A Phase 3, Randomized, Multi-center Clinical Trial to Evaluate the Efficacy and Safety of Neu-BoNT/A in Treatment of Primary Axillary Hyperhidrosis.

BACKGROUND: Botulinum toxin type A is widely used to treat primary axillary hyperhidrosis and has proven to be an effective and safe approach. Onabotulinumtoxin A was approved by the FDA as a treatment for primary axillary hyperhidrosis. This study aimed to evaluate the efficacy and safety of Neu-BoNT/A in subjects diagnosed with primary axillary hyperhidrosis. METHODS: The Hyperhidrosis Disease Severity Scale, gravimetric measurement of sweat, and Global Assessment Scale were analyzed at weeks 4, 8, 12, and 16 to determine the effect of treatment. Adverse events, physical examination, and vital signs were monitored. RESULTS: Subjects treated with Neu-BoNT/A showed statistically significant improvement by all 3 methods at weeks 4, 8, 12, and 16 (P value = 0.00). There were no severe adverse events or significant changes in vital signs, physical examination, or laboratory tests. CONCLUSION: Neu-BoNT/A can be effectively and safely used for primary axillary hyperhidrosis. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Distinct Patterns and Aetiology of Chromonychia.

Abnormal colouring of the nails may be a sign of underlying systemic or local disorders. This study investigated the prevalence and causes of chromonychia as a whole, as well as of each subtype. Among 163 patients with chromonychia, trauma was the pathogenesis in up to 20.9% (34/163) of cases. The most common subtype was melanonychia (54.0%; 88/163), followed by leukonychia (23.9%), red (8.6%), green (6.7%), yellow (4.9%) and blue (1.8%) nails. Nail matrix naevus (33.3%; 29/88) was the most common cause of melanonychia, while skin diseases (41.0%; 16/39), such as psoriasis (75%, 12/16) and alopecia areata (18.8%; 3/16), in addition to systemic diseases (33.3%; 13/39) including anaemia (38.5%, 5/13) and chronic renal failure (15.4%; 2/13) were the dominant causes of leukonychia. As chromonychia may be the first or only sign of an underlying disorder, it should alert physicians and patients to the need for a prompt and thorough evaluation.

Anatomic mapping and clinicopathologic analysis of benign acral melanocytic neoplasms: A comparison between adults and children.

BACKGROUND: The clinicopathologic features of benign acral melanocytic neoplasms (BAMNs) remain poorly understood. OBJECTIVE: To define the clinicopathologic features of BAMNs. METHODS: We analyzed clinical data and mapped BAMNs anatomically. We also reviewed the histopathologic features of BAMNs and compared these between adults and children. RESULTS: We included 396 cases of BAMN: 335 adults and 61 children (376 acquired and 20 congenital lesions). Anatomic mapping revealed that the nonweight-bearing portion of the foot was the most common site in adults (120/335, 35.8%) and the forefoot the most common site in children (17/61, 27.9%) for BAMNs. The long axes of the BAMNs paralleled the dermatoglyphic lines on the palms and soles, as did most tissue sections. The lesion diameters were <5.7 mm in all acquired lesions. Histopathologically, we diagnosed 69 lentigo simplex, 201 junctional, 114 compound, 8 intradermal, and 4 blue nevi. Corneal pigmentation, nests located between rete ridges, dendrite prominence, and cytologic atypia were all significantly more common in children than adults. LIMITATIONS: The retrospective study design and acquiring patients from a single institution of a single country limited the research results. CONCLUSION: BAMNs develop most commonly on nonweight-bearing regions of the soles in adults and on the forefoot in children. The long axis of the lesion follows the dermatoglyphics, and cytologic atypia is more common in children.

Light-emitting diodes downregulate cathelicidin, kallikrein and toll-like receptor 2 expressions in keratinocytes and rosacea-like mouse skin.

