Development and Validation of a Nomogram for Assessing Survival in Patients With COVID-19 Pneumonia.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has spread worldwide and continues to threaten peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help in the clinical management of COVID-19, but a prediction model that is reliable and valid is still lacking. METHODS: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital, Wuhan, China. These patients were randomly grouped into a training (60%) and a validation (40%) cohort. In the training cohort, LASSO regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the 3 variables was built for clinical use. AUCs, concordance indexes (C-index), and calibration curves were used to evaluate the efficiency of the nomogram in both training and validation cohorts. RESULTS: Hypertension, higher neutrophil-to-lymphocyte ratio, and increased NT-proBNP values were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The 3 predictors were further used to build a prediction nomogram. The C-indexes of the nomogram in the training and validation cohorts were 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14-day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort this was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- and 21-day survival also showed high coherence between the predicted and actual probability of survival. CONCLUSIONS: We built a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model has good performance and might be utilized clinically in management of COVID-19.

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain.

Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg-1· d-1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg-1· d-1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.

Pharmacological inhibition of the NLRP3 inflammasome as a potential target for cancer-induced bone pain.

Cancer-induced bone pain (CIBP) remains a major challenge in patients suffering from bone metastases because of the complex mechanisms and unsatisfactory treatments. Emerging evidence have shown that activation of inflammasomes contribute to the development of inflammatory and neuropathic pain. However, the role of spinal inflammasomes in CIBP remains unclear. In the present study, we explored the specific cellular mechanisms of NLRP3 inflammasome in the process of CIBP in rats. MCC950 is a small molecule inhibitor of the NLRP3 inflammasome that exhibits remarkable activity in inflammatory diseases. Our behavioral results confirmed that both single and persistent treatment with MCC950 markedly attenuated CIBP-related mechanical allodynia. The expression of NLRP3 inflammasome, including NLRP3, ASC, Caspase-1, were significantly increased in a time-dependent manner. Furthermore, spinal IL-1ß, cleaved by cysteine-aspartic acid protease, was upregulated in this study. Chronic administration with MCC950 restored the protein expression of NLRP3 inflammasome and significantly suppressed the upregulation of IL-1ß. Spinal NLRP3 inflammasome might be a novel therapeutic target for treatment of CIBP.

Berberine protects against ischemia-reperfusion injury: A review of evidence from animal models and clinical studies.

Ischemia-reperfusion (I/R) injury is accompanied with high morbidity and mortality and has seriously negative social and economic influences. Unfortunately, few effective therapeutic strategies are available to improve its outcome. Berberine is a natural medicine possessing multiple beneficial biological activities. Emerging evidence indicates that berberine has potential protective effects against I/R injury in brain, heart, kidney, liver, intestine and testis. However, up-to-date review focusing on the beneficial role of berberine against I/R injury is not yet available. In this paper, results from animal models and clinical studies are concisely presented and its mechanisms are discussed. We found that berberine ameliorates I/R injury in animal models via its anti-oxidant, anti-apoptotic and anti-inflammatory effects. Moreover, berberine also attenuates I/R injury by suppressing endoplasmic reticulum stress and promoting autophagy. Additionally, regulation of periphery immune system may also contributes to the beneficial effect of berberine against I/R injury. Although clinical evidence is limited, the current studies indicate that berberine may attenuate I/R injury via inhibiting excessive inflammatory response in patients. Collectively, berberine might be used as an alternative therapeutic strategy for the management of I/R injury.

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models.

Cancer-induced bone pain is one of the most severe types of pathological pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced bone pain due to the opioids' side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory pain, but has never been proven to treat cancer-induced bone pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced bone pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced bone pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated-Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced bone pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced bone pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades.

Minocycline as a promising therapeutic strategy for chronic pain.

Chronic pain remains to be a clinical challenge due to insufficient therapeutic strategies. Minocycline is a member of the tetracycline class of antibiotics, which has been used in clinic for decades. It is frequently reported that minocycline may has many non-antibiotic properties, among which is its anti-nociceptive effect. The results from our lab and others suggest that minocycline exerts strong analgesic effect in animal models of chronic pain including visceral pain, chemotherapy-induced periphery neuropathy, periphery injury induced neuropathic pain, diabetic neuropathic pain, spinal cord injury, inflammatory pain and bone cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of minocycline in preclinical studies. Due to a good safety record when used chronically, minocycline may become a promising therapeutic strategy for chronic pain in clinic.

Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain.

Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future.

Interleukin-6: an emerging regulator of pathological pain.

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund's adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

[Spinal gastrin-releasing peptide system mediates sexual function of males: advances in studies].

