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Meng-Huan Tsai,1 Chun-Chieh Chen,1– 3 Chih-Hsiang Chang,1– 3 Yuhan Chang,1– 3 Pang-Hsin Hsieh,1– 3 Chih-Chien Hu1– 3 1Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan; 2Bone and Joint Research Center, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan; 3College of Medicine, Chang Gung University, Taoyuan, 33305, TaiwanCorrespondence: Chih-Chien Hu, Bone and Joint Research Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan, 33305, Taiwan, Tel +886-3-3281200, ext. 2420, Email chihchienhu@hotmail.comBackground: Revision total hip arthroplasty (RTHA) for loosening the femoral stem is a technical challenge. Distally fixed, full-porous-coated long stems are widely accepted as the standard selection for these revisions. However, the success of primary stems in RTHA is not well known.Methods: This study enrolled 24 patients with aseptic loosening of the femoral stem who underwent RTHA using primary stems. Another 72 patients with aseptic loosening who underwent RTHA using full-porous-coated long stems were matched in terms of operation date, proximal femoral bone stock (Paprosky classification), sex, and age. The primary and secondary outcomes of failure were the need for revision for any reason and the radiographic change in the stem respectively.Results: In the primary stem group, one patient had a periprosthetic fracture and received a second RTHA 2 years after the previous one. The primary outcome’s 5-and 10-year survival rates were both 95.8%. For the matched comparison group, one patient had an immediate periprosthetic fracture of the femoral shaft requiring further open reduction internal fixation surgery. Another patient had a full-porous-coated long stem breakage 6 years postoperatively, which required a second RTHA. The primary outcome’s 5-and 10-year survival rates were 98.6% and 97.2%, respectively.Conclusion: Primary stems can achieve non-inferior clinical success compared to a full-porous-coated long stem for aseptic stem loosening RTHA in patients with adequate proximal femoral bone stock.Keywords: revision total hip arthroplasty, aseptic loosening, primary stem, full-porous-coated long stem

Background: The association of lumbar spine instability between laminectomy and laminotomy has been clinically studied, but the corresponding in vitro biomechanical studies have not been reported. We investigated the hypothesis that the integrity of the posterior complex (spinous process-interspinous ligament-spinous process) plays an important role on the postoperative spinal stability in decompressive surgery.Methods: Eight porcine lumbar spine specimens were studied. Each specimen was tested intact and after two decompression procedures. All posterior components were preserved in Group A (Intact). In Group B (Bilateral laminotomy), the inferior margin of L4 lamina and superior margin of L5 lamina were removed, but the L4-L5 supraspinous ligament was preserved. Fenestrations were made on both sides. In Group C (Laminectomy) the lamina and spinous processes of lower L4 and upper L5 were removed. Ligamentum flavum and supraspinous ligament of L4-L5 were removed. A hydraulic testing machine was used to generate an increasing moment up to 8400 N-mm in flexion and extension. Intervertebral displacement at decompressive level L4-L5 was measured by extensometerResults: The results indicated that, under extension motion, intervertebral displacement between the specimen in intact form and at two different decompression levels did not significantly differ (P > 0.05). However, under flexion motion, intervertebral displacement of the laminectomy specimens at decompression level L4-L5 was statistically greater than in intact or bilateral laminotomy specimens (P = 0.0000963 and P = 0.000418, respectively). No difference was found between intact and bilateral laminotomy groups. (P > 0.05).Conclusion: We concluded that a lumbar spine with posterior complex integrity is less likely to develop segment instability than a lumbar spine with a destroyed anchoring point for supraspinous ligament. [ABSTRACT FROM AUTHOR]

Background: Initial promise of a stand-alone interbody fusion cage to treat chronic back pain and restore disc height has not been realized. In some instances, a posterior spinal fixation has been used to enhance stability and increase fusion rate. In this manuscript, a new stand-alone cage is compared with conventional fixation methods based on the finite element analysis, with a focus on investigating cage-bone interface mechanics and stress distribution on the adjacent tissues.Methods: Three trapezoid 8 degrees interbody fusion cage models (dual paralleled cages, a single large cage, or a two-part cage consisting of a trapezoid box and threaded cylinder) were created with or without pedicle screws fixation to investigate the relative importance of the screws on the spinal segmental response. The contact stress on the facet joint, slip displacement of the cage on the endplate, and rotational angle of the upper vertebra were measured under different loading conditions.Results: Simulation results demonstrated less facet stress and slip displacement with the maximal contact on the cage-bone interface. A stand-alone two-part cage had good slip behavior under compression, flexion, extension, lateral bending and torsion, as compared with the other two interbody cages, even with the additional posterior fixation. However, the two-part cage had the lowest rotational angles under flexion and torsion, but had no differences under extension and lateral bending.Conclusion: The biomechanical benefit of a stand-alone two-part fusion cage can be justified. This device provided the stability required for interbody fusion, which supports clinical trials of the cage as an alternative to circumferential fixations. [ABSTRACT FROM AUTHOR]

Evaluating the dynamic interaction of microorganisms and mammalian cells is challenging due to the lack of suitable platforms for examining interspecies interactions in biologically relevant coculture conditions. In this work, we demonstrate the interaction between probiotic bacteria ( Lactococcus lactis and Escherichia coli ) and A498 human cancer cells in vitro , utilizing a hydrogel-based platform in a label-free manner by infrared spectroscopy. The L. lactis strain recapitulated in the compartment system secretes polypeptide molecules such as nisin, which has been reported to trigger cell apoptosis. We propose a mid-infrared (IR) spectroscopic imaging approach to monitor the variation of biological components utilizing kidney cells (A498) as a model system cocultured with bacteria. We characterized the biochemical composition (i.e., nucleic acids, protein secondary structures, and lipid conformations) label-free using an unbiased measurement. Several IR spectral features, including unsaturated fatty acids, β-turns in protein, and nucleic acids, were utilized to predict cellular response. These features were then applied to establish a quantitative relationship through a multivariate regression model to predict cellular dynamics in the coculture system to assess the effect of nisin on A498 kidney cancer cells cocultured with bacteria. Overall, our study sheds light on the potential of using IR spectroscopic imaging as a label-free tool to monitor complex microbe-host cell interactions in biological systems. This integration will enable mechanistic studies of interspecies interactions with insights into their underlying physiological processes.

