Efficacy of Lasers for the Management of Dermatophyte Toenail Onychomycosis.

BACKGROUND: Onychomycosis is a chronic fungal nail infection caused predominantly by dermatophytes, and less commonly by nondermatophyte molds and Candida species. Onychomycosis treatment includes oral and topical antifungals, the efficacy of which is evaluated through randomized, double-blind, controlled trials for US Food and Drug Administration approval. The primary efficacy measure is complete cure (complete mycologic and clinical cure). The secondary measures are clinical cure (usually ≤10% involvement of target nail) and mycologic cure (negative microscopy and culture). Some lasers are US Food and Drug Administration approved for the mild temporary increase in clear nail; however, some practitioners attempt to use lasers to treat and cure onychomycosis. METHODS: A systematic review of the literature was performed in July of 2020 to evaluate the efficacy rates demonstrated by randomized controlled trials of laser monotherapy for dermatophyte onychomycosis of the great toenail. RESULTS: Randomized controlled trials assessing the efficacy of laser monotherapy for dermatophyte toenail onychomycosis are limited. Many studies measured cure rates by means of nails instead of patients, and performed only microscopy or culture, not both. Only one included study reported mycologic cure rate in patients as negative light microscopy and culture (0%). The combined clinical cure rates in short- and long-pulsed laser studies were 13.0%-16.7% and 25.9%, respectively. There was no study that reported the complete cure rate; however, one did report treatment success (mycologic cure [negative microscopy and culture] and ≤10% clinical involvement) in nails as 16.7%. CONCLUSIONS: The effectiveness of lasers as a therapeutic intervention for dermatophyte toenail onychomycosis is limited based on complete, mycologic, and clinical cure rates. However, it may be possible to use different treatment parameters or lasers with a different wavelength to increase the efficacy. Lasers could be a potential management option for older patients and onychomycosis patients with coexisting conditions such as diabetes, liver, and/or kidney diseases for whom systemic antifungal agents are contraindicated or have failed.

Artificial hair implantation for hair restoration.

BACKGROUND: Androgenetic alopecia (AGA) is the most common cause of hair loss in men and women. Artificial hair implantation is considered an alternative treatment when the donor area is depleted or unsuitable for hair transplantation. The use of artificial hair implants remains controversial, particularly because this practice has been banned by the US FDA. OBJECTIVE: To summarize various aspects of artificial hair implantation. METHODS: We discuss the history of artificial hair implantation, development of new biocompatible fibers (Biofibre®, Nido Z-type), patient eligibility for this treatment, implantation technique, follow-up, immune response to the implanted fibers, and post-implantation complications. We performed a methodological quality assessment of the clinical studies that investigated artificial hair implantation using the Canadian Institute of Health Economics (IHE) Quality Appraisal Tool for Case Series (Interventional). RESULTS: Although the studies evaluating the use of artificial hair fibers appear promising, the methodological quality of most of them was between 'poor' and 'fair', due to lack of randomization, absence of control groups, improper study design, and inappropriate outcome measures. CONCLUSIONS: Artificial hair implantation has been received with skepticism among physicians due to the complications reported. Further high-quality research needs to be performed to ascertain the safety and efficacy of artificial hair implantation.

Microneedling for Hair Loss.

BACKGROUND: Microneedling is a relatively novel therapeutic modality introduced in the 1990s where small, fine needles are used to create micro punctures in the skin. It is a minimally invasive procedure used for various dermatological conditions, including androgenetic alopecia (AGA). OBJECTIVE AND METHODS: We comprehensively summarize the literature regarding microneedling in dermatology. We performed linear multivariable regressions to synthesize evidence from the clinical trials that investigated the efficacy of microneedling for AGA. Studies eligible for quantitative analyses were assessed for evidence quality. RESULTS: The exact mechanism of microneedling action is yet to be determined, with theories that include the wound-healing cascade. Microneedling monotherapy significantly increased total hair count more than topical minoxidil 5% (ß = 12.29; p < 0.001). The combination treatment of microneedling with topical 5% minoxidil increased total hair count significantly compared to monotherapy with microneedling (ß = 7.63, p < 0.05). Increasing the overall treatment duration of microneedling and reducing the frequency of microneedling sessions may positively influence an increase in total hair count. CONCLUSION: There are limited studies that investigate microneedling as a monotherapy for hair loss since majority of the trials combine it with other therapies such as topical minoxidil or platelet-rich plasma. While preliminary results look promising, further investigation of microneedling as a monotherapy in larger, randomized controlled trials will help determine its safety and efficacy, and place in treating AGA.

