Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Effects of biological agents on glycogen metabolism in psoriasis patients: A systematic review and meta-analysis.

The effectiveness and safety of biological agents for treating psoriasis have been confirmed; however, their effects on glucose metabolism biomarkers in psoriasis patients remain unclear. A systematic review and meta-analysis were performed according to PRISMA guidelines. The final analysis enrolled 12 studies, including eight randomized controlled trial (RCT) (n = 5628 patients) and four observational cohort studies (OBSs) (n = 393 patients). The meta-analysis comprising nine studies (six RCTs and three OBSs) revealed a slight reduction in the levels of HOMA-IR associated with the use of biological therapies in OBS (biological therapies vs. traditional therapies: WMD = -0.2, CI = -0.10 to 0.50, p = 0.02). Although a considerable number of studies were analysed, our review did not show a significant alteration in HOMA-IR levels among patients treated with biological therapies such as IL-17 inhibitors and IL-12/23 inhibitors at weeks 12-16 in RCTs. We also did not observe remarkable alterations in the fasting plasma glucose levels of patients in both OBS and RCT. Additional RCT on a larger scale and duration is required to provide more conclusive evidence regarding the effect of biological agents on glycogen metabolism in psoriasis.

Interleukin-7 regulates CD127 expression and promotes CD8+ T cell activity in patients with primary cutaneous melanoma.

BACKGROUND: Interleukin (IL)-7 signaling through CD127 is impaired in lymphocytes in cancers and chronic infections, resulting in CD8+ T cell exhaustion. The mechanisms underlying CD8+ T cell responses to IL-7 in melanoma remain not completely elucidated. We previously showed reduced IL-7 level in melanoma patients. Thus, the aim of this study was to investigate the effect of IL-7 regulation on CD127 expression and CD8+ T cell responses in melanoma. METHODS: Healthy controls and primary cutaneous melanoma patients were enrolled. Membrane-bound CD127 (mCD127) expression on CD8+ T cells was determined by flow cytometry. Soluble CD127 (sCD127) protein level was measured by ELISA. Total CD127 and sCD127 mRNA level was measured by real-time PCR. CD8+ T cells were stimulated with recombinant human IL-7, along with signaling pathway inhibitors. CD8+ T cells were co-cultured with melanoma cell line, and the cytotoxicity of CD8+ T cells was assessed by measurement of lactate dehydrogenase expression. RESULTS: Plasma sCD127 was lower in melanoma patients compared with controls. The percentage of CD8+ T cells expressing mCD127 was higher, while sCD127 mRNA level was lower in peripheral and tumor-infiltrating CD8+ T cells from melanoma patients. There was no significant difference of total CD127 mRNA expression in CD8+ T cells between groups. IL-7 stimulation enhanced total CD127 and sCD127 mRNA expression and sCD127 release by CD8+ T cells. However, mCD127 mRNA expression on CD8+ T cells was not affected. This process was mainly mediated by phosphatidylinositol 3-kinase (PI3K) pathway. CD8+ T cells from melanoma patients exhibited decreased cytotoxicity. IL-7 stimulation promoted CD8+ T cell cytotoxicity, while inhibition of PI3K dampened IL-7-induced elevation of CD8+ T cell cytotoxicity. CONCLUSION: The current data suggested that insufficient IL-7 secretion might contribute to CD8+ T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.

Lithographic pattern quality enhancement of DMD lithography with spatiotemporal modulated technology.

In this paper, we propose spatiotemporal modulation projection lithography (STPL) technology, which is a spatiotemporal modulation technology applied to the conventional digital micromirror device (DMD) projection lithography system. Through coordinating the micro-movement of the piezoelectric stage, the flexible pattern generation of DMD, and the exposure time, the proposed STPL enables us to fabricate a microstructure with smooth edges, accurate linewidth, and accurate line position. Further application on fabricating a diffraction lens has been implemented. The edge sawtooth of the Fresnel zone plate fabricated by using the STPL is reduced to 0.3 µm, the error between the actual measured linewidth and the ideal linewidth is only within ±0.1µm, and the focal length is 15 mm, which is basically consistent with the designed focal length. These results indicated that STPL can serve a significant role in the micromanufacturing field for achieving high-fidelity microdevices.

