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Background: Screening and treating healthcare workers (HCWs) for latent tuberculosis infection (LTBI) are essential for tuberculosis (TB) infection control. Adverse drug reactions (ADRs) to anti-TB drugs present challenges to patient safety and treatment completion. Objective: This study investigated the association between human leukocyte antigen (HLA) alleles and the risk of ADRs, especially drug hypersensitivity (DHS) and hepatotoxicity, in HCWs with LTBI receiving isoniazid (INH) and rifampin (RIF) therapy. Methods: Korean HCWs with LTBI who received a 3 month INH and RIF regimen were included in this study. HLA genotyping was performed on HCWs who experienced ADRs during treatment, as well as the control group consisted of individuals who did not develop ADRs. Results: Of the 67 patients, 29 (43.2%) experienced ADRs during INH and RIF therapy. The HLA-A*11:01 allele was more frequent in patients with DHS without hepatotoxicity (DSH+/H−) compared to the control group (DHS−/H−) (4/9, 44.4% vs. 3/38, 7.9%; odd ratio [OR], 8.554; 95% confidence interval [CI], 1.415–59.869; p = 0.018). Conversely, HLA-DPB1*05:01 was associated with an increased risk of hepatotoxicity regardless of DHS (10/20, 50% vs. 5/38, 13.2%; OR, 5.323; 95% CI, 1.493–21.518; p = 0.011). In the DHS with hepatotoxicity group (DHS+/H+), HLA-DPB1*05:01 was present in a higher proportion (3/5, 60% vs. 5/38, 13.2%; OR, 8.912; 95% CI, 1.110–92.993; p = 0.037), whereas HLA-A*11:01 was not observed in this group. Conclusions: The HLA-A*11:01 allele was associated with an increased risk of DHS without hepatotoxicity, whereas the HLA-DPB1*05:01 allele was associated with an increased risk of hepatotoxicity.

Background: Screening and treating healthcare workers (HCWs) for latent tuberculosis infection (LTBI) are essential for tuberculosis (TB) infection control. Adverse drug reactions (ADRs) to anti-TB drugs present challenges to patient safety and treatment completion. Objective: This study investigated the association between human leukocyte antigen (HLA) alleles and the risk of ADRs, especially drug hypersensitivity (DHS) and hepatotoxicity, in HCWs with LTBI receiving isoniazid (INH) and rifampin (RIF) therapy. Methods: Korean HCWs with LTBI who received a 3 month INH and RIF regimen were included in this study. HLA genotyping was performed on HCWs who experienced ADRs during treatment, as well as the control group consisted of individuals who did not develop ADRs. Results: Of the 67 patients, 29 (43.2%) experienced ADRs during INH and RIF therapy. The HLA-A*11:01 allele was more frequent in patients with DHS without hepatotoxicity (DSH+/H−) compared to the control group (DHS−/H−) (4/9, 44.4% vs. 3/38, 7.9%; odd ratio [OR], 8.554; 95% confidence interval [CI], 1.415–59.869; p = 0.018). Conversely, HLA-DPB1*05:01 was associated with an increased risk of hepatotoxicity regardless of DHS (10/20, 50% vs. 5/38, 13.2%; OR, 5.323; 95% CI, 1.493–21.518; p = 0.011). In the DHS with hepatotoxicity group (DHS+/H+), HLA-DPB1*05:01 was present in a higher proportion (3/5, 60% vs. 5/38, 13.2%; OR, 8.912; 95% CI, 1.110–92.993; p = 0.037), whereas HLA-A*11:01 was not observed in this group. Conclusions: The HLA-A*11:01 allele was associated with an increased risk of DHS without hepatotoxicity, whereas the HLA-DPB1*05:01 allele was associated with an increased risk of hepatotoxicity. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

Limited studies have examined the intestinal microbiota composition in relation to Crohn’s disease (CD) prognosis. We analyzed the differences in microbial communities and relevant metabolic pathways associated with prognostic variables in patients with CD. We applied 16S rRNA gene sequencing to analyze a cohort of 1110 CD and healthy control (HC) fecal samples. We categorized patients with CD into good (CD-G), intermediate (CD-I) and poor (CD-P) prognosis groups, according to the history of using biologics and intestinal resection. Microbiota α-diversity decreased more in CD-P than CD-G and CD-I. Microbiota ß-diversity in CD-P differed from that in CD-G and CD-I. Thirteen genera and 10 species showed differential abundance between CD-G and CD-P groups. Escherichia coli (p = 0.001) and species Producta (p = 0.01) and genera Lactobacillus (p = 0.003) and Coprococcus (p = 0.01) consistently showed differences between CD-G and CD-P groups after adjusting for confounding variables. Functional profiling suggested that the microbial catabolic pathways and pathways related to enterobacterial common antigen and lipopolysaccharide biosynthesis were better represented in the CD-P group than in the CD-G group, and E. coli were the top contributors to these pathways. CD prognosis is associated with altered microbiota composition and decreased diversity, and E. coli might be causally involved in CD progression, and may have adapted to live in inflammatory environments.

