Clinical Application of Optical Genome Mapping for Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy that mainly affects skeletal muscle. FSHD1 accounts for 95% of all FSHD cases and can be diagnosed based on the pathogenic contraction of the D4Z4-repeat array on chromosome 4q35. Genetic diagnosis of FSHD1 is challenging because of the large size and repetitive nature of the D4Z4 region. We evaluated the clinical applicability of optical genome mapping (OGM) for the genetic diagnosis of FSHD1. Methods: We included 25 individuals with clinically confirmed or suspected/probable FSHD and their families. Ultra-high-molecular-weight DNA from peripheral blood was labeled, stained, and imaged using a single-molecule OGM platform (Bionano Genomics Saphyr system). D4Z4 repeat size and haplotype information were analyzed using the manufacturer's dedicated pipeline. We also compared the workflow and test time between Southern blot analysis and OGM. Results: We obtained concordant OGM and Southern blot results with 10 samples from patients with clinically confirmed FSHD. The D4Z4 repeat size differed within 1 unit between the Southern blot analysis and OGM. Among nine patients with clinically suspected or probable FSHD, six patients were confirmed to have pathogenic contractions by OGM. In our cohort, one de novo mosaic FSHD1 patient was successfully diagnosed with OGM. Moreover, OGM has a more straightforward and less time-consuming workflow than Southern blot analysis. Conclusions: OGM enables accurate and reliable detection of pathogenic contraction of the D4Z4-repeat array and is a valuable tool for the genetic diagnosis of FSHD1.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Global carrier frequency and predicted genetic prevalence of patients with pathogenic sequence variants in autosomal recessive genetic neuromuscular diseases.

Genetic neuromuscular diseases are clinically and genetically heterogeneous genetic disorders that primarily affect the peripheral nerves, muscles, and neuromuscular junctions. This study aimed to identify pathogenic variants, calculate carrier frequency, and predict the genetic prevalence of autosomal recessive neuromuscular diseases (AR-NMDs). We selected 268 AR-NMD genes and analyzed their genetic variants sourced from the gnomAD database. After identifying the pathogenic variants using an algorithm, we calculated the carrier frequency and predicted the genetic prevalence of AR-NMDs. In total, 10,887 pathogenic variants were identified, including 3848 literature verified and 7039 manually verified variants. In the global population, the carrier frequency of AR-NMDs is 32.9%, with variations across subpopulations ranging from 22.4% in the Finnish population to 36.2% in the non-Finnish European population. The predicted genetic prevalence of AR-NMDs was estimated to be 24.3 cases per 100,000 individuals worldwide, with variations across subpopulations ranging from 26.5 to 41.4 cases per 100,000 individuals in the Latino/Admixed American and the Ashkenazi Jewish populations, respectively. The AR-NMD gene with the highest carrier frequency was GAA (1.3%) and the variant with the highest allele frequency was c.-32-13 T>G in GAA with 0.0033 in the global population. Our study revealed a higher-than-expected frequency of AR-NMD carriers, constituting approximately one-third of the global population, highlighting ethnic heterogeneity in genetic susceptibility.

Is Prophylactic Antibiotic Use Necessary Before Dental Procedures in Primary and Revision TKA? A Propensity Score-matched, Large-database Study.

