Mindfulness programs for problematic usage of the internet: A systematic review and meta-analysis.

Introduction: Problematic usage of the internet (PUI) is an umbrella term for a range of uncontrolled, excessive, and potentially harmful online behaviors. Recently, numerous studies have examined the potential of mindfulness programs (MPs) for reducing PUI. We conducted a comprehensive systematic review and meta-analysis in this emerging field. Methods: We searched eight databases from inception to October 18, 2022, with no language restrictions. We included randomized controlled trials (RCTs) and nonrandomized trials (NRTs). The primary outcome was change in self-reported PUI, the secondary outcome was change in screen time. Results: Of 3,473 identified records, 19 RCTs and 20 NRTs with a total of 1,549 participants were included. Participation in an MP was associated with large reductions in PUI in between-group analysis in RCTs (k = 19; g = -1.67; 95% CI -2.15, -1.19) and in within-group pre-post analysis in all studies (k = 35; g = -1.67; 95% CI -1.99, -1.36). Screen time showed a medium reduction in within-group pre-post analysis (k = 10; g = -0.65; 95% CI -0.90, -0.41). The effects for PUI remained significant in a series of sensitivity analyses, such as excluding low quality studies, excluding outliers, adjusting for publication bias, or using follow-up data. Heterogeneity between studies was high and the overall quality of evidence was rated low. Discussion and conclusions: MPs are probably effective in reducing PUI and might be effective in reducing screen time. Shortcomings in the quality of evidence highlight the need for high-quality controlled trials with long-term follow-ups to confirm results.

Effects of a leave-on product on the strength of the dermoepidermal junction: An exploratory, intraindividual, randomized controlled trial in older adults with dry skin.

Background and Aims: Skin aging is associated with dry skin and a decrease of the strength of the dermoepidermal adhesion, which increases the risk for lacerations (skin tears). Application of leave-on products improves dry skin and seems to reduce skin tear incidence. The aim of this study was to measure the effects of a humectant containing leave-on product on the strength of the dermoepidermal junction in older adult participants with dry skin. Methods: A randomized controlled trial using a split body design was conducted. One forearm was randomly selected and treated with a lipophilic leave-on product containing 5% urea for 8 weeks. The other forearm was the control. The parameters stratum corneum hydration (SCH), transepidermal water loss, pH, roughness, epidermal thickness and skin stiffness were measured at the baseline, Weeks 4 and 8. At Week 8, suction blisters were created and time to blistering was measured. Blister roofs and interstitial fluid were analyzed for Interleukin-1α, 6 and 8. Results: Twelve participants were included. After 8 weeks treatment, SCH was higher (median difference 11.6 AU), and the overall dry skin score (median difference -1) and median roughness (Rz difference -12.2 µm) were lower compared to the control arms. The median group difference for Interleukin-1α was -452 fg/µg total protein (TP) in the blister roofs and -2.2 fg/µg TP in the blister fluids. The median time to blister formation was 7.7 min higher compared to the control arms. Conclusion: The regular application of humectant containing leave-on products improves dry skin and seems to lower inflammation and contribute to the strengthening of the dermoepidermal adhesion. This partly explains how the use of topical leave-on products helps to prevent skin tears.

Topical Delivery of Tofacitinib in Dermatology: The Promise of a Novel Therapeutic Class Using Biodegradable Dendritic Polyglycerol Sulfates.

Inflammatory skin diseases, such as psoriasis, atopic dermatitis, and alopecia areata, occur when the regulatory tolerance of the innate immune system is disrupted, resulting in the activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory signaling pathway by interleukin 6 (IL-6) and other key inflammatory cytokines. JAK inhibitors, such as tofacitinib, bind to these enzymes which are coupled to receptors on cell surfaces and block the transcription of inflammatory cytokine-induced genes. The first topical applications are being marketed, yet insufficient effects regarding indications, such as alopecia areata, suggest that improved delivery technologies could help increase the efficacy. In this study, we used sulfated dendritic polyglycerol with caprolactone segments integrated in its backbone (dPGS-PCL), with a molecular weight of 54 kDa, as a degradable carrier to load and solubilize the hydrophobic drug tofacitinib (TFB). TFB loaded in dPGS-PCL (dPGS-PCL@TFB), at a 11 w/w% loading capacity in aqueous solution, showed in an ex-vivo human skin model better penetration than free TFB in a 30:70 (v/v) ethanol/water mixture. We also investigated the anti-inflammatory efficacy of dPGS-PCL@TFB (0.5 w/w%), dPGS-PCL, and free TFB in the water/ethanol mixture by measuring their effects on IL-6 and IL-8 release, and STAT3 and STAT5 activation in ex vivo skin models of simulated inflamed human skin. Our results suggest that dPGS-PCL@TFB reduces the activation of STAT3 and STAT5 by increasing the penetration of the tofacitinib. However, no statistically significant differences with respect to the inhibition of IL-6 and IL-8 were observed in this short incubation time.

