Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

Macrophage inhibitory factor alters the functionality of macrophages and their involvement in disease pathogenesis of active generalized vitiligo patients.

INTRODUCTION: In autoimmune dermatitis patients, a macrophage migration inhibitory factor (MIF) is widely used to determine the severity of the diseases with other clinical parameters. Moreover, in vitiligo, MIF has shown significant positive correlation with the VASI (Vitiligo Area Scoring Index) score of both generalized and localized vitiligo patients. MIF function as pro-inflammatory cytokine and inhibited random migration of macrophages from inflammation loci. Hence, activated macrophage infiltrates promote the diseases pathogenesis. Till date, macrophages and involvement of their secreted MIF in disease severity of vitiligo patients remains undetermined. MATERIAL AND METHOD: The frequency of both M1 and M2 macrophages was evaluated in active GV patients (n = 20) using flow cytometry in blood and in tissues by confocal microscopy (n = 10). Relative m-RNA expression and cytokine profiling of pro and anti-inflammatory mediators were estimated in PBMCs and in serum of patients. Lastly, concentration of nitric oxide and phagocytic activity from macrophages of active patients were calculated to understand the diseases pathology in detail. RESULT: Both in circulation as well as in tissues, the infiltration of M1 macrophages was increased in active GV patients, while the percentage of M2 macrophages was comparable to healthy tissues. Aberrant expression of pro and anti-inflammatory molecules including IL-1ß, IL-6, TNF-α, IL-12 and MIF impair the cellular hemostasis and induce systematic inflammation. Elevated nitric oxide and higher phagocytic activity of macrophages enhanced the destruction and/or depigmentation of melanocytes causing vitiligo. CONCLUSION: Elevated macrophages in both tissue and blood enhanced the secretion of MIF and other inflammatory mediators that further enforce the production of nitric oxide, activation and phagocytic activity of macrophages against melanocytes and melanocytes antigens. As a result, destruction of melanocytes and melanin production occurred and caused the depigmentation and/or white macules on the skin.

Predictive Performance of 1 H-NMR Metabolomics-Derived Biomarkers of Bacterial Vaginosis.

ABSTRACT: 1 H-NMR metabolomics-derived biomarkers maltose, acetate, formate, and lactate have excellent potential as predictive biomarkers for bacterial vaginosis with an area under curve of 0.97 (95% confidence interval, 0.88-1.00), sensitivity of 0.90, and specificity of 0.95.

The shadow pandemic: rising syphilis rates in the wake of coronavirus (COVID-19).

The coronavirus disease 2019 (COVID-19) aftermath left an alarming surge in syphilis cases, contradicting the previously stable trajectory of the infection. US Centers for Disease Control and Prevention also reported a 38% increase in primary and secondary syphilis in 2021 compared to 2019 in the United States, prompting a retrospective analysis at our tertiary care centre in New Delhi, India. There was a persistent linear rise, surpassing pre-COVID levels. Male clinic attendees, exhibit a pronounced increase, likely due to the influence of MSM. Online sexual activity during lockdowns and redirected healthcare resources have possibly contributed to this trend. Urgent measures include strengthened surveillance data collection and public health response, awareness promotion, and early, free treatment. The syphilis surge may signify a broader, undiagnosed STI pandemic, necessitating comprehensive intervention and surveillance.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the International Vitiligo Task Force Part 1: towards a new management algorithm.

BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.

Asian guidelines for condyloma acuminatum.

The present guidelines aim to provide comprehensive information on genital condyloma acuminata, including the epidemiology, clinical features, diagnosis and management. The guidelines provide evidence-based recommendations on the diagnosis, prevention and treatment of genital condyloma acuminata in adults in Asia, including patients with HIV co-infection. METHODOLOGY: A PubMed search was performed, using the keywords "condyloma acuminata", "anal wart", "anogenital wart", "genital wart" and "genital HPV". A total of 3031 results were found in publications during last six years. A careful review of the titles and abstracts was done to find all the studies pertaining to epidemiology, clinical features, diagnosis, treatment and prevention of condyloma acuminata. DIAGNOSIS: Various diagnostic procedures described are: 1. PCR (LE: 2b). 2. Serology (LE: 2b). 3. In-situ hybridization (LE: 3). PREVENTION: 1. Vaccination (LE: 1a): Quadrivalent vaccine reduced the frequency of anogenital warts in both vaccinated and unvaccinated contacts. According to the update Advisory Committee on Immunization Practices (ACIP) recommendations, the following protocol is recommended: (a). HPV vaccination at age 11 or 12 years for both males and females. (b). Catch-up vaccination for all persons through age 26 years. (c). Shared clinical decision-making regarding potential HPV vaccination for persons aged 27-45 years, who are at risk of new HPV infection. 2. Male circumcision (LE: 2a): conflicting evidence. HIV AND CONDYLOMA ACUMINATA: In HIV-affected individuals, the course of HPV is more aggressive, with a greater risk of treatment resistance, increased chances of intraepithelial neoplasia as well as cancers. TREATMENT: Physician administered. 1. Photodynamic therapy (LE: 1a). 2. Laser (LE: 2b). 3. Surgery (LE: 1a). 4. Electrosurgery (LE: 2c). 5. Cryotherapy (LE: 1b). 6. Immunotherapy (LE: 1b). 7. Podophyllin (LE: 1b). Provider administered. 1. Imiquimod 5%(LE: 1a). 2. Podophyllotoxin (LE: 1b). 3. Sinecatechins (LE: 1a). 4. Cidofovir (LE: 3). 5. 5- Fluorouracil (LE: 1a). 6. Interferon (LE: 1a).