BACKGROUND: The question of whether dental procedures increase the risk of periprosthetic joint infection (PJI) in patients who have undergone total joint arthroplasty (TJA) remains controversial. QUESTIONS/PURPOSES: (1) Are dental procedures associated with an increased incidence of PJI in the setting of either primary or revision TKA after controlling for relevant potentially confounding variables? (2) Is the administration of prophylactic antibiotics before dental procedures associated with any differences in this risk? (3) Which factors are associated with increased incidence of PJI after dental procedures? METHODS: This nationwide, retrospective, comparative, large-database study evaluated 591,602 patients who underwent unilateral primary or revision TKA between 2009 and 2019 using the Health Insurance Review and Assessment Service data in South Korea, in which all people in South Korea were registered and to which all medical institutions must charge any procedures they performed. The study population was divided into 530,156 patients with dental procedures and 61,446 patients without dental procedures based on whether the patients underwent a dental procedure at least 1 year after the index surgery. After propensity score matching, patients were classified into a dental (n = 182,052) and a nondental cohort (n = 61,422). The dental cohort was then divided into two groups: 66,303 patients with prophylactic antibiotics and 115,749 patients without prophylactic antibiotics based on prophylactic antibiotic use. After propensity score matching, patients were categorized into prophylactic (n = 66,277) and nonprophylactic (n = 66,277) cohorts. Propensity score matching was used to control for covariates including posttraumatic arthritis associated with PJI risk according to the dental procedure and prophylactic antibiotic use among the cohorts. After propensity score matching, the standardized mean difference was confirmed to be less than 0.1 for all variables. Kaplan-Meier survival analyses, log-rank tests, and Cox proportional hazards regression analysis was performed. RESULTS: Dental procedures were not associated with an increase in PJI risk after primary (adjusted HR 1.56 [95% CI 0.30 to 8.15]; p = 0.60) or revision TKA (adjusted HR 1.74 [95% CI 0.90 to 3.34]; p = 0.10). Additionally, use of prophylactic antibiotics was not associated with a reduced PJI risk after the index surgery, either for primary (adjusted HR 1.28 [95% CI 0.30 to 5.42]; p = 0.74) or revision TKA (adjusted HR 0.74 [95% CI 0.45 to 1.23]; p = 0.25). Although surgery type and prophylactic antibiotic use exhibited no influence on PJI occurrence after dental procedures, posttraumatic arthritis was associated with PJI. The adjusted HR for posttraumatic arthritis was 4.54 (p = 0.046). CONCLUSION: Our findings suggest that dental procedures were not associated with an increased risk of PJI for up to 2 years after the dental procedure in patients who underwent either primary or revision TKA. Based on these findings, there is insufficient rationale for the use of prophylactic antibiotics before dental procedures in patients who have undergone primary or revision TKA. LEVEL OF EVIDENCE: Level III, therapeutic study.

Visible-Light Communication with Lighting: RGB Wavelength Division Multiplexing OLEDs/OPDs Platform.

A multichannel/multicolor visible light communication (VLC) system using entirely organic components, including organic light emitting diodes (OLEDs) and organic photodiodes (OPDs), is developed to demonstrate indoor lighting applications where the integration of OLEDs and OPDs has significant potential. To achieve this, tricolor (Red/Green/Blue(R/G/B))-selective OPD arrays for the receiver and tricolor OLED arrays for the emitter are developed. For (R/G/B)-selective OPDs, a Fabry-Pérot electrode to enhance color selectivity and a thick junction structure to effectively accommodate a wide range of driving voltages are introduced. For tricolor OLEDs, fluorescent-emitting materials are used to enhance the operating frequency in addition to introducing a cavity structure to achieve narrow emission. Utilizing these spectrally refined tricolor OPDs/OLEDs, a VLC system is designed for indoor lighting applications, and a systematic analysis of their signal-to-interference ratio dependence on the distance or angle between the transmitter and receiver is performed. The study's findings indicate the importance of emission angle-dependent wavelength shift of the OLED and the luminosity function, which varies with wavelength, in the R/G/B mixed-white-light-based VLC systems. Finally, the feasibility of VLC using tricolor OPDs/OLEDs in the real-life context of indoor white-color lighting is demonstrated, showing that the transmitted data patterns well-matched the received data patterns.

Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma.

BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.

Analysis of radiographic factors affecting the significant differences in knee alignment between hip-to-talus and hip-to-calcaneus radiographs after opening-wedge high tibial osteotomy.

