Post-marketing safety concerns with abrocitinib: a real-world pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: Abrocitinib was newly approved for treatment of moderate-to-severe atopic dermatitis. The present study was to assess abrocitinib-related adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of abrocitinib-related AEs. RESULTS: A total of 3,177,744 reports of AEs were collected from the FAERS database, of which 1370 reports were identified with abrocitinib as the primary suspect drug. Abrocitinib-induced adverse events (AEs) occurred across 27 system organ classes (SOCs). A total of 68 preferred terms (PTs) with significant disproportionality, meeting the criteria of all four algorithms simultaneously, were identified. Unexpected significant AEs, such as increased blood cholesterol, venous embolism, hypoacusis, cellulitis, and tuberculosis, might also occur. The median onset time for abrocitinib-associated AEs was 182 days (interquartile range [IQR] 47-527 days). CONCLUSIONS: The results of this study were consistent with clinical observations. Additionally, unexpected safety signals for abrocitinib were identified, which provided supportive information for the safety profile of abrocitinib. Prospective clinical studies are warranted to validate these findings.

Large-Scale Proteome Profiling Identifies Biomarkers Associated with Suspected Neurosyphilis Diagnosis.

Neurosyphilis (NS) is a central nervous system (CNS) infection caused by Treponema pallidum (T. pallidum). NS can occur at any stage of syphilis and manifests as a broad spectrum of clinical symptoms. Often referred to as "the great imitator," NS can be easily overlooked or misdiagnosed due to the absence of standard diagnostic tests, potentially leading to severe and irreversible organ dysfunction. In this study, proteomic and machine learning model techniques are used to characterize 223 cerebrospinal fluid (CSF) samples to identify diagnostic markers of NS and provide insights into the underlying mechanisms of the associated inflammatory responses. Three biomarkers (SEMA7A, SERPINA3, and ITIH4) are validated as contributors to NS diagnosis through multicenter verification of an additional 115 CSF samples. We anticipate that the identified biomarkers will become effective tools for assisting in diagnosis of NS. Our insights into NS pathogenesis in brain tissue may inform therapeutic strategies and drug discoveries for NS patients.

Analysing the causal relationship between potentially protective and risk factors and cutaneous melanoma: A Mendelian randomization study.

BACKGROUND: Previous observational studies reported altered melanoma risks in relation to many potential factors, such as coffee intake, smoking habits and photodamage-related conditions. Considering the susceptibility of epidemiological studies to residual confounders, there remains uncertainty about the actual causal roles of these reported factors in melanoma aetiology. OBJECTIVES: This study aims to investigate the causal association between cutaneous melanoma (CM) and previously reported factors: coffee intake, alcohol consumption, lifetime smoking, socioeconomic status (SES), ease of skin tanning, childhood sunburn and facial ageing, providing insight into its underlying aetiology and preventative strategies. METHODS: We utilized a two-sample MR analysis on data from the largest meta-analysis summary statistics of confirmed cutaneous melanoma including 30,134 patients. Genetic instrumental variables were constructed by identifying single nucleotide polymorphisms (SNPs) that associate with corresponding factors. Inverse variance weighted (IVW) was the primary MR method. For sensitivity and heterogeneity, MR Egger, weighted median, simple mode, weighted mode and MR Egger intercept tests were examined. RESULTS: Cutaneous melanoma risks were found to be elevated in association with a predisposition towards ease of skin tanning (IVW: OR = 2.842, 95% CI 2.468-3.274, p < 0.001) and with childhood sunburn history (IVW: OR = 6.317, 95% CI 4.479-8.909, p < 0.001). Repeated MR after removing potential confounders and outliers demonstrated resolved horizontal pleiotropy and statistically significant results that closely mirrored the initial findings. Other potential factors, such as coffee intake, alcohol consumption, smoking and socioeconomic status (SES), indicated insignificant effects on melanoma risk in the analysis, and therefore, our Mendelian randomization study does not support their roles in modifying melanoma risks. CONCLUSIONS: Our extensive MR analysis provides strong evidence of the causative role of ease of skin tanning and childhood sunburn history in elevating melanoma risk. Curtailing ultraviolet radiation (UVR) exposure may be the single best preventative strategy to reduce melanoma risk.

