Repurposed Tocilizumab in Patients with Severe COVID-19.

The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25-0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11-0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19-induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available.

Obstructive Sleep Apnea is Associated with an Increased Prevalence of Polycythemia in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are associated with polycythemia. However, there still remain unanswered questions about the relationship between overlap syndrome (OVS), where OSA and COPD coexist, and polycythemia. Here, we aimed to establish the prevalence of polycythemia in OVS patients and to explore the impact of OSA on polycythemia. PATIENTS AND METHODS: Patients with COPD underwent overnight polysomnography (PSG), pulmonary function tests, echocardiography, and complete blood counts. All patients were ethnic Han Chinese and free of prolonged oral corticosteroid use, hematological system disease, severe systemic disease, and other sleep-disordered breathing. OVS was defined as COPD patients with an apnea-hypopnea index ≥15 events/h, and polycythemia was defined as an Hb >165 g/L in men and >160 g/L in women. RESULTS: Eight-hundred and eighty-six patients with COPD were included in the analysis. The prevalence of polycythemia was significantly higher in OVS patients than COPD-alone patients (6.4% vs 2.9%, p < 0.05). The prevalence of polycythemia increased with OSA severity (χ 2 = 7.885, p = 0.007), but not in GOLD grade 3-4 COPD patients (χ 2 = 0.190, p = 0.663). After adjusting for confounders, percentage of total sleep time with SaO2 <90% (TS90) remained independently associated with an increased odds of polycythemia (OR 1.030, 95% CI 1.015-1.046) and, with an increase in TS90, the hemoglobin increased, especially in GOLD grade 1-2 patients (p < 0.05). CONCLUSION: Patients with OVS have a higher prevalence of polycythemia than those with COPD alone, and TS90 is an independent factor for polycythemia, especially in GOLD1-2 COPD patients.

Associations between daytime and nighttime plasma orexin A levels and cognitive function in patients with obstructive sleep apnea.

The relationship between plasma orexin A (OXA) levels and cognitive function in patients with obstructive sleep apnea (OSA) remains unclear. This study aimed to evaluate associations between daytime and nighttime plasma OXA levels and cognitive function in patients with OSA. Subjects with suspected OSA underwent overnight polysomnography (PSG), Montreal Cognitive Assessment (MoCA), and Epworth Sleepiness Scale (ESS) assessment. Subjects were considered controls or having OSA according to the apnea-hypopnea index (AHI). Daytime and nighttime plasma OXA levels were determined by ELISA. Receiver-operating characteristics curves were used to evaluate the diagnostic value of plasma OXA levels for assessing cognitive impairment in OSA patients. One hundred and six subjects met the inclusion criteria. MoCA scores and plasma OXA concentrations were significantly lower in OSA patients than controls (p < 0.01). Patients with moderate and severe OSA had significantly lower MoCA scores than controls and mild OSA patients (p < 0.01). Daytime and nighttime OXA levels were significantly lower in OSA patients with cognitive impairment than those without cognitive impairment (p < 0.01). Both daytime and nighttime plasma OXA levels in patients with OSA were positively correlated with MoCA scores and nadir SaO2, negatively correlated with AHI, oxygen desaturation index, and percentage of time spent with an SaO2 below 90% (all p < 0.05), and not correlated with ESS scores. The optimal threshold of daytime plasma OXA to diagnose OSA with cognitive impairment was 49.34 pg/ml, with a sensitivity of 80.0% and a specificity of 74.3%. We concluded that plasma OXA concentrations might be related to cognitive function and daytime plasma OXA levels have diagnostic value for assessing cognitive impairment in OSA patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00387-4.

Orexin A improves the cognitive impairment induced by chronic intermittent hypoxia in mice.

