Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial.

BACKGROUND: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials. OBJECTIVE: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis. METHODS: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale. RESULTS: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events. CONCLUSIONS: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

[Study on epidemic characteristics and etiology of community acquired pneumonia in Guangzhou from 2009 to 2012].

OBJECTIVE: To investigate the epidemic characteristics and pathogenic spectrum of community acquired pneumonia (CAP) in Guangzhou from 2009 to 2012. METHOD: 14 major comprehensive hospitals were selected from 11 districts as sentinel hospitals for CAP cases surveillance, including 18 982 223 in total during the 4 years. The characteristics of pathogenic spectrum of CAP were stratified and analyzed by year, age and season. RESULTS: 18 982 223 cases were included in the surveillance from year 2009 to 2012, in which 56 618 cases were CAP. The number of CAP cases increased from 8677 in year 2009 to 19 947 in year 2012 in Guangzhou; while the percentage of visits for CAP raised from 0.22% (8677/3 893 800) to 0.41% (19 947/4 839 766). The difference showed statistical significance (χ(2) = 2693.00, P < 0.05). Among the hospitalized CAP cases, 66.05% (10 954/16 585) were aged ≤ 5 years old or > 66 years old. The percentage of cases infected by a single pathogen was 88.11% (14 613/16 585), while co-infected cases accounted for 4.17% (691/16 585). Bacteria accounted for the largest proportion of 65.25% (10 821/16 585) as a single pathogen, followed by mycoplasma 13.54% (2245/16 585), virus 9.01% (1494/16 585) and chlamydia 0.32% (53/16 585). The proportion of virus infection was increasing from 4.74% to 11.64%. The difference showed statistical significance (χ(2) = 135.32, P < 0.05). Bacteria infection was the leading causes for CAP cases in all age groups; however the percentage increased with the increasing of ages. The rate of bacterial infection was increased from 48.35% (2993/6191) among children aged ≤ 5 years old to 81.31% (3873/4763) among adults aged over 65 years (χ(2) = 1632.00, P < 0.05). The rate of atypical pathogens (mycoplasma, chlamydia) for children ( ≤ 15 years old) (25.99%, 1805/6945) was higher than that for adults aged ≥ 16 years old (5.12%, 494/9640) (χ(2) = 2.11, P < 0.05). The effect from season on the pathogenic spectrum was not observed.433 hospitalized CAP cases were dead from 2009 to 2012. Case fatality rate was highest among people aged over 65 years old (4.70%, 224/4763) and lowest among children aged between 6 to 15 years old (0.27%, 2/754). CONCLUSION: The incidence of community acquired pneumonia was rising in Guangzhou from 2009 to 2012. Bacteria was the dominant pathogen. Children and old people were the high-risk population of community acquired pneumonia; while co-infection was still at low level.

Topical Ozone Accelerates Diabetic Wound Healing by Promoting Re-Epithelialization through the Activation of IGF1R-EGFR Signaling.

Ozonated oil increases the healing of chronic diabetic wounds, but the underlying mechanisms remain unclear. We investigated the effect of topical ozonated oil on wound healing in mice with diabetes with diet-induced obesity and further elucidated the role of EGFR and IGF1R signaling in diabetic wound healing. We found that topical ozonated oil accelerated wound healing; increased phosphorylation of IGF1R, EGFR, and VEGFR; and improved vascularization at the wound leading edge in mice with diabetes with diet-induced obesity. Exposure of normal epidermal keratinocytes to ozonated medium (20 µM for 2 hours daily) increased cell proliferation and migration distance by increasing phosphorylation of IGF1R and EGFR and downstream phosphoinositide 3-kinase, protein kinase B, and extracellular signal-regulated kinase. These findings shed light on the mechanism for topical ozone action in chronic wounds and support its potential therapeutic application.

Association between climatic factors and varicella incidence in Guangzhou, Southern China, 2006-2018.

