Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility.

Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis.

Cardiac and renal outcomes of direct oral anticoagulants in patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation therapy with warfarin or direct oral anticoagulants (DOACs) is the mainstay for stroke prevention in patients with non-valvular atrial fibrillation (AF). The DOACs might have a lower risk of declining renal function than warfarin. This study aimed to compare renal outcomes among rivaroxaban, edoxaban, dabigatran, and warfarin. METHOD: This cohort study identified 2203 adults with AF who started anticoagulation therapy between 1 July 2013 and 31 December 2020, in a clinical database at a single centre. Inverse probability of treatment weighting was adopted to balance baseline characteristics among four anticoagulants treatment groups. The primary outcome was a composite of cardiac and renal outcomes, involving a ≥30% decline in estimated glomerular filtration rate (eGFR), renal failure and cardiovascular death. RESULTS: After propensity score weighting, dabigatran was associated with significantly lower risks of a ≥30% decline in eGFR (hazard ratio [HR]: .69, 95% confidence interval [CI]: .497-.951, p = .0237), doubling of the serum creatinine level (HR: .49, 95% CI: .259-.927, p = .0282) and the cardiac and renal outcome composite (HR: .67, 95% CI: .485-.913, p = .0115) than warfarin. Rivaroxaban and edoxaban did not show significant protective effects on renal outcomes compared to warfarin. CONCLUSION: In this study, patients treated with dabigatran had significantly reduced risks of declining renal function and composite cardiac and renal events than those treated with warfarin. However, rivaroxaban and edoxaban were not associated with lower risks of any renal outcomes than warfarin. More studies are warranted to investigate and compare the impact of renal function between different DOACs in patients with AF.

Outcomes of different pulmonary rehabilitation protocols in patients under mechanical ventilation with difficult weaning: a retrospective cohort study.

BACKGROUND: The endeavor of liberating patients from ventilator dependence within respiratory care centers (RCCs) poses considerable challenges. Multiple factors contribute to this process, yet establishing an effective regimen for pulmonary rehabilitation (PR) remains uncertain. This retrospective study aimed to evaluate existing rehabilitation protocols, ascertain associations between clinical factors and patient outcomes, and explore the influence of these protocols on the outcomes of the patients to shape suitable rehabilitation programs. METHODS: Conducted at a medical center in northern Taiwan, the retrospective study examined 320 newly admitted RCC patients between January 1, 2015, and December 31, 2017. Each patient received a tailored PR protocol, following which researchers evaluated weaning rates, RCC survival, and 3-month survival as outcome variables. Analyses scrutinized differences in baseline characteristics and prognoses among three PR protocols: protocol 1 (routine care), protocol 2 (routine care plus breathing training), and protocol 3 (routine care plus breathing and limb muscle training). RESULTS: Among the patients, 28.75% followed protocol 1, 59.37% protocol 2, and 11.88% protocol 3. Variances in age, body-mass index, pneumonia diagnosis, do-not-resuscitate orders, Glasgow Coma Scale scores (≤ 14), and Acute Physiology and Chronic Health Evaluation II (APACHE) scores were notable across these protocols. Age, APACHE scores, and abnormal blood urea nitrogen levels (> 20 mg/dL) significantly correlated with outcomes-such as weaning, RCC survival, and 3-month survival. Elevated mean hemoglobin levels linked to increased weaning rates (p = 0.0065) and 3-month survival (p = 0.0102). Four adjusted models clarified the impact of rehabilitation protocols. Notably, the PR protocol 3 group exhibited significantly higher 3-month survival rates compared to protocol 1, with odds ratios (ORs) ranging from 3.87 to 3.97 across models. This association persisted when comparing with protocol 2, with ORs between 3.92 and 4.22. CONCLUSION: Our study showed that distinct PR protocols significantly affected the outcomes of ventilator-dependent patients within RCCs. The study underlines the importance of tailored rehabilitation programs and identifies key clinical factors influencing patient outcomes. Recommendations advocate prospective studies with larger cohorts to comprehensively assess PR effects on RCC patients.

Different Anti-inflammatory Drugs on High-Sensitivity C-Reactive Protein in Patients After Percutaneous Coronary Intervention: A Pilot Randomized Clinical Trial.

