Omics analyses of Rehmannia glutinosa dedifferentiated and cambial meristematic cells reveal mechanisms of catalpol and indole alkaloid biosynthesis.

BACKGROUND: Rehmannia glutinosa is a rich source of terpenoids with a high medicinal reputation. The present study compared dedifferentiated cells (DDCs) and cambial meristematic cells (CMCs) cell cultures of R. glutinosa for terpenoid (catalpol) and indole alkaloid (IA) biosynthesis. In this regard, we used widely targeted metabolomics and transcriptome sequencing approaches together with the comparison of cell morphology, cell death (%), and catalpol production at different time points. RESULTS: We were able to identify CMCs based on their morphology and hypersensitivity to zeocin. CMCs showed higher dry weight content and better catalpol production compared to DDCs. The metabolome analysis revealed higher concentrations of IA, terpenoids, and catalpol in CMCs compared to DDCs. The transcriptome sequencing analysis showed that a total of 27,201 genes enriched in 139 pathways were differentially expressed. The higher catalpol concentration in CMCs is related to the expression changes in genes involved in acetyl-CoA and geranyl-PP biosynthesis, which are precursors for monoterpenoid biosynthesis. Moreover, the expressions of the four primary genes involved in monoterpenoid biosynthesis (NMD, CYP76A26, UGT6, and CYP76F14), along with a squalene monooxygenase, exhibit a strong association with the distinct catalpol biosynthesis. Contrarily, expression changes in AADC, STR, and RBG genes were consistent with the IA biosynthesis. Finally, we discussed the phytohormone signaling and transcription factors in relation to observed changes in metabolome. CONCLUSIONS: Overall, our study provides novel data for improving the catalpol and IA biosynthesis in R. glutinosa.

The impact of multi-level interventions on the second-wave SARS-CoV-2 transmission in China.

BACKGROUND: A re-emergence of COVID-19 occurred in the northeast of China in early 2021. Different levels of non-pharmaceutical interventions, from mass testing to city-level lockdown, were implemented to contain the transmission of SARS-CoV-2. Our study is aimed to evaluate the impact of multi-level control measures on the second-wave SARS-CoV-2 transmission in the most affected cities in China. METHODS: Five cities with over 100 reported COVID-19 cases within one month from Dec 2020 to Feb 2021 were included in our analysis. We fitted the exponential growth model to estimate basic reproduction number (R0), and used a Bayesian approach to assess the dynamics of the time-varying reproduction number (Rt). We fitted linear regression lines on Rt estimates for comparing the decline rates of Rt across cities, and the slopes were tested by analysis of covariance. The effect of non-pharmaceutical interventions (NPIs) was quantified by relative Rt reduction and statistically compared by analysis of variance. RESULTS: A total of 2,609 COVID-19 cases were analyzed in this study. We estimated that R0 all exceeded 1, with the highest value of 3.63 (1.36, 8.53) in Haerbin and the lowest value of 2.45 (1.44, 3.98) in Shijiazhuang. Downward trends of Rt were found in all cities, and the starting time of Rt < 1 was around the 12th day of the first local COVID-19 cases. Statistical tests on regression slopes of Rt and effect of NPIs both showed no significant difference across five cities (P = 0.126 and 0.157). CONCLUSION: Timely implemented NPIs could control the transmission of SARS-CoV-2 with low-intensity measures for places where population immunity has not been established.

Heterogeneity in Estimates of Incidence and Prevalence of Narcolepsy: A Systematic Review and Meta-Regression Analysis.