OBJECTIVE: To analyze the correlation between climatic factors and the incidence of varicella in Guangzhou, and improve the prevention measures about public health. METHODS: Data for daily climatic variables and varicella incidence from 2006 to 2018 in Guangzhou were collected from the Guangzhou Meteorological Bureau and the National Notifiable Disease Report System. Distributed lag nonlinear models were applied to evaluate the association between climatic factors and varicella incidence. RESULTS: The nonlinear effects of meteorological factors were observed. At lag day21，when the mean temperature was 31.8 °C, the relative risk was the highest as 1.11 (95% CI: 1.07-1.16). When the diurnal temperature range was 24.0 °C at lag day 20, the highest RR was 1.11 (95% CI: 1.05-1.17). For rainfall, the highest RR was 1.09 (95% CI: 1.01-1.19) at lag day 21，when the aggregate rainfall was 160 mm. When air pressure was 1028 hPa, the highest RR was 1.08 (95% CI: 1.04-1.13) at lag day 21. When wind speed was 0.7 m/s, the highest RR was 1.07 (95% CI: 1.04-1.11) at lag day 7. When the hours of sunshine were 9.0 h at lag day 21, the RR was highest as 1.04 (95% CI: 1.02-1.05). Aggregate rainfall, air pressure, and sunshine hours were positively correlated with the incidence of varicella, which was inconsistent with the wind velocity. Mean temperature showed a reverse U-shape curve relationship with varicella, while the diurnal temperature range showed a binomial distribution curve. The extreme effect of climatic factors on the varicella cases was statistically significant, apart from the extremely low effect of rainfall. CONCLUSION: Our preliminary results offered fundamental knowledge which might be benefit to give an insight into epidemic trends of varicella and develop an early warning system. We could use our findings about influential factors to strengthen the intervention and prevention of varicella.

Effect of meteorological factors on scarlet fever incidence in Guangzhou City, Southern China, 2006-2017.

OBJECTIVE: To explore the relationship between meteorological factors and scarlet fever incidence from 2006 to 2017 in Guangzhou, the largest subtropical city of Southern China, and assist public health prevention and control measures. METHODS: Data for weekly scarlet fever incidence and meteorological variables from 2006 to 2017 in Guangzhou were collected from the National Notifiable Disease Report System (NNDRS) and the Guangzhou Meteorological Bureau (GZMB). Distributed lag nonlinear models (DLNMs) were conducted to estimate the effect of meteorological factors on weekly scarlet fever incidence in Guangzhou. RESULTS: We observed nonlinear effects of temperature, relative humidity, and wind velocity. The risk was the highest when the weekly mean temperature was 31 °C during lag week 14, yielding a relative risk (RR) of 1.48 (95% CI: 1.01-2.17). When relative humidity was 43.5% during lag week 0, the RR was 1.49 (95% CI: 1.04-2.12); the highest RR (1.55, 95% CI: 1.20-1.99) was reached when relative humidity was 93.5% during lag week 20. When wind velocity was 4.4 m/s during lag week 13, the RR was highest at 3.41 (95% CI: 1.57-7.44). Positive correlations were observed among weekly temperature ranges and atmospheric pressure with scarlet fever incidence, while a negative correlation was detected with aggregate rainfall. The cumulative extreme effect of meteorological variables on scarlet fever incidence was statistically significant, except for the high effect of wind velocity. CONCLUSION: Weekly mean temperature, relative humidity, and wind velocity had double-trough effects on scarlet fever incidence; high weekly temperature range, high atmospheric pressure, and low aggregate rainfall were risk factors for scarlet fever morbidity. Our findings provided preliminary, but fundamental, information that may be useful for a better understanding of epidemic trends of scarlet fever and for developing an early warning system. Laboratory surveillance for scarlet fever should be strengthened in the future.

Transmission risk of avian influenza virus along poultry supply chains in Guangdong, China.

OBJECTIVES: Avian influenza viruses (AIVs) poise significant risk to human health and the poultry industry. We evaluated the transmission risk along the poultry supply chain. METHODS: During October 2015 and July 2016, four rounds of cross-sectional surveys were performed to characterize AIV spread in farms, transport vehicles, slaughterhouses, wholesale and retail live poultry markets (LPMs). Poultry cloacal and oral swabs, environmental swabs, bioaerosol samples and human sera were collected. Poultry and environmental samples were tested for AIVs by rRT-PCR, further subtyped by next generation sequencing. Previous human H9N2 infections were identified by hemagglutination inhibition and microneutralization tests. Logistic regression was fitted to compare AIV transmission risk in different settings. RESULTS: AIVs was detected in 23.9% (424/1771) of the poultry and environmental samples. AIV detection rates in farms, transport vehicles, wholesale and retail LPMs were 4.5%, 11.1%, 30.3% and 51.2%, respectively. 5.2%, 8.3% and 12.8% of the poultry workers were seropositive in farms, wholesale and retail LPMs, respectively. The regression analysis showed that virus detection and transmission risk to human increased progressively along the poultry supply chain. CONCLUSIONS: Strengthening control measures at every level along the poultry supply chain, using a one health approach, is crucial to control AIV circulation.