Clinical and Laboratory Characteristics, Neuroimaging Alternations and Treatment Response of 25 HIV-Negative General Paresis Patients.

Purpose: General paresis is a common type of neurosyphilis featuring progressive cognitive deterioration. The lack of a golden standard of diagnosis and its nonspecific clinical manifestations resulted in a high rate of misdiagnoses. This study aims to investigate the clinical, laboratory and radiological presentations of general paresis and enrich its knowledge for timely diagnoses. Patients and methods: The study collected hospitalized patients admitted for general paresis from September 2002 to November 2022. Their socio-demographical and medical status, clinical presentations, cognitive assessments, laboratory and radiographical manifestations and treatment information were collected retrospectively. Results: A total of 20 males and 5 females were included. Patients' ages ranged from 30 to 66 years (average 50.3 years). The average and median time for diagnosing general paresis was 14.1 months and 10.0 months respectively. The most frequent initial symptom is memory deterioration (68.0%). Impaired calculative ability and memory deterioration were the most frequent cognitive anomalies, as found in 50% and 45.4% of subjects during examination. The mean and median scores of MoCA was 16.7 and 17 respectively. Serological tests revealed positive TPPA for all patients and a median RPR titer at 1:64 positive. All CSF samples with TPPA and FTA-ABS results reported positivity. The MRI manifestations of general paresis include patchy or speckled hyperintensities (70.8%) and cerebral atrophy (45.8%). The most common lesioned sites in MRI were the ventricular and paraventricular area (50.0%) and temporal lobes (45.8%). For treatment, penicillin-based anti-syphilitic plans were adopted in 17 patients (68.0%). Conclusion: The clinical features and radiological alternations of general paresis patients often exhibited diverse and nonspecific alternations. However, some specific clinical manifestations and auxiliary examinations can provide meaningful clues for the identification and differential diagnosis of this disease.

Assessing the quality of care for skin malignant melanoma on a global, regional, and national scale: a systematic analysis of the global burden of disease study from 1990 to 2019.

Malignant melanoma (MM) is a highly aggressive form of skin cancer with increasing global incidence rates, particularly in developed countries. Variations in the prevalence and quality of care provided to patients with melanoma exist across different regions and across different sex and age. Assessing the global burden of melanoma and evaluating the quality of care can provide valuable insights for developing targeted interventions in certain underperforming regions and improving patient outcomes. This study aimed to systematically analyze the Global Burden of Disease Study from 1990 to 2019 to assess the quality of care for skin malignant melanoma on a global scale. We conducted a comprehensive literature review and extracted data on melanoma incidence, mortality, and disability-adjusted life years (DALYs) from the Global Burden of Disease Study. We incorporated these variables using principal component analysis (PCA) to form an informative single variable of quality of care index (QCI) and analyzed its spatial-temporal variations as well as disparities across age, sex and socio-demographic index (SDI). The overall Quality of Care Index (QCI) for melanoma improved from 82.81 in 1990 to 91.29 in 2019. The QCI score showed a positive correlation with socioeconomic status across regions. Australia ranked highest in QCI (99.96), while Central African Republic, and Kiribati had the lowest scores. China and Saudi Arabia showed significant QCI improvement, while the QCI of the Democratic People's Republic of Korea, Zimbabwe, and Guam decreased from 1990 to 2019. The highest QCI scores were observed in the age groups of 20-39 years old (93.40-94.65). Gender disparities narrowed globally in these three decades, but lower Socio-demographic Index (SDI) regions showed increased gender inequities. Our findings highlighted the spatial-temporal variations in the quality of care of MM as well as its disparities across different SDI levels, age groups and sex. These findings offer valuable insights and guidance for implementing focused interventions and resource allocation to enhance the quality of care and overall outcomes for MM worldwide, especially for underperforming regions.

Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study.

RESULTS: The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.

Intravesical injection of botulinum toxin type a may be an effective treatment option for autonomic dysreflexia in patients with high-level spinal cord injury.

OBJECTIVE: To evaluate the efficacy of intravesical injection of botulinum toxin type A (BTX-A) for neurogenic detrusor overactivity (DO) in reducing the frequency and severity of autonomic dysreflexia (AD). DESIGN: A cross-sectional nonrandomized trial with before (baseline) and after (follow-up) assessments. SETTING: A single spinal cord injury (SCI) rehabilitation center in China. PARTICIPANTS: Twenty-five patients with SCI at or above T6 and a history of AD who underwent urodynamic studies (UDS) before and 3 months after BTX-A injection. INTERVENTIONS: Received bladder injection treatment wtih 200 U BTX-A. OUTCOME MEASURES: The maximum detrusor pressure(Pdetmax) and voume at first DO(VFIDC), baseline and overall maximum systolic blood pressure (SBP) during UDS, and scores of Incontinence Specific Quality of Life Instrument (IQoL) were recorded before and 3 months after the injection. The change in SBP (ΔSBP) from baseline to maximum SBP during UDS was calculated to assess the severity. The frequency of AD was recorded using ambulatory blood pressure monitoring during a 24 h period before and 3 months after the injection. RESULTS: BTX-A injection decreased the Pdetmax and increased the VFIDC and mean urine volume per catheterization increased. The maximum SBP and the ΔSBP during UDS decreased significantly decreased after the injection (151.44 ± 13.92 vs 133.32 ± 9.20 mmHg and 49.44 ± 12.81 vs 33.08 ± 9.11 mmHg respectively, P < 0.05). The frequency of bladder-related ADs (i.e. performed a clean intermittent catheterization or leakage) during a 24-h period significantly decreased from 11.04 ± 1.81-7.88 ± 2.15 (P < 0.001). CONCLUSIONS: BTX-A decreases the severity of SBP increase and the number of AD episodes 3 months after intravesical injection.

Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth.

Human skin comprises stratified squamous epithelium and dermis with various stromal cells and the extracellular matrix (ECM). The basement membrane (BM), a thin layer at the top of the dermis, serves as a unique niche for determining the fate of epidermal stem cells (EpSCs) by transmitting physical and biochemical signals to establish epidermal cell polarity and maintain the hierarchical structure and function of skin tissue. However, how stem cell niches maintain tissue homeostasis and control wound healing by regulating the behavior of EpSCs is still not completely understood. In this study, a hierarchical skin proteome map is constructed using spatial quantitative proteomics combined with decellularization, laser capture microdissection, and mass spectrometry. The specific functions of different structures of normal native skin tissues or tissues with a dermatologic disease are analyzed in situ. Transforming growth factor-beta (TGFß)-induced protein ig-h3 (TGFBI), an ECM glycoprotein, in the BM is identified that could enhance the growth and function of EpSCs and promote wound healing. Our results provide insights into the way in which ECM proteins facilitate the growth and function of EpSCs as part of an important niche. The results may benefit the clinical treatment of skin ulcers or diseases with refractory lesions that involve epidermal cell dysfunction and re-epithelialization block in the future.

Toward Assessment of Sound Localization in Disorders of Consciousness Using a Hybrid Audiovisual Brain-Computer Interface.