Efficient skin interactions of graphene derivatives: challenge, opportunity or both?

Interactions between graphene, with its wide deployment in consumer products, and skin, the body's largest organ and first barrier, are highly relevant with respect to toxicology and dermal delivery. In this work, interaction of polyglycerol-functionalized graphene sheets, with 200 nm average lateral size and different surface charges, and human skin was studied and their potential as topical delivery systems were investigated. While neutral graphene sheets showed no significant skin interaction, their positively and negatively charged counterparts interacted with the skin, remaining in the stratum corneum. This efficient skin interaction bears a warning but also suggests a new topical drug delivery strategy based on the sheets' high loading capacity and photothermal property. Therefore, the immunosuppressive drug tacrolimus was loaded onto positively and negatively charged graphene sheets, and its release measured with and without laser irradiation using liquid chromatography tandem-mass spectrometry. Laser irradiation accelerated the release of tacrolimus, due to the photothermal property of graphene sheets. In addition, graphene sheets with positive and negative surface charges were loaded with Nile red, and their ability to deliver this cargo through the skin was investigated. Graphene sheets with positive surface charge were more efficient than the negatively charged ones in enhancing Nile red penetration into the skin.

Ciprofloxacin-Loaded Polyvinylpyrrolidone Foils for the Topical Treatment of Wound Infections with Methicillin-Resistant Staphylococcus aureus (MRSA).

Bacterial infections are a constant challenge in the management of acute and chronic wounds. Chronic wounds, such as diabetic foot ulcers, have increased significantly in the last few years due to the rise of an aging population. A better understanding of the infectious pathophysiological mechanisms is urgently needed along with new options for the treatment of wound infections and wound-healing disorders. New advances in the preparation of biocompatible dressing materials that can be loaded with antimicrobial drugs may improve the topical treatment of infected wounds. In this study, we investigated the antimicrobial activity of polyvinylpyrrolidone (PVP) foils loaded with ciprofloxacin (Cipro-foils) in the presence of acetic acid as a co-solvent. We used ex vivo human wounds that were infected with two bacterial strains: methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (PAO1). The effectiveness of the treatment was demonstrated by the quantification of the living bacteria extracted from the wound and the detection of released immunological mediators in skin extracts and in the skin culture media. We found that Cipro-foils effectively treated the infection with both PAO1 and MRSA. Other than PAO1, MRSA had no lytic activity toward skin proteins. MRSA infections increased cytokines' expression and release. Interestingly, treatment with Cipro-foils could partially counteract these effects.

Quality of life in children and adolescents with alopecia areata-A systematic review.

Alopecia areata (AA) is an autoimmune-mediated non-scarring hair loss whose stigmatizing effect may have a severe psychosocial impact. AA has been reported to be correlated with bullying, reduced quality of life (QoL) and psychiatric comorbidities. The effect of AA on QoL in adult patients has been systematically reviewed and found to be detrimental. No systematic evaluation of QoL in children with AA has been performed. The aim of this review is to systematically describe QoL in the child and adolescent population affected by AA. A systematic review of multiple databases and grey literature sources was conducted. Search terms included, but were not limited to, alopecia areata and quality of life. Only studies reporting results on health-related QoL in children and adolescents were included. We evaluated the studies regarding the risk of bias, and conceptual rigour concerning the quality of life and performed a descriptive synthesis of findings. Eight studies met the inclusion criteria, encompassing 358 participants with AA and 64 healthy peers. Seven studies were quantitative using four different standardized questionnaires and scores to measure QoL. One study used a qualitative design. All studies described impairment of children and adolescents' QoL by AA. The most consistently affected QoL domain was embarrassment and self-consciousness. Further psychosocial implications of AA included bullying and limiting participation in school or spare time activities. Existing evidence indicates a substantial impact of AA on QoL in children. In daily clinical practice as well as for developing new treatments QoL in paediatric AA plays a critical role. It should be considered a key outcome in clinical research and decision-making.