Pre-fenestration endovascular repair of aortic diseases in patients with zone 2 segment: A single-center experience.

OBJECTIVE: The present study aims to analyze the outcomes of three cases of pre-fenestration and branch stent-graft endovascular repair of aortic disease with zone 2 aortic lesions. METHODS: From August 2017 to June 2018, three patients with zone 2 aortic lesions underwent thoracic endovascular repair with innominate artery, left common carotid artery, and left subclavian artery recannulation using pre-fenestration and branched stent-grafts to preserve the patency of the aortic arch branches. RESULTS: The technical success rate was 100%. One patient had a proximal type I endoleak with no need for additional treatment. The overall mortality was 0%. All branches were patent. The follow-up period lasted for 2-15 months, with one patient lost to follow-up. There were no conversions to open surgical repair, aortic rupture, paraplegia, or retrograde type A aortic dissection. CONCLUSION: The use of a pre-fenestration and branch stent-graft for the thoracic endovascular repair of zone 2 aortic lesions is a feasible and effective method for aortic arch branch revascularization. The risk of this surgical procedure is high, requiring significant expertise. The procedure should be conducted only in experienced centers. Durability concerns should be assessed in future studies with long-term follow-up.

Influence of defect distribution on the thermoelectric properties of FeNbSb based materials.

Doping and alloying are important methodologies to improve the thermoelectric performance of FeNbSb based materials. To fully understand the influence of point defects on the thermoelectric properties, we have used density functional calculations in combination with the cluster expansion and Monte Carlo methods to examine the defect distribution behaviors in the mesoscopic FeNb1-xVxSb and FeNb1-xTixSb systems. We find that V and Ti exhibit different distribution behaviors in FeNbSb at low temperature: forming the FeNbSb-FeVSb phase separations in the FeNb1-xVxSb system but two thermodynamically stable phases in FeNb1-xTixSb. Based on the calculated effective mass and band degeneracy, it seems the doping concentration of V or Ti in FeNbSb has little effect on the electrical properties, except for one of the theoretically predicted stable Ti phases (Fe6Nb5Ti1Sb6). Thus, an essential methodology to improve the thermoelectric performance of FeNbSb should rely on phonon scattering to decrease the thermal conductivity. According to the theoretically determined phase diagrams of Fe(Nb,V)Sb and Fe(Nb,Ti)Sb, we propose the (composition, temperature) conditions for the experimental synthesis to improve the thermoelectric performance of FeNbSb based materials: lowering the experimental preparation temperature to around the phase boundary to form a mixture of the solid solution and phase separation. The point defects in the solid solution effectively scatter the short-wavelength phonons and the (coherent or incoherent) interfaces introduced by the phase separation can additionally scatter the middle-wavelength phonons to further decrease the thermal conductivity. Moreover, the induced interfaces could enhance the Seebeck coefficient as well, through the energy filtering effect. Our results give insight into the understanding of the impact of the defect distribution on the thermoelectric performance of materials and strengthen the connection between theoretical predictions and experimental measurements.