A collection of neurons in the upper lumbar spinal cord (lumbar segments 3 and 4) of male rats project to the lower lumbar spinal cord (lumbar segments 5 and 6) and release a gastrin-releasing peptide (GRP) to the somatic and autonomic regions, which are known to regulate male sexual reflexes. The GRP plays some special functions when bound to the specific GRP receptor (GRPR). The spinal GRP system is regulated by androgens. Accumulating evidence shows that GRP plays an important role in rat penile erection and ejaculation, and pharmacological stimulation of GRPRs with a specific agonist can restore penile reflexes and ejaculation in castrated male rats. Therefore, the GRP system appears to be a potential therapeutic target for the treatment of erectile dysfunction or ejaculatory dysfunction. The present paper briefly reviews the recent studies on the role of the spinal GRP system in regulating the sexual function of males.

Global Burden of Lung Cancer Attributable to Household Fine Particulate Matter Pollution in 204 Countries and Territories, 1990 to 2019.

INTRODUCTION: Household particulate matter (PM) air pollution is substantially associated with lung cancer. Nevertheless, the global burden of lung cancer attributable to household PM2.5 is still uncertain. METHODS: In this study, data from the Global Burden and Disease Study 2019 are used to thoroughly assess the burden of lung cancer associated with household PM2.5. RESULTS: The number of deaths and disability-adjusted life-years (DALYs) attributable to household PM2.5 was found to be 0.08 million and 1.94 million, respectively in 2019. Nevertheless, the burden of lung cancer attributable to household PM2.5 decreased from 1990 to 2019. At the sociodemographic index (SDI) district level, the middle SDI region had the most number of lung cancer deaths and DALYs attributable to household PM2.5. Moreover, the burden of lung cancer was mainly distributed in low-SDI regions, such as Sub-Saharan Africa. Conversely, in high-SDI regions, the age-standardized mortality rate and age-standardized DALY rate of lung cancer attributable to household PM2.5 exhibit the most rapid declines. The burden of lung cancer attributable to household PM2.5 is heavier for men than for women. The sex difference is more obvious in the elderly. CONCLUSIONS: The prevalence of lung cancer attributable to household PM2.5 has exhibited a declining trend from 1990 to 2019 owing to a concurrent decline in household PM2.5 exposure.

Cancer burden attributable to risk factors, 1990-2019: A comparative risk assessment.

An up-to-date comprehensive assessment of the cancer burden attributable to risk factors is essential for cancer prevention. We analyzed the population attributable fraction (PAF) of cancer disability-adjusted life years (DALYs) attributable to 11 level 2 risk factors using data from the Global Burden and Disease Study (GBD) 2019. We highlighted that almost half of the cancer DALYs can be preventable by modifying relevant risk factors. The attributable cancer DALYs increased by 60.42%-105.0 million from 1990 to 2019. Tobacco, dietary risks, alcohol use, high body-mass index, and air pollution were the top five risk factors. The PAFs attributable to high fasting plasma glucose, high body-mass index, and low physical activity have increased worldwide from 1990 to 2019. Unsafe sex was the leading risk factor for women before age of 54. Tailored prevention programs targeted at specific populations should be scaled up to reduce the cancer burden in the future.

Effect of PM2.5 air pollution on the global burden of lower respiratory infections, 1990-2019: A systematic analysis from the Global Burden of Disease Study 2019.

Particulate matter (PM) air pollution is closely related to lower respiratory infections (LRIs). However, the global LRI burden attributable to PM remains unclear. Here, we provide a comprehensive assessment of the PM2.5-attributable LRI burden using data from the Global Burden and Disease Study (GBD) 2019. We found that PM2.5 air pollution contributed to approximately 0.7 million deaths and 37.6 million disability-adjusted life years (DALYs) of LRIs in 2019. The LRI burden attributable to PM2.5 has decreased from 1990 to 2019, with a more pronounced decrease in household PM2.5 than in ambient PM2.5. Unlike the decreasing trend in LRI burden due to household PM2.5 worldwide, nearly one fifth of countries experienced an increase of LRI burden due to ambient PM2.5. The burden was unevenly distributed to less developed countries, mainly in Sub-Saharan Africa. All age groups experienced a decrease in the PM2.5-attributable burden, with the most significant decrease in children younger than 10 years. Notably, individuals aged 20-84 years experienced an increase in the LRI burden attributable to ambient PM2.5. Males had higher burden than females in the elder age and higher SDI regions. This study provided an evidence-based guidance for the prevention of LRIs and control of PM2.5 air pollution.