Purpose: Periprosthetic joint infection (PJI) is a leading cause of joint arthroplasty failure, potentially leading to critical complications like vertebral osteomyelitis (VO). The factors contributing to VO after PJI and the outcomes for these patients are not well understood. Our study aims to (1) identify risk factors for VO following PJI and (2) assess the clinical outcomes in these cases., Methods: We included PJI patients treated surgically at our centre from January 2006 to December 2020, excluding those with simultaneous VO post-PJI. Our focus was on patients with VO occurring after PJI, monitored for at least 5 years. Analysis included patient comorbidities, PJI treatment approaches, pathogen identification and clinical outcomes., Results: Of 1701 PJI cases, 21 (1.23%) developed VO. Key risk factors for VO post-PJI were identified: systemic inflammatory response syndrome, substance misuse, polymicrobial infection and undergoing at least three stages of resection arthroplasty (odds ratios: 1.86, 54.28, 52.33 and 31.88, respectively). Adverse outcomes were noted in VO patients, with recurrent VO in 6/21 and repeated PJIs in 18/21 cases., Conclusions: Patients with PJI, especially those with certain risk factors, have an increased likelihood of developing VO and encountering negative outcomes. The potential role of bacteremia in the development of VO after PJI needs further exploration., Level of Evidence: Level III., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: The burden of asymptomatic left ventricular dysfunction (LVD) is greater than that of heart failure; however, a cost-effective tool for asymptomatic LVD screening has not been well validated. We aimed to prospectively validate an artificial intelligence (AI)-enabled electrocardiography (ECG) algorithm for asymptomatic LVD detection and evaluate its cost-effectiveness for opportunistic screening., Methods: In this prospective observational study, patients undergoing ECG at outpatient clinics or health check-ups were enrolled in 2 hospitals in Taiwan. Patients were stratified into LVD (left ventricular ejection fraction ≤ 40%) risk groups according to a previously developed ECG algorithm. The performance of AI-ECG was used to conduct a cost-effectiveness analysis of LVD screening compared with no screening. Incremental cost-effectiveness ratio (ICER) and sensitivity analyses were used to examine the cost-effectiveness and robustness of the results., Results: Among the 29,137 patients, the algorithm demonstrated areas under the receiver operating characteristic curves of 0.984 and 0.945 for detecting LVD within 28 days in the 2 hospital cohorts. For patients not initially scheduled for ECG, the algorithm predicted future echocardiograms (high-risk, 46.2%; medium-risk, 31.4%; low-risk, 14.6%) and LVD (high-risk, 26.2%; medium-risk, 3.4%; low-risk, 0.1%) at 12 months. Opportunistic screening with AI-ECG could result in a negative ICER of -$7,439 for patients aged 65 years, with consistent cost-savings across age groups and particularly in men. Approximately 91.5% of the cases were found to be cost-effective at the willingness-to-pay threshold of $30,000 in the probabilistic analysis., Conclusions: The use of AI-ECG for asymptomatic LVD risk stratification is promising, and opportunistic screening in outpatient clinics has the potential to reduce costs., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Understanding the molecular and physical complexity of the tissue microenvironment (TiME) in the context of its spatiotemporal organization has remained an enduring challenge. Recent advances in engineering and data science are now promising the ability to study the structure, functions, and dynamics of the TiME in unprecedented detail; however, many advances still occur in silos that rarely integrate information to study the TiME in its full detail. This review provides an integrative overview of the engineering principles underlying chemical, optical, electrical, mechanical, and computational science to probe, sense, model, and fabricate the TiME. In individual sections, we first summarize the underlying principles, capabilities, and scope of emerging technologies, the breakthrough discoveries enabled by each technology and recent, promising innovations. We provide perspectives on the potential of these advances in answering critical questions about the TiME and its role in various disease and developmental processes. Finally, we present an integrative view that appreciates the major scientific and educational aspects in the study of the TiME., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Nutritional administration in acute pancreatitis (AP) management has sparked widespread discussion, yet contradictory mortality results across meta-analyses necessitate clarification. The optimal nutritional route in AP remains uncertain. Therefore, this study aimed to compare mortality among nutritional administration routes in patients with AP using consistency model., Methods: This study searched four major databases for relevant randomized controlled trials (RCTs). Two authors independently extracted and checked data and quality. Network meta-analysis was conducted for estimating risk ratios (RRs) with 95% confidence interval (CI) based on random-effects model. Subgroup analyses accounted for AP severity and nutrition support initiation., Results: A meticulous search yielded 1185 references, with 30 records meeting inclusion criteria from 27 RCTs (n = 1594). Pooled analyses showed the mortality risk reduction associated with nasogastric (NG) (RR = 0.34; 95%CI: 0.16-0.73) and nasojejunal (NJ) feeding (RR = 0.46; 95%CI: 0.25-0.84) in comparison to nil per os. Similarly, NG (RR = 0.45; 95%CI: 0.24-0.83) and NJ (RR = 0.60; 95%CI: 0.40-0.90) feeding also showed lower mortality risk than total parenteral nutrition. Subgroup analyses, stratified by severity, supported these findings. Notably, the timing of nutritional support initiation emerged as a significant factor, with NJ feeding demonstrating notable mortality reduction within 24 and 48 h, particularly in severe cases., Conclusion: For severe AP, both NG and NJ feeding appear optimal, with variations in initiation timings. NG feeding does not appear to merit recommendation within the initial 24 h, whereas NJ feeding is advisable within the corresponding timeframe following admission. These findings offer valuable insights for optimizing nutritional interventions in AP., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Background: Radiation proctitis (RP) is a significant complication of pelvic radiation. Effective treatments for chronic RP are currently lacking. We report a case where chronic RP was successfully managed by metformin and butyrate (M-B) enema and suppository therapy., Case Presentation: A 70-year-old Asian male was diagnosed with prostate cancer of bilateral lobes, underwent definitive radiotherapy to the prostate of 76 Gy in 38 fractions and six months of androgen deprivation therapy. Despite a stable PSA nadir of 0.2 ng/mL for 10 months post-radiotherapy, he developed intermittent rectal bleeding, and was diagnosed as chronic RP. Symptoms persisted despite two months of oral mesalamine, mesalamine enema and hydrocortisone enema treatment. Transition to daily 2% metformin and butyrate (M-B) enema for one week led to significant improvement, followed by maintenance therapy with daily 2.0% M-B suppository for three weeks, resulting in continued reduction of rectal bleeding. Endoscopic examination and biopsy demonstrated a good therapeutic effect., Conclusions: M-B enema and suppository may be an effective treatment for chronic RP., (© 2024. The Author(s).)

Biting midges, notably those within the Ceratopogonidae family, have long been recognized for their epidemiological significance, both as nuisances and vectors for disease transmission in vertebrates. Despite their impact, genomic insights into these insects, particularly beyond the Culicoides genus, remain limited. In this study, we assembled the Forcipomyia taiwana (Shiraki) genome, comprising 113 scaffolds covering 130.4 Mbps-with the longest scaffold reaching 7.6 Mbps and an N50 value of 2.6 Mbps-marking a pivotal advancement in understanding the genetic architecture of ceratopogonid biting midges. Phylogenomic analyses reveal a shared ancestry between F. taiwana and Culicoides sonorensis Wirth & Jones, dating back approximately 124 million years, and highlight a dynamic history of gene family expansions and contractions within the Ceratopogonidae family. Notably, a substantial expansion of the odorant receptor (OR) gene family was observed, which is crucial for the chemosensory capabilities that govern biting midges' interactions with their environment, including host seeking and oviposition behaviors. The distribution of OR genes across the F. taiwana genome displays notable clusters on scaffolds, indicating localized tandem gene duplication events. Additionally, several collinear regions were identified, hinting at segmental duplications, inversions, and translocations, contributing to the olfactory system's evolutionary complexity. Among the 156 ORs identified in F. taiwana, 134 are biting midge-specific ORs, distributed across three distinct clades, each exhibiting unique motif features that distinguish them from the others. Through weighted gene co-expression network analysis, we correlated distinct gene modules with sex and reproductive status, laying the groundwork for future investigations into the interplay between gene expression and adaptive behaviors in F. taiwana. In conclusion, our study not only highlights the unique olfactory repertoire of ceratopogonid biting midges but also sets the stage for future studies into the genetic underpinnings of their unique biological traits and ecological strategies., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: This study aimed to report the long-term survival of fixed-bearing medial unicompartmental knee arthroplasty (UKA) with a mean of 14-year follow-up, and to determine possible risk factors of failure., Methods: We retrospectively evaluated 337 fixed-bearing medial UKAs implanted between 2003 and 2014. Demographic and radiographic parameters were measured, including pre-operative and post-operative anatomical femorotibial angle (aFTA), posterior tibial slope (PTS), and anatomical medial proximal tibial angle (aMPTA). Multivariate logistic regression analysis was applied to figure out risk factors., Results: The mean follow-up time was 14.0 years. There were 32 failures categorized into implant loosening (n = 11), osteoarthritis progression (n = 7), insert wear (n = 7), infection (n = 4), and periprosthetic fracture (n = 3). Cumulative survival was 91.6% at 10 years and 90.0% at 15 years. No statistically significant parameters were found between the overall survival and failure groups. Age and hypertension were significant factors of implant loosening with odds ratio (OR) 0.909 (p = 0.02) and 0.179 (p = 0.04) respectively. In the insert wear group, post-operative aFTA and correction of PTS showed significance with OR 0.363 (p = 0.02) and 0.415 (p = 0.03) respectively. Post-operative aMPTA was a significant factor of periprosthetic fracture with OR 0.680 (p < 0.05)., Conclusions: The fixed-bearing medial UKA provides successful long-term survivorship. Tibial component loosening is the major cause of failure. Older age and hypertension were factors with decreased risk of implant loosening., (© 2024. The Author(s).)

