Search Results (82)

Background: Retinol is a mainstay of dermatological care due to its central role in epidermal differentiation, skin barrier repair, and tissue regeneration. However, its clinical use is limited by poor physicochemical stability, rapid photodegradation, and frequent skin intolerance, particularly in individuals with impaired skin barrier function. Supramolecular biovectorization strategies could overcome these limitations. Objectives: This study aimed to evaluate the impact of third-generation dendritic poly-L-lysine (PLL_G3; 22 kDa, ~7 nm) on retinol stability, skin tolerance, and skin functional performance. Methods: A supramolecular retinol-poly-L-lysine complex was characterized in terms of encapsulation efficiency and physicochemical stability using HPLC and UV spectroscopy under oxidative, thermal, and photochemical stress. The stability of the formulation was evaluated as hydrophilic emulsion over a three-month period. Skin functional efficacy was evaluated by corneometric analysis of stratum corneum hydration after topical application, as well as by clinical assessment of tolerance and efficacy after repeated daily use over 28 days in subjects presenting xerosis, defined as dry to very dry skin. Results: Retinol remained structurally intact in the PLL_G3 matrix, confirming a reversible, non-covalent encapsulation mechanism. The formulation exhibited high physicochemical stability, with only minimal changes after prolonged UV exposure. Corneometric measurements showed a rapid and sustained increase in skin hydration, reaching +61.5% two hours after application. After 28 days of repeated use, the formulation was well tolerated, with no signs of irritation or sensitization, and demonstrated significant improvements in skin dryness, suppleness, and comfort. Conclusions: PLL_G3-based supramolecular vectorization significantly improves stability, tolerance, and functional hydration of the skin by retinol. By enabling controlled release while preserving the integrity of the epidermal barrier, poly-L-lysine dendrimers represent a clinically relevant strategy for safer and more effective topical use of retinol, particularly on sensitive, xerotic, inflammatory, and photoaged skin. Full article

Chronic hyperglycemia profoundly impairs skin integrity, with dermatological complications affecting up to half of patients with diabetes mellitus. The objective of this study was to describe the spectrum, frequency, and clinical characteristics of skin lesions in patients with diabetes mellitus and to evaluate whether specific cutaneous signs are associated with an increased risk of subsequently developing type 2 diabetes. This retrospective observational study evaluated 960 cases admitted to the Dermatology Clinic of “Sf. Spiridon” Emergency County Clinical Hospital, Iași, between 2017 and 2022, complemented by an 11-year longitudinal follow-up (2011–2016). Ulcerative lesions predominated (85.7%), followed by inflammatory manifestations (12.4%), while classical diabetes-specific dermatoses represented <2% of cases. Poor glycemic control (HbA1c > 7%) was documented in 94.2% of patients, with the most severe lesions occurring in those with HbA1c > 10%. In the longitudinal analysis, patients who later developed diabetes initially presented significantly higher rates of xerosis, pruritus, and callus compared with the controls. Multivariate logistic regression identified xerosis (OR 4.70) and pruritus (OR 3.41) as independent predictors of future diabetes. These findings suggest that certain dermatological signs may serve as early non-invasive markers of metabolic dysfunction and highlight the importance of routine skin examination in diabetes risk stratification. Full article

Background: Atopic dermatitis (AD) is a chronic, relapsing inflammatory dermatosis that is characterized by pruritus, xerosis, and age-dependent clinical heterogeneity. Accurately diagnosing AD remains challenging due to the absence of specific biomarkers and the broad spectrum of conditions that may mimic its presentation. A wide range of inflammatory, infectious, and genetic disorders resemble AD, including seborrheic dermatitis, psoriasis, contact dermatitis, scabies, dermatophytosis, and nummular eczema, as well as rare immunodeficiency and metabolic conditions. This review summarizes the evolution of the clinical features of pediatric AD across infancy, childhood, and adolescence, with a focus on key differential diagnoses. Recognizing age-specific patterns and potential mimickers is essential for improving diagnostic accuracy and guiding appropriate management in pediatric AD. Methods: This study was designed as a narrative review. A structured literature search was conducted of PubMed/MEDLINE for studies published between January 2001 and March 2026 using predefined keywords related to AD, childhood, diagnosis, and differential. Clinical trials, randomized controlled trials, systematic reviews, meta-analyses, and guidelines or consensus documents were included. Studies focusing exclusively on adults or lacking clinical relevance were excluded. A qualitative synthesis was performed due to the heterogeneity in study designs and outcomes. Results: This review demonstrates that pediatric atopic dermatitis exhibits marked age-dependent clinical heterogeneity, with distinct morphological features and lesion distribution patterns across infancy, childhood, and adolescence. Furthermore, the substantial clinical overlap with a broad spectrum of inflammatory, infectious, and genetic disorders—combined with the absence of specific diagnostic biomarkers—significantly complicates accurate differential diagnosis and increases the risk of misclassification. Conclusions: The recognition of age-specific patterns and potential mimickers is essential for improving diagnostic accuracy and guiding appropriate management in pediatric AD. Full article