The gut microbiota has been linked to blood lipids. However, the relationship between the gut microbiome and other lipid markers like apolipoproteins A1 (apoA1) and B (apoB) as well as classical lipid markers in Asians remain unclear. Here, we examined the associations between gut microbial diversity and taxonomic compositions with both apolipoproteins and lipid markers in a large number of Korean patients. The fecal 16S rRNA gene sequencing data from 1141 subjects were analyzed and subjects were categorized into control group (G0) or abnormal group (G1) according to blood lipid measurements. The microbial diversity and several taxa of the gut microbiota were significantly associated with triglyceride, apoA1, and apoB levels, but not with total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. The alpha diversity of the gut microbiota was inversely associated with high triglyceride level. Interestingly, G1 of apoA1 showed increased microbial richness and distinct microbial community compared with G0 of apoA1. A high abundance of Fusobacteria and low abundance of Oscillospira were found in the hypertriglyceridemia group. In this large-scale study, we identified associations of gut microbiota with apolipoproteins and classical lipid markers, indicating that the gut microbiota may be an important target for regulating blood lipids.

Gut dysbiosis is regarded as a pathogenetic factor of nonalcoholic fatty liver disease (NAFLD), but its role in NAFLD persistence is unknown. We investigated the influence of the gut microbiota on persistent NAFLD. This cohort study included 766 subjects with 16S ribosomal RNA (rRNA) gene sequencing data from fecal samples at baseline who underwent repeated health check-up examinations. Fatty liver was determined using ultrasound at baseline and follow-up. Participants were categorized into four groups: none (control), developed, regressed, or persistent NAFLD. The persistent NAFLD group had lower richness compared with the control group. Significant differences were also found in both non-phylogenic and phylogenic beta diversity measures according to NAFLD persistence. Pairwise comparisons indicated that taxa abundance mainly differed between the control and persistent NAFLD groups. A relative high abundance of Fusobacteria and low abundance of genera Oscillospira and Ruminococcus of the family Ruminococcaceae and genus Coprococcus of the family Lachnospiraceae were found in the persistent NAFLD group. Based on the functional predictions, pathways related to primary and secondary bile acid biosynthesis were highly detected in the persistent NAFLD group compared with the control group. These findings support that the composition of the gut microbiome associated with dysregulation of bile acid biosynthetic pathways may contribute to the persistence of NAFLD. This is the first cohort study to demonstrate the influence of microbiota on persistent NAFLD. Our findings may help identify potential targets for therapeutic intervention in NAFLD.

The changes in the gut microbiota of healthy hepatitis B virus (HBV) carriers, including asymptomatic and non-cirrhotic subjects, have been rarely scrutinized. From 1463 faecal samples in health examinees, in total 112 subjects, including 36 hepatitis B surface antigen (HBsAg)-positive and 76 control subjects, were included. Twenty-eight of 36 HBsAg-positive individuals (78%) showed normal alanine aminotransferase (ALT) levels (normal ALT group), whereas eight subjects exhibited elevated ALT levels (22%, high ALT group). By using 16S rRNA gene sequencing, the distance between normal and high ALT groups among HBsAg-positive subjects showed a significant separation after the pairwise comparison of weighted UniFrac distance (permutational analysis of variance q-value = 0.039), when compared with the distances to the control group. In comparison with the control group, the normal ALT group had Anaerostipes as a significant taxon that showed a positive association (Coefficient (Coef.) = 0.028, q = 0.039). Desulfovibrio (Coef. = 0.54, q = 0.014) and Megasphaera (Coef. = 1.41, q = 0.030) showed positive correlations, and Acidaminococcus (Coef. = −1.31, q = 4.15 × 10−75) exhibited a negative correlation with high ALT level. Gut microbial composition was different according to HBV-induced serum ALT levels, indicative of a potential link between gut and liver metabolism.

Platelet count reflects the severity and prognosis of multiple diseases. Additionally, alterations in gut microbiota have been linked to several chronic diseases. The purpose of this study was to investigate the association between gut microbiota and platelet count. We selected 1268 subjects with fecal 16S RNA gene sequencing data from a Healthcare Screening Center cohort. Based on the third quartile of platelets (277 × 109/L), we compared the gut microbiota between the upper quartile (n = 321) and lower three quartiles groups (n = 947). The upper quartile group had lower alpha diversity based on observed amplicon sequence variants (q = 0.004) and phylogenetic index (q < 0.001) than the lower three quartiles group. Significant differences were also found in the weighted UniFrac distance (q = 0.001) and Jaccard dissimilarity (q = 0.047) beta diversity measures between the two groups. Compared with the lower three quartiles group, the upper quartile group exhibited decreased relative abundances of the genus Faecalibacterium, which was also inversely correlated with the platelet count. Increased platelet count was associated with reduced diversity in gut microbiota and lower abundances of Faecalibacterium with beneficial gut bacteria spices F. prausnitzii, suggesting that an increased platelet count, even within normal range, may adversely affect gut microbial diversity and composition.

