Dermatology Commons^™

The Epidemiology Of Skin Cancer At Dr. Cipto Mangunkusumo National Central General Hospital From 2014 To 2017, Larisa Paramitha Wibawa, Melody Febriana Andardewi, Inge Adi Kristanti, Riesye Arisanty

Journal of General - Procedural Dermatology and Venereology Indonesia

Background: The incidence of skin cancer has been increasing over the past decades globally. At present, there is no valid national cancer data in Indonesia. The purpose of this study is to evaluate the increment of skin cancer cases at Dr. Cipto Mangunkusumo National General Hospital, Jakarta.

Methods: In this retrospective descriptive study, we evaluated all pigmented skin tumor cases from June 2014 to June 2017. Data were obtained from the Department of Anatomical Pathology and medical records at Dr. Cipto Mangunkusumo National General Hospital. Data were compared with previous reports.

Results: From 263 skin cancer cases, …

Langerhans Cell Histiocytosis: Diagnosis And Management, Lusiana Lusiana, Hikari Ambara Sjakti, Githa Rahmayunita, Tjut Nurul Alam Jacoeb, Inge Ade Krisanti

Journal of General - Procedural Dermatology and Venereology Indonesia

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal clonal proliferation of Langerhans dendritic cells. The incidence of LCH is 1 to 3 cases per 1 million children worldwide, and occurs most frequently in children of 1–4 years of age. The etiopathogenesis of LCH, whether it is neoplastic or reactive, is still controversial. Langerhans cell histiocytosis has a wide spectrum of clinical features, and dermatological abnormalities usually occur early. The most frequent lesions are elevated yellowish-red translucent papules about 1–2 mm in diameter and generally located in seborrheic areas. The most recent classification (the Histiocyte Society study 2017) …

The Use Of Systemic Medications In Pediatric Dermatoses: A Review, Shanthi Narla, Githa Rahmayunita, Rinadewi Astriningrum, Tor Shwayder, Ariyati Yosi, Henry W. Lim

Journal of General - Procedural Dermatology and Venereology Indonesia

Research has begun to illustrate a favorable efficacy and side-effect profile for many systemic agents used in pediatric dermatological conditions (i.e. atopic dermatitis, psoriasis, scleroderma, alopecia areata, chronic spontaneous urticaria, autoimmune blistering disorders, and hidradenitis suppurativa) despite not having extensive randomized clinical trials. The purpose of this article is to summarize the available data on the treatment regiments, safety, and efficacy of systemic immunosuppressants, including the newer biologics, focusing on the most up-to-date systematic reviews or randomized clinical trials. The review demonstrates that many of the present studies lack data on long-term efficacy and consist of small patient populations. Further …

Recurrent Basal Cell Carcinoma With Maxillary Bone Invasion, Adhimukti T. Sampurna, Eva Riani, Inge Ade Kristanti, Yayi Dwina, Kuniaki Ohara

Journal of General - Procedural Dermatology and Venereology Indonesia

Background: Basal cell carcinoma (BCC) is a malignant, slow growing, and locally invasive skin tumor. Advanced and neglected BCC may invade adjacent structures. The 5-year recurrence rates of facial BCCs are 4.1% after excision and 2.5% after Mohs Micrographic Surgery (MMS). The number of BCC cases invading the bones of the head and neck region is limited.

Case Illustration: A 75-year-old male complained of bleeding and ulcer enlargement on the right cheek expanding to the right nasal ala for 1 month. The patient had a history of an enlarged and painful lenticular nodule with a hyperpigmented spot that …

Identification Of The Kaposi's Sarcoma-Associated Herpesvirus (Kshv) Surface Glycoprotein Targets Of Human Kshv-Specific Neutralizing Antibody Responses, Yasaman Mortazavi

School of Biological Sciences: Dissertations, Theses, and Student Research

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the etiological agent of Kaposi’s sarcoma (KS), and is also associated with two B cell malignancies, primary effusion lymphoma and multicentric Castleman's disease. The distribution of KSHV varies globally with high prevalence in some areas of sub-Saharan Africa (SSA), where seroprevalence can be as high as 80%. It is estimated that nearly 44,000 new cases of KS emerge annually globally, with the highest incidents occurring in Africa, where KSHV is endemic. Currently, there is no prophylactic vaccine against KSHV, and efforts to develop prophylactic vaccines have been limited. …

Acne Severity And Sleep Quality In Adults., Kory P Schrom, Sayeeda Ahsanuddin, Michelle Baechtold, Raghav Tripathi, Amy Ramser, Elma Baron