Behavioral assessment of sound localization in the Coma Recovery Scale-Revised (CRS-R) poses a significant challenge due to motor disability in patients with disorders of consciousness (DOC). Brain-computer interfaces (BCIs), which can directly detect brain activities related to external stimuli, may thus provide an approach to assess DOC patients without the need for any physical behavior. In this study, a novel audiovisual BCI system was developed to simulate sound localization evaluation in CRS-R. Specifically, there were two alternatively flashed buttons on the left and right sides of the graphical user interface, one of which was randomly chosen as the target. The auditory stimuli of bell sounds were simultaneously presented by the ipsilateral loudspeaker during the flashing of the target button, which prompted patients to selectively attend to the target button. The recorded electroencephalography data were analyzed in real time to detect event-related potentials evoked by the target and further to determine whether the target was attended to or not. A significant BCI accuracy for a patient implied that he/she had sound localization. Among eighteen patients, eleven and four showed sound localization in the BCI and CRS-R, respectively. Furthermore, all patients showing sound localization in the CRS-R were among those detected by our BCI. The other seven patients who had no sound localization behavior in CRS-R were identified by the BCI assessment, and three of them showed improvements in the second CRS-R assessment after the BCI experiment. Thus, the proposed BCI system is promising for assisting the assessment of sound localization and improving the clinical diagnosis of DOC patients.

Chinese guidelines on the clinical application of 5-aminolevulinic acid-based photodynamic therapy in dermatology (2021 edition).

Photodynamic Therapy with 5-aminolevulinic acid (ALA-PDT) has been widely applied in the treatment of skin diseases in China. To further standardize, guide, and promote the clinical applications of ALA-PDT in dermatology, the Chinese Society of Dermatology, Chinese Association of Rehabilitation Dermatology, Photomedicine Therapeutic Equipment Group of Committee on Skin Disease, and Cosmetic Dermatology of China Association of Medical Equipment invited relevant experts engaged in ALA-PDT to revise and update the first edition of "Clinical application of 5-aminolevulinic acid-based photodynamic therapy: an expert consensus statement" and establish a more current edition, to provide an updated reference for Chinese dermatologists in clinical practice. In the guideline, the expert group reached consensus opinions on ALA-PDT with regard to mechanisms of action, therapeutic protocol, clinical applications, adverse reactions and countermeasures, precautions, care, and evaluation of efficacy.

The Great Imitator: Atypical Cutaneous Manifestations of Primary Syphilitic Chancre.

Objective To analyze the reasons of misdiagnosis of primary syphilitic chancre and strengthen the understanding of atypical features of this disease. Methods A case series of twenty-seven challenging primary syphilis patients who were not immediately recognized as chancre was included in our study. The clinical data including the patients' age, sex, skin lesions, HIV status, syphilis serologic test results, treatment, and follow-up results were collected. Hematoxylin-eosin and immunohistochemistry staining of skin biopsy sections were reviewed. Results Four female cases with extragenital chancres presenting as erythema or erosive skin lesions on the nipple were misdiagnosed as Paget's disease or eczema. The disorder of missed or misdiagnosed male cases manifested as syphilitic balanitis or multiple chancres on the penis root and adjacent pubis rather than coronal sulcus or frenum. Patients with nonreactive nontreponemal tests at initial presentation were also easily missed or misdiagnosed. Conclusion Primary syphilis presenting as multiple lesions rather than a single chancre, at atypical locations, or with a nonreactive nontreponemal test result, tends to be missed or misdiagnosed.

Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis.

