Efficacy and Safety of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Current therapeutic options for atopic dermatitis (AD) are limited. Janus kinase (JAK) inhibitors may be viable alternatives. OBJECTIVES: To assess the efficacy and safety of JAK inhibitors for AD treatment. METHODS: We searched PubMed, Embase, the Cochrane Controlled Register of Trials, Web of Science, Global Resource of Eczema Trials database, and ClinicalTrials.gov from inception to September 1, 2020. Randomized clinical trials (RCTs) comparing JAK inhibitors with placebo/vehicle treatment for AD patients were included. The primary study outcomes included (1) the change (%) from the Eczema Area and Severity Index (EASI) baseline expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI), and (2) the Investigator's Global Assessment (IGA) response and safety outcomes expressed as relative risk (RR) and 95% CI. RESULTS: We included 14 RCTs published in 13 studies (3,822 patients). Treatment with JAK inhibitors significantly improved IGA response (RR 2.83, 95% CI 2.25-3.56, p < 0.001) and EASI score (WMD -28.82, 95% CI -34.48 to -23.16, p < 0.001). JAK inhibitor treatment achieved the largest improvement in both IGA response (RR 3.59, 95% CI 2.66-4.84, p < 0.001) and EASI score (WMD -42.00, 95% CI -48.64 to -35.36, p < 0.001) by week 4 of treatment. Topical JAK inhibitors were significantly more efficacious than oral inhibitors. Upadacitinib treatment for 4 weeks was most effective in reducing EASI score (WMD -53.92, 95% CI -69.26 to -38.58, p < 0.001), while abrocitinib for 4 weeks led to the most effective IGA response (RR 5.47, 95% CI 2.74-10.93, p < 0.001). There was no difference in the frequency of adverse events (AEs) leading to discontinuation; however, JAK inhibitors use, especially abrocitinib, led to a higher incidence of treatment-emergent AEs (RR 1.25, 95% CI 1.10-1.42, p = 0.001). CONCLUSION: Our results imply that JAK inhibitors are an effective and safe AD treatment. Nevertheless, further trials with longer duration and head-to-head comparisons of different JAK inhibitors are needed.

Mdivi-1 alleviates atopic dermatitis through the inhibition of NLRP3 inflammasome.

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin-related protein 1 (Drp1)-dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1 has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi-1 on experimental AD. We firstly detected the effects of mdivi-1 on primary human keratinocytes in an inflammatory cocktail-induced AD-related inflammation in vitro. Results showed that mdivi-1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase-1, GSDMD-NT, mature interleukin (IL)-1ß and IL-18 in keratinocytes under AD-like inflammation. Next, mouse model of AD-like skin lesions was induced by epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) and mdivi-1 (25 mg/kg/day, days 5-33 during construction of AD model) was intraperitoneally injected into DNCB-induced mice. AD mice with mdivi-1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL-4, IL-5 and IL-13 in the lesional tissues. Indeed, mdivi-1 significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB-treated skin tissues. Mechanically, mdivi-1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF-κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi-1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi-1 might exert this function by inhibiting mitochondrial fission and subsequently blocking NF-κB pathway.

Home-Based Computerized Cognitive Training for Postoperative Cognitive Dysfunction After Lung Transplantation in Elderly Population: A Randomized Controlled Trial.

Postoperative cognitive dysfunction is a severe outcome after lung transplantation, especially in the elderly lung transplant recipients. Home-based computerized cognitive training (CCT) is a widely used intervention for cognition improvement, but its efficacy has not been validated in this population. A randomized controlled trial was conducted to analyze the effect of CCT on elderly lung transplant recipients. The participants received either an 8-week CCT intervention or usual care. The changes of cognitive function were assessed between preintervention (T1), postintervention (T2), and 12 weeks postintervention (T3). Among the 46 participants, 91.3% completed the interventions. The CCT group performed better than the control group on Digit-Span Forward Test (T3: p = 0.0044) and Verbal Fluency Test (T3: p = 0.0331), indicating the efficacy of CCT on verbal memory in the elderly lung transplant recipients. Although varied impacts were observed on different cognitive domains, it seems promising to use CCT on the elderly population after lung transplantation.

Effect of hypoglycemia on cognitive performance in older patients with diabetes: A meta-analysis.

GOALS: The goal of this study was to use meta-analysis to compile information from various studies to investigate the existence and severity of cognitive impairment in elderly diabetes patients who have hypoglycemic episodes. MATERIALS AND TECHNIQUES: For research studies on the relationship between hypoglycemia and cognitive decline or dementia in persons older than 45 years, we searched the PubMed, EMBASE, Cochrane Library, CNKI, WanFang, CBM and VIP databases for the period 1989 to 2022. We conducted random effects inverse variance on the meta-analysis and used the I2 statistic to assess heterogeneity. RESULT: We selected 44 of the 518 studies we retrieved, 7 being appropriate for meta-analysis. Six thousand and forty-five individuals were involved in total. Both types of older diabetic patients with hypoglycemia performed considerably worse on tests of general intelligence than control participants (standardized mean difference, 0.58; 95% CI, 0.88-0.28). Also, elderly type-2 diabetes patients with hypoglycemic episodes had significantly worse memory performance (standardized mean difference, 0.19; 95% CI, 0.29-0.09). Additionally, we found that older type-2 diabetes patients with hypoglycemia had significantly poorer psychomotor function than those without hypoglycemia (standardized mean difference, 0.51; 95% CI, 0.38-0.63).

