A Narrative Literature Review of the Established Safety of Human Serum Albumin Use as a Stabilizer in Aesthetic Botulinum Toxin Formulations Compared to Alternatives.

Despite more than 80 years of use in a number of conditions, including in critically ill patients, comments have recently arisen regarding the safety and efficacy of human serum albumin (HSA) as a therapeutic product and stabilizer/excipient in botulinum neurotoxins. This review summarizes the literature on the safety of HSA. Beyond decades of safe use, the largest clinical dataset of HSA safety is a large meta-analysis of HSA supplier data, which found only an extremely remote risk of serious adverse events across millions of doses of therapeutic concentrations of HSA. There is a paucity of literature identifying HSA-specific adverse events when used as a stabilizer/excipient; however, studies of HSA-containing botulinum neurotoxins (BoNTs) suggest that adverse events are not related to HSA. Polysorbates, which are synthetically produced and not physiologically inert, are contained in pending or new-to-market BoNT formulations. In contrast to HSA, evidence exists to suggest that polysorbates (particularly PS20/PS80) can cause serious adverse events (e.g., hypersensitivity, anaphylaxis, and immunogenicity).

Five-point liquid rhinoplasty: Results from a retrospective analysis of a novel standardized technique and considerations on safety.

BACKGROUND: Nonsurgical aesthetic improvement of the nose with hyaluronic acid (HA) fillers is becoming increasingly popular but comes with important safety considerations. AIMS: To assess the safety and effectiveness of the standardized "five-point liquid rhinoplasty" approach. METHODS: This was a retrospective, single-center analysis of consecutive adult patients undergoing nonsurgical aesthetic treatment of the nose. All had one of the three main indications (insufficient nasal projection, nasal hump, or deep glabella) and were injected using HA fillers with high elastic modulus. Treatments were given using some or all of the injection points of the "five-point liquid rhinoplasty" technique: P1 (nasal tip, 0.2-0.3 ml supracartilaginous); P2 (nasal root, 0.1-0.2 ml supraperiostal); P3 (cartilaginous dorsum, 0.1-0.2 ml supracartilaginous/supraperiostal); P4 (subnasal, 0.1-0.2 ml supraperiostal); and P5 (nasal alar, 0.1-0.2 ml per side supraperiostal). The risk of complications was minimized by injecting deep and staying in the midline as far as possible. RESULTS: Twenty patients were enrolled (n = 15 female [75%]; mean age: 37.8 ± 11.7 years). The mean volume of filler used was 0.66 ± 0.35 ml per patient. Nineteen subjects (95%) said they were "very satisfied" with results, and the physician was also "very satisfied" with outcomes in 19 patients (95%). Two individuals experienced hematoma, which was managed conservatively; there were no other significant complications. CONCLUSIONS: The "five-point liquid rhinoplasty" is a simple and effective method designed to maximize safety. It offers a good alternative to surgery in selected patients.

Cell-Free Blood Cell Secretome (BCS) Counteracts Skin Aging: Multi-Center Prospective Regenerative Aesthetic Medicine Study Using Exokine®.

Background: The "Inflammation Theory of Ageing" identifies pro-inflammatory cytokines and oxidative damage as one cause of cellular and mitochondrial deterioration and aging. Cell-free blood cell secretome (BCS) also known as autologous conditioned serum (ACS) has shown anti-inflammatory and regenerative mode of action in musculoskeletal disorders and radicular compression. Aim: To confirm that BCS can improve signs of skin aging from a previous study in a multi-center setting. Methods: Prospective, one-armed, multi-center interventional therapeutic study. Ninety-five women with skin firmness loss were treated with four intra-dermal injection sessions in both cheeks at 0, 2, 4 and 6 weeks. BCS was processed with Exokine® medical device according to manufacturer's instructions. Primary endpoints were cutometric R0 and R3 at 12 and 24 weeks. GAIS, FACE-QTM, Patient Attractivity Self-Assessment and safety were evaluated. Results: Mean skin firmness (R0) improved significantly from baseline 0.40 mm to 0.38 mm at week 12 and to 0.36 mm at week 24. Mean skin tiring (R3) improved significantly from baseline 0.45 mm to 0.42 mm at week 12 and to 0.40 at week 24. FACE-QTM "Satisfaction with Skin" significantly improved from baseline to weeks 12, 24 and 48. So did "Satisfaction with Facial Appearance" and "Psychological and Social Function". "Satisfaction with Decision" and "Satisfaction with Outcome" were stable at week 24 and 48. At week 48 patients assessed their age 1.68 years younger vs Baseline. FACE-QTM aging appraisal improves from Baseline 52.94 to 65.23 at week 48. GAIS, by both physicians and patients, confirm improvement of skin. Conclusion: For up to 48 weeks four intra-dermal injections with cell-free BCS increase facial skin firmness and resilience to tiring and patients' satisfaction with their facial appearance and skin. Patients perceive their face as younger. BCS has the ability to sustainably rejuvenate facial skin safely. Study Registration: Registration on German clinical trials register: DRKS00013014.

