2022年 · 第135卷第12期

One billion people currently suffer from respiratory diseases globally, and most of them are living in developing countries. Respiratory diseases spread negative effects widely to both life expectancy and disability-adjusted life years (DALYs) in the population. The most recent update evidence of the 2019 Global Burden of Disease Study report revealed that 454.6 million people worldwide had a chronic respiratory disease, with an increase of 39.8% compared to 1990^[1]; the disease has led to 3.97 million deaths in 2019, with an increase of 28.5% since 1990, and accounted for 1035.3 DALYs per 100,000 population (103.5 million total DALYs, with an increase of 20.8% since 1990). The most prevalent chronic respiratory diseases were chronic obstructive pulmonary disease (COPD) (global prevalence: 2.6%) and asthma (global prevalence: 3.4%). More than 10 million people are infected with tuberculosis and 1.4 million people die of it each year, making it the most common lethal infectious disease, just ranked after the coronavirus disease 2019 (COVID-19) pandemic.^[2]The current pandemic has claimed the lives of >6 million people, primarily due to respiratory causes.^[3]Lung cancer kills 1.8 million people each year and is the leading cancer death.^[4]In 2019, respiratory diseases have comprised three of the top ten causes of death according to the World Health Organization (WHO), leading to >8 million annual deaths.^[5]

Also known as the Devil’s Triangle or Hurricane Alley, the Bermuda Triangle is an area of the Atlantic Ocean with vertices in Miami, San Juan de Puerto Rico, and Bermuda, which has been credited for causing mass disappearances and a number of wrecks over the years. While people love to throw around conspiracy theories about each of these Bermuda Triangle stories, there may be perfectly logical explanations for all of them.^[1]A resemblance of the Bermuda Triangle to airway diseases can be made. Asthma, bronchiectasis, and chronic obstructive pulmonary disease (COPD) are the three most prevalent chronic inflammatory airway diseases.^[2]It is estimated that 5%–10% of the general all-ages population suffers from asthma,^[3]and 8%–10% of adults suffer from COPD.^[4,5]The prevalence of bronchiectasis is largely unknown, but it is estimated that it can affect 350 to 500 individuals per 100,000 inhabitants, especially in the elderly.^[6,7]It is widely recognized that these three diseases are greatly underdiagnosed.^[8]

Response to immune checkpoint inhibitors (ICIs) is affected by multiple factors. This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer (NSCLC) patients.

The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People’s Hospital between May 2019 and July 2020 were retrospectively analyzed. Metastatic sites included liver, bone, brain, adrenal gland, pleura, and contralateral lung. Progression-free survival (PFS) and overall survival (OS) were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method. Organ-specific disease control rate (OSDCR) of different individual metastatic sites was evaluated.

Forty NSCLC patients meeting the criteria were identified. The presence of liver metastasis was significantly associated with shorter PFS (3.1 vs. 15.5 months, P = 0.0005) and OS (11.1 months vs. not reached, P = 0.0016). Besides, patients with bone metastasis tend to get shorter PFS (4.2 vs. 15.5 months, P = 0.0532) rather than OS (P = 0.6086). Moreover, the application of local treatment could numerically prolong PFS in patients with brain metastasis (15.5 vs. 4.3 months, P = 0.1894). More metastatic organs involved were associated with inferior PFS (P = 0.0052) but not OS (P = 0.0791). The presence of liver metastasis or bone metastasis was associated with more metastatic organs (Phi[φ]: 0.516, P = 0.001). The highest OSDCR was observed in lung (15/17), and the lowest in the liver (1/4).

Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC. ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis, thus patients with this type of metastasis might require more aggressive combination strategies.

The risk for chronic kidney disease (CKD) is influenced by genetic predisposition, sex, and lifestyle. Previous research indicates that coffee is a potentially protective factor in CKD. The current study aims to investigate whether sex disparity exists in the coffee–CKD association, and whether genetic risk of CKD or genetic polymorphisms of caffeine metabolism affect this association.

A total of 359,906 participants from the UK Biobank who were enrolled between 2006 and 2010 were included in this prospective cohort study, which aimed to estimate the hazard ratios for coffee intake and incident CKD using a Cox proportional hazard model. Allele scores of CKD and caffeine metabolism were additionally adjusted for in a subsample with qualified genetic data (n = 255,343). Analyses stratified by genetic predisposition, comorbidities, and sex hormones were performed. Tests based on Bayesian model averaging were conducted to ascertain the robustness of the results.

Coffee was inversely associated with CKD in a dose-dependent manner. The effects of coffee did not differ across different strata of genetic risk for CKD, but were more evident among slower genetically predicted caffeine metabolizers. Significant sex disparity was observed (P value for interaction = 0.013), in that coffee drinking was only associated with the risk reduction of CKD in females. Subgroup analysis revealed that testosterone and sex hormone-binding globulin (SHBG), but not estradiol, modified the coffee–CKD association.

In addition to the overall inverse coffee–CKD association that was observed in the general population, we could also establish that a sex disparity existed, in that females were more likely to experience the benefit of the association. Testosterone and SHBG may partly account for the sex disparity.

Previous studies have shown that inflammation plays an important role in intracranial atherosclerotic stenosis (ICAS). The platelet-to-lymphocyte ratio (PLR) has recently emerged as a potential inflammatory biomarker. This study aimed to explore the association of the PLR with ICAS in a Chinese Han population.

A total of 2134 participants (518 with ICAS, 1616 without ICAS) were enrolled in this study. ICAS was defined as atherosclerotic stenosis >50% or the occlusion of several main intracranial arteries. Multivariable logistic regression analyses were used to assess the association of the PLR with ICAS. Additional subgroup analyses were performed according to age (<60 vs. ≥ 60 years) and acute ischemic stroke.

Multivariate regression analysis showed that a high PLR was associated with a higher risk of ICAS in all participants (P < 0.001). Compared with the lowest quartile, the fourth PLR quartile was significantly associated with ICAS (OR 1.705, 95% confidence interval 1.278–2.275, P < 0.001). In the subgroups stratified by age, an association between the PLR and ICAS was found in the late-life group (P < 0.001), but not in the mid-life group (P = 0.650). In the subgroups stratified by acute ischemic stroke, the relationship between an elevated PLR and a higher risk of ICAS remained unchanged (stroke group, P < 0.001; non-stroke group, P = 0.027).

An elevated PLR was associated with a higher risk of ICAS in a Chinese Han population. The PLR might serve as a potential biomarker for ICAS in the elderly population.

Gastroparesis is a debilitating medical condition with limited treatment options. Gastric per-oral pyloromyotomy (G-POEM) has emerged as a promising treatment option with remarkable short-term clinical success shown in multiple studies. While the post-procedure protocol is not standardized across many centers, the majority of the centers observes these patients in the hospital after the procedure for monitoring. In this single-center prospective study, we evaluated the safety and feasibility of same day discharge after the G-POEM procedure.

All the patients with refractory gastroparesis undergoing G-POEM from October 2019 to March 2020 were enrolled. A total of 25 patients were enrolled in the procedure. Based on the pre-defined criteria, patients were either discharged on the same day after the procedure or admitted to the hospital for further observation. The patient and procedure-related data were extracted from the chart review. Univariate analysis was performed (chi-squared test) on categorical variables after organizing categorical variables as numeric counts or percentages. The student t test was performed on continuous variables after reporting as mean and standard deviation. For analysis with a smaller sample size, Fisher exact and Mann–Whitney tests were used.

A total of 25 patients were enrolled. The technical success of G-POEM was 100% and clinical success was 80% (20/25) at 1-month follow-up. Of the 25 patients, 9 patients (36%) were discharged on the same day according to the procedure from the recovery unit. Of the remaining 16 patients who were admitted to the hospital post-procedure, 10 (40%) were admitted due to procedure-related causes while other admissions were either pre-planned or due to social reasons. The average Charlson comorbidity index was lower in the same day discharge group (P < 0.05). The number of patients requiring double myotomy was higher in the same day discharge group (P < 0.05). The overall complication rate of G-POEM in the study cohort was 12% (3/25) with all complications being mild without any severe adverse events.