Prevalence of cutaneous manifestations in COVID-19: A meta-analysis.

The global epidemic of coronavirus disease 2019 (COVID-19) endangers more and more people. Many studies on cutaneous manifestations related to COVID-19 have emerged, but their prevalence has varied widely. The objective of this study was to conduct a meta-analysis estimating the prevalence of skin manifestations in COVID-19. Four databases PubMed, Web of Science, CBM, and CNKI were searched, and the results were screened by two reviewers. A random-effects model was used to evaluate the overall prevalence. Heterogeneity was assessed by I2 . Further subgroup analyses were conducted by region, sample size, sex, age, and severity of COVID-19. A funnel plot and Egger's test were performed to assess publication bias. The pooled prevalence of cutaneous manifestation of 61 089 patients in 33 studies was 5.6% (95% confidence intervals [CI] = 0.040-0.076, I2  = 98.3%). Severity of COVID-19 was probably the source of heterogeneity. Studies with sample size <200 report higher prevalence estimates (10.2%). The prevalence of detailed types was as follows: maculopapular rash 2%, livedoid lesions 1.4%, petechial lesions 1.1%, urticaria 0.8%, pernio-like lesions 0.5%, vesicular lesions 0.3%. Petechial lesions and livedoid lesions contain a higher proportion of severe patients than other skin manifestations. The prevalence rates of pernio-like lesions, urticaria and petechial lesions vary greatly in different regions.

The differential impact of air pollutants on acute urticaria and chronic urticaria: a time series analysis.

Several studies have revealed a relationship between short-term exposure to air pollution and the exacerbation of certain skin conditions. This study was developed to expand on these findings by exploring the potential association between exposure to air pollutants including particulate matter, sulfur dioxide, and ozone and the incidence of acute and chronic urticaria in Shenyang, China, from 2016 to 2018. Exposure-response relationships between daily mean concentrations of these airborne pollutants and visits to outpatient dermatological clinics for acute urticaria and chronic urticaria were evaluated via a time series analysis approach using a generalized additive model. This analysis revealed that a 10 µg/m3 increase in daily mean O3_8h concentrations was associated with a 0.36% (95% CI, 0.31-0.41%), 0.35% (95% CI, 0.30-0.40%), and 0.34% (95% CI, 0.29-0.39%) increase in the number of outpatient visits for acute urticaria on that day (lag0), lagging day 1 (lag1), and lagging day 2 (lag2), respectively. O3 levels also had a similar but weaker effect on the frequency of patients seeking outpatient care for chronic urticaria. These analyses also revealed that estimated 0.47% (95% CI, 0.41-0.52%) and 0.46% (95% CI, 0.40-0.51%) increases in dermatological outpatient acute urticaria visits were observed for every 10µg/m3 rise in O3_8h concentrations on cumulative lagging days (lag01 and lag02). Increases in particulate matter (PM2.5, PM10) levels had a similar cumulative effect on patients with chronic urticaria. In summary, these results suggest that short-term O3, PM2.5, and PM10 exposure can increase the risk of acute urticaria and chronic urticaria.

Recent advances in shikonin for the treatment of immune-related diseases: Anti-inflammatory and immunomodulatory mechanisms.

Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood. This review article provides a comprehensive overview of the recent advancements in the use of shikonin for the treatment of immune-related diseases. The article also delves into the anti-inflammatory and immunoregulatory mechanisms of shikonin and offers insights into the inflammation and immunopathogenesis of related diseases. Overall, this article serves as a valuable resource for researchers and clinicians working in this field. These findings not only provide significant new information on the effects and mechanisms of shikonin but also establish a foundation for the development of clinical applications in treating autoimmune diseases.

Mapping knowledge structures and theme trends of atopic dermatitis: a co-word biclustering and quantitative analysis of the publication between 2015 and 2019.

BACKGROUND: Atopic dermatitis (AD) has been a hot research direction of dermatologists for a long time. However, the knowledge structures and theme trends for AD have not yet been studied bibliometrically. OBJECTIVE: To investigate the distribution pattern and knowledge structure of AD related literatures in PubMed. METHODS: Bibliographic information was generated by the Bibliographic Item Co-Occurrence Matrix Builder (BICOMB). A visual matrix was created by the gCLUTO software. GraphPad Prism 5 software was used to construct a Strategic diagram analysis. Ucinet 6.0 software and NetDraw 2.084 software were used to generate a social network analysis (SNA). RESULTS: Among all the extracted MeSH terms and subheadings, 77 MeSH terms/MeSH subheadings with a high-frequency were identified, and hot topics were gathered together into 6 groups. In the strategic diagram, immunology, microbiology, and drug therapy of AD were fully developed. In contrast, prevention, pathology, genetics, metabolism, administration, cost of illness, quality of life therapeutic paradigm, and immunosuppressive agents of AD were considerably immature offering prospective scope for further research. CONCLUSIONS: The results may potentially aid in describing an all-round grasp of the current research areas and furnish guidelines for the researchers for beginning new projects.