Diabetes mellitus affects an estimated 589 million adults globally, and cutaneous manifestations occur in up to 70% of affected individuals during the course of the disease. The objective of this narrative review is to examine the intersection of diabetes mellitus, skin aging, cosmetic dermatologic procedures, and regenerative therapies, with an emphasis on evidence-based best practices and clinical considerations. While the impaired wound healing associated with diabetes has been extensively studied, the aesthetic implications of diabetic skin disease remain comparatively underexplored. Individuals with diabetes frequently exhibit features of accelerated cutaneous aging, including premature wrinkling, dyschromia, xerosis, alopecia, and other cosmetically significant dermatoses that may negatively impact quality of life. In parallel, the demand for aesthetic dermatologic procedures among patients with diabetes has increased substantially; however, evidence-based recommendations guiding the safe and effective use of cosmetic interventions in this population remain limited. Diabetic skin demonstrates accelerated biological aging driven by complex pathophysiological mechanisms, including the accumulation of advanced glycation end products, chronic low-grade inflammation, oxidative stress, microvascular dysfunction, and neuropathy. These processes partially overlap with chronological aging and photoaging but are mechanistically distinct and may influence tissue repair, inflammatory responses, and the safety profile of commonly performed aesthetic procedures such as chemical peels, laser resurfacing, dermal fillers, neuromodulators, and microneedling. Emerging regenerative approaches, including platelet-rich plasma, platelet lysate, and mesenchymal stromal cell-derived products such as exosomes and secretomes, have attracted increasing attention as biologically targeted strategies for cutaneous rejuvenation. Nevertheless, clinical evidence specifically addressing aesthetic interventions in diabetic populations remains limited. A diabetes-informed approach to aesthetic dermatology that considers metabolic status, procedure selection, and post-procedural monitoring is therefore essential to optimize safety and therapeutic outcomes. Full article

Background: Chronic Kidney Disease-associated Pruritus (CKD-aP) is a frequent, debilitating, and often underestimated symptom in clinical practice, with significant impacts on quality of life, sleep, mental health, and therapeutic adherence. This study aimed to develop a structured, person-centered nursing care overview for the management of CKD-aP. Methods: A comprehensive narrative review of the recent scientific literature on CKD-aP was conducted, adapting the conceptual domains of the European Specialist Nurses Organisation (ESNO) Common Training Framework (CTF) to nephrology nursing practice. The theoretical model guiding the work was Virginia Henderson’s paradigm, selected for its consistency with care models focused on promoting independence and meeting fundamental human needs. The study would answer the main research question “Which nursing evidence, tools, and strategies can support integrated, patient-centered management of CKD-aP?”. Results: A structured nursing care process was developed, articulated in sequential phases (assessment, problem definition, planning, intervention, and re-evaluation), visually represented in an operational flowchart and supported by validated clinical tools. The model emphasizes the nurse’s role in the multidimensional management of the symptom, incorporating educational, relational, therapeutic, and coordination-focused interventions. Conclusions: This proposal contributes to nephrology nursing practice by providing a theoretical and practical framework to standardize the management of CKD-aP. It promotes a holistic, evidence-based approach tailored to individual care needs, establishing a foundation for future clinical, educational, and research developments. Full article