This research proposes a magnetic field sensor with spatial orientation ability. Through the assistance of a magnetic flux concentrator, out-of-plane magnetic flux can be concentrated and guided into the planar magnetic cores of a fluxgate sensor. A printed circuit board is used to construct the basic planar structure, on which the proposed three-dimensional magnetic flux concentrator and magnetic cores are assembled. This reduces the alignment error of the coils and improves the reliability of the sensor. Three-axis sensing is achieved by using the second harmonic signals from selected sensing coil pairs. The magnetometer exhibits a linear range to 130 μT. At an excitation frequency of 50 kHz, the measured sensitivities are 257.1, 468.8, and 258.8 V/T for the X-, Y-, and Z-axis sensing modes, respectively. This sensor utilizes only one sensing mechanism for the vector field, making it suitable for IoT applications, especially for assessing mechanical posture or position.

As biological enzymes regulate metabolic processes, alkaline phosphatase (ALP) is a critical diagnostic indicator associated with many diseases. To accurately measure the enzyme activity, nanozymactic materials can offer sensitive strategies for ALP detection. However, nanozymes often lack specific target binding sites, and the presence of common co-components, e. g., metal ions, may cause false-positive or false-negative results in enzyme activity determination. Herein, we developed a colorimetric assay for ALP detection using metal-free nanozymatic carbon dots (CDs). The ALP hydrolysis of pyrophosphate ions (PPi) to phosphate ions (Pi) induces a "turn-on" response based on the nanozyme activity. This PPi-induced inhibition mechanism is extensively studied via the Michaelis-Menten model, revealing that PPi acts as a noncompetitive inhibitor for CDs at a binding site distinct from the common nanozyme active site. With superior responses to ALP substrates, a highly sensitive and selective method is established for sensing ALP activity with a linear range of 0.010-0.200 U/L and a detection limit of 0.009 U/L. This finding explores the recognition and binding behavior of nanozymes, allowing for precise and reliable measurements even in complex samples, and represents a significant breakthrough for nanozyme-based assays in biological analysis., (© 2023 Wiley-VCH GmbH.)

IMP-3 expression is a poor prognostic factor of melanomas and it promotes melanoma cell migration and invasion by a pathway modulating HMGA2 mRNA expression. We tried to identify other putative targets of IMP-3. We identified putative IMP-3-binding RNAs, including AKT1, MAPK3, RB1 and RELA, by RNA immunoprecipitation coupled with next-generation sequencing. IMP-3 overexpression increased AKT and RELA levels in MeWo cells. siRNAs against AKT1 and RELA inhibited MeWo/Full-length IMP-3 cell migration. IMP-3 knockdown of A2058 cells decreased AKT1 and RELA expression and lowered migration ability. Co-transfection of A2058 cells with AKT1- or RELA-expressing plasmids with IMP-3 siRNA restored the inhibitory effects of IMP-3 knockdown on migration. HMGA2 did not influence AKT1 and RELA expression in melanoma cells. Human melanoma samples with high IMP-3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP-3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The vascular endothelium acts as a dynamic interface between blood and tissue. TNF-α, a major regulator of inflammation, induces endothelial cell (EC) transcriptional changes, the overall response dynamics of which have not been fully elucidated. In the present study, we conducted an extended time-course analysis of the human EC response to TNF, from 30 min to 72 h. We identified regulated genes and used weighted gene network correlation analysis to decipher coexpression profiles, uncovering two distinct temporal phases: an acute response (between 1 and 4 h) and a later phase (between 12 and 24 h). Sex-based subset analysis revealed that the response was comparable between female and male cells. Several previously uncharacterized genes were strongly regulated during the acute phase, whereas the majority in the later phase were IFN-stimulated genes. A lack of IFN transcription indicated that this IFN-stimulated gene expression was independent of de novo IFN production. We also observed two groups of genes whose transcription was inhibited by TNF: those that resolved toward baseline levels and those that did not. Our study provides insights into the global dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. Data for all coding and noncoding genes is provided on the Web site (http://www.endothelial-response.org/). These findings may be useful in understanding the role of ECs in inflammation and in developing TNF signaling-targeted therapies., (Copyright © 2023 The Authors.)

Background: H2A.X is an H2A variant histone in eukaryotes, unique for its ability to respond to DNA damage, initiating the DNA repair pathway. H2A.X replacement within the histone octamer is mediated by the FAcilitates Chromatin Transactions (FACT) complex, a key chromatin remodeler. FACT is required for DEMETER (DME)-mediated DNA demethylation at certain loci in Arabidopsis thaliana female gametophytes during reproduction. Here, we sought to investigate whether H2A.X is involved in DME- and FACT-mediated DNA demethylation during reproduction., Results: H2A.X is encoded by two genes in Arabidopsis genome, HTA3 and HTA5. We generated h2a.x double mutants, which displayed a normal growth profile, whereby flowering time, seed development, and root tip organization, S-phase progression and proliferation were all normal. However, h2a.x mutants were more sensitive to genotoxic stress, consistent with previous reports. H2A.X fused to Green Fluorescent Protein (GFP) under the H2A.X promoter was highly expressed especially in newly developing Arabidopsis tissues, including in male and female gametophytes, where DME is also expressed. We examined DNA methylation in h2a.x developing seeds and seedlings using whole genome bisulfite sequencing, and found that CG DNA methylation is decreased genome-wide in h2a.x mutant endosperm. Hypomethylation was most striking in transposon bodies, and occurred on both parental alleles in the developing endosperm, but not the embryo or seedling. h2a.x-mediated hypomethylated sites overlapped DME targets, but also included other loci, predominately located in heterochromatic transposons and intergenic DNA., Conclusions: Our genome-wide methylation analyses suggest that H2A.X could function in preventing access of the DME demethylase to non-canonical sites. Overall, our data suggest that H2A.X is required to maintain DNA methylation homeostasis in the unique chromatin environment of the Arabidopsis endosperm., (© 2023. The Author(s).)

Motivation: Gene co-expression measurements are widely used in computational biology to identify coordinated expression patterns across a group of samples. Coordinated expression of genes may indicate that they are controlled by the same transcriptional regulatory program, or involved in common biological processes. Gene co-expression is generally estimated from RNA-Sequencing data, which are commonly normalized to remove technical variability. Here, we demonstrate that certain normalization methods, in particular quantile-based methods, can introduce false-positive associations between genes. These false-positive associations can consequently hamper downstream co-expression network analysis. Quantile-based normalization can, however, be extremely powerful. In particular, when preprocessing large-scale heterogeneous data, quantile-based normalization methods such as smooth quantile normalization can be applied to remove technical variability while maintaining global differences in expression for samples with different biological attributes., Results: We developed SNAIL (Smooth-quantile Normalization Adaptation for the Inference of co-expression Links), a normalization method based on smooth quantile normalization specifically designed for modeling of co-expression measurements. We show that SNAIL avoids formation of false-positive associations in co-expression as well as in downstream network analyses. Using SNAIL, one can avoid arbitrary gene filtering and retain associations to genes that only express in small subgroups of samples. This highlights the method's potential future impact on network modeling and other association-based approaches in large-scale heterogeneous data., Availability and Implementation: The implementation of the SNAIL algorithm and code to reproduce the analyses described in this work can be found in the GitHub repository https://github.com/kuijjerlab/PySNAIL., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: Cancer care-related greenhouse gas (GHG) emissions harm human health. Many cancer drugs are administered at greater-than-necessary doses, frequencies, and durations. Alternative dosing strategies may enable reductions in cancer care GHG emissions without compromising patient outcomes., Materials and Methods: We used streamlined life-cycle analysis in a case-control simulation to estimate the relative reductions in GHG emissions that would be expected to result from using each of three alternative dosing strategies of trastuzumab (6-month adjuvant treatment duration, once every 4-week dosing, and both) in human epidermal growth factor receptor 2 (HER2)+ breast cancer. Using primary data and conversion factors from the environmental science literature, we estimated per-patient relative reduction in GHG emissions and, using SEER data, health impacts (in terms of disability-adjusted life-years [DALYs] and excess mortality per kg CO 2 ) on bystanders for each alternative dosing strategy., Results: Compared with the trastuzumab dosing strategy commonly used at baseline (12-month duration of adjuvant therapy and once every 3-week dosing in all settings), adoption of both 6-month adjuvant trastuzumab and once every 4-week trastuzumab dosing would reduce GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. We estimate that US-based adoption of alternative trastuzumab dosing would reduce annual DALYs and excess lives lost due to environmental impact of US-based trastuzumab therapy for HER2+ breast cancer by 1.5 and 0.9, respectively., Conclusion: Alternative dosing strategies may materially reduce the population health impacts of cancer care by reducing environmental impact. Regulatory decision making and health technology assessments should consider a treatment's environmental and population health impacts. Clinical trials of alternative dosing strategies are justified on the basis of environmental and population health impacts.

Characterizing inter-tumor heterogeneity is crucial for selecting suitable cancer therapy, as the presence of diverse molecular subgroups of patients can be associated with disease outcome or response to treatment. While cancer subtypes are often characterized by differences in gene expression, the mechanisms driving these differences are generally unknown. We set out to model the regulatory mechanisms driving sarcoma heterogeneity based on patient-specific, genome-wide gene regulatory networks. We developed a new computational framework, PORCUPINE, which combines knowledge on biological pathways with permutation-based network analysis to identify pathways that exhibit significant regulatory heterogeneity across a patient population. We applied PORCUPINE to patient-specific leiomyosarcoma networks modeled on data from The Cancer Genome Atlas and validated our results in an independent dataset from the German Cancer Research Center. PORCUPINE identified 37 heterogeneously regulated pathways, including pathways representing potential targets for treatment of subgroups of leiomyosarcoma patients, such as FGFR and CTLA4 inhibitory signaling. We validated the detected regulatory heterogeneity through analysis of networks and chromatin states in leiomyosarcoma cell lines. We showed that the heterogeneity identified with PORCUPINE is not associated with methylation profiles or clinical features, thereby suggesting an independent mechanism of patient heterogeneity driven by the complex landscape of gene regulatory interactions., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)

CHH methylation (mCHH) increases gradually during embryogenesis across dicotyledonous plants, indicating conserved mechanisms of targeting and conferral. Although it is suggested that methylation increase during embryogenesis enhances transposable element silencing, the detailed epigenetic pathways underlying this process remain unclear. In Arabidopsis , mCHH is regulated by both small RNA-dependent DNA methylation (RdDM) and RNA-independent Chromomethylase 2 (CMT2) pathways. Here, we conducted DNA methylome profiling at five stages of Arabidopsis embryogenesis, and classified mCHH regions into groups based on their dependency on different methylation pathways. Our analysis revealed that the gradual increase in mCHH in embryos coincided with the expansion of small RNA expression and regional mCHH spreading to nearby sites at numerous loci. We identified distinct methylation dynamics in different groups of mCHH targets, which vary according to transposon length, location, and cytosine frequency. Finally, we highlight the characteristics of transposable element loci that are targeted by different mCHH machinery, showing that short, heterochromatic TEs with lower mCHG levels are enriched in loci that switch from CMT2 regulation in leaves, to RdDM regulation during embryogenesis. Our findings highlight the interplay between the length, location, and cytosine frequency of transposons and the mCHH machinery in modulating mCHH dynamics during embryogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Lee, Park, Shin, Frost, Hsieh, Shin, Fischer, Hsieh and Choi.)

Purpose: The advantages of unicompartmental knee arthroplasty (UKA) have led to the procedure being increasingly performed worldwide. However, revision surgery is required after UKA failure. According to the literature review, the choice of implant in revision surgery remains a debatable concern. This study analyzed the clinical results of different types of prostheses used in treating failed UKA., Materials and Methods: This is a retrospective review of 33 failed medial UKAs between 2006 and 2017. Demographic data, failure reason, types of revision prostheses, and the severity of bone defects were analyzed. The patients were classified into three groups: primary prosthesis, primary prosthesis with a tibial stem, and revision prosthesis. The implant survival rate and medical cost of the procedures were compared., Results: A total of 17 primary prostheses, 7 primary prostheses with tibial stems, and 9 revision prostheses were used. After a mean follow-up of 30.8 months, the survival outcomes of the three groups were 88.2%, 100%, and 88.9%, respectively (P = 0.640). The common bone defect in tibia site is Anderson Orthopedic Research Institute [AORI] grade 1 and 2a (16 versus 17). In patients with tibial bone defects AORI grade 2a, the failure rates of primary prostheses and primary prostheses with tibial stems were 25% and 0%, respectively., Conclusions: The most common cause for UKA failure was aseptic loosening. The adoption of a standardized surgical technique makes it easier to perform revision surgeries. Primary prostheses with tibial stems provided higher stability, leading to a lower failure rate due to less risk of aseptic loosening in patients with tibial AORI grade 2a. In our experience, we advise surgeons may try using primary prostheses in patients with tibial AORI grade 1 and primary prostheses with tibial stems in patients with tibial AORI grade 2a., (© 2023. The Author(s).)

