Short-term effect of meteorological factors on the risk of rheumatoid arthritis hospital admissions: A distributed lag non-linear analysis in Hefei, China.

Rheumatoid arthritis (RA) is an autoimmune disease, mainly characterized by erosional arthritis. The proportion of adults suffering from RA is about 0.5%-1%. There have been reports on the association of rainfall and traffic-related air pollutants with RA hospitalization rates. However, there have been no studies on the association of diurnal temperature range (DTR) and relative humidity (RH) with RA hospitalization rates. This study aimed to examine the short-term association of DTR, RH and other meteorological factors with the hospital admission rate of RA patients, while excluding the interference of PM2.5, SO2, NO2, CO and O3 atmospheric pollutants. We collected daily RA occupancy rate and meteorological factor data in Hefei city from 2015 to 2018 and used the generalized additive model (GAM) combined with the distributed lag nonlinear model (DLNM) for time series analysis, and further stratified analysis by gender and age. Single-day and cumulative-day risk estimates of RA admissions were expressed as relative risk (RR) and its 95% confidence interval (95% CI). For the cumulative-day lag model, high RH was statistically significant after cumulative lag 0-8 days, and the effect gradually increases. Stratified analysis shows that females seem to be more susceptible to high or extremely high DTR and RH exposure, and extremely high DTR exposure may increase the risk of RA admission in all populations. In conclusion, this study found that high DTR and high RH exposure increased the risk of hospitalization in RA patients and provided clues to the potential association between other meteorological factors and RA.

Ankylosing Spondylitis Patients Display Aberrant ERAP1 Gene DNA Methylation and Expression.

BACKGROUND: Endoplasmic reticulum aminopeptidase 1 (ERAP1) is known to participate in the pathogenesis of ankylosing spondylitis (AS). This study aimed to evaluate the relationship between promoter methylation and mRNA levels of ERAP1 and AS susceptibility. METHODS: DNA methylation levels of 100 AS patients and 100 healthy controls (HCs) were tested using a targeted bisulfite sequencing assay. To verify the results of DNA methylation, mRNA levels of ERAP1 were measured in 20 AS patients and HCs used quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: The DNA methylation levels of two CpG islands containing 31 loci in ERAP1 promoter were measured. ERAP1_1 (P< .001) and ERAP1_2 (P< .001) islands were significantly hypermethylated in AS patients compared with HCs. In the verification study, the mRNA levels of ERAP1 were significantly decreased in AS patients. The ROC curve analysis showed that the sensitivity, specificity and area under curve were 0.717, 0.737, and 0.779 of differential methylated CpG loci of ERAP1 for AS diagnosis. In AS patients, the methylation levels of EARP1 were associated with family history, non-steroidal anti-inflammatory drugs use, X-ray classification, and clinical manifestations. CONCLUSIONS: Our study demonstrated that the ERAP1 gene is significantly hypermethylated, and mRNA levels of EARP1 decreased, in AS patients. Our findings suggested that the aberrant methylation of ERAP1 promoter may be involved in the pathogenesis of AS and could be considered as a diagnostic tool and therapeutic target of AS.Abbreviations AS: Ankylosing Spondylitis; AUC: Area Under Curve; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; CI: Confidence Interval; CpG: Cytosine-guanine Dinucleotide; CRP: C-reactive Protein; ERAP1: Endoplasmic Reticulum Aminopeptidase 1; ESR: Erythrocyte Sedimentation Rate; EWAS: Epigenome-Wide Association Study; HLA: Human Leukocyte Antigen; OR: Odds Ratio; PCR: Polymerase Chain Reaction; ROC: Receiver Operating Characteristic; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs.

Association of methylation level and transcript level in TRAF5 gene with ankylosing spondylitis: a case-control study.