ABSTRACT: Colchicine reduces atherothrombotic cardiovascular events in coronary artery disease because of its anti-inflammatory effect. However, the effects of the other anti-inflammatory drugs in coronary artery disease remain unclear. This study included 132 patients aged 18-80 years who completed the planned percutaneous coronary interventions and were treated with aggressive secondary prevention strategies for 4 weeks. The subjects were randomly assigned to 1 of the following treatment groups for 4 weeks: (1) control: no additional intervention; (2) colchicine: 0.5 mg once a day; (3) tranilast: 0.1 g thrice a day; or (4) oridonin: 0.5 g thrice a day. The primary outcome was the percentage change in high-sensitivity C-reactive protein (hsCRP) levels at the end of 4 weeks. In total, 109 patients completed the study. The mean age was 58.33 years, 81 (74.31%) were male, and 28 (25.69%) were female. The percentage changes in hsCRP after 4 weeks of treatment were -11.62%, -48.28%, -21.60%, and -7.81%, in the control, colchicine, tranilast, and the oridonin groups, respectively. Compared with the control group, only the colchicine group showed significantly greater reduction in hsCRP levels ( P = 0.022). In targeted proteomic analysis, proteins associated with neutrophil activation (azurocidin, myeloperoxidase, and myeloblastin), platelet aggregation (glycoprotein VI), and endothelial damage (galectin-3) were reduced with colchicine therapy. These results show that of 3 anti-inflammatory drugs only colchicine could reduce hsCRP in patients after percutaneous coronary interventions.

The impact of perioperative ketamine or esketamine on the subjective quality of recovery after surgery: a meta-analysis of randomised controlled trials.

BACKGROUND: This meta-analysis aimed to evaluate the impact of ketamine/esketamine on postoperative subjective quality of recovery (QoR). METHODS: MEDLINE, Embase, Cochrane library, and Google Scholar were searched for randomised controlled trials (RCTs) that examined the impacts of perioperative ketamine/esketamine use and postoperative QoR. The primary outcome was subjective QoR (QoR-9, QoR-15, QoR-40) on postoperative day (POD) 1-3, whereas the secondary outcomes included pain severity, anxiety scores, depression scores, risk of adverse events (i.e. nausea, vomiting, dizziness, drowsiness), and length of stay. RESULTS: The analysis included 18 RCTs (1554 participants; ketamine: seven trials, esketamine: 11 trials), of which 15 were conducted in China. Ketamine/esketamine improved the QoR scores on PODs 1 and 2 compared with the control (standardised mean difference [SMD]: 0.63, P<0.0001 for POD 1; SMD: 0.56, P=0.04 for POD 2), without beneficial effect on POD 3. Subgroup analyses revealed significant differences in QoR scores on POD 1 by regimen (SMD: esketamine 1.14, ketamine 0.01) and country (SMD: China 0.82, other countries -0.21). The emotional domain of QoR was improved from PODs 1 to 3, whereas the other domains were only improved on POD 1. Lower postoperative anxiety (SMD: -0.48, P=0.003) and depression (SMD: -0.72, P=0.001) scores were also observed with ketamine/esketamine use. Furthermore, pain severity was reduced on PODs 1 and 2, with no difference in the risk of adverse events or length of stay. CONCLUSIONS: This meta-analysis demonstrated that ketamine/esketamine use in the perioperative period is associated with improved early subjective QoR, pain severity, and psychological symptoms without an increase in the likelihood of adverse events. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023477580).

Supraperiosteal fat repositioning with midface lift in lower eyelid blepharoplasty: an 18-year experience.

PURPOSE: To assess the clinical outcomes of fat repositioning via supraperiosteal dissection with midface lift for correction of tear trough deformity in a large Asian patient population. METHODS: Retrospectively review 1152 Asian patients who underwent fat repositioning to the supraperiosteal plane with a midface lift between 2005 and 2022. Surgical technique, postoperative course, and complications were recorded. At the 6-month postoperative follow-up, the degree of patient satisfaction was assessed. RESULTS: A total of 2304 eyes from 1152 patients with an average follow-up of 10 months. These procedures were performed using a transforniceal approach in 185 patients (16%) or a transcutaneous skin excision approach in 967 patients (84%). Among the patients who underwent the transcutaneous technique, seven individuals (0.6%) experienced effective treatment of lower lid ectropion through lateral tarsal strip procedures. Nine patients (0.7%) required revision surgery to address the remaining lateral fat pad due to inadequate lateral orbital fat excision during the initial procedure. At the 6-month follow-up, most patients reported a high level of satisfaction, with 800 patients (78%) expressing extreme satisfaction and 196 patients (19.1%) reporting satisfaction with the improvement in their appearance. No one reported facial numbness, lower eyelid or cheek paralysis, newly developed diplopia or granuloma formation. CONCLUSION: The procedure of fat repositioning involving supraperiosteal dissection and a midface lift, whether performed using a transforniceal approach or a transcutaneous skin excision approach, in lower eyelid blepharoplasty proves to be a secure and auspicious surgical technique for rectifying tear trough deformity and attaining a pleasing aesthetic outcome.

CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway.

Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

Genetic predisposition to sarcoidosis.

Sarcoidosis is a complex systemic disease with clinical heterogeneity based on varying phenotypes and natural history. The detailed etiology of sarcoidosis remains unknown, but genetic predisposition as well as environmental exposures play a significant role in disease pathogenesis. We performed a comprehensive review of germline genetic (DNA) and transcriptomic (RNA) studies of sarcoidosis, including both previous studies and more recent findings. In this review, we provide an assessment of the following: genetic variants in sarcoidosis susceptibility and phenotypes, ancestry- and sex-specific genetic variants in sarcoidosis, shared genetic architecture between sarcoidosis and other diseases, and gene-environment interactions in sarcoidosis. We also highlight the unmet needs in sarcoidosis genetic studies, including the pressing requirement to include diverse populations and have consistent definitions of phenotypes in the sarcoidosis research community to help advance the application of genetic predisposition to sarcoidosis disease risk and manifestations.

Association between neighborhood availability of physical activity facilities and cognitive performance in older adults.

The existing evidence on the contextual influence of the availability of local facilities for physical activity on the cognitive health of elderly residents is sparse. This study examined the association between neighborhood physical activity facilities and cognitive health in older individuals. A cohort study of community-dwelling older adults was performed using baseline data and follow-up data from the Taiwan Biobank. Cognitive health was measured in 32,396 individuals aged 60-70 years using the Mini-Mental State Examination (MMSE) with follow-up information on 8025 participants. The district was used as the proxy for local neighborhood. To determine neighborhood physical activity facilities, school campuses, parks, activity centers, gyms, swimming pools, and stadiums were included. Multilevel linear regression models were applied to examine the associations of neighborhood physical activity facilities with baseline MMSE and MMSE decline during follow-up, with adjustment for individual factors and neighborhood socioeconomic characteristics. Multilevel analyses revealed that there was a neighborhood-level effect on cognitive health among older adults. After adjusting for compositional and neighborhood socioeconomic characteristics, baseline MMSE was higher in individuals living in the middle- (beta = 0.12, p-value = 0.140) and high-density facility (beta = 0.22, p-value = 0.025) groups than in the low-density group (p-value for trend-test = 0.031). MMSE decline during follow-up was slower in the middle- (beta = 0.15, p-value = 0.114) and high-density facility (beta = 0.27, p-value = 0.052) groups than in the low-density group (p-value for trend-test = 0.032). Greater neighborhood availability of physical activity facilities was associated with better cognitive health among older residents. These findings have implications for designing communities and developing strategies to support cognitive health of an aging population.

Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model.

For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.

Diagnostic value of multiple b-value diffusion-weighted imaging in discriminating the malignant from benign breast lesions.

OBJECTIVE: The conventional breast Diffusion-weighted imaging (DWI) was subtly influenced by microcirculation owing to the insufficient selection of the b values. However, the multiparameter derived from multiple b-value exhibits more reliable image quality and maximize the diagnostic accuracy. We aim to evaluate the diagnostic performance of stand-alone parameter or in combination with multiparameter derived from multiple b-value DWI in differentiating malignant from benign breast lesions. METHODS: A total of forty-one patients diagnosed with benign breast tumor and thirty-eight patients with malignant breast tumor underwent DWI using thirteen b values and other MRI functional sequence at 3.0 T magnetic resonance. Data were accepted mono-exponential, bi-exponential, stretched-exponential, aquaporins (AQP) model analysis. A receiver operating characteristic curve (ROC) was used to evaluate the diagnostic performance of quantitative parameter or multiparametric combination. The Youden index, sensitivity and specificity were used to assess the optimal diagnostic model. T-test, logistic regression analysis, and Z-test were used. P value < 0.05 was considered statistically significant. RESULT: The ADCavg, ADCmax, f, and α value of the malignant group were lower than the benign group, while the ADCfast value was higher instead. The ADCmin, ADCslow, DDC and ADCAQP showed no statistical significance. The combination (ADCavg-ADCfast) yielded the largest area under curve (AUC = 0.807) with sensitivity (68.42%), specificity (87.8%) and highest Youden index, indicating that multiparametric combination (ADCavg-ADCfast) was validated to be a useful model in differentiating the benign from breast malignant lesion. CONCLUSION: The current study based on the multiple b-value diffusion model demonstrated quantitatively multiparametric combination (ADCavg-ADCfast) exhibited the optimal diagnostic efficacy to differentiate malignant from benign breast lesions, suggesting that multiparameter would be a promising non-invasiveness to diagnose breast lesions.