METTL3-mediated HPV vaccine enhances the effect of anti PD-1 immunotherapy to alleviate the development of cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) develops from epithelial keratinocytes by dysregulation of self-renewal and differentiation. Recent studies have found that the size and number of cSCC tumors gradually decrease or even disappear after HPV vaccination. However, the role of the HPV vaccine in the cSCC mechanism is poorly understood. OBJECTIVE: The aim of this study is to investigate the effect and mechanism of the HPV vaccine in cSCC. METHODS: Immunofluorescence was used to study the immune infiltrating cells in the tumor tissues of patients with cSCC. The effects of the HPV vaccine on cSCC cells and tissues were studied by Cell Culture, Real-time PCR, Western Blot, Cytotoxicity Assay, Enzyme-linked Immunosorbent Assay, m6A Blotting, CCK-8 Assay, m6A Ribonucleic acid Methylation Quantification and tumor transplantation. RESULTS: The HPV vaccine enhanced the toxic effect of CD8+T cells on cSCC cells and promoted the secretion of multiple cytokines by CD8+T cells. In addition, HPV vaccines can increase tumor sensitivity to anti-PD-1 therapy by downregulating METTL3 in tumor tissue, with the combination of HPV vaccine and PD-1 monoclonal antibodies producing enhanced immune cell infiltration compared to PD-1 blockade alone. STUDY LIMITATIONS: It is important to note the limitations of this study, including the small sample size, the construction of the mouse model, and the choice of HPV vaccine and PD-1 monoclonal antibody, which may limit the generalization of our findings to a wider population. CONCLUSIONS: It is hoped that this research will contribute to a deeper understanding of the role of the HPV vaccine in the treatment of cSCC. HPV vaccine is expected to become an important approach to alleviate the development of cSCC.

Paradoxical reaction to IL-17A inhibitor: a case report and literature review.

Objective: A case of pustular psoriasis after treatment with secukinumab in a patient with plaque psoriasis is reported, which is the first case in China. To summarize the clinical characteristics of patients who developed the rare paradoxical reaction and treatment options received IL-17A antagonist therapy, we conducted a further literature review. Methods: Data were analyzed from a patient with plaque psoriasis who developed pustular psoriasis after treatment with secukinumab. A comprehensive review of relevant domestic and international literature was conducted, focusing on cases that met our inclusion criteria for analysis and synthesis. Results: Anti IL-17A therapy may lead to type conversion, with reported cases more prevalent in women and varying in onset time, predominantly involving palmoplantar pustulosis. Conclusion: Given the increasing use of IL-17A antagonists in psoriasis treatment, it is crucial to monitor for rare adverse reactions, including the paradoxical induction of pustular psoriasis.

Case report: A novel PTCH1 frameshift mutation leading to nevoid basal cell carcinoma syndrome.

A patient presenting with several basal cell carcinomas, pigmented nevi, and developmental defects was diagnosed with nevoid basal cell carcinoma syndrome. Gene panel sequencing and Sanger sequencing were used to identify a novel heterozygous frameshift mutation, c.1312dupA:p.Ser438Lysfs, in exon 9 of PTCH1. I-Tasser and PyMol analyses indicated that the mutated protein patched homolog 1 (PTCH1) lacked 12 transmembrane domains and the intracellular and extracellular rings of ECD2 compared with the wild-type protein, resulting in a remarkably different structure from that of the wild-type protein. This case extends our knowledge of the mutation spectrum of NBCCS.

Tildrakizumab for moderate-to-severe plaque psoriasis in Chinese patients: A 12-week randomized placebo-controlled phase III trial with long-term extension.

BACKGROUND: There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. METHODS: In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. RESULTS: At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician's Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs . 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs . 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. CONCLUSION: Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05108766.

Case report: Post-streptococcal pustulosis after subcutaneous injection of secukinumab.

An acute diffuse pustular eruption occurred in a patient after secukinumab injection and then the clinical presentation has been related to streptococcus infection after it has been isolated from throat swabs. Pustulosisacuta generalisata was definitively diagnosed. Antibiotic treatment had a poor effect, but the response to glucocorticoids was better.

Vacancy-mediated anomalous phononic and electronic transport in defective half-Heusler ZrNiBi.

