A morphological analysis of calcium hydroxylapatite and poly-l-lactic acid biostimulator particles.

Injectable fillers, pivotal in aesthetic medicine, have evolved significantly with recent trends favoring biostimulators like calcium hydroxylapatite (CaHA-CMC; Radiesse, Merz Aesthetics, Raleigh, NC) and poly-l-lactic acid (PLLA; Sculptra Aesthetics, Galderma, Dallas, TX). This study aims to compare the particle morphology of these two injectables and examine its potential clinical implications. Utilizing advanced light and scanning electron microscopy techniques, the physical characteristics of CaHA-CMC and PLLA particles were analyzed, including shape, size, circularity, roundness, aspect ratio, and quantity of phagocytosable particles. The findings reveal several morphological contrasts: CaHA-CMC particles exhibited a smooth, homogenous, spherical morphology with diameters predominantly ranging between 20 and 45 µm, while PLLA particles varied considerably in shape and size, appearing as micro flakes ranging from 2 to 150 µm in major axis length. The circularity and roundness of CaHA-CMC particles were significantly higher compared to PLLA, indicating a more uniform shape. Aspect ratio analysis further underscored these differences, with CaHA-CMC particles showing a closer resemblance to circles, unlike the more oblong PLLA particles. Quantification of the phagocytosable content of both injectables revealed a higher percentage of phagocytosable particles in PLLA. These morphological distinctions may influence the tissue response to each treatment. CaHA-CMC's uniform, spherical particles may result in reduced inflammatory cell recruitment, whereas PLLA's heterogeneous particle morphology may evoke a more pronounced inflammatory response.

The Role of Calcium Hydroxylapatite (Radiesse) as a Regenerative Aesthetic Treatment: A Narrative Review.

For decades, a wide variety of natural and synthetic materials have been used to augment human tissue to improve aesthetic outcomes. Dermal fillers are some of the most widely used aesthetic treatments throughout the body. Initially, the primary function of dermal fillers was to restore depleted volume. As biomaterial research has advanced, however, a variety of biostimulatory fillers have become staples in aesthetic medicine. Such fillers often contain a carrying vehicle and a biostimulatory material that induces de novo synthesis of major structural components of the extracellular matrix. One such filler, Radiesse (Merz Aesthetics, Raleigh, NC), is composed of calcium hydroxylapatite microspheres suspended in a carboxymethylcellulose gel. In addition to immediate volumization, Radiesse treatment results in increases of collagen, elastin, vasculature, proteoglycans, and fibroblast populations via a cell-biomaterial-mediated interaction. When injected, Radiesse acts as a cell scaffold and clinically manifests as immediate restoration of depleted volume, improvements in skin quality and appearance, and regeneration of endogenous extracellular matrices. This narrative review contextualizes Radiesse as a regenerative aesthetic treatment, summarizes its unique use cases, reviews its rheological, material, and regenerative properties, and hypothesizes future combination treatments in the age of regenerative aesthetics.

Cellulite Pathophysiology and Psychosocial Implications.

BACKGROUND: Cellulite is a highly prevalent aesthetic condition in postpubertal women. OBJECTIVE: The objective of this article was to describe the latest data on the pathophysiology of cellulite and to highlight the psychosocial aspects that should be considered when treating cellulite. METHODS: A roundtable meeting was convened to discuss and share views on the latest data on the pathophysiology and psychosocial aspects of cellulite. The participants' experience helped guide a narrative review on this topic. RESULTS: The pathophysiology of cellulite primarily involves fibrous septal changes. Strategies targeting the fibrous septa have shown the most consistent efficacy, while showing inconsistent or short-term results when targeting the other components of cellulite, such as decreased dermal thickness, vascular alterations, and inflammation. Female sex, increased age, and high body mass index contribute to cellulite pathophysiology. CONCLUSION: Patients seeking treatment for cellulite are willing to endure numerous treatments, high cost, temporary and/or delayed results, and invasive procedures with potential adverse effects. Psychological discomfort has been reported among patients with cellulite, and understanding their behaviors and psychological characteristics can help clinicians provide better care to these patients seeking treatment.

Cellulite: Clinical Challenges and Future Perspectives.

