Erratum: Vitamin D Deficiency and Increased Risk of Bladder Carcinoma: A Meta-Analysis

<b><i>Background/Aims: </i></b>Vitamin D status in relation to bladder carcinoma risk was still inconsistent. This study was carried out to evaluate the relationship between vitamin D status and bladder carcinoma risk through a meta-analysis approach. <b><i>Methods: </i></b>Pubmed, Web of Science, CNKI, and Embase were searched systemically to find eligible studies from the earliest available date to April 16, 2015. The search terms “vitamin D”, “25-hydroxyvitamin D”, “bladder cancer” or “bladder carcinoma” were used to retrieve relevant studies. The exposure of interest was intake of vitamin D or serum vitamin D levels, and the outcome of interest was bladder carcinoma incidence or mortality. The pooled risk ratio (RR) values and their 95%CIs were calculated through meta-analysis. <b><i>Results: </i></b>Seven studies with a total of 62,141 participants met the inclusion criteria and were finally included into the meta-analysis. There was no heterogeneity among those included studies (I² = 0%, P = 0.53). The pooled RR of bladder carcinoma for the lowest category versus the highest category of vitamin D was 1.34 (95% CI 1.17-1.53, P < 0.0001). Sensitivity analysis by omitting one study by turns showed all the pooled RRs were statistically significant. Meta-analysis of 5 studies reporting outcomes of serum vitamin D levels also showed that the low serum vitamin D level was associated with increased risk of bladder carcinoma (RR = 1.32, 95%CI 1.15-1.52, P = 0.0001). No obvious risk of publication bias was observed. <b><i>Conclusion: </i></b>Vitamin D deficiency is associated with increased risk of bladder carcinoma in present study

Supplementary Material for: Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

<p>Endoplasmic reticulum (ER) stress arises when excessive improperly folded proteins accumulate in the ER lumen. When ER stress occurs, the unfolded protein response (UPR) is subsequently activated to restore ER proteostasis. However, severe ER stress leads to apoptosis. Recent studies have suggested that cisplatin cytotoxicity may be related to ER stress. The purpose of this study was to determine whether ER stress participates in cochlear cell apoptosis in a cisplatin-induced ototoxicity rat model and to also determine the possible relationship between ER stress and hearing loss. Our results revealed that treatment with cisplatin upregulated the expression of active caspase-12 in cochlear cells, which is indicative of cisplatin-induced activation of ER-specific apoptosis. Increased expression of C/EBP homologous protein (CHOP) and cleaved caspase-9 suggested a close relationship between severe ER stress and mitochondria-dependent apoptosis in the cochlear cells of cisplatin-treated rats. In addition, we found that tauroursodeoxycholic acid (TUDCA), a promoter of ER proteostasis, had a protective effect on cisplatin-induced hearing loss. These results demonstrate that ER stress is involved in the cisplatin-induced apoptosis of cochlear cells in vivo.</p

PowerPoint Slides for: Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome

<p><b><i>Background:</i></b> Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in <i>SLC12A3</i>. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS. <b><i>Methods:</i></b> Sixty-seven patients with GS underwent <i>SLCl2A3</i> analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored. <b><i>Results:</i></b> Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m²) and 32 patients with abnormal glucose metabolism. <b><i>Conclusions:</i></b> We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes.</p

Supplementary Material for: HPA1-29w genotyping and the foundation for the platelet apheresis registry in Jiangsu province of China by MassARRAY spectrometry

Introduction: This study aimed to investigate the allele frequencies of the human platelet antigens HPA-1-29w system in Jiangsu (China) and establish the platelet apheresis registry in blood donors. Methods: HPA genotyping was performed using the MassARRAY iPLEX® platform. Allele and genotype frequencies were estimated by direct counting and tested for Hardy–Weinberg equilibrium. The transfusion mismatch probability was calculated for every HPA specificity. Results: The HPA allele frequencies in the Jiangsu Han population of HPA-1b, -2b, -3b, -4b, -5b, -6b, -11b, -15b, and -21b were 0.0055, 0.0530, 0.4116, 0.0015, 0.0155, 0.0162, 0.0003, 0.5317, and 0.0070, respectively, in which a heterozygote of HPA-11a/b was first detected in China. Only allele a was detected for HPA-7-10w、-12-14w、-16-20w and -22-29w quasi-systems. The highest mismatch rate of HPA genes in 1640 platelet donors was the HPA-15 system, followed by the HPA-3 system with a rate of 37.4% and 36.71%, respectively. Conclusion: China’s largest-scale platelet registry of HPA-1-29w has been explored. The MassARRAY platform may help to found the platelet apheresis registry which would be useful to provide matching platelets and lead to a more accurate, effective, and safe transfusion for patients with platelet therapy