Studies of vacancy-mediated anomalous transport properties have flourished in diverse fields since these properties endow solid materials with fascinating photoelectric, ferroelectric, and spin-electric behaviors. Although phononic and electronic transport underpin the physical origin of thermoelectrics, vacancy has only played a stereotyped role as a scattering center. Here we reveal the multifunctionality of vacancy in tailoring the transport properties of an emerging thermoelectric material, defective n-type ZrNiBi. The phonon kinetic process is mediated in both propagating velocity and relaxation time: vacancy-induced local soft bonds lower the phonon velocity while acoustic-optical phonon coupling, anisotropic vibrations, and point-defect scattering induced by vacancy shorten the relaxation time. Consequently, defective ZrNiBi exhibits the lowest lattice thermal conductivity among the half-Heusler family. In addition, a vacancy-induced flat band features prominently in its electronic band structure, which is not only desirable for electron-sufficient thermoelectric materials but also interesting for driving other novel physical phenomena. Finally, better thermoelectric performance is established in a ZrNiBi-based compound. Our findings not only demonstrate a promising thermoelectric material but also promote the fascinating vacancy-mediated anomalous transport properties for multidisciplinary explorations.

Randomized, Placebo-Controlled, Multicenter Clinical Study on the Efficacy and Safety of Lidocaine Patches in Chinese Patients with Postherpetic Neuralgia.

INTRODUCTION: To evaluate the efficacy and safety of lidocaine patches in Chinese patients with postherpetic neuralgia (PHN). METHODS: Patients were randomized to receive lidocaine patches or placebo every day for 4 weeks. Efficacy endpoints included the decrease of analogue scale score (VAS) value at week 4, 2 and 1 and the percentage of patients that achieved a 30% decrease of VAS value. Safety analyses were conducted as well. RESULTS: Two hundred forty Chinese patients were randomized. At week 1, lidocaine patch-treated patients had a higher clinical response versus placebo, and at week 4, the mean (SD) decreases of VAS value compared to the baseline were 14.01 (14.35) in the treatment group and 9.36 (12.03) in the placebo group (p = 0.0088). Overall, the safety profile in the treatment group was consistent with that observed in the placebo group [adverse event (AE) incidence rate: 33.33% versus 37.29%, p = 0.5857]. CONCLUSIONS: Lidocaine patches resulted in improved clinical response versus placebo in the treatment of PHN patients and were well tolerated.

Epidemiology of urticaria in China: a population-based study.

BACKGROUND: Urticaria is a common skin disease characterized by episodes of wheals, and it has a negative effect on patients' quality of life. Large-scale population-based epidemiological studies of urticaria are scarce in China. The aim of this survey was to determine the prevalence, clinical forms, and risk factors of urticaria in the Chinese population. METHODS: This survey was conducted in 35 cities from 31 provinces, autonomous regions, and municipalities of China. Two to three communities in each city were selected in this investigation. Participants completed questionnaires and received dermatological examinations. We analyzed the prevalence, clinical forms, and risk factors of urticaria. RESULTS: In total, 44,875 questionnaires were distributed and 41,041 valid questionnaires were collected (17,563 male and 23,478 female participants). The lifetime prevalence of urticaria was 7.30%, with 8.26% in female and 6.34% in male individuals ( P  < 0.05). The point prevalence of urticaria was 0.75%, with 0.79% in female and 0.71% in male individuals ( P  < 0.05). Concomitant angioedema was found in 6.16% of patients. Adults had a higher prevalence of urticaria than adolescents and children. Living in urban areas, exposure to pollutants, an anxious or depressed psychological status, a personal and family history of allergy, thyroid diseases, and Helicobacter pylori infection were associated with a higher prevalence of urticaria. Smoking was correlated with a reduced risk of urticaria. CONCLUSION: This study demonstrated that the lifetime prevalence of urticaria was 7.30% and the point prevalence was 0.75% in the Chinese population; women had a higher prevalence of urticaria than men. Various factors were correlated with urticaria.

A randomized, double-blind phase III study to demonstrate the clinical similarity of biosimilar SCT630 to reference adalimumab in Chinese patients with moderate to severe plaque psoriasis.

