation, skin tone, overall brightness, and moistness. Investigator-rated scoring on the Global Aesthetic Improvement Scale (GAIS) demonstrated that 67.6% of subjects were much improved/improved at day 14, and 63.1% remained improved at day 60. Overall, 76.2% and 79.0% of subjects were very pleased/pleased/mostly pleased with the appearance of their infraorbital and lateral canthal areas at day 60. Adverse events comprised one case of mild canthal erythema, and one case of mild eye irritation, both of which were respectively resolved. CONCLUSIONS: This pilot study demonstrated that the topical multipotent growth factor formulation was safe, effective and well tolerated for periorbital skin rejuvenation.

Consensus Recommendations for Optimal Augmentation of the Asian Face with Hyaluronic Acid and Calcium Hydroxylapatite Fillers.

BACKGROUND: Although the use of filling agents for soft-tissue augmentation has increased worldwide, most consensus statements do not distinguish between ethnic populations. There are, however, significant differences between Caucasian and Asian faces, reflecting not only cultural disparities, but also distinctive treatment goals. Unlike aesthetic patients in the West, who usually seek to improve the signs of aging, Asian patients are younger and request a broader range of indications. METHODS: Members of the Asia-Pacific Consensus group-comprising specialists from the fields of dermatology, plastic surgery, anatomy, and clinical epidemiology-convened to develop consensus recommendations for Asians based on their own experience using cohesive polydensified matrix, hyaluronic acid, and calcium hydroxylapatite fillers. RESULTS: The Asian face demonstrates differences in facial structure and cosmetic ideals. Improving the forward projection of the "T zone" (i.e., forehead, nose, cheeks, and chin) forms the basis of a safe and effective panfacial approach to the Asian face. Successful augmentation may be achieved with both (1) high- and low-viscosity cohesive polydensified matrix/hyaluronic acid and (2) calcium hydroxylapatite for most indications, although some constraints apply. CONCLUSION: The Asia-Pacific Consensus recommendations are the first developed specifically for the use of fillers in Asian populations. CLINCIAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Cohesive Polydensified Matrix Hyaluronic Acid for Fine Lines.

BACKGROUND: Fine lines and crepey skin are dermal manifestations of multilevel, age-related volume loss. It is, therefore, logical to combine intradermal volumetry for fine lines with subcutaneous volumetry for contours. This publication provides evidence- and experience-based rationales for application of cohesive polydensified matrix hyaluronic acid filler (Belotero Balance). METHODS: Evidence level II data demonstrate efficacy of this product and longevity for up to a year or more with intradermal, superficial blanch injection. Its softness, flow tendencies, and homogeneous tissue integration are informed by low elasticity (G') and viscosity, high cohesivity, and high tan delta. Ultrastructural analysis confirms variable-density cross-linking, intended to confer resilience, and absence of detectable particles, minimizing Tyndall effect. RESULTS: Scientific properties of Belotero Balance predict its 3-dimensional tissue expansion with prominent horizontal vectoring. We define this as superficial flow volumetry. High cohesivity and resilience can maintain structural integrity in typically mobile facial areas with strong muscular forces, uneven pressure, and significant hyaluronidase activity. This facilitates a natural appearance, both in repose and animation. CONCLUSIONS: Based on available evidence and experience, cohesive polydensified matrix hyaluronic acid is a notably efficacious fine line filler. The ideal fine line filler would restore dermis structurally and dynamicaly-moving as one with it, efficaciously expanding it, withstanding mechanical stress, swelling minimally, and potentially stimulating collagenesis. The relative contributions of space-filling, water binding, and collagenesis have implications for efficacy. A focus of current research is to determine the impact of filler cohesivity and tissue integration on these ideal qualities.

Cohesivity of Hyaluronic Acid Fillers: Development and Clinical Implications of a Novel Assay, Pilot Validation with a Five-Point Grading Scale, and Evaluation of Six U.S. Food and Drug Administration-Approved Fillers.

BACKGROUND: Biophysical characteristics of hyaluronic acid gel fillers reflect individual manufacturing processes. They confer rheologic properties that provide scientific rationale with Evidence Level II clinical correlation for selection of appropriate fillers for specific clinical applications. Cohesivity, a key property, maintains gel integrity, contributes to tissue support with natural contours, and diminishes surface irregularities. In this publication, a new, standardized visual assay for hyaluronic acid cohesivity is presented, applied, and discussed. METHODS: Colored hyaluronic acid gel specimens were automatically extruded under standardized conditions into sterile water stirred at a constant rate. Based on 90 digital images showing ratios of intact to dispersed gel during assay of 10 Communauté Européenne-marked fillers, the five-point visual Gavard-Sundaram Cohesivity Scale was developed. Six plastic surgeons and dermatologists performed pilot validation of the scale, subsequently used to evaluate six U.S. Food and Drug Administration-approved fillers. RESULTS: Validation of the Gavard-Sundaram Cohesivity Scale showed substantial repeatability and interrater consistency. Mean cohesivity scores from three assays of each tested filler showed significant differences. Cohesivity was high for Cohesive Polydensified Matrix (Belotero Balance), medium-high for Hylacross (Juvéderm Ultra 2/Ultra XC and Ultra 3/Ultra Plus XC), low-medium for Vycross (Juvéderm Voluma), and low for non-animal-stabilized hyaluronic acid (Restylane and Perlane). CONCLUSIONS: An evidence-based approach requires clinical corroboration of in vitro data. This new, reproducible cohesivity assay may have value together with elasticity (G') and viscosity measurements to understand and leverage distinct tissue distribution patterns and clinical behaviors of different hyaluronic acid products. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Safety of Microfocused Ultrasound With Visualization in Patients With Fitzpatrick Skin Phototypes III to VI.

IMPORTANCE: A microfocused ultrasound (MFU) system is a safe and effective aesthetic treatment for tightening and lifting skin in the facial and neck areas. This open-label, nonrandomized trial was performed to further demonstrate the safety of MFU for improving laxity of the skin of the face and neck in 52 adults with Fitzpatrick skin types III to VI. OBSERVATIONS: Before treatment with MFU, the skin tissue of each participant was assessed and ultrasound imaging was performed on the treatment area to ensure appropriate acoustic transducer coupling. Treatment was performed from March 23, 2011, to July 20, 2011. Following treatment, there were 3 reported adverse events described as raised areas of mild edema or welts (2 events) and moderately severe prolonged erythema with mild scabbing (1 event). All events resolved after 90 days without sequelae. Analysis was conducted from Janaury 18, 2012, to March 13, 2013. CONCLUSIONS AND RELEVANCE: The adverse events that occurred in this trial were temporary and associated with treatment technique. When performed by trained physicians, MFU is safe in patients with Fitzpatrick skin types III to VI. LEVEL OF EVIDENCE: 4. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01368965.