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Sara Moradi Tuchayi,1 Ying Wang,1 Isaac J Pence,1 Alex Fast,1 Anat Stemmer-Rachamimov,2 Conor L Evans,1 R Rox Anderson,1 Lilit Garibyan1 1Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA, USA; 2Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA, USACorrespondence: Lilit Garibyan, Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street-Thier 2, Boston, MA, 02114, USA, Tel +1 617-726-2005, Email lgaribyan@mgh.harvard.eduBackground: Cryoneurolysis uses tissue cooling as an opioid-sparing, long-lasting treatment for peripheral nerve pain. A nerve-selective method for cryoneurolysis by local injection of ice-slurry was developed to allow cryoneurolysis to be performed with a standard needle and syringe, similar to peripheral nerve blocks. Since the treatment of patients with chronic pain may require repeated injections, we investigated the safety and tolerance of repeated treatments in a rat model.Methods: Three repeated ice-slurry treatments, given 6 weeks apart were performed around the rat sciatic nerve. Nerve and surrounding tissues were collected up to 4 months after the third treatment for analysis. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths and axon structure. Immunofluorescence (IF) staining was used to study effects on axon density. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on sciatic nerve and surrounding tissue.Results: Histologic and CARS image analysis of nerve tissue collected months after three injections demonstrated recovery of nerve structure, myelin organization and axon density to baseline levels, without any residual inflammation, scarring or neuroma formation. No inflammation or scarring was detected in surrounding skin and muscle tissues.Conclusion: Repeated ice-slurry injections cause temporary, nerve-selective and reversible changes in the peripheral nerve. There was no histologic damage to surrounding skin and muscle tissues. Repeated treatments with injectable ice-slurry for cryoneurolysis appear to be safe and well tolerated. Clinical studies for patients with chronic pain are warranted.Keywords: pain treatment, slurry, cooling, multiple treatments

Competing Interests: DISCLOSURES.: Mass General Hospital (MGH), employer of Dr. Garibyan, holds the trademark for “Magic Wand Initiative.”

Background: People with Neurofibromatosis Type 1 (NF1) suffer disfigurement and pain when hundreds to thousands of cutaneous neurofibromas (cNFs) appear and grow throughout life. Surgical removal of cNFs under anesthesia is the only standard therapy, leaving surgical scars., Objective: Effective, minimally-invasive, safe, rapid, tolerable treatment(s) of small cNFs that may prevent tumor progression., Methods: Safety, tolerability, and efficacy of 4 different treatments were compared in 309, 2-4 mm cNFs across 19 adults with Fitzpatrick skin types (FST) I-IV: radiofrequency (RF) needle coagulation, 755 nm alexandrite laser with suction, 980 nm diode laser, and intratumoral injection of 10 mg/mL deoxycholate. Regional pain, clinical responses, tumor height and volume (by 3D photography) were assessed before, 3 and 6 months post-treatment. Biopsies were obtained electively at 3 months., Results: There was no scarring or adverse events > grade 2. Each modality significantly (P < .05) reduced or cleared cNFs, with large variation between tumors and participants. Alexandrite laser and deoxycholate were fast and least painful; 980 nm laser was most painful. Growth of cNFs was not stimulated by treatment(s) based on height and volume values at 3 and 6 months compared to baseline., Limitations: Intervention was a single treatment session; dosimetry has not been optimized., Conclusions: Small cNFs can be rapidly and safely treated without surgery., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cryolipolysis has revolutionized the field of cosmetic dermatology as a nonsurgical procedure, utilizing controlled cooling to selectively destroy fat cells., Aims and Methods: This review article will focus on the future prospects of cryolipolysis, considering advancements in current technology as well as innovations that hold promise for the future. We will explore emerging trends in cryolipolysis, considering novel applicator designs, combination therapies, an innovative injectable treatment approach, and the evolving role of this technology in the field of cosmetic dermatology., Conclusion: The future holds promise for advances in cryolipolysis using both the noninvasive topical cooling approach and the novel injectable ice-slurry technology., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Reduction in visceral adipose tissue (VAT) mass reduces body weight and metabolic disease risk in obese patients. However surgical removal of VAT is highly invasive and thus not clinically feasible. We developed an injectable ice slurry for selective reduction of adipose tissue through cryolipolysis. The aim of this study was to investigate safety, feasibility and mechanism of ice slurry-induced cryolipolysis of VAT. Perigonadal VAT in diet-induced obese mice and rats was subjected to slurry or sham treatment. Body weight and blood chemistry were monitored for 56 days post-treatment. Histological analysis and molecular studies were performed to elucidate mechanisms of fat reduction. Treatment of VAT was well tolerated in all animals. Slurry induced adipocyte cell death via selective cryolipolysis; significant weight loss was noted at day 21 post-treatment. RNA sequencing from treated VAT samples showed increased expression of genes involved in inflammation, immune response, collagen biosynthesis and wound healing, and decreased expression of adipokines. This study demonstrates that slurry treatment is safe and effective in inducing cryolipolysis of VAT and subsequent weight loss in mice. Ice slurry is promising as a minimally-invasive treatment to reduce visceral adipose tissue., (© 2023. Springer Nature Limited.)

