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In this study, the authors constructed structural equation models in order to determine the relationship between students’ learning attitudes and their computational thinking perspectives and programming empowerment. The purpose is to understand students’ perceived competence to use computational thinking effectively, along with their computer programming learning attitude regarding the C++ programming language for one semester (2 hours per week, 36 total learning hours). A total of 495 students specializing in the medical field participated in the study. Structural equation models were constructed according to three adapted scales: the computer programming learning attitude scale, the computational thinking perspectives scale, and the programming empowerment scale. The computer programming learning attitude scale is based on three factors: willingness, negativity, and necessity. The computational thinking perspectives scale also considers three factors: the ability to express, the ability to connect, and the ability to question. The programming empowerment scale is composed of four factors: meaningfulness, impact, creative self-efficacy, and programming self-efficacy. The results showed that a positive learning attitude will positively affect computational thinking perspectives and programming empowerment. However, when students have a negativity attitude, feeling that they are being forced to learn the C++ programming language, their computational thinking perspectives and programming empowerment will be negatively affected. In order to promote students’ learning attitude, various teaching strategies, teaching curriculum design, and pedagogy design could be further explored.

With a 5-year survival rate of less than 50%, ovarian high-grade serous carcinoma (HGSC) is one of the most highly aggressive gynecological malignancies affecting women today. The high mortality rate of HGSC is largely attributable to delays in diagnosis, as most patients remain undiagnosed until the late stages of -disease. There are currently no recommended screening tests for ovarian cancer and there thus remains an urgent need for new diagnostic methods, particularly those that can detect the disease at early stages when clinical intervention remains effective. While diagnostics for ovarian cancer share many of the same technical hurdles as for other cancer types, the low prevalence of the disease in the general population, coupled with a notable lack of sensitive and specific biomarkers, have made the development of a clinically useful screening strategy particularly challenging. Here, we present a detailed review of the overall landscape of ovarian cancer diagnostics, with emphasis on emerging methods that employ novel protein, genetic, epigenetic and imaging-based biomarkers and/or advanced diagnostic technologies for the noninvasive detection of HGSC, particularly in women at high risk due to germline mutations such as BRCA1/2. Lastly, we discuss the translational potential of these approaches for achieving a clinically implementable solution for screening and diagnostics of early-stage ovarian cancer as a means of ultimately improving patient outcomes in both the general and high-risk populations.

In biomedical and epidemiological studies, gene-environment (G-E) interactions play an important role in the etiology and progression of many complex diseases. In ultra-high-dimensional survival genomic data, two common approaches (marginal and joint models) are proposed to determine important interaction biomarkers. Most existing methods for detecting G-E interactions (marginal Cox model and marginal accelerated failure time model) are limited by a lack of robustness to contamination/outliers in response outcome and prediction biomarkers. In particular, right-censored survival outcomes and ultra-high-dimensional feature space make relevant feature screening even more challenging.In this paper, we utilize the non-parametric Kendall's partial correlation method to obtain pure correlation to determine the importance of G-E interactions concerning clinical survival data under a marginal modeling framework.A series of simulated scenarios are conducted to compare the performance of our proposed method (Kendall's partial correlation) with some commonly used methods (marginal Cox's model, marginal accelerated failure time model, and censoring quantile partial correlation approach). In real data applications, we utilize Kendall's partial correlation method to identify G-E interactions related to the clinical survival results of patients with esophageal, pancreatic, and lung carcinomas using The Cancer Genome Atlas clinical survival genetic data, and further establish survival prediction models.Overall, both simulation with medium censoring level and real data studies show that our method performs well and outperforms existing methods in the selection, estimation, and prediction accuracy of main and interacting biomarkers. These applications reveal the advantages of the non-parametric Kendall's partial correlation approach over alternative semi-parametric marginal modeling methods. We also identified the cancer-related G-E interactions biomarkers and reported the corresponding coefficients with

