Safety, immunogenicity, and protective effective of inhaled COVID-19 vaccines: A systematic review and meta-analysis.

This study aimed to examine the safety, immunogenicity and protective effective of inhaled COVID-19 vaccines (ICVs). Literature research was done through EMBASE, Cochrane, PubMed, and Web of Science up to 10 March 2024. Pooled estimates with corresponding 95% confidence intervals (CI) were computed and compared using the random effects and common effects model. Of the 15 studies, 11 analyzed safety, 13 analyzed immunogenicity, and 3 analyzed protective effective. The results showed a favorable safety profile of ICVs for primary vaccination series, however it does not always seem to produce the expected immune response and protective effective. Meta-analysis of ICVs booster vaccinations (BVs) showed that the levels of neutralizing antibody Geometric mean titer (nAb-GMT) with aerosolised Ad5-nCoV (AAd5-nCoV) were all higher than those with inactivated vaccine (INA-nCoV) (standard mean difference (SMD) = 2.32; 95% CI: 1.96-2.69) and intramuscular Ad5-nCoV (IMAd5-nCoV) (SMD = 0.31; 95% CI: 0.14-0.48) against the original strain of SARS-CoV-2. Importantly, we also observed similar results in the omicron variant. In addition, ICV in BVs has high mucosal immunity to IgA antibodies. The risk of adverse events was comparable or lower for AAd5-nCoV compared to INA-nCoV or IMAd5-nCoV. Current evidence shows that the safety profile of ICVs were well. The booster dose of AAd5-nCoV had a high immune response (including mucosal immunity) and provided protection against COVID-19 caused by the SARS-CoV-2 omicron variant. Further studies are needed to investigate the long-term safety of intranasal vaccine booster protection and various types of ICVs.

Pleiotropic Role of Rainbow Trout CXCRs in Response to Disease and Environment: Insights from Transcriptional Signatures and Structure Analysis.

Chemokines are cytokines with chemoattractant capacities that exert their physiological functions through the binding of chemokine receptors. Thus, chemokine and receptor complexes exert important roles in regulating development and homeostasis during routine immune surveillance and inflammation. Compared to mammals, the physiology and structure of chemokine receptors in fish have not been systematically studied. Furthermore, the salmonid-specific whole genome duplication has significantly increased the number of functional paralogs of chemokine receptors. In this context, in the current study, trout exhibited 17 cxcr genes, including 12 newly identified and 5 previously identified receptors. Interestingly, gene expression of brain cxcr1 and cxcr4, kidney cxcr3 and cxcr4, and spleen cxcr3, cxcr4, and cxcr5 subtypes were altered by bacterial infection, whereas brain cxcr1, kidney cxcr1 and cxcr7, and liver cxcr2, cxcr3, and cxcr4 subtypes were changed in response to environmental changes. Based on protein structures predicted by ColabFold, the conserved amino acids in binding pockets between trout CXCR4.1 subtypes and human CXCR4 were also analyzed. Our study is valuable from a comparative point of view, providing new insights into the identification and physiology of salmonid chemokine receptors.

Efficacy of adjuvant-associated COVID-19 vaccines against SARS-CoV-2 variants of concern in randomized controlled trials: A systematic review and meta-analysis.

BACKGROUND: Adjuvants may enhance the efficacy of vaccines. however, the efficacy of adjuvant-associated COVID-19 vaccines (ACVs) remains unclear since the emergence of the COVID-19 pandemic. This study aimed to address this gap by conducting a systematic review and meta-analysis of the efficacy of ACVs against Severe Acute Respiratory Syndrome Coronavirus 2 CoV (SARS-CoV-2) variants of concern (VOC). METHODS: A systematic search was conducted of randomized controlled trials (RCTs) evaluating the vaccine efficacy (VE) of ACVs against VOC (alpha, beta, gamma, delta, or Omicron), up to May 27, 2023. The DerSimonian-Laird random-effects model was used to assess VE with 95% confidence intervals (CI) through meta-analysis. Cochrane Risk of Bias tools were used to assess the risk of bias in RCTs. RESULTS: Eight RCTs with 113,202 participants were included in the analysis, which incorporated 4 ACVs [Matrix-M (NVX-CoV2373), Alum (BBV152), CpG-1018/Alum (SCB-2019), and AS03 (CoVLP]). The pooled efficacy of full vaccination with ACVs against VOC was 88.0% (95% CI: 83.0-91.5). Full vaccination was effective against Alpha, Beta, Delta, and Gamma variants, with VE values of 93.66% (95% CI: 86.5-100.74), 64.70% (95% CI: 41.87-87.54), 75.95% (95% CI: 67.9-83.99), and 91.26% (95% CI: 84.35-98.17), respectively. Currently, there is a lack of RCT evidence regarding the efficacy of ACVs against the Omicron variant. CONCLUSION: In this meta-analysis, it should be that full vaccination with ACVs has high efficacy against Alpha or Gamma variants and moderate efficacy against Beta and Delta variants. Notably, with the exception of the aluminum-adjuvanted vaccine, the other ACVs had moderate to high efficacy against the SARS-CoV-2 variant. This raises concerns about the effectiveness of ACVs booster vaccinations against Omicron.