Objectives: Excess pericardial adipose tissue (PAT) is associated with a higher risk of cardiovascular diseases. Currently, available methods for reducing PAT volume include weight loss through diet and exercise, weight loss with medications, and bariatric surgery. However, these methods are all limited by low patient compliance to maintain the results. We have developed an injectable ice slurry that could selectively target and reduce subcutaneous adipose tissue volume. The aim of this study was to investigate the feasibility and safety of using injectable slurry to selectively reduce PAT volume in a preclinical large animal model., Methods: PAT in Yucatan swine was injected with slurry or room temperature control solution. All animals were imaged with baseline chest computed tomography (CT) before slurry injection and at 2 months after injection to quantify PAT volume. Specimens from injected and noninjected PAT were harvested for histology., Results: Slurry treatment of PAT was well tolerated in all animals. Slurry-induced selective cryolipolysis in treated PAT. CT imaging showed decrease in PAT volume in treated area at 8 weeks posttreatment compared to baseline, that was significantly different from control solution treated group (median [range]: -29.66 [-35.07 to -27.92]% vs. -1.50 [-11.69 to 8.69]% in control animals respectively, p < 0.05)., Conclusions: This study demonstrated that slurry injection into PAT is feasible in a large animal model. Slurry injection was safe and effective in inducing selective cryolipolysis in PAT and reducing PAT volume. Slurry reduction of PAT could potentially serve as a novel treatment for cardiovascular diseases., (© 2023 Wiley Periodicals LLC.)

