Most patients with primary hepatocellular carcinoma (HCC) have a history of chronic hepatitis B and usually present with varying degrees of cirrhosis. Owing to the special nature of liver anatomy, the blood vessel wall in the liver parenchyma is thin and prone to bleeding. Heavy bleeding and blood transfusion during hepatectomy are independent risk factors for liver cancer recurrence and death. Various clinical methods have been used to reduce intraoperative bleeding, and the Pringle method is most widely used to prevent blood flow to the liver.To investigate the effect of half-hepatic blood flow occlusion after patients with HCC and cirrhosis undergo hepatectomy.This retrospective study included 88 patients with HCC and liver cirrhosis who underwent hepatectomy in our hospital from January 2017 to September 2020. Patients were divided into two groups based on the following treatment methods: the research group (n = 44), treated with half-hepatic blood flow occlusion technology and the control group (n = 44), treated with total hepatic occlusion. Differences in operation procedure, blood transfusion, liver function, tumor markers, serum inflammatory response, and incidence of surgical complications were compared between the groups.The operation lasted longer in the research group than in the control group (273.0 ± 24.8 min vs 256.3 ± 28.5 min, P < 0.05), and the postoperative anal exhaust time was shorter in the research group than in the control group (50.0 ± 9.7 min vs 55.1 ± 10.4 min, P < 0.05). There was no statistically significant difference in incision length, surgical bleeding, portal block time, drainage tube indwelling time, and hospital stay between the research and control groups (P > 0.05). Before surgery, there were no significant differences in serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin, and prealbumin levels between the research and control groups (P > 0.05). Conversely, 24 and 72 h after the operation the respective serum ALT (378.61 ± 77.49 U/L and 246.13 ± 54.06 U/L) and AST (355.30 ± 69.50 U/L and 223.47 ± 48.64 U/L) levels in the research group were significantly lower (P < 0.05) than those in the control group (ALT, 430.58 ± 83.67 U/L and 281.35 ± 59.61 U/L; AST, 416.49 ± 73.03 U/L and 248.62 ± 50.10 U/L). The operation complication rate did not significantly differ between the research group (15.91%) and the control group (22.73%; P > 0.05).Half-hepatic blood flow occlusion technology is more beneficial than total hepatic occlusion in reducing liver function injury in hepatectomy for patients with HCC and cirrhosis.
We explore the use of traditional and contemporary hidden Markov models (HMMs) for sequential physiological data analysis and sepsis prediction in preterm infants. We investigate the use of classical Gaussian mixture model based HMM, and a recently proposed neural network based HMM. To improve the neural network based HMM, we propose a discriminative training approach. Experimental results show the potential of HMMs over logistic regression, support vector machine and extreme learning machine.
Abstract Background Emerging metabolomics-based studies suggested links between amino acids metabolism and non-alcoholic fatty liver disease (NAFLD) risk, however, whether there exists an aetiological role of amino acid metabolism in NAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and NAFLD risk. Methods We performed two-sample Mendelian randomisation (MR) analyses using summary level data from genome-wide association studies (GWAS) to assess causal relationships between genetically predicted circulating levels of amino acids and NAFLD risk. Data from the largest GWAS on NAFLD (8,434 cases and 770,180 controls) were used in discovery MR analysis, and from a GWAS on NAFLD (1,483 cases and 17,781 controls) where NAFLD cases were diagnosed using liver biopsy, were used in replication MR analysis. Wald ratios or multiplicative random-effect inverse variance weighted (IVW) methods were used in the main MR analysis, and weighted median and MR-Egger regression analysis were used in sensitivity analyses. We additionally performed an MR conservative analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. Findings We found that genetically predicted higher alanine (OR=1.45, 95% CI 1.15-1.83) and lower glutamine (OR = 0.81, 95% CI 0.66-1.00) levels were associated with a higher risk of developing NAFLD. Results from MR sensitivity analyses and conservative analysis supported the main findings. Interpretation Genetically predicted higher circulating levels of alanine was associated with an increased risk of NAFLD, whereas higher glutamine was associated with a decreased risk of NAFLD. Funding This work was supported by Xinhua Hospital, Shanghai Jiao Tong University School of Medicine (2021YJRC02). Research in context Evidence before this study Recent metabolomics studies revealed associations between circulating levels of several amino acids and non-alcoholic fatty liver