Background: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. Methods: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. Results: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR] adj 1.61 [95% CI, 1.42–1.84]; P adj , 1.72 [95% CI, 1.49–1.99]; P P interaction 0.51; major coronary events: HR, 0.82 [0.75–0.90] versus HR, 0.88 [0.75–1.04]; P interaction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% ( P interaction 0.14) and for major coronary events 2.0% versus 0.7% ( P interaction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69–0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54–0.94]); any PCI (HR, 0.77 [0.69–0.86]); PCI for de novo lesions (HR, 0.76 [0.66–0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63–0.91]). Conclusions: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

Drawing on the resource-based view, this study examines how parent-subsidiary resource linkages in terms of resource commitment and resource similarity affect the performance of the parent firm. By using the data from 199 Taiwanese firms investing in China, the results of this study show that resource commitment has an inverted U-shaped relationship with the parent firm performance, whereas the relationship between resource similarity and the parent firm performance is U-shaped. In addition, this study also finds that organizational slack and parent involvement moderate these relationships. This study provides important theoretical and managerial implications for international business management.

Digital nucleic acid amplification testing (dNAAT) and analysis techniques, such as digital polymerase chain reaction (PCR), have become useful clinical diagnostic tools. However, nucleic acid (NA) sample preparation preceding dNAAT is generally laborious and performed manually, thus creating the need for a simple sample preparation technique and a facile coupling strategy for dNAAT. Therefore, we demonstrate a simple workflow which automates magnetic bead-based extraction of NAs with a one-step transfer to dNAAT. Specifically, we leverage droplet magnetofluidics (DM) to automate the movement of magnetic beads between small volumes of reagents commonly employed for NA extraction and purification. Importantly, the buffer typically used to elute the NAs off the magnetic beads is replaced by a carefully selected PCR solution, enabling direct transfer from sample preparation to dNAAT. Moreover, we demonstrate the potential for multiplexing using a digital high-resolution melt (dHRM) after the digital PCR (dPCR). The utility of this workflow is demonstrated with duplexed detection of bacteria in a sample imitating a coinfection. We first purify the bacterial DNA into a PCR solution using our DM-based sample preparation. We then transfer the purified bacterial DNA to our microfluidic nanoarray to amplify 16S rRNA using dPCR and then perform dHRM to identify the two bacterial species.

An ultralow-power $K$ -band low-noise amplifier (LNA) for next generation radio astronomical receivers fabricated in 65-nm CMOS technology is presented in this letter. A gate–source transformer feedback is utilized for the simultaneous noise and impedance matching. In order to achieve high gain with limited dc power consumption ( $P_{\mathrm {dc}}$ ), a single-ended neutralization technique is applied to the circuit. According to measurement, the proposed $K$ -band LNA achieves a 19.1-dB small signal gain with 2.8-GHz 3-dB bandwidth (21.2–24 GHz) and noise figure of 3.6 dB with only 0.99 mW $P_{\mathrm {dc}}$ . To the best of author’s knowledge, this LNA shows the highest figure of merit (FoM), which is 7071 1/W, among published $K$ -band low-power LNAs.

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C 20 mg/dl.

In view of the increasing prevalence of gestational diabetes mellitus (GDM) and the increased risks of delivering a macrosomic infant, developing preeclampsia, and suffering a perinatal death due to GDM, GDM has emerged as a growing public health problem. Although the placenta was suggested to play a crucial role in the pathology of GDM, the mechanisms that induce the development of GDM are still obscure. Fibrinogen-like protein (FGL)-1 is a hepatokine that plays an important role in hepatogenesis, as well as in nonalcoholic fatty liver disease and diabetes. Although FGL-1 is also expressed by the placenta, the pathophysiological role of FGL-1 in GDM is still unknown. In this study, FGL-1 levels were evaluated in 45 subjects with (n = 16) or without (n = 29) GDM. We found that FGL-1 was mainly expressed by placental trophoblasts, and FGL-1 expression was significantly higher in subjects with GDM. FGL-1 increased trophoblast proliferation through an extracellular signal-regulated kinase 1/2-dependent pathway. In addition, plasma concentrations of FGL-1 were higher in subjects with GDM, and the increased circulating FGL-1 might contribute to systemic insulin resistance. FGL-1 disrupted the gluconeogenic action of insulin in HepG2 cells, and decreased insulin-induced glucose uptake by L6 myotubes. Taken together, placental FGL-1 possibly plays a role in the impairment of insulin function in the development of GDM, and it might be a novel biomarker for diagnosing GDM.