Supplementary Material for: Infusion-Related Reactions Induced by Cadonilimab (PD-1/CTLA-4 Bispecific Antibody): Seven Case Reports

Introduction: Cadonilimab (AK104) is an innovative human programmed cell death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody. Compared with the combination therapy of PD-1 and CTLA-4 blockers, less cellular toxicity of cadonilimab was significantly manifested. As one of the characteristic adverse effects of cadonilimab, infusion-related reactions (IRRs) represent fever, chills, rash, decreased blood pressure, and other symptoms. Case Presentation: Here, we documented seven cases of IRRs after the administration of cadonilimab. The symptoms of IRRs were relieved after the discontinuation of cadonilimab and the administration of diphenhydramine, dexamethasone, and cimetidine. Notably, 3 patients were able to tolerate the subsequent cadonilimab therapy under the pretreatment. Conclusion: In this study, we discovered that cadonilimab-related IRRs might be lessened or prevented by administering medication and the proper pretreatment and lowering the infusion rate

Supplementary Material for: Genetic Burden Analyses of Phenotypes Relevant to Aging in the Berlin Aging Study II (BASE-II)

<p><b><i>Background:</i></b> Body mass index (BMI), bone mineral density (BMD), and telomere length are phenotypes that modulate the course of aging. Over 40% of their phenotypic variance is determined by genetics. Genome-wide association studies (GWAS) have recently uncovered >100 independent single-nucleotide polymorphisms (SNPs) showing genome-wide significant (p < 5 × 10^-8) association with these traits. <b><i>Objective:</i></b> To test the individual and combined impact of previously reported GWAS SNPs on BMI, BMD, and relative leukocyte telomere length (rLTL) in ∼1,750 participants of the Berlin Aging Study II (BASE-II), a cohort consisting predominantly of individuals >60 years of age. <b><i>Methods:</i></b> Linear regression analyses were performed on a total of 101 SNPs and BMI, BMD measurements of the femoral neck (FN) and lumbar spine (LS), and rLTL. The combined effect of all trait-specific SNPs was evaluated by generating a weighted genomic profile score (wGPS) used in the association analyses. The predictive capability of the wGPS was estimated by determining the area under the receiver operating curve (AUC) for osteoporosis status (determined by BMD) with and without the wGPS. <b><i>Results:</i></b> Five loci showed experiment-wide significant association with BMI (<i>FTO</i> rs1558902, p = 1.80 × 10^-5) or BMD (<i>MEPE</i> rs6532023, p_FN = 5.40 × 10^-4, p_LS = 1.09 × 10^-4; <i>TNFRSF11B</i> rs2062377, p_LS = 8.70 × 10^-4; <i>AKAP11 </i>rs9533090, p_LS = 1.05 × 10^-3; <i>SMG6 </i>rs4790881, p_FN = 3.41 × 10^-4) after correction for multiple testing. Several additional loci showed nominally significant (p < 0.05) association with BMI and BMD. The trait-specific wGPS was highly significantly associated with BMD (p < 2 × 10^-16) and BMI (p = 1.10 × 10^-6). No significant association was detected for rLTL in either single-SNP or wGPS-based analyses. The AUC for osteoporosis improved modestly from 0.762 (95% CI 0.733-0.800) to 0.786 (95% CI 0.756-0.823) and 0.785 (95% CI 0.757-0.824) upon inclusion of the FN- and LS-BMD wGPS, respectively. <b><i>Conclusion:</i></b> Our study provides an independent validation of previously reported genetic association signals for BMI and BMD in the BASE-II cohort. Additional studies are needed to pinpoint the factors underlying the proportion of phenotypic variance that remains unexplained by the current models.</p

Supplementary Material for: Association between Triglyceride-Glucose Index and 1-year Recurrent Stroke after Acute Ischemic Stroke: Results from the Xi’an Stroke Registry Study of China