The orexin neuron in lateral hypothalamus (LH) was involved in the regulation of sleep-wake cycle. However, the effect of orexin A (OXA) on cognitive impairment resulting from diverse diseases remains controversial. In this study, we investigated the effect of OXA on cognitive impairment induced by chronic intermittent hypoxia (CIH) in mice. Adult (10 weeks old) male C57BL/6 mice were randomly divided into the following four groups: normoxia control (NC)+normal saline (NS), NC + OXA, CIH + NS and CIH + OXA group. Following the CIH mice models establishment, OXA was injected into the right lateral ventricles of mice by a micro-injection system. Water maze test was used to assess spatial memory abilities of the mice. The expression of OXA and c-Fos in LH were analyzed by immunofluorescence staining. Apoptotic cell death and oxidative stress in hippocampus were evaluated using multiple methods including TUNEL, western blot and biochemical analysis. Behavioral tests revealed that CIH significantly increased the escape latency and time of arriving platform, of which were markedly decreased by OXA treatment. Similarly, the CIH + NS group was worse than NC + NS group in terms of the number of platform crossing and time in the target quadrant, of which were also significantly improved by OXA treatment. The number of OXA + neuron in LH was decreased, but the percentage of c-Fos+/OXA + neuron in LH was remarkably increased by CIH. Furthermore, we found that micro-injection of OXA attenuated CIH-induced apoptotic cell death and oxidative stress in the hippocampus. Our results suggested that OXA might improve cognitive impairment induced by CIH through inhibiting hippocampal apoptosis and oxidative stress.

Orexin-A inhibits cerebral ischaemic inflammatory injury mediated by the nuclear factor-κB signalling pathway and alleviates stroke-induced immunodepression in mice.

Cerebral ischaemia is accompanied by infectious complications due to immunosuppression, known as stroke-induced immunodepression (SIID). Orexin-A (OXA), a neuropeptide produced in the hypothalamus, has been reported to have neuroprotective properties after stroke and is known to modulate inflammatory processes in peripheral tissues. The aim of this study was to determine the effects of orexin-A (OXA) on cerebral ischaemic inflammatory injury and SIID following experimental stroke. Cerebral ischaemia was induced in C57/BL6 mice by middle cerebral artery occlusion (MCAO). A mouse model of pneumonia and poststroke pneumococcal pneumonia was established by intratracheal inoculation with S. pneumoniae in a normal mouse or MCAO mouse model on the third day. We found that OXA postconditioning inhibited cerebral ischaemic inflammatory injury. The mechanism involved downregulation of the NF-κB signalling pathway. In addition, OXA may serve as a potential treatment target for attenuating stroke-induced immunodepression in mice.

Cigarette smoking induces aberrant N6-methyladenosine of DAPK2 to promote non-small cell lung cancer progression by activating NF-κB pathway.

N6-methyladenosine (m6A) has recently emerged as an important regulatory mechanism for gene expression and aberrant m6A modification plays an important role in tumor progression. Emerging evidence has shown that aberrant m6A modification induced by cigarette smoking is involved in carcinogenesis, but whether cigarette smoking affects m6A modification and thus deteriorates to non-small cell lung cancer (NSCLC) is still unclear. Here, we identified a tumor suppressor gene-DAPK2 which was significantly associated with poor prognosis of NSCLC patients, especially in patients with a smoking history. Low levels of DAPK2 were detected in smokers and in NSCLC tissues. Cigarette smoking induced aberrant N6-methyladenosine modification of DAPK2, which resulted in decreased DAPK2 mRNA stability and expression of its mRNA and protein. This modification was mediated by the m6A "writer" METTL3 and the m6A "reader" YTHDF2. Mechanistically, we further demonstrated that DAPK2 functions as a tumor suppressor and downregulation of DAPK2 substantially enhances the proliferation and migration abilities in vitro and in vivo by activating NF-κB signaling pathway. Notably, the BAY 11-7085, a NF-κB signaling selective inhibitor, was shown to efficiently suppressed downregulation of DAPK2-induced oncogenic phenotypes of NSCLC cells. Our study reveals that cigarette smoking induces aberrant N6-methyladenosine of DAPK2 to promote NSCLC progression, which provides new insight into the mechanisms of NSCLC progression and a specific therapeutic target for NSCLC patients with a smoking history.