Cathelicidin (LL-37), Toll-like receptor 2 (TLR-2) and kallikreins (KLKs) are key inflammatory mediators in rosacea. Laser or light-based devices have been successfully used for rosacea. We investigated the effects of light-emitting diodes (LEDs) on LL-37, KLKs, TLR-2 and protease activity in cultured normal human epidermal keratinocytes (NHEKs) and rosacea-like mouse skin (RLMS). LL-37, KLK5, KLK7 and vitamin D receptor were induced by 1α, 25-dihydroxyvitamin D3 (VD3 ) and TLR-2 by Ad-CMV transfection in cultured NHEKs. NHEKs were subjected to LED irradiation at differing wavelengths (480-940 nm) and fluences (1-40 J/cm2 ). Inflammatory mediators were analysed with RT-PCR and real-time PCR and protease activity analysis and immunocytofluorescence staining were performed for NHEKs. Changes in RLMS induced by LL-37 peptide were evaluated with real-time PCR, immunohistochemical staining and enzyme-linked immunosorbent assay. In NHEKs, LED at 630 and 940 nm significantly attenuated LL37, KLK5 and TLR-2 mRNA expressions. Protease activity was significantly suppressed at 630, 850 and 940 nm. In the RLMS, LL-37, KLK5 and PAR-2 mRNA expressions significantly decreased at 24 and 48 hours after LED irradiation was performed three times at 630 and 940 nm. mCAMP and IL-8 protein levels and protease activity after LED irradiation were lower than those in RLMS control groups. LED at 630 and 940 nm downregulated TLR-2, KLK5 and LL-37 expressions and protease activity in NHEK and RLMS. Thus, LEDs may be promising for rosacea treatment. However, clinical trials are required for further study.

Other primary systemic cancers in patients with melanoma: Analysis of balanced acral and nonacral melanomas.

BACKGROUND: Although other primary systemic cancers in patients with melanoma have been studied, there have been few focusing on acral melanomas. OBJECTIVES: We assessed other primary systemic cancers in patients with acral and nonacral melanomas. METHODS: We analyzed other primary cancers in 452 patients with melanoma from 1994 to 2013. Metachronous cancers were defined as those given a diagnosis more than 2 months after diagnosis of melanoma. The others were considered prechronous or synchronous cancers. RESULTS: Among 51 cases of other primary cancers, gastrointestinal cancer (35.3%, n = 18/51) was the most common, followed by thyroid (17.6%), lung (11.8%), and breast (5.9%). Those were more prevalent in the acral melanoma group (12.8%, n = 31/243) compared with the nonacral melanoma group (9.6%, n = 20/209). Of 23 cases of metachronous cancer, the risk was the highest in bone marrow, followed by oral cavity, bladder, colon, lung, and thyroid. Among 28 cases of prechronous or synchronous cancers, gastrointestinal tract (35.7%, n = 10/28) was the most common site, followed by thyroid (17.9%), breast (10.7%), and lung (7.1%). LIMITATIONS: The study is limited by a small number of patients. CONCLUSION: Careful follow-up and imaging studies are necessary for early detection of other primary cancers and metastatic lesions in patients with melanoma.

Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and type 2 diabetes. Thioredoxin-interacting protein (TXNIP) regulates the cellular redox state and metabolism and has been linked to many diseases, including diabetes. Therefore, we examined the role of TXNIP in hepatic steatosis in vitro and in vivo. METHODS: Lipogenic and inflammatory proteins produced by hepatocytes treated with palmitic acid (PA) or transfected with TXNIP or Txnip siRNA were measured by Western blotting. Lipid accumulation was assessed using Oil Red O staining. Protein interactions were assessed by immunoprecipitation and proximity ligation assay. Hepatic protein levels were measured by Western blotting from wild type or Txnip(-/-) mice fed a high-fat diet (HFD) or chow diet. Livers from NAFLD patients were compared with normal liver by immunohistochemistry. RESULTS: PA increased TXNIP, and inflammatory and lipogenic proteins in both AML12 and H4IIE cells. It also increased the peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), which mediated the expression of lipogenic markers and lipid accumulation. In addition, PA increased protein arginine methyltransferase-1 (PRMT1) and PRMT1 siRNA abolished the increase in lipogenic markers with PGC-1α. Furthermore, TXNIP interacted with PRMT1 in PA-treated hepatocytes. In vivo, levels of lipogenic proteins, inflammatory molecules, PGC-1α, and PRMT1 were increased in the livers of HFD mice compared with those fed a chow diet, and were ameliorated in HFD Txnip(-/-) mice. Moreover, TXNIP, PRMT1, and PGC-1α were elevated in the livers of human NAFLD patients. CONCLUSIONS: TXNIP mediates hepatic lipogenesis via PRMT1 and PGC-1α regulation and inflammation in vitro and in vivo, implying that targeting TXNIP and PRMT1 is a potential therapeutic approach for treatment of NAFLD.