Methyl methacrylate (MMA) is an important petrochemical with many applications. However, its manufacture has a large environmental footprint. Combined biological and chemical synthesis (semisynthesis) may be a promising alternative to reduce both cost and environmental impact, but strains that can produce the MMA precursor (citramalate) at low pH are required. A non-conventional yeast, Issatchenkia orientalis , may prove ideal, as it can survive extremely low pH. Here, we demonstrate the engineering of I. orientalis for citramalate production. Using sequence similarity network analysis and subsequent DNA synthesis, we selected a more active citramalate synthase gene ( cimA ) variant for expression in I. orientalis . We then adapted a piggyBac transposon system for I. orientalis that allowed us to simultaneously explore the effects of different cimA gene copy numbers and integration locations. A batch fermentation showed the genome-integrated- cimA strains produced 2.0 g/L citramalate in 48 h and a yield of up to 7% mol citramalate/mol consumed glucose. These results demonstrate the potential of I. orientalis as a chassis for citramalate production., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Cell cycle progression plays a vital role in regulating proliferation, metabolism, and apoptosis. Three-dimensional (3D) cell cultures have emerged as an important class of in vitro disease models, and incorporating the variation occurring from cell cycle progression in these systems is critical. Here, we report the use of Fourier transform infrared (FT-IR) spectroscopic imaging to identify subtle biochemical changes within cells, indicative of the G1/S and G2/M phases of the cell cycle. Following previous studies, we first synchronized samples from two-dimensional (2D) cell cultures, confirmed their states by flow cytometry and DNA quantification, and recorded spectra. We determined two critical wavenumbers (1059 and 1219 cm -1 ) as spectral indicators of the cell cycle for a set of isogenic breast cancer cell lines (MCF10AT series). These two simple spectral markers were then applied to distinguish cell cycle stages in a 3D cell culture model using four cell lines that represent the main stages of cancer progression from normal cells to metastatic disease. Temporal dependence of spectral biomarkers during acini maturation validated the hypothesis that the cells are more proliferative in the early stages of acini development; later stages of the culture showed stability in the overall composition but unique spatial differences in cells in the two phases. Altogether, this study presents a computational and quantitative approach for cell phase analysis in tissue-like 3D structures without any biomarker staining and provides a means to characterize the impact of the cell cycle on 3D biological systems and disease diagnostic studies using IR imaging.

Objectives: Staphylococcus argenteus is generally more susceptible to antibiotic treatments than Staphylococcus aureus; however, the study showed that the daptomycin/vancomycin-resistant S. argenteus was isolated from a patient with repeated antibiotic treatments. In this study, the methicillin- and vancomycin-susceptible S. argenteus isolates were used to characterize the phenotypes of S. argenteus after vancomycin passages in vitro., Methods: Eleven S. argenteus isolates were used for passaging under different concentrations of vancomycin. The minimal inhibitory concentration (MIC) of vancomycin was determined by the agar dilution assay, and the biofilm mass of the passaged variants was quantified by the crystal violet staining assay and observed under the confocal microscope., Results: The MIC of vancomycin for eight of 11 S. argenteus isolates was increased from ≤2 µg/mL to ≤4-8 µg/mL after vancomycin passages. Two variants with the high-level vancomycin-intermediate (vancomycin MIC ≤8 µg/mL) phenotype were identified, and the parental strains of these variants did not have the heterogeneous vancomycin-intermediate population determined by the population profile analysis. Further, three S. argenteus isolates showed an increase in biofilm production and icaA transcription after the low-dose (2 µg/mL) vancomycin passages., Conclusions: S. argenteus is capable of acquiring a vancomycin-tolerant phenotype and/or converting to a strong biofilm producer after vancomycin passages, which could contribute to the decrease of their antibiotic susceptibility., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To implement an all-day artificial intelligence (AI)-based system to facilitate chest pain triage in the emergency department., Methods: The AI-based triage system encompasses an AI model combining a convolutional neural network and long short-term memory to detect ST-elevation myocardial infarction (STEMI) on electrocardiography (ECG) and a clinical risk score (ASAP) to prioritize patients for ECG examination. The AI model was developed on 2907 twelve-lead ECGs: 882 STEMI and 2025 non-STEMI ECGs., Results: Between November 1, 2019, and October 31, 2020, we enrolled 154 consecutive patients with STEMI: 68 during the AI-based triage period and 86 during the conventional triage period. The mean ± SD door-to-balloon (D2B) time was significantly shortened from 64.5±35.3 minutes to 53.2±12.7 minutes (P=.007), with 98.5% vs 87.2% (P=.009) of D2B times being less than 90 minutes in the AI group vs the conventional group. Among patients with an ASAP score of 3 or higher, the median door-to-ECG time decreased from 30 minutes (interquartile range [IQR], 7-59 minutes) to 6 minutes (IQR, 4-30 minutes) (P<.001). The overall performances of the AI model in identifying STEMI from 21,035 ECGs assessed by accuracy, precision, recall, area under the receiver operating characteristic curve, F1 score, and specificity were 0.997, 0.802, 0.977, 0.999, 0.881, and 0.998, respectively., Conclusion: Implementation of an all-day AI-based triage system significantly reduced the D2B time, with a corresponding increase in the percentage of D2B times less than 90 minutes in the emergency department. This system may help minimize preventable delays in D2B times for patients with STEMI undergoing primary percutaneous coronary intervention., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

New psychoactive substances (NPS) have increasingly been illegally synthesized and used around the world in recent years. Due to the large volume and the variety of NPS, most do not have sufficient information about their addictive potential and harmful effects to human subjects. This makes it difficult to evaluate these potential substances of abuse. This study aims to build a database based on Taiwan's controlled substances, to provide quick structural and pharmacological feedback. Taiwan Controlled Substances Database (TCSD) includes the collection of controlled substances, relevant experimental and structural information, as well as computational features such as molecular fingerprints and descriptors. Two types of structural search were added: substructure search and topological fingerprint similarity search. A web framework was used to enhance accessibility and usability (https://cs2search.cmdm.tw)., Competing Interests: Declaration of Competing Interest Authors declare there are no financial and nonfinancial conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

We have developed a novel molecular diagnostic platform (photothermal bead-based nucleic acid amplification test; pbbNAAT) that greatly improves the low sensitivity of direct loop-mediated isothermal amplification (LAMP) and allows for specific detection of LAMP amplicons in complex samples. The pbbNAAT integrates specific ligand-functionalized polypyrrole-coated iron oxide particles (PPy@IOs) capable of photothermal conversion and single-molecule magnetic capture of target analytes, the released nucleic acid, and LAMP-amplified products under external light energy control and magnetic manipulations. This allows for sample pretreatment, pbbLAMP amplification, and subsequent amplicon detection with bead-based ELISA in a one-stop microreactor without loss. In addition, photonic heating with PPy@IOs and external light control provide instant and uniform heating for thermolysis and pbbLAMP implementations. Moreover, it generates higher primer annealing stringency for LAMP primers in pbbLAMP; thus, it can detect pathogen-specific DNA accurately and promptly in pathogen-spiked complex materials. The sample pretreatment procedure of pbbNAAT can greatly reduce inhibitors originating from complex samples, which enables the maintenance of maximal enzyme activities for highly sensitive detection. More importantly, the pbbLAMP assay coupled with magnetic capture permits subsequent bead-based ELISA detection to determine true positive LAMP amplicons on PPy@IOs. The pbbNAAT platform has a high tolerance to inhibitors originating from complex samples, high analytical specificity, and limitation of detection (LoD) as low as 8 CFU/reaction to detect E. coli spiked in human whole blood, bovine milk, and can be completed in less than 1 h. Therefore, we believe that pbbNAAT can serve as a suitable direct LAMP platform for on-site POCTs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Climate change mitigation has been one of the world's most salient issues for the past three decades. However, global policy attention has been partially diverted to address the COVID-19 pandemic for the past 2 y. Here, we explore the impact of the pandemic on the frequency and content of climate change discussions on Twitter for the period of 2019 to 2021. Consistent with the "finite pool of worry" hypothesis both at the annual level and on a daily basis, a larger number of COVID-19 cases and deaths is associated with a smaller number of "climate change" tweets. Climate change discussion on Twitter decreased, despite 1) a larger Twitter daily active usage in 2020 and 2021, 2) greater coverage of climate change in the traditional media in 2021, 3) a larger number of North Atlantic Ocean hurricanes, and 4) a larger wildland fires area in the United States in 2020 and 2021. Further evidence supporting the finite pool of worry is the significant relationship between daily COVID-19 cases/deaths on the one hand and the public sentiment and emotional content of climate change tweets on the other. In particular, increasing COVID-19 numbers decrease negative sentiment in climate change tweets and the emotions related to worry and anxiety, such as fear and anger.