More than Nail Deep: The Effect of Efinaconazole 10% Treatment on the Quality of Life in Patients with Onychomycosis: A post hoc Study.

INTRODUCTION: Onychomycosis is a common, difficult-to-treat fungal nail infection. Clinical signs include nail discoloration and thickening, which patients often find embarrassing, causing a negative impact on their quality of life (QOL). METHODS: In this post hoc study, we analyze the effect of efinaconazole 10% solution on a patient's QOL using patient-reported scores from the OnyCOE-t™ questionnaire (appearance, stigma, physical problems, symptom frequency, symptom bothersomeness, treatment satisfaction, and overall problem). Higher scores corresponded to better functioning, thus higher QOL. RESULTS: Efinaconazole 10% treatment and clinical efficacy were positively correlated with improved QOL in all domains for all groups, except with symptom bothersomeness (how much the onychomycosis symptoms worried or concerned the patient) for female patients <40 years. While still showing improvement in most domains during efficacious treatment, female and younger patients reported lower QOL scores than their male and older counterparts, despite having better clinical outcomes at follow-ups. DISCUSSION: Female and younger patients appear to be more emotionally bothered by their symptoms, regardless of treatment success or improvement of their nail's appearance, suggesting that onychomycosis is more than nail deep and has a greater psychological effect on these patients. Therefore, younger female patients may require more assurance and mental support.

Cure Rates of Control Interventions in Randomized Trials for Onychomycosis Treatments: A Systematic Review and Meta-Analysis.

Background: The efficacy of antifungals for onychomycosis has been determined in randomized controlled trials (RCTs); interestingly their control arms have demonstrated some therapeutic effects. These controls constitute either placebos (inert pills) or vehicles (all but the antifungal component of the creams). The objective of this research was to determine (i) whether RCT controls exhibited statistically-relevant efficacy rates (i.e. beyond the "placebo effect"), (ii) whether oral and topical controls differed in their efficacies, and (iii) if the efficacy rates of the controls correlated with those of the active comparator associated with that control.

Methods: RCTs of oral and topical monotherapies for dermatophyte toenail onychomycosis were identified through a systematic literature search. For our meta-analyses of cure rates the double arcsine transformation was used. The N-1 chi squared test was used to determine whether the cure rates significantly differed between topical and oral controls. Correlation was investigated using Kendall rank correlation tests.

Results: The pooled mycological, complete, and clinical cure rates of all control interventions (n = 19 trials) were 9%, 1%, and 6%, respectively. The pooled efficacy rates for oral and topical controls were: mycological cure rate, 7% and 12% (p=0.0016); complete cure rate, 1% for both; and clinical cure rate, 4% and 8%, respectively (p=0.0033). For oral RCTs, the respective cure rates of the active therapies were not correlated with controls. However, for topical RCTs, as the mycological and clinical cure rates of the active therapy increased, so did those of the topical vehicle associated with the active therapy in question, and vice versa.

Conclusions: The topical vehicle cure rates were often higher than the oral placebo cure rates, likely due to the presence of non-antifungal chemicals (e.g. moisturizers, urea) with antifungal and debriding properties, which are not present in oral controls.

Fungal Lung.

Foot and nail care specialists spend a great portion of their day using nail drills to reduce nail thickness and smooth foot calluses. This process generates a large amount of dust, some of which is small enough to breathe in and deposit into the deepest regions of the respiratory tract, potentially causing health problems. Foot and nail dust often contains fungi, from both fungus-infected and healthy-appearing nails. Although the majority of healthy individuals can tolerate inhaled fungi, the immune systems of older, immunocompromised, and allergy-prone individuals often react using the inflammatory T helper cell type 2 pathway, leading to mucus overproduction, bronchoconstriction, and, in severe cases, lung tissue damage. To protect vulnerable podiatry professionals, wearing a surgical mask, using a water spray suppression system on nail drills, installing air filtration systems, and considering drilling technique can help reduce exposure to nail dust.

Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering.

The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to diversify antigen receptor genes and combat viral infections. These processes, initiated by specific DNA-editing enzymes, often result in mistargeted induction of genome lesions that initiate and drive cancers. Like other molecules involved in human health and disease, the DNA-editing enzymes of the immune system have been intensively studied in humans and mice, with little attention paid (< 1% of published studies) to the same enzymes in evolutionarily distant species. Here, we present a systematic review of the literature on the characterization of one such DNA-editing enzyme, activation-induced cytidine deaminase (AID), from an evolutionary comparative perspective. The central thesis of this review is that although the evolutionary comparative approach represents a minuscule fraction of published works on this and other DNA-editing enzymes, this approach has made significant impacts across the fields of structural biology, immunology, and cancer research. Using AID as an example, we highlight the value of the evolutionary comparative approach in discoveries already made, and in the context of emerging directions in immunology and protein engineering. We introduce the concept of 5-dimensional (5D) description of protein structures, a more nuanced view of a structure that is made possible by evolutionary comparative studies. In this higher dimensional view of a protein's structure, the classical 3-dimensional (3D) structure is integrated in the context of real-time conformations and evolutionary time shifts (4th dimension) and the relevance of these dynamics to its biological function (5th dimension).

Low-dose isotretinoin versus minocycline in the treatment of rosacea.

Rosacea is a common inflammatory facial skin condition affecting the adult population. Its papulopustular subtype is mainly treated pharmacologically by topical and oral antibiotics. For severe or antibiotics-recalcitrant disease, daily low-dose isotretinoin has also been reported to be effective. However, no previous study has assessed the efficacy of once-weekly administered isotretinoin for papulopustular rosacea. For this purpose, a retrospective comparative study was conducted. For severe rosacea, 40 mg/week isotretinoin (24 patients) was administered. For mild to moderate rosacea, once-weekly 20 mg/week isotretinoin (28 patients) was compared with 100 mg/day minocycline (24 patients). Treatment courses lasted 4 to 7 months. Forty milligrams per week isotretinoin was highly effective for severe rosacea, achieving complete response (over 90% improvement) in 62.5% of patients and partial response (50%-90% improvement) in additional 29.2% of patients. Twenty milligrams per week isotretinoin and hundred milligrams per day minocycline showed comparable efficacy for mild to moderate rosacea (complete response of 10.7% vs 8.3% and partial response of 28.6% vs 33.3%, respectively). This study demonstrates that that the use of a weekly low-dose isotretinoin is an effective treatment for papulopustular rosacea, including among patients with severe disease.

The shifting preferences of patients and physicians in nonsurgical hair loss treatment.

BACKGROUND: There are multiple etiologies for hair thinning and loss, including genetic, hormonal, immune, scaring, and infectious. Hair loss treatment involves both surgical intervention and nonsurgical therapies such as pharmaceuticals, haircare products, vitamins, and low-level laser therapy (LLLT). While pharmaceuticals have been extensively researched, the efficacy of other therapies remains inconclusive. With so many available treatments, consumers often research their options using search engines such as Google and/or seek help from hair restoration physicians. AIMS: To identify and analyze changing trends in international consumer and physician interest in nonsurgical hair loss therapies. METHODS: Worldwide trends in Google searches of hair loss products (2004-2020) were compared with product prescription frequency surveys from members of the International Society of Hair Restoration Surgery (2004-2019, ~29% response rate). RESULTS: Minoxidil and finasteride were the most prescribed hair loss treatments, while "minoxidil" was the most "Googled" term. Generic products were searched more often than their brand counterparts. Nutritionals and haircare prescriptions increased over time. LLLT was also increasingly prescribed, with Internet searches increasing following government regulation announcements. The COVID-19 pandemic initially negatively affected hair loss treatment searches, which have since returned to, and surpassed, pre-pandemic levels. CONCLUSION: Regulations and social media have influence on consumer interest in hair loss products. A weak economy and coronavirus fears may persuade consumers to turn to cheaper hair loss treatment alternatives. Hair restoration specialists need to keep abreast of online trends to communicate effectively with their patients. Patients should be cognizant of the safety and efficacy of hair restoration treatments.