Immunogenicity and safety of adjuvant-associated COVID-19 vaccines: A systematic review and meta-analysis of randomized controlled trials.

Background: The benefits and risks of adjuvant-associated COVID-19 vaccines (ACVs) are unclear. The study aimed to assess the immunogenicity and safety of ACVs compared with controls (placebo or the same vaccine without adjuvants [NACVs]). Methods: Randomized controlled trials sourced from PubMed, EMBASE, Web of Science, and Cochrane Library were systematically reviewed. Evaluators extracted information independently. The evidence quality was assessed using random-effects models. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results: Of the 33 studies, 27 analyzed immunogenicity (n = 9069, ACVs group; n = 3757, control), and 26 analyzed safety (n = 58669, ACVs groups; n = 30733 control). Compared with controls, full vaccination with ACVs produced significant immune responses (relative risk [RR] of seroneutralization reaction, 12.3; 95 % confidence interval [95 % CI], 6.92-21.89; standardized mean deviation of geometric mean titer 3.96, 95 % CI, 3.35-4.58). Additionally, ACVs produced significant immunoreactivity compared with NACVs only (P < 0.05). Furthermore, full vaccination with ACVs significantly increased the risk of local and systemic adverse reactions (AEs) compared with controls. However, vaccination with ACVs did not significantly increase the risk of systemic and localized AEs compared with vaccination with NACVs only (P > 0.05). It was observed that ACVs had a lower risk of all-cause mortality than controls (RR, 0.51; 95 % CI 0.30-0.87). It was further found that ACVs produced nAb response against all sublines of the Omicron variant, but the antibody titers were lower than those for the SARS-CoV-2 original strain. Conclusions: The findings of this meta-analysis demonstrate that ACVs may have a superior effect and an acceptable safety in preventing COVID-19. Although these results suggest the potential of ACVs, further studies are required.

Immunogenicity and effectiveness of COVID-19 booster vaccination among people living with HIV: a systematic review and meta-analysis.

Background: The effect of booster vaccinations with the coronavirus virus disease (COVID-19) vaccine on people living with HIV (PLWH) remains unknown. In this study, we aimed to investigate the immunogenicity and effectiveness of booster doses of the COVID-19 vaccine in PLWH. Methods: Literature research was done through the PubMed, Embase, Cochrane Review, and Web of Science databases up to 4 July 2023. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. Randomized control trials and observational studies were both considered for inclusion. Results: We included 35 eligible studies covering 30,154 PLWH. The pooled immune response rate (IRR) of PLWH after the COVID-19 booster vaccination was 97.25% (95% confidence interval [CI], 93.81-99.49), and similar to healthy control (HC) (risk ratio [RR] = 0.98, 95% CI, 0.96-1.00). The pooled IRR for PLWH with CD4+ T-cell counts ≤ 200 was 86.27 (95% CI, 65.35-99.07). For Omicron variants, the pooled IRR for PLWH after booster dose was 74.07% (95% CI, 58.83-89.30), and the risk of IRR was reduced by 10% in PLWH compared with HC (RR = 0.90, 95% CI, 0.80-1.00). The T-cell immune response of PLWH was found to be comparable to HC (p ≥ 0.05). Subgroup analyses revealed that mRNA vaccines produced a relatively high IRR in PLWH compared to other vaccines. In addition, the results showed that booster vaccination appeared to further reduce the risk of COVID-19-related infections, hospitalizations, and deaths compared with the primary vaccination. Conclusion: It was shown that booster vaccination with the COVID-19 vaccine provided a high IRR in PLWH and still produced a desirable moderate IRR in PLWH with a CD4+ T-cell count of ≤ 200. Importantly, the humoral and T-cell responses to booster vaccination in PLWH were comparable to HC, and similar results were observed with the SARS-CoV-2 Omicron variant. Our review strongly emphasizes the effect of mRNA vaccine booster vaccination in PLWH on eliciting desirable protective IRR. Furthermore, booster vaccination appears to further reduce the risk of COVID-19 infection, hospitalization, and death in PLWH compared to primary vaccination. However, more evidence is needed to confirm its effectiveness.