BACKGROUND: Optimal alignment after opening-wedge high tibial osteotomy (OWHTO) is crucial for obtaining good clinical results. A hip-to-calcaneus radiograph (HCR) appears to reflect the true mechanical axis. However, no study has been reported using the HCR in patients who underwent OWHTO. We aimed to analyze the radiographic factors affecting the significant difference in the weight-bearing line (WBL) ratio between two radiographs after opening-wedge high tibial osteotomy (OWHTO). METHODS: This retrospective study included 51 patients who underwent both hip-to-talus radiographs (HTR) and HCR after OWHTO. The patients were divided into two groups; a consistent group (WBL ratio difference between postoperative HTR and HCR < 5%; N = 35) and an inconsistent group (> 5%; N = 16). Radiographic variables for lower extremity alignment, knee and ankle joints, and clinical scores were evaluated. The receiver operating characteristic curve was used to determine the threshold of radiographic variables that induced inconsistencies between the two radiographs. RESULTS: The mean postoperative WBL ratio in the HCR of the inconsistent group was significantly higher than that of the consistent group (57.7 ± 13.2% and 49.1 ± 11.6%, respectively) (P = 0.02). The preoperative and postoperative ankle joint line obliquity (AJLO) and preoperative lateral distal tibia ground surface angle (LDTGA) were significantly different between the two groups (P < 0.05). The preoperative AJLO (odds ratio 0.784, confidence interval 0.655-0.939, P = 0.008) significantly affected WBL ratio inconsistency. The cutoff value of the preoperative AJLO was 3.16°. However, clinical scores did not differ significantly between the two groups. CONCLUSION: The pre-and postoperative AJLO and the preoperative LDTGA were significantly different between the two groups. Among these variables, only preoperative AJLO negatively affected the inconsistency in WBL ratios between the two radiographs (HTT and HTC). Therefore, it should be considered to prevent postoperative overcorrection of the true mechanical axis after OWHTO, even though we corrected it properly. Level of evidence Level IV.

Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach.

Background: Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies. Dysferlinopathy, caused by a dysferlin gene mutation, usually presents in late adolescence with muscle weakness, degenerative muscle changes are often accompanied by inflammatory infiltrates, often resulting in a misdiagnosis as polymyositis. Objective: To identify differential biological pathways and hub genes related to polymyositis, dermatomyositis and dysferlinopathy using bioinformatics analysis for understanding the pathomechanisms and providing guidance for therapy development. Methods: We analyzed intramuscular ribonucleic acid (RNA) sequencing data from seven dermatomyositis, eight polymyositis, eight dysferlinopathy and five control subjects. Differentially expressed genes (DEGs) were identified by using DESeq2. Enrichment analyses were performed to understand the functions and enriched pathways of DEGs. A protein-protein interaction (PPI) network was constructed, and clarified the gene cluster using the molecular complex detection tool (MCODE) analysis to identify hub genes. Results: A total of 1,048, 179 and 3,807 DEGs were detected in DM, PM and dysferlinopathy, respectively. Enrichment analyses revealed that upregulated DEGs were involved in type 1 interferon (IFN1) signaling pathway in DM, antigen processing and presentation of peptide antigen in PM, and cellular response to stimuli in dysferlinopathy. The PPI network and MCODE cluster identified 23 genes related to type 1 interferon signaling pathway in DM, 4 genes (PDIA3, HLA-C, B2M, and TAP1) related to MHC class 1 formation and quality control in PM, and 7 genes (HSPA9, RPTOR, MTOR, LAMTOR1, LAMTOR5, ATP6V0D1, and ATP6V0B) related to cellular response to stress in dysferliniopathy. Conclusion: Overexpression of genes related to the IFN1 signaling pathway and major histocompatibility complex (MHC) class I formation was identified in DM and PM, respectively. In dysferlinopathy, overexpression of HSPA9 and the mTORC1 signaling pathway genes was detected.

Conditional diagnostic accuracy according to inflammation status and age for diagnosing tuberculous effusion.

BACKGROUND: Tuberculous effusion varies from lymphocyte-dominant to neutrophilic effusion according to inflammation status. The criteria of adenosine deaminase (ADA) and lymphocyte/neutrophil (L/N) ratio have yet not been evaluated across different disease conditions. METHODS: Patients who conducted pleural fluid analysis from 2009 to 2019 at Asan Medical Center were included. Criteria (ADA of 50 and L/N ratio of 0.75) were evaluated by quantile subgroups according to age, C-reactive protein (CRP), white blood cell (WBC), and lactate dehydrogenase (LD) by the Monte Carlo simulation method to diagnose tuberculosis. The model for the ADA and L/N ratio was evaluated by AUROC. RESULTS: Among the 2,918 reviewed cases, 2034 were included with 229 (11.26%) tuberculosis cases. The mean baseline ADA AUROC was 0.88 across all patients. Increased CRP and WBC showed high proportions of neutrophilic tuberculous effusion, with low sensitivity of approximately 45% and 33% in the fifth WBC and CRP groups, respectively. The AUROC of the models decreased with the increase in WBC and CRP groups (ADA model: 0.69 [the top quantile WBC group], 0.74 [the top quantile CRP group]). The AUROC of the models did not show a trend according to the increase in LD and age. CONCLUSION: Inflammatory status affects the diagnostic metrics for tuberculous effusion due to the progression of tuberculous effusion. Clinicians should consider the low accuracy of tuberculous effusion criteria in high-inflammatory conditions when diagnosing tuberculosis.