Correlations between inflammatory cytokine levels and degree of pigmentation in acral melanomas.

Cutaneous melanoma, a highly aggressive skin tumor, is characterized by complex signaling pathways in terms of its pathogenesis and progression. Although the degree of pigmentation in melanoma determines its progression, metastasis, and prognosis, its association with inflammatory cytokines remains unclear. Thus, we evaluated the associations between melanoma pigmentation and plasma levels of inflammatory cytokines; furthermore, we investigated the potential variations in this relationship across the primary anatomic sites of melanoma. We enrolled patients with cutaneous melanoma who visited Chonnam National University Hwasun Hospital between January 2021 and December 2021. The anatomical sites of melanoma were categorized as acral and non-acral sites. The degree of pigmentation was quantified using computer software. In total, nine inflammatory cytokines were analyzed, including interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). This study included 80 melanoma patients. Of these, 53 had acral melanoma and 27 had non-acral melanoma. Overall, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, and IFN-γ demonstrated significant correlations with diminished pigmentation. Furthermore, in the acral melanoma patients group, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α revealed significant correlations with diminished pigmentation. Our results reveal significant associations between melanoma pigmentation and various cytokine levels, particularly in acral melanoma patients; these associations can be influenced by factors related to acral melanoma, such as physical stress or trauma. These correlations may also provide directions for the treatment of acral melanoma.

Facial Dermatoses Associated With Mask-Wearing in the COVID-19 Era: A Nationwide, Cross-Sectional, Multicenter, Questionnaire-based Study.

BACKGROUND: Daily usage of facial masks during coronavirus disease 2019 pandemic influenced on facial dermatoses. OBJECTIVE: This study investigated the impact of mask-wearing habits on facial dermatoses. METHODS: A nationwide, observational, questionnaire-based survey was conducted from July through August 2021, involving 20 hospitals in Korea. RESULTS: Among 1,958 facial dermatoses, 75.9% of patients experienced aggravation or development of new-onset facial dermatoses after wearing masks. In aggravated or newly developed acne patients (543 out of 743), associated factors were healthcare provider, female gender, and a long duration of mask-wearing. Irritating symptoms, xerosis, and hyperpigmentation were more frequently observed in this group. Aggravated or newly developed rosacea patients (515 out of 660) were likely to be female, young, and have a long duration of mask-wearing per day. Seborrheic dermatitis patients who experienced aggravation or de novo development (132 out of 184) were younger, and they more frequently involved the chin and jaw in addition to the nasolabial folds and both cheeks. Contact dermatitis patients (132 out of 147) with aggravation or de novo development tended to be female, involve both cheeks, and complain of pruritus. Aggravated or newly developed atopic dermatitis patients (165 out of 224) were more likely to be female, and had a higher baseline investigator global assessment score before mask-wearing. CONCLUSION: Clinical features and factors related to aggravation were different according to the types of facial dermatoses.

Consensus Report on Truncal Acne: The Korean Acne and Rosacea Society Experts Panel.