Fatal congenital copper transport defect caused by a homozygous likely pathogenic variant of SLC31A1.

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.

Fabrication of hydrolase responsive diglycerol based Gemini amphiphiles for dermal drug delivery applications.

Since biocatalysts manoeuvre most of the physiological activities in living organisms and exhibit extreme selectivity and specificity, their use to trigger physicochemical change in polymeric architectures has been successfully used for targeted drug delivery. Our major interest is to develop lipase responsive nanoscale delivery systems from bio-compatible and biodegradable building blocks. Herein, we report the synthesis of four novel non-ionic Gemini amphiphiles using a chemo-enzymatic approach. A symmetrical diglycerol has been used as a core that is functionalised with alkyl chains for the creation of a hydrophobic cavity, and for aqueous solubility (polyethylene glycol) monomethyl ether (mPEG) is incorporated. Such systems can exhibit a varied self-assembly behaviour leading to the observance of different morphological structures. The aggregation behaviour of the synthesised nanocarrier was studied by dynamic light scattering (DLS) and critical aggregation concentration (CAC) measurements. The nanotransport potential of amphiphiles was investigated for hydrophobic guest molecules, i.e. Nile red, nimodipine and curcumin. Cytotoxicity of the amphiphiles was studied using HeLa and MCF7 cell lines at different concentrations, i.e. 0.05, 0.1, and 0.5 mg mL-1. All nanocarriers were found to be non-cytotoxic up to a concentration of 0.1 mg mL-1. Confocal laser scanning microscopy (cLSM) study suggested the uptake of encapsulated dye in the cytosol of the cancer cells within 4 h, thus implying that amphiphilic systems can efficiently transport hydrophobic drug molecules into cells. The biomedical application of the synthesised Gemini amphiphiles was also investigated for dermal drug delivery. In addition, the enzyme-mediated release study was performed that demonstrated 90% of the dye is released within three days. All these results supported the capability of nanocarriers in drug delivery systems.

[Frontal fibrosing alopecia-update]. / Frontal fibrosierende Alopezie ­ aktuelles Wissen.

The number of patients presenting with frontal fibrosing alopecia (FAA) is increasing not only in hair clinics. The recognition of the peculiar clinical pattern and associated symptoms is an important prerequisite to ensure adequate counseling and therapeutic management of the patients. Experimental studies and a range of case series give first insights into the pathogenesis, possible trigger factors, clinical course of disease and treatment options. The clinical spectrum of FFA extends beyond the typical recession of the frontal hair line initially observed in postmenopausal women. Younger women, men and rarely adolescents may also be affected. Band-like extension to the occiput, diffuse bitemporal hair thinning, eyebrow and body hair involvement as well as facial papules are part of the clinical spectrum. Similar to lichen planopilaris, inflammation and fibrosis with involvement of the stem cell region result in permanent loss of hair follicles. Which additional factors contribute to the characteristic pattern remains to be elucidated. Currently, therapeutic management largely relies on anti-inflammatory treatment with combined topical, intralesional and systemic administration depending on disease activity. The chronic progressive course, sometimes even in the absence of pronounced inflammation remains a challenge for both the affected individuals and the treating physicians. Controlled studies are required to develop evidence-based recommendations and to explore novel treatment strategies.

Effects of Adipose-Derived Stem Cells and Their Conditioned Medium in a Human Ex Vivo Wound Model.