The Growing Problem of Antifungal Resistance in Onychomycosis and Other Superficial Mycoses.

Superficial mycoses are becoming increasingly resistant to current antifungal medications. As alternative therapeutic options are limited, the increasing frequency of reports of antifungal resistance is alarming. This epidemic parallels the rise of antibiotic resistance; however, the significance of this problem has yet to gain global attention. Here, we discuss the reports of antifungal resistance from around the world, present our own experience with treatment-resistant infections, and examine alternative treatment strategies. The majority of reports of recalcitrant infections indicate terbinafine resistance as the causative factor. Single-point mutations in the squalene oxidase gene is the most reported mechanism of resistance to terbinafine. Mixed infections of dermatophytes with non-dermatophyte molds and/or yeasts are becoming more prevalent and contributing to the resistant nature of these infections. The key to selecting an effective antifungal therapy for a recalcitrant infection is identification of the infectious organisms(s) and testing susceptibility of the organism(s) to antifungal drugs. Combination and sequential therapy regimens are options, but both require active monitoring for hepatic and renal function, drug interactions, and other adverse effects. Selected topical antifungals with a wide spectrum of activity may also be considerations in some clinical presentations. Innovative treatment regimens and novel therapeutics are needed to overcome the rising epidemic of antifungal resistance.

Once Weekly Application of Urea 40% and Bifonazole 1% Leads to Earlier Nail Removal in Onychomycosis.

INTRODUCTION: Onychomycosis is a chronic nail fungal infection resulting in nail damage and a decreased quality of life. Chemical avulsion of the nail with urea and bifonazole -removes fungally infected debris, increasing antifungal treatment efficacy and penetration. Previous clinical ob-servations describe patients who applied their urea and -bifonazole ointment less frequently, achieving earlier nail removal. In this study, we analyzed the relationship between duration of urea and bifonazole application and time to nail avulsion. METHODS: χ2 tests, multiple regression analysis, and ANOVA were performed to analyze the similarities between treatment regimens (daily, every 3 days, or once a week), association of regimens or patient characteristics to nail removal, and compare time to nail removal between each regimen, respectively. RESULTS: Daily application of ointment and sealing resulted in an average length of time (±SD) to nail removal of 18.7 days (±6.8 days); once every 3 days resulted in nail removal at 12.7 days (±6.2 days) and once per week at 11 days (±4.46 days) (p < 0.001). Age was the only patient factor that affected duration to nail removal. CONCLUSION: Once weekly application of ointment with sealing for a 1-week duration is associated with a decrease in time to complete chemical avulsion of the nail by approximately 1 week.

Changing trends in surgical hair restoration: Use of Google Trends and the ISHRS practice census survey.

BACKGROUND: Hair loss affects most people at some point in their lifetime, causing anxiety and decreased self-esteem. There are multiple surgical and nonsurgical treatments available, with the surgical options having greater and longer-lasting effects. Such treatments have evolved over time with advances in technology and research, with numerous patients researching these treatments on Google. Many surgeons who provide these treatments belong to the International Society of Hair Restoration Surgeons (ISHRS). AIMS: To investigate trends in surgical hair restoration treatment from both the surgeon and patient perspectives. METHODS: Patient epidemiological and surgical data from the ISHRS were combined with search trend data from Google to analyze changing trends in surgical hair restoration treatment. RESULTS: Worldwide Internet searches for "hair transplant" have increased from 2004 to the present. Follicular unit excision (FUE) has supplanted follicular unit transplant (FUT) as the most popular hair transplant performed. Since 2004, there has been an increase in both nonsurgical and surgical female patients. Beard and eyebrow transplants have increased in popularity. Google searches follow this trend. Nonsurgical treatments such as platelet-rich plasma (PRP) are being searched more frequently. Hair restoration clinics and Google searches were affected adversely by the COVID-19 pandemic. CONCLUSION: Technological advances in available therapies, improvement in delivery systems, changes in hair fashion, and global events have direct impact on hair restoration treatments offered by physicians and researched by patients. It is in the best interest of all hair restoration providers to keep abreast of changing technologies and treatment trends to stay at the forefront of their profession.