INTRODUCTION: Narcolepsy is a chronic neurological disorder. The diagnostic criteria of narcolepsy evolve from clinical symptoms to molecular biomarkers, along with the understanding of its clinical nature and pathogenesis. Estimates of incidence and prevalence of narcolepsy vary between studies, while the contribution of changing diagnostic criteria to the variation remains unclear. We aimed to explore sources of heterogeneity in estimates of incidence and prevalence, with a particular focus on diagnostic criteria. METHODS: We searched 5 databases for observational studies on the incidence or prevalence of narcolepsy published before October 14, 2021. Subgroup analyses and meta-regression were used to assess the impact of diagnostic criteria on incidence/prevalence of narcolepsy after adjusting for age-group, region, study period, vaccination status, index date, and type of narcolepsy. RESULTS: Thirty-five studies were selected from 2,833 articles. The estimates of incidence and prevalence were wide-ranging with high heterogeneity (incidence I2 = 99.8%; prevalence I2 = 99.7%), from 0.06 to 6.56 per 100,000 person-years for incidence and from 1.05 to 79.40 per 100,000 population for prevalence, respectively. Totally 10 diagnostic criteria were used, including the 1st revised edition of International Classification of Diseases (ICSD-1), ICSD-2, ICSD-3, the 8th revision of International Classification of Diseases (ICD-8), ICD-9, ICD-10, Brighton collaboration case definition (Brighton), Mayo classification, the Ullanlinna Narcolepsy Scale, and clinical symptoms with the multiple sleep latency test. ICD tended to provide higher estimates of incidence/prevalence than Brighton (incidence odds ratio [OR] 1.38, [95% CI: 1.02, 1.86]; prevalence OR 1.50, [95% CI: 1.04, 2.39]). No significant difference was found in estimates of two rates between ICSD and Brighton. The incidence was higher for children than adults (OR 1.61, [95% CI: 1.25, 2.07]) and for individuals vaccinated with Pandemrix than those unvaccinated (OR 6.49, [95% CI: 3.86, 10.91]). CONCLUSIONS: Estimates of incidence/prevalence of narcolepsy could not be pooled reliably with substantial heterogeneity. Incidence/prevalence studies using ICSD and Brighton provided lower estimates than studies using ICD and other criteria. Diagnostic criteria should be standardized when comparing or pooling the incidence/prevalence to understand the epidemiology of narcolepsy. Future studies are needed to focus on the at-risk population for the etiology investigation of narcolepsy.

Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta.

Receptor interacting protein kinase 4 (RIPK4) has been reported to function as an oncogenic role in several types of cancers. The aim of this study was to evaluate the role of RIPK4 in ovarian cancer (OC) cells and to elucidate the mechanism behind this effect. In this study, the GEPIA database was used to analyze the RIPK4 expressions in OC tissues and overall survival. qRT-PCR and western blot assay were performed to detect the expressions of RIPK4 and protein kinase C delta (PRKCD) in OC cells. In addition, cell proliferation was assessed by CCK-8 and colony formation assay while cell invasion and migration were evaluated by transwell, wound healing and western blot assay. The interaction of RIPK4 and PRKCD was analyzed by the STRING database and the bioGRID database, and verified with co-immunoprecipitation. Herein, we describe that RIPK4 expression was upregulated in OC tissues and cells and was associated with poor overall survival. RIPK4 silencing repressed the proliferation, migration, and invasion of OC cells. Mechanistically, PRKCD was highly expressed in OC cells and was combined with RIPK4. PRKCD was highly positively associated with RIPK4 in OC and was regulated by RIPK4. Moreover, PRKCD overexpression reversed the inhibitory effects of RIPK4 silencing on OC cell proliferation, migration, and invasion. RIPK4 functions as an oncogene in OC cells via at least partially binding to PRKCD, which might represent a novel therapeutic strategy for improving survival for patients with OC.

Influenza-associated disease burden in mainland China: a systematic review and meta-analysis.

