Anti-Integrin αvß6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis.

BACKGROUND & AIMS: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvß6 (anti-αvß6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvß6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS: Anti-αvß6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvß6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvß6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS: Anti-αvß6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvß6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvß6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvß6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvß6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Environmental Factors Associated with Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.

BACKGROUND & AIMS: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers. METHODS: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing. RESULTS: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting FCP or LMR. CONCLUSION: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis.

Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis.

OBJECTIVE: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. DESIGN: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. RESULTS: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). CONCLUSION: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.

Facet-Dependent Passivation for Efficient Perovskite Solar Cells.

Understanding the interplay between the surface structure and the passivation materials and their effects associated with surface structure modification is of fundamental importance; however, it remains an unsolved problem in the perovskite passivation field. Here, we report a surface passivation principle for efficient perovskite solar cells via a facet-dependent passivation phenomenon. The passivation process selectively occurs on facets, which is observed with various post-treatment materials with different functionality, and the atomic arrangements of the facets determine the alignments of the passivation layers. The profound understanding of facet-dependent passivation leads to the finding of 2-amidinopyridine hydroiodide as the material for a uniform and effective passivation on both (100) and (111) facets. Consequently, we achieved perovskite solar cells with an efficiency of 25.10% and enhanced stability. The concept of facet-dependent passivation can provide an important clue on unidentified passivation principles for perovskite materials and a novel means to enhance the performance and stability of perovskite-based devices.

Mediterranean-Like Dietary Pattern Associations With Gut Microbiome Composition and Subclinical Gastrointestinal Inflammation.

BACKGROUND & AIMS: Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD. METHODS: As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters. RESULTS: DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota. CONCLUSIONS: Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease.

BACKGROUND & AIMS: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease. METHODS: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function. RESULTS: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R2 = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6). CONCLUSIONS: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.

Genome-wide identification and characterization of the lettuce GASA family in response to abiotic stresses.

BACKGROUND: Lettuce is one of the most extensively farmed vegetables in the world, and it prefers cool growing conditions. High temperatures promote premature bolt formation, reducing quality and yield. The gibberellic acid-stimulated Arabidopsis (GASA) family genes play critical roles in plant growth, development, and stress responses. However, the biological functions of GASA proteins in lettuce have yet to be thoroughly investigated. RESULTS: Using genome-wide analysis, 20 GASAs were identified in lettuce including, three groups of LsGASA proteins based on the phylogenetic analysis. Except for one, all GASA proteins included a conserved GASA domain with 12 cysteine residues. Cis-element analysis showed that LsGASAs were closely associated with light, phytohormones, and stress resistance. Five segmental and three tandem duplication events were observed in the LsGASA family based on duplication analysis. GASA synteny analysis among lettuce, Arabidopsis, tobacco, and rice revealed that LsGASA5 is highly collinear with all species. Six of the 20 LsGASA showed increased expression patterns at specific time points in the shoot apical meristem when subjected to heat stress. According to gene expression analysis, the majority of GASA were highly expressed in flowers compared to other organs, and six GASA exhibited highly increased expression levels in response to NaCl, abscisic acid, and gibberellin treatment. Furthermore, LsGASA proteins are predominantly found in the plasma membrane and/or the cytosol. CONCLUSIONS: This study provides a comprehensive characterization of LsGASA genes for their diversity and biological functions. Moreover, our results will be useful for further studies on the function of lettuce GASA in abiotic stress- and heat-induced bolting signaling.

Automated diagnosis of flatfoot using cascaded convolutional neural network for angle measurements in weight-bearing lateral radiographs.

OBJECTIVES: Diagnosis of flatfoot using a radiograph is subject to intra- and inter-observer variabilities. Here, we developed a cascade convolutional neural network (CNN)-based deep learning model (DLM) for an automated angle measurement for flatfoot diagnosis using landmark detection. METHODS: We used 1200 weight-bearing lateral foot radiographs from young adult Korean males for the model development. An experienced orthopedic surgeon identified 22 radiographic landmarks and measured three angles for flatfoot diagnosis that served as the ground truth (GT). Another orthopedic surgeon (OS) and a general physician (GP) independently identified the landmarks of the test dataset and measured the angles using the same method. External validation was performed using 100 and 17 radiographs acquired from a tertiary referral center and a public database, respectively. RESULTS: The DLM showed smaller absolute average errors from the GT for the three angle measurements for flatfoot diagnosis compared with both human observers. Under the guidance of the DLM, the average errors of observers OS and GP decreased from 2.35° ± 3.01° to 1.55° ± 2.09° and from 1.99° ± 2.76° to 1.56° ± 2.19°, respectively (both p < 0.001). The total measurement time decreased from 195 to 135 min in observer OS and from 205 to 155 min in observer GP. The absolute average errors of the DLM in the external validation sets were similar or superior to those of human observers in the original test dataset. CONCLUSIONS: Our CNN model had significantly better accuracy and reliability than human observers in diagnosing flatfoot, and notably improved the accuracy and reliability of human observers. KEY POINTS: • Development of deep learning model (DLM) that allows automated angle measurements for landmark detection based on 1200 weight-bearing lateral radiographs for diagnosing flatfoot. • Our DLM showed smaller absolute average errors for flatfoot diagnosis compared with two human observers. • Under the guidance of the model, the average errors of two human observers decreased and total measurement time also decreased from 195 to 135 min and from 205 to 155 min.

Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic Bacillus licheniformis.

Antibiotic resistance is one of the world's most urgent public health problems, and novel antibiotics to kill drug-resistant bacteria are needed. Natural product-derived small molecules have been the major source of new antibiotics. Here we describe a family of antibacterial metabolites isolated from a probiotic bacterium, Bacillus licheniformis. A cross-streaking assay followed by activity-guided isolation yielded a novel antibacterial metabolite, bacillimidazole G, which possesses a rare imidazolium ring in the structure, showing MIC values of 0.7-2.6 µg/mL against human pathogenic Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and a lipopolysaccharide (LPS)-lacking Acinetobacter baumannii ΔlpxC. Bacillimidazole G also lowered MICs of colistin, a Gram-negative antibiotic, up to 8-fold against wild-type Escherichia coli MG1655 and A. baumannii. We propose a biosynthetic pathway to the characterized metabolites based on precursor-feeding studies, a chemical biological approach, biomimetic total synthesis, and a biosynthetic gene knockout method.

Higher survival rate in total knee arthroplasty after high tibial osteotomy than that after unicompartmental knee arthroplasty.

PURPOSE: The objective of this study was to evaluate the survival rates and complications in TKA after UKA and HTO as compared with primary TKA using national health data. It was hypothesized that survival and complication rates would be worse in patients with a history of UKA or HTO compared to primary TKA. METHODS: Based on a list of patients who underwent TKA from Korean National Health Insurance database, 315,071 underwent primary TKA (group A); 2177 TKA after HTO (group B); and 1284 TKA after UKA (group C). Revision rates were compared between the groups using log-rank tests and adjusted hazard ratios (HR) of groups B and C were compared with those of the reference group (group A). A total of 1000 TKA matched patients were assigned to groups B and C according to propensity score for comparing revision rates after TKA and perioperative complication rates between TKA after HTO and UKA. RESULTS: The overall revision rate was 2.1% in group A, 2.0% in group B, and 4.2% in group C. The revision rate until 10 years after TKA was significantly higher in group B (p = 0.03) or C (p < 0.0001) than in group A. The hazard ratios for revision was significantly higher in group A than in groups B and C at 10 years after index TKA (1.4 in group B and 3.7 in group C). The result of the comparison using PSM between TKA after HTO and UKA showed that TKA after HTO had lower risk of revision than TKA after UKA (HR: 0.41 at 10 years). However, no statistically significant differences in the perioperative complication rate between the two groups were found. (NS, not significant) CONCLUSIONS: TKA after UKA or HTO showed a significantly higher risk of revision than primary TKA. While TKA after HTO showed lower risk of revision than TKA after UKA, no significant differences in complications between TKA after UKA and HTO were found. Thus, surgeons must be aware of the low survival rate in TKA after UKA or HTO, especially in TKA after UKA. LEVEL OF EVIDENCE: III (Retrospective cohort study).

Can convertible metal-backed glenoid components replace cemented polyethylene glenoid components in anatomical total shoulder arthroplasty?

BACKGROUND: Anatomical total shoulder arthroplasty (aTSA) has been used to manage degenerative diseases such as primary osteoarthritis. An increase in the use of this procedure has led to several developments in humeral and glenoid components to improve patient outcomes. This study aimed to compare clinical and radiological outcomes of the newly-introduced convertible metal-backed glenoid components with cemented polyethylene glenoid components in aTSA, and to determine whether the new component would be comparable to a conventional one for reducing the burden of future revision or conversion surgeries. METHODS: Medical records of fifty patients who underwent aTSA with at least two years of follow-up were retrospectively reviewed. Eighteen patients received convertible metal-backed glenoid components with vitamin E1-coated liner (MB group), while thirty-two patients received conventional cemented polyethylene glenoid components (PE group). Pre- and postoperative clinical and radiological outcomes (acromion-greater tuberosity angle [AGA] and humeral lateral offset [LO]) at final follow-up were assessed. Radiolucent lines (RLLs) and loosening around the humeral and glenoid components were also evaluated. RESULTS: Clinical outcomes improved after surgery in both groups (all p < 0.001). The arc of rotation measured by AGA improved postoperatively in both groups (all p < 0.001), and AGA and LO were not different according to the type of glenoid components (all p > 0.05). Overall complication rates including RLLs of PE and MB groups were 43.8% (14/32) and 16.7% (3/18), respectively (p = 0.031). Although the PE group had more RLLs than did the MB group (p < 0.05), related symptoms and/or glenoid implant loosening were not observed in both groups. Subscapularis failure occurred in two patients in the PE group and in one in the MB group. CONCLUSION: The convertible metal-backed glenoid implant with vitamin E1-coated liner may be a good alternative for considering the potential for an easier conversion to reverse total shoulder arthroplasty.