Identification, characterization, and transcription of serotonin receptors in rainbow trout (Oncorhynchus mykiss) in response to bacterial infection and salinity changes.

Serotonergic system is involved in the regulation of physiological functions and behavioral traits including cognition, memory, aggression, stress coping, appetite and immunomodulation. Serotonin exerts its functions via binding distinct serotonin receptors which are classified into 7 groups. Salmonid exhibits expanded functional gene copies due to salmonid-specific whole genome duplication. However, serotonin receptor (htr) repertoire is not fully identified in rainbow trout (Oncorhynchus mykiss). In this study, we identified 39 htr genes, including 14 htr1, 4 htr2, 4 htr2 like, 3 htr3, 4 htr4, 2 htr5, 2 htr6, and 6 htr7 subtypes. We investigated physiological functions of serotonin receptors in response to bacterial pathogens exposure and salinity changes. We showed htr1, htr2, htr4 and htr7 subtypes were associated with immunomodulation in response to Vibrio anguillarum or Aeromonas salmonicida infection. Saltwater (salinity of 15) transfer significantly altered htr1, htr2, htr4, and htr7 subtypes, suggesting trout Htr was associated with osmoregulation. We further showed residues interacted with inverse agonist (methiothepin) and serotonin analogue (5-Carboxamidotryptamine) were conserved between trout and human, suggesting exogenous ligands targeting human HTRs might have a role in aquaculture. This study showed duplicated trout Htrs might be physiologically neofunctionalized and potentially exhibit pleiotropic effects in regulating immunomodulation and osmoregulation.

The causal relationship between metabolic factors, drinking, smoking and intrahepatic cholangiocarcinoma: a Mendelian randomization study.

Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. While multiple risk factors for iCCA have been established, metabolic diseases (obesity, diabetes, NAFLD, dyslipidemia, and hypertension) and other risk factors, including smoking and drinking, are still controversial due to their potential confounders. Here, Mendelian randomization (MR) analysis was performed to identify the causal relationship between them. Method: In this study, we obtained GWAS data related to exposures from corresponding large genome-wide association studies. Summary-level statistical data for iCCA were obtained from the UK Biobank (UKB). We performed a univariable MR analysis to identify whether genetic evidence of exposure was significantly associated with iCCA risk. A multivariable MR analysis was conducted to estimate the independent effects of exposures on iCCA. Results: Univariable and multivariable MR analysis based on the large GWAS data indicated that there is little evidence to support the genetic role of metabolic factors, smoking, drinking, and NAFLD in iCCA development (P >0.05). In contrast to most current studies, their impact on iCCA development, if any, might be smaller than we thought. The previous positive results might be due to the comorbidities between diseases and potentially unavoidable confounding factors. Conclusion: In this MR study, we found no strong evidence to support causal associations between metabolic factors, NAFLD, smoking, drinking, and iCCA risk.

Transcriptome analysis of liver, gill and intestine in rainbow trout (Oncorhynchus mykiss) symptomatically or asymptomatically infected with Vibrio anguillarum.