Ambulatory and Primary Care Articles

Poor sleep quality is extremely prevalent, with about one third of adults in the USA obtaining less than the recommended amount of sleep. In addition, poor sleep quality has been linked to an increased risk of many conditions, including diabetes, hypertension, psychiatric conditions, and overall all-cause mortality. Research has shown that sleep disturbance does impact skin disease, although many details of this relationship are still unclear. The goal of this study is to determine if there is a relationship between acne severity and sleep quality in adults. Forty subjects with acne were recruited from dermatology clinics in Cleveland, OH, to …

From Clinical Phenotype To Genotypic Modelling: Incidence And Prevalence Of Recessive Dystrophic Epidermolysis Bullosa (Rdeb), Shaundra Eichstadt, Jean Y. Tang, Daniel C. Solis, M. Peter Marinkovich, Nedra Whitehead, Fang Fang, Stephen W. Erickson, Mary E. Ritchey, Max Colao, Kaye Spratt, Amir Shaygan, Mark Ahn, Kavita Y. Sarin

Engineering and Technology Management Faculty Publications and Presentations

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the …

Immune-Mediated Colitis From Dual Checkpoint Inhibitors., Nishanth Thalambedu, Yasir Khan, Qian Zhang, Shristi Khanal, Ammar Ashfaq

Abington Jefferson Health Papers

Melanoma is a deadly disease with immunotherapy treatment options that emerged in the last few years and have changed the disease outcome. However, it is associated with immune-related toxic effects despite improving survival. We present the case of a 53-year-old woman who had two weeks of diarrhea after she was treated with dual immunotherapy agents for her advanced melanoma. The final workup revealed pancolitis, possibly due to immunotherapy adverse effects. Initial conservative treatment, unfortunately, did not lead to a clinical improvement until a steroid was introduced. We are reporting this case to alert our fellow physicians about the immune-mediated toxicities …

Molluscum Contagiosum Infection With Features Of Primary Cutaneous Anaplastic Large Cell Lymphoma., Doaa Shalabi, John Ringe, Jason B. Lee, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

CD30+ T cell pseudolymphomas (CD30+ PSL) are a group of benign inflammatory cutaneous disorders that can develop in settings of viral infections or drug reactions. Owing to their histological similarities to malignant lymphomas, these benign infiltrates are occasionally misdiagnosed as malignant, causing significant concerns for patients and physicians. Herein, we report a patient with CD30+ PSL associated with molluscum contagiosum whose initial biopsy revealed atypical large CD30-expressing cells, leading to a misdiagnosis of primary cutaneous anaplastic large cell lymphoma and referral to our cutaneous lymphoma clinic. We report this case to demonstrate that reactive CD30+ infiltrate associated with molluscum contagiosum …

Why Medical (And Dermatologic) Practice Has Become So Convoluted: The Complexity/Convolutional/Obfuscatory Kleptocracies., W. Clark Lambert, Jennifer L. Parish, Lawrence Charles Parish, Shreya Patel, Loka Thangamathesvaran, Amer Ali Almosshen

Department of Dermatology and Cutaneous Biology Faculty Papers

Consider dermatology (or medical) practice from the aspect of those who manage, and seek to glean a profit from, medical management corporations, including but not limited to third party payers. Although much of the complexity burden thrust upon doctors’ offices is borne by the offices and doctors, there is also much that is borne by the companies, and the entire process appears to make no sense whatsoever. How can the business professionals who run these outfits make such blunders? Let us approach this question by examining another industry: fast food franchising.

Hypotrichosis With Juvenile Macular Dystrophy: Combination Of Whole-Genome Sequencing And Genome-Wide Homozygosity Mapping Identifies A Large Deletion In Cdh3 Initially Undetected By Whole-Exome Sequencing-A Lesson From Next-Generation Sequencing., Amir Hossein Saeidian, Hassan Vahidnezhad, Leila Youssefian, Soheila Sotudeh, Meisam Sargazi, Sirous Zeinali, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder characterized by abnormal growth of scalp hair and juvenile macular degeneration leading to blindness. We have explored the genetic basis of HJMD in a large consanguineous family with 12 affected patients, 1-76 years of age, with characteristic phenotypes.