Targeting the Main Sources of Reactive Oxygen Species Production: Possible Therapeutic Implications in Chronic Pain.

Humans have long been combating chronic pain. In clinical practice, opioids are first- choice analgesics, but long-term use of these drugs can lead to serious adverse reactions. Finding new, safe and effective pain relievers that are useful treatments for chronic pain is an urgent medical need. Based on accumulating evidence from numerous studies, excess reactive oxygen species (ROS) contribute to the development and maintenance of chronic pain. Some antioxidants are potentially beneficial analgesics in the clinic, but ROS-dependent pathways are completely inhibited only by scavenging ROS directly targeting cellular or subcellular sites. Unfortunately, current antioxidant treatments donot achieve this effect. Furthermore, some antioxidants interfere with physiological redox signaling pathways and fail to reverse oxidative damage. Therefore, the key upstream processes and mechanisms of ROS production that lead to chronic pain in vivo must be identified to discover potential therapeutic targets related to the pathways that control ROS production in vivo. In this review, we summarize the sites and pathways involved in analgesia based on the three main mechanisms by which ROS are generated in vivo, discuss the preclinical evidence for the therapeutic potential of targeting these pathways in chronic pain, note the shortcomings of current research and highlight possible future research directions to provide new targets and evidence for the development of clinical analgesics.

Trends and risk factors of global incidence, mortality, and disability of genitourinary cancers from 1990 to 2019: Systematic analysis for the Global Burden of Disease Study 2019.

Background: The incidence of kidney, bladder, and prostate cancer ranked ninth, sixth, and third in male cancers respectively, meanwhile, the incidence of testicular cancer also increased gradually in the past 30 years. Objective: To study and present estimates of the incidence, mortality, and disability of kidney, bladder, prostate, and testicular cancer by location and age from 1990 to 2019 and reveal the mortality risk factors of them. Materials: The Global Burden of Diseases Study 2019 was used to obtain data for this research. The prediction of cancer mortality and incidence was based on mortality-to-incidence ratios (MIRs). The MIR data was processed by logistic regression and adjusted by Gaussian process regression. The association between the socio-demographic index and the incidence or disease burden was determined by Spearman's rank order correlation. Results: Globally in 2019, there were 371,700 kidney cancer cases with an age-standardized incidence rate (ASIR) of 4.6 per 100,000, 524,300 bladder cancer cases, with an ASIR of 6.5 per 100,000, 1,410,500 prostate cancer cases with an ASIR of 4.6 per 100,000 and 109,300 testicular cancer incident cases with an ASIR of 1.4 per 100,000, the ASIR of these four cancers increased by 29.1, 4, 22, and 45.5% respectively. The incidence rate of the four cancers and the burden of kidney cancer were positively correlated with the socio-demographic index (SDI), regions with a higher SDI faced more of a burden attributable to these four cancers. High body-mass index has surpassed smoking to be the leading risk factor in the past thirty years for kidney cancer mortality. Smoking remained the leading risk factor for cancer-related mortality for bladder cancer and prostate cancer and the only risk factor for prostate cancer. However, the contribution of high fasting plasma glucose to bladder cancer mortality has been increasing. Conclusion: The incidence of bladder, kidney, prostate, and testicular cancer is ever-increasing. High-income regions face a greater burden attributable to the four cancers. In addition to smoking, metabolic risk factors may need more attention.

Global, Regional, and National Burden of CKD due to Glomerulonephritis from 1990 to 2019: A Systematic Analysis from the Global Burden of Disease Study 2019.

BACKGROUND: CKD is becoming a major human health concern. Limited quantitative assessments of the burden of CKD due to glomerulonephritis have been performed. We performed a comprehensive analysis of the disease burden to update the epidemiology of this disease. METHODS: Incidence, prevalence, deaths, and disability-adjusted life-years (DALYs) data and percent changes in these indicators were extracted from Global Burden of Disease Study 2019 to analyze the burden of CKD due to glomerulonephritis. RESULTS: Globally, there were 606,300 (95% uncertainty interval [UI], 560,100 to 658,100) incident patients, 17,300,000 (95% UI, 16,100,000 to 18,600,000) prevalent patients, 183,700 (95% UI, 146,300 to 228,900) deaths, and 6,900,000 (95% UI, 5,900,000 to 8,100,000) DALYs of CKD due to glomerulonephritis in 2019. Compared with those in 1990, the numbers of incident patients, prevalent patients, deaths, and DALYs increased by 77%, 81%, 100%, and 66%, respectively. Most of the disease burden was concentrated in countries with lower sociodemographic index. In Central Latin America, the disease burden was much higher than expected on the basis of its sociodemographic index. Decomposition analysis showed that population aging and growth were the two major drivers of the increase in DALYs. Frontier analysis revealed considerable opportunities to reduce the age-standardized DALYs in the middle of the sociodemographic-index spectrum. Although middle-aged and elderly individuals accounted for the majority of the disease burden, the highest incidence rate was observed in children aged 1-4 years. CONCLUSIONS: The disease burden of CKD due to glomerulonephritis has increased worldwide, especially in regions and countries with lower sociodemographic indexes.