disease (NAFLD) risk. Most of these studies were conducted with a focus on the profiling of amino acids between individuals with NAFLD and healthy subjects, which suggested the altered amino acid metabolism might be a consequence of NAFLD rather than a causal risk factor for NAFLD. We searched PubMed for studies in any language using the search terms “amino acids” AND “Non-alcoholic fatty liver disease OR NAFLD OR fatty liver” AND “Mendelian randomisation OR Mendelian randomization”, and found few studies on the causal effects of circulating amino acids on NAFLD risk. Thus, whether there is an aetiological role of amino acids in NAFLD development remains unknown. Added value of this study In the present study, we systematically investigated the causal effects of genetically predicted circulating levels of 20 amino acids on NAFLD risk using data from large-scale genome-wide association studies in up to 778,614 individuals of European ancestry. We utilised a state-of-art causal inference approach, that is Mendelian randomisation, to construct layers of evidence. Overall, we found that among 20 amino acids, genetically predicted higher circulating levels of alanine was associated with an increased risk of NAFLD, whereas higher glutamine was associated with a decreased risk of NAFLD. Implications of all the available evidence Our study is the first to systematically assess the causal relationships between levels of plasma amino acids and the development of NAFLD using multi-omics (i.e., genomic and metabolomic) data from large-scale human studies. Our results suggest the potential for the glutamine supplementation or alanine depletion for personalized nutrition in NAFLD prevention and treatment.
We read with great interest two manuscripts by Ji et al. and Valenti et al. Recently, Ji et al. found that patients with coronavirus disease 2019 (COVID-19) had a higher risk of liver injury or severe outcomes, and meanwhile, patients with non-alcoholic fatty liver disease (NAFLD) had an increased risk of progression to severe COVID-19 infection.[1]Ji D. Qin E. Xu J. Zhang D. Cheng G. Wang Y. et al.Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study.J Hepatol. 2020; 73: 451-453Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar However, more recently, Valenti et al. found that metabolic-associated fatty liver disease (MAFLD) may not associate with the susceptibility and severity of COVID-19.[2]Valenti L. Jamialahmadi O. Romeo S. Lack of genetic evidence that fatty liver disease predisposes to COVID-19.J Hepatol. 2020; 73: 709-711Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Thus, causal relationships between COVID-19 and NAFLD still remain unclear. In this work, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine causal relationships between COVID-19 susceptibility/severity (including COVID-19 infection, COVID-19 hospitalization, and severe COVID-19 symptoms) and NAFLD. MR is a causal inference approach that uses genetic variants as instrumental variables (IVs) to draw causal inferences between risk factors and health outcomes in observational study settings. It could overcome problems of confounding and reverse causality and is widespread for assessing causal relationships.[3]Davey Smith G. Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies.Hum Mol Genet. 2014; 23: R89-R98Crossref PubMed Scopus (1687) Google Scholar For COVID-19, we used data from the latest and largest genome-wide association study (GWAS), COVID-19 Host Genetics Initiative (COVID-19 HGI) (N = 2,586,691), which was released on June 15, 2021.[4]COVID-19 Host Genetics InitiativeThe COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic.Eur J Hum Genet. 2020; 28: 715-718Crossref PubMed Scopus (461) Google Scholar Three subgroups of European ancestry COVID-19 case-control studies included Group 1: COVID-1-infected cases vs. population (case = 87,870 and control = 2,210,804), Group 2: hospitalized COVID-19 cases vs. population (case = 17,992 and control = 1,810,493), and Group 3: very severe respiratory confirmed COVID-19 cases vs. population (case = 4,606 and control = 702,801). Group 1 and Group 2 used the latest Round 6 data, and Group 3 used Round 5 data due to lacking of the latest wave of European ancestry data. We used the latest European ancestry UK Biobank (UKB) GWAS results of NAFLD (1,687 cases and 398,277 controls), which were based on TOPMed imputed data and analyzed using SAIGE (https://pheweb.org/UKB-TOPMed/). The NAFLD outcome in UKB GWAS was defined according to the ICD-9 571.8 "Other chronic non-alcoholic liver disease". Although this definition of NAFLD might not include all clinical or histological cases, we found that the top hits of this GWAS included previously identified loci for NAFLD. The COVID-19 GWAS was adjusted for sex, ancestry and date of sample collection, and the UKB GWAS was adjusted for sex, birth year and first 4 principal components. All the genetic IVs selected in our study were genome-wide