Influenza causes substantial morbidity and mortality. Many original studies have been carried out to estimate disease burden of influenza in mainland China, while the full disease burden has not yet been systematically reviewed. We did a systematic review and meta-analysis to assess the burden of influenza-associated mortality, hospitalization, and outpatient visit in mainland China. We searched 3 English and 4 Chinese databases with studies published from 2005 to 2019. Studies reporting population-based rates of mortality, hospitalization, or outpatient visit attributed to seasonal influenza were included in the analysis. Fixed-effects or random-effects model was used to calculate pooled estimates of influenza-associated mortality depending on the degree of heterogeneity. Meta-regression was applied to explore the sources of heterogeneity. Publication bias was assessed by funnel plots and Egger's test. We identified 30 studies eligible for inclusion with 17, 8, 5 studies reporting mortality, hospitalization, and outpatient visit associated with influenza, respectively. The pooled influenza-associated all-cause mortality rates were 14.33 and 122.79 per 100,000 persons for all ages and ≥ 65 years age groups, respectively. Studies were highly heterogeneous in aspects of age group, cause of death, statistical model, geographic location, and study period, and these factors could explain 60.14% of the heterogeneity in influenza-associated mortality. No significant publication bias existed in estimates of influenza-associated all-cause mortality. Children aged < 5 years were observed with the highest rates of influenza-associated hospitalizations and ILI outpatient visits. People aged ≥ 65 years and < 5 years contribute mostly to mortality and morbidity burden due to influenza, which calls for targeted vaccination policy for older adults and younger children in mainland China.

Case Fatality Risk of the First Pandemic Wave of Coronavirus Disease 2019 (COVID-19) in China.

BACKGROUND: To assess the case fatality risk (CFR) of COVID-19 in mainland China, stratified by region and clinical category, and estimate key time-to-event intervals. METHODS: We collected individual information and aggregated data on COVID-19 cases from publicly available official sources from 29 December 2019 to 17 April 2020. We accounted for right-censoring to estimate the CFR and explored the risk factors for mortality. We fitted Weibull, gamma, and log-normal distributions to time-to-event data using maximum-likelihood estimation. RESULTS: We analyzed 82 719 laboratory-confirmed cases reported in mainland China, including 4632 deaths and 77 029 discharges. The estimated CFR was 5.65% (95% confidence interval [CI], 5.50-5.81%) nationally, with the highest estimate in Wuhan (7.71%) and lowest in provinces outside Hubei (0.86%). The fatality risk among critical patients was 3.6 times that of all patients and 0.8-10.3-fold higher than that of mild-to-severe patients. Older age (odds ratio [OR], 1.14 per year; 95% CI, 1.11-1.16) and being male (OR, 1.83; 95% CI, 1.10-3.04) were risk factors for mortality. The times from symptom onset to first healthcare consultation, to laboratory confirmation, and to hospitalization were consistently longer for deceased patients than for those who recovered. CONCLUSIONS: Our CFR estimates based on laboratory-confirmed cases ascertained in mainland China suggest that COVID-19 is more severe than the 2009 H1N1 influenza pandemic in hospitalized patients, particularly in Wuhan. Our study provides a comprehensive picture of the severity of the first wave of the pandemic in China. Our estimates can help inform models and the global response to COVID-19.

Case fatality risk of novel coronavirus diseases 2019 in China.

OBJECTIVE: The outbreak of novel coronavirus disease 2019 (COVID-19) imposed a substanal health burden in mainland China and remains a global epidemic threat. Our objectives are to assess the case fatality risk (CFR) among CO VID-19 patients detected in mainland China, stratified by clinical category and age group. METHODS: We collected individual information on laboratory-confirmed COVID-19 cases from publicly available official sources from December 29, 2019 to February 23, 2020. We explored the risk factors associated with mortality. We used methods accounting for right-censoring and survival analyses to estimatethe CFR among detected cases. RESULTS: Of 12,863 cases reported outside Hubei, we obtained individual records for 9,651 cases, including 62 deaths and 1,449 discharged cases. The deceased were significantly older than discharged cases (median age: 77 vs 39 years, p<0.001). 58% (36/62) were male. Older age (OR 1.18 per year; 95% CI: 1.14 to 1.22), being male (OR 2.02; 95% CI: 1.02 to 4.03), and being treated in less developed economic regions (e.g., West and Northeast vs. East, OR 3.93; 95 %Cl:1.74 to 8.85) were mortality risk factors. The estimated CFR was 0.89-1.24% among all cases. The fatality risk among critical patients was 2-fold higher than that among severe and critical patients, and 24-fold higher than that among moderate, severe and critical patients. CONCLUSIONS: Our estimates of CFR based on laboratory-confirmed cases ascertained outside of Hubei suggest that COVID-19 is not as severe as severe acute respiratory syndrome and Middle East respiratory syndrome, but more similar to the mortality risk of 2009 H1N1 influenza pandemic in hospitalized patients. The fatality risk of COVID-19 is higher in males and increases with age. Our study improves the severity assessment of the ongoing epidemic and can inform the COVID-19 outbreak response in China and beyond.