Over the past 70 years, sunscreens have evolved from beach products designed to prevent sunburn to more cosmetically elegant skincare products intended to protect against multiple long-term adverse consequences of characteristically low-intensity daily UV and visible light exposure. Sunscreen testing and labeling intended to quantify such protection are unfortunately often misunderstood by users and have also led to illegal misleading and potentially dangerous industry practices. Changes in regulatory requirements, better policing, and more informative sunscreen labeling would benefit users and their physician advisors., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To identify and solve unmet needs and bring new therapies to patients, clinicians at all levels must engage in innovation. The Magic Wand Initiative, a program based at Massachusetts General Hospital-Wellman Center for Photomedicine, created a 10-months course called the Virtual Magic Wand (VMW) program that is a curriculum that teaches the biomedical innovation pathway to dermatologists and engages them in this creative process. This study aims to identify the impact of the VMW program on participants and consider the potential benefits of an innovation curriculum. The authors conducted semi-structured interviews in which alumni of the VMW program were asked about their experiences with innovation before, during, and after the program. Using grounded theory methodology, data were analyzed using deductive coding methods. The most cited benefit of the program was the opportunity to network (n = 12, 100%)-specifically, the mentorship opportunities (n = 10, 83%) and specialty-specific peer groups (n = 9, 75%). Other benefits included a change in mindset regarding their clinical work (n = 11, 92%) and learning the process of innovation (83%). Among barriers, lack of time (n = 7, 58%), knowledge (n = 6, 50%), and resources (n = 5, 42%), were the most mentioned. All alumni interviewed have stayed engaged in the field of biomedical innovation after their completion of the VMW program. These findings show that the VMW program positively impacted the lives and careers of participants. This study identified some of the systemic reasons that deter physicians from regularly engaging in innovation and provides guidance for how to design other innovation programs and further support the advancement of medicine., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cutaneous pain is a common symptom of skin disease, and available therapies are inadequate. We developed a neural selective and injectable method of cryoneurolysis with ice slurry, which leads to a long-lasting decrease in mechanical pain. The aim of this study is to determine whether slurry injection reduces cutaneous pain without inducing the side effects associated with conventional cryoneurolysis. Using the rat sciatic nerve, we examined the effects of slurry on nerve structure and function in comparison with the effects of a Food and Drug Administration‒approved cryoneurolysis device (Iovera). Coherent anti-Stokes Raman scattering microscopy and immunofluorescence staining were used to investigate histological effects on the sciatic nerve and on downstream cutaneous nerve fibers. Complete Freund's Adjuvant model of cutaneous pain was used to study the effect of the slurry on reducing pain. Structural changes in myelin induced by slurry were comparable with those induced by Iovera, which uses much colder temperatures. Compared with that of Iovera, the decrease in mechanical pain due to slurry was less profound but lasted longer without signs of dysesthesia. Slurry did not cause a reduction of epidermal nerve fibers or a change in thermal pain sensitivity. Slurry-treated rats showed reduced cutaneous mechanical pain in response to Complete Freund's Adjuvant. Slurry injection can be used to successfully reduce cutaneous pain without causing dysesthesia., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Cryolipolysis uses tissue cooling to solidify lipids, preferentially damaging lipid-rich cells. Topical cooling is popular for the reduction of local subcutaneous fat. Injection of biocompatible ice-slurry is a recently introduced alternative. We developed and verified a quantitative model that simulates the heat exchange and phase changes involved, offering insights into ice-slurry injection for treating subcutaneous fat., Methods: Finite element method was used to model the spatial and temporal progression of heat transfer between adipose tissue and injected ice-slurry, estimating dose-response relationships between properties of the slurry and size of tissue affected by cryolipolysis. Phase changes of both slurry and adipose tissue lipids were considered. An in vivo swine model was used to validate the numerical solutions. Oils with different lipid compositions were exposed to ice-slurry in vitro to evaluate the effects of lipid freezing temperature. Microscopy and nuclear magnetic resonance (NMR) were performed to detect lipid phase changes., Results: A ball of granular ice was deposited at the injection site in subcutaneous fat. Total injected ice content determines both the effective cooling region of tissue, and the duration of tissue cooling. Water's high latent heat of fusion enables tissue cooling long after slurry injection. Slurry temperature affects the rate of tissue cooling. In swine, when 30 ml slurry injection at -3.5°C was compared to 15 ml slurry injection at -4.8°C (both with the same total ice content), the latter led to almost twice faster tissue cooling. NMR showed a large decrease in diffusion upon lipid crystallization; saturated lipids with higher freezing temperatures were more susceptible to solidification after ice-slurry injection., Conclusions: Total injected ice content determines both the volume of tissue treated by cryolipolysis and the cooling duration after slurry injection, while slurry temperature affects the cooling rate. Lipid saturation, which varies with diet and anatomic location, also has an important influence., (© 2022 Wiley Periodicals LLC.)

Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (- 5 to - 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (- 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (- 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective., (© 2022. The Author(s).)

Competing Interests: Conflicts of interest None disclosed.