significant (p <5×10-8) with minor allele frequency greater than 1%. After linkage disequilibrium (LD) clumping (clumping with window = 10,000 kb, R2 = 0.001 in PLINK 1.9), there were 7 single nucleotide polymorphisms (SNPs) remaining for COVID-19 infection, 10 SNPs for hospitalized COVID-19, 8 SNPs for severe COVID-19, and 4 SNPs for NAFLD, respectively (Fig. 1A). In the main MR analysis, we performed separate two-sample MR analyses with three COVID-19 phenotypes (i.e., COVID-19 infection, COVID-19 hospitalization, and COVID-19 severity) as exposures and NAFLD as the outcome. To further understand the causal effect of NAFLD on each COVID-19 phenotype, 4 genome-wide significant SNPs for NAFLD were selected as IVs. For the main analysis, we implemented the multiplicative random effect inverse-variance weighted (IVW) method to generate a causal estimate using the TwoSampleMR package.[5]Hemani G. Zheng J. Elsworth B. Wade K.H. Haberland V. Baird D. et al.The MR-Base platform supports systematic causal inference across the human phenome.Elife. 2018; 7Crossref PubMed Scopus (2573) Google Scholar Moreover, we conducted sensitivity analyses, including MR Egger regression, weighted median, and MR-PRESSO, to account for potential heterogeneity and horizontal pleiotropy (supplementary information). p values less than 0.05 were considered statistically significant. As shown in Fig. 1, the IVW analysis generated little evidence of a causal effect of COVID-19 infection (odds ratio (OR) 1.054; 95% CI 0.696 –1.596), COVID-19 hospitalization (OR 0.973; 95% CI 0.750–1.263), and severe COVID-19 (OR 0.919; 95% CI 0.839–1.007) on NAFLD. Meanwhile, NAFLD did not appear to have a causal effect on COVID-19 infection (OR 0.991; 95% CI 0.970–1.013), hospitalization (OR 0.991; 95% CI 0.896–1.096) or severe COVID-19 (OR 0.904; 95% CI 0.731–1.118). All the sensitivity analyses showed broadly consistent results. No significant horizontal pleiotropy was detected by MR Egger regression or MR-PRESSO. Detailed MR Egger regression intercepts and MR-PRESSO global test results are presented in Table S1-S2. There was no evidence derived from this work to support causal relationships between COVID-19 susceptibility/severity and NAFLD, which are consistent with results from previous genetic studies.[2]Valenti L. Jamialahmadi O. Romeo S. Lack of genetic evidence that fatty liver disease predisposes to COVID-19.J Hepatol. 2020; 73: 709-711Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,[6]Bianco C. Baselli G. Malvestiti F. Santoro L. Pelusi S. Manunta M. et al.Genetic insight into COVID-19-related liver injury.Liver Int. 2021; 41: 227-229Crossref PubMed Scopus (9) Google Scholar On the contrary, Innes et al. found that the rs738409 C>G variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is well studied in the genetic regulation of NAFLD and liver injury, played a protective role in COVID-19 severity.[7]Innes H. Buch S. Barnes E. Hampe J. Marjot T. Stickel F. The rs738409 G allele in PNPLA3 is associated with a reduced risk of COVID-19 mortality and hospitalization.Gastroenterology. 2021; 160: 2599-2601 e2592Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Previous observational studies revealed that COVID-19-infected patients had an increased risk of liver injury,[8]Zhang C. Shi L. Wang F.S. Liver injury in COVID-19: management and challenges.Lancet Gastroenterol Hepatol. 2020; 5: 428-430Abstract Full Text Full Text PDF PubMed Scopus (1308) Google Scholar,[9]Marjot T. Webb G.J. Barritt A. St Moon A.M. Stamataki Z. Wong V.W. et al.COVID-19 and liver disease: mechanistic and clinical perspectives.Nat Rev Gastroenterol Hepatol. 2021; 18: 348-364Crossref PubMed Scopus (229) Google Scholar however, unmeasured/unmeasurable confounding cannot be ruled out in conventional multivariable regression analysis. In fact, our findings derived from the MR analysis could minimize confounding bias or reverse causation.[3]Davey Smith G. Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies.Hum Mol Genet. 2014; 23: R89-R98Crossref PubMed Scopus (1687) Google Scholar It is worthy of note that collider bias, which could distort the relationship between exposures and outcomes, existed in many observational studies and cannot be completely overcome by MR.[10]Griffith G.J. Morris T.T. Tudball M.J. Herbert A. Mancano G. Pike L. et al.Collider bias undermines our understanding of COVID-19 disease risk and severity.Nat Commun. 2020; 11: 5749Crossref PubMed Scopus (439) Google Scholar To investigate the potential impact of collider bias on the MR estimation, we replicated the bidirectional two-sample MR analysis using data from a previously published GWAS by Namjou et al., where genetic associations might be biased due to adjusting for a collider variable (e.g., BMI). Details on methods, results, and directed acyclic graph are included in the supplementary information. Future larger randomly sampled cohort studies on COVID-19 and NAFLD and rigorous statistical analysis might be helpful to minimize the impact of collider bias. In conclusion, we found little evidence to support a causal relationship between COVID-19 susceptibility/severity and NAFLD. The authors received no financial support to produce this work. All authors drafted and reviewed this manuscript. The authors declare no conflicts of interest that relate to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the supplementary data to this article: Download .pdf (.63 MB) Help with pdf files Multimedia component 1 Download .pdf (.26 MB) Help with pdf files Multimedia component 2