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Although EGFR-TKIs can cause various adverse events (AEs), their profiles have not been fully elucidated in Thai patients. This study aimed to determine the incidence, characteristics, severity, and duration of the first AEs and to evaluate their association with tumor response in patients with NSCLC receiving EGFR-TKIs. Method: This retrospective cohort study was conducted at a super-tertiary care hospital in Thailand. Patients with NSCLC who received EGFR-TKIs between August 2021 and July 2024 were included. Descriptive statistics were used to summarize safety profiles and tumor response. The association between AEs and objective response was assessed using logistic regression. Results: A total of 187 patients were included in this study. Overall, 177 AEs were observed in patients receiving erlotinib, osimertinib, or gefitinib. The most common cutaneous AEs were rash (30.7%), xerosis (24.1%), and acneiform rash (19.3%), while diarrhea (20.3%) was the most frequent gastrointestinal toxicity. Most AEs were grade 1–2 and occurred within 1 month after treatment initiation. In multivariable logistic regression analysis, pruritus (OR 8.26, 95% CI: 1.00–67.75, p = 0.049) and treatment line (OR 0.27, 95% CI: 0.10–0.68, p = 0.006) were independently associated with objective response. Conclusion: Most of the AEs occurred early during EGFR-TKI therapy, with cutaneous reactions being the most common and generally mild to moderate. Pruritus and treatment line were independently associated with objective response, suggesting that pruritus may serve as a potential clinical indicator of treatment response and highlighting the importance of monitoring of the EGFR-TKI-related AEs during therapy. Full article

Amivantamab plus lazertinib (amivantamab+lazertinib) is a novel combination therapy used to treat epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although this regimen has demonstrated clinical efficacy in locally advanced or metastatic NSCLC, it is associated with a range of dermatologic adverse events that may develop rapidly and require prompt intervention. Early management of these side effects is critical for maintaining oncologic treatment, optimizing clinical outcomes, and improving patients’ quality of life. Cases: We present four patients with EGFR-mutated NSCLC who experienced dermatologic adverse events during amivantamab+lazertinib therapy. Two developed severe facial papulopustular eruptions, and two presented with necrotic folliculitis with sanguineous scalp erosions. Additional dermatologic manifestations included paronychia, pruritus, xerosis, mucositis, and trichomegaly. Notably, one patient experienced milder dermatologic side effects due to early initiation of a dermatologic prophylactic regimen. Conclusions: Dermatologic adverse events during amivantamab+lazertinib therapy are frequent and may be more severe than those typically observed with EGFR inhibitors. Early prophylactic measures and timely intervention are essential for managing these adverse events, supporting treatment adherence, and maximizing the therapeutic efficacy of this combined oncologic regimen. Full article

Objective: This study aimed to design and clinically evaluate a bespoke cosmetic formulation tailored to individual skin characteristics and user preferences, focusing on hydration and barrier recovery in mature, therapy-affected skin. In addition, this study aimed to explore the feasibility and short-term outcomes of a structured, biometry-driven personalization approach applied within a single-subject case study design. Materials and Methods: A personalized dermato-cosmetic formulation incorporating melatonin, astaxanthin, low-molecular-weight hyaluronic acid, allantoin, yarrow oil (Achillea millefolium), lecithin, cholesterol, and arginine was developed based on objective biophysical assessment of the skin. A clinical case evaluation was conducted in a male subject over 55 years of age (Fitzpatrick phototype III) presenting persistent xerosis and dehydration following completed oncologic therapy. Quantitative skin biometry was performed at baseline and after 28 days of daily application, assessing hydration at six anatomical sites, sebum secretion, pigmentation and erythema indices, elasticity, and stratum corneum turnover and scaling. Results: After 28 days, sebum secretion increased by more than 100%, indicating partial restoration of the lipid barrier. Hyperpigmented areas decreased from 7.2% to 2.3%, while skin elasticity improved from 25% to 44%. A reduction of 8% in the erythema index suggested decreased vascular reactivity. Hydration levels improved consistently across all evaluated sites, and epidermal renewal was enhanced, as evidenced by reduced scaling and smoother skin surface. The melanin index remained stable throughout the study period. Conclusions: This pilot evaluation shows that bespoke cosmetic formulations, customized to individual skin biometry and preferences, can yield measurable improvements in hydration, barrier repair, elasticity, pigmentation uniformity, and epidermal renewal within 28 days, even in skin compromised by previous oncologic therapy. Given the single-subject nature of this pilot evaluation, these findings cannot be generalized to broader populations but rather highlight the importance of personalization and objective skin assessment in guiding individualized dermato-cosmetic formulation strategies. Personalized dermato-cosmetology using objective biophysical assessment may be a promising future strategy for effective, consumer-centered skincare. Full article

