Profiles of Cough and Associated Risk Factors in Nonhospitalized Individuals With SARS-CoV-2 Omicron Variant Infection: Cross-Sectional Online Survey in China.

BACKGROUND: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. OBJECTIVE: The aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. METHODS: In this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. RESULTS: There were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). CONCLUSIONS: Cough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

Disparities in the Outcomes of Acute Pulmonary Embolism in Hospitalized Patients with Hematologic Malignancy and Solid Tumor.

This study aimed to compare the clinical burden and healthcare utilization outcomes of hematologic versus solid malignancies in patients hospitalized with acute pulmonary embolism (PE). This population-based, retrospective study extracted and analyzed the discharge data from the 2016-2018 US National Inpatient Sample (NIS) of hospitalized patients with a primary diagnosis of acute PE and a subsequent diagnosis of hematologic malignancies or solid tumors. Prolonged length-of-stay (LOS) was defined as ≥75th percentile LOS of the study cohort. Unfavorable discharge was defined as discharged to nursing home or long-term facility. Univariate and multivariate regression analyses were conducted to determine associations between cancer type, presence of unstable PE, and in-hospital outcomes in acute PE patients. Patients with acute PE with solid tumors had higher rates of in-hospital deaths and unfavorable discharge than those with hematologic malignancies (6.4% versus 3.2%, P < 0.001; 14.0% versus 11.2%, P = 0.01, respectively). Acute PE patients with hematologic malignancies had a lower risk of in-hospital death (aOR: 0.43, 95% CI: 0.31-0.60), unfavorable discharge (aOR: 0.76, 95% CI: 0.63-0.92), and prolonged LOS (aOR: 0.83, 95% CI: 0.71-0.98) than those with solid tumors. Stratified analysis showed that male patients aged <60 years with hematologic malignancies had a lower risk of prolonged LOS (aOR: 0.70, 95% CI: 0.52-0.94; aOR: 0.85, 95% CI: 0.68-1.05) and unfavorable discharge (aOR: 0.40, 95% CI: 0.22-0.71; aOR: 0.65, 95% CI: 0.50-0.85) than those with solid tumors. In the comparison of the outcomes of acute PE with hematologic malignancies and solid tumors, patients with hematologic malignancy had a lower risk of in-hospital deaths, prolonged LOS, and unfavorable discharge than those with solid tumors.

Pathogenesis and management of gastroesophageal reflux disease-associated cough: a narrative review.

Background and Objective: Gastroesophageal reflux disease (GERD)-associated cough is defined as a special GERD with a predominant cough symptom and is a common cause of chronic cough. This review summarizes our current understanding on the pathogenesis and management of GERD-associated cough. Methods: Main literatures on the pathogenesis and management of GERD-associated cough were reviewed and our understandings derived from the published studies were showed then. Key Content and Findings: Although esophageal-tracheobronchial reflex mainly underlies the pathogenesis of GERD-associated cough, its counterpart-tracheobronchial-esophageal reflex might exist and initiate the cough due to reflux induced by upper respiratory tract infection through the signaling of transient receptor potential vanilloid 1 linking airway and esophagus. The presence of reflux-associated symptoms such as regurgitation and heartburn along with coughing suggests an association between cough and GERD, which is supported by the objective evidence of abnormal reflux as detected by reflux monitoring. Although there is no general consensus, esophageal reflux monitoring provides the main diagnostic criteria for GERD-associated cough. Despite that acid exposure time and symptom associated probability are useful and mostly employed reflux diagnostic criteria, they are imperfect and far from being the gold standard. Acid suppressive therapy has long been recommended as the first choice for GERD-associated cough. However, the overall benefits of proton pump inhibitors have been controversial and need to be further assessed, especially in patients with cough due to non-acid reflux. Neuromodulators have demonstrated potential therapeutic effects for refractory GERD-associated cough, for which anti-reflux surgery may also be a promising treatment option. Conclusions: Tracheobronchial-esophageal reflex might initiate reflux-induced cough provoked by the upper respiratory tract infection. It is necessary to optimize the current standards and to explore new criteria with higher diagnostic potency. Acid suppressive therapy is the first choice for GERD-associated cough, followed by neuromodulators and anti-reflux surgery for refractory GERD-associated cough.

Antitussive efficacy of the current treatment protocol for refractory chronic cough: our real-world experience in a retrospective cohort study.

BACKGROUND: The management of refractory chronic cough (RCC) is a great challenge. Neuromodulators have long been used for RCC with imperfect efficacy. OBJECTIVES: We summarized the outcomes of the current treatments used at our specialist cough clinic, which provides a guideline-led service and real-world experience for the future management of RCC. DESIGN: This is a single-centre retrospective observational cohort study. METHODS: Consecutive RCC patients (the first clinic visit between January 2016 and May 2021) were included into this observational cohort study. Medical records in the Chronic Cough Clinical Research Database were fully reviewed using uniform criteria. The included subjects were followed-up for at least 6 months after the final clinic visit via instant messages with the link to self-scaled cough-associated questionnaires. RESULTS: Overall, 369 RCC patients were analysed with a median age of 46.6 years and a cough duration of 24.0 months. A total of 10 different treatments were offered. However, 96.2% of patients had been prescribed at least one neuromodulator. One-third of patients had alternative treatments prescribed given the poor response to the initial therapy and 71.3% favourably responded to at least one of the treatments. Gabapentin, deanxit, and baclofen had comparable therapeutic efficacy (56.0%, 56.0%, and 62.5% respectively; p = 0.88) and overall incidences of adverse effects (28.3%, 22.0%, and 32.3% respectively; p = 0.76). However, 19.1 (7.7-41.8) months after the last clinic visit, 65.0% reported improvement (24.9%) or control of their cough (40.1%); 3.8% reported a spontaneous remission and 31.2% still had a severe cough. Both HARQ (n = 97; p < 0.001) and LCQ (n = 58; p < 0.001) demonstrated marked improvement. CONCLUSION: Trying different neuromodulators is a pragmatic strategy for RCC, which helped around two-thirds of patients. Relapse is common on withdrawal or reduction of dosage. Novel medication for RCC is an urgent clinical need. PLAIN LANGUAGE SUMMARY: This is the first report that fully represented a guideline-led treatment protocol for refractory chronic cough (RCC) based on a large series of patients, which evaluated the short- and long-term effects of the currently available treatments for RCC. We found that the therapeutic trial of different neuromodulators is a pragmatic strategy, which helped around two-thirds of patients. Gabapentin, deanxit (flupentixol/melitracen), and baclofen had similar therapeutic outcomes. This study may offer real-world experience for the future management of RCC.

The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI.

Monocytes and macrophages are the two major cell types involved in innate immunity. Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing proteins, mRNAs, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs). However, it is still unclear whether monocyte-derived exosomes are involved in the communication between monocytes and macrophages. In this study, we analyzed the differentially expressed lncRNA profiles in monocytes isolated from blood samples of healthy controls and acute lung injury (ALI) patients. We focused our study on investigating the signaling downstream of CLMAT3 (colorectal liver metastasis-associated transcript 3), a lncRNA that regulated proinflammatory cytokine genes. We revealed that CLMAT3 specifically targeted CtBP2 (C-terminal binding protein 2) and repressed its expression. Elevated CtBP2 acted as a coactivator to assemble a transcriptional complex with histone acetyltransferase p300 and NF-κB (nuclear factor κB) subunits. In vitro coculture and in vivo injection of ALI monocyte-derived exosomes increased the production of proinflammatory cytokines. Importantly, the administration of two CtBP2 inhibitors, NSC95397 and MTOB, could significantly reverse CtBP2-mediated transactivation. Collectively, our results support a model in which monocyte-derived exosomal CLMAT3 activates the CtBP2-p300-NF-κB complex to induce proinflammatory cytokines, thus contributing to the pathogenesis of ALI.

The role of ATP in cough hypersensitivity syndrome: new targets for treatment.

Clinically, chronic cough can be effectively controlled in most patients by etiological treatment; however, there remain a small number of patients whose cough has unidentifiable etiology or where treatment efficacy is poor following etiology identification, whose condition is described as unexplained chronic cough or refractory chronic cough. Patients with refractory chronic or unexplained chronic cough commonly have increased cough reflex sensitivity, which has been described as cough hypersensitivity syndrome. The adenosine triphosphate (ATP)-gated P2X3 receptor may be a key link in the activation of sensory neurons that regulate cough reflexes and has recently draw attention as a potential target for the treatment of refractory chronic cough, with a number of clinical studies validating the therapeutic effects of P2X3 receptor antagonists in patients with this condition. As the energy source for various cells in vivo, ATP localizes within cells under normal physiological conditions, and has physiological functions, including in metabolism; however, under some pathological circumstances, ATP can act as a neuromodulator and is released into the extracellular space in large quantities as a signal transduction molecule. In addition, ATP is involved in regulation of airway inflammation and the cough reflex. Here, we review the generation, release, and regulation of ATP during airway inflammation and its role in the etiology of cough hypersensitivity syndrome, including the potential underlying mechanism.

Gut microbiota regulate tumor metastasis via circRNA/miRNA networks.

BACKGROUND: Increasing evidence indicates that gut microbiota plays an important role in cancer progression. However, the underlying mechanism remains largely unknown. Here, we report that broad-spectrum antibiotics (ABX) treatment leads to enhanced metastasis by the alteration of gut microbiome composition. METHODS: Cancer LLC and B16-F10 cell metastasis mouse models, and microarray/RNA sequencing analysis were used to reveal the regulatory functions of microbiota-mediated circular RNA (circRNA)/microRNA (miRNA) networks that may contribute to cancer metastasis. RESULTS: The specific pathogen-free (SPF) mice with ABX treatment demonstrated enhanced lung metastasis. Fecal microbiota transplantation (FMT) from SPF mice or Bifidobacterium into germ-free mice significantly suppressed lung metastasis. Mechanistically, gut microbiota impacts circRNA expression to regulate levels of corresponding miRNAs. Specifically, such modulations of gut microbiota inhibit mmu_circ_0000730 expression in an IL-11-dependent manner. Bioinformatics analysis combined with luciferase reporter assays revealed reciprocal repression between mmu_circ_0000730 and mmu-miR-466i-3p. We further showed that both mmu-miR-466i-3p and mmu-miR-466 f-3p suppresses a number of genes involved in epithelial-mesenchymal transition (EMT) and stemness of cancer stem cells such as SOX9. CONCLUSIONS: These results provide evidence of a previously unrecognized regulatory role of non-coding RNAs in microbiota-mediated cancer metastasis, and thus, the microbiome may serve as a therapeutic target.

Efficacy and safety of rescue stenting following failed mechanical thrombectomy for anterior circulation large vessel occlusion: propensity score analysis.

PURPOSE: To evaluate the effectiveness and safety of rescue stenting (RS) after failed mechanical thrombectomy (MT) for patients with large artery occlusion in the anterior circulation. METHODS: Consecutive patients who experienced failed reperfusion and subsequently did or did not undergo RS at 16 comprehensive stroke centers were enrolled from January 2015 to June 2018. Propensity score matching was used to achieve baseline balance between the patient groups. Symptomatic intracranial hemorrhage (sICH) at 48 hours and the modified Rankin Scale scores and mortality at 3 months in the two groups were compared. RESULTS: A total of 90 patients with RS and 117 patients without RS after failed MT were enrolled. Propensity score matching analysis selected 132 matched patients. The good outcome rate was significantly higher in matched patients with RS than in those without RS (36.4% vs 19.7%, p=0.033), whereas the sICH (13.6% vs 21.2%, p=0.251) and mortality (31.9% vs 43.9%, p=0.151) were not significantly different between the groups. CONCLUSIONS: RS seems to be an effective safe choice for patients with large vessel occlusion of the anterior circulation who underwent failed MT.

Regulation of androgen receptor splice variant AR3 by PCGEM1.

The androgen receptor (AR) is required for prostate development and is also a major driver of prostate cancer pathogenesis. Thus androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, castration resistance due to expression of constitutively active AR splice variants is a significant challenge to prostate cancer therapy; little is known why effectiveness of ADT can only last for a relatively short time. In the present study, we show that PCGEM1 interacts with splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65, as determined by RNA precipitation and Western blot, suggesting a role for PCGEM1 in alternative splicing. In support of this possibility, PCGEM1 is correlated with AR3, a predominant and clinically important form of AR splice variants in prostate cancer. Moreover, androgen deprivation (AD) induces PCGEM1 and causes its accumulation in nuclear speckles. Finally, we show that the AD-induced PCGEM1 regulates the competition between hnRNP A1 and U2AF65 for AR pre-mRNA. AD promotes PCGEM1 to interact with both hnRNP A1 and U2AF65 with different consequences. While the interaction of PCGEM1 with hnRNP A1 suppresses AR3 by exon skipping, its interaction with U2AF65 promotes AR3 by exonization. Together, we demonstrate an AD-mediated AR3 expression involving PCGEM1 and splicing factors.