Objective: This study investigated the psychological impact on, coping behaviors of, and traumatic stress experienced by healthcare workers during the early stage of the COVID-19 pandemic and formulated effective support strategies that can be implemented by hospitals and government policymakers to help healthcare staff overcome the pandemic., Methods: This cross-sectional study recruited clinical healthcare workers at a regional hospital in Nantou County, Taiwan. The questionnaire collected personal characteristics, data on the impact and coping behaviors of the pandemic, and Impact of Event Scale-Revised (IES-R). A total of 354 valid questionnaires were collected. The statistical methods employed were univariate and multivariate stepwise regression, and logistic regression., Results: Perceived impact and coping behaviors were found to be moderate in degree, and traumatic stress was lower than that in other countries. However, our data identified the following subgroups that require special attention: those with young age, those living with minor children, nurses, those with self-rated poor mental health, and those with insufficient COVID-19-related training., Conclusion: Managers should pay particular attention to helping healthcare workers in high-risk groups, strengthen COVID-19 training, provide adequate protective equipment and shelter, and offer psychological counseling., Competing Interests: The authors have declared that no competing interests exist.

Objective: To implement an all-day online artificial intelligence (AI)-assisted detection of ST-elevation myocardial infarction (STEMI) by prehospital 12-lead electrocardiograms (ECGs) to facilitate patient triage for timely reperfusion therapy., Methods: The proposed AI model combines a convolutional neural network and long short-term memory (CNN-LSTM) to predict STEMI on prehospital 12-lead ECGs obtained from mini-12-lead ECG devices equipped in ambulance vehicles in Central Taiwan. Emergency medical technicians (EMTs) from the 14 AI-implemented fire stations performed the on-site 12-lead ECG examinations using the mini portable device. The 12-lead ECG signals were transmitted to the AI center of China Medical University Hospital to classify the recordings as "STEMI" or "Not STEMI". In 11 non-AI fire stations, the ECG data were transmitted to a secure network and read by available on-line emergency physicians. The response time was defined as the time interval between the ECG transmission and ECG interpretation feedback., Results: Between July 17, 2021, and March 26, 2022, the AI model classified 362 prehospital 12-lead ECGs obtained from 275 consecutive patients who had called the 119 dispatch centers of fire stations in Central Taiwan for symptoms of chest pain or shortness of breath. The AI's response time to the EMTs in ambulance vehicles was 37.2 ± 11.3 s, which was shorter than the online physicians' response time from 11 other fire stations with no AI implementation (113.2 ± 369.4 s, P < 0.001) after analyzing another set of 335 prehospital 12-lead ECGs. The evaluation metrics including accuracy, precision, specificity, recall, area under the receiver operating characteristic curve, and F1 score to assess the overall AI performance in the remote detection of STEMI were 0.992, 0.889, 0.994, 0.941, 0.997, and 0.914, respectively. During the study period, the AI model promptly identified 10 STEMI patients who underwent primary percutaneous coronary intervention (PPCI) with a median contact-to-door time of 18.5 (IQR: 16-20.8) minutes., Conclusion: Implementation of an all-day real-time AI-assisted remote detection of STEMI on prehospital 12-lead ECGs in the field is feasible with a high diagnostic accuracy rate. This approach may help minimize preventable delays in contact-to-treatment times for STEMI patients who require PPCI., Competing Interests: Author P-HH was employed by Ever Fortune AI Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Wang, Liu, Tsai, Wu, Hsieh, Wei, Shih, Shiao, Hwang, Wu, Hsu and Chang.)

Objectives: Radiology and medical imaging are important yet often an underrepresented facet of medical education. Notably, there is concern among radiologists that students do not receive enough radiology exposure and that they struggle to interpret image findings on entering residency. Therefore, this survey aims to identify how medical students perceive the radiology curriculum and to determine gaps in delivery., Material and Methods: Students were recruited from United States (US) medical schools and given a 21-question survey assessing their perception of the radiology curriculum as well as asking about their confidence levels regarding medical imaging. The inclusion criteria were age >18 and enrolled in US medical school. The surveys were completed in April-July 2020 by students across the US. Objective parameters were measured as percentage correct, while subjective parameters used a 4-point Likert scale., Results: A total of 472 medical students across 31 medical schools completed the surveys with a response rate of 69%. Responses represented all class years within medical schools and showed equal distribution among the future career plans. Students responded that didactic lectures were the most common teaching method and that radiologists were their primary teachers during preclinical education. Students were unfamiliar with the American College of Radiology appropriateness criteria with 65% responding they had never heard of it and 33% reporting that they have heard of it but never used it. In assessing students' perceptions of radiology education, 72% of students responded that they received too little, and 28% of students responded, "Just right." <1% of students responded that there was "Too much" radiology in their curriculum., Conclusion: Radiologists are increasing their educational representation in medical school curricula. Despite this, radiology continues to be under-represented with students desiring more exposure to medical imaging. Integrating the student's perceptions with existing curricula suggests that efforts should focus on increasing awareness of which studies are appropriate and teaching students how to systematically interpret an image., Competing Interests: There are no conflicts of interest., (© 2022 Published by Scientific Scholar on behalf of Journal of Clinical Imaging Science.)

Objective: Multiple long-term conditions (MLTCs) are prevalent in rheumatoid arthritis (RA) and associated with worse outcomes and greater economic burden. However, little is known about the impact of MLTCs on the cost-of-illness (COI) in early RA, including direct and indirect costs. The objective of this study was to quantify this impact on COI., Methods: The Scottish Early Rheumatoid Arthritis study is a national cohort of adults with new-onset RA. Direct costs were estimated applying relevant unit costs to health resource utilisation; indirect costs were measured by productivity loss due to health conditions. Two-part models were used, adjusting for age, gender, baseline functional disability and health-related quality of life. The Charlson Comorbidity Index score was calculated using ICD-10 diagnoses. Individuals were defined as 'RA alone', 'RA plus LTC' and 'RA plus MLTCs' according to the number of coexisting LTCs., Results: Data were available for 818 participants. Average annualised direct costs incurred by people with early RA plus MLTCs (£4444; 95% CI £3100 to £6371) were twice as, and almost five times higher than, those with a single LTC (£2184; 95% CI £1596 to £2997) and those without LTC (£919; 95% CI £694 to £1218), respectively. Indirect costs incurred by RA plus MLTCs (£842; 95% CI £377to £1521) were 3.1 times higher than RA alone (£530; 95% CI £273to £854). The relative proportion of direct costs increased with LTC category, ranging from 77.2% to 84.1%. In addition to increased costs with LTCs, costs also increased with age and were higher for men regardless of LTC category., Conclusions: MLTCs impact on COI early in the course of RA. The presence of LTCs is associated with significant increases in both direct and indirect costs among people with early RA., Competing Interests: Competing interests: ICMJE disclosure forms uploaded during the submission process., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Nontuberculous mycobacteria periprosthetic joint infection (NTMPJI) is a rare complication of hip or knee joint arthroplasty. The experience for outcomes of NTMPJI treatment is still limited. The objective of this study was to investigate the outcome of hip or knee nontuberculous mycobacteria periprosthetic joint infection following treatment with two-stage exchange arthroplasty., Material and Methods: From 1995 to 2020, 12 patients with NTMPJI were treated with two-stage exchange arthroplasty at our institution. We collected and analyzed variables including demographic data, comorbidity, microbiological data, treatment outcome and antibiotic formula in bone cement., Results: Mycobacterium abcessus ( n = 6) and Mycobacterium chelonae ( n = 2) constitute the majority of the cases. Five patients had early-onset PJIs and the other seven patients were late onset. The success rate of two-stage exchange arthroplasty was 66.7% (8 of 12). Three patients experienced infection relapse, and one patient had soft tissue compromise complication. Post-operative antibiotic therapy may not improve the success rate (4 of 6 cases, 66.7%). Based on in vitro study, the most commonly used effective antibiotic in bone cement spacer for nontuberculous mycobacteria was amikacin., Conclusions: nontuberculous mycobacteria is a rare cause of PJIs and should be suspected especially in relatively immunocompromised patients. Resection arthroplasty with staged reimplantation is the preferred approach. Prolonged post-operative antibiotic therapy before reimplantation may not improve the success rate. Delayed revision surgery may not be needed and can be performed once C-reactive protein level is normal after a drug holiday.

Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (C trough ) and population and individual likelihoods of C trough exceeding trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment-associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of C trough being above MEC as standard of care 6 mg/kg every 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Infrared (IR) spectroscopic imaging instruments' performance can be characterized and optimized by an analysis of their limit of detection (LOD). Here we report a systematic analysis of the LOD for Fourier transform IR (FT-IR) and discrete frequency IR (DFIR) imaging spectrometers. In addition to traditional measurements of sample and blank data, we propose a decision theory perspective to pose the determination of LOD as a binary classification problem under different assumptions of noise uniformity and correlation. We also examine three spectral analysis approaches, namely, absorbance at a single frequency, average of absorbance over selected frequencies and total spectral distance - to suit instruments that acquire discrete or contiguous spectral bandwidths. The analysis is validated by refining the fabrication of a bovine serum albumin protein microarray to provide eight uniform spots from ∼2.8 nL of solution for each concentration over a wide range (0.05-10 mg/mL). Using scanning parameters that are typical for each instrument, we estimate a LOD of 0.16 mg/mL and 0.12 mg/mL for widefield and line scanning FT-IR imaging systems, respectively, using the spectral distance approach, and 0.22 mg/mL and 0.15 mg/mL using an optimal set of discrete frequencies. As expected, averaging and the use of post-processing techniques such as minimum noise fraction transformation results in LODs as low as ∼0.075 mg/mL that correspond to a spotted protein mass of ∼112 fg/pixel. We emphasize that these measurements were conducted at typical imaging parameters for each instrument and can be improved using the usual trading rules of IR spectroscopy. This systematic analysis and methodology for determining the LOD can allow for quantitative measures of confidence in imaging an analyte's concentration and a basis for further improving IR imaging technology.

Background: Patients with multiple prosthetic joints are at risk of developing periprosthetic joint infections (PJIs). We aimed to determine whether PJI development at one site may lead to infection at another prosthetic joint site and assess the risk factors leading to this subsequent infection., Methods: We reviewed all cases (294 patients with first-time PJI [159 hips, 135 knees]) with PJI treated at our institute between January 1994 and December 2020. The average follow-up period was 11.2 years (range 10.1-23.2). Patients were included if they had at least one other prosthetic joint at the time of developing a single PJI (96 patients). Patients with synchronous PJI were excluded from the study. The incidence of metachronous PJI was assessed, and the risk factors were determined by comparing different characteristics between patients without metachronous PJI., Results: Of the 96 patients, 19.79% developed metachronous PJI. The identified causative pathogen was the same in 63.16% of the patients. The time to developing a second PJI was 789.84 days (range 10-3386). The identified risk factors were PJI with systemic inflammatory response syndrome, ≥3 stages of resection arthroplasty, and PJI caused by methicillin-resistant Staphylococcus aureus., Conclusion: PJI may predispose patients to subsequent PJI in another prosthesis with identified risks. Most causative organisms of metachronous PJI were the same species as those of the first PJI. We believe that bacteremia may be involved in pathogenesis, but further research is required., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adaptive immune receptor repertoires (AIRR) are key targets for biomedical research as they record past and ongoing adaptive immune responses. The capacity of machine learning (ML) to identify complex discriminative sequence patterns renders it an ideal approach for AIRR-based diagnostic and therapeutic discovery. To date, widespread adoption of AIRR ML has been inhibited by a lack of reproducibility, transparency, and interoperability. immuneML (immuneml.uio.no) addresses these concerns by implementing each step of the AIRR ML process in an extensible, open-source software ecosystem that is based on fully specified and shareable workflows. To facilitate widespread user adoption, immuneML is available as a command-line tool and through an intuitive Galaxy web interface, and extensive documentation of workflows is provided. We demonstrate the broad applicability of immuneML by (i) reproducing a large-scale study on immune state prediction, (ii) developing, integrating, and applying a novel deep learning method for antigen specificity prediction, and (iii) showcasing streamlined interpretability-focused benchmarking of AIRR ML., Competing Interests: Competing Interests V.G. declares advisory board positions in aiNET GmbH and Enpicom B.V. VG is a consultant for Roche/Genentech.