To explore the association between methylation level and transcript level of TNF receptor-associated factor 5 (TRAF5) gene with ankylosing spondylitis (AS) in Chinese Han population. Methylation and mRNA expression level of the TRAF5 gene were tested in 98 patients and 98 healthy controls. Among the 21 CpG sites, methylation levels at eight sites were significantly different between AS patients and healthy controls. However, only three sites remained significantly different after the correction by the Benjamini-Hochberg method. Compared with controls, the CpG island of TRAF5 gene promoter was highly methylated in AS patients, and the relative mRNA expression level of TRAF5 was significantly reduced in AS patients. And the mRNA level was negatively correlated with the methylation level of TRAF5 gene in AS patients (rs = -0.453, P < 0.001). Subgroup analyses indicated that there was no significant difference in the level of methylation between groups of different status of HLA-B27 and medications in AS patients. Multiple linear regression showed that disease-modifying antirheumatic drugs could reduce methylation levels of AS patients after adjusting for the effects of other drugs. In conclusion, the hypermethylation of the TRAF5 might contribute to the pathogenesis of AS, but many open questions remain.

Short-term effects of ambient temperature and pollutants on the mortality of respiratory diseases: A time-series analysis in Hefei, China.

BACKGROUND: The air pollution has become an important environmental health problem due to its adverse health effect. The objective of this study was to investigate the effects of ambient temperature and pollutants on mortality of respiratory diseases (RD) in Hefei, China, a typical inland city. METHODS: Nonlinear exposure-response dependencies and delayed effects of urban daily mean temperature (DMT) and pollutants were evaluated by distributed lag non-linear models (DLNM). To further explore this effect, different genders and ages were also examined by stratified analysis. RESULTS: A total of 12876 deaths from RD were collected from January 1, 2014 to December 31, 2018 in Hefei, China. There was a U-shaped correlation between DMT and RD mortality, and the RD mortality rised by 11.6% (95% CI: 2.2-22.0%) when the DMT was 35.8 °C (reference temperature is 20 °C). The results show that risk of death with short-term exposure to elevated concentrations of PM10 and SO2 was not significant. The maximum hysteresis and cumulative relative risk (RR) of RD mortality were 1.012 (95% CI: 1.003 ~ 1.021, lag 0 day) and 1.072 (95% CI: 1.014 ~1.133, lag 10 days) for each 10 µg/m3 augment in NO2; 1.005 (95% CI: 1.001-1.009, lag 0 day) and 1.027 (95% CI: 1.004-1.051, lag 10 days) for each 10 µg/m3 augment in O3; a negative association between CO exposure and the cumulative risk of death was observed (RR = 0.964, 95% CI: 0.935-0.993, lag 07 days). Subgroup analysis showed the effect of high temperatures, NO2, O3 and CO exposure was still statistically significant for the elderly and male. CONCLUSION: The present study found that short-term exposure to high temperature, NO2, O3 and CO were significantly associated with the risk of RD mortality and male as well as elderly are more susceptible to these factors.

Epigenetics of ankylosing spondylitis: Recent developments.

Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease which mainly affects the spine, sacroiliac joint and peripheral joints. To date, the exact causes and pathogenesis of AS still remain unknown. It is considered that the pathogenesis of AS is associated with genetic, infection, environment, immunity and other factors. Among them, the role of genetic factors in the pathogenesis of AS has been studied most deeply. However, over the past few years, the function of environmental predisposition and epigenetic modification in the pathogenesis of AS has received extensive attention. This paper summarizes the recent progress in the epigenetics of AS, including abnormal epigenetic modifications at AS-associated genomic loci, such as DNA methylation, histone modification, microRNA, and so on. In summary, the findings of this review attempt to explain the role of epigenetic modification in the occurrence and development of AS. Nevertheless, there are still unknown and complicated aspects worth exploring to deepen our understanding of the pathogenesis of AS.

The association between gaseous pollutants and non-accidental mortality: a time series study.