Efficacy of add-on montelukast in nonasthmatic eosinophilic bronchitis: the additive effect on airway inflammation, cough and life quality.

BACKGROUND: The efficacy of montelukast (MONT), a cysteinyl leukotriene receptor antagonist, in nonasthmatic eosinophilic bronchitis (NAEB), especially its influence on cough associated life quality is still indefinite. We evaluated the efficacy of MONT combined with budesonide (BUD) as compared to BUD monotherapy in improving life quality, suppressing airway eosinophilia and cough remission in NAEB. METHODS: A prospective, open-labeled, multicenter, randomized controlled trial was conducted. Patients with NAEB (aged 18-75 years) were randomized to inhaled BUD (200 µg, bid) or BUD plus oral MONT (10 µg, qn) for 4 weeks. Leicester cough questionnaire (LCQ) life quality scores, cough visual analog scale (CVAS) scores, eosinophil differential ratio (Eos), and eosinophil cationic protein (ECP) in induced sputum were monitored and compared. RESULTS: The control and MONT groups contained 33 and 32 patients, respectively, with similar baseline characteristics. Significant with-in group improvement in CVAS, LCQ scores, Eos, and ECP was observed in both groups during treatment. After 2-week treatment, add-on treatment of MONT was significantly more effective than BUD monotherapy for CVAS decrease and LCQ scores improvement (both P < 0.05). Similar results were seen at 4-week assessment (both P < 0.05). 4-week add-on therapy of MONT also resulted in a higher percentage of patients with normal sputum Eos (<2.5%) and greater decrease of ECP (both P < 0.05). CONCLUSIONS: MONT combined with BUD was demonstrated cooperative effects in improvement of life quality, suppression of eosinophilic inflammation, and cough remission in patients with NAEB.

Effects of phosphodiesterase 4 inhibitor on cough response in guinea pigs sensitized and challenged with ovalbumin.

BACKGROUND: There is currently considerable interest in the potential value of selective inhibitors of cyclic nucleotide phosphodiesterase 4 in the treatment of asthma. However, whether they influence eosinophilic airway inflammation-associated cough remains unclear. The objective of this study was to investigate the effects of selective phosphodiesterase 4 inhibitor SB207499 on cough response and airway inflammation in guinea pigs sensitized and challenged with ovalbumin. METHODS: Forty sensitized guinea pigs were randomly divided into four groups: control (n = 10), challenge (n = 10), SB207499 (n = 10) and aminophylline (n = 10), then challenged with aerosol of 1% ovalbumin or saline. Two hours later, animals were intraperitoneally injected with either saline, 25 mg/kg of SB207499 or aminophylline. At the 24th hour, the injection was repeated with 2.5 mg/kg and 25 mg/kg SB207499 or aminophylline, then cough response to inhaled capsaicin and airway responsiveness to methacholine inducing a 150% of the peak airway pressure to the baseline (PC150) was measured. Finally, total cell number and differentials in bronchoalveolar lavage fluid were analysed. RESULTS: The cough frequency per 3 minutes and PC150 in the challenge group were (22 +/- 4) times/3 minutes and (198 +/- 54) microg/ml, which were significantly different from (6 +/- 2) times/3 minutes and (691 +/- 81) microg/ml in the control group (P < 0.05, respectively). The injection of 25 mg/kg SB207499 significantly inhibited the increased cough response and airway hyperresponsiveness, the cough frequency and PC150 in guinea pigs were (13 +/- 2) times/3 minutes and (680 +/- 81) microg/ml (P < 0.05), which differed significantly from (18 +/- 2) times/3 minutes and (400 +/- 86) microg/ml after the administration of the same dose of aminophylline (P < 0.05). The inhibition of SB207499 on cough response was dose-dependent. Similarly, SB207499 decreased the total cell number and percentage of eosinophils in bronchoalveolar lavage fluid to (2.1 +/- 0.5) x 10(6)/ml and (20 +/- 5)% respectively, which were significantly different from (3.2 +/- 0.5) x 10(6)/ml and (29 +/- 5)% in the aminophylline group (P < 0.05, respectively) or (4.2 +/- 0.7) x 10(6)/ml and (35 +/- 4)% in the challenge group (P < 0.05, respectively). CONCLUSION: Phosphodiesterase 4 inhibitor may be more useful than aminophylline for cough associated with eosinophilic airway inflammation via inhibiting airway inflammation and airway hyperresponsiveness.