[mRNA and protein expression of haptoglobin in lesions of condyloma acuminatum].

OBJECTIVE: To investigate the expression of haptoglobin in the lesions of condyloma acuminatum (CA) at the mRNA and protein level, and to explore its role in the pathogenesis of CA. METHODS: The expressions of haptoglobin protein and mRNA in the skin tissues of 30 patients with CA and 20 normal controls were detected by immunohistochemistry(IHC), Western blot, and hybridization in situ. RESULTS: The in situ hybridization study showed that haptoglobin mRNA was expressed in the epidermal cells in the lesions of CA. The distribution of haptoglobin mRNA expression in the lesions of CA was similar to that of the normal controls, and the expression of haptoglobin mRNA in CA was higher than that of the normal controls. There was a significant difference in the positive expression of haptoglobin mRNA between the CA group and the control group (P<0.05). The immunohistochemical study showed that haptoglobin protein was expressed in the whole layers of epidermal keratinocytes in the lesions of CA at a high level and stronger staining was seen in the stratum basale and stratum spinosum. Haptoglobin protein was expressed predominantly in the stratum basale in normal skin tissues, while weak staining was seen below the stratum spinosum.There was a significant difference in the mean gray value between the CA group and control group (P<0.05). Western blot showed that the haptoglobin expression in CA lesions significantly increased compared with the normal skins (P<0.05). CONCLUSION: The expression of haptoglobin mRNA in the CA lesions obviously increases and the epidermal cells in the CA lesions are able to synthesize haptoglobin protein. Haptoglobin in the CA lesions may involve in the local immunity escape by preventing Langerhans cell functional maturation and inhibiting the immunocompetence of keratinocyte.

Increased 5-hydroxymethylcytosine and Ten-eleven Translocation Protein Expression in Ultraviolet B-irradiated HaCaT Cells.

BACKGROUND: DNA hydroxymethylation refers to a chemical modification process in which 5-methylcytosine (5mC) is catalyzed to 5- hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins. Recent studies have revealed that aberrant TETs expression or 5hmC level may play important roles in the occurrence and development of various pathological and physiological processes including cancer and aging. This study aimed to explore the relation between aberrant DNA hydroxymethylation with skin photoaging and to investigate the levels of TETs, 5mC, and 5hmC expression 24 h after 40 mJ/cm2 and 80 mJ/cm2 doses of ultraviolet B (UVB) irradiation to HaCaT cells. METHODS: To explore whether aberrant DNA hydroxymethylation is also related to skin photoaging, 40 mJ/cm2 and 80 mJ/cm2 doses of UVB were chosen to treat keratinocytes (HaCaT cells). After 24 h of UVB irradiation, 5mC and 5hmC levels were determined by immunohistochemistry (IHC) and immunofluorescence (IF), and at the same time, the expression levels of matrix metalloproteinase 1 (MMP-1) and TETs were assessed by reverse transcription-polymerase chain reaction or Western blot analysis. RESULTS: After 40 mJ/cm2 and 80 mJ/cm2 doses of UVB exposure, both IHC and IF results showed that 5hmC levels increased significantly, while the 5mC levels did not exhibit significant changes in HaCaT cells, compared with HaCat cells without UVB exposure. Moreover, compared with HaCat cells without UVB exposure, the levels of TET1, TET2, and TET3 mRNA and protein expression were significantly upregulated (mRNA: P = 0.0022 and 0.0043 for TET1; all P < 0.0001 for TET2; all P = 0.0006 for TET3; protein: P = 0.0012 and 0.0006 for TET1; all P = 0.0022 for TET2; and all P = 0.0002 for TET3), and the levels of MMP-1 mRNA expression increased dose dependently in 40 mJ/cm2 and 80 mJ/cm2 UVB-irradiated groups. CONCLUSION: UVB radiation could cause increased 5hmC and TET expression, which might become a novel biomarker in UVB-related skin aging.

[Apoptosis of psoriatic keratinocytes and the severity of patients' condition].