To evaluate the effects of gaseous pollutants (SO2, NO2) on non-accidental mortality of residents in Hefei city, we collected non-accidental deaths, air pollutants and meteorological data of Hefei city from 2014 to 2017. After controlling confounding factors with Poisson generalized additive model, we analyzed the relationship between air pollutants and non-accidental mortality and used subgroup analysis to identify susceptible groups. The number of non-accidental deaths during the study period was 42,116, with an average of 28.83 per day. The average concentrations of SO2 and NO2 were 16.08 µg/m3 and 39.10 µg/m3, respectively. In the single-pollutant model, every 10 µg/m3 increase in SO2 and NO2 concentrations was significantly associated with non-accidental mortality, and there was a significant lag effect. SO2 increased the risk of non-accidental death by 4.93% (95% CI: 1.94% ~ 8.00%) at lag0-3. In addition, male, the elderly, non-elderly and low-education people were more susceptible (P < 0.05). NO2 increased the risk of non-accidental death by 2.11% (95% CI: 1.18% ~ 3.05%) at lag0-1 and had an effect on all subgroups (P < 0.05). For every 10 µg/m3 increase in SO2 and NO2, the two-pollutant model showed that the risk of non-accidental death, respectively, increased by 3.34% (95% CI: 0.29% ~ 6.50%) and 1.82% (95% CI: 0.85% ~ 2.79%), suggesting that the effect was weakened. Our study suggested that SO2 and NO2 were associated with non-accidental mortality, and there were lag effects. Therefore, environmental management should be strengthened and health protection education should be carried out for different groups.

Anti-CD74 antibodies in spondyloarthritis: A systematic review and meta-analysis.

OBJECTIVE: There is still an unmet need for a simple and reliable biomarker for the diagnosis of spondyloarthritis. Recent studies indicated that anti-CD74 antibody could act as a biomarker for spondyloarthritis. Therefore, this review aims to evaluate the levels of anti-CD74 IgG and IgA antibodies in spondyloarthritis and the diagnostic value of anti-CD74 antibodies. METHODS: PubMed, Web of Science and Medline were comprehensively searched from inception to August 7th, 2019. The pooled standard mean difference (SMD) with 95% confidence interval (CI) was used to estimate the differences of the levels of anti-CD74 IgG and IgA antibodies between spondyloarthritis patients and controls. Sensitivity, specificity and summary receiver operating characteristics (SROC) curve were used for evaluating the diagnostic value of anti-CD74 antibodies. The use of fixed-effect or random-effects model depended on heterogeneity. RESULTS: Among 55 searched studies, 9 studies were finally included for analysis. Anti-CD74 IgG and IgA antibodies were both significantly increased in spondyloarthritis patients compared with matched controls (IgG: SMD = 0.88, 95% CI = 0.55 to 1.21; IgA: SMD = 0.98, 95% CI = 0.68 to 1.28). The pooled sensitivity, specificity and area under the SROC curve of anti-CD74 IgG antibodies were 0.61, 0.90 and 0.8881, while these indicators of anti-CD74 IgA antibodies were 0.59, 0.95 and 0.8671, respectively. CONCLUSION: Anti-CD74 IgG and IgA antibodies were significantly increased in spondyloarthritis patients and suggest a high diagnostic specificity of spondyloarthritis. Anti-CD74 antibody could potentially be a biomarker for the diagnosis of spondyloarthritis, but many open questions remain.

Comparative efficacy and safety of biologics in moderate to severe plaque psoriasis: a multiple-treatments meta-analysis.

OBJECTIVE: To compare the efficacy and safety of biologics for patients with moderate to severe plaque psoriasis. METHODS: We systematically reviewed 60 randomized controlled trials (34,020 participants), which compared 14 biological drugs for treatment of moderate to severe plaque psoriasis. The main assessment criteria were ≥ 90 % reductions in Psoriasis Area and Severity Index (PASI 90) and the number of patients who reported treatment-emergent adverse events (AEs). Secondary criteria were ≥ 75 % reductions in Psoriasis Area and Severity Index (PASI 75), Physician's Global Assessment 0/1 (PGA 0/1) and infections. RESULTS: This network meta-analysis showed that biologics were significantly more effective than placebo. Ixekizumab, risankizumab, and bimekizumab were among the most effective treatments, and tildrakizumab, guselkumab and risankizumab were better than the other drugs with respect to safety. Risankizumab and guselkumab performed relatively stable with respect to both efficacy and safety. At the class level, blockers of interleukin (IL)-17A showed favorable efficacy while inhibitors of the p19 subunit of IL-23 were best tolerated of all efficient biologics. CONCLUSIONS: Ixekizumab was the most effective biologic in PASI 90, while IL-23p19 inhibitors, risankizumab and guselkumab performed relatively stable with respect to efficacy and safety.

Red Cell Distribution Width and Mean Platelet Volume in Patients With Ankylosing Spondylitis: A Systematic Review and Meta-analysis.