Adult stem cells have been extensively investigated for tissue repair therapies. Adipose-derived stem cells (ASCs) were shown to improve wound healing by promoting re-epithelialization and vascularization as well as modulating the inflammatory immune response. In this study, we used ex vivo human skin cultured in a six-well plate with trans-well inserts as a model for superficial wounds. Standardized wounds were created and treated with allogeneic ASCs, ASCs conditioned medium (ASC-CM), or cell culture medium (DMEM) supplemented with fetal calf serum (FCS). Skin viability (XTT test), histology (hematoxylin and eosin, H and E), ß-catenin expression as well as inflammatory mediators and growth factors were monitored over 12 days of skin culture. We observed only a moderate time-dependent decrease in skin metabolic activity while skin morphology was preserved, and re-epithelialization occurred at the wound edges. An increase in ß-catenin expression was observed in the newly formed epithelia, especially in the samples treated with ASC-CM. In general, increased growth factors and inflammatory mediators, e.g., hepatocytes growth factor (HGF), platelet-derived growth factor subunit AA (PDGF-AA), IL-1α, IL-7, TNF-α, and IL-10, were observed over the incubation time. Interestingly, different expression profiles were observed for the different treatments. Samples treated with ASC-CM significantly increased the levels of inflammatory cytokines and PDGF-AA with respect to control, whereas the treatment with ASCs in DMEM with 10% FCS resulted in significantly increased levels of fibroblast growth factor-basic (FGF-basic) and moderate increases of immunomodulatory cytokines. These results confirm that the wound microenvironment can influence the type of mediators secreted by ASCs and the mode as to how they improve the wound healing process. Comparative investigations with pre-activated ASCs will elucidate further aspects of the wound healing mechanism and improve the protocols of ACS application.

Alopecia areata - Current understanding and management.

Alopecia areata (AA) is a chronic, immune-mediated disease characterized by acute or chronic non-scarring hair loss, with a heterogeneity in clinical manifestations ranging from patchy hair loss to complete scalp and body hair loss. An overview of the up-to-date pathophysiology and the underlying signaling pathways involved in AA together with diagnostic and therapeutic recommendations will be provided. Current treatments, including topical, systemic and injectable interventions show varying response and frequent relapses reflecting the unmet clinical need. Thus, the new emerging concepts and therapeutic approaches, including Janus kinase inhibitors are eagerly awaited. Traditional and emerging therapies of AA will be discussed, in order to provide physicians with guidance for AA management. Since the latter is so challenging and often tends to take a chronic course, it can have an enormous psychosocial burden on patients, compromising their quality of life and often causing depression and anxiety. Therefore, the psychosocial aspects of the disease need to be evaluated and addressed, in order to implement appropriate psychological support when needed.

Molecular characterization of xerosis cutis: A systematic review.

BACKGROUND: Xerosis cutis or dry skin is a highly prevalent dermatological disorder especially in the elderly and in patients with underlying health conditions. In the past decades, numerous molecular markers have been investigated for their association with the occurrence or severity of skin dryness. The aim of this review was to summarize the molecular markers used in xerosis cutis research and to describe possible associations with different dry skin etiologies. METHODS: We conducted a systematic review of molecular markers of xerosis cutis caused by internal or systemic changes. References published between 1990 and September 2020 were searched using 'MEDLINE', 'EMBASE' and 'Biological abstracts' databases. Study results were summarized and analyzed descriptively. The review protocol was registered in PROSPERO database (CRD42020214173). RESULTS: A total of 21 study reports describing 72 molecules were identified including lipids, natural moisturizing factors (NMFs), proteins including cytokines and metabolites or metabolic products. Most frequently reported markers were ceramides, total free fatty acids, triglycerides and selected components of NMFs. Thirty-one markers were reported only once. Although, associations of these molecular markers with skin dryness were described, reports of unclear and/or no association were also frequent for nearly every marker. CONCLUSION: An unexpectedly high number of various molecules to quantify xerosis cutis was found. There is substantial heterogeneity regarding molecular marker selection, tissue sampling and laboratory analyses. Empirical evidence is also heterogeneous regarding possible associations with dry skin. Total free fatty acids, total ceramide, ceramide (NP), ceramide (NS), triglyceride, total free amino acids and serine seem to be relevant, but the association with dry skin is inconsistent. Although the quantification of molecular markers plays an important role in characterizing biological processes, pathogenic processes or pharmacologic responses, it is currently unclear which molecules work best in xerosis cutis.

Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model.

INTRODUCTION: Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin. METHODS: In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium. RESULTS: We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release. CONCLUSION: Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs.