During the past decade, we have entered an era of biologics for the treatment of Crohn’s disease and ulcerative colitis. The therapeutic goal of inflammatory bowel disease (IBD) management has ...evolved from symptom control and clinical remission to mucosal healing or even deep remission. Histological remission for ulcerative colitis and transmural healing of Crohn’s disease are potential future goals. With the adoption of the treat-to-target concept, and given the need for tight control of IBD activity, therapeutic drug monitoring (TDM) is an important element of precision medicine. TDM involves the measurement of serum biologics and anti-drug antibodies levels, to confirm whether the right drug with the right dosage was prescribed to reach the right serum levels. TDM may help clinicians adjust biologics based on objective biomarkers instead of using empirical dosage escalation or making symptom-based therapeutic adjustments. Well-established reactive TDM algorithms have been proposed, and emerging evidence supports the clinical application of a proactive TDM strategy to enhance the duration of effective biologics and improve clinical outcomes. Recently, the proactive TDM strategy was shown to avoid the secondary loss of response to biologics, and improve long-term clinical outcomes in IBD patients. This review summarizes data from trials, and practice guidelines, on the clinical application of proactive and reactive TDM strategies for the daily care of biologic-treated IBD patients.
Influenza is a severe respiratory illness that continually threatens global health. It has been widely known that gut microbiota modulates the host response to protect against influenza infection, ...but mechanistic details remain largely unknown. Here, we took advantage of the phenomenon of lethal dose 50 (LD
) and metagenomic sequencing analysis to identify specific anti-influenza gut microbes and analyze the underlying mechanism.
Transferring fecal microbes from mice that survive virulent influenza H7N9 infection into antibiotic-treated mice confers resistance to infection. Some gut microbes exhibit differential features to lethal influenza infection depending on the infection outcome. Bifidobacterium pseudolongum and Bifidobacterium animalis levels are significantly elevated in surviving mice when compared to dead or mock-infected mice. Oral administration of B. animalis alone or the combination of both significantly reduces the severity of H7N9 infection in both antibiotic-treated and germ-free mice. Functional metagenomic analysis suggests that B. animalis mediates the anti-influenza effect via several specific metabolic molecules. In vivo tests confirm valine and coenzyme A produce an anti-influenza effect.
These findings show that the severity of influenza infection is closely related to the heterogeneous responses of the gut microbiota. We demonstrate the anti-influenza effect of B. animalis, and also find that the gut population of endogenous B. animalis can expand to enhance host influenza resistance when lethal influenza infection occurs, representing a novel interaction between host and gut microbiota. Further, our data suggest the potential utility of Bifidobacterium in the prevention and as a prognostic predictor of influenza.
We investigated the utility of transient elastography (TE) for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty‐eight cholestatic infants (9‐87 days of ...age) with direct bilirubin level >1 mg/dL were enrolled. Liver stiffness measurement (LSM) by TE was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non‐BA cholestatic infants. A receiver operating characteristic (ROC) curve analysis showed that an LSM >7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%; specificity = 97%; area under the curve AUC = 85.3%; P = 0.0001). Cholestatic infants with an LSM >7.7 kPa were more likely to be diagnosed with BA (odds ratio OR = 128; P < 0.001). Very early measurement of LSM after hepatoportoenterostomy (HPE) is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months post‐HPE. Five of the BA subjects were awaiting or had received liver transplantation (LT), and they had a significantly higher LSM measured 1 week post‐HPE than that in the other BA subjects (26.0 vs. 10.8 kPa; P = 0.006). A Cox proportional analysis demonstrated that the need for LT was significantly higher in BA subjects with LSM >16 kPa measured 1 week post‐HPE than other BA subjects (hazard ratio HR = 10.16; P = 0.04). Conclusion: LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM post‐HPE may predict complications and the need for early LT in infants with BA. (Hepatology 2018).
Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected ...subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.
Background & Aims Immunoprophylaxis reduces but does not completely eradicate hepatitis B virus (HBV) transmission. This prospective study aims at assessing the rate and risk factors of maternally ...transmitted HBV infection. Methods We enrolled 303 mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg) under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4–8 months and/or 1–3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. Results HBeAg-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 vs. 2.7 ± 1.4 log10 copies/ml, p <0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5–9.5 log10 copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with risk of infection (adjusted odds ratio for each log10 copy/ml increase, 3.49; 95% confidence interval (CI), 1.63–7.48; p = 0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log10 copies/ml were 6.6% (95% CI, 0.5–12.6%; p = 0.033), 14.6% (95% CI, 5.6–23.6%; p = 0.001), and 27.7% (95% CI, 13.1–42.4%; p <0.001), respectively. Conclusions Additional strategies to further reduce transmission should be considered in mothers with a viral load above 7–8 log10 copies/ml.