OBJECTIVE: The results of previous studies regarding the relationship between red cell distribution width (RDW) or mean platelet volume (MPV) levels and ankylosing spondylitis (AS) are inconsistent. Therefore, we conducted this meta-analysis to systematically evaluate the associations. METHODS: The Web of Science, PubMed, and Cochrane Library (as of February 14, 2019) were used to retrieve relevant articles. Pooled standard mean difference (SMD) and its 95% confidence interval (CI) were calculated. All statistical analyses were performed using the "meta" and "metafor" packages of the R 3.5.1 software. RESULTS: Nine studies on RDW, including 775 AS patients and 972 healthy controls, and 8 studies on MPV, including 743 AS patients and 571 healthy controls, were included. The results showed that RDW levels were significantly higher in AS patients (SMD = 0.67; 95% CI, 0.30 to 1.05; p < 0.001) compared with healthy controls, whereas MPV levels (SMD = 0.01; 95% CI, -0.28 to 0.30; p = 0.929) were not significantly different from healthy controls. CONCLUSIONS: Our current study shows that the elevated levels of RDW may be associated with AS, whereas MPV levels may be not associated with AS.

Serum Levels of Hepcidin in Rheumatoid Arthritis and Its Correlation with Disease Activity and Anemia: A Meta-analysis.

Present studies on serum hepcidin levels in patients with rheumatoid arthritis (RA) are inconsistent. We aimed to synthetically evaluate the relationship between hepcidin and RA, and the correlation of serum hepcidin levels and RA disease activity as well as anemia associated with RA. Multiple electronic databases were searched. Pooled standard mean difference (SMD) with 95% confidence interval (CI) and correlation coefficients between hepcidin levels and rheumatoid factor (RF), disease activity for 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) were calculated. Totally, 13 articles were available for this meta-analysis. The results revealed that serum levels of hepcidin were higher in RA patients compared to healthy controls (SMD = 0.573, 95% CI = 0.317 to 0.829, p < .001); RA patients with anemia had higher serum hepcidin levels than RA patients without anemia (SMD = 0.400, 95% CI = 0.080 to 0.720, p = .014); RA patients with pure ACD had higher serum hepcidin levels than RA patients with ACD and IDA (SMD = 0.658, 95% CI = 0.018 to 1.299, p = .044). Moreover, the result of correlation coefficients identified a significant positive correlation between hepcidin levels and RF, DAS28 as well as ESR. Serum hepcidin levels may be closely associated with the development of RA.

Calprotectin in spondyloarthritis: A systematic review and meta-analysis.

OBJECTIVE: There is still an unmet need for a simple and reliable biomarker for diagnosis and disease activity of spondyloarthritis. Recent studies indicated that calprotectin could act as a biomarker for spondyloarthritis. Therefore, this systematic review and meta-analysis aims to evaluate the levels of serum and fecal calprotectin in spondyloarthritis and the associations with disease activity. METHODS: PubMed, Web of Science and Cochrane Library were comprehensively searched from inception to July 1st, 2019. The pooled standard mean differences (SMDs) were used to estimate the differences of the levels of serum and fecal calprotectin between spondyloarthritis patients and controls. Spearman correlation coefficients were used for evaluating the associations between the levels of serum and fecal calprotectin and disease activity of spondyloarthritis patients. The use of fixed-effect or random-effects model depended on heterogeneity. RESULTS: Among 257 searched studies, 20 studies were finally included for analysis. Serum and fecal calprotectin were both significantly increased in spondyloarthritis patients compared to matched controls (SMD = 1.49, 95% CI = 0.91 to 2.08; SMD = 2.29, 95% CI = 0.25 to 4.33). The pooled correlation coefficients between serum or fecal calprotectin and CRP, ESR, BASDAI and BASFI were 0.353, 0.228, 0.225, 0.131 and 0.185, 0.163, 0.280, 0.196 respectively. CONCLUSION: Our study indicated that serum and fecal calprotectin were significantly increased in spondyloarthritis patients, and associated with disease activity. Serum and fecal calprotectin were potential biomarkers for the diagnosis and disease activity of spondyloarthritis.

The influence of birth month on total and cardiovascular mortality: a population-based surveillance study.