Validated 5 - Point photonumeric scales for the assessment of hand atrophy.

OBJECTIVE: Quantifying the degree of dorsal hand atrophy is a challenging endeavor, but often necessary, in both the clinical and the research setting. The aim of this investigation was to create and consecutively validate a 5-point photonumeric scale for assessment of dorsal hand atrophy. MATERIAL AND METHODS: A medical team created a novel 5-point photonumeric scale. Twelve international raters were involved in the digital validation, while five raters performed a live validation. RESULTS: For the digital validation of the Croma Hand Atrophy Assessment Scale, a total of 72 subjects (58 females, 14 males) with a mean age of 43.0 ± 14.4 years [18-73 years] were assessed. For the live validation, 88 subjects (73 females, 15 males) with a mean age of 45.0 ± 14.1 years [20-73 years] were rated. The results revealed almost perfect intra-rater (ICC: 0.90 [95% CI: 0.88-0.92]) and inter-rater agreements (ICC: 0.85 [95% CI: 0.81-0.89] and 0.86 [95% CI:0.82-0.89]) in the digital validation and substantial intra-rater (ICC: 0.79 [95% CI: 0.75-0.82]) and inter-rater agreements (ICC: 0.75 [95% CI: 0.68-0.81] and ICC: 0.67 [95% CI: 0.54-0.77]) in the live validation. CONCLUSION: The created scale to assess dorsal hand atrophy has been shown to provide substantial-to-almost perfect agreement in the digital and live validation cycles and reached comparable intra-rater and inter-rater agreement to already published and validated scales. It is expected that the created scale will help physicians and researchers in the assessment of hand atrophy in the clinical and research setting in the future.

Validated 5-point photonumeric scales for the assessment of the periorbital region.

OBJECTIVE: The objective of this investigation was to create and validate 5-point photonumeric scales for the assessment of dynamic crow's feet, static crow's feet, and infraorbital hollows. MATERIAL AND METHODS: Three novel 5-point photonumeric scales were created by a medical team. A total of 12 raters from all over the world performed a digital validation, and a total of 5 raters a live validation of the created scale. RESULTS: The statistical analysis revealed almost perfect intra-rater and inter-rater reliability in the digital validation of the scales for the assessment of static and dynamic crow's feet as well as infraorbital hollows. In the live validation, both crow's feet scales showed almost perfect intra-rater reliability, while the Croma Infraorbital Hollow Assessment Scale showed substantial intra-rater reliability. Inter-rater reliability was substantial for all three scales in the live validation. All three scales, the Croma Dynamic Crow's Feet Assessment Scale, Croma Static Crow's Feet Assessment Scale, and Croma Infraorbital Hollow Assessment Scale, were validated digitally and in a live setting. CONCLUSION: The created scales to assess infraorbital hollowing, dynamic and static crow's feet have been shown to provide substantial to almost perfect agreement in the digital and live validation and can thus be considered as helpful tools in the clinical and research setting. While technical methods and appliances to assess the degrees of severity of age-dependent features are advancing, validated scales are of great importance due to their ease of use and, as shown by the validations, reliability, and reproducibility.

