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.

Estimating the burden of vitiligo: a systematic review and modelling study.

BACKGROUND: Vitiligo is a chronic autoimmune disease characterised by depigmented skin patches, which can pose substantial psychosocial challenges particularly in individuals with dark skin tones. Despite its impact on quality of life, there is an absence of standardised global epidemiological data. We sought to address this gap with the present study. METHODS: In this study we did a systematic review and modelling analysis to estimate the global, regional, and national prevalence and incidence of vitiligo. We did a comprehensive search of nine digital libraries (PubMed, Embase, Web of Science, Scientific Electronic Library Online, KCI Korean Journal Database, Russian Science Citation Index, Western Pacific Region Index Medicus, Informit, and Health Research and Development Information Network) from inception up to May 25, 2023. We included cross-sectional or cohort studies reporting the incidence rate or prevalence of vitiligo, or data from which incidence rate or prevalence could be calculated, in the general population of a country or area of a country. Summary estimate data were extracted. A main outcome was to estimate the worldwide, regional, and country-specific lifetime prevalence of vitiligo diagnosed by physicians or dermatologists among the general population and in adults and children (as per age groups defined in included studies). We used a Bayesian hierarchical linear mixed model to estimate prevalence, and calculated number of affected individuals using the UN population structure in 2022. In estimating lifetime prevalence, studies reporting point or period prevalence were excluded. Our other main outcome was to estimate incidence rates of vitiligo, but due to a small number of studies, the data on incidence were presented in a descriptive summary. This study was registered on PROSPERO, CRD42023390433. FINDINGS: Our search identified 22 192 records, of which 90 studies met our inclusion criteria. Of these studies, six focused on the incidence of vitiligo, 79 reported on the prevalence of vitiligo, and five provided data on both incidence and prevalence. 71 studies reported on lifetime prevalence. In the most recent years studied, incidence rates in the general population ranged from 24·7 cases (95% CI 24·3-25·2) per 100 000 person-years in South Korea in 2019, to 61·0 cases (60·6-61·4) in the USA in 2017. In individual studies, incidence rates showed an increasing trend over the periods studied. The global lifetime prevalence of vitiligo diagnosed by a physician or dermatologist was estimated at 0·36% (95% credible interval [CrI] 0·24-0·54) in the general population (28·5 million people [95% CrI 18·9-42·6]), 0·67% (0·43-1·07) in the adult population (37·1 million adults [23·9-58·9]), and 0·24% (0·16-0·37) in the child population (5·8 million children [3·8-8·9]). Vitiligo prevalence was higher in adults than in children across all regions. Central Europe and south Asia reported the highest prevalence (0·52% [0·28-1·07] and 0·52% [0·33-0·82], respectively, in the general population). INTERPRETATION: This study highlights the need for standardised epidemiological data collection globally to inform public health policies and improve vitiligo diagnosis and management. Emphasis on the impact on individuals with darker skin tones is crucial to reducing stigma and improving quality of life. Furthermore, our study highlights the need to conduct more research in regions and populations that have been historically under-represented, to effectively address the worldwide burden of vitiligo. FUNDING: None.

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.

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.

The performance of an artificial intelligence-based computer vision mobile application for the image diagnosis of genital dermatoses: a prospective cross-sectional study.

BACKGROUND: There is a huge demand-supply gap between the incidence of genital dermatoses (including sexually transmitted infections and non-venereal genital dermatoses) and physicians trained to manage them. OBJECTIVES: To find out the performance of an artificial intelligence (AI)-based mobile application in the image diagnosis of genital dermatoses, and to compare it with primary care physicians (PCPs) and dermatologists. METHODS: Photos of the genital diseases of consecutive patients presenting to the STD and genital diseases clinic were included. The gold standard diagnosis was established by the consensus of two certified dermatologists after examination and one positive investigation. Image diagnoses by the DermaAId application, two PCPs, and two dermatologists were recorded and compared to the gold standard diagnosis and to each other. RESULTS: A total of 257 genital disease images, including 95 (37.0%) anogenital warts, 60 (22.2%) lichen sclerosus, 20 (7.8%) anogenital herpes, 15 (5.8%) tinea cruris, 14 (5.4%) molluscum contagiosum, 9 (3.5%) candidiasis, 8 (3.1%) scabies, 6 (2.3%) squamous cell carcinomas, were included. The top-1 correct diagnosis rate of the application was 68.9%, compared to the 50.4% of the PCPs and 73.2% of the dermatologists. The application significantly outperformed PCPs with regard to the correlation with the gold standard diagnosis (P < 0.0001), and matched that of the dermatologists. CONCLUSIONS: AI-based image diagnosis platforms can potentially be a low-cost rapid decision support tool for PCPs, integrated with syndromic management programs and direct-to-consumer services, and address healthcare inequities in managing genital dermatoses.

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.