BACKGROUND: Existing cellulite interventions pose various clinical challenges related mostly to ecchymosis and recovery time. OBJECTIVE: To discuss the current treatment options for minimizing recovery time, efficacy of these options, and investigations into possible future approaches. METHODS: A roundtable meeting was convened to discuss and share views on the clinical challenges seen in the present practice of cellulite treatments along with future approaches and mitigation strategies. The participants' views helped guide a narrative review on this topic. RESULTS: Cosmetic clinicians have a range of new interventions to choose from for cellulite improvement, each with different benefits and safety aspects. Bruising is a typical side effect that is seen with treatments targeting the fibrous septa, such as subcision and injectable treatments, and in some cases may produce long-lasting hyperpigmentation from postinflammatory hyperpigmentation or hemosiderin staining. Various strategies that could potentially mitigate bruising and other adverse effects of cellulite treatment are under clinical investigation, including, but not limited to, different injection techniques and dilutions, compression garments, cold packs, arnica gel, pulsed dye laser treatment, intralesional epinephrine, and tranexamic acid. CONCLUSION: Clinical challenges including varying treatment outcomes and certain treatment sequelae remain, and further research is needed to prevent side effects and improve treatment outcomes.

A Novel 3-Point Injection Technique for OnabotulinumtoxinA in the Upper Depressor Anguli Oris.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA (ONA) injections to the depressor anguli oris (DAO) to improve downturned mouth. PATIENTS AND METHODS/MATERIALS: This prospective, placebo-controlled, study enrolled subjects aged 18 to 65 years. Injections were performed using a novel 3-point technique in the upper DAO (1.5 U/injection site). The primary end point was a DAO contraction scale 1-grade improvement. Subjective evaluation was performed using the Global Aesthetic Improvement Scale (GAIS). RESULTS: Ten subjects received ONA and 10 placebo (saline) injections. In ONA-treated subjects, DAO scores showed significant improvements at Weeks 4 and 12 ( p < .001) compared with baseline. No significant difference between visits was observed for placebo-injected subjects. Global Aesthetic Improvement Scale scores showed that 100% of subjects were improved compared with baseline at Week 4% and 90% at Week 12. By contrast, 90% and 80% of placebo-treated subjects had "no change" in their DAO appearance at Weeks 4 and 12. Subject GAIS assessments matched the live evaluator at Week 4; 60% continued to report improvement at Week 12. Treatment was well tolerated. CONCLUSION: OnabotulinumtoxinA injections to the DAO using a 3-point technique provide clinically meaningful improvements in appearance. Treatment was well tolerated and in most individuals lasted at least 12 weeks. IDENTIFIER: ClinicalTrials.gov NCT04240535.

Spectrum of diseases associated with pyoderma gangrenosum and correlation with effectiveness of therapy: New insights on the diagnosis and therapy of comorbid hidradenitis suppurativa.

Pyoderma gangrenosum (PG) has been linked to various underlying systemic diseases; many associations are based on case reports or small case series, including hidradenitis suppurativa. Literature examining systemic therapies according to underlying comorbid condition is limited. The study objective was to investigate comorbid diseases of PG and correlate disease associations with effectiveness of therapeutic interventions. Using Johns Hopkins Medical Institutions medical records, 220 patients had an ICD-9 code of 686.01 for PG between 1 January 2006 and 30 June 2015, of whom 130 patients met rigorous inclusion/exclusion criteria for PG (non-peristomal). The 130 PG patients in our study were 69% female, 58% Caucasian, and 35% African American. Documented comorbid conditions included inflammatory bowel disease (IBD; 35%), rheumatoid arthritis (RA; 12%), hidradenitis suppurativa (HS; 14%), and monoclonal gammopathy (12%). PG patients with HS versus without HS were more likely to be African-American (83% vs. 28%; P < 0.001) and had an earlier mean age of PG onset (38 vs. 48 years; P = 0.02). Strikingly, 53% of female African-American patients with PG onset prior to age 40 had comorbid HS. Comorbid inflammatory bowel disease was observed in 38% of PG patients with RA, 28% of PG patients with HS, and 27% of PG patients with monoclonal gammopathy. Of the 32 patients who received infliximab for active PG, complete ulcer healing was observed in 83% (5/6) of patients with comorbid HS versus 31% (8/26) of patients without HS (Fisher exact P = 0.03). Screening patients for associated systemic disease for multiple related illnesses is essential. Effectiveness of systemic therapy may depend upon the underlying systemic disease; hidradenitis suppurativa may be a specific example.