Validated 5-point photonumeric scales for the assessment of the jowls and chin.

OBJECTIVE: The objective of this investigation was to create and to examine the reproducibility and validity of 5-point photonumeric assessment scales that allow objective assessment of chin retrusion and jawline sagging using a digital and a live validation. MATERIAL AND METHODS: Two new 5-point photonumeric scales created to assess chin projection and jawline sagging were validated by 12 experts in a digital validation and by 5 experts in a live validation setting. Intra-rater agreement and inter-rater agreement were assessed. RESULTS: For the digital validation, an almost perfect intra-rater (Kappa: 0.89 [95% CI: 0.86-0.91]) and almost perfect inter-rater agreement in both sessions (Kappa: 0.80 [95% CI: 0.74-0.86] and 0.80 [95% CI: 0.74-0.86]) was achieved for the Croma Chin Projection Assessment Scale, while intra-rater agreement (Kappa: 0.88 [95% CI: 0.85-0.91]) was almost perfect for the Croma Jawline Sagging Assessment Scale and inter-rater agreement being substantial in the first session (Kappa: 0.76 [95% CI: 0.71-0.81]) and almost perfect in the second session (Kappa: 0.81 [95%CI: 0.76-0.85]). For the live validation, intra-rater agreement was almost perfect for the Croma Chin Projection Assessment Scale (Kappa: 0.82 [95%CI: 0.74-0.90]) and the Croma Jawline Sagging Assessment Scale (Kappa: 0.83 [95%CI: 0.77-0.89]), while inter-rater agreement was substantial in both sessions for both scales. CONCLUSION: The created chin and jawline photonumeric grading scales are valid and reliable tools for assessing chin projection and jawline sagging. The scales will be of value for standardized chin evaluation and quantifying outcomes in clinical research and daily practice.

Consensus on the Use of Hyaluronic Acid Fillers from the Cohesive Polydensified Matrix Range: Best Practice in Specific Facial Indications.

BACKGROUND: As the treatment indications for the Cohesive Polydensified Matrix® hyaluronic acid (CPM-HA) portfolio continue to expand and diversify, injectors new to the range or those who are expanding the treatments they offer may be unsure of the optimal product and injection technique for specific facial areas. Each product in the CPM-HA portfolio has been intentionally designed to provide the best physical properties for a specific indication and target tissue. This document has been developed to provide a comprehensive, one-stop reference for clinicians using the portfolio. METHODS: An international panel of experts in the field of aesthetic medicine convened to develop guidelines on effective and safe injection technique when performing treatments with the CPM-HA range of soft-tissue fillers. RESULTS: Consensus members considered treatment indications in the upper, middle and lower face. Landmark deficiencies and anatomical considerations are described for each indication and consensus recommendations provided on the optimal product, injection depth and treatment technique. This is supplemented by the experts advice on avoidance of complications. Throughout, an evidence-based approach to selection of products and injection techniques is provided. The result is a fully tailored approach to a range of indications covering the full portfolio of CPM-HA products, including the newest addition for skin revitalization. CONCLUSION: The recommendations in this consensus document are provided to assist clinicians in the selection of CPM-HA products, administration techniques and depths of injection with the aim of providing seamless and natural treatment results, enhanced safety and patient satisfaction.

Global Recommendations on COVID-19 Vaccines and Soft Tissue Filler Reactions: A Survey-Based Investigation in Cooperation With the International Society for Dermatologic and Aesthetic Surgery (ISDS).