Rainbow trout (Oncorhynchus mykiss), an important economic cold-water fish worldwide, is severely threatened by viruses and bacteria in the farming industry. The vibriosis outbreak has caused a significant setback to aquaculture. Vibrio anguillarum, one of the common disease-causing vibriosis associated with severe lethal vibriosis in aquaculture, infects fish mainly by adsorption and invasion of the skin, gills, lateral line and intestine. To investigate the defense mechanism of rainbow trout against the pathogen after infection with Vibrio anguillarum, trout were intraperitoneally injected by Vibrio anguillarum and divided into symptomatic group (SG) and asymptomatic group (AG) according to the phenotype. RNA-Seq technology was used to evaluate the transcriptional signatures of liver, gill and intestine of trout injected with Vibrio anguillarum (SG and AG) and corresponding control groups (CG(A) and CG(B)). The GO and KEGG enrichment analyses were used to investigate the mechanisms underlying the differences in susceptibility to Vibrio anguillarum. Results showed that in SG, immunomodulatory genes in the cytokine network were activated and tissue function-related genes were down-regulated, while apoptosis mechanisms were activated. However, AG responded to Vibrio anguillarum infection by activating complement related immune defenses, while metabolism and function related genes were up-regulated. Conclusively, a rapid and effective immune and inflammatory response can successfully defend Vibrio anguillarum infection. However, a sustained inflammatory response can lead to tissue and organ damage and cause death. Our results may provide a theoretical basis for breeding rainbow trout for disease resistance.

Estimation of the population, death, and quality of life in Shaanxi Province, western China: a cross-sectional study.

BACKGROUND: Measuring the health of the population is of great significance to the development of a region. We aimed to estimate the population, probability of death, and quality of life in western China. METHODS: We calculated the age-specific mortality rate and prevalence rate of diseases and injuries using the Full Population Database and the Home Page of Inpatient Medical Record. We used multiple interpolation methods to insert missing information from the death data and the model of Kannisto to adjust the mortality rate for elderly individuals. The age-specific prevalence rate of diseases and injuries was adjusted according to the standard ratio of age and methods of equal proportional allocation. Life expectancy was calculated by a life table, and the quality of life was estimated using the Sullivan method. RESULTS: The total population continued to increase in 2015 to 2019 in the Shaanxi Province, China. The mortality rate of children under five has improved, and the mortality rate of people over 65 is decreasing year by year. Life expectancy increased from 74.66 years in 2015 to 77.19 years in 2019. Even with the total risk of disease and injury, the health-adjusted life expectancy increased by 1.90 years within 5 years, and the number of unhealthy years significantly improved. Health-adjusted life expectancy increased by 1.75 years when only considered the ten major disease systems (tumors; endocrinology, nutrition and metabolism; mental and behavioral disorders; nervous system; sensory diseases; circulatory system; respiratory system; digestive system; genitourinary system; musculoskeletal system and connective tissue), and the number of unhealthy years increased slightly. CONCLUSIONS: In the past five years, Shaanxi Province has made progress in improving life expectancy and controlling the development of chronic diseases. It is necessary to take specific preventive measures and improve the quality of basic public health services.

Relative effectiveness of bivalent COVID-19 vaccine: a systematic review and meta-analysis.

Objective: The rapid development of COVID-19 bivalent vaccines (BVs) has encompassed both the original virus strains and the variant strain. However, the effectiveness of BVs is largely unknown. Therefore, we conducted a systematic review and meta-analysis of the effectiveness of BVs. Methods: Literature research was conducted through PubMed, Cochrane Library, Embase, and Web of Science up until November 4, 2023. Both randomized control trials and observational studies were considered for inclusion. Pooled estimates were calculated using a random effects model. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in cohort and case-control studies. Results: A total of 1,174 articles were reviewed and 22 eligible studies were included. All included studies were observational (15 cohort studies, 7 case-control studies). The total number of participants was 39,673,160, and the number of people vaccinated with BVs as an intervention group was 11,585,182. Two mRNA BVs were mainly involved, including the ancestral strain and the BA.1 or BA.4-5 variants. Meta-analysis results showed, compared with the monovalent vaccines (MVs), the relative effectiveness (rVE) of the BVs in COVID-19-associated infections/symptomatic infections, illnesses, hospitalizations, and deaths was 30.90% [95% confidence interval (CI), 8.43-53.37], 39.83% (95% CI, 27.34-52.32), 59.70% (95% CI, 44.08-75.32), and 72.23% (95% CI, 62.08-82.38), respectively. For those aged 50 years and older, BVs provided an additional 49.69% (95% CI, 41.44-57.94) effective protection compared with MVs. During the dominance period of the omicron XBB variant strain, BVs provided an additional 47.63% (95% CI, 27.45-67.82) effective protection compared with MVs. Conclusion: Our findings show that the rVE of BVs in preventing COVID-19-associated infections, symptomatic infections, illnesses, hospitalizations, and deaths is higher compared to MVs. Particularly for people over 50 years of age and during the Omicron variant XBB dominance phase, BVs provided superior protection. Therefore, BVs may have a broader application in the prevention and control of coronaviruses variant.