Introduction: The triglyceride-glucose (TyG) index is reported to be related to poor functional outcomes and all-cause mortality post-stroke. However, the association between TyG index and recurrent stroke after acute ischemic stroke (AIS) has not been well described. We aimed to identify whether the TyG index was associated with 1-year recurrent stroke after AIS. Methods: Baseline patient information was collected at admission, and the TyG index was calculated. Recurrent stroke events were followed up at 1, 3, 6, and 12 months after diagnosis. We then examined the association between the TyG index and risk of 1-year recurrent stroke using multivariable Cox regression models and restricted cubic spline analyses. Results: Among 2,288 participants, the mean TyG index was 8.8 0.7. Those in the fourth quartile (Q4) demonstrated higher recurrent stroke risk than those in Q1 (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI], 0.98–2.72; p = 0.059). Subgroup analysis revealed a sex-specific association between TyG index and recurrent stroke (p for interaction = 0.022). Additionally, restricted cubic splines analyses showed a non-linear association between the TyG index and 1-year recurrent stroke. In females, patients in the Q4 had a 2.95-fold increased recurrent stroke risk than did patients in the Q1 (adjusted HR =2.95; 95% CI, 1.09–7.94; p = 0.032); the risk increased when the TyG index was > 8.73. However, no significant correlation was observed in males. Conclusion: A non-linear association was found between the TyG index and 1-year recurrent stroke risk. Subsequently, a high TyG index could predict an increased 1-year recurrent stroke risk in female AIS patients

Supplementary Material for: Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

<b><i>Background/Aims:</i></b> Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. <b><i>Methods:</i></b> IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis <i>in vitro</i> and <i>in vivo</i> was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. <b><i>Results:</i></b> Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4⁺ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells <i>in vivo</i>. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. <b><i>Conclusion:</i></b> IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease

Supplementary Material for: Association between Triglyceride-Glucose Index and 1-year Recurrent Stroke after Acute Ischemic Stroke: Results from the Xi’an Stroke Registry Study of China

Introduction: The triglyceride-glucose (TyG) index is reported to be related to poor functional outcomes and all-cause mortality post-stroke. However, the association between TyG index and recurrent stroke after acute ischemic stroke (AIS) has not been well described. We aimed to identify whether the TyG index was associated with 1-year recurrent stroke after AIS. Methods: Baseline patient information was collected at admission, and the TyG index was calculated. Recurrent stroke events were followed up at 1, 3, 6, and 12 months after diagnosis. We then examined the association between the TyG index and risk of 1-year recurrent stroke using multivariable Cox regression models and restricted cubic spline analyses. Results: Among 2,288 participants, the mean TyG index was 8.8 0.7. Those in the fourth quartile (Q4) demonstrated higher recurrent stroke risk than those in Q1 (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI], 0.98–2.72; p = 0.059). Subgroup analysis revealed a sex-specific association between TyG index and recurrent stroke (p for interaction = 0.022). Additionally, restricted cubic splines analyses showed a non-linear association between the TyG index and 1-year recurrent stroke. In females, patients in the Q4 had a 2.95-fold increased recurrent stroke risk than did patients in the Q1 (adjusted HR =2.95; 95% CI, 1.09–7.94; p = 0.032); the risk increased when the TyG index was > 8.73. However, no significant correlation was observed in males. Conclusion: A non-linear association was found between the TyG index and 1-year recurrent stroke risk. Subsequently, a high TyG index could predict an increased 1-year recurrent stroke risk in female AIS patients

Supplementary Material for: Association between Triglyceride-Glucose Index and 1-year Recurrent Stroke after Acute Ischemic Stroke: Results from the Xi’an Stroke Registry Study of China

Introduction: The triglyceride-glucose (TyG) index is reported to be related to poor functional outcomes and all-cause mortality post-stroke. However, the association between TyG index and recurrent stroke after acute ischemic stroke (AIS) has not been well described. We aimed to identify whether the TyG index was associated with 1-year recurrent stroke after AIS. Methods: Baseline patient information was collected at admission, and the TyG index was calculated. Recurrent stroke events were followed up at 1, 3, 6, and 12 months after diagnosis. We then examined the association between the TyG index and risk of 1-year recurrent stroke using multivariable Cox regression models and restricted cubic spline analyses. Results: Among 2,288 participants, the mean TyG index was 8.8 0.7. Those in the fourth quartile (Q4) demonstrated higher recurrent stroke risk than those in Q1 (adjusted hazard ratio [HR] = 1.63; 95% confidence interval [CI], 0.98–2.72; p = 0.059). Subgroup analysis revealed a sex-specific association between TyG index and recurrent stroke (p for interaction = 0.022). Additionally, restricted cubic splines analyses showed a non-linear association between the TyG index and 1-year recurrent stroke. In females, patients in the Q4 had a 2.95-fold increased recurrent stroke risk than did patients in the Q1 (adjusted HR =2.95; 95% CI, 1.09–7.94; p = 0.032); the risk increased when the TyG index was > 8.73. However, no significant correlation was observed in males. Conclusion: A non-linear association was found between the TyG index and 1-year recurrent stroke risk. Subsequently, a high TyG index could predict an increased 1-year recurrent stroke risk in female AIS patients