Causes of Injury and Litigation in Cutaneous Laser Surgery: An Update From 2012 to 2020.

OBJECTIVE: To identify common causes of injury and liability claims related to cutaneous laser surgery from 2012 to 2020. MATERIALS AND METHODS: Search of online national legal database of public legal documents regarding cutaneous laser surgery litigation. RESULTS: From 2012 to 2020, 69 cases of liability claims due to a cutaneous laser surgery device were identified. Of these, 49 (71%) involved a nonphysician operator (NPO); 12 incidents (17%) involved non-core physician operators performing the procedure; 6 cases (9%) involved a plastic surgeon operator; and 2 cases (3%) involved a dermatologist operator. Laser hair removal was most litigated (44 cases, 64%), followed by laser skin rejuvenation (20 cases, 30%). Thirty-six of 69 cases had a discernible outcome, 53% (n = 19) rendered judgements in favor of the plaintiff, with a mean indemnity payment of $320,975 (range, $1,665-$1.5 million). CONCLUSION: Previous work evaluating trends in laser surgery litigation from 1985 to 2012 identified increasing injury and legal action when performed by NPOs. Data from this study are consistent with these previous findings. Both studies demonstrate that NPOs account for most cases of legal action with an increasing proportion of cases being performed by NPOs. In this study, unsupervised NPOs comprise nearly three-quarters of laser surgery lawsuits, but the data may underestimate the frequency of injury and litigation caused by unsupervised NPOs.

Mass migration and climate change: Dermatologic manifestations.

Major changes in climate resulting in mass migrations have unique dermatologic implications for global vulnerable populations. Dermatologic manifestations commonly accompany the infectious and communicable diseases that proliferate in the settings of confinement, crowding, and limited sanitation associated with mass migration. Ectoparasitic infestations abound in refugee camps, and poor nutrition, hygiene, and compromised immunity put refugees at an increased risk for more dangerous infectious diseases carried by these ectoparasites. Climate change also profoundly affects the worldwide distribution of various vector-borne illnesses, thereby leading to the emergence of various communicable diseases in previously nonendemic areas. Natural disasters not only disrupt important lifesaving treatments, but also challenge various infectious disease control measures that are critical in preventing rapid transmission of highly infectious diseases. This article reviews the infectious diseases commonly found in these scenarios and provides an in-depth discussion of important implications for the dermatologist.

A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts.

Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.

Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

IMPORTANCE: Extramammary Paget disease (EMPD), a rare intraepithelial adenocarcinoma, poses a therapeutic challenge with high postoperative recurrence rates and a limited number of effective local treatment options. OBJECTIVE: To describe the use and efficacy of a topical combination of fluorouracil and calcipotriene as a palliative therapy for refractory EMPD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series of 3 women with recurrent, refractory EMPD was conducted at Beth Israel Deaconess Medical Center, Boston, Massachusetts and Washington University School of Medicine, St Louis, Missouri. All patients were treated with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream or ointment. MAIN OUTCOMES AND MEASURES: Clinical and histopathological findings. RESULTS: All 3 women (1 in her 50s, 2 in their 70s) presented with recurrent EMPD (vulvar, perianal, and perioral) after surgery and/or irradiation, and their EMPD was refractory to treatment with imiquimod, 5%, cream. Owing to disease progression and/or intolerable adverse effects from imiquimod, the patients began treatment with a 1:1 mixture of fluorouracil, 5%, cream and calcipotriene, 0.005%, cream. This treatment, which was well tolerated, was followed by clinical improvement in symptoms and appearance of the lesions in all 3 cases and histopathological signs of decreased tumor burden in 2 cases. Patients applied the combination topical therapy to affected areas with differing frequencies, ranging from 1 to 2 days per month to 4 consecutive days every 2 weeks. CONCLUSIONS AND RELEVANCE: Extramammary Paget disease frequently recurs even after aggressive surgical management and can be refractory to many topical and locoregional therapies. Palliative treatment with a combination of fluorouracil and calcipotriene may be a viable option for patients with recurrent, refractory EMPD.