This systematic review examines chronic kidney disease-associated pruritus (CKD-aP) as a complex clinical manifestation in patients undergoing hemodialysis. Traditionally considered a secondary symptom of end-stage renal disease, emerging evidence now positions CKD-aP as a multidimensional disorder with substantial pathogenic influence on patient outcomes. Using the PRISMA 2020 methodology, we critically evaluated 54 peer-reviewed studies published between 2020 and 2025. Our synthesis highlights a convergence of five mechanistic frameworks underpinning CKD-aP: elevated levels of uremic toxins originating from gut microbial dysbiosis, immune activation driven by IL-31 and other pro-inflammatory cytokines, heightened peripheral and central neural sensitization, dysregulation of endogenous opioid receptor pathways favoring μ-receptor activation, and xerosis-related epidermal barrier dysfunction. These mechanisms contribute to a systemic cycle of microinflammation, pruritogenic signaling, and neural hyperexcitability. We also identified and compared validated assessment tools—including the NRS, VAS, Skindex-10, and the UP-Dial scale—that facilitate standardized quantification of disease burden. While available treatments such as gabapentinoids and phototherapy offer partial relief, targeted therapies—including κ-opioid receptor agonists—represent a major advancement, although long-term effectiveness and accessibility remain under investigation. Growing scientific consensus establishes CKD-aP as a priority therapeutic target in hemodialysis care, underscoring the need for integrated, mechanism-based management strategies to improve quality of life and clinical outcomes. This work represents a narrative systematic review, integrating evidence from mechanistic, translational, and clinical studies to critically examine the biological pathways underlying CKD-associated pruritus. Full article

Background/Objectives: Uremic pruritus is a common complication in patients with end-stage kidney disease undergoing maintenance hemodialysis. Despite its high prevalence and substantial impact on sleep, psychological well-being, and overall quality of life, its pathophysiology remains multifactorial and incompletely understood. This narrative review summarizes contemporary evidence (2015–2025) on therapeutic strategies for uremic pruritus, with an emphasis on emerging treatments and evolving mechanistic insights. Methods: A PubMed search was conducted for original clinical studies published between 1 January 2015, and 31 October 2025, evaluating treatments for uremic pruritus in adult hemodialysis patients. Eligible study designs included randomized controlled trials and observational interventional studies. Non-English articles, pediatric studies, peritoneal dialysis studies, reviews, case reports, and studies of mixed-etiology pruritus were excluded. Earlier literature was reviewed to contextualize epidemiology and pathophysiology. Results: The review identifies multiple interacting mechanisms—including uremic toxins, immune dysregulation, mineral abnormalities, xerosis, neuropathic changes, and dysregulated opioid signaling—contributing to itch generation. Topical therapies, especially emollients and humectants, consistently improved symptoms with excellent safety profiles. Optimization of dialysis adequacy and membrane selection showed benefit in selected patients. Among systemic therapies, gabapentinoids demonstrated the most robust efficacy but required cautious dosing. Sertraline, nalbuphine, and difelikefalin showed significant antipruritic effects in controlled trials. Emerging therapies, including AST-120, omega-3 fatty acids, and the biologic dupilumab, demonstrated promising but preliminary results. Conclusions: Management of uremic pruritus requires a multifaceted, individualized approach integrating skin-directed therapies, dialysis optimization, and targeted systemic treatments. Ongoing research is needed to identify reliable biomarkers and to develop safer, more effective, mechanism-based therapies. Full article