BACKGROUND: Recent reports have surfaced from the United States Food and Drug Administration hearings in December 2020 regarding the COVID-19 vaccines and study participants who developed facial and/or lip swelling after receiving the newly developed drug. Despite an incidence rate of 0.02% in the vaccine arm of the Moderna mRNA-1273 trial, concerns have been expressed about the association of adverse reactions following soft tissue filler injections and the COVID-19 vaccines. The International Society for Dermatologic and Aesthetic Surgery (ISDS) understands these concerns and has designed the following study. METHODS: A global survey was designed to capture the incidence of adverse events related to: (1) previous soft tissue filler injections, (2) soft tissue filler injections during positive testing for COVID-19, and (3) soft tissue filler injections during and after receiving any of the COVID-19 vaccines globally available. RESULTS: The information of 106 survey participants from 18 different countries was analyzed. 80.2% (n=85) never experienced any adverse reaction following their soft tissue filler injection whereas 15.1% (n=16) experienced swelling and 4.7% (n=5) experienced pain that lasted longer than two days. Of those who received at least one dose of the COVID-19 vaccine (n=78), 94.9% reported not to have experienced any adverse reaction related to their previous soft tissue filler injection, whereas 5.1% (n=4) reported to have perceived pain that lasted longer than two days. CONCLUSION: The data collected does not support the concern for an increased risk of developing adverse reactions following soft tissue filler injections associated with the COVID-19 vaccines compared to that risk associated with other previously described triggers or the default risk following soft tissue filler injections. J Drugs Dermatol. 20(4):374-378. doi:10.36849/JDD.2021.6041.

Facial Skin Revitalization with Cohesive Polydensified Matrix-HA20G: Results from a Randomized Multicenter Clinical Study.

BACKGROUND: There is a growing interest in the application of hyaluronic acid (HA) derivatives in skin quality improvement. The aim of this study was to confirm safety and effectiveness of cohesive polydensified matrix-hyaluronic acid + glycerol (CPM-HA20G; Belotero Revive) in revitalization of early-onset photodamaged facial skin. METHODS: A total of 159 subjects with early signs of facial photodamaged skin were randomized in a 2:1 ratio to multiple- or single-dose treatment with CPMHA20G. Effectiveness assessments included biophysical measurements of skin hydration; elasticity, firmness, and roughness; investigator- and subject-assessed Global Aesthetic Improvement Scales; and FACE-Q Skin Changes and Treatment Satisfaction questionnaires. RESULTS: In both treatment groups, skin hydration improved from baseline to all follow-up visits in subjects with dry or very dry skin. This improvement was significant at week 16 after initial treatment in the multiple-dose group (P = 0.0013). Investigator- and subject-reported outcomes showed that the majority of subjects across all skin hydration types benefited from treatment, with higher satisfaction rates observed in the multiple-dose group. According to investigator-assessed Global Aesthetic Improvement Scale, 90.7% of subjects at week 12 in the multiple-dose and 74.6% of subjects at week 4 in the single-dose group were rated as at least "improved." All related treatment-emergent adverse events were transient, expected injection-site reactions of mild to moderate intensity. CONCLUSIONS: Effectiveness of CPM-HA20G for skin hydration in subjects with dry or very dry skin was demonstrated up to 9 months after last injection. Overall, CPM-HA20G demonstrated effective and safe use in facial skin revitalization among subjects with early-onset photodamaged skin.

Recommendations for Dermatology Office Reopening in the Era of COVID-19.

The COVID-19 pandemic, originating in Wuhan, China, has become a major public health and economic challenge for countries around the world. As of May 08, 2020, there are over 3 million COVID-19 cases, and 250,000 COVID-19- associated deaths in 215 countries. As more data is collected, updated infection control measures are continuously released and published by government, public health authorities, and physician specialty associations. Across the globe, dermatological practices have had to limit their operations to varying degrees to facilitate disease control, but as the pandemic subsides, they will broaden their operations. In light of the uncertainty surrounding safe and effective practice of medical and aesthetic dermatology in the era of COVID-19, fourteen international experts in the field contributed to recommendations for effective infection control protocols and practice management modifications. While guidance from the World Health Organization and local public health officials comes first, these recommendations are crafted as a starting point for dermatologists worldwide to commence either reopening their doors to patients or expanding available service offerings. This can help ensure that patients receive needed care in the short term and improve long term practice viability. J Drugs Dermatol. 2020;19(7):e-1-e-9. doi:10.36849/JDD.2020.5293.

Delayed Inflammatory Reactions to Hyaluronic Acid Fillers: A Literature Review and Proposed Treatment Algorithm.