Drug-induced hypersensitivity syndrome with high procalcitonin levels due to piperacillin/tazobactam and meropenem: A case report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and life-threatening adverse drug reaction. It is characterized by a long latency period with rash, hematological abnormalities, and visceral damage. Clinical manifestations of DRESS vary. Thus, accurate clinical diagnosis and identification are essential to ensure timely treatment commencement for improving prognosis and speeding up recovery. We report the case of a 66-year-old male patient with a drug reaction induced by a beta-lactam antibiotic, piperacillin/tazobactam (Pip/Taz). This resulted in the manifestation of both eosinophilic and systemic symptoms. Ten days after the Pip/Taz treatment commencement, the patient developed hyperthermia and elevated serum procalcitonin (PCT), leading to a misdiagnosis of an exacerbated infection. Meropenem treatment was then started. However, after 72 h, the patient developed a generalized rash, eosinophilia, hematological abnormalities, and visceral damage. Moreover, PCT levels were significantly elevated. All these symptoms were associated with DRESS. The sensitizing drug was discontinued, and glucocorticoids were administered, resulting in gradual subsiding of symptoms and decreases in serum PCT levels. Clinicians should be aware that elevated PCT serum levels may be a diagnostic biomarker for DRESS, which requires specific treatment. Furthermore, studies are warranted to further evaluate and elucidate the role of PCT in response to DRESS.

Genome-Wide Mapping of Plasma IgG N-Glycan Quantitative Trait Loci Identifies a Potentially Causal Association between IgG N-Glycans and Rheumatoid Arthritis.

Observational studies highlight associations of IgG N-glycosylation with rheumatoid arthritis (RA); however, the causality between these conditions remains to be determined. Standard and multivariable two-sample Mendelian randomization (MR) analyses integrating a summary genome-wide association study for RA and IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) data were performed to explore the potentially causal associations of IgG N-glycosylation with RA. After correcting for multiple testing (p < 2 × 10-3), the standard MR analysis based on the inverse-variance weighted method showed a significant association of genetically instrumented IgG N-glycan (GP4) with RA (odds ratioGP4 = 0.906, 95% confidence interval = 0.857-0.958, p = 5.246 × 10-4). In addition, we identified seven significant associations of genetically instrumented IgG N-glycans with RA by multivariable MR analysis (p < 2 × 10-3). Results were broadly consistent in sensitivity analyses using MR_Lasso, MR_weighted median, MR_Egger regression, and leave-one-out analysis with different instruments (all p values <0.05). There was limited evidence of pleiotropy bias (all p values > 0.05). In conclusion, our MR analysis incorporating genome-wide association studies and IgG N-glycan-QTL data revealed that IgG N-glycans were potentially causally associated with RA. Our findings shed light on the role of IgG N-glycosylation in the development of RA. Future studies are needed to validate our findings and to explore the underlying physiological mechanisms in the etiology of RA.

Association Between Living Risk and Healthy Life Years Lost Due to Multimorbidity: Observations From the China Health and Retirement Longitudinal Study.

Background: Multimorbidity has an effect on life expectancy, while its effect on healthy life years is unclear. This study aims to investigate the associations between healthy life years lost due to multimorbidity and living risk. Methods: The participants of The China Health and Retirement Longitudinal Study (CHARLS) were assessed at four visits between 2011 (baseline) and 2018. At baseline, 13,949 individuals were administered surveys. A combined score based on seven health-related factors was calculated, and the participants were classified into 3 groups based on living risk. We used the adjusted Cox regression methods to examine the associations between living risk groups and multimorbidity. We estimated the healthy life years lost due to multimorbidity using the Sullivan method. Results: A total of 9,091 adults aged 45 years or older (mean age of 59.55 ± 9.50 years with one disease, 52.60% women) were analyzed in the CHARLS. The probability of no multimorbidity over 7 years decreased from 0.9947 to 0.9697 in the low-risk group, whereas the probability of multimorbidity in low living risk was lower than that of high living risk, ranging from HR 1.253 (95% CI.992-1.581; P = 0.058) to 1.431 (1.05-1.949; P = 0.023) in sex, and ranging from HR 1.340 (95% CI 1.106-1.623; P = 0.003) to 2.002 (1.058-3.787; P = 0.033) in area. At 45 years, the healthy life years lost in men was <0.27 years compared to women in the low-risk group. Hypertension increased the risk of multimorbidity with an HR of 1.5 (95% CI 1.21-1.91; P < 0.001) in men. In urban areas, participants with diabetes had 3.2 times (95% CI 1.75-5.94, P < 0.001) higher risk of multimorbidity than participants without diabetes. Conclusions: These findings indicate that a low-risk lifestyle could decrease the loss of healthy life years under multimorbidity. The probability of multimorbidity in women and in urban areas was high. Hypertension was correlated with the hazard risk of multimorbidity.