Background/Objectives: Chronic pruritus is a common and distressing symptom in geriatric dermatology, often intensified by age-related changes and frailty. Frailty, reflecting physiological decline and reduced resilience, may increase itch perception, yet its link to pruritus severity remains unclear. Our study aims to evaluate the association between pruritus severity and frailty in older dermatology patients and identify related clinical and dermatologic factors. Methods: A total of 171 patients aged ≥65 years with pruritus lasting more than six weeks were included. Pruritus was measured using the Visual Analog Scale (VAS) and 5-D Itch Scale, while frailty was assessed by the FRAIL scale. Xerosis severity was rated by the Overall Dryness Score (ODS), and data on itch duration, comorbidities, and medications were analyzed. Statistical significance was defined as p < 0.05. Results: The mean VAS and 5-D Itch scores were 6.2 ± 2.6 and 12.5 ± 3.1. Itch severity increased significantly across frailty categories (p < 0.001). Strong correlations were found between VAS and itch duration (r = 0.79, p < 0.001), ODS (r = 0.66, p < 0.001), and medication count (r = 0.56, p < 0.001). Similar associations were seen for 5-D Itch (r = 0.61, 0.64, and 0.54; p < 0.001). Age and comorbidities showed no significant correlation (p > 0.05). Conclusions: Pruritus severity in older adults was associated with xerosis, frailty, and polypharmacy, while no significant association with age was observed in univariable analyses. Incorporating frailty screening, ODS evaluation, and geriatric consultation into dermatologic care may improve management and quality of life in older adults with chronic pruritus. These findings reflect associations rather than causal relationships, as the cross-sectional design does not permit inference of directionality. Full article

Background: Tyrosine kinase inhibitors (TKIs) are crucial to treating endocrine-related malignancies, including advanced thyroid cancers and neuroendocrine tumors, but their benefit is tempered by cutaneous adverse events (CAEs) that impair adherence and quality of life. Objective: To summarize the dermatologic toxicities of TKIs used in endocrine oncology and provide practical, multidisciplinary guidance for prevention and management. Methods: Narrative synthesis of clinical trial reports, post-marketing studies, and specialty guidelines pertinent to lenvatinib, vandetanib, cabozantinib, and other commonly used TKIs, integrating dermatologic and endocrine perspectives on mechanisms and care pathways. Results: VEGFR-targeted TKIs frequently cause hand–foot skin reaction, xerosis, fissuring, paronychia, and impaired wound healing; multikinase inhibition also produces alopecia, pigmentary changes, and mucositis. Epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) inhibition with vandetanib is associated with acneiform eruption, photosensitivity, and nail fragility. Pathogenesis reflects on-target inhibition of VEGF/EGFR signaling leading to keratinocyte dysfunction, vascular fragility, and altered eccrine mechanics. Early risk stratification, patient education, and bundle-based prophylaxis (emollients, keratolytics, urea-based creams, sun protection) reduce incidence and severity. Grade-based algorithms combining topical corticosteroids/antibiotics, dose interruptions or reductions, and short systemic courses (e.g., doxycycline, antihistamines) enable symptom control while maintaining anticancer intensity. Close coordination around procedures minimizes wound-healing complications. Conclusions: Dermatologic toxicities are predictable, mechanism-linked, and manageable with proactive, multidisciplinary care. Standardized prevention and treatment pathways tailored to specific TKIs—particularly lenvatinib, vandetanib, and cabozantinib—can preserve dose intensity, optimize quality of life, and sustain antineoplastic efficacy. Full article

Background/Objectives: Mechanical alloknesis (m-alloknesis), the sensation of itch evoked by normally non-pruritic mechanical stimuli, is commonly observed in dry skin-associated conditions, such as xerosis, atopic dermatitis (AD), and psoriasis. Janus kinase (JAK) inhibitors are currently used to treat AD and suppress inflammation and itch. However, their specific roles in the modulation of m-alloknesis remain unclear. Therefore, in this study, we investigated the effects of various oral JAK inhibitors on m-alloknesis using a murine model of AD. Methods: An AD-like phenotype was induced in mice through the repeated topical application of an ointment containing Dermatophagoides farinae (house dust mite) extract. The mice were then orally treated with one of three JAK inhibitors: the JAK1/2 inhibitor baricitinib, the JAK1-selective inhibitor abrocitinib, or the JAK2-selective inhibitor AZ960. M-alloknesis was evaluated by quantifying scratching behavior in response to 30 controlled mechanical stimuli applied to lesional skin. Results: The JAK inhibitor treatments did not affect skin barrier integrity, dermatitis severity, or spontaneous scratching behavior. However, baricitinib and abrocitinib significantly reduced m-alloknesis scores, whereas AZ960 had no effect. Conclusions: These results suggest that JAK1 signaling plays a critical role in the induction of m-alloknesis in AD. Selective JAK1 inhibition is a promising therapeutic strategy for attenuating m-alloknesis and improving quality of life for patients with AD, independent of general skin inflammation and barrier function. Full article