OBJECTIVES: Co-infection of syphilis and HIV remains hard to manage and its morbidity shows a rising tendency. Syphilis has been associated with increased risk of HIV acquisition in high-risk groups, especially in men who have sex with men (MSM). This systematic review and meta-analysis estimates the effect of syphilis infection on subsequent HIV acquisition, and assesses its difference between MSM and other high-risk populations. METHODS: Five electronic databases were searched for literature published to 21 September 2019 without language restrictions. Longitudinal studies that enrolled key populations to compare the incidence of HIV with and without syphilis exposure were included. We used a random-effects model to estimate the effect of syphilis infection on HIV acquisition among high-risk populations, which include MSM, sex workers, serodiscordant couples, people who inject drugs and attendees of STD clinics. RESULTS: A total of 17 cohorts and 5 case-control studies involving 65 232 participants were included. HIV incidence showed a two-time increase after syphilis exposure, compared with a control group (relative risk (RR) 2.67 (95% CI 2.05 to 3.47); p<0.05 for prevalence; RR 3.21 (95% CI 2.26 to 4.57); p=0.419 for incidence). No significant differences were observed between MSM and other high-risk groups in syphilis infection prevalence (RR 2.60 (95% CI 1.78 to 3.80); p<0.05 vs RR, 2.98 (95% CI 2.15 to 4.14); p<0.05; ratio of relative risk 0.76 (95% CI 0.49 to 1.17)). CONCLUSIONS: Syphilis infection increases the risk of HIV acquisition in high-risk populations. There is no evidence to suggest MSM are at greater risk than other high-risk populations. Prompt diagnosis, timely treatment, preventive interventions against syphilis infection would be a worthwhile investment for reducing HIV incidence. Strategies to combat stigma and discrimination targeted at MSM are pragmatically needed.

Risk Factors for the Co-infection with HIV, Hepatitis B and C Virus in Syphilis Patients.

Syphilis, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) share transmission routes. Syphilis infection can increase the risk of acquiring and transmitting HIV in key populations. The aims of this study were to investigate the risk factors and co-infection patterns for HIV, HBV and HCV in patients with syphilis. A retrospective study was conducted of 2,412 patients with syphilis (1,922 (79.68%) with latent syphilis, 336 (13.93%) with secondary syphilis, 78 (3.23%) with primary syphil-is, 72 (2.99%) with tertiary syphilis, and 4 (0.17%) with congenital syphilis). Positive results were odserved in 8.21% (134/1,620) of patients tested for HIV, 5.75% (82/1,427) for HBV, and 1.02% (14/1,374) for HCV, respectively. Multivariate logistic regression analysis found that male sex (adjusted odds ratio (AOR) 26.03; 95% confidence interval (CI) 10.37-65.36), age <55 years, especially age group 25-34-years (AOR 8.06; 95% CI 4.16-15.61), diagnosed at the Department of Infectious Disease (AOR 19.16; 95% CI 9.74-37.69), patients from Southern China, which is a geographical area south of the Qinling-Huaihe line (AOR 1.86; 95% CI 1.06-3.26) and having a rapid plasma reagin titre ≥1:32 (AOR 1.88; 95% CI 1.12-3.15) were independently associated with HIV infection. Risk factors for HBV co-infection in patients with syphilis, including male sex (AOR 1.78; 95% CI 1.12-2.83) and living in Southern China (AOR 4.66; 95% CI, 2.36-9.17) were also identified.

Clinicopathological characteristics and prognosis of amelanotic acral melanoma: A comparative study with pigmented acral melanoma.

We compared the clinicopathological features and prognosis between 16 amelanotic acral melanomas versus 56 pigmented acral melanomas. Amelanotic acral melanomas showed a thicker Breslow thickness (all had a Breslow thickness > 1 mm), more frequent ulceration (15/16, 93.7%) and lower HMB-45 positive rate than pigmented acral melanomas. However, a significant difference in survival was not observed.

Peripheral blood mononuclear cell microRNA profiles in syphilitic patients with serofast status.