Abstract Background Previous observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways. Methods We performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (N case =61,000, N control =577,000), AF (N case =60,620, N control =970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight. Results Genetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22–1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16–1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association. Conclusions Cardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases.
Abstract Aim The aim was to investigate the causal relationship between puberty timing and plasma metabolites, accounting for birth weight, childhood and adulthood adiposity. Materials and Methods The meta‐analysis of genome‐wide association studies (GWAS) for puberty timing was extracted from the ReproGen Consortium, involving 329 345 women of European ancestry. Summary data for 174 plasma metabolites were retrieved from a recently conducted cross‐platform GWAS that involved a meta‐analysis of three cohort studies (i.e. the Fenland, European Prospective Investigation into Cancer‐Norfolk and INTERVAL studies) and three publicly available studies and included up to 86 507 participants. We conducted a two‐sample Mendelian randomization (MR) analysis to infer the causal relationship of puberty timing on 174 plasma metabolites, complemented by a two‐step and multivariable Mendelian randomization (MVMR) analysis to assess direct and indirect effects. Additionally, summary‐level data from the UK Biobank were used for our replication analysis. Results The results of the two‐sample MR provide moderate evidence supporting a causal relationship between puberty timing and 23 of 174 plasma metabolites (i.e. 7 acylcarnitines, 8 amino acids, 2 biogenic amines and 6 lysophosphatidylcholines). Even after single‐nucleotide polymorphisms associated with birth weight and childhood adiposity were excluded, causal effects persisted for 16 metabolites (i.e. 8 acylcarnitines, 4 amino acids, 2 biogenic amines and 2 lysophosphatidylcholines). The two‐step MR analysis provided evidence that the relationship between puberty timing and plasma metabolites was mediated by adulthood adiposity. Additionally, moderate evidence emerged for an independent causal effect of puberty timing on 10 metabolites through an MVMR analysis (i.e. 5 acylcarnitines, 2 amino acids, 1 biogenic amine, 1 lysophosphatidylcholine and 1 phosphatidylcholine). Furthermore, the replication analysis suggested the robustness of our results. Conclusions In summary, our study provides compelling evidence that puberty timing has a causal influence on certain plasma metabolites, although this influence is largely mediated by adulthood adiposity.
BACKGROUND In fall 2020, all public K‐12 schools reopened in broadly 3 learning models. The hybrid model was considered a mid‐risk option compared with remote and in‐person learning models. The current study assesses school‐based coronavirus disease 2019 (COVID‐19) spread in the early fall using a national data set. METHODS We assess COVID‐19 case growth rates from August 10 to October 14, 2020 based on a crowdsourcing data set from the National Education Association. The study follows a retrospective cohort design with the baseline exposures being 3 teaching models: remote learning only, hybrid, and in‐person learning. To assess the consistency of our findings, we estimated the overall, as well as region‐specific (Northeast, Midwest, South, and West) and poverty‐specific (low, mid, and high) COVID‐19 case‐growth rates. In addition, we validated our study sample using another national sample survey data. RESULTS The baseline was from 617 school districts in 48 states, where 47% of school districts were in hybrid, 13% were in remote, and 40% were in‐person. Controlling for state‐level risk and rural‐urban difference, the case growth rates for remote and in‐person were lower than the hybrid (odds ratio [OR]: 0.963, 95% confidence interval [CI]: 0.960‐0.965 and OR: 0.986, 95% CI: 0.984‐0.988, respectively). A consistent result was found among school districts in all 4 regions and each poverty level. CONCLUSIONS Hybrid may not necessarily be the next logical option when transitioning from the remote to in‐person learning models due to its consistent higher case growth rates than the other 2 learning models.