Influenza-attributable years of life lost in older adults in a subtropical city in China, 2012-2017: A modeling study based on a competing risks approach.

OBJECTIVE: The aim of this study was to estimate influenza-attributable years of life lost (YLL) in older adults in subtropical Hefei, China during the years 2012-2017, based on a competing risks approach. METHODS: The quasi-Poisson model was fitted to weekly numbers of all-cause deaths by 5-year age groups for older adults ≥60 years of age. The product of the weekly influenza-like illness consultation rate and the proportion of specimens that tested positive for influenza was taken as the measurement of influenza activity, which was incorporated into the model as an exploratory variable. Excess deaths associated with influenza were calculated by subtracting baseline deaths (setting influenza activity to zero) from fitted deaths. Influenza-attributable YLL accounting for competing risks was estimated using restricted mean lifetime survival analysis. RESULTS: The annual influenza-attributable YLL was highest in the 75-79 years age group (565 per 100,000 persons, 95% confidence interval 550-580), followed by the 80-84, 70-74, 85-89, 65-69, and 60-64 years age groups. Influenza A(H3N2) virus was associated with higher YLL than A(H1N1) and B viruses. Influenza-attributable YLL accounted for 1.03-1.53% of total YLL, and the proportion would be overestimated to 2.91-7.34% if the traditional Kaplan-Meier method ignoring competing risks was used. CONCLUSIONS: Although influenza-associated mortality increased with age, influenza-attributable YLL was found to be highest in the 75-79 years age group.

Postoperative adverse respiratory events in preschool patients with inhaled foreign bodies: an analysis of 505 cases.

OBJECTIVES: To identify the risk factors associated with postoperative adverse respiratory events in preschool-aged children with inhaled foreign bodies (FBs) undergoing rigid bronchoscopy. BACKGROUND: Foreign bodies aspiration is the most common cause of admission in pediatric emergency in otolaryngology service. Performance of rigid bronchoscopy is the standard treatment for removal of FBs in children. In some cases, severe respiratory events (complete laryngospasm and pneumothorax) may cause anesthesia-related morbidity and mortality. However, the association between patient-related factors and postoperative complications in preschool-aged children with inhaled FBs undergoing rigid bronchoscopy is unclear. METHODS: We carried out a large prospective, single-institution review of anesthesia for 505 American Society of Anesthesiologists I-III preschool children aged ≤7 with inhaled FBs undergoing rigid bronchoscopy. Patients with postoperative adverse respiratory events were classified into two groups: the minor events group [hemorrhage, minor desaturation, and partial laryngospasm (wheezing, stridor, and dyspnea)) and the major events group (complete laryngospasm, including major desaturation, and pneumothorax). RESULTS: The incidence of postoperative adverse respiratory events was 9.5% in preschool-aged children with inhaled FBs undergoing rigid bronchoscopy. Preoperative respiratory impairment was associated with an increased risk for the complicate (P < 0.01). Pneumothorax occurred in 4 (0.8%) patients. There was 1 (0.2%) death from severe respiratory-related complications. CONCLUSIONS: Preoperative respiratory impairment may develop the patients with FBs into postoperative adverse respiratory events.