Fabrications of the Flexible Non-Enzymatic Glucose Sensors Using Au-CuO-rGO and Au-CuO-rGO-MWCNTs Nanocomposites as Carriers.

A flexible, non-enzymatic glucose sensor was developed and tested on a polyethylene terephthalate (PET) substrate. The sensor's design involved printing Ag (silver) as the electrode and utilizing mixtures of either gold-copper oxide-modified reduced graphene oxide (Au-CuO-rGO) or gold-copper oxide-modified reduced graphene oxide-multi-walled carbon nanotubes (Au-CuO-rGO-MWCNTs) as the carrier materials. A one-pot synthesis method was employed to create a nanocomposite material, consisting of Au-CuO-rGO mixtures, which was then printed onto pre-prepared flexible electrodes. The impact of different weight ratios of MWCNTs (0~75 wt%) as a substitute for rGO was also investigated on the sensing characteristics of Au-CuO-rGO-MWCNTs glucose sensors. The fabricated electrodes underwent various material analyses, and their sensing properties for glucose in a glucose solution were measured using linear sweep voltammetry (LSV). The LSV measurement results showed that increasing the proportion of MWCNTs improved the sensor's sensitivity for detecting low concentrations of glucose. However, it also led to a significant decrease in the upper detection limit for high-glucose concentrations. Remarkably, the research findings revealed that the electrode containing 60 wt% MWCNTs demonstrated excellent sensitivity and stability in detecting low concentrations of glucose. At the lowest concentration of 0.1 µM glucose, the nanocomposites with 75 wt% MWCNTs showed the highest oxidation peak current, approximately 5.9 µA. On the other hand, the electrode without addition of MWCNTs displayed the highest detection limit (approximately 1 mM) and an oxidation peak current of about 8.1 µA at 1 mM of glucose concentration.

Microwave Imaging of Anisotropic Objects by Artificial Intelligence Technology.

In this paper, we present the microwave imaging of anisotropic objects by artificial intelligence technology. Since the biaxial anisotropic scatterers have different dielectric constant components in different transverse directions, the problems faced by transverse electronic (TE) polarization waves are more complex than those of transverse magnetic (TM) polarization waves. In other words, measured scattered field information can scarcely reconstruct microwave images due to the high nonlinearity characteristic of TE polarization. Therefore, we first use the dominant current scheme (DCS) and the back-propagation scheme (BPS) to compute the initial guess image. We then apply a trained convolution neural network (CNN) to regenerate the microwave image. Numerical results show that the CNN possesses a good generalization ability under limited training data, which could be favorable to deploy in image processing. Finally, we compare DCS and BPS reconstruction images for anisotropic objects by the CNN and prove that DCS is better than BPS. In brief, successfully reconstructing biaxial anisotropic objects with a CNN is the contribution of this proposal.

Versatile and Accessible Magnetic Diagnosis Platform with Different Types of Magnetic Particles for Liquid and Solid Biopsies.

The diagnosis of liquid and solid biopsies by different instruments makes the clinic loading difficult in many aspects. Given the compositions of magnetic particles (MPs) with diverse characterizations and the innovative acoustic type of vibration sample magnetometer (VSM), the versatile, accessible magnetic diagnosis platform was proposed to meet clinical demands, such as low loading for multiple biopsies. In liquid biopsies of alpha-fetoprotein (AFP) standard solutions and subject serums, molecular concentration was analyzed from saturation magnetization by the soft type of Fe3O4 MPs with AFP bioprobe coating. In the phantom mixture simulated as bounded MPs in tissue, the bounded MPs was evaluated from the area of the hysteresis loop by hard type of cobalt MPs without bio-probes coating. Not only a calibration curve was founded for many hepatic cell carcinoma stages, but also microscale images verified the Ms increase due to magnetic protein clusters, etc. Hence, its wide populations in clinics could be expected.