Objectives: There is growing evidence that excess adipose tissue within the head and neck contributes to obstructive sleep apnea (OSA), particularly in obese patients. This subset of the population is often difficult to treat with surgical therapies. We theorized that a novel, transcervical method of injectable cryoablation using ice-slurry can achieve low temperatures without causing neurovascular damage or airway distress in a swine model., Methods: Four Yorkshire pigs were injected with ice-slurry comprised of normal saline and 10% glycerol cooled to -6°C via a transcervical, ultrasound guided approach. Direct laryngoscopy was used to confirm accurate placement of the slurry. Thermocouple placement at the needle-tip was used to measure temperatures at injection site. Swine were monitored for clinical signs of tongue necrosis and airway edema for 2 months, and then euthanized. Twelve biopsy samples from the base of the tongue were collected for histology. These were assessed for presence of tissue damage, inflammation and collagen formation by a blinded board-certified pathologist., Results: Tongue tissue temperature below 10°C was achieved for 13.5 ± 1.1 min. Minimum tissue temperature was -4 ± 0.6°C. There was no clinical or pathological evidence of tongue damage to include damage to the lingual nerve or artery. There was some histologic evidence of new collagen formation in areas of the tongue., Conclusions: Transcervical ultrasound-guided ice-slurry injection is feasible, well-tolerated at temperatures previously shown to be capable of selectively targeting adipose tissue in the base of the tongue in a preclinical swine model, without causing neurovascular damage or airway distress when properly injected., Competing Interests: R. Rox Anderson, Lilit Garibyan, and William Farinelli are inventors in patents related to this work, owned by the Massachusetts General Hospital. R. Rox Anderson, Lilit Garibyan, Sara Moradi Tuchayi, Ying Wang, and William Farinelli hold equity in a startup company which will commercialize this technology. The company had no involvement in this study. The authors declare no other competing interests., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Patient-centered and physician-led innovations are key to promoting physicians as visionary leaders in the healthcare system especially during times of crises. COVID-19 has inspired some promising recent advancements within medicine worth noting, including improvements in telemedicine, 3-D printed personal protective equipment (PPE) and ventilators, drug and vaccine development, sterilization of PPE allowing for reuse, and point of care testing; they highlight a broader lesson for how we might innovate better within medicine, even after the crisis has passed. As such, with the complexities of modern-day medicine, to continue to foster this culture of innovation, it is paramount that going forward, medical education adapt and embrace an innovation curriculum that prepares physicians and healthcare workers to work with their communities and researchers to confidently tackle any challenges that may present. Integrating innovation into our careers and medical training is important for advancement of the field and to be able to handle challenges that may present to the healthcare system., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist., (© 2022 The Authors.)

Medical innovation is crucial to advancing our field, and physicians have the potential to play a leading role due to their daily patient care experiences. The objective of this study was to evaluate the interest in, and barriers to participating in innovation. Two surveys were conducted; the first cross-sectional survey was conducted among attendees of the Advancing Innovation in Dermatology Forum in Feburary 2019. The second survey was conducted among trainees (resident/fellows) and faculty dermatologists at Brown, Emory, Iowa, Stanford, and Vanderbilt Universities between June and November 2019. Demographic data were collected, as well as factors involved with identifying problems, developing solutions, training in innovation, and perceived barriers to innovation. In the first survey, the greatest perceived benefits include bringing joy to one's work and increasing professional fulfillment with work. Innovation was also perceived to decrease burnout. In the second survey of academic centers, faculty more commonly expressed interest in identifying problems (p  = 0.04), and was also more confident in their ability to generate solutions to these problems as compared to trainees (p < 0.01). Major barriers to participating in innovation processes included lack of time and lack of training or education in innovation. Both trainees and faculty groups noted a lack of knowledge in creating prototypes, understanding regulatory approval for medical products, and inexperience with pitching to investors or obtaining funding. These cross-sectional needs assessment surveys found a strong interest in innovation coupled with a lack of education in innovation processes. These findings suggest an urgent need and opportunity for providing formal training to empower dermatologists with the tools to lead innovation within our field., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Clinicians play a critical role in recognizing, initiating, and adopting innovative solutions to clinical problems. Increasing clinician involvement in problem-based innovation will help identify and solve unmet medical needs. The overall objective of our program was to increase clinician involvement in problem-based innovation. We pioneered and piloted the "Magic Wand" Initiative (MWI) at Massachusetts General Hospital Department of Dermatology, by inviting clinical faculty to voluntarily participate in problem-driven innovation. The primary outcome was the number of unmet clinical needs identified and pursued by clinicians, who were 'activated' to initiate problem-based innovation. Other objectives were to enhance clinician-to-clinician dialogue and to develop specific strategic framework for clinician-led, problem-driven research. This pilot MWI was started in 2013 with an announcement at dermatology faculty meeting inviting all clinical faculty to participate on volunteer basis. Academic dermatologists were the main participants in this program. They also contacted, collaborated and worked with research faculty, industry experts and lawyers. Out of 30 unmet needs identified by clinicians participating in MWI, eight are actively being pursued by clinicians. Three of those cases presented here have achieved publications, grant funding, prototype devices and product for patient use. In conclusion, MWI is an innovative approach that educates and equips clinician to identify and solve problems and engages them as leaders in their healthcare ecosystem. MWI has achieved concrete measurable success, affirming that if clinicians are empowered and supported to identify and solve existing unmet medical problems, new and innovative solutions can be invented to improve patient care., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Increased neck circumference is a major risk factor for obstructive sleep apnea (OSA). New data suggest that increased adipose tissue in the neck may be a contributory cause of OSA. The aim of this study was to investigate safety and efficacy of a recently developed injectable ice slurry in selective reduction of neck adipose tissue in a mouse model., Methods: We used the New Zealand obese mice that have increased volume of anterior neck fat, and are commonly used in OSA studies. MRI imaging was used to measure changes in fat tissue volume., Results: Thirty animals were used in this study. Volumetric measurements in MRI images showed thatchanges in anterior neck adipose tissue volume from baseline in treated mice was significantly different in comparison with the control group (-1.09/kg ± 0.33/kg vs 0.68/kg ± 0.37/kg; p < 0.01 by two-tailed Student's t test). Histological analysis of samples from the treated area of the neck did not show scarring or damage to the surrounding tissues., Conclusions: Injection of ice slurry safely, effectively, and selectively reduces upper airway fat in New Zealand obese mice without scarring or damage to surrounding tissue. Our results suggest that slurry injection may be a novel and minimally invasive method of removing neck adipose tissue. This intervention should be further investigated to determine its suitability for treatment of OSA.