METHODS: We first applied genome-wide homozygosity mapping to 10 affected individuals for linkage analysis to identify the genomic region of the defective gene. All affected individuals shared a 7.2 Mb region of homozygosity on chromosome 16q21-22.3, which harbored 298 genes, including CDH3, previously associated with HJMD. However, whole-exome sequencing (WES) …

Treatment Of Basal Cell Carcinoma With Vismodegib, Sunitha Johns, Katlyn Brown, Emily Loudermilk, Crystal Zheng, Anh Dao Le, Sophocles Chrissobolis

Pharmacy and Wellness Review

The most prevalent nonmelanoma skin cancers are basal cell carcinoma (BCC) and locally advanced basal cell carcinoma (aBCC). Current, effective first-line treatments for BCC aim to remove and destroy cancerous skin cells through excision surgery, Mohs surgery, radiation therapy and cryotherapy, while treatment of aBCC remains limited. An emerging treatment option for aBCC that promotes tumor size reduction is vismodegib, a pharmaceutical product approved in 2012 by the U.S. Food and Drug Administration (FDA). Vismodegib was approved for the treatment of aBCC, metastasized HCC (mBCC) or recurrent BCC after surgery as well as for use in adults who are not …

Trametinib And Dabrafenib: New Agents For Advanced Stage Melanoma, Kelsey Weisenburger, Kevin Krivanek, Armond Cosiano, Kasie Bellmann, Mark E. Olah

Pharmacy and Wellness Review

Melanoma, the deadliest form of skin cancer, is caused primarily by exposure to ultraviolet radiation. Tumor formation occurs early in disease progression and can easily metastasize. The development of the disease can be described by one of four stages, characterized by tumor size and risk of spreading. The B-rafprotein plays an important role in cell proliferation and has the ability to develop a mutation for continuous activation, resulting in uncontrolled cell growth. Sixty percent of melanomas possess a V600E mutation in the BRAF gene. Recently, drug developers have turned the focus of melanoma treatments toward preventing the activation of the …

Evidence For The Potential Use Of Polyphenols And Their Derivatives In Moderating Allergic Immune Responses, Jamie Kellner, Lindsay Mark, Kasie Bellmann, Kelly Shields

Pharmacy and Wellness Review

Polyphenols are naturally occurring compounds that are found within numerous plant sources. They have a wide variety of structures and functions and have potential clinical uses in multiple disease states. Emerging studies involving polyphenols have demonstrated their antioxidative properties, as well as reduced risks of cardiovascular diseases and certain types of cancer. Due to these discoveries, there has been a marked increase in research related to the chemical properties of polyphenols and their potential uses in prevention of common acquired and inherited disease states. This article focuses on the effects that some polyphenolic compounds exert on immune function in regard …

Overview Of Stevens-Johnson Syndrome And Toxic Epidermal Necrolysis, Christina Spinaris, Sarah Kradel, Tara Tokar, Zachary Crawford, Michael M. Milks

Pharmacy and Wellness Review

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologic reactions that typically present due to drug hypersensitivity. These reactions present with serious mucocutaneous manifestations that can lead to significant morbidity and mortality. The pathogeneses of SJS and TEN have yet to be clearly elucidated, but three potential immunologic mechanisms have been defined in literature: granulysin, Fas-FasL, and perforin and granzyme B. Medications have been immunologically linked as the primary causative agents of SJS/TEN. Corticosteroids, intravenous immunoglobulin administration (IVIG) and cyclosporine have been employed as treatments; however, none have resulted in consistent positive outcomes. Pharmacists have a significant role in …

Pigmented Melanoma Cell Migration Study On Murine Syngeneic B16f10 Melanoma Cells Or Tissue Transplantation Models, Maria-Cristina Predoi, Ion Mîndrilă, Sandra Alice Buteică, Ovidiu Marcel Mărginean, Bogdan Mîndrilă, Mihaela Niculescu

Journal of Mind and Medical Sciences

Melanoma is a lethal form of skin cancer with poor prognosis, especially due to the early metastatic feature. Recent studies have shown that the melanin pigment influences the nanomechanical properties and, therefore, the metastatic behavior of the melanoma cells. We aimed to study the growth of subcutaneously transplanted syngeneic melanoma tissue in female C57BL/6 mice harvested from a mouse with a four-week B16F10 melanoma. Also, we studied the effect of the melanin pigment loading on the peritumoral migratory abilities of melanoma cells. Even when the syngeneic transplant was different (cultured cells vs. tumor tissue), the morphological features and the tumor …

Relating The Gut Metagenome And Metatranscriptome To Immunotherapy Responses In Melanoma Patients., Brandilyn A. Peters, Melissa Wilson, Una Moran, Anna Pavlick, Allison Izsak, Todd Wechter, Jeffrey S. Weber, Iman Osman, Jiyoung Ahn

Department of Medical Oncology Faculty Papers

BACKGROUND: Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

METHODS: In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression.