Dural rupture and subsequent spinal cord herniation due to closed wound suction drainage after spinal surgery.

Closed wound suction drains are commonly used in spinal surgery. Severe neurological complications related to their use are rare. Here, we report a case of a dural rupture and subsequent spinal cord herniation related to the use of closed suction drains after posterior decompression and fixation surgery for spinal metastasis.

Water Extract of Capsella bursa-pastoris Mitigates Doxorubicin-Induced Cardiotoxicity by Upregulating Antioxidant Enzymes.

Doxorubicin (DOX), an effective chemotherapeutic drug, causes cardiotoxicity in a cumulative and dose-dependent manner. The aim of this study is to investigate the effects of hot-water extract of Capsella bursa-pastoris (CBW) on DOX-induced cardiotoxicity (DICT). We utilized H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells to evaluate the effects of CBW on DOX-induced cell death. Superoxide dismutase (SOD) levels, reactive oxygen species (ROS) production, and oxygen consumption rate were measured in H9c2 cells. C57BL/6 mice were treated with DOX and CBW to assess their impact on various cardiac parameters. Human-induced pluripotent stem-cell-derived cardiomyocytes were also used to investigate DOX-induced electrophysiological changes and the potential ameliorative effects of CBW. UPLC-TQ/MS analysis identified seven flavonoids in CBW, with luteolin-7-O-glucoside and isoorientin as the major compounds. CBW inhibited DOX-induced death of H9c2 rat cardiomyocytes but did not affect DOX-induced death of MDA-MB-231 human breast cancer cells. CBW increased SOD levels in a dose-dependent manner, reducing ROS production and increasing the oxygen consumption rate in H9c2 cells. The heart rate, RR interval, QT, and ST prolongation remarkably recovered in C57BL/6 mice treated with the combination of DOX and CBW compared to those in mice treated with DOX alone. Administration of CBW with DOX effectively alleviated collagen accumulation, cell death in mouse heart tissues, and reduced the levels of creatinine kinase (CK) and lactate dehydrogenase (LDH) in serum. Furthermore, DOX-induced pathological electrophysiological features in human-induced pluripotent stem-cell-derived cardiomyocytes were ameliorated by CBW. CBW may prevent DICT by stabilizing SOD and scavenging ROS. The presence of flavonoids, particularly luteolin-7-O-glucoside and isoorientin, in CBW may contribute to its protective effects. These results suggest the potential of CBW as a traditional therapeutic option to mitigate DOX-induced cardiotoxicity.

Comparison of survival rates between total knee arthroplasty after a previous anterior cruciate ligament reconstruction and primary total knee arthroplasty via propensity score matching.

INTRODUCTION: Although the survival rate of total knee arthroplasty (TKA) in patients treated with anterior cruciate ligament reconstruction (ACLR) is not as favorable as that in patients treated with primary TKA without ligament reconstruction, the exact survival rates and complications associated with these procedures are still controversial. Therefore, the purpose of the current study was to compare the revision rates of TKA in patients with knee osteoarthritis (OA) with a previous ACLR and those of patients with primary TKA with no history of knee surgery by using propensity score matching analysis. MATERIALS AND METHODS: A list of patients who underwent TKA from January 1, 2008 to May 31, 2019 was obtained from the Korean National Health Insurance database. Among these, 460 patients underwent TKA in a knee with a previous ACLR and 569,766 patients who underwent primary TKA due to degenerative OA. We performed propensity scoring matching to compare the revision rates including septic revision due to prosthetic joint infection after TKA and perioperative complication rates within 90 days after revision TKA between the two groups. RESULTS: Matched patients were assigned to one of the two groups (group A: 2,201 patients who underwent TKA due to primary OA, group B: 448 patients who underwent TKA in a knee with a previous ACLR) based on the propensity score. The total number of revisions per 1000 person-years was significantly higher in group B than in group A (10.16 vs 4.66, respectively). Group B showed a higher risk of revision than group A at 10 years post-TKA (hazard ratio: 2.49, 95% confidence interval: 1.30-4.77). However, group B showed a similar risk of septic revision as group A (p = 0.44). Perioperative complications within 90 days after TKA showed no significant differences between the groups. CONCLUSIONS: Surgeons should be aware of the relatively higher revision rate of TKA in patients who had previously undergone an ACLR compared to that in patients who underwent primary TKA.