Background: Postoperative pain caused by trauma to nerves and tissue around the surgical site is a major problem. Perioperative steps to reduce postoperative pain include local anesthetics and opioids, the latter of which are addictive and have contributed to the opioid epidemic. Cryoneurolysis is a nonopioid and long-lasting treatment for reducing postoperative pain. However, current methods of cryoneurolysis are invasive, technically demanding, and are not tissue-selective. This project aims to determine whether ice slurry can be used as a novel, injectable, drug-free, and tissue-selective method of cryoneurolysis and resulting analgesia., Methods: The authors developed an injectable and selective method of cryoneurolysis using biocompatible ice slurry, using rat sciatic nerve to investigate the effect of slurry injection on the structure and function of the nerve. Sixty-two naïve, male Sprague-Dawley rats were used in this study. Advanced Coherent anti-Stokes Raman Scattering microscopy, light, and fluorescent microscopy imaging were used at baseline and at various time points after treatment for evaluation and quantification of myelin sheath and axon structural integrity. Validated motor and sensory testing were used for evaluating the sciatic nerve function in response to ice slurry treatment., Results: Ice slurry injection can selectively target the rat sciatic nerve. Being injectable, it can infiltrate around the nerve. The authors demonstrate that a single injection is safe and selective for reversibly disrupting the myelin sheaths and axon density, with complete structural recovery by day 112. This leads to decreased nocifensive function for up to 60 days, with complete recovery by day 112. There was up to median [interquartile range]: 68% [60 to 94%] reduction in mechanical pain response after treatment., Conclusions: Ice slurry injection selectively targets the rat sciatic nerve, causing no damage to surrounding tissue. Injection of ice slurry around the rat sciatic nerve induced decreased nociceptive response from the baseline through neural selective cryoneurolysis.

Background: Cryolipolysis is a noninvasive method for removal of subcutaneous fat for body contouring. Conventional cryolipolysis with topical cooling requires extracting heat from subcutaneous fat by conduction across the skin, thus limiting the amount and the location of the fat removed. The authors hypothesized that local injection of a physiological ice slurry directly into target adipose tissue would lead to more efficient and effective cryolipolysis., Methods: Injectable slurries containing 20 percent and 40 percent ice content were made using common parenteral agents (normal saline and glycerol), then locally injected into the subcutaneous fat of swine. Ultrasound imaging, photography, histological, and gross tissue responses were monitored before and periodically up to 8 weeks after injection., Results: Fat loss occurred gradually over several weeks following a single ice slurry injection. There was an obvious and significant 55 ± 6 percent reduction in adipose tissue thickness compared with control sites injected with the same volume of melted slurry (p < 0.001, t test). The amount of fat loss correlated with the total volume of ice injected. There was no scarring or damage to surrounding tissue., Conclusion: Physiological ice slurry injection is a promising new strategy for selective and nonsurgical fat removal.