Syphilis is a chronic sexually transmitted disease caused by infection with Treponema pallidum, which can invade various system organs, leading to clinical manifestations such as neurosyphilis, ocular syphilis, and cardiovascular syphilis and seriously endangering human health. Serofast status is a common outcome after syphilis treatment that presents an important clinical problem. At present, the etiology of serofast status remains unknown. A systematic investigation of the microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with serofast status or secondary syphilis and of healthy control subjects was conducted using small RNA-seq. The expression of miRNAs was further confirmed by real-time fluorescence quantitative PCR (qPCR) assays. The data reveal a specific miRNA expression profile that was displayed in cells from patients with serofast status. Known and novel predicted (np)-miRNAs were also identified and verified, such as miR-338-5p, np-miR-163, np-miR-128, np-miR-244, and np-miR-5, which together may be used as indicators for treatment evaluation. The functions of genes targeted by the miRNAs differentially expressed in serofast status patients were further analyzed; these genes were found to be involved in various biological functions, such as T-cell receptor signaling pathways, metabolism, and growth. Our study presents the first systematic landscape of miRNAs in PBMCs from patients with serofast status and proposes specific miRNAs linked with serofast status. Our results provide further evidence that serofast status is closely related to host immune function. Additionally, the miRNA expression profile in PBMCs of patients with serofast status generated by this work offers insight into the complex immune network in humans. We hope our results can provide new insights into the pathogenesis of serofast status.

Amelanotic melanoma.

Cutaneous amelanotic melanoma (AM) is a rare amelanotic or a hypomelanotic subtype of melanoma, comprising only 0.4-27.5% of all melanoma cases. The mean age of the patients is over 50 years, and the male/female ratio varies from 0.5 to 4. Patients with red hair, type I skin, freckles, lack of nevi on the back, a sun-sensitive phenotype, or previous AM history are more likely to develop AMs. As AMs lack pigmentation, their appearances vary and can mimic many benign and malignant conditions, thus presenting a diagnostic challenge. AMs are composed of greater proportions of nodular melanoma, acral lentiginous melanoma, and desmoplastic melanoma than pigmented melanomas. They also present with thicker Breslow thickness, higher mitotic rate, more frequent ulceration, higher tumor stage, and lower survival than pigmented melanomas.

CASC2: An emerging tumour-suppressing long noncoding RNA in human cancers and melanoma.

Deregulation of long noncoding RNAs (lncRNAs) has been implicated in tumourigenesis. Cancer Susceptibility Candidate 2 (CASC2) is a lncRNA downregulated in multiple cancer types, including endometrial, lung, gastric and colorectal cancers. CASC2 functions as a tumour-suppressive lncRNA though multiple mechanisms, such as sequestration of oncogenic microRNAs and repression of Wnt/ß-catenin signalling. Pertinent to clinical practice, the use of CASC2 as a prognostic marker has been demonstrated in sporadic studies. These findings suggested that CASC2 might play an important role in human cancers and melanoma. More efforts are warranted to examine the function role of CASC2 in other cancer types. Further validation is also needed to promote its development to be a clinically utilizable prognostic biomarker.

Immune consequences induced by photodynamic therapy in non-melanoma skin cancers: a review.

Photodynamic therapy (PDT) is widely used in dermatology to treat precancerous skin lesions and superficial non-melanoma skin cancers (NMSCs), including premalignant actinic keratosis, cutaneous squamous cell carcinoma in situ, and superficial basal cell carcinoma. The long-term cure rates of PDT range from 70 to 90% in NMSC patients, with excellent cosmetic results and good tolerance. However, the mechanism of action of PDT on tumors is complex. PDT not only kills tumor cells directly but also rapidly recruits immune cells to release inflammatory mediators to activate antitumor immunity. PDT-induced tumor death, also called immunogenic cell death, can trigger both innate and adaptive immune response, further enhancing the antitumor effect. For instance, inoculation of tumor cells killed via PDT to animals triggered a stronger antitumor immunity in vivo than tumor cell lysates produced by other treatments. More importantly, many immunotherapy regimens based on the immune effect of PDT have been developed and demonstrated to be a promising therapeutic method for cancer in pre-clinical trials. Therefore, increasing efforts have been undertaken to investigate the immune responses associated with PDT. In the present review, we first introduce the antitumor effect and the associated mechanisms of PDT in cancers. Then, we summarize studies on the immune responses induced by PDT in NMSCs. We also discuss the potential mechanisms underlying the process.

Long non-coding RNAs in melanoma.

Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma development, the involvement of regulatory non-coding RNAs remain unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY-IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.