OBJECTIVE: To investigate the correlation between the apoptosis of psoriatic keratinocytes (KCs) in the psoriatic lesions and patient's condition. METHODS: Thirty patients with psoriasis were included. Activated caspase-3 was examined by colorimetric method in skin biopsy specimens. The apoptotic KCs were detected with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay in skin biopsy specimens. The severities of 26 patients with psoriasis vulgaris (PV) were assessed using the PASI scoring system and the severities of psoriatic lesions. RESULTS: Apoptotic indexes (AI) were higher in the pustular psoriatic lesions than those in the vulgaris psoriatic lesions (P<0.05). In 26 patients with PV, AI and activated caspase-3 in the lesions were significantly higher in the progressive stage than those in the static and the regressive stages (P<0.05). There were no correlations between PASI and AI or the expression of activated caspase-3 in PV lesions (P>0.05). The severities of psoriatic lesions were positively correlated to AI or the expression of activated caspase-3 in PV lesions (P<0.05). CONCLUSION: The amount of apoptotic KCs may be related to varied types, stages of psoriasis, and severities of psoriatic lesions.

[Effects of BCG-PSN on serum levels of IL-4 and IL-12 in patients with condyloma acuminatum].

OBJECTIVE: To determine the effects of polysaccharide nucleic acid fraction of bacillus calmette guerin (BCG-PSN) on serum levels of interleukin-4 (IL-4) and interleukin-12 (IL-12) in patients with condyloma acuminatum (CA) and to investigate the mechamism of immunoregulation of BCG-PSN on CA. METHODS: Sixty CA cases were randomly divided into 2 groups. The serum levels of IL-4 and IL-12 were respectively measured by Double-antibody sandwich ELISA method before and after the treatment. The serum levels of IL-12 and IL-4 of health control were also measured. The recurrent rate of each group was used as an index to assess the effect of BCG-PSN in CA patients. RESULTS: Compared with healthy controls, the serum levels of IL-12 in patients with CA were decreased significantly (P < 0.05), while the serum levels of IL-4 were increased significantly (P < 0.05) before the treatment. The serum levels of IL-12 were negatively correlated with the serum levels of IL-4 (r = -0.287, P < 0.05). After the treatment, the serum levels of IL-12 were increased significantly( P < 0.05), and the serum levels of IL4 were decreased significantly (P < 0.05) in the treatment group. But in the control group, the serum levels of IL-12 and IL-4 were similar before and after the treatment (P > 0.05). The recurrent rate of treatment group was significantly lower than that of the control group (chi2 = 4.356, P < 0.05). CONCLUSIONS: There is an imbalance of Th1/Th2 cytokines production in patients with condyloma acuminatum. BCG-PSN could increase the serum level of IL-12 and decrease the serum level of IL-4 in CA patients. BCG-PSN could decrease the recurrent rate of CA. The effect may be related to the regulation and modulation of BCG-PSN to Thl/Th2 cytokines imbalance,which then enhances the cellular immunity in CA patients.

Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors.

Ganglioside GM3 mediates adipocyte insulin resistance, but the role of GM3 in diabetic wound healing, a major cause of morbidity, is unclear. The purpose of this study was to determine whether GM3 depletion promotes diabetic wound healing and directly activates keratinocyte (KC) insulin pathway signaling. GM3 synthase (GM3S) expression is increased in human diabetic foot skin, ob/ob and diet-induced obese diabetic mouse skin, and in mouse KCs exposed to increased glucose. GM3S knockout in diet-induced obese mice prevents the diabetic wound-healing defect. KC proliferation, migration, and activation of insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R) are suppressed by excess glucose in wild-type cells, but increased in GM3S (-/-) KCs with supplemental glucose. Co-immunoprecipitation of IR, IR substrate 1 (IRS-1), and IGF-1R, and increased IRS-1 and Akt phosphorylation accompany receptor activation. GM3 supplementation or inhibition of IGF-1R or PI3K reverses the increased migration of GM3S(-/-) KCs, whereas IR knockdown only partially suppresses migration.

Deacetylated GM3 promotes uPAR-associated membrane molecular complex to activate p38 MAPK in metastatic melanoma.