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

BACKGROUND AND AIMS: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development. METHODS: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis. RESULTS: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation. CONCLUSIONS: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.

A comparative study of 21,194 UKAs and 49,270 HTOs for the risk of unanticipated events in mid-age patients from the national claims data in South Korea.

BACKGROUND: Both high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) are well-established treatments for medial knee osteoarthritis (OA). However, over the past 20 years, results of comparisons of long-term survival rates and outcomes have remained controversial. Furthermore, in patients at the boundary age, from 50 to 70 years, considering age as a treatment indication, selecting a surgical method is difficult. Therefore, we aimed to investigate conversion rates to total knee arthroplasty (TKA) and perioperative adverse outcomes between the two surgical methods in mid-age patients. METHODS: We extracted data from the Korean National Health Insurance claims database. A total of 70,464 patients aged between 50 and 70 years, considered as mid-age patients were included in the final study population. We used a multivariable Cox proportional hazard regression model, adjusting for potential confounders such as age, sex, insurance type, region of residence, hospital type, comorbidities, and the Charlson comorbidity Index (CCI). RESULTS: Of the 70,464 patients, 21,194 were treated with UKA and 49,270 were treated with HTO. HTO showed a higher risk of revision than UKA at five, and 10 years and during the whole observation period. The incidence of deep vein thromboembolism, and surgical site infection was significantly higher in UKA than in HTO. CONCLUSIONS: It is important to choose an appropriate surgical method considering that UKA has better results in terms of long-term survival rates but may have a higher incidence of various complications.

Subacute Thyroiditis After Receiving the mRNA COVID-19 Vaccine (Moderna): The First Case Report and Literature Review in Korea.

Subacute thyroiditis (SAT) is a painful thyroiditis that often requires steroid therapy. Here, we report the first case of severe SAT in a patient who received the first dose of mRNA coronavirus disease 2019 (COVID-19) vaccination. A 34-year-old man without a viral prodrome felt a lump when swallowing 5 days after his first dose of mRNA-1273 (Moderna) vaccination. Ten days after vaccination, the patient visited the hospital and was advised to rest and take nonsteroidal anti-inflammatory drugs. He revisited the hospital 10 days later as symptoms aggravated with anterior neck pain, headache, fatigue, muscle weakness, and weight loss. Thyroid hormone levels and inflammatory markers were consistent with thyrotoxicosis. A thyroid ultrasound scan revealed typical SAT findings. His symptoms rapidly improved after receiving prednisone. A week later, the patient successfully completed his second dose of the vaccine. The thyroid function test results were nearly normal 1 month after the completion of the vaccination. We report this case to raise awareness of the occurrence of SAT after COVID-19 vaccination. As the risk of COVID-19 outweighs the minor risks of the vaccine, managing the side effects of the first vaccine dose is crucial to complete COVID-19 vaccination.

Significant Therapeutic Effects of Adult Human Neural Stem Cells for Spinal Cord Injury Are Mediated by Monocyte Chemoattractant Protein-1 (MCP-1).

The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult human brain, which have the essential characteristics of NSCs. The objective of this study was to characterize the therapeutic effects of ahNSCs isolated from the temporal lobes of focal cortical dysplasia type IIIa for SCI and to elucidate their treatment mechanisms. Results showed that the recovery of motor functions was significantly improved in groups transplanted with ahNSCs, where, in damaged regions of spinal cords, the numbers of both spread and regenerated nerve fibers were observed to be higher than the vehicle group. In addition, the distance between neuronal nuclei in damaged spinal cord tissue was significantly closer in treatment groups than the vehicle group. Based on an immunohistochemistry analysis, those neuroprotective effects of ahNSCs in SCI were found to be mediated by inhibiting apoptosis of spinal cord neurons. Moreover, the analysis of the conditioned medium (CM) of ahNSCs revealed that such neuroprotective effects were mediated by paracrine effects with various types of cytokines released from ahNSCs, where monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) was identified as a key paracrine mediator. These results of ahNSCs could be utilized further in the preclinical and clinical development of effective and safe cell therapeutics for SCI, with no available therapeutic options at present.

Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.

BACKGROUND & AIMS: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. METHODS: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. RESULTS: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10-4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029). CONCLUSIONS: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.