There is little evidence about the impact of birth month on total and cardiovascular disease mortality in developing countries. We evaluated these associations using the population health registration data of Hefei City, China from 2014 to 2017. After controlling for the fixed effects of gender, education, and occupation, we fitted the Cox proportional hazard regression model to assess the relationship between birth month and mortality. Hazard ratio (HR) with corresponding 95% confidence interval (CI) was calculated. All data analyses were performed by R 3.6.0 software. The data of 44 665 participants were analyzed in the study. Compared to people born in January, people born between May and October had higher total and cardiovascular mortality, being highest in June, respectively, HR: 1.130 (95%CI: 1.074 to 1.190) and HR: 1.200 (95%CI: 1.115 to 1.290). After stratification by gender, males born in June had highest risk total and cardiovascular mortality, with an increase in risk of 14.8% and 24.7%, respectively. For females, highest risk of total mortality was increased by 11.1% in those born in July, while those born in December had highest increase in cardiovascular mortality risk by 15.7%. Our results indicate in Hefei City, China month of birth is associated with total and cardiovascular disease mortality.

Association between diurnal temperature range and outpatient visits for hand, foot, and mouth disease in Hefei, China: a distributed lag nonlinear analysis.

We aimed to quantify the relationship between the outpatient visits of hand, foot, and mouth disease (HFMD) and diurnal temperature range (DTR). The data of daily HFMD outpatient visits and meteorological parameters were obtained. A distributed lag nonlinear model combined with generalized linear model was used to estimate simultaneously nonlinear and delayed effects between DTR and daily HFMD outpatient visits after controlling confounding factors. A total of 15,275 HFMD visits were enrolled. DTR was significantly associated with HFMD outpatient visits in children. High DTR (P75: 11.4 °C) and extreme DTR (P95: 15.3 °C) were compared with 8.5 °C, and HFMD visits increased by a maximum of 3.93% (95% CI: 1.82 to 6.07%) and 4.47% (95% CI: 0.45 to 8.65%) in single-day lag effect, respectively. Furthermore, the extreme DTR effect decreased with the lag time and lasted for 10 days. Cumulative lag effects with markedly increasing percent of visits are over 64.88%. Furthermore, the effects were most pronounced among female children and children aged 0-2 years. Our study suggested that DTR changes were associated with HFMD outpatient visits, and populations of female and aged 0-2 years were more sensitive.

B7-H3: A promising therapeutic target for autoimmune diseases.

B7-H3 as a newly identified costimulatory molecule that belongs to B7 ligand family, is broadly expressed in both lymphoid and non-lymphoid tissues. The overexpression of B7-H3 has been verified to be correlated with the poor prognosis and poor clinical outcome of several human cancers. In recent years, researchers reveal that B7-H3 is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren's syndrome (SS), ankylosing spondylitis (AS), etc. In this review, we will discuss the biological function of B7-H3 and summarize the progress made over past years regarding its role in the occurrence and development of autoimmune diseases. The insights gained from these findings could serve as the foundation for future therapies of these diseases.

Association between IL-17A and IL-17F gene polymorphism and susceptibility in inflammatory arthritis: A meta-analysis.

OBJECTIVES: The association between Interleukin (IL)-17A and IL-17F gene polymorphism with inflammatory arthritis were inconsistent among previous studies. This meta-analysis aimed to determine the association between IL-17A and IL-17F gene polymorphism with ankylosing spondylitis (AS), osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: We searched Medline up to August 2019. The summary Odds Ratio (OR) with corresponding 95% confidence intervals (CIs) was calculated to evaluate the relationship between IL-17A and IL-17F gene polymorphism with genetic susceptibility of AS, OA and RA. RESULTS: A total of 19 studies with 5298 cases and 5675 healthy controls were included. There were significant associations between rs2275913 G allele with OA, RA susceptibility (P < .05) but not AS. Subgroup analysis by ethnicity indicated that rs763780 C allele was closely related to AS and OA in Caucasian populations (P < .001) but not Mongolians. A significant association between rs763780 and RA susceptibility was detected in Caucasian populations (P < .05). CONCLUSION: IL-17F gene rs763780 C allele confers increased risk of inflammatory arthritis in Caucasians; IL-17A gene rs2275913 G allele are protective for OA susceptibility in Mongolians. More well-designed studies with larger sample size are needed to elucidate the role of IL-17A gene rs2275913 G allele in inflammatory arthritis, especially AS.