GM3, the simplest ganglioside, regulates cell proliferation, migration, and invasion by influencing cell signaling at the membrane level. Although the classic N-acetylated form of GM3 (NeuAcLacCer) is commonly expressed and has been well studied, deacetylated GM3 (NeuNH2LacCer, d-GM3) has been poorly investigated, despite its presence in metastatic tumors but not in noninvasive melanomas or benign nevi. We have recently found that d-GM3 stimulates cell migration and invasion by activating urokinase plasminogen activator receptor (uPAR) signaling to augment matrix metalloproteinase-2 (MMP-2) function. However, the mechanisms by which d-GM3/uPAR increase MMP-2 expression and activation are not clear. By modifying the expression of d-GM3 genetically and biochemically, we found that decreasing d-GM3 expression inhibits, whereas overexpressing d-GM3 stimulates, p38 mitogen-activated protein kinase (MAPK) activity to influence MMP-2 expression and activation. p38 MAPK (p38) activation requires the formation of a membrane complex that contains uPAR, caveolin-1, and integrin α5ß1 in membrane lipid rafts. In addition, knocking down or inhibiting focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), or Src kinase significantly reduces d-GM3-induced p38 phosphorylation and activation. Taken together, these results suggest that d-GM3 enhances the metastatic phenotype by activating p38 signaling through uPAR/integrin signaling with FAK, PI3K, and Src kinase as intermediates. Elucidation of the mechanisms by which d-GM3, a newly discovered, potential biomarker of metastatic melanomas, promotes cell metastasis will help us to understand the function of d-GM3 in metastatic melanomas and may lead to novel GM3-based cancer therapies.

[Evaluation on the risks of H5, H7 and H9 avian influenza infections in Guangzhou: using data from the 2006-2012 avian influenza surveillance program].

OBJECTIVE: To analyze the results of avian influenza surveillance program in Guangzhou from 2006 to 2012 and to evaluate the risk of infections with H5, H7 and H9 subtypes avian influenza viruses. METHODS: Avian influenza surveillance system in Guangzhou consisted five components:serum surveillance on occupational population, environmental specimen surveillance of avian influenza virus, avian flu emergency surveillance, influenza viruses surveillance on ILI patient and surveillance on pneumonia of unknown causes. Hemagglutination inhibition test was conducted to detect the antibodies against H5, H7 and H9 while RT-PCR was used to test the nucleic acid of H5, H7 and H9 viruses. RESULTS: From 2006 to 2012, 4103 serum specimens were collected from occupational populations and the overall positive rate of H5/H7/H9 antibodies was 3.82% . The antibody positive rates for H5, H7 and H9 were 0.22% ,0.00% and 3.70% respectively. 4 serum specimens for H5 and H9 simultaneously showed antibody positive. The positive rate of H9 among occupational populations(4.21%)appeared higher than that from the control population(2.16%). 2028 specimens were collected from poultry sites and 55 samples found positive for H5 nucleic acid (positive rate:2.71%), 14 samples positive for H9 nucleic acid (positive rate:0.69%), 5 specimens, simultaneously positive for H5 and H9 nucleic acids. However, none of the samples showing H7 nucleic acid positive. From 2006 to 2012, all the tested H5/H7/H9 virus were negative from the respiratory/serum specimens among those close contacts of patients or high risk groups through the avian flu emergency surveillance program,ILI patient influenza virus surveillance programs or pneumonia of unknown causes surveillance program. CONCLUSION: Contamination of H5/H9 avian influenza virus did exist in the poultry sites in Guangzhou, especially in the wet Markets. The H5/H9 avian influenza virus caused asymptomatic infection was proved to be existed within the population exposed to the poultry, suggesting that the poultry occupational population in Guangzhou was under the risk of avian influenza virus infection.

[Female urogenital mycoplasma infection and drug sensitivity status in Changsha].

OBJECTIVE: To survey mycoplasma infection in female urogenital tract and analyze the drug sensitivity of mycoplasma in Changsha. METHODS: Ureaplasma urealyticum (Uu) and Mycoplasma hominis (Mh) were detected in 6566 cases of female urogenital tract infection by means of mycoplasma culture and drug sensitivity reagent kit. Sensitivity tests for 10 antibiotics were also performed. RESULTS: A total of 2938 cases were mycoplasma-positive (positivity rate of 44.75%), including 2469 Uu-positive cases (37.6%), 52 Mh-positive cases (0.08%) and 417 cases positive for both Uu and Mh (6.35%). Josamycin, doxycycline, clarithromycin and azithromycin were more effective against Uu infection. Josamycin, doxycycline and thiamphenicol were more effective against Mh infection. Mixed infection with Uu and Mh was more resistant to most antibiotics but Josamycin and doxycycline. CONCLUSION: The female urogenital mycoplasma infection results mainly from Uu. Compared with simple Uu or Mh infection, mixed infection with Uu and Mh has significantly greater resistance to a wider variety of drugs. Josamycin and doxycycline are the primary choice for female urogenital mycoplasma infection in Changsha.