In light of the increasing prevalence of obesity, a large proportion of patients are taking weight loss medications or undergoing weight loss procedures. The typical paradigm for treating obesity begins with lifestyle interventions and progresses to medical treatments, and when nonsurgical interventions have failed, procedural techniques are considered. The effect of these interventions on the skin and dermatologic conditions has not been reviewed in depth. Herein, we review the impact of weight loss on pre-existing dermatologic conditions, as well as the development of novel skin changes and consequences of redundant skin after these interventions., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Onychomycosis is a challenging nail condition to treat. The gold standard treatment relies on long-term systemic therapy, which carries risks of potential side effects and drug interactions. Topical alternatives exist; however, treatment outcomes remain disappointing. In this article, we review newer topical formulations that are approved by the United States Food and Drug Administration, as well as other topical drugs that are still undergoing clinical trials. Lasers and energy-based devices have also been used for the treatment of onychomycosis; however, standardized parameters and clear treatment endpoints have yet to be specified. Currently, device-based therapies are considered as options for improving the cosmetic appearance of nails. The use of lasers to improve the penetration of topical antifungal treatments as possible combination treatments is also reviewed., Competing Interests: FUNDING:No funding was provided for this study. DISCLOSURES:The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2019. Matrix Medical Communications. All rights reserved.)

Background: The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation., Objective: We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice., Methods: Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge., Results: Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI +/- mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand-driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge., Conclusion: These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Hair loss is both a common chief complaint by patients and a clinical challenge for physicians, especially general practitioners, yet few dermatological problems yield as much patient satisfaction when resolved as hair loss. The diagnosis is often attributed to androgen-related hair loss, while other causes, some of which are life-threatening but treatable, are overlooked. We searched for relevant literature on hair loss and supported these findings with our clinical experience to identify seven major systemic etiologies of hair loss, ranging from infectious agents to consumption of unsafe supplements. Many causes are only described in the literature through case studies, though some original articles and meta-analyses are available. Careful history taking, proper examination techniques, and judicious use of laboratory tests are essential to reach at the correct diagnosis in a cost-effective manner when performing patient work-up. Such methodical evaluation of hair loss can result in the appropriate treatment plan and provide significant patient satisfaction. Key messages Hair loss is a common chief complaint and a difficult challenge for both general practitioners and dermatology consultants. We identified seven major categories of systemic hair loss etiology and present a framework for their clinical evaluation. A methodical approach to hair loss can result in the appropriate treatment plan and provide significant patient satisfaction.

Cryolipolysis is a noninvasive, skin cooling treatment for local fat reduction that causes prolonged hypoesthesia over the treated area. We tested the hypothesis that cryolipolysis can attenuate nociception of a range of sensory stimuli, including stimuli that evoke itch. The effects of cryolipolysis on sensory phenomena were evaluated by quantitative sensory testing (QST) in 11 healthy subjects over a period of 56 days. Mechanical and thermal pain thresholds were measured on treated and contralateral untreated (control) flanks. Itch duration was evaluated following histamine iontophoresis. Unmyelinated epidermal nerve fiber and myelinated dermal nerve fiber densities were quantified in skin biopsies from six subjects. Cryolipolysis produced a marked decrease in mechanical and thermal pain sensitivity. Hyposensitivity started between two to seven days after cryolipolysis and persisted for at least thirty-five days post treatment. Skin biopsies revealed that cryolipolysis decreased epidermal nerve fiber density, as well as dermal myelinated nerve fiber density, which persisted throughout the study. In conclusion, cryolipolysis causes significant and prolonged decreases in cutaneous sensitivity. Our data suggest that controlled skin cooling to specifically target cutaneous nerve fibers has the potential to be useful for prolonged relief of cutaneous pain and might have a use as a research tool to isolate and study cutaneous itch-sensing nerves in human skin.