Objectives: Oral isotretinoin remains the most effective therapy for severe acne, but its exceptional efficacy is often accompanied by relatively frequent adverse effects. In this study, we quantified the frequency- and dose-related predictors of clinical and biochemical adverse effects during isotretinoin treatment in routine Polish practice. Methods: The records of 370 patients (mean age: 28 ± 12 years) who began isotretinoin treatment between June 2020 and June 2025 were reviewed. The mean daily isotretinoin and cumulative isotretinoin doses were 23.4 ± 9.1 mg and 88.3 ± 31.5 mg/kg, respectively. The adverse events documented at two-monthly visits were correlated with age and dosing. Lipid, hepatic, thyroid and prolactin panels were compared with age- and sex-matched controls using χ² statistics and odds ratios (ORs). Results: Xerosis (70%), retinoid dermatitis (20%) and cheilitis (15.5%) predominated. Hand eczema rose with higher daily isotretinoin doses (ρ = 0.082; p = 0.037), whereas pruritus declined with greater cumulative isotretinoin exposure (ρ = −0.088; p = 0.037). Retinoid dermatitis was linked to a younger age (ρ = −0.080; p = 0.0286), whereas desquamation increased slightly with age (ρ = +0.083 p = 0.0228). Overall, dyslipidemia was twice as common as in the controls (OR: 2.06; 95% CI: 1.49–2.86; p-value: <0.0001), which was driven by an elevated total cholesterol (OR: 1.93; 95% CI: 1.34–2.77; p-value: 0.0004), LDL (OR: 3.40; 95% CI: 2.26–5.10; p-value: <0.0001) and triglycerides (OR: 1.95; 95% CI: 1.20–3.17; p-value: 0.0062) and decreased HDL (OR: 2.68; 95% CI: 1.75–4.10; p-value: <0.0001). Interestingly, hyperprolactinemia occurred eight-fold more often (OR: 8.42; 95%; 95% CI: 2.97–23.84; p-value: <0.00001). Aminotransferase and TSH elevations were infrequent and statistically non-significant. Conclusions: At moderate cumulative doses, isotretinoin was generally well tolerated; however, clinically relevant lipid and prolactin disturbances were frequent. Routine lipid and endocrine monitoring, early emollient prophylaxis and dose individualization are recommended to ensure safe isotretinoin usage in everyday practice. Full article

Background: Pedal fissures present challenges for affected individuals, from cosmetic concerns to potential infection risks. Urea 40% was previously a common treatment for pedal fissures, particularly in its prescription form, but its use has declined and it is now widely available over the counter and is no longer covered by many insurance plans. Alternatives to prescription urea 40% often contain additional ingredients, such as salicylic acid. Although a common exfoliant in dermatologic treatments, salicylic acid can cause burning and exacerbate irritation, particularly when used on pedal fissures, thus hindering healing. This study aimed to assess the efficacy of urea 40% compared with a novel skin barrier repair cream designed to address pedal fissures without the irritation while still providing healing results. The novel skin barrier repair cream uses natural ingredients without fragrances or dyes and incorporates hyaluronic acid, which helps the skin retain moisture and stay hydrated without breaking down the surrounding tissue. Methods: This double-blind study enrolled 48 participants who were assessed every 2 weeks over 28 days of treatment. Participants were divided into two groups, each receiving either urea 40% or the novel skin barrier repair cream for daily use. Follow-up visits included detailed records of xerosis and fissure progression, with parameters analyzed for comparative efficacy. Results: Significant improvement in function was observed in the group treated with the novel skin barrier repair cream. The results showed minimal statistical difference in healing between the novel skin barrier repair cream and urea 40% across all measured parameters. Conclusions: The novel skin barrier repair cream provides a comparably effective treatment for pedal fissures without additional side effects. This finding highlights the potential of the novel skin barrier repair cream as a viable alternative to the currently available over-thecounter formulations, addressing both effectiveness and affordability in managing pedal fissures. Full article