Positive Predictive Values of Anaphylaxis Diagnosis in Claims Data: A Multi-Institutional Study in Taiwan.

Real-world data sources can facilitate essential understanding of the epidemiological features of anaphylaxis. However, the accuracy of case-identifying definitions based on diagnosis codes for anaphylaxis in healthcare databases remains understudied. We conducted a cross-sectional study analyzing claims data from the largest multi-institutional healthcare system in Taiwan during 2017-2021. We included patients with incident anaphylaxis identified by either ICD-10-CM codes for anaphylaxis (Group 1) or ICD-10-CM codes for severe allergic or drug adverse events and additional modifier codes for acute allergy events (Group 2). We randomly selected 20% of the cases to determine the positive predictive value (PPV) of anaphylaxis case-identifying definitions in Groups 1 and 2 after review of electronic medical records by two physicians. From the original cohort (n = 2,176), we randomly selected 433 patients with either a diagnosis of anaphylaxis (Group 1), or a diagnosis of severe allergic and drug adverse events with additional modifier codes for acute allergy events (Group 2). In Group 1, we judged 135 / 170 patients as true anaphylaxis cases, giving a PPV of 79.4% (95% CI: 73.3-85.5). In Group 2, we judged 47 / 263 patients as true anaphylaxis cases, giving a PPV of 17.9% (95% CI: 13.3-22.5). In conclusion, acceptable PPVs were observed when anaphylaxis cases were identified by ICD-10-CM codes for anaphylaxis, but not by ICD-10-CM codes for severe allergic or drug adverse event with additional modifier codes for acute allergy events. Our multi-institutional findings could serve as a fundamental reference for further studies of anaphylaxis based on real-world healthcare databases.

Effectiveness and Safety of Dabigatran Reversal with Idarucizumab in the Taiwanese Population: A Comparison Based on Eligibility for Inclusion in Clinical Trials.

Background and Objectives: The effectiveness and safety of idarucizumab for the reversal of the effects of dabigatran have been proven. However, there remains a paucity of literature comprehensively investigating outcomes in real-world patients. This is especially true when comparing patients who were eligible for inclusion in the RE-VERSE AD trial with patients who were ineligible. As the prescription of dabigatran has become increasingly popular, the generalizability of the results to real-world populations has come into question due to the broad variability of real-world patients receiving dabigatran. Our study aimed to identify all patients who were prescribed idarucizumab and examined how effectiveness and safety varied among those patients who were eligible and ineligible for the trial. Materials and Methods: This retrospective cohort study analyzed the largest medical database in Taiwan. We enrolled all patients who were prescribed and received idarucizumab from when it became available in Taiwan up until May 2021. A Total of 32 patients were included and analyzed, and they were further divided into subgroups based on their eligibility for inclusion in the RE-VERSE AD trial. Multiple outcomes were evaluated, including successful hemostasis rate, complete reversal efficacy of idarucizumab, 90-day thromboembolic events, intra-hospital mortality, and adverse event rate. Results: In our study, we found that 34.4% of real-world cases of idarucizumab use were ineligible for the RE-VERSE AD trials. The eligible group had higher successful hemostasis rates (95.2% vs. 80%) and anticoagulant effect reversal rates compared to the ineligible group (73.3% vs. 0%). The mortality rates were 9.5%, compared to 27.3% in the ineligible group. Few adverse effects (n = 3) and 90-day thromboembolic events (n = 1) were observed in either group. Among the ineligible cases, all acute ischemic stroke patients (n = 5) received definite, timely treatments without complications. Conclusions: Our study demonstrated the real-world effectiveness and safety of idarucizumab infusion for trial-eligible patients and all acute ischemic stroke patients. However, although it seems to be effective and safe, idarucizumab appears to be less effective in other trial-ineligible patients. Despite this result, our study provides further evidence for extending the applicability of idarucizumab in real-world scenarios. Our study suggests that idarucizumab can be a safe and effective option for reversing the anticoagulant effect of dabigatran, particularly for eligible patients.