Relationship between Preoperative Hemoglobin and Hospital Stays in Patients Receiving Prime Total Knee Arthroplasty.

Previous evidence has shown that preoperative hemoglobin is related to poor prognosis after primary total knee arthroplasty. Reviewing cohort research was conducted at the third-level academic medical center in Singapore and involved 2,676 patients. Population statistics, complications, preoperative hemoglobin (Hb) levels, length of hospital stay (LOS), and readmission information of thirty days were obtained. Anemia was defined based on the World Health Organization (WHO). LOS extension was with the definition as no less than six days with >1/75 LOS corresponding to the data. According to the study requirements, we finally collected 2273 patients. We plotted the relationship between hemoglobin levels and length of stay. We analyzed 2273 patients, with 140 cases of Hb ≤ 11.0 g/dL, 831 cases of Hb 11.0-12.9 g/dL, and the other 1320 cases of Hb ≥ 13.0 g/dL. The mean age of patients with prolonged LOS (68.4 ± 8.2 years) was higher than that of patients with familiar LOS (65.9 ± 8.0 years). In addition, patients with extended LOS had higher ASA-PS values, a history of cerebrovascular accidents (CVA), diabetes mellitus (DM), and ischemic heart disease (IHD) (P < 0.001), repeated surgery within 30 days, HB, and operative time (min) (P < 0.01). Variables independently related to increased risk of extended LOS included general anesthesia (GA) (adjusted OR (aOR) 1.4, P=0.005, P=0.005), CVA (aOR 3.0, P < 0.001), DM (aOR 1.4, P=0.032), and HB < 11 g/dL. Variables increased LOS included HB ≥ 13 g/dL (aOR 0.4, P < 0.001) and Hb 11.0-12.9 g/dL (aOR 0.5, P=0.001). Hb was 14 g/dL, and LOS decreased by at least 0.24 days for each 1 g increase in preoperative Hb before the inflection point (95%CI 0.12 to 0.36, P=0.0001). Anemia is familiar in patients receiving elective total knee arthroplasty (TKA) in Singapore. Thus, this study describes that the preoperative hemoglobin was associated with length of stay. We found that on the left where HB was 14, length of stay decreased with increased hemoglobin values. We recommend preoperative correction of anemia to determine the diagnosis.

Tumor-promoting properties of karyopherin ß1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1.

The nuclear import receptor karyopherin ß1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.

Therapeutic Effects of Shikonin on Skin Diseases: A Review.

Shikonin is one of the primary active components extracted from the dried root ofZicao (Lithospermum erythrorhizon, Onosma paniculata, or Arnebia euchroma), a traditional Chinese herbal medicine. Shikonin is known to not only exert anti-proliferative, anti-inflammatory, and anti-angiogenic activities, but also play a crucial role in triggering the production of reactive oxygen species, suppressing the release of exosomes, and inducing apoptosis. Increasing evidence suggests that shikonin has a protective effect against skin diseases, including psoriasis, melanoma, and hypertrophic scars. In order to evaluate the application potential of shikonin in the treatment of skin diseases, this review is the first of its kind to provide comprehensive and up-to-date information regarding the uses of shikonin and its derivatives on skin diseases and its underlying mechanisms. In this review, we have focused on the signaling pathways and cellular targets involved in the anti-dermatosis effects of shikonin to bridge the gaps in the literature, thereby providing scientific support for the research and development of new drugs from a traditional medicinal plant.

Sulforaphane has a therapeutic effect in an atopic dermatitis murine model and activates the Nrf2/HO­1 axis.

Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4­dinitrochlorobenzene (DNCB)­induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB­induced AD and sulforaphane­treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB­induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB­induced AD mice. Western blot assays revealed that the expression levels of nuclear factor­E2­related factor 2 (Nrf2) and heme oxygenase-1 (HO­1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB­induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO­1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.

Anti-IL-33 Antibody Has a Therapeutic Effect in an Atopic Dermatitis Murine Model Induced by 2, 4-Dinitrochlorobenzene.

IL-33 is a new member of the IL-1 family that plays a role in allergic disease. In this study, we evaluated the potential on the inhibition of atopic dermatitis (AD) of anti-mouse IL-33 antibody (αIL-33Ab) using 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice model. We treated mice with αIL-33Ab via subcutaneous injection of each DNCB treatment 1 h later from day 1 to day 33 for 14 times. A control group received tacrolimus. Skin lesion and scratching behavior were compared. Ear thickness, dermatitis score, eosinophils and mast cells infiltration, and serum IgE levels were also analyzed. Correlations between serum IL-33 as well as soluble(s) ST2 and AD disease activity index in human AD were also investigated. DNCB-induced AD-like mice treated with αIL-33Ab showed improved AD-like symptoms. Eosinophils and mast cells infiltration and serum IgE levels were also significantly reduced by αIL-33Ab. Our study suggests that blockade of IL-33 has a curative effect on AD.