There have been few large-scale studies on the relationship between smoking and gut microbiota. We investigated the relationship between smoking status and the composition of gut microbiota. This was a population-based cross-sectional study using Healthcare Screening Center cohort data. A total of 758 men were selected and divided into three groups: never (n = 288), former (n = 267), and current smokers (n = 203). Among the three groups, there was no difference in alpha diversity, however, Jaccard-based beta diversity showed significant difference (p = 0.015). Pairwise permutational multivariate analysis of variance (PERMANOVA) tests between never and former smokers did not show a difference; however, there was significant difference between never and current smokers (p = 0.017) and between former and current smokers (p = 0.011). Weighted UniFrac-based beta diversity also showed significant difference among the three groups (p = 0.038), and pairwise PERMANOVA analysis of never and current smokers showed significant difference (p = 0.01). In the analysis of bacterial composition, current smokers had an increased proportion of the phylum Bacteroidetes with decreased Firmicutes and Proteobacteria compared with never smokers, whereas there were no differences between former and never smokers. In conclusion, gut microbiota composition of current smokers was significantly different from that of never smokers. Additionally, there was no difference in gut microbiota composition between never and former smokers.

Thymic stromal lymphopoietin (TSLP) is crucial for Th2-mediated inflammation. Sepsis is a serious systemic inflammatory reaction with organ dysfunction by infection. However, the function of TSLP during sepsis is poorly understood. Thus, we investigated a role and regulatory mechanism of TSLP during sepsis. Sepsis was induced by lipopolysaccharides (LPS) or Escherichia coli DH5α injection in mice. TSLP levels were measured in human subjects, mice, and macrophages. TSLP deficiency or murine double minute 2 (MDM2) deficiency was induced using siRNA or an MDM2 inhibitor, nutlin-3a. We found that TSLP levels were elevated in serum of patients and mice with sepsis. TSLP deficiency lowered liver damage and inflammatory cytokine levels in mice with sepsis. TSLP was produced by the MDM2/NF-κB signaling pathway in LPS-stimulated macrophages. TSLP downregulation by an MDM2 inhibitor, nutlin-3a, alleviated clinical symptoms and septic inflammatory responses. Pharmacological inhibition of TSLP level by cisplatin reduced the septic inflammatory responses. Altogether, the present results show that TSLP exacerbates septic inflammation via the MDM2 signaling pathway, suggesting that TSLP may be a potential target for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Background: postoperative atelectasis is a significant clinical problem during thoracic surgery with one-lung ventilation. Intraoperative deep neuromuscular blockade can improve surgical conditions, but an increased risk of residual paralysis may aggravate postoperative atelectasis. Every patient was verified to have full reversal before extubation. We compared the effect of deep versus moderate neuromuscular blockade on postoperative atelectasis quantitatively using chest computed tomography. Methods: patients undergoing thoracic surgery were randomly allocated to two groups: moderate neuromuscular blockade during surgery (group M) and deep neuromuscular blockade during surgery (group D). The primary outcome was the proportion and the volume of postoperative atelectasis measured by chest computed tomography on postoperative day 2. The mean values of the repeatedly measured intraoperative dynamic lung compliance during surgery were also compared. Result: the proportion of postoperative atelectasis did not differ between the groups (1.32 [0.47–3.20]% in group M and 1.41 [0.24–3.07]% in group D, p = 0.690). The actual atelectasis volume was 38.2 (12.8–61.4) mL in group M and 31.9 (7.84–75.0) mL in group D (p = 0.954). Some factors described in the lung protective ventilation were not taken into account and might explain the atelectasis in both groups. The mean lung compliance during one-lung ventilation was higher in group D (26.6% in group D vs. 24.1% in group M, p = 0.026). Conclusions: intraoperative deep neuromuscular blockade did not affect postoperative atelectasis when compared with moderate neuromuscular blockade if full reversal was verified.

Seizures in infancy have highly variable courses and underlying etiologies. However, there are only a few long-term follow-up studies regarding infantile-onset epilepsy. Therefore, we aimed to describe the clinical courses, seizure outcomes, and risk factors of infantile-onset epilepsy followed up for more than 10 years in a tertiary center. Methods: Data of the patients with epilepsy, diagnosed under the age of 12 months and followed up for more than 10 years, were retrieved from the electronic medical records of Asan Medical Center Children’s Hospital. The patients’ medical records were retrospectively reviewed, and clinical outcomes were assessed based on the duration of seizure freedom at the last follow-up. Results: Of the 146 patients, 103 (70.5%) entered at least one remission, of whom epilepsy was resolved in 46 (31.5%). Forty-nine (33.6%) were found to be intractable at last contact. Delayed development, neurological deficits, and later onset (>3 months) were significantly associated with intractable epilepsies (p < 0.01). Conclusions: This study demonstrated that many patients with infantile-onset epilepsy can experience seizure remission. However, in some cases, early onset epilepsy was highly associated with various comorbidities and intractable seizures. Therefore, appropriate diagnosis and treatment are necessary to prevent further neuropsychiatric complications.