A 30-Year-Old Man with HIV, Fever, and a Rash.

Patients who present with papular rashes have a wide differential diagnosis particularly in the setting of immune compromise. A 30-year-old male diagnosed with HIV since 2009, never on antiretroviral therapy, with a nadir CD4 count of 333 cells/mm3 and a current viral load of 44,300 copies/mL, presented with a diffuse monomorphic papular eruption that began on his trunk and extremities and subsequently spread to the penis and scrotum, sparing the distal acral sites. A thorough infectious workup revealed a positive rapid plasma reagin (RPR) and varicella IgM and IgG antibodies. Interestingly, the patient had been diagnosed and treated for syphilis in the past with a recent downtrending RPR drawn prior to hospitalization. Repeat RPR was elevated and a preliminary histopathology report demonstrated folliculocentric inflammation with lymphocytes, plasma cells, and polymorphonuclear leukocyte predominance supported the diagnosis of syphilis. After receiving intramuscular penicillin G benzathine, he developed intermittent fevers and new papules. Intravenous (IV) acyclovir was initiated for presumed disseminated varicella given his positive varicella-zoster virus IgM and IgG. However, final pathology results revealed a large spirochete burden. The fevers and rash progression were attributed to the development of a Jarisch-Herxheimer reaction. IV acyclovir was discontinued and he completed a course of intramuscular penicillin G benzathine. He was also given a course of doxycycline for rectal chlamydia which was diagnosed during hospitalization.

A 92-Year-Old Male with Eosinophilic Asthma Presenting with Recurrent Palpable Purpuric Plaques.

Churg-Strauss syndrome or eosinophilic granulomatosis with polyangiitis is a systemic vasculitis affecting the small and medium-sized vasculature. It is commonly associated with asthma and eosinophilia. Most patients are diagnosed at around the age of 40. We report a case of biopsy-confirmed Churg-Strauss syndrome in a 92-year-old male with a history of eosinophilic asthma and peripheral eosinophilia who was later diagnosed with Churg-Strauss syndrome.

Exploring cell-based tolerance strategies for hand and face transplantation.

Broader clinical application of reconstructive hand and face transplantation is hindered by the need for lifelong immunosuppression for allograft maintenance. In this review, we summarize various cell-based approaches to tolerance induction currently under investigation in both clinical and pre-clinical models to alleviate the need for chronic immunosuppression. These include strategies to induce mixed hematopoietic chimerism, therapy with T and B regulatory cells, regulatory macrophages, tolerogenic dendritic cells, and mesenchymal stem cells. The vascularized, intragraft bone components inherent to reconstructive transplants serve as a continuous source of donor-derived hematopoietic cells, and make hand and face transplants uniquely well suited for cell-based approaches to tolerance that may ultimately tilt the risk-benefit balance for these life-changing, but not life-saving, procedures.

Classification of mandible defects and algorithm for microvascular reconstruction.

BACKGROUND: Composite mandibular tissue loss results in significant functional impairment and cosmetic deformity. This study classifies patterns of mandibular composite tissue loss and describes a microvascular treatment algorithm. METHODS: A retrospective review of microvascular composite mandibular reconstruction from July of 2005 to April of 2013 by the senior surgeon at the R Adams Cowley Shock Trauma Center and at The Johns Hopkins Hospital yielded 24 patients with a mean follow-up of 17.9 months. Causes of composite mandibular defects included tumors, osteoradionecrosis, trauma, infection, and congenital deformity. Patients with composite tissue loss were classified according to missing subunits. RESULTS: A treatment algorithm based on composite mandibular defects and microvascular reconstruction was developed and used to treat 24 patients. A type 1 defect is a unilateral dentoalveolar defect not crossing the midline and not extending into the angle of the mandible. A type 2 defect is a unilateral defect extending beyond the angle. A type 3 defect is a bilateral defect not involving the angles. A type 4 defect is a bilateral defect with extension into at least one angle. Type 2 defects were the predominant group. Patients had microvascular reconstruction using either fibula flaps (n = 19) or iliac crest flaps (n = 5). Complications included infection, partial necrosis, plate fracture, dehiscence, and microvascular thrombosis. CONCLUSION: This novel classification system and treatment algorithm allows for a consistent and reliable method of addressing composite mandibular defects and focuses on recipient vasculature and donor free flap characteristics.