Diagnostic concordance between Amsel's criteria and the Nugent scoring method in the assessment of bacterial vaginosis.

Bacterial vaginosis (BV) is diagnosed by the microbiological Nugent scoring method or clinical Amsel's criteria. Assessment of 404 vaginal samples (293 women) identified 110 (27.2%), 108 (26.7%) and 161 (39.9%) samples to be BV-positive using Nugent's method, standard Amsel's criteria and simplified Amsel's criteria respectively. The sensitivity, specificity, and kappa statistic (κ) for standard and simplified Amsel's criteria were 71.8% (95% CI=62.4-80.0), 90.1% (95% CI=62.4-86.1), 0.62 (95% CI=0.53-0.72) and 88.2% (95% CI=80.6-93.6), 78.2% (95% CI=73.1-82.8), 0.58 (95% CI=0.49-0.67), respectively. A combination of vaginal pH and clue cells exhibited the highest concordance (κ=0.64, 95% CI=0.54-0.74) with Nugent's method and may be used for simplified BV diagnosis.

Resurgence of syphilis, the great imitator.

Syphilis, one of the earliest diseases to be discovered in humans, still remains an enigma when it comes to its myriad manifestations and changing epidemiological profiles. There has been a surge in cases in the last few decades due to various factors. The human immunodeficiency virus (HIV) epidemics, global travel, increased incidence of male to male sexually transmitted diseases, online relationships culminating in casual sex are few of the important factors. Increased awareness could also be a factor for increased diagnosis. The multitude of clinical features especially when it comes to secondary syphilis and the rare tertiary manifestations, which can mimic various systemic disorders still pose a diagnostic challenge to the best of venereologists and physicians. This review aims to discuss the causes of resurgence in syphilis and few recent developments in pathogenesis, which could have led to this resurgence.

Dendritic cells and their associated pro-inflammatory cytokines augment to the inflammatory milieu in vitiligo skin.

BACKGROUND AND AIM: Vitiligo is a progressive, autoimmune, hypomelanotic acquired disorder of skin which is characterized by depigmentation. The initial immunological events of this diseases are still at enigma that includes breach of immune tolerance, and defect in antigen presentation. Hence, we aimed to explore role of Dendritic cells (DCs) and its associated cytokines in the pathogenesis of generalized vitiligo (GV) patients. METHODOLOGY: For this case-control study, 20 active patients and controls were enrolled. Phenotypic characterization of myeloid and plasmacytoid DCs (mDCs, pDCs) were done by flow-cytometry. Primary culture of DCs was done by monocyte differentiation supplemented with rIL-4 and rGM-CSF. Functional analysis DCs related cytokines and co-stimulatory molecules (CD80, CD40) was done by ELISA and qPCR respectively. Tissue localization of DCs was evaluated by immunohistochemistry. RESULT: The frequency of mDCs (0.3715% v/s 0.188%) and pDCs (0.2331% v/s 0.1156%) were elevated in patients as compared to controls. Circulatory level of IL-12, TNF-α were significantly higher whereas IFN-α was decreased in patients than controls. Similar results were obtained in the culture supernatants of patients. Relative mRNA expression profiling of co-stimulatory molecules (CD80, CD40) were found to be up regulated in patient's skin. Tissue localization of Langerhans cells (Langerin, CD1a+) were found to be significantly higher in patients. CONCLUSION: Elevated frequency of mDCs and pDCs along with elevated levels of IL-12, TNF-α and CD80, CD40 may contribute in defective antigen presentation of DCs. Altered pro-inflammatory and anti-inflammatory cytokines along with tissue localization of Langerhans cells might be involved in the pathogenesis of GV. These DCs associated cytokines can be explored as a therapeutic target in future.

A convolutional neural network architecture for the recognition of cutaneous manifestations of COVID-19.

During the COVID-19 pandemic, dermatologists reported an array of different cutaneous manifestations of the disease. It is challenging to discriminate COVID-19-related cutaneous manifestations from other closely resembling skin lesions. The aim of this study was to generate and evaluate a novel CNN (Convolutional Neural Network) ensemble architecture for detection of COVID-19-associated skin lesions from clinical images. An ensemble model of three different CNN-based algorithms was trained with clinical images of skin lesions from confirmed COVID-19 positive patients, healthy controls as well as 18 other common skin conditions, which included close mimics of COVID-19 skin lesions such as urticaria, varicella, pityriasis rosea, herpes zoster, bullous pemphigoid and psoriasis. The multi-class model demonstrated an overall top-1 accuracy of 86.7% for all 20 diseases. The sensitivity and specificity of COVID-19-rash detection were found to be 84.2 ± 5.1% and 99.5 ± 0.2%, respectively. The positive predictive value, NPV and area under curve values for COVID-19-rash were 88.0 ± 5.6%, 99.4 ± 0.2% and 0.97 ± 0.25, respectively. The binary classifier had a mean sensitivity, specificity and accuracy of 76.81 ± 6.25%, 99.77 ± 0.14% and 98.91 ± 0.17%, respectively for COVID-19 rash. The model was robust in detection of all skin lesions on both white and skin of color, although only a few images of COVID-19-associated skin lesions from skin of color were available. To our best knowledge, this is the first machine learning-based study for automated detection of COVID-19 based on skin images and may provide a useful decision support tool for physicians to optimize contact-free COVID-19 triage, differential diagnosis of skin lesions and patient care.