RESULTS: Higher …

Anterior Subcapsular Cataract Secondary To Black Mold Exposure, Katherine B. Lynch Od, Bruce A. Teitelbaum Od

Optometric Clinical Practice

A case report of a 31-year-old woman who developed anterior subacapsular cataracts, and associated dermatological signs, after exposure to black mold. While atopic illness is commonly seen in childhood, a growing body of literature supports adult onset atopic dermatitis. Anterior subcapsular cataracts are pathognomonic for atopic illness, and can support a definitive and expedited dermatologic diagnosis of adult onset disease.

Ecthyma Gangrenosum In An Immunocompromised Patient Without Detectable Bacteremia, Jonathan Miles, Alex Mari, Matthew Crabtree, Vinod Nambudiri, Jilian Sansbury

Dermatology

Ecthyma gangrenosum (EG) is typically pathognomonic of Pseudomonas aeruginosa bacteremia among immunocompromised patients, particularly with underlying malignancy. Recently, other pathogens and clinical histories have been implicated, challenging the classic picture of patients with EG. The cutaneous findings in patients follow a pattern of lesion progression from indurated pustules and hemorrhagic vesicles evolving to necrotic ulcers with central black eschar and surrounding erythema. While lesions typically occur on the perineum or lower extremities, their presence has also been described elsewhere. Herein, we describe a case of an immunocompromised man with chronic lymphocytic leukemia and multiple myeloma actively undergoing chemotherapy presenting with …

Treatment Of Podoconiosis With Complicating Polyinfections Within Rural African Villages: A Case Study, Amanda R. Beering, Abigail R. Florence, Soon Bahrami Md

Journal of Refugee & Global Health

This case study aims to provide a treatment plan for the treatment of podoconiosis with complicating polyinfections in a resource poor setting. A second objective is to help healthcare providers teach preventive measures to villagers in affected regions.

Slc36a1-Mtorc1 Signaling Drives Acquired Resistance To Cdk4/6 Inhibitors., Akihiro Yoshida, Yiwen Bu, Shuo Qie, John Wrangle, E. Ramsay Camp, E. Starr Hazard, Gary Hardiman, Renée De Leeuw, Karen E. Knudsen, J. Alan Diehl

Department of Cancer Biology Faculty Papers

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X …

High-Dose Finasteride Is An Effective Treatment Modality For Androgenic Alopecia In Postmenopausal Women, Joshua T. Gaudette

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Oliveira-Soares R, Silva JE, Correia M, André M. Finasteride 5 mg/day treatment of patterned hair loss in normo-androgenetic postmenopausal women. International Journal of Trichology. 2013;5(1):22-25. doi: 10.4103/0974-7753.114709.

Quantifying Skin Photodamage With Spatial Frequency Domain Imaging: Statistical Results, Jeffrey B. Travers, Chien Poon, Trevor J. Bihl, Benjamin Rinehart, Christina E. Borchers, Daniel J. Rohrbach, Samia Borchers, Julian J. Trevino, Max Rubin, Heidi Donnelly, Karl Kellawan, Lydia Carpenter, Shalini Bahl, Craig A. Rohan, Elizabeth Muennich, Scott Guenthner, Holly Hahn, Ali Rkein, Marc Darst, Nico Mousdicas, Elizabeth E. Cates, Ulas Sunar

Dermatology Faculty Publications

We investigated the change in optical properties and vascular parameters to characterize skin tissue from mild photodamage to actinic keratosis (AK) with comparison to a published photodamage scale. Multi-wavelength spatial frequency domain imaging (SFDI) measurements were performed on the dorsal forearms of 55 adult subjects with various amounts of photodamage. Dermatologists rated the levels of photodamage based upon the photographs in blinded fashion to allow comparison with SFDI data. For characterization of statistical data, we used artificial neural networks. Our results indicate that optical and vascular parameters can be used to quantify photodamage and can discriminate between the stages as …

Eosinophilic Dermatosis Of Hematologic Malignancy Responding To Dupilumab In A Patient With Chronic Lymphocytic Leukemia., Annie Jin, Bobak T. Pousti, Kevin T. Savage, Nicholas K. Mollanazar, Jason B. Lee, Sylvia Hsu

Department of Dermatology and Cutaneous Biology Faculty Papers

Leukemia cutis (LC) and eosinophilic dermatosis of hematologic malignancy (EDHM) are rare cutaneous manifestations of hematologic malignancies. Various therapeutic options have been reported, with largely underwhelming responses. We present a patient with chronic lymphocytic leukemia (CLL) with concomitant LC and EDHM who was treated with dupilumab.