Stem cell-based approaches to improve nerve regeneration: potential implications for reconstructive transplantation?

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across "gaps" in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.

Smoking is not associated with severe dysplasia or invasive carcinoma in resected intraductal papillary mucinous neoplasms.

INTRODUCTION: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are precursor lesions that progress to invasive cancer through progressively worsening dysplasia. Although smoking is an established risk factor for pancreatic adenocarcinoma, potential associations with IPMN grade of dysplasia remain unclear. METHODS: Pancreatic resections for IPMN from 1995 to 2013 were retrospectively reviewed. A total of 446 patients in which the smoking status was documented were identified. RESULTS: Smoking history was positive in 47% of patients. Of smokers, 50% had branch-duct, 14% had main-duct, and 36% had mixed-type IPMN. Patients with main-duct IPMN were more commonly smokers (65%), compared to smoking history in 46% with mixed and 44% with branch-duct IPMN (p = 0.03). High-grade dysplasia occurred in 25% of smokers and 21% of nonsmokers (p = 0.32), and invasive carcinoma in 25% of smokers and 25% nonsmokers (p = 0.95). On multivariate analysis, duct size was independently associated with high-grade dysplasia (OR = 3.17, 95% CI = 1.79-5.64, p < 0.001). Presence of mural nodules (OR = 3.34, 95% CI = 1.82-6.12, p < 0.001), duct size (OR = 3.87, 95% CI = 2.21-6.75, p < 0.001), and symptoms (OR = 7.10, 95% CI = 3.80-13.08, p < 0.001), but not smoking history (OR = 1.10, 95% CI = 0.64-1.88, p = 0.73), were independent predictors of invasive carcinoma. Median overall survival was 70 months for smokers and 88 months for nonsmokers (p = 0.68). CONCLUSION: Positive smoking history correlated with duct type classification but does not appear to be a risk factor for harboring high-grade dysplasia or invasive carcinoma in IPMNs.

Taming inflammation by targeting cytokine signaling: new perspectives in the induction of transplantation tolerance.

Transplantation tolerance remains an elusive goal, partly due to limitations in our understanding of the interplay between inflammatory mediators and their role in the activation and regulation of T lymphocytes. Although multiple mechanisms acting both centrally and peripherally are responsible for tolerance induction, the signaling pathways leading to activation or regulation of adaptive immunity are often complex, branched, redundant and modulated by the microenvironment's inflammatory milieu. Accumulating evidence clearly indicates that inflammatory cytokines limit the tolerogenic potential of immunomodulatory protocols by supporting priming of the immune system and counteracting regulatory mechanisms, ultimately promoting rejection. In this review, we summarize recent progress in the development of novel therapeutics to manipulate this inflammatory environment and achievements in targeted inhibition of inflammatory cytokine signaling. Ultimately, robust transplant tolerance induction will probably require a multifaceted, holistic approach that integrates the various mechanisms of tolerance induction, incorporates the dynamic alterations in costimulatory requirements of alloreactive T cells, while maintaining endogenous mechanisms of immune regulation.

Facial transplantation: the first 9 years.

Since the first facial transplantation in 2005, 28 have been done worldwide with encouraging immunological, functional, psychological, and aesthetic outcomes. Unlike solid organ transplantation, which is potentially life-saving, facial transplantation is life-changing. This difference has generated ethical concerns about the exposure of otherwise young and healthy individuals to the sequelae of lifelong, high-dose, multidrug immunosuppression. Nevertheless, advances in immunomodulatory and immunosuppressive protocols, microsurgical techniques, and computer-aided surgical planning have enabled broader clinical application of this procedure to patients. Although episodes of acute skin rejection continue to pose a serious threat to face transplant recipients, all cases have been controlled with conventional immunosuppressive regimens, and no cases of chronic rejection have been reported.