BACKGROUND AND OBJECTIVES: There is a wide diversity of opinions regarding the management of delayed inflammatory reactions (DIRs) secondary to hyaluronic acid (HA)-based fillers. The plethora of approaches has led the authors to conduct a review regarding management and treatment of DIRs as well as establish therapeutic guidelines for this purpose. MATERIALS AND METHODS: A review of the literature was performed through databases such as PubMed using keywords including HA-fillers and complications, delayed HA filler sequelae and therapy, soft tissue and dermal filler reactions and management. Additionally, a survey comprised of questions regarding the management and treatment of DIRs was sent to 18 physicians highly experienced with soft-tissue filler injections in 10 countries. Their answers and recommendations were analyzed and debated amongst these panelists. RESULTS: Sixteen panelists favored antibiotic therapy as first-line treatment for DIRs, specifically dual antibiotic therapy consisting of a fluoroquinolone along with a tetracycline or macrolide for a period of 3-6 weeks. The majority refrained from the use of intralesional (IL) or systemic steroids except in the case of disfiguring or recalcitrant reactions. IL hyaluronidase was recommended by 13 panelists; however, some preferred a watchful waiting approach for a period of 48 hours to 2 weeks prior to IL hyaluronidase, and in cases where antibiotics did not lead to improvement. CONCLUSION: A consensus was reached and summarized to propose a clear, easy-to-follow, stepwise algorithm for the treatment of DIRs.

The Bidirectional Movement of the Frontalis Muscle: Introducing the Line of Convergence and Its Potential Clinical Relevance.

BACKGROUND: Cosmetic treatment of the forehead using neuromodulators is challenging. To avoid adverse events, the underlying anatomy has to be understood and thoughtfully targeted. Clinical observations indicate that eyebrow ptosis can be avoided if neuromodulators are injected in the upper forehead, despite the frontalis muscle being the primary elevator. METHODS: Twenty-seven healthy volunteers (11 men and 16 women) with a mean age of 37.5 ± 13.7 years (range, 22 to 73 years) and of diverse ethnicity (14 Caucasians, four African Americans, three Asians, and six of Middle Eastern descent) were enrolled. Skin displacement vector analyses were conducted on maximal frontalis muscle contraction to calculate magnitude and direction of forehead skin movement. RESULTS: In 100 percent of investigated volunteers, a bidirectional movement of the forehead skin was observed: the skin of the lower forehead moved cranially, whereas the skin of the upper forehead moved caudally. Both movements converged at a horizontal forehead line termed the line of convergence, or C-line. The position of the C-line relative to the total height of the forehead was 60.9 ± 10.2 percent in men and 60.6 ± 9.6 percent in women (p = 0.941). Independent of sex, the C-line was located at the second horizontal forehead line when counting from superior to inferior (men, n = 2; women, n = 2). No difference across ethnicities was detected. CONCLUSIONS: The identification of the C-line may potentially guide practitioners toward more predictable outcomes for forehead neuromodulator injections. Injections above the C-line could mitigate the risk of neuromodulator-induced brow ptosis.

Prevention of Progression of Lipedema With Liposuction Using Tumescent Local Anesthesia: Results of an International Consensus Conference.

BACKGROUND: Lipedema is a chronic, progressive disorder of subcutaneous adipose tissue that usually affects the lower extremities of women. Also known as "two-body syndrome," the fat accumulations in lipedema are unsightly and painful. The disorder is well-known in Europe but is largely unrecognized and underdiagnosed in the United States. OBJECTIVE: To hold the First International Consensus Conference on Lipedema with the purpose of reviewing current European guidelines and the literature regarding the long-term benefits that have been reported to occur after lymph-sparing liposuction for lipedema using tumescent local anesthesia. METHODS: International experts on liposuction for lipedema were convened as part of the First International Congress on Lipedema in Vienna, Austria, June 9 to 10, 2017. RESULTS: Multiple studies from Germany have reported long-term benefits for as long as 8 years after liposuction for lipedema using tumescent local anesthesia. CONCLUSION: Lymph-sparing liposuction using tumescent local anesthesia is currently the only effective treatment for lipedema.

