European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

VACCINE HESITANCY - FROM PARENTAL DISTRUST TO COVID-19 CONSPIRACIES.

Worldwide studies continuously confirm that vaccination is a safe and effective method of combating various infectious diseases and a key component of global public health programs. However, the vaccination status of a population is often lower than needed to achieve collective immunity. A key reason that affects lower vaccination coverage is vaccine hesitancy, identified as one of the ten greatest threats to global public health. So far, vaccine hesitancy has been most investigated in the context of parental refusal of children vaccination. The emergence of the COVID-19 pandemic and the development of its vaccines put vaccine hesitancy further in the focus of investigators as well as healthcare workers and policy makers. We have witnessed its immediate effects on public health and mortality rates as well as even more extreme ways of vaccine refusal than previously documented. The aim of this review article is to summarize relevant scientific understandings of vaccine hesitancy, including its psychological determinants, insights from parental refusal of child vaccination, medical distrust, and conspiracy theories related to the COVID-19 pandemic, as well as recommendations for public health services for combating vaccine hesitancy.

Painful and Itchy Dermatoses Carry the Highest Psychological Burden for Dermatovenereological Patients.

BACKGROUND: Most dermatovenereological diseases are not life-threatening but nevertheless are highly prevalent disorders. Psychosocial aspects of skin diseases and physical symptoms strongly influence patient's quality of life (QoL) which results in the development of different coping mechanisms in patient's behaviour. Development of psychiatric comorbidity in patients with skin diseases is well known. On the other hand, little is known about psychological comorbidity associated with dermatovenereological diseases. Aims of this study were to investigate QoL and psychological burden among dermatovenereological patients. SUBJECTS AND METHODS: Two hundred and ninety patients suffering from different dermatological and venereological diseases participated in the study, divided into three study groups: itchy/painful dermatoses, non-itchy/non-painful dermatoses and venereological diseases. Participants completed standardized psychological questionnaires: Dermatology Specific Quality of Life (DSQL), Beck Depression Inventory (BDI) and State and Trait Anxiety Inventory (STAI). Intensity of the disease and localisation of the lesions were also assessed. RESULTS: Physical aspect of QoL was mostly influenced by itchy/painful dermatoses but psychological aspect and everyday activities and choices were mostly affected by patients with non-itchy/non-painful dermatoses and venereological diseases. 4.1% of participants had serious depressive symptoms, 11.5% had high and very high anxiety symptoms as state and 15.6% as trait. However, participants with severe skin conditions were more depressed, while participants with always and sometimes exposed lesions were more anxious. CONCLUSION: It is essential to recognise subgroups of dermatovenereological patients whose treatment approach should be interdisciplinary. Further studies are needed to detect psychosocial needs of patients with venereological diseases.

CAN SKIN BE A MARKER FOR INTERNAL MALIGNANCY? EVIDENCE FROM CLINICAL CASES.

Although there are many single case reports on paraneoplastic dermatoses in the literature, there are very rare articles containing multiple cases. A retrospective study was performed to examine paraneoplastic dermatoses and accompanying malignancies based on skin manifestations and appropriate diagnostic evaluations. We recorded outcomes, current conditions, and surgical/oncologic treatments. Analysis revealed paraneoplastic dermatoses in 17 patients with various skin lesions, i.e. eczematous dermatitis, vasculitis, subacute cutaneous lupus erythematosus, pruritus, chronic urticaria/angioedema, alopecia areata, flushing, bullous pemphigoid, dermatomyositis, and localized scleroderma (morphea). They were associated with different solid and hematologic malignancies (3 gastric, 2 prostate, 2 bladder, 2 thyroid, and 2 lymphoma), along with 1 case each of the following: lung, hepatocellular, esophageal, endometrial, kidney, and multiple myeloma. The majority of skin lesions gradually regressed after malignancy treatment. To our knowledge, our three cases of paraneoplastic eczematous dermatitis are the first to be associated with gastric, prostate and endometrial cancer. Additionally, we report a case of a patient with alopecia areata of the beard associated with thyroid cancer. Early malignancy detection based on skin markers makes early introduction of surgical/oncologic therapy possible and usually leads to skin lesion regression while reducing revolving door visits to specialists and the (financial) burden on the healthcare system.