Abstract Azole antifungal drugs are commonly used to treat vulvovaginal candidiasis (VVC). The nephrotoxicity and developmental toxicity of azole drugs have not been systematically analyzed in the real world. We used the FDA Adverse Event Reporting System (FAERS) to investigate the adverse events (AEs) associated with imidazole therapy for VVC. FAERS data (from quarter 1 2004 to quarter 3 2022) were retrieved using OpenVigil 2.1, and AEs were retrieved and standardized according to the Medical Dictionary for Regulatory Activities (MedDRA). In the top 10 System Organ Class (SOC), all four drugs have been found to have kidney and urinary system diseases and pregnancy. We found significant signals, including clotrimazole [bladder transitional cell carcinoma, (report odds ratio, ROR = 291.66)], [fetal death, (ROR = 10.28)], ketoconazole[nephrogenic anemia (ROR = 22.1)], [premature rupture of membranes (ROR = 22.91 46.45, 11, 3)], Miconazole[hematuria (ROR = 19.03)], [neonatal sepsis (ROR = 123.71)], [spontaneous abortion (ROR = 5.98)], Econazole [acute kidney injury (ROR = 4.41)], [spontaneous abortion (ROR = 19.62)]. We also discovered new adverse reactions that were not reported. Therefore, when using imidazole drugs for treatment, it is necessary to closely monitor the patient's renal function, pay attention to the developmental toxicity of the fetus during pregnancy, and be aware of potential adverse reactions that may occur.
Abstract Background On the present trajectory, COVID is inevitably becoming a global epidemic, leading to concerns regarding the pandemic potential in China and other countries. Objective In this study, we use the time-dependent reproduction number (R t ) to comprise the COVID transmissibility across different countries. Methods We used data from Jan 20, 2019, to Feb 29, 2020, on the number of newly confirmed cases, obtained from the reports published by the CDC, to infer the incidence of infectious over time. A two-step procedure was used to estimate the R t . The first step used data on known index-secondary cases pairs, from publicly available case reports, to estimate the serial interval distribution. The second step estimated the R t jointly from the incidence data and the information data in the first step. R t was then used to simulate the epidemics across all major cities in China and typical countries worldwide. Results Based on a total of 126 index-secondary cases pairs from 4 international regions, we estimated that the serial interval for SARS-2-CoV was 4.18 (IQR 1.92 – 6.65) days. Domestically, R t of China, Hubei province, Wuhan had fallen below 1.0 on 9 Feb, 10 Feb and 13 Feb (R t were 0.99±0.02, 0.99±0.02 and 0.96±0.02), respectively. Internationally, as of 26 Feb, statistically significant periods of COVID spread (R t >1) were identified for most regions, except for Singapore (R t was 0.92±0.17). Conclusions The epidemic in China has been well controlled, but the worldwide pandemic has not been well controlled. Worldwide preparedness and vulnerability against COVID-19 should be regarded with more care. What is already known on this subject? The basic reproduction number (R0) and the-time-dependent reproduction number (Rt) are two important indicators of infectious disease transmission. In addition, Rt as a derivative of R0 could be used to assess the epidemiological development of the disease and effectiveness of control measures. Most current researches used data from earlier periods in Wuhan and refer to the epidemiological features of SARS, which are possibly biased. Meanwhile, there are fewer studies discussed the Rt of COVID-19. Current clinical and epidemiological data are insufficient to help us understand the full view of the potential transmission of this disease. What this study adds? We use up-to-data observation of the serial interval and cases arising from local transmission to calculate the Rt in different outbreak level area and every province in China as well as five-top sever outbreak countries and other overseas. By comparing the Rt, we discussed the situation of outbreak around the world.
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