Association of dietary patterns with obesity and metabolically healthy obesity phenotype in Chinese population: a cross-sectional analysis of China Multi-Ethnic Cohort Study.

Metabolically healthy obesity (MHO) might be an alternative valuable target in obesity treatment. We aimed to assess whether alternative Mediterranean (aMED) diet and Dietary Approaches to Stop Hypertension (DASH) diet were favourably associated with obesity and MHO phenotype in a Chinese multi-ethnic population. We conducted this cross-sectional analysis using the baseline data of the China Multi-Ethnic Cohort study that enrolled 99 556 participants from seven diverse ethnic groups. Participants with self-reported cardiometabolic diseases were excluded to eliminate possible reverse causality. Marginal structural logistic models were used to estimate the associations, with confounders determined by directed acyclic graph (DAG). Among 65 699 included participants, 11·2 % were with obesity. MHO phenotype was present in 5·7 % of total population and 52·7 % of population with obesity. Compared with the lowest quintile, the highest quintile of DASH diet score had 23 % decreased odds of obesity (OR = 0·77, 95 % CI 0·71, 0·83, Ptrend < 0·001) and 27 % increased odds of MHO (OR = 1·27, 95 % CI 1·10, 1·48, Ptrend = 0·001) in population with obesity. However, aMED diet showed no obvious favourable associations. Further adjusting for BMI did not change the associations between diet scores and MHO. Results were robust to various sensitivity analyses. In conclusion, DASH diet rather than aMED diet is associated with reduced risk of obesity and presents BMI-independent metabolic benefits in this large population-based study. Recommendation for adhering to DASH diet may benefit the prevention of obesity and related metabolic disorders in Chinese population.

Identification and characterization of mkk genes and their expression profiles in rainbow trout (Oncorhynchus mykiss) symptomatically or asymptomatically infected with Vibrio anguillarum.

Mitogen-activated protein kinase kinases (MKKs) are intermediate kinases of mitogen-activated protein kinases (MAPKs) signaling pathways. MKKs are activated by mitogen-activated protein kinase kinase kinase (MKKK) and then the activated MKKs trigger the activation of downstream MAPKs. MAPK signaling pathways play an important role in regulating immune functions including apoptosis and inflammation. However, studies on identification and characterization of mkk repertoire in rainbow trout (Oncorhynchus mykiss) are still limited. Trout experienced 4 rounds (4R) of whole genome duplication (WGD), thus exhibiting increased paralogs of mkks with potentially functional diversity. In this study, we identified 17 mkk genes in trout and the following bacterial challenge (Vibrio anguillarum) studies showed functional diversity of different mkk subtypes. Vibrio anguillarum infection resulted in significantly up-regulated mkk2 subtypes in spleen and liver, and mkk4b3 in spleen, suggesting immunomodulation was regulated by activation of ERK, p38 and JNK pathways. Compared to other mkk subtypes, mkk6s were down-regulated in symptomatic group, rather than asymptomatic group. The organisms present negative feedback on MAPK activation, thus reducing extra damage to cells. We observed down-regulated mkk6s with up-regulated genes (dusp1 & dusp2) involved in negative feedback of MAPK activation. Based on these results, we might propose the distinct expression patterns of genes associated with MAPK pathways resulted in different phenotypes and symptoms of trout in response to bacterial challenge.

Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.

Novel DNA methylation loci and genes showing pleiotropic association with Alzheimer's dementia: a network Mendelian randomization analysis.