Pioneers In Dermatology And Venereology: An Interview With Prof. Lawrence C. Parish., Lawrence Charles Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Perforating Granuloma Annulare Appearing As A Psoriasiform Lesion., Benjamin M Witkoff, Nedyalko N Ivanov, Shannon C Trotter

Ambulatory and Primary Care Articles

We present a 54-year-old Caucasian female with a history of diabetes mellitus, multiple sclerosis, and ulcerative colitis who presented with nail dystrophy, polyarthralgia in her hands and hips, myalgia, proximal myopathy, dactylitis, and psoriasiform-appearing progressive, painful plaques on the dorsal aspect of her hands. Histologic examination of the lesion from the left index finger revealed an interstitial and necrobiotic granulomatous dermatitis with connective tissue mucin deposition associated with a perivascular lymphoid infiltrate. Additionally, there was focal transepidermal elimination of the necrobiotic material. She was diagnosed with perforating granuloma annulare (PGA). We are unaware of any other cases of PGA in …

Intralesional Corticosteroids For Long-Term Control Of Primary Cutaneous Marginal Zone Lymphoma Without Systemic Involvement, Pragya Tiwari, John Hall, Anand Rajpara, Carol Stanford, Daniel Aires

Marshall Journal of Medicine

Primary cutaneous marginal zone lymphoma (PCMZL) is a B cell lymphoma with a very low metastatic rate. Radiographic monitoring for internal involvement may be indicated initially. Favored treatments include radiation and excision. Radiation has high risk of local recurrence. Excision carries risk of infection and scarring. We report successful long-term treatment of recurrent PCMZL via intralesional steroid injections into new lesions as they arose. This was preferred by the patient over her prior radiation and surgical treatments. Intralesional steroids have the advantages of being simple and well tolerated, without exposure to ionizing radiation, or to the infection and scarring associated …

Assessment Of The Risk And Characterization Of Non-Melanoma Skin Cancer In Kindler Syndrome: Study Of A Series Of 91 Patients., Sara Guerrero-Aspizua, Claudio J. Conti, Maria Jose Escamez, Daniele Castiglia, Giovanna Zambruno, Leila Youssefian, Hassan Vahidnezhad, Luis Requena, Peter Itin, Gianluca Tadini, Ivelina Yordanova, Ludovic Martin, Jouni Uitto, Cristina Has, Marcela Del Rio

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Kindler Syndrome (KS) is a rare genodermatosis characterized by skin fragility, skin atrophy, premature aging and poikiloderma. It is caused by mutations in the FERMT1 gene, which encodes kindlin-1, a protein involved in integrin signalling and the formation of focal adhesions. Several reports have shown the presence of non-melanoma skin cancers in KS patients but a systematic study evaluating the risk of these tumors at different ages and their potential outcome has not yet been published. We have here addressed this condition in a retrospective study of 91 adult KS patients, characterizing frequency, metastatic potential and body distribution of …

Transmissible Dermatological Diseases Affecting Syrian Refugees In Lebanon, Nisrine Kawa, Edith Hanna, Abdul Rahman Bizri

Journal of Refugee & Global Health

The Syrian war led many to seek shelter in Lebanon, creating a major refugee crisis. Displaced populations in crowded unequipped settlements are vulnerable to infectious diseases. The burden and incidence of various transmissible skin conditions affecting Syrian refugees in Lebanon and their impact on the Lebanese public health system were evaluated. Literature regarding these conditions among Syrian refugees in host countries, and epidemiological data from the Lebanese Ministry of Public Health Surveillance Unit and primary health-care network were reviewed. Lebanon has witnessed skin disorder outbreaks associated with the Refugee crisis, mainly leishmaniasis, scabies and lice infestations with little data about …

Ulcus Vulvae Acutum - A Rare Case, Irene Dorthy Santoso, Ika Anggraini, Wresti Indriatmi, Yudo Irawan, Hanny Nilasari, Melani Marissa, Sondang P. Sirait, Rahadi Rihatmadja

Journal of General - Procedural Dermatology and Venereology Indonesia

Background: Ulcus vulvae acutum, also known as Lipschütz ulcer, is a rare condition characterized by multiple, painful, and acute genital ulceration in young women without venereal infections, associated with systemic symptoms like malaise, fever, and inguinal lymphadenopathy.

Case Illustration: A 24-year-old woman developed multiple and painful vulvar ulcers that recurred for almost a year. The patient was primarily diagnosed and treated as genital herpes in several hospitals with only slight improvement and no complete healing. The patient came to our hospital for examinations to rule out sexually-transmitted infection (STI) (genital herpes, syphilis, HIV, and chancroid) and possibility of …