Background: A number of patients with end-stage renal disease (ESRD) undergo total knee arthroplasty (TKA) due to advanced knee joint osteoarthritis. There are few studies describing the incidence, morbidities, mortality rate, and cost analysis regarding ESRD patients receiving TKA., Methods: We retrospectively retrieved patient data from National Health Insurance Research Database in Taiwan during 2005-2011, and evaluated the outcomes of TKA in patients with (ESRD group) and without ESRD (non-ESRD group). Patients' demographic data, comorbidities, mortality, and in-hospital cost were recorded., Results: A total of 578 TKAs and 110,895 TKAs were identified in the ESRD and non-ESRD group, respectively. The incidence of patients receiving TKA was higher in the ESRD than in non-ESRD group by at least 2 folds. The ESRD group showed significantly more medical complications (pneumonia, peptic ulcer disease, and acute myocardial infarction) after surgery. In prosthesis-related complications, the ESRD group also had more periprosthetic joint infections, and prosthetic loosenings by one year. The one-year mortality rate was more than 6 times higher in the ESRD than in the non-ESRD group. The ESRD group had higher in-hospital medical expense than the non-ESRD group, especially when there were complications, even when the dialysis-related costs were exempted., Conclusion: The complication rate, mortality rate, and cost were higher in the ESRD patients receiving TKA. When considering TKA in ESRD patients, it is crucial to weigh the risks against benefits of TKA, and have a thorough discussion with the patients., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (Copyright © 2020 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Intrapapillary capillary loops (IPCLs) are microvascular structures that correlate with the invasion depth of early squamous cell neoplasia and allow accurate prediction of histology. Artificial intelligence may improve human recognition of IPCL patterns and prediction of histology to allow prompt access to endoscopic therapy for early squamous cell neoplasia where appropriate., Methods: One hundred fifteen patients were recruited at 2 academic Taiwanese hospitals. Magnification endoscopy narrow-band imaging videos of squamous mucosa were labeled as dysplastic or normal according to their histology, and IPCL patterns were classified by consensus of 3 experienced clinicians. A convolutional neural network (CNN) was trained to classify IPCLs, using 67,742 high-quality magnification endoscopy narrow-band images by 5-fold cross validation. Performance measures were calculated to give an average F1 score, accuracy, sensitivity, and specificity. A panel of 5 Asian and 4 European experts predicted the histology of a random selection of 158 images using the Japanese Endoscopic Society IPCL classification; accuracy, sensitivity, specificity, positive and negative predictive values were calculated., Results: Expert European Union (EU) and Asian endoscopists attained F1 scores (a measure of binary classification accuracy) of 97.0% and 98%, respectively. Sensitivity and accuracy of the EU and Asian clinicians were 97%, 98% and 96.9%, 97.1%, respectively. The CNN average F1 score was 94%, sensitivity 93.7%, and accuracy 91.7%. Our CNN operates at video rate and generates class activation maps that can be used to visually validate CNN predictions., Conclusions: We report a clinically interpretable CNN developed to predict histology based on IPCL patterns, in real time, using the largest reported dataset of images for this purpose. Our CNN achieved diagnostic performance comparable with an expert panel of endoscopists., (Copyright © 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Parent-of-origin-dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin-specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA-producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions-the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Chronic hepatitis C (CHC) is a major cause of cirrhosis, hepatocellular carcinoma (HCC), and mortality. Eliminating hepatitis C virus (HCV) can greatly improve long-term outcomes. Several direct-acting antiviral agents (DAAs), including sofosbuvir (SOF) plus different NS5A inhibitors, as well as non-SOF-based DAAs, including glecaprevir/pibrentasvir (GLE/PIB), have been approved for treating CHC genotype-2 (GT-2) patients in Taiwan. However, there is limited real-world effectiveness data regarding these different regimens. Thus, we aimed to evaluate the real-world efficacy in CHC GT-2 patients who underwent these DAA regimens. We retrospectively enrolled CHC GT-2 patients who were treated with SOF-based DAAs or GLE/PIB at a single medical center. A total of 704 enrolled patients were treated with either SOF + ribavirin (RBV), SOF/daclatasvir (DCV) ± RBV, SOF/ledipasvir (LDV) ± RBV, SOF/velpatasvir (VEL) ± RBV, or with GLE/PIB. The overall sustained virological response (SVR) rate was 97.9%. The SVR rate was significantly lower in the SOF + RBV group (95.6%) than in the non-SOF + RBV (98.9%) group, especially compared to the SOF/DCV (100%) and GLE/PIB groups (99.5%). Among patients treated with SOF + RBV, cirrhotic patients had significantly lower SVR rates than noncirrhotic patients (89.4% vs 98.2%). Multivariate analysis showed that patients with a younger age, hepatitis B virus coinfection, baseline cirrhosis, or those who received SOF + RBV were less likely to achieve SVR. In conclusion, for CHC GT-2 patients, SOF in combination with DCV, LDV, or VEL, as well as GLE/PIB, achieved similar high efficacies, regardless of cirrhosis, treatment experience, or chronic kidney disease status. Therefore, the use of DAA therapy to eradicate HCV should not be delayed in these populations., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Aims: To develop an artificial intelligence-based approach with multi-labelling capability to identify both ST-elevation myocardial infarction (STEMI) and 12 heart rhythms based on 12-lead electrocardiograms (ECGs)., Methods and Results: We trained, validated, and tested a long short-term memory (LSTM) model for the multi-label diagnosis of 13 ECG patterns (STEMI + 12 rhythm classes) using 60 537 clinical ECGs from 35 981 patients recorded between 15 January 2009 and 31 December 2018. In addition to the internal test above, we conducted a real-world external test, comparing the LSTM model with board-certified physicians of different specialties using a separate dataset of 308 ECGs covering all 13 ECG diagnoses. In the internal test, the area under the curves (AUCs) of the LSTM model in classifying the 13 ECG patterns ranged between 0.939 and 0.999. For the external test, the LSTM model for multi-labelling of the 13 ECG patterns evaluated by AUC was 0.987 ± 0.021, which was superior to those of cardiologists (0.898 ± 0.113, P  < 0.001), emergency physicians (0.820 ± 0.134, P  < 0.001), internists (0.765 ± 0.155, P  < 0.001), and a commercial algorithm (0.845 ± 0.121, P  < 0.001). Of note, the LSTM model achieved an accuracy of 0.987, AUC of 0.997, and precision, recall, and F 1 score of 0.952, 0.870, and 0.909, respectively, in detecting STEMI., Conclusions: We demonstrated the usefulness of an LSTM model in the multi-labelling detection of both rhythm classes and STEMI in competitive testing against board-certified physicians. This AI tool exceeding the cardiologist-level performance in detecting STEMI and rhythm classes on 12-lead ECG may be useful in prioritizing chest pain triage and expediting clinical decision-making in healthcare., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Following the initial identification of the 2019 coronavirus disease (covid-19), the subsequent months saw substantial increases in published biomedical research. Concerns have been raised in both scientific and lay press around the quality of some of this research. We assessed clinical research from major clinical journals, comparing methodological and reporting quality of covid-19 papers published in the first wave (here defined as December 2019 to May 2020 inclusive) of the viral pandemic with non-covid papers published at the same time., Methods: We reviewed research publications (print and online) from The BMJ, Journal of the American Medical Association (JAMA), The Lancet, and New England Journal of Medicine, from first publication of a covid-19 research paper (February 2020) to May 2020 inclusive. Paired reviewers were randomly allocated to extract data on methodological quality (risk of bias) and reporting quality (adherence to reporting guidance) from each paper using validated assessment tools. A random 10% of papers were assessed by a third, independent rater. Overall methodological quality for each paper was rated high, low or unclear. Reporting quality was described as percentage of total items reported., Results: From 168 research papers, 165 were eligible, including 54 (33%) papers with a covid-19 focus. For methodological quality, 18 (33%) covid-19 papers and 83 (73%) non-covid papers were rated as low risk of bias, OR 6.32 (95%CI 2.85 to 14.00). The difference in quality was maintained after adjusting for publication date, results, funding, study design, journal and raters (OR 6.09 (95%CI 2.09 to 17.72)). For reporting quality, adherence to reporting guidelines was poorer for covid-19 papers, mean percentage of total items reported 72% (95%CI:66 to 77) for covid-19 papers and 84% (95%CI:81 to 87) for non-covid., Conclusions: Across various measures, we have demonstrated that covid-19 research from the first wave of the pandemic was potentially of lower quality than contemporaneous non-covid research. While some differences may be an inevitable consequence of conducting research during a viral pandemic, poor reporting should not be accepted.

Background: Deep-learning algorithms to annotate electrocardiograms (ECGs) and classify different types of cardiac arrhythmias with the use of a single-lead ECG input data set have been developed. It remains to be determined whether these algorithms can be generalized to 12-lead ECG-based rhythm classification., Methods: We used a long short-term memory (LSTM) model to detect 12 heart rhythm classes with the use of 65,932 digital 12-lead ECG signals from 38,899 patients, using annotations obtained by consensus of 3 board-certified electrophysiologists as the criterion standard., Results: The accuracy of the LSTM model for the classification of each of the 12 heart rhythms was ≥ 0.982 (range 0.982-1.0), with an area under the receiver operating characteristic curve of ≥ 0.987 (range 0.987-1.0). The precision and recall ranged from 0.692 to 1 and from 0.625 to 1, respectively, with an F 1 score of ≥ 0.777 (range 0.777-1.0). The accuracy of the model (0.90) was superior to the mean accuracies of internists (0.55), emergency physicians (0.73), and cardiologists (0.83)., Conclusions: We demonstrated the feasibility and effectiveness of the deep-learning LSTM model for interpreting 12 common heart rhythms according to 12-lead ECG signals. The findings may have clinical relevance for the early diagnosis of cardiac rhythm disorders., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)