Differences in Resumption of Orthopedic Surgery According to Characteristics of Surgery during COVID-19 Pandemic: National Registry Data.

Background: Healthcare services have been restricted after the coronavirus disease 2019 (COVID-19) outbreak. With the pandemic still ongoing, the patterns of orthopedic surgery might have changed. The purpose of this study was to determine whether the reduced volumes of orthopedic surgery were recovered over time. Among the trauma and elective surgery, which accounted for most orthopedic surgical procedures, we also sought to elucidate whether the changes in the volumes of orthopedic surgery differed according to the type of surgery. Methods: The volumes of orthopedic surgery were analyzed using the Health Insurance Review and Assessment Service of Korea databases. The surgical procedure codes were categorized depending on the characteristics of the procedures. The actual volumes of surgery were compared with the expected volumes to elucidate the effect of COVID-19 on surgical volumes. The expected volumes of surgery were estimated using Poisson regression models. Results: The reducing effect of COVID-19 on the volumes of orthopedic surgery weakened as COVID-19 continued. Although the total volumes of orthopedic surgery decreased by 8.5%-10.1% in the first wave, those recovered to a 2.2%-2.8% decrease from the expected volumes during the second and third waves. Among the trauma and elective surgery, open reduction and internal fixation and cruciate ligament reconstruction decreased as COVID-19 continued, while total knee arthroplasty recovered. However, the volumes of hemiarthroplasty of the hip did not decrease through the year. Conclusions: The number of orthopedic surgeries, which had decreased due to COVID-19, tended to recover over time, although the pandemic was still ongoing. However, the degree of resumption differed according to the characteristics of surgery. The findings of our study will be helpful to estimate the burden of orthopedic surgery in the era of persistent COVID-19.

Clinical significance of anti-NT5c1A autoantibody in Korean patients with inflammatory myopathies.

To explore the clinical significance of anti-cytosolic 5'-nucleoditase 1A (NT5c1A) antibody seropositivity in inflammatory myopathies, we measured anti-NT5c1A antibodies and analyzed their clinical features. Anti-NT5c1A antibodies were measured in the sera of 103 patients with inflammatory myopathies using an enzyme-linked immunosorbent assay. Positivity for anti-NT5c1A antibody was found in 13 (12.6%) of 103 patients with inflammatory myopathy. Anti-NT5c1A antibody was most frequently identified in patients with inclusion body myositis (IBM) (8/20, 40%), followed by dermatomyositis (2/13, 15.4%), immune-mediated necrotizing myopathy (2/28, 7.1%), and polymyositis (1/42, 2.4%). In eight patients with the anti-NT5c1A antibody-seropositive IBM, the median age at symptom onset was 54 years (interquartile range [IQR]: 48-57 years), and the median disease duration was 34 months (IQR: 24-50 months]. Knee extension weakness was greater than or equal to hip flexion weakness in eight (100%) patients, and finger flexion strength was less than shoulder abduction in three (38%) patients. Dysphagia symptoms were found in three (38%) patients. The median serum CK level was 581 IU/l (IQR: 434-868 IU/L]. Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment. Although anti-NT5c1A antibody is known to be associated with IBM, seropositivity has also been noted in non-IBM inflammatory myopathies, and is insufficient to have clinical significance by itself. These findings have important implications for interpreting anti-NT5c1A antibody test results as the first study in Korea.

Transcriptome profiling of skeletal muscles from Korean patients with Bethlem myopathy.