BACKGROUND: More than half of acne patients have truncal acne on their chest, back, and shoulders. However, since most studies on acne have focused on the face, data on clinical characteristics and proper management for truncal acne are insufficient. OBJECTIVE: To establish a Korean Acne Rosacea Society (KARS) consensus for experts' perception and treatment patterns of truncal acne. METHODS: We conducted two rounds of the Dephi technique to gather expert opinion and reach a consensus on truncal acne. The first round comprised 48 questionnaires focusing on various aspects such as epidemiology, clinical features, diagnosis, treatment, prognosis and more, while second rounds consisted of 26 questionnaires. RESULTS: A total of 36 dermatologists (36/38 KARS members, 94.7%) completed this survey. In the first-round survey, consensus was reached on 20 out of the 48 questions (41.7%). In the second-round questionnaire, consensus was achieved on 9 of the 26 questions (34.6%). The most unresponsive lesion to truncal acne treatment was scars (atrophic/hypertrophic). The most commonly used treatments for each non-inflammatory and inflammatory truncal acne lesions were selected to use topical retinoids (78.1% of the responders) and oral antibiotics (93.8% of the responders). CONCLUSION: Our study has yielded valuable insights into the epidemiology, clinical manifestations, diagnosis, treatment, and quality of life of patients with truncal acne. We anticipate that this study will inspire further comprehensive research for individuals with truncal acne.

Amelanotic acral melanomas: clinicopathological, BRAF mutation, and KIT aberration analyses.

BACKGROUND: Amelanotic acral melanoma (AAM) is very rare and difficult to diagnose both clinically and pathologically. Complete-type AAM shows no black to brown pigmentation in the lesion, whereas incomplete-type AAM shows focal or subtle pigmentation. AAM has been the subject of few investigations. OBJECTIVES: We analyzed the clinicopathological features, BRAF mutations, and KIT aberrations in 35 Korean AAM cases. METHODS: We included 28 cases of complete-type and 7 cases of incomplete-type AAM. RESULTS: In all, 26 AAMs (45.7%) were located on the feet of patients, 21 of which (82.9%) showed ulceration. Sixteen cases developed in subungual areas. Nodular melanoma was the most common histopathological subtype (63.6%). The most frequent cell types affected were epithelioid and spindled. HMB-45 staining was strongly positive in 66.7% of AAMs; 4 (12.1%) were negative for HMB-45, and 3 of these were complete-type AAMs. Of 33 total patients, BRAF mutations were detected in 2 AAM cases, and KIT aberrations were present in 11 cases (33.3%). Four cases (12.1%), all of which were complete-type AAMs, had KIT mutations. KIT aberrations were weakly correlated with c-kit staining. Twenty patients were TNM stage I or II, and mean survival was 30.14 ± 4.54 months. LIMITATIONS: The study is limited by the small number of patients. CONCLUSION: Physicians should be aware of rare and hard-to-diagnose AAMs. We expect that tyrosine kinase inhibitors would be effective for KIT-mutated patients with complete-type AAMs.

Nasal tip cutaneous metastases secondary to lung carcinoma: three case reports and a review of the literature.

Cutaneous metastatic carcinoma of the nose is a rare presentation associated with lung cancer. We report here 3 cases of cutaneous metastatic carcinoma of the nose that originated from lung cancer. Two men, age 61 and 76 years, with lung cancers were referred for evaluation of a tumour on the tip of the nose. The third patient, a 57-year-old man, had developed a rosacea-like tumour on the tip of the nose; although he had no history of internal cancer, whole-body positron-emission tomography-computed tomography revealed a primary lung cancer. Skin biopsies of all 3 cases showed metastatic squamous cell carcinoma, and all primary lung cancers were squamous cell carcinomas. Only 3 patients are described here, and further reports are needed to substantiate this interesting phenomenon. When an elderly patient presents to dermatology with a tumour on the nose with or without known internal cancer, it is necessary to approach the diagnosis with caution.

Epidemiology and survival analysis of Merkel cell carcinoma in South Korea: a nationwide, multicenter retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, of which most research has been conducted in Caucasians. Therefore, the clinicopathological features and prognosis of Merkel cell carcinoma in Asians are still scarce. The aim of this study is to investigate the epidemiology and survival of MCC in South Korea and provide representative information regarding MCC in Asia. METHODS: This was a retrospective, nationwide, multicenter study conducted in 12 centers across South Korea. Patients with pathologically proven MCC were included in the study. The clinicopathological features and clinical outcomes of the patients were investigated. Overall survival (OS) was analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using Cox regression analysis. RESULTS: A total of 161 patients with MCC were evaluated. The mean age was 71 years with a female predominance. OS was significantly different among the stages. Among clinicopathological features, multivariate Cox regression analysis demonstrated that only the stage at diagnosis was associated with poorer overall survival. CONCLUSIONS: The results of our study suggest that the incidence of MCC was higher in females than in males and that there was a higher rate of local disease at the time of diagnosis. Among the variable clinicopathological features, disease stage at diagnosis was the only significant prognostic factor for MCC in South Korea. The findings of this nationwide, multicenter study suggest that MCC has distinct features in South Korea compared with other countries.