Google search trends in onychomycosis: Influences of flip flops and advertising.

BACKGROUND: Onychomycosis is a fungal infection of the nail, affecting 5.5% of the population. Individuals affected by this disease experience increased anxiety about this disorder and a decreased quality of life. There are multiple available treatments across the globe, leading people to search online for information on the various therapies. AIMS: To analyze Google search trends of fungal infection and treatment keywords and the influence of different geographical locations, season, regulatory decisions, and advertisements on these trends. METHODS: In May, 2020 we used Google Trends to determine the relative interest of various fungal infection and treatment keywords worldwide and in the US, the UK, Canada, and Australia. Notable peaks were investigated for contemporaneous news events. RESULTS: In general, searches for toenail fungus and associated treatment terms peak during the summer months. Interest in individual treatments peaks when a product is launched, is the subject of an advertising campaign, or becomes more available to the public through approval or reclassification. Yeast infection, thrush, and ringworm terms are consistently searched more often than toenail fungus, jock itch, or foot fungus; all terms are most popular in the summer months, with toenail fungus reaching annual popularity one month prior to jock itch. DISCUSSION: In general, interest in toenail fungus and treatments is the highest when social anxiety about toenail appearance and the occurrence of fungal infection is the greatest. Curiosity about treatment products increases with their availability and visibility to the public. Combining the power of seasonal interest and advertising generates the greatest search profile for onychomycosis treatments.

Expansions, diversification, and interindividual copy number variations of AID/APOBEC family cytidine deaminase genes in lampreys.

Cytidine deaminases of the AID/APOBEC family catalyze C-to-U nucleotide transitions in mRNA or DNA. Members of the APOBEC3 branch are involved in antiviral defense, whereas AID contributes to diversification of antibody repertoires in jawed vertebrates via somatic hypermutation, gene conversion, and class switch recombination. In the extant jawless vertebrate, the lamprey, two members of the AID/APOBEC family are implicated in the generation of somatic diversity of the variable lymphocyte receptors (VLRs). Expression studies linked CDA1 and CDA2 genes to the assembly of VLRA/C genes in T-like cells and the VLRB genes in B-like cells, respectively. Here, we identify and characterize several CDA1-like genes in the larvae of different lamprey species and demonstrate that these encode active cytidine deaminases. Structural comparisons of the CDA1 variants highlighted substantial differences in surface charge; this observation is supported by our finding that the enzymes require different conditions and substrates for optimal activity in vitro. Strikingly, we also found that the number of CDA-like genes present in individuals of the same species is variable. Nevertheless, irrespective of the number of different CDA1-like genes present, all lamprey larvae have at least one functional CDA1-related gene encoding an enzyme with predicted structural and chemical features generally comparable to jawed vertebrate AID. Our findings suggest that, similar to APOBEC3 branch expansion in jawed vertebrates, the AID/APOBEC family has undergone substantial diversification in lamprey, possibly indicative of multiple distinct biological roles.

Biochemical Regulatory Features of Activation-Induced Cytidine Deaminase Remain Conserved from Lampreys to Humans.

Activation-induced cytidine deaminase (AID) is a genome-mutating enzyme that initiates class switch recombination and somatic hypermutation of antibodies in jawed vertebrates. We previously described the biochemical properties of human AID and found that it is an unusual enzyme in that it exhibits binding affinities for its substrate DNA and catalytic rates several orders of magnitude higher and lower, respectively, than a typical enzyme. Recently, we solved the functional structure of AID and demonstrated that these properties are due to nonspecific DNA binding on its surface, along with a catalytic pocket that predominantly assumes a closed conformation. Here we investigated the biochemical properties of AID from a sea lamprey, nurse shark, tetraodon, and coelacanth: representative species chosen because their lineages diverged at the earliest critical junctures in evolution of adaptive immunity. We found that these earliest-diverged AID orthologs are active cytidine deaminases that exhibit unique substrate specificities and thermosensitivities. Significant amino acid sequence divergence among these AID orthologs is predicted to manifest as notable structural differences. However, despite major differences in sequence specificities, thermosensitivities, and structural features, all orthologs share the unusually high DNA binding affinities and low catalytic rates. This absolute conservation is evidence for biological significance of these unique biochemical properties.