Bethlem myopathy is one of the collagens VI-related muscular dystrophies caused by mutations in the collagen VI genes. The study was designed to analyze the gene expression profiles in the skeletal muscle of patients with Bethlem myopathy. Six skeletal muscle samples from 3 patients with Bethlem myopathy and 3 control subjects were analyzed by RNA-sequencing. 187 transcripts were significantly differentially expressed, with 157 upregulated and 30 downregulated transcripts in the Bethlem group. Particularly, 1 (microRNA-133b) was considerably upregulated, and 4 long intergenic non-protein coding RNAs, LINC01854, MBNL1-AS1, LINC02609, and LOC728975, were significantly downregulated. We categorized differentially expressed gene using Gene Ontology and showed that Bethlem myopathy is strongly associated with the organization of extracellular matrix (ECM). Kyoto Encyclopedia of Genes and Genomes pathway enrichment reflected themes with significant enrichment of the ECM-receptor interaction (hsa04512), complement and coagulation cascades (hsa04610), and focal adhesion (hsa04510). We confirmed that Bethlem myopathy is strongly associated with the organization of ECM and the wound healing process. Our results demonstrate transcriptome profiling of Bethlem myopathy, and provide new insights into the path mechanism of Bethlem myopathy associated with non-protein coding RNAs.

Clinical and Radiological Features of Korean Patients With Anti-HMGCR Myopathy.

BACKGROUND AND PURPOSE: To understand the characteristics of Korean patients with anti-3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR) myopathy, we measured anti-HMGCR antibodies and analyzed the clinical, radiological, and pathological features of patients with anti-HMGCR myopathy. METHODS: We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy, 36 patients with genetic myopathy, and 63 healthy subjects using an enzyme-linked immunosorbent assay. We tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy. RESULTS: Positivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years. Ten (59%) of the patients with anti-HMGCR positivity had taken statins. The titer of anti-HMGCR antibodies was significantly higher in the statin-naïve group (median=230 U/mL, interquartile range=170-443 U/mL) than in the statin-exposed group (median=178 U/mL, interquartile range=105-210 U/mL, p=0.045). The most common symptom was proximal muscle weakness in 15 patients (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/mL. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group (p=0.027). CONCLUSIONS: Our study was the first to measure anti-HMGCR antibodies in inflammatory myopathy. It has provided new findings, including the suggestion of the coexistence of other MSAs in Korean patients.

Relationship Between Coronavirus Disease 2019 Vaccination Rates and Rare But Potentially Fatal Adverse Events: A Regression Discontinuity Analysis of Western Countries.

BACKGROUND: Owing to limited experience with the new vaccine platforms, discussion of vaccine safety is inevitable. However, media coverage of adverse events of special interest could influence the vaccination rate; thus, evaluating the outcomes of adverse events of special interest influencing vaccine administration is crucial. METHODS: We conducted regression discontinuity in time analysis to calculate the local average treatment effect (LATE) using datasets from Our World in Data and Johns Hopkins University Center for Systems Science and Engineering. For the United States, the United Kingdom, and Europe, the cutoff points were April 23rd and June 23rd, April 7th, and the 14th week of 2021, respectively. RESULTS: The LATE of the Advisory Committee on Immunization Practices (ACIP) meeting held on April 23rd was -0.249 for all vaccines, -0.133 (-0.189 to -0.076) for Pfizer, -0.064 (-0.115 to -0.012) for Moderna, and -0.038 (-0.047 to -0.030) for Johnson & Johnson. Discontinuities were observed for all three types of vaccines in the United States. The June 23rd meeting of the ACIP (mRNA vaccines and myocarditis) did not convene any discontinuities. Furthermore, there was no significant drop in the weekly average vaccination rates in Europe following the European Medicines Agency (EMA) statement on April 7th. Conversely, there was a significant drop in the first-dose vaccination rates in the United Kingdom related to the EMA report. The first-dose vaccination rate for all vaccines changed by -0.104 (-0.176 to -0.032). CONCLUSION: Although monitoring and reporting of adverse events of special interest are important, a careful approach towards public announcements is warranted.