Study on the Impact of Psoriasis on Quality of Life: Psychological, Social and Financial Implications.

BACKGROUND: Psoriasis is a chronic and stigmatising disease with significant and hard to meet clinical needs in patient management. Psoriasis is a relatively common disease, affecting up to 2% of the population. The impact of psoriasis on quality of life is significant given its chronicity and visibility. Psychological stress is a well-established systemic triggering factor in psoriasis. It has been associated with initial presentation of the disease as well as exacerbations of pre-existing psoriasis. The purpose of this study is to assess the psychological, social and financial implications of psoriasis. SUBJECTS AND METHODS: 51 patients participated in this study. After dermatological examination and determination of Psoriasis Area and Severity Index score, patients were referred to a psychological consult. Assessment was done through questionnaires concerning quality of life, depression, anxiety, illness perception, financial domain and personal data. RESULTS: Results of our study indicate that psoriasis has a strong impact on patients' life. It influences working habits, poses a significant financial burden, but most of all, significantly impairs their quality of life and psychological status. CONCLUSION: Psoriasis poses a substantial threat to several dimensions in patient's quality of life. Patients feel that the current treatment, although often effective, does not provide a satisfactory long-term solution. Thus, long-term psychologic support for patients with psoriasis is desirable.

Challenges and strategies in dermatologic therapy-Personalized medicine, patient safety, and pharmacoeconomics.

Skin conditions are among the most prevalent and disabling diseases affecting millions of people worldwide. Recently, there have been significant changes in dermatologic clinical practice. Advances in knowledge of disease pathophysiology have led to significant breakthroughs in diagnostics and therapy, as well as discovery of new treatment modalities. Additionally, research focusing on differences between individual patients has resulted in the growth of personalized medicine. Health care professionals are focusing on tailoring therapy to the individual characteristics of each patient, which in turn leads to improved quality of care and management of each individual. Of note, patient safety may be compromised when applying or taking dermatologic therapy as a result of medical error, patient noncompliance, adverse effects, or drug interactions. It is therefore of great importance to minimize, and if possible prevent these risks. Finally, the appraisal of health care goods and services currently does not only analyze the safety and efficacy of treatment, but also considers the economic impact on the cost of health care. Consequently, pharmacoeconomic evaluation has become an essential step in the introduction of new dermatologic treatments and the rational use of pharmaceuticals.

Mission impossible: Dermal delivery of growth factors via microneedling.

The clinical application of transdermal delivery has been limited to lipophilic drugs with a molecular weight of less than 500 Da. The development of polymeric microneedles enabled the transdermal delivery of larger proteins and drugs. Extensive research has been conducted on the molecular size, solubility, pH, concentration, and polarity of transdermal delivery; however, the maximal molecular weight for transdermal microneedle delivery has not been established. Clinicians often use simple microneedles to deliver high molecular weight growth factors of platelet-rich plasma across the skin; thus, we set out to explore the feasibility of delivering growth factors through microneedling. In this communication, we present histological evidence that microneedling do not enhance transdermal delivery of growth factors and thus provide no clinical benefit.

Tretinoin enhances minoxidil response in androgenetic alopecia patients by upregulating follicular sulfotransferase enzymes.