Background & Aims Hepatitis B virus (HBV) infection was hyperendemic in Taiwan before the implementation of the universal infant hepatitis B immunization program, which was launched in 1984. Five ...previous seroepidemiologic surveys were conducted at 0, 5, 10, 15, and 20 years after the launch of the vaccination program. Methods We enrolled 3332 subjects younger than 30 years of age, with approximately 100 of them in each age cohort. Subjects were recruited voluntarily from schools and other institutions in Taipei, as in previous surveys. HBV seromarkers included hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). HBV DNA levels were measured in anti-HBc positive/HBsAg negative subjects (anti-HBc only). Results The HBsAg, anti-HBs, and anti-HBc seropositive rates were very different between subjects born after the program in 2009 and the baseline group in 1984 (0.9% vs. 10%, 55.9% vs. 24.5%, and 7.0% vs. 28%, respectively). In this 6th survey, we showed that HBsAg prevalence further decreased in the vaccinated cohorts. A positive maternal HBsAg status was found in 86% of vaccine failures. Serum HBV DNA was detected in 4.2% (6/142) of anti-HBc positive/HBsAg negative subjects, with a low level of HBV DNA. All of these six subjects’ HBV were genotype C. Conclusions The universal infant HBV immunization program in Taiwan has completed its 25-year follow-up and its efficacy in young adults is clear. The continued decrease in HBsAg prevalence suggests that the elimination of HBV infection is becoming a reality.
A universal hepatitis B virus (HBV) vaccination program has been implemented in Taiwan since 1984. A total of 1611 individuals in Taipei were enrolled to monitor long-term efficacy. The prevalences ...of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody in the vaccinated birth cohort were lower than in those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, respectively; P < .0001). Three vaccine-failure carriers all were born to HBsAg-carrier mothers, probably due to no antiviral intervention during pregnancy. Occult HBV infection was rare in the postvaccination era. High vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminate HBV transmission.
Background and Aim
Achalasia often presents with chronic food stasis and fermentation in the esophageal lumen, which may lead to alterations of the esophageal microbiome, with associated mucosal ...inflammation and dysplastic changes. The study aims to evaluate the characteristics of the esophageal microbiome in achalasia and changes of the esophageal microbiome before and after peroral endoscopic myotomy (POEM).
Methods
This is a prospective case–control study. This study enrolled patients with achalasia and asymptomatic subjects as control group. Endoscopic brushing for esophageal microbiome collection was performed in all subjects, with additional follow‐up endoscopy and brushing 3 months after POEM in achalasia patients. The composition of the esophageal microbiome was determined and compared between (1) achalasia patients and asymptomatic controls and (2) achalasia patients before and after POEM.
Results
Thirty‐one achalasia patients (mean age 53.5 ± 16.2 years; male 45.2%) and 15 controls were analyzed. We observed a distinct esophageal microbial community structure in achalasia patients, with increased Firmicutes and decreased Proteobacteria when compared with the control group at the phylum level. The discriminating enriched genera in achalasia patients were Lactobacillus, followed by Megasphaera and Bacteroides, and the amount of Lactobacillus was associated with the severity of achalasia. Twenty patients were re‐examined after POEM, and a high prevalence of erosive esophagitis (55%) was noted, alongside an increase in genus Neisseria and decrease in Lactobacillus and Bacteroides.
Conclusions
The altered esophageal microenvironment in achalasia leads to dysbiosis with a high abundance of genus Lactobacillus. Increased Neisseria and decreased Lactobacillus were observed after POEM. The long‐term effect of microbial changes warrants further study.
The calmodulin binding transcription activator (CAMTA) is a transcription factor that is widely present in eukaryotes with conserved structure. It contributes to the response to biotic and abiotic ...stresses and promotes the growth and development of plants. Although previous studies have investigated the number and function of CAMTAs in some species, there is still a lack of comprehensive understanding of the evolutionary process, phylogenetic relationship, expression patterns, and functions of CAMTAs in plants. Here we identified 465 CMATA genes from 112 plants and systematically studied the origin of CAMTA family, gene expansion, functional differentiation, gene structure, and conservative motif distribution. Based on these analyses, we presented the evidence that CAMTA family was originated from chlorophyta, and we speculated that CAMTA might experience obvious structure variation during its early evolution, and that the number of CAMTA genes might gradually increase in higher plants. To reveal potential functions of CAMTA genes, we analyzed the expression patterns of 12 representative species and found significant species specificity, tissue specificity, and developmental stage specificity of CAMTAs. The results also indicated that the CAMTA genes might promote the maturation and senescence. The expression levels and regulatory networks of CAMTAs revealed that CAMTAs could enhance cold tolerance of rice by regulating carbohydrate metabolism-related genes to accumulate carbohydrates or by modulating target genes together with other transcription factors. Our study provides an insight into the molecular evolution of CAMTA family and lays a foundation for further study of related biological functions.
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