The Effect of Capsaicin on Neuroinflammatory Mediators of Rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin disease with a pathophysiological mechanism that remains unclear. Recently, dysregulation of the sensory nerve system has been implicated in the development of this condition. OBJECTIVE: This study aimed to investigate the effect of capsaicin on neuroinflammatory mediators in rosacea. In addition, this study aimed to evaluate the attenuating effects of capsazepine, a transient receptor potential vanilloid type 1 (TRPV1) antagonist. METHODS: We obtained skin tissue from both rosacea patients and normal individuals for an in vivo study. In addition, normal human epidermal keratinocytes (NHEKs) were cultured, and treated with capsaicin and capsazepine for an in vitro study. Quantitative changes in neuroinflammatory mediators were evaluated by semi-quantitative reverse transcription-polymerase chain reaction (PCR), real-time PCR, enzyme-linked immunosorbent assay, and immunofluorescence staining. RESULTS: The data showed the increase of TRPV1, TRPV4, cathelicidin (LL37) and tumor necrosis factor-α (TNF-α) in skin tissue by real-time PCR. In addition, the data showed that cathelicidin (LL37), kallikrein-5 (KLK-5), TNF-α, vascular endothelial growth factor (VEGF), interleukin (IL)-1α, IL-1ß, IL-8, and protease-activated receptor 2 (PAR2) increased in capsaicin-treated NHEKs. Capsazepine attenuated the expression of TRPV1 and other mediators, except for IL-8, in capsaicin-treated NHEKs. CONCLUSION: We confirmed that TRPV1, TRPV4, cathelicidin (LL37) and TNF-α are increased in rosacea skin, and that capsaicin is associated with increase of neuroinflammatory mediators such as LL37, KLK-5, TNF-α, VEGF, IL-1α, IL-1ß, IL-8, and PAR2. Modulators or inhibitors of neuroinflammatory mediators including TRPV1 could be potential therapeutic option in the treatment of patients with rosacea.

Cutaneous Photorejuvenation of Light Emitting Diodes via the Melatonin Membrane Receptor Pathway.

BACKGROUND: Melatonin receptors are present in the human skin and retina. These receptors can be stimulated by light emitting diodes (LEDs) at specific wavelengths, thereby inducing cutaneous photorejuvenation. However, the underlying mechanism remains unclear. OBJECTIVE: To evaluate the influence of LEDs at specific wavelengths on melatonin membrane receptor (MT1) and cutaneous photorejuvenation via the MT1 pathway in vitro. METHODS: Normal human dermal fibroblasts (HDFs) were irradiated using LEDs at different wavelengths (410~940 nm) at a dose of 1 J/cm². MT1 activity was evaluated after melatonin stimulation and LED irradiation. Thereafter, the expressions of collagen (COL) and matrix metalloproteinases (MMPs), with and without luzindole (MT1/2 receptor antagonist), were investigated via semi-quantitative reverse transcription polymerase chain reaction (PCR), real-time PCR, western blotting, and enzyme-linked immunosorbent assay. RESULTS: In HDFs, the MT1 mRNA and protein levels increased significantly in response to melatonin (dose, 50 nM) (p<0.01) and LED irradiation at 595, 630, 850, and 940 nm (p<0.01). LED irradiation up-regulated COL type I and down-regulated MMP-1. Compared to LED irradiation without luzindole, LED irradiation with luzindole produced no significant increase in COL type I mRNA and protein levels (p<0.01). CONCLUSION: We found that LED irradiation induces collagen synthesis and MMP-1 inhibition in HDFs via MT1 activation. Additionally, multiple LED wavelengths (595, 630, 850, and 940 nm) stimulated MT1 in HDFs, unlike in the eyes, where only blue light induced plasma melatonin suppression. This suggests the possibility of the melatoninergic pathway in photorejuvenation.