Treating the Lips and Its Anatomical Correlate in Respect to Vascular Compromise.

Treating the lips to increase facial attractiveness and youthfulness is challenging when trying to consider ethnic differences in an increasingly more diverse society. Multiple injection techniques are currently available for treating lip contour and volume, but a validation in the cadaveric model under the aspects of safety has not been performed yet. The injection techniques presented in this study are based on the experience and personal selection of the authors. The authors have assessed, treated, and evaluated for more than 20 years patients from the Middle East and Central Europe. Cadaveric verification was performed for each of the presented techniques to identify the positioning of the injected product inside the lips and its relation to the superior/inferior labial arteries. The results of the anatomic analyses revealed that in 58.3% of the performed injections, the product was placed close to the superior/inferior labial arteries. In 60.0% of the cases, applications using a needle placed the injected product in endangered locations, whereas 57.1% of the cases using cannulas placed the product in endangered locations (i.e., in the vicinity of the superior/inferior labial arteries). This anatomic study revealed that injected material into the lips is frequently placed in close proximity to labial arteries representing a high risk for intra-arterial applications, leading to tissue loss (necrosis) and potential end-arterial embolism (potential blindness). Nevertheless, treatment of the lips should be a multistep approach focusing first on the far (upper and middle face) and close (labiomandibular and labiomental) perioral regions.

Consensus Recommendations for Combined Aesthetic Interventions Using Botulinum Toxin, Fillers, and Microfocused Ultrasound in the Neck, Décolletage, Hands, and Other Areas of the Body.

BACKGROUND: The popularity of aesthetic procedures in the face has led to greater disparity between treated areas and those that still show evidence of true age. Although many areas of the body often require multiple treatment procedures for optimal rejuvenation, combination therapy for specific areas is not yet well defined. OBJECTIVE: To develop recommendations for the optimal combination and ideal sequence of botulinum toxin (BoNT), hyaluronic acid, calcium hydroxylapatite (CaHA), and microfocused ultrasound with visualization in nonfacial areas across all skin phototypes. METHODS: Fifteen specialists convened under the guidance of a certified moderator. Consensus was defined as approval from 75% to 94% of all participants, whereas agreement of ≥95% denoted a strong consensus. RESULTS: Recommendations have been provided for the neck, décolletage, and hands and include the timing and sequence of specific procedures when used concurrently or over several treatment sessions. Position statements are offered in lieu of consensus for the upper arms, abdomen, buttocks, and knees. CONCLUSION: Nonfacial rejuvenation often requires multiple procedures for optimal results in individuals with significant age-related changes. Further clinical studies are recommended to raise awareness of non-facial indications and provide clinicians with the best evidence for best treatment practices.

Consensus Recommendations for Combined Aesthetic Interventions in the Face Using Botulinum Toxin, Fillers, and Energy-Based Devices.

BACKGROUND: The aging process is a complex interplay of intrinsic and extrinsic factors across multiple layers of the face. Accordingly, combining aesthetic interventions targeting different manifestations of aging often leads to better results than single modalities alone. However, no guidelines for a pan-facial approach using multiple interventions have been published to date. OBJECTIVE: To develop consensus recommendations for the optimal combination and ideal sequence of botulinum toxin (BoNT), hyaluronic acid, calcium hydroxylapatite, and microfocused ultrasound with visualization (MFU-V) in persons of all Fitzpatrick skin types. METHODS AND MATERIALS: Fifteen specialists convened under the guidance of a certified moderator. Consensus was defined as approval from 75% to 94% of all participants, whereas agreement of ≥95% denoted a strong consensus. RESULTS: Optimal aesthetic treatment of the face begins with a thorough patient assessment and an individualized treatment plan. Spacing consecutive treatments 1 to 2 weeks apart allows for resolution of side effects and/or to assess results. For same-day treatments, BoNT and fillers may be performed together in either sequence, whereas MFU-V is recommended before injectable agents. CONCLUSION: Expert consensus supports a combination approach using multiple modalities in specific sequence for the safe and effective treatment of the aging face.