INTRODUCTION: This phase III study aimed to compare the efficacy, safety, and immunogenicity of SCT630 with the reference adalimumab. METHODS: A total of 367 Chinese patients with moderate-to-severe plaque psoriasis were randomly assigned to receive 80 mg of SCT630 or adalimumab subcutaneously at week 1, 40 mg at week 2, then 40 mg biweekly. At week 16, those with 50 % or more improvement in psoriasis area and severity index (PASI) were eligible to enter an extension period up to week 52. Patients on SCT630 continued the same treatment, whereas patients receiving adalimumab were re-randomized at a ratio of 1:1 to adalimumab or SCT630 group. The primary endpoint was percentage improvement in PASI at week 16. Other endpoints included PASI 50/75/90/100, Physician's Global Assessment, Dermatology Life Quality Index, safety, and immunogenicity. RESULTS: PASI improvement at week 16 was 85.07 % for SCT630 and 84.82 % for adalimumab. The mean difference (3.10 %, 95 % CI: -1.875 %, 8.066 %) was within the equivalence interval. Other efficacy endpoints, safety and immunogenicity profiles were similar across the two groups. There were no safety or immunogenicity difference between switched/continued groups. CONCLUSION: This phase III study demonstrated the equivalences in efficacy, safety and immunogenicity of SCT630 to adalimumab in patients with moderate to severe psoriasis.

A KRT6A and a Novel KRT16 Gene Mutations in Chinese Patients with Pachyonychia Congenita.

BACKGROUND: Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis characterized by palmoplantar keratoderma, nail dystrophy, cystic lesions, follicular hyperkeratosis, mucosal leukokeratoses, hyperhidrosis, hoarseness, and, rarely, natal teeth. Five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 and KRT17, have been found to be associated with PC. METHODS: Using polymerase chain reaction and Sanger sequencing techniques, the purpose of the present study was to investigate the clinical features associated with PC and discover disease-associated variants. The KRT6A, KRT16, KRT17, and KRT6B exonic and flanking region sequences were amplified and directly sequenced to detect mutations. RESULTS: Across two independent instances of PC, we identified a previously reported c.1393T>C (p.Tyr465His) mutation in exon 7 of KRT6A, and a novel c.1237G>C (p.Glu413Gln) heterozygous missense mutation in exon 6 of the KRT16 gene. CONCLUSION: Through phenotype-genotype analysis among PC pedigrees, confirmed diagnoses of PC-K6a and PC-K16 were made in the two patients who presented with symptoms of PC. A new pathogenic mutation site in PC-K16 was potentially discovered.

Induction of T helper 17 cell response by interleukin-7 in patients with primary cutaneous melanoma.

Interleukin (IL)-7 plays a vital role in proliferation and activation of T cells, however, its signaling through CD127 is impaired in T cells in cancers and chronic infections. The mechanisms underlying T helper 17 (Th17) cell responses by IL-7 in melanoma remain not fully understood. The aim of this study was to assess the effect of IL-7 signaling on Th17 responses in patients with primary cutaneous melanoma. Healthy and primary cutaneous melanoma donors were selected for this study of Th17 cell function. IL-17+CD4+ Th17 cells and CD127 expression on Th17 cells were determined by flow cytometry. Cytokine level was measured by ELISA. Peripheral and tissue-infiltrating CD4+ T cells were isolated using magnetic beads, and then stimulated with IL-7 and/or signal transducer and activator of transcription 5 inhibitor. Activated signaling molecules were analyzed by flow cytometry. Peripheral and tumor-infiltrating Th17 cells percentage was decreased, while peripheral IL-7 level was also reduced in melanoma patients. There was no significant difference of CD127 expression on Th17 cells between melanoma patients and controls. Antiapoptotic protein Bcl-2 was downregulated, whereas proapoptotic protein-activated caspase-3 was upregulated in peripheral and tissue-infiltrating Th17 cells in melanoma patients. Higher concentration of IL-7 (10 ng/mL), but not lower IL-7 concentration (1 ng/mL), promoted Bcl-2 expression and decreased caspase-3 expression in Th17 cells in melanoma patients. Inhibition of signal transducer and activator of transcription 5 resulted in the downregulation of Bcl-2 while upregulation of caspase-3 in Th17 cells. The present data suggested that reduced IL-7 responsiveness might be insufficient for Th17 activation in patients with primary cutaneous melanoma.