G-POEM is a safe and effective method of treatment for refractory GP with higher clinical success in short-term follow-up. The same day discharge after G-POEM is safe and feasible in >50% of patients with close periprocedural monitoring.

Psoriasis is a chronic systemic inflammatory disease, and hyperuricemia is a common comorbidity in patients with psoriasis. However, there are limited reports on the relationship between serum uric acid levels and biological treatment efficacy. The purposes of this study were to compare the differences in serum uric acid levels between patients with psoriasis and healthy controls and analyze the risk of hyperuricemia.

A total of 196 patients with psoriasis and 191 age- and sex-matched healthy controls were enrolled in this retrospective cohort study. One hundred and twenty-seven patients with severe psoriasis were treated with biologics. Sixty-eight patients received adalimumab, and 59 patients received secukinumab. Serum uric acid levels were measured at baseline, week 24, and week 48 of treatment.

Patients with psoriasis had higher serum uric acid levels than healthy controls (6.4 ± 1.7 mg/dL vs. 5.7 ± 1.5 mg/dL, P < 0.001). Hyperuricemia was found in 33.7% (66/196) of patients with psoriasis, which was significantly higher than that in healthy controls (13.1% [25/191], P < 0.001). Serum uric acid levels and hyperuricemia were not related to the severity of psoriasis (P > 0.05). No significant changes in serum uric acid levels and hyperuricemia were observed following adalimumab treatment (P > 0.05). The serum uric acid level in patients treated with secukinumab was 6.7 ± 1.6 mg/dL at week 24, which was not statistically different from that at baseline (6.6 ± 1.4 mg/dL, P = 0.885). Serum uric acid levels were significantly decreased at week 48 (6.3 ± 1.5 mg/dL vs. 6.6 ± 1.4 mg/dL, P = 0.007) in patients treated with secukinumab. Secukinumab had no significant effect on hyperuricemia either (P > 0.05).

The serum uric acid levels and prevalence of hyperuricemia in patients with psoriasis were significantly higher than those in healthy controls. Secukinumab treatment for 48 weeks successfully decreased serum uric acid levels in patients with psoriasis, whereas adalimumab had no significant effect on serum uric acid levels.

The dermoscopic features of rosacea have already been reported. However, the current findings are incomplete, and little is known about phymatous rosacea. Hence, this study aimed to summarize and compare the dermoscopic features and patterns of three rosacea subtypes (erythematotelangiectatic [ETR], papulopustular [PPR], and phymatous [PHR]) in the Chinese Han population and to evaluate whether these features differ with patients’ genders, ages, and durations.

Dermoscopic images of 87 rosacea patients were collected in non-polarized and polarized dermoscopy contact modes at 20-fold magnification. Dermoscopic features, including vessels, scales, follicular findings, and other structures, were summarized and evaluated.

The reticular linear vessels and red diffuse structureless areas of ETR were distinctive. For PPR, red diffuse structureless areas, reticular linear vessels, yellow scales, follicular plugs, and follicular pustules were typical dermoscopic criteria. The common dermoscopic features of PHR were: orange diffuse structureless areas, linear vessels with branches, perifollicular white color, orange focal structureless areas, and white lines. The following features statistically differed among the three rosacea subtypes: reticular linear vessels (P < 0.001), unspecific linear vessels (P= 0.005), linear vessels with branches (P < 0.001), yellow scales (P = 0.001), follicular plugs (P < 0.001), perifollicular white color (P < 0.001), red diffuse structureless areas (P = 0.022), orange diffuse structureless areas (P < 0.001), red focal structureless areas (P = 0.002), orange focal structureless areas (P = 0.003), white lines (P < 0.001), follicular pustules (P < 0.001), and black vellus hairs (P < 0.001).

The dermoscopic patterns of ETR are red diffuse structureless areas and reticular linear vessels. For PPR, the pattern comprehends combinations of red diffuse structureless areas, reticular linear vessels, yellow scales, follicular plugs, and follicular pustules. Meanwhile, PHR is characterized by remarkable orange diffuse structureless areas, linear vessels with branches, perifollicular white color, orange focal structureless areas, and white lines.

The CHA₂DS₂–VASc score was initially applied to stratify stroke risk in patients with atrial fibrillation (AF) and was found to be effective in predicting all-cause mortality outcomes. To date, it is still unclear whether circulating long non-coding RNAs (lncRNAs) as emerging biomarkers, can improve the predictive power of the CHA₂DS₂–VASc score in stroke and all-cause mortality.

Candidate lncRNAs were screened by searching the literature and analyzing previous RNA sequencing results. After preliminary verification in 29 patients with AF, the final selected lncRNAs were evaluated by Cox proportional hazards regression in 192 patients to determine whether their relative expression levels were associated with stroke and all-cause mortality. The c-statistic, net reclassification improvement (NRI), and integrated discrimination improvement of the patients were calculated to evaluate the discrimination and reclassification power for stroke and all-cause mortality when adding lncRNA expression levels to the CHA₂DS₂–VASc score model.

Five plasma lncRNAs associated with stroke and all-cause mortality in AF patients were selected in our screening process. Patients with elevated H19 levels were found to have a higher risk of stroke (hazard ratio [HR] 3.264, 95% confidence interval [CI]: 1.364–7.813, P = 0.008). Adding the H19 expression level to the CHA₂DS₂–VASc score significantly improved the discrimination and reclassification power of the CHA₂DS₂–VASc score for stroke in AF patients. In addition, the H19 level showed a marginally significant association with all-cause mortality (HR 2.263, 95% CI: 0.889–5.760, P = 0.087), although it appeared to have no significant improvement for the CHA₂DS₂–VASc model for predicting all-cause mortality.

Plasma expression of H19 was associated with stroke risk in AF patients and improved the discriminatory power of the CHA₂DS₂–VASc score. Therefore, lncRNA H19 served as an emerging non-invasive biomarker for stroke risk prediction in patients with AF.

Total ankle replacement (TAR) is a viable option for the treatment of end-stage ankle arthritis. In China, the INBONE-II implant is the only total ankle prosthesis approved since 2016. The purpose of this study is to report a large sample of findings for the TAR with INBONE-II prosthesis.

A total of 64 patients with end-stage ankle arthritis, who underwent primary TAR using INBONE-II by the same surgeon from 2016 to 2019, at a single institution were included in this retrospective, single-center study. Clinical data, radiographic findings, survival rate, and complications were recorded and assessed pre-operatively and at the most recent follow-up.

A total of 64 patients were available for follow-up at least 2 years after surgery; the mean follow-up duration for clinical outcomes was 37.9 months (24–59 months), and for radiographic findings was 22.8 months (12–59 months). There were significant improvements (P < 0.01) in the American Orthopedic Foot and Ankle Society hindfoot scale, the visual analog scale for pain, and the Short Form-36. There were statistically significant differences between pre-operative and post-operative comparisons of the talar tilt angle (TT) and the tibial lateral surface angle (TLS) in the radiographic findings (TT from 4.7 ± 4.3° to 1.3 ± 1.3°, TLS from 80.4 ± 7.7° to 87.4 ± 2.3°, P < 0.01). There was no statistically significant difference in improvement of the tibial anterior surface angle (P = 0.14). Ten complications (all low grade) were recorded according to the Glazebrook classification system. The survivorship of the prosthesis was 100% (64/64).

Patients who underwent TAR with INBONE-II prosthesis demonstrated significant improvements in all measures of pain and function as well as in radiographic findings. High survival and a low incidence of complications were observed in this study.

Epigenetics, and especially DNA methylation, contributes to the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). This study aimed to investigate the role of DNA methylation in SALS using whole blood of SALS patients.

In total, 32 SALS patients and 32 healthy controls were enrolled in this study. DNA was isolated from whole blood collected from the participants. DNA methylation profiles were generated using Infinium MethylationEPIC BeadChip.

We identified 34 significant differentially methylated positions (DMPs) in whole blood from SALS patients, compared with the healthy controls. Of these DMPs, five were hypermethylated and 29 were hypomethylated; they corresponded to 13 genes. For the DMPs, ATAD3B and BLK were hypermethylated, whereas DDO, IQCE, ABCB1, DNAH9, FIGN, NRP1, TMEM87B, CCSAP, ST6GALNAC5, MYOM2, and RUSC1-AS1 were hypomethylated. We also identified 12 differentially methylated regions (DMRs), related to 12 genes (NWD1, LDHD, CIS, IQCE, TNF, PDE1C, LGALS1, CSNK1E, LRRC23, ENO2, ELOVL2, and ELOVL2-AS1). According to data from the Kyoto Encyclopedia of Genes and Genomes database, DNAH9 and TNF are involved in the amyotrophic lateral sclerosis (ALS) pathway. Correlation analysis between clinical features and DNA methylation profiling indicated that the methylation level of ELOVL2 and ARID1B was positively associated with the age of onset (r = 0.86, adjust P = 0.001) and disease duration (r = 0.83, adjust P = 0.01), respectively.

We found aberrant methylation in DMP- and DMR-related genes, implying that many epigenetic alterations, such as the hypomethylation of DNAH9 and TNF, play important roles in ALS etiology. These findings can be helpful for developing new therapeutic interventions.

Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.

A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen-activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope.

First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N-terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.

Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

To the Editor:The incidence of hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT) is approximately 1.4%.^[1]Owing to direct cancer cell dissemination into the systemic circulation, HCC-IVCTT is frequently associated with synchronous and metachronous extrahepatic metastasis. Without treatment, the median survival time is only 3 months for patients with HCC-IVCTT.

To the Editor: Female patients with inflammatory bowel disease (IBD) have lower fertility rates and take longer time to conceive than the healthy population. How to improve the fertility in patients with IBD is a critical challenge. A recent study implied that microbiota play an important role in the reproductive endocrine system throughout a woman’s lifetime by interacting with estrogens, androgens, insulin, and other hormones.^[1]Host-bacterial interaction is sex-dependent, as studies have shown the ability of microbiota to modulate gonadal sex hormones. Putting forward the concept that gut microbiota dysbiosis may negatively affect reproductive fitness, fecal microbiota transplantation (FMT) is an effective way of remodeling gut microbiota. The improved methodology of FMT based on the automatic washing process and the related delivering consideration was named as washed microbiota transplantation (WMT),^[2]which was released as consensus statement by the FMT-standardization Study Group in 2019.^[3]Washed preparation of fecal microbiota changes the transplantation related safety, quantitative method, and delivery of microbiota suspension. The present study aimed to retrospectively assess whether the fertility of patient with IBD could benefit from WMT.

To the Editor:Macrosomia is of growing prevalence and concern worldwide. In China, there has been a marked increase in the prevalence of macrosomia over the past few decades as a result of economic development and improvements in living standards. The increased prevalence of macrosomia has caused a huge burden at both the population and individual levels for China. In addition, the number of multiparas increased significantly especially after the "two-child policy" and "three-child policy" were put into effect and it was usually thought that the birthweight is higher and women are more likely to deliver macrosomia in the subsequent pregnancy than the first pregnancy. However, large studies on the prevalence and characteristics of macrosomia in both the first and subsequent pregnancy in China are limited. Therefore, we aim to explore the prevalence and characteristics of macrosomia in both the first and subsequent pregnancy in a multicenter retrospective study in China.