Retraction: Three Cases of Autoimmune Progesterone Dermatitis.

[This retracts the article on p. 479 in vol. 29, PMID: 28761298.].

Keratinocytes-Derived Reactive Oxygen Species Play an Active Role to Induce Type 2 Inflammation of the Skin: A Pathogenic Role of Reactive Oxygen Species at the Early Phase of Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by chronic, relapsing skin inflammation (eczema) with itchy sensation. Keratinocytes, which are located at the outermost part of our body, are supposed to play important roles at the early phase of type 2 inflammation including AD pathogenesis. OBJECTIVE: The purpose of this study was to evaluate whether keratinocytes-derived reactive oxygen species (ROS) could be produced by the allergens or non-allergens, and the keratinocytes-derived ROS could modulate a set of biomarkers for type 2 inflammation of the skin. METHODS: Normal human epidermal keratinocytes (NHEKs) were treated with an allergen of house dust mites (HDM) or a non-allergen of compound 48/80 (C48/80). Then, biomarkers for type 2 inflammation of the skin including those for neurogenic inflammation were checked by reverse transcriptase-polymerase chain reaction and western immunoblot experiments. RESULTS: HDM or C48/80 was found to upregulate expression levels of our tested biomarkers, including type 2 T helper-driving pathway (KLK5, PAR2, and NFκB), epithelial-cell-derived cytokines (thymic stromal lymphopoietin, interleukin [IL]-25, IL-33), and neurogenic inflammation (NGF, CGRP). The HDM- or C-48/80-induced expression levels of the biomarkers could be blocked by an antioxidant treatment with 5 mM N-acetyl-cysteine. In contrast, pro-oxidant treatment with 1 mM H2O2 could upregulate expression levels of the tested biomarkers in NHEKs. CONCLUSION: Our results reveal that keratinocytes-derived ROS, irrespective to their origins from allergens or non-allergens, have a potential to induce type 2 inflammation of AD skin.

Congenital pigment synthesizing melanoma of the scalp.

The pigment synthesizing melanoma, so-called animal type melanoma, is a rare variant of melanoma that is characterized by prominent melanin production and an unpredictable prognosis. Congenital onset of this melanoma is exceedingly rare. A 2-month-old Korean girl had a black nodule and a satellite black macule on the scalp which were noticed at birth. She received a surgical resection 3 months later because of rapidly growing lesions and the histopathologic features of a pigment synthesizing melanoma. Two months later, she returned with cervical area swelling, and the excised multiple lymph nodes showed metastatic malignant melanoma. The exact origin and pathogenesis of congenital pigment synthesizing melanoma is different from the more common forms of melanoma and remains poorly understood.

Analysis of relation between skin elasticity and the entropy of skin image using near-infrared and visible light sources.

Skin elasticity has been regarded as one of the main indicators of skin condition. Current measurement devices for skin elasticity are mostly expensive for home-use and should contact the skin surface. As a first step to develop improved methods, we focus on the relation between skin elasticity and the entropy of skin images. Reduced skin elasticity causes wrinkles. It spreads frequency components and increases their randomness in the frequency domain. The randomness is quantified as entropy, which is a measure of the disorder of a system in physics. Therefore, skin elasticity is expected to have a negative relation with entropy. This tendency can be improved by applying penetration depth characteristics according to the wavelength of light. From cheeks and forehead of 12 Korean adults, skin images are acquired with three different light sources (470 nm, 870 nm and broadband light) and skin elasticity is measured. The root mean square error between the measured data and the fitted model is "0.27" (870 nm), "0.49" (broadband light) and "1.42" (470 nm). Furthermore, the results are analyzed by classifying by sex, age and measurement area. This study demonstrates the possibility of developing noncontact home-use devices to measure skin elasticity in the future.