Acne vulgaris is a nearly universal cutaneous inflammatory disease. Excess sebum production is an integral part of disease pathogenesis. Medical therapies that reduce sebum excretion result in clinical improvement of acne. Given the preferential susceptibility of lipid-containing cells to cold, we investigated the hypothesis that controlled local skin cooling causes preferential injury to sebaceous glands, in murine and swine models using a range of temperatures as low as -10 °C, and then on the backs of human subjects. In mouse ears, peak histologic damage occurred 72 hours after treatment; eosinophilic necrotic plugs formed within sebaceous glands, and the number of glands was significantly reduced up to 1 week post treatment. Cooling disrupted sebocyte cell membranes, alkaline phosphatase activity, and significantly reduced sebocyte lipid content. In human volunteers, cooling damaged sebaceous glands and reduced sebum output for 2 weeks, with minimal injury to surrounding tissues. Selective cryolysis of sebaceous glands is achievable through brief, non-invasive skin cooling, suggesting that controlled cooling could be developed as an effective treatment for acne vulgaris.

Importance: Cryolipolysis is the noninvasive reduction of fat with localized cutaneous cooling. Since initial introduction, over 650,000 cryolipolysis treatment cycles have been performed worldwide. We present a previously unreported, rare adverse effect following cryolipolysis: paradoxical adipose hyperplasia., Observations: A man in his 40s underwent a single cycle of cryolipolysis to his abdomen. Three months following his treatment, a gradual enlargement of the treatment area was noted. This enlargement was a large, well-demarcated subcutaneous mass, slightly tender to palpation. Imaging studies revealed accumulation of adipose tissue with normal signal intensity within the treatment area., Conclusions and Relevance: Paradoxical adipose hyperplasia is a rare, previously unreported adverse effect of cryolipolysis with an incidence of 0.0051%. No single unifying risk factor has been identified. The phenomenon seems to be more common in male patients undergoing cryolipolysis. At this time, there is no evidence of spontaneous resolution. Further studies are needed to characterize the pathogenesis and histologic findings of this rare adverse event.

Background and Objectives: Cryolipolysis is a noninvasive and well-tolerated treatment for reduction of localized subcutaneous fat. Although several studies demonstrate the safety and efficacy of this procedure, volumetric fat reduction from this treatment has not been quantified. This prospective study investigated the change in volume of fat after cryolipolysis treatment using three-dimensional (3D) photography., Materials and Methods: A prospective study of subjects treated with cryolipolysis on the flank (love handle) was performed at Massachusetts General Hospital. Volume measurements were performed with a Canfield Scientific Vectra three-dimensional camera and software to evaluate the amount of post procedure volume change. Clinical outcomes were assessed with caliper measurements, subject surveys, and blinded physician assessment of photographs., Results: Eleven subjects were enrolled in this study. Each subject underwent a single cycle of cryolipolysis to one flank. The untreated flank served as an internal control. The follow-up time after treatment was 2 months. The mean amount of calculated absolute fat volume loss using 3D photography from baseline to 2 months follow-up visit was 56.2 ± 25.6 from the treatment site and 16.6 ± 17.6 cc from the control (P < 0.0001). A mean absolute difference of 39.6 cc between the treated and untreated sides was calculated at 2 months post-treatment. Comparison of caliper measurements from baseline to 2 months post-treatment demonstrated significant reduction of the treated flank from 45.6 ± 5.8 mm at baseline to 38.6 ± 4.6 mm at 2 months post-treatment (P < 0.001). The untreated flank did not show significant reduction with caliper measurements demonstrating 45.3 ± 5.0 mm at baseline and 44.6 ± 5.1 mm at 2 months post-treatment (P = 0.360). No unexpected side effects or adverse events were reported. Post-treatment satisfaction surveys demonstrated 82% of subjects were satisfied with the results., Conclusions: Cryolipolysis is a safe, well-tolerated, and effective noninvasive fat removal methodology that on average leads to 39.6 cc of fat loss of the treated flank at 2 months after a single treatment cycle., (© 2013 Wiley Periodicals, Inc.)