Effects of the excitation or inhibition of basal forebrain cholinergic neurons on cognitive ability in mice exposed to chronic intermittent hypoxia.

Cognitive impairment of obstructive sleep apnea syndrome (OSAS) patients is related to the basal forebrain (BF) cholinergic neurons. To further investigate the effect of the excitation or inhibition of BF cholinergic neurons on cognitive ability, we employed a chronic intermittent hypoxia (CIH) mice model and implanted microinjection cannulas in the BFs for targeted intervention, finally performed the behavioral experiments and examined immunohistochemistry and biochemical changes in the BFs. The results showed that (1) CIH induced cognitive decline in mice. (2) The excitation of BF cholinergic neurons attenuated cognitive decline, while the inhibition of these neurons aggravated cognitive impairment. (3) Microinjection of adenosine into the BF aggravated cognitive decline, while caffeine improved cognitive ability. (4) CIH induced BF cholinergic neuron injury in mice. (5) The excitation of BF cholinergic neurons alleviated cholinergic neuron injury, while the inhibition of these neurons aggravated this injury. (6) Microinjection of adenosine into the BF aggravated cholinergic neuron injury, while caffeine alleviated this injury. (7) CIH induced endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BFs of mice. (8) The excitation of BF cholinergic neurons mitigated endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BF in mice, while the inhibition of BF cholinergic neurons worsened these responses in the BF. (9) Microinjection of adenosine into the BF aggravated endoplasmic reticulum stress, oxidative stress and the inflammatory response, while caffeine alleviated these responses. This work indicates that CIH induces BF cholinergic neuron injury through multiple pathways, including endoplasmic reticulum stress, oxidative stress and the inflammatory response, thereby leading to cognitive dysfunction in mice. BF cholinergic neurons play a vital role in these pathways, thus reducing cholinergic neuron injury and restoring cognitive function in mice. Adenosine, which is an upstream modifier of acetylcholine, also plays an important role in altering cognitive ability.

Effect of Body Mass Index on Lung Function in Chinese Patients with Chronic Obstructive Pulmonary Disease: A Multicenter Cross-Sectional Study.

Objective: The aim of this study was to explain "obesity paradox" in chronic obstructive pulmonary disease (COPD) by evaluating the effect of body mass index (BMI) on lung function in Chinese patients with COPD. Methods: A total of 1644 patients diagnosed with COPD were recruited from four Chinese tertiary hospitals and were divided into four groups including underweight, normal weight, overweight and obese according to BMI classification standard. The medical data of these patients were collected and used for the multiple linear regression analyses. Results: After adjustment for age, sex, educational level, economic status, smoking status, alcohol consumption, duration of COPD history, events of acute exacerbation in previous year, hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular disease and osteoporosis, BMI had a curvilinear correlation with the forced expiratory volume in the first second (FEV1) in patients with Global Initiative for Obstructive Lung Disease (GOLD) 1-2 grade (first-order coefficient ß, 0.09; 95% CI, 0.03-0.16; second-order coefficient ß, -0.002; 95% CI, -0.003--0.001; P<0.01). However, BMI had a positive correlation with FEV1 in patients with GOLD 3-4 grade (ß, 0.01; 95% CI, 0.008-0.017; P<0.01) when BMI was used as a quantitative variable. When BMI was used as a qualitative variable, only FEV1 in overweight group with GOLD 1-2 grade was significantly higher than that of normal weight group (P<0.01). Interestingly, both overweight and obese groups had higher FEV1 in GOLD 3-4 grade compared with normal weight group (ß, 0.06; 95% CI, 0.02-0.11; ß, 0.11; 95% CI, 0.04-0.18; P<0.01). The effect of BMI on predicted percentage of FEV1 (FEV1%) was similar to that of FEV1 in different GOLD grades. Conclusion: Obesity only had a protective effect on lung function in COPD patients with GOLD 3-4 grade rather than GOLD 1-2 grade. Trial Registry: ClinicalTrials.gov, No.: NCT03182309, URL: www.clinicaltrials.gov.