H19 Increases IL-17A/IL-23 Releases via Regulating VDR by Interacting with miR675-5p/miR22-5p in Ankylosing Spondylitis.

Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor ß (TGF-ß) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.

Neutrophil lymphocyte ratio in patients with ankylosing spondylitis: A systematic review and meta-analysis.

Objective: The aim of this meta-analysis was to investigate the association of neutrophil lymphocyte ratio (NLR) with AS (ankylosing spondylitis) patients.Methods: PubMed, Web of Science, Cochrane Library, Elsevier Science Direct and Google Scholar databases (up to 30 September 2018) were searched to collect all pertinent articles. The pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random effects model.Results: Totally 10 studies contained 765 AS patients and 701 healthy controls were included in our meta-analysis. The results indicated that there were significant statistical differences between AS patients and healthy controls in NLR (SMD = 0.418, 95%CI = 0.239-0.598, p < .001). Meanwhile, the results of subgroup analysis showed, in the subgroup of C-reactive protein (CRP) ≥10 and the two subgroups of BASDAI (the Bath AS Disease Activity Index), NLR levels in AS were significantly higher than in control (all p < .001). The results of subgroup analysis and meta-regression suggested that BASDAI and CRP were likely associated with NLR in AS patients.Conclusion: The current meta-analysis provides evidence that NLR is a reasonable measure to detect systemic inflammation in AS patients. Besides, NLR may be able to indicate disease activity in patients with AS.

Ambient temperature and non-accidental mortality: a time series study.

Under the background of global climate change, the present study aimed to evaluate the effects of daily mean temperature and diurnal temperature range (DTR) on the non-accidental mortality. Poisson generalized linear model (PGLM) combined with distributed lag non-linear model (DLNM) was used to evaluate these effects after adjusting the relative humidity and major air pollutants. All effects were presented as relative risk (RR), with 75th percentiles of daily mean temperature and DTR compare with their lowest RRs corresponding values. Daily mean temperature was associated with the non-accidental mortality with a U-shaped curve, and the non-accidental mortality increased by 1.8% (95% CI: 0.7~3.0%) when the temperature was 24.4 °C (20 °C as the reference). Additionally, the non-accidental mortality increased by 1.4% (95% CI: 0.1~2.7%) on lag6 day when DTR was 11.3 °C (7 °C as the reference). The elderly (≥ 65 years) were more susceptible to daily mean temperature and DTR, and females were more susceptible to high DTR effect than males. Our study provides evidence that daily mean temperature and DTR are significantly associated with non-accidental mortality and have delayed effects. Both females and elderly people are vulnerable to the potential adverse effects.

Comparative Efficacy and Safety of Common Therapies in Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.

OBJECTIVES: At present, there are many therapies for treating keloids and hypertrophic scars, but there is still a lack of treatments that are relatively balanced in efficacy and safety. The study aims to evaluate comprehensively efficacy and safety of common therapies in keloids and hypertrophic scars. METHODS: The literature search was conducted up to May 2019. The traditional meta-analysis was performed on 17 therapies. Bayesian network meta-analysis was conducted on the four most common treatments. The outcome indicators were the numbers of patients with good-to-excellent effect, Vancouver Scar Scale (VSS) and adverse events. RESULTS: There was no significant difference in the efficacy of triamcinolone acetonide (TAC) compared with other monotherapies except for silicone gel sheet and neodymium-yttrium-aluminum-garnet in primary indicator. The combination therapies were superior to TAC, and the results were consistent after the pooled analysis (RR = 0.522, 95% CI 0.332-0.823). The level of VSS in TAC group was higher than that in 5-flurouracil (5-FU) and TAC + 5-FU group, but lower than that in verapamil (VER) group. And the patients treated with TAC were less safe than those treated with verapamil (P = 0.013). Surface under cumulative ranking ranked verapamil and TAC + 5-FU as the favorable efficacy therapies in terms of primary indicator and ranked TAC + 5-FU as the best therapy for VSS, while VER was ranked as the worst. CONCLUSION: This meta-analysis showed that TAC + 5-FU may be the most effective therapy, while verapamil may be a better therapeutic strategy for safety. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.