Minoxidil sulfate is the active metabolite required to exert the vasodilatory and hair growing effects of minoxidil. For hair growth, sulfotransferase enzymes expressed in outer root sheath of the hair follicle sulfonate minoxidil. The large intra-subject variability in follicular sulfotransferase was found to predict minoxidil response and thus explain the low response rate to topical minoxidil in the treatment of androgenetic alopecia. A method to increase minoxidil response would be of significant clinical utility. Retinoids have been reported to increase minoxidil response. The purported mechanism of action was retinoid modulation of skin permeation to minoxidil; however, evidence to the contrary supports retinoids increase dermal thickness. In order to elucidate the effect of topical retinoids on minoxidil response, we studied the effect of topical tretinoin on follicular sulfotransferase. In this study, we demonstrate that topical tretinoin application influences the expression of follicular sulfotransferase. Of clinical significance, in our cohort, 43% of subjects initially predicted to be nonresponders to minoxidil were converted to responders following 5 days of topical tretinoin application. To the best of our knowledge, this is the first study to elucidate the interaction mechanism between topical minoxidil and retinoids and thus provides a pathway for the development of future androgenetic alopecia treatments.

Styling without shedding: Novel topical formula reduces hair shedding by contracting the arrector pili muscle.

Approximately 40% of women experience excessive hair shedding during styling (e.g., hair brushing). Previously, we demonstrated that topically applied phenylephrine, a potent α1 adrenergic receptor agonist, can be used to contract the arrector pili muscle of the follicular unit; thus, increasing the force required to pluck hair and reducing shedding during brushing. While demonstrating efficacy, phenylephrine has several drawbacks when applied to the scalp, including the possibility cardiovascular events. We hypothesized that a high concentration of a weak α1 agonist would allow for: (a) rapid penetration through the stratum corneum eliciting a quick response; (b) a low probability of cardiac adverse events owing to the low receptor binding affinity; and (c) an efficacy of the weak α1 agonist similar to that of phenylephrine at the local site of application. Accordingly, we developed a novel topical solution, AB-102, containing a high concentration of a weak α1 agonist. Several studies were conducted to test the safety and efficacy of AB-102. In a dose escalating safety study, utilizing a wearable holter monitor, we observed no cardiac or hemodynamic adverse events. In addition, in a controlled efficacy study, AB-102 reduced the number of hairs shed during brushing by up to 77% (average of 38%).

Characterization of follicular minoxidil sulfotransferase activity in a cohort of pattern hair loss patients from the Indian Subcontinent.

Several studies have established that sulfotransferase enzyme activity in the outer root sheath of plucked hair follicles predicts response to topical minoxidil in the treatment of pattern hair loss. However, the prevalence of this enzyme activity among Indian patients has not been studied. Additionally, no reports in the literature characterize sulfotransferase activity based on sex, age, duration of hair loss, grade of hair loss, and family history. In this study we utilized a sulfotransferase activity assay first reported by Goren et al. We characterize the follicular sulfotransferase activity of 120 pattern hair loss patients visiting a dermatology outpatient clinic in India. Overall, 40.8% of patients with pattern hair loss had low levels of sulfotransferase. Surprisingly, 49.3% of men had low levels of sulfotransferase compared to 26.6% of women. No correlation was found between sulfotransferase activity and age, duration of hair loss, grade of hair loss, or family history. A sub-analysis of patient reported outcomes (PRO) validated previous findings that sulfotransferase enzyme activity is a predictive marker for minoxidil response in pattern hair loss patients.

Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.

We describe a case of twins with sporadic Gorlin syndrome. Both twins had common Gorlin syndrome features including calcification of the falx cerebri, multiple jaw keratocysts, and multiple basal cell carcinomas, but with different expressivity. One brother also had benign testicular mesothelioma. We propose this tumor type as a possible new feature of Gorlin syndrome. Gorlin syndrome is a rare autosomal dominant disorder characterized by both developmental abnormalities and cancer predisposition, with variable expression of various developmental abnormalities and different types of tumors. The syndrome is primarily caused by mutations in the Patched 1 (PTCH1) gene, although rare mutations of Patched 2 (PTCH2) or Suppressor of Fused (SUFU) genes have also been found. Neither founder mutations nor hot spot locations have been described for PTCH1 in Gorlin syndrome patients. Although de novo mutations of the PTCH1 gene occur in almost 50% of Gorlin syndrome cases, there are a few recurrent mutations. Our twin patients were carriers of a de novo mutation in the PTCH1 gene, c.3364_3365delAT (p.Met1122ValfsX22). This is, to our knowledge, the first Gorlin syndrome-causing mutation that has been reported four independent times in distant geographical locations. Therefore, we propose the location of the described mutation as a potential hot spot for mutations in PTCH1.