To the Editor: Cesarean section (CS) resolves dystocia and serious pregnancy-related complications but also has adverse outcomes such as long recovery time, uterine rupture, and dangerous placenta previa in future pregnancies. The increase in cesarean section rates (CSRs) worldwide has drawn the attention of international scholars.^[1]In China, the CSR has increased since the 1980s, reaching 54.47% in 2011.^[2]This present study sought to provide updated information on the changes in the CSR, and reasons for the changes in Beijing from 2012 to 2017 as a guide for obstetricians and to develop strategies to reduce the CSR.

To the Editor:As of July 4, 2021, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has affected >0.18 billion individuals and caused >3.9 million deaths worldwide.^[1]Currently, the only method to radically overcome this pandemic is extensive vaccination. However, the clinical trials assessing most vaccines against SARS-CoV-2 have excluded patients with hematological tumors. Thus, only limited data are available in hematological tumor patients with respect to vaccine safety, tolerability, and effectiveness. The lack of such data in hematologic tumor patients leads to hesitation towards the immunization approach and undermines current policies regarding vaccination. Currently, six vaccines against SARS-CoV-2 are available in China. However, vaccination agencies in most communities in China do not allow or recommend vaccination for hematological tumor patients. Therefore, acquiring the safety data of SARS-CoV-2 vaccines in such patients is imperative for individual choice and public health policies.

To the Editor:Epithelial ovarian cancer has the highest mortality rate among all gynecologic cancers. Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. Although most ovarian cancer patients are initially sensitive to platinum, many eventually develop drug-resistant diseases.^[1]However, the exact mechanism of platinum resistance is still unclear.^[2]Through DNA microarray analyses of a cisplatin-resistant human ovarian cancer cell line (A2780_CP) and the parental cell line (A2780), we found that the fibroblast growth factor 21 (FGF21) gene was extremely upregulated by 18.74-fold in A2780cp cells compared with that in A2780 cells. The upregulated and downregulated genes identified in the microarray analyses were involved in various biological processes including the regulation of metabolic process and response to growth factors [Supplementary Figure 1, http://links.lww.com/CM9/B12]. Pathway analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway was involved in cisplatin resistance [Supplementary Figure 2, http://links.lww.com/CM9/B12].

To the Editor:Hypotrichosis with juvenile macular dystrophy (HJMD, OMIM: 601553) is a rare autosomal recessive disorder characterized by short and sparse hair, progressive macular degeneration, decreased visual acuity, and even blindness in early life. Mutations responsible for HJMD have been identified in the cadherin 3 gene (CDH3, OMIM: 114021) on chromosome 16q22.1. This gene encodes P-cadherin, a calcium-dependent cell–cell adhesion protein that plays a significant role in the development of hair follicles^[1]and the retinal pigmented epithelium.^[2]To date, 30 HJMD pedigrees and 20 sporadic cases involving 36 mutations in theCDH3gene have been reported.

To the Editor:Irreversible electroporation (IRE) ablation mainly relies on the high-intensity pulsed electric energy instead of Joule heat.^[1]Compared with thermal ablation, IRE is traditionally considered as a non-thermal modality. Recentin vitroandex vivostudies have shown that IRE ablation may be associated with a certain thermal effect, and the ablation temperature mainly depends on the dynamic balance between the accumulated ablation energy and heat dissipation.^[2,3]

To the Editor:Interleukin (IL)-33, also named IL-1F11 is the 11th member of IL-1 family. The human IL-33 gene is located on the short arm of chromosome nine at 9p24.1. As a 31-kDa cytokine, IL-33 is constitutively expressed in endothelial and epithelial cells of barrier tissues. IL-33 cleaved by caspase-1 or caspase-3 is passively released from necrotic cells to maintain homeostasis and eliminate threats. IL-33 can also be cleaved by chymases, tryptases, and serine proteases, a process that converts IL-33 into various bioactive isoforms in different cell types.

To the Editor: Idiopathic cough is associated with laryngeal hypersensitivity and chronic pain syndromes. Idiopathic cough can be diagnosed when patients have no cause of chronic cough after treatment of cough. Patients with chronic cough experience impaired quality of life (QOL), interruption of daily activity, and depression. Therefore, better approaches to refractory chronic cough are needed.^[1]