Multiomic Signatures of Chronic Beryllium Disease Bronchoalveolar Lavage Cells Relate to T-Cell Function and Innate Immunity.

Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected proteins in the lung to identify molecular signatures and networks associated with BeS and CBD. BAL cell DNA and RNA were profiled using microarrays from CBD (n = 30), BeS (n = 30), and control subjects (n = 12). BAL fluid proteins were measured using Olink Immune Response Panel proteins from CBD (n = 22) and BeS (n = 22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multiomic integration methods identified correlated features between datasets. We identified 1,546 differentially expressed genes in CBD versus control subjects and 204 in CBD versus BeS. Of the 101 shared transcripts, 24 have significant cis relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation analysis, including genes not previously identified in CBD. A multiomic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated control subjects from remaining samples. The top features on component one were enriched for T-lymphocyte function, and the top features on component two were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD versus BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multiomic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multiomic signatures of CBD that differentiated it from BeS and control subjects.

Postdiagnosis Aspirin Use Associated With Decreased Biliary Tract Cancer-Specific Mortality in a Large Nationwide Cohort.

BACKGROUND AND AIMS: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes. CONCLUSIONS: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC.

Clinical phenotyping in sarcoidosis using cluster analysis.

BACKGROUND: Most phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes. METHODS: We performed a retrospective cohort study of 554 sarcoidosis cases to identify distinct phenotypes of sarcoidosis based on 29 clinical features. Model-based clustering was performed using the VarSelLCM R package and the Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher's exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters. RESULTS: Cluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype (1) supranormal lung function and majority Scadding stage 2/3; phenotype (2) supranormal lung function and majority Scadding stage 0/1; phenotype (3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype (4) obstructive lung function and majority Scadding stage 2/3; phenotype (5) restrictive lung function and majority Scadding stage 2/3; phenotype (6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Although there were differences in the percentages, all Scadding stages were encompassed by all of the phenotypes, except for phenotype 1, in which none were Scadding stage 4. Clusters 4, 5, 6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores. CONCLUSIONS: Cluster analysis produced 6 sarcoidosis phenotypes that demonstrated less severe and severe phenotypes. Phenotypes 1, 2, 3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4, 5, 6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects and to empower clinicians to identify those with more severe disease versus those who have less severe disease, independent of Scadding stage.

Highly efficient magnetic ablation and the contrast of various imaging using biocompatible liquid-metal gallium.

BACKGROUND: Although the powerful clinical effects of radiofrequency and microwave ablation have been established, such ablation is associated with several limitations, including a small ablation size, a long ablation time, the few treatment positioning, and biosafety risks. To overcome these limitations, biosafe and efficient magnetic ablation was achieved in this study by using biocompatible liquid gallium as an ablation medium and a contrast medium for imaging. RESULTS: Magnetic fields with a frequency (f) lower than 200 kHz and an amplitude (H) × f value lower than 5.0 × 109 Am-1 s-1 were generated using the proposed method. These fields could generate an ablation size of 3 cm in rat liver lobes under a temperature of approximately 300 °C and a time of 20 s. The results of this study indicate that biomedical gallium can be used as a contrast medium for the positioning of gallium injections and the evaluation of ablated tissue around a target site. Liquid gallium can be used as an ablation medium and imaging contrast medium because of its stable retention in normal tissue for at least 3 days. Besides, the high anticancer potential of gallium ions was inferred from the self-degradation of 100 µL of liquid gallium after around 21 days of immersion in acidic solutions. CONCLUSIONS: The rapid wireless ablation of large or multiple lesions was achieved through the simple multi-injection of liquid gallium. This approach can replace the currently favoured procedure involving the use of multiple ablation probes, which is associated with limited benefits and several side effects. METHODS: Magnetic ablation was confirmed to be highly efficient by the consistent results obtained in the simulation and in vitro tests of gallium and iron oxide as well as the electromagnetic specifics and thermotherapy performance comparison detailed in this study Ultrasound imaging, X-ray imaging, and magnetic resonance imaging were found to be compatible with the proposed magnetic ablation method. Self-degradation analysis was conducted by mixing liquid gallium in acidic solutions with a pH of approximately 5-7 (to imitate a tumour-containing microenvironment). X-ray diffraction was used to identify the gallium oxides produced by degraded gallium ions.