Previous genome-wide association studies (GWAS) have identified potential genetic variants involved in the risk of Alzheimer's dementia, but their underlying biological interpretation remains largely unclear. In addition, the effects of DNA methylation and gene expression on Alzheimer's dementia are not well understood. A network summary data-based Mendelian randomization (SMR) analysis was performed integrating cis- DNA methylation quantitative trait loci (mQTL) /cis- gene expression QTL (eQTL) data in the brain and blood, as well as GWAS summarized data for Alzheimer's dementia to evaluate the pleiotropic associations of DNA methylation and gene expression with Alzheimer's dementia and to explore the complex mechanisms underpinning Alzheimer's dementia. After correction for multiple testing (false discovery rate [FDR] P < 0.05) and filtering using the heterogeneity in dependent instruments (HEIDI) test (PHEIDI>0.01), we identified dozens of DNA methylation sites and genes showing pleiotropic associations with Alzheimer's dementia. We found 22 and 16 potentially causal pathways of Alzheimer's dementia (i.e., SNP→DNA methylation→Gene expression→Alzheimer's dementia) in the brain and blood, respectively. Approximately two-thirds of the identified DNA methylation sites had an influence on gene expression and the expression of almost all the identified genes was regulated by DNA methylation. Our network SMR analysis provided evidence supporting the pleiotropic association of some novel DNA methylation sites and genes with Alzheimer's dementia and revealed possible causal pathways underlying the pathogenesis of Alzheimer's dementia. Our findings shed light on the role of DNA methylation in gene expression and in the development of Alzheimer's dementia.

Transcriptional Profiles of Genes Related to Stress and Immune Response in Rainbow Trout (Oncorhynchus mykiss) Symptomatically or Asymptomatically Infected With Vibrio anguillarum.

Rainbow trout (Oncorhynchus mykiss) is one of the most common aquaculture fish species worldwide. Vibriosis disease outbreaks cause significant setbacks to aquaculture. The stress and immune responses are bidirectionally modulated in response to the health challenges. Therefore, an investigation into the regulatory mechanisms of the stress and immune responses in trout is invaluable for identifying potential vibriosis treatments. We investigated the transcriptional profiles of genes associated with stress and trout immune functions after Vibrio anguillarum infection. We compared the control trout (CT, 0.9% saline injection), asymptomatic trout (AT, surviving trout with minor or no symptoms after bacteria injection), and symptomatic trout (ST, moribund trout with severe symptoms after bacteria injection). Our results showed activated immunomodulatory genes in the cytokine network and downregulated glucocorticoid and mineralocorticoid receptors in both AT and ST, indicating activation of the proinflammatory cytokine cascade as a common response in AT and ST. Moreover, the AT specifically activated the complement- and TNF-associated immune defenses in response to V. anguillarum infection. However, the complement and coagulation cascades, as well as steroid hormone homeostasis in ST, were disturbed by V. anguillarum. Our studies provide new insights toward understanding regulatory mechanisms in stress and immune functions in response to diseases.

Clinical and Genetic Characteristics of Atypical Hemolytic Uremic Syndrome in Children: A Chinese Cohort Study.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare but critical illness. To this date, few studies have reported on the disease in Chinese children. METHODS: We studied a Chinese pediatric cohort to delineate the clinical characteristics, genotypes, and prognosis. Ninety-one patients with aHUS were enrolled in this study. RESULTS: Fifty-nine children (64.8%) had anti-complement-factor-H autoantibody-associated aHUS (anti-CFH aHUS). Of these children, 21 (46.7%) had complement factor-H-related protein 1 (CFHR1) homozygous deletion, and most patients with CFHR1 homozygous deletion also had complement factor-H-related protein 3 (CFHR3) homozygous deletions (76.2%). Using gene sequencing of 15 candidate genes, we identified 14 genetic variants in 46 aHUS patients, including 5 pathogenic or like pathogenic variants and 9 variants of uncertain significance. The average follow-up time was 46.1 ± 28 months. Among patients with anti-CFH aHUS, there was a correlation between CFHR1 homozygous deletion and patients with persistent proteinuria (odds ratio [OR] 6.954, 95% confidence interval [CI] 1.033-46.821, p = 0.046). As of the last follow-up, ESRD or deaths occurred in 3.6% of the children with anti-CFH aHUS and 26.7% of children with aHUS who were negative for anti-CFH. CONCLUSIONS: Anti-complement-factor-H antibody positivity is the main cause of morbidity in Chinese children with aHUS. There may be a correlation between CFHR1 homozygous deletion and persistent proteinuria. Comprehensive assessment of anti-CFH antibodies and genetic variants is essential for the management of aHUS children.