Epidemiology and comorbidities in idiopathic pulmonary fibrosis: a nationwide cohort study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is frequently accompanied by comorbidities, with the management of these comorbidities crucial for clinical outcomes. This study investigated the prevalence, incidence, changes over time, and clinical impact of comorbidities in IPF patients, based on nationwide claims data in South Korea. METHODS: This retrospective cohort study utilised nationwide health claim data in South Korea between 2011 and 2019. Patients with IPF were defined as those with ICD-10 code J84.1 and Rare Intractable Disease code V236 who made at least one claim per year. Patients were classified by sex, age, pirfenidone use and burden of comorbidities, and differences among groups were determined. RESULTS: The yearly prevalence rate of IPF increased from 7.50 to 23.20 per 100,000 people, and the yearly incidence rate increased from 3.56 to 7.91 per 100,000 person-years over time. The most common respiratory comorbidity was chronic obstructive pulmonary disease (37.34%), followed by lung cancer (3.34%), whereas the most common non-respiratory comorbidities were gastro-oesophageal reflux disease (70.83%), dyslipidaemia (62.93%) and hypertension (59.04%). The proportion of some comorbidities differed by sex, age and use of pirfenidone. The proportion of lung cancer was higher in patients treated with pirfenidone, whereas the proportion of anxiety and depression were lower in patients not treated with pirfenidone. Charlson comorbidity index ≥ 4 was associated with increases in hospitalisations and total medical costs. CONCLUSIONS: The yearly prevalence and incidence of IPF and comorbidities in Korea increased over time. These comorbidities affected the use of pirfenidone and medical resources.

Venous thromboembolism in patients with idiopathic pulmonary fibrosis, based on nationwide claim data.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a known risk factor for venous thromboembolism (VTE). However, it is currently unknown which factors are associated with an increase of VTE in patients with IPF. OBJECTIVES: We estimated the incidence of VTE in patients with IPF and identified clinical characteristics related to VTE in patients with IPF. DESIGN AND METHODS: De-identified nationwide health claim data from 2011 to 2019 was collected from the Korean Health Insurance Review and Assessment database. Patients with IPF were selected if they had made at least one claim per year under the J84.1 [International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10)] and V236 codes of rare intractable diseases. We defined the presence of VTE as at least one claim of pulmonary embolism and deep vein thrombosis ICD-10 codes. RESULTS: The incidence rate per 1000 person-years of VTE was 7.08 (6.44-7.77). Peak incidence rates were noted in the 50-59 years old male and 70-79 years old female groups. Ischemic heart disease, ischemic stroke, and malignancy were associated with VTE in patients with IPF, with an adjusted hazard ratio (aHR) of 1.25 (1.01-1.55), 1.36 (1.04-1.79), and 1.53 (1.17-2.01). The risk for VTE was increased in patients diagnosed with malignancy after IPF diagnosis (aHR = 3.18, 2.47-4.11), especially lung cancer [hazard ratio (HR) = 3.78, 2.90-4.96]. Accompanied VTE was related to more utilization of medical resources. CONCLUSION: Ischemic heart disease, ischemic stroke, and malignancy, especially lung cancer, were related to higher HR for VTE in IPF.

Anti-titin antibodies are associated with myocarditis in patients with myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) can affect cardiac muscles with variable presentations. Myocarditis is a rare but potentially serious cardiac manifestation of MG. Although thymomas and anti-titin antibodies have been suggested as risk factors for myocarditis in patients with MG, their independent influence on myocarditis has rarely been assessed. METHODS: A retrospective chart review was conducted on 247 patients diagnosed with MG who were tested for anti-titin antibodies. Myocarditis was diagnosed on the basis of the European Society of Cardiology 2013 Task Force criteria for clinically suspected myocarditis. Patients were classified into myocarditis-positive and myocarditis-negative groups. Multivariate analysis was performed to analyze the risk factors for myocarditis. RESULTS: Of the 247 patients, 25 (10.1%) were myocarditis-positive and 222 (89.9%) were myocarditis-negative. Anti-titin antibody positivity was higher in the myocarditis-positive group than in the myocarditis-negative group (68.0% vs. 28.4%, p < 0.001). A history of MG crisis was more frequent in the myocarditis-positive group than in the myocarditis-negative group (64.0% vs. 10.4%, p < 0.001). The presence of anti-titin antibodies (odds ratio [OR] 7.906; confidence interval [CI] 2.460-25.401) and MG crisis (OR 24.807; CI 7.476-82.311) was significantly associated with myocarditis. The Cox regression model showed that the anti-titin antibody levels (hazard ratio [HR] 3.639; 95% CI 1.557-8.505) and MG crisis (HR 6.137; 95% CI 2.639-14.272) were significant risk factors for the development of myocarditis. CONCLUSION: The presence of anti-titin antibody was associated with myocarditis in patients with MG, whereas thymoma was not. Although rare, early suspicion of myocarditis could be required, especially in patients with MG having anti-titin antibodies.

Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis.

BACKGROUND: We aimed to evaluate the diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) for anti-muscle specific tyrosine kinase (MuSK) antibody (Ab) in a large cohort of anti-acetylcholine receptor (AChR) Ab-negative generalized myasthenia gravis (MG), and also to investigate clinical contexts for the diagnosis of MuSK MG. METHODS: A retrospective study of 160 patients with a clinical suspicion of AChR Ab-negative generalized MG was performed. The serum samples were tested for anti-clustered AChR Ab by cell-based assay (CBA), anti-MuSK Ab by ELISA, CBA and/or radioimmunoprecipitation assay (RIPA). Clinical data were compared between anti-MuSK Ab-positive MG and double seronegative (AChR and MuSK) MG groups. RESULTS: After excluding non-MG and clustered AChR Ab-positive patients, we identified 89 patients as a cohort of AChR Ab-negative generalized MG. Anti-MuSK Ab was positive by ELISA in 22 (24.7%) patients. While CBA identified five additional anti-MuSK Ab-positive patients, the results of ELISA were mostly consistent with CBA and RIPA with Cohen's kappa of 0.80 and 0.90, respectively (p < 0.001). The most frequent differential diagnosis was motor neuron disease particularly of bulbar onset which showed remarkably overlapping clinical and electrophysiological features with MuSK MG at presentation. CONCLUSION: While confirming the highest sensitivity of CBA for detecting anti-MuSK Ab, our results highlight the clinical pitfalls in making a diagnosis of MuSK MG and may support a diagnostic utility of MuSK-ELISA in clinical practice.

Medial Meniscus Posterior Root Repair Restores Contact Pressure and Contact Area to Its Native State Even After Opening-Wedge High Tibial Osteotomy: A Cadaveric Biomechanical Study.

PURPOSE: To elucidate the effect of medial meniscus posterior root (MMPR) repair during opening-wedge high tibial osteotomy (OWHTO) in terms of contact pressure (CP) and contact area (CA). METHODS: Nine fresh-frozen human cadaveric knee specimens were included. Each specimen was tested under 9 conditions comprising 3 different degrees of correction during OWHTO (neutral, 5° of valgus, and 10° of valgus) and 3 different types of MMPR conditions (intact, torn, and repaired). The prepared specimens were attached to a customized tibiofemoral jig in a fully extended state. The CP and CA generated by a tibiofemoral axial load of 650 N was recorded using the Tekscan sensor's pressure mapping software. Statistical analysis was performed using a repeated measures analysis of variance. RESULTS: The increased CP and decreased CA in torn MMPR was decreased and increased, respectively, to the intact MMPR after repairing, irrespective of whether OWHTO was performed. The mean CP at a correction angle of 5° of valgus was 0.4067 ± 0.0768 MPa for intact MMPR, which increased to 0.7340 ± 0.1593 MPa for the torn MMPR and decreased to 0.3614 ± 0.0639 MPa for the repaired MMPR. In addition, the proportion of decrease in CP and increase in CA after MMPR repair was constant, compared with the torn MMPR, irrespective of the degree of correction during OWHTO. CONCLUSIONS: MMPR repair decreases CP and increases CA, irrespective of whether OWHTO is performed. The biomechanical advantage of repairing torn MMPR is maintained, regardless of the degree of correction during OWHTO. CLINICAL RELEVANCE: Both OWHTO and MMPR repair are known to protect the medial compartment of the knee. However, there are concerns in performing 2 procedures simultaneously. Results of our study showed that concurrent repair of the MMPR during OWHTO is useful for protecting the medial compartment of the knee with respect to tibiofemoral contact biomechanics.