NOTALGIA PARESTHETICA.

- Notalgia paresthetica is a common, although under-recognized condition characterized by localized chronic pruritus in the upper back, most often affecting middle-aged women. Apart from pruritus, patients may present with a burning or cold sensation, tingling, surface numbness, tenderness and foreign body sensation. Additionally, patients often present with hyperpigmented skin at the site of symptoms. The etiology of this condition is still poorly understood, although a number of hypotheses have been described. It is widely accepted that notalgia paresthetica is a sensory neuropathy caused by alteration and damage to posterior rami of thoracic spinal nerves T2 through T6. To date, no well-defined treatment has been found, although many treatment modalities have been reported with varying success, usually providing only temporary relief.

THE PREVALENCE OF ONYCHOMYCOSIS IN THE ZAGREB AREA - THE ROLE OF SABOURAUD AGAR WITHOUT CYCLOHEXIMIDE IN DIAGNOSIS AND THERAPY.

- Mycological analysis is considered the gold standard in the diagnosis of very common fungal diseases of nails. The purpose of the article is to present the prevalence of onychomycosis obtained by using direct microscopic examination (DME) and cultivation on Sabouraud media without cycloheximide. The quantitative retrospective research was conducted on 2706 patients of both sexes (mostly middle-aged to elderly) with various toenail lesions, who had undergone mycological analyses in the Mycological Laboratory of our Department of Dermatovenereology in 2013 and 2014. Analysis of the results obtained revealed that there were 35.4% of positive DME results; of these, there were 39.2% of dermatophytes, 59.1% of yeasts and 1.7% of molds. The percentage of dermatophytes (Trichophyton spp.) was twice as high in men as in women. A considerable percentage (12%) of mixed isolates was also observed. Particularly worrisome was the high percentage (one-third) of suppressed and insufficiently developed dermatophytes (a possible indicator of inappropriate preparation of patients for mycological analysis). Cultivation on culture media without cycloheximide requires frequent inspections because of the fast-growing molds while not allowing sporulation for a great number of dermatophytes. However, it has certain advantages, i.e. it offers an insight into the wide range of the present fungi. As part of the biofilm, they can be potentially pathogenic in dystrophic nails under certain circumstances because, according to our results, the percentage of dermatophytes does not change substantially with aging; however, what does change is the percentage of molds, yeasts and mixed isolates.

Prevalence of hair shedding among women.

Hair shedding in female patients is a frequent complaint in dermatological, endocrinological, and gynecological consults. Previously, the Sinclair Hair Shedding Scale was developed to assess normal versus excessive hair shedding in female pattern hair loss (FPHL) subjects. However, the prevalence of hair shedding in females not suffering from FPHL is unknown. To gain better understanding of hair shedding in the general population, we recruited 300 subjects visiting a public hospital for conditions other than alopecia. Of the 300 subjects recruited, 263 did not suffer from FPHL. Among those subjects, approximately 40% reported experiencing excessive hair shedding (as defined by the Sinclair Hair Shedding Scale) on hair washing days. In comparison, in our subject population, approximately 60% of subjects with FPHL reported excessive hair shedding on hair washing days. To best of our knowledge, this is the first study to quantify the prevalence of hair shedding in women. While, no treatment currently exists for this condition, we hope that this study would encourage physicians and researchers to address this frequent concern.

Combined therapy for resistant vitiligo lesions: NB-UVB, microneedling, and topical latanoprost, showed no enhanced efficacy compared to topical latanoprost and NB-UVB.