Health burden of unbalanced fatty acids intake from 1990 to 2019: A global analysis.

BACKGROUND: Unbalanced fatty acids intake is associated with a range of health outcomes; however, the impact on human health remains unclear globally. We aim to provide a comprehensive assessment of the health effect of unbalanced fatty acids intake on a global scale. METHODS: We analyzed the trends of summary exposure value (SEV) and the attributable burden of unbalanced fatty acids intake, including diet low in polyunsaturated fatty acids (low PUFAs), diet low in seafood omega-3 fatty acids (low seafood-(ω-3)-PUFAs), and diet high in trans fatty acids (high TFAs) from 1990 to 2019 using data from Global Burden of Disease Study 2019. FINDINGS: The global fatty acids intake was far from the optimal level. High-income North America had the highest SEV of diet of high TFAs, while less-developed regions located in Saharan Africa had the highest SEVs of low PUFAs and low seafood-(ω-3)-PUFAs. The attributable burden was unequally distributed to less-developed regions. Males had lower SEVs but higher attributable burden than females and this gender gap was particularly pronounced before the age of 59. The young population had a higher SEV of diet of low PUFAs, comparable SEV of low seafood-(ω-3)-PUFAs but lower SEV of high TFAs than the elderly population. CONCLUSIONS: This study underpinned the high prevalence of unbalanced fatty acids intake worldwide and provided evidence-based guidance for identifying at-risk populations and developing effective strategies to improve fatty acids intake in the future. FUNDING: The study was funded by Shanxi Province "136" Revitalization Medical Project Construction Funds and the Fundamental Research Funds for the Central Universities.

Galectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases.

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of ß-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

Clinical Applications of Liquid Biopsy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognosis in the world. The low rate of early diagnosis, as well as the high risk of postoperative metastasis and recurrence, led to the poor clinical prognosis of HCC patients. Currently, it mainly depends on serum markers, imaging examination, and tissue biopsy to diagnose and determine the recurrence and metastasis of HCC after treatments. Nevertheless, the accuracy and sensitivity of serum markers and imaging for early HCC diagnosis are suboptimal. Tissue biopsy, containing limited tissue samples, is insufficient to reveal comprehensive tumor biology information and is inappropriate to monitor dynamic tumor progression due to its invasiveness. Thus, low invasive diagnostic methods and novel biomarkers with high sensitivity and reliability must be found to improve HCC detection and prediction. As a non-invasive, dynamic, and repeatable detection method, "liquid biopsy", has attracted much attention to early diagnosis and monitoring of treatment response, which promotes the progress of precision medicine. This review summarizes the clinical applications of liquid biopsy in HCC, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosome in early diagnosis, prognostic evaluation, disease monitoring, and guiding personalized treatment.

Wnt signaling: A prospective therapeutic target for chronic pain.

Despite the rapid advance over the past decades to design effective therapeutic pharmacological interventions, chronic pain remains to be an unresolved healthcare concern. Long term use of opioids, the first line analgesics, often causes detrimental side effects. Therefore, a profound understanding of the mechanisms underlying the development and maintenance of chronic pain states is urgently needed for the management of chronic pain. Substantial evidence indicates aberrant activation of Wnt signaling pathways in sciatic nerve, dorsal root ganglia and spinal cord dorsal horn in rodent models of chronic pain. Moreover, growing evidence shows that pharmacological blockage of aberrant activation of Wnt signaling pathways attenuates pain behaviors in animal models of chronic pain. Importantly, both intrathecal injection of Wnt agonists and Wnt ligands to naïve rats lead to the development of mechanical allodynia, which was inhibited by Wnt inhibitors. In this review, we summarized and discussed the therapeutic potential of pharmacological inhibitors of Wnt signaling in chronic pain in preclinical studies. These evidence showed that aberrant activation of Wnt signaling pathways contributed to chronic pain via enhancing neuroinflammation, regulating synaptic plasticity and reducing intraepidermal nerve fiber density. However, these findings raise further questions. Overall, despite the future challenges, these pioneering studies suggest that Wnt signaling is a promising therapeutic target for chronic pain.