Vitiligo is depigmenting disorder of the skin and mucous membranes but despite various therapeutic options, complete and satisfactory treatment of vitiligo still remains a challenge. Therapeutic success also varies depending on the localization of lesions; hands and bony prominents are considered to be resistant to treatment. We investigated feasibility of treating resistant bilateral symmetrical vitiligo vulgaris and acrofacialis lesions with combination of narrowband UVB and topical prostaglandins (0.005% latanoprost solution) with or without Dermaroller 0.5 mm needle length-assisted microneedling. Frequency of repigmentation onset was generally low (37.8%) and pronounced repigmentation was infrequently seen (26-50% repigmentation in 20.8%, and >50% repigmentation in only 8.8% of repigmenting lesions). Our study, however, showed that latanoprost can be used in combination with NB-UVB phototherapy to induce repigmentation in some vitiligo lesions in resistant-to-treatment location, while addition of skin microneedling seems not to improve the treatment outcome and possibly needs modification.

Platelet-rich plasma as a novel treatment for lichen planopillaris.

Treatment of lichen planopillaris (LPP) remains a significant challenge due to the irreversible damage inflicted on hair follicles combined with the low efficacy of existing treatments. We hypothesized that growth factors released by the use of platelet-rich plasma (PRP) may arrest the development of LPP. To test our hypothesis, we treated an LPP patient that has failed previous treatments with a new PRP regimen. Following PRP treatment and six months follow-up, the patient experienced complete regression of itching and hair shedding. To the best of our knowledge, this is the first report of successful treatment of LPP with a PRP regimen.

Mixed vitiligo of Blaschko lines: a newly discovered presentation of vitiligo responsive to combination treatment.

Vitiligo, depigmenting disorder of the skin and mucous membranes, affects up to 1% of the population worldwide. It is classified into four major types: segmental, non-segmental, mixed, and unclassified type. Non-segmental vitiligo refers to non-dermatomal distribution of lesions, while dermatomal distribution of lesions is present in patients with segmental vitiligo. Segmental vitiligo can also follow Blaschko lines - pathways of epidermal cell migration and proliferation during the development of the fetus. Here, we present patient with segmental and non-segmental vitiligo following Blaschko lines with excellent therapeutic response to combined therapy. Prior to our report, a case of segmental and non-segmental vitiligo followed by Blaschko lines was never described, therefore we suggest the term "mixed vitiligo of Blaschko lines" to describe this entity. This is also a rare case in which 90% repigmentation was achieved in patient with segmental and nonsegmental vitiligo following Blaschko lines in only 2 months of combined therapy.

Quality of Life in Families with Children with Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common childhood disease of increasing prevalence that not only changes the life of the affected children, but also affects the social and emotional functioning of their families. OBJECTIVES: The aim of our study was to assess the quality of life (QOL) of parents with children with AD and its predictors. METHODS: One hundred seventy-one parents of children with AD attending the outpatient Pediatric Dermatology Unit, Children's Hospital Zagreb, participated in the study. The severity of AD was estimated using the Scoring Atopic Dermatitis (SCORAD) index. Parents were asked to complete the Croatian version of the Family Dermatology Life Quality Index (FDLQI), the Patient-Oriented (PO) SCORAD, the Perceived Stress Scale (PSS), and a general questionnaire during a regular follow-up visit. RESULTS: Family QOL is significantly correlated with the SCORAD score (correlation coefficient [r] = 0.578), PO SCORAD (r = 0.447), itching (r = 0.528), sleeplessness (r = 0.583), and PSS (r = 0.464). When these factors were entered into a regression analysis, they predicted as much as 67% of the variance of QOL (FDLQI), with significant predictors being PO SCORAD, PO sleeplessness, and PSS, and they remained significant even after controlling for a number of general and medical factors. CONCLUSIONS: The severity of illness as perceived by dermatologists and parents is similar, and itching, sleeplessness, and perceived stress are strong QOL predictors of parents caring for children with AD.