Objectives Traditional antimicrobial susceptibility testing (AST) is growth dependent and time-consuming. With rising rates of drug-resistant infections, a novel diagnostic method is critically needed that can rapidly reveal a pathogen’s antimicrobial susceptibility to guide appropriate treatment. Recently, RNA sequencing has been identified as a powerful diagnostic tool to explore transcriptional gene expression and improve AST. Methods RNA sequencing was used to investigate the potential of RNA markers for rapid molecular AST using Klebsiella pneumoniae and ciprofloxacin as a model. Downstream bioinformatic analysis was applied for optimal marker selection. Further validation on 11 more isolates of K. pneumoniae was performed using quantitative real-time PCR. Results From RNA sequencing, we identified RNA signatures that were induced or suppressed following exposure to ciprofloxacin. Significant shifts at the transcript level were observed as early as 10 min after antibiotic exposure. Lastly, we confirmed marker expression profiles with concordant MIC results from traditional culture-based AST and validated across 11 K. pneumoniae isolates. recA, coaA and metN transcripts harbour the most sensitive susceptibility information and were selected as our top markers. Conclusions Our results suggest that RNA signature is a promising approach to AST development, resulting in faster clinical diagnosis and treatment of infectious disease. This approach is potentially applicable in other models including other pathogens exposed to different classes of antibiotics.

Context Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine that improves insulin sensitivity in animals. However, serum ANGPTL6 concentration was found to be higher in human participants with diabetes or metabolic syndrome in cross-sectional studies, implying that ANGPTL6 may be induced to counteract hyperglycemia. Objective To investigate whether serum ANGPTL6 can predict incident diabetes and explore whether glucose or insulin can regulate ANGPTL6 expression and secretion. Design This cohort study included adults without diabetes at baseline who were followed every 2 years for incident diabetes. Serum ANGPTL6 concentrations were measured at baseline and during oral glucose tolerance tests (OGTTs). A hepatic cell line, HepG2, and diet-induced obesity mouse model were used to evaluate the response of ANGPTL6 expression and secretion to hyperglycemia and the metabolic syndrome. Results We recruited 1103 participants without diabetes at baseline. During the 4.22-year follow-up, 113 (10.2%) participants developed incident diabetes. Serum ANGPTL6 was negatively associated with the incidence of diabetes (adjusted hazard ratio, 0.77; P = 0.042). However, serum ANGPTL6 level was higher in participants with prediabetes (P = 0.018) and was elevated during OGTT. In HepG2 cells, treatment with glucose, but not insulin, induced ANGPTL6 expression. Hepatic ANGPTL6 expression and serum ANGPTL6 concentrations were significantly higher in mice fed with a high-fat diet than in those fed with a standard chow (both P < 0.05). Conclusion A high serum ANGPTL6 level is associated with a low incidence of diabetes in humans. ANGPTL6 is expressed and secreted in response to hyperglycemia to maintain glucose homeostasis.

This paper presents a G-band on-off -keying transmitter and a G-Band receiver in 65-nm bulk CMOS process. The proposed transmitter includes a high-efficiency push–push voltage-controlled oscillator (VCO) with body-bias and a switch-based modulator using the folded coupled-line topology. The benefits of the folded coupled-line in switch design are theoretically analyzed and proved. The receiver utilized a topology based on envelope detector and inverter-chain-based output buffer. The standalone VCO demonstrates a peak dc-RF efficiency of 4.1% at 209 GHz with 1.02 dBm output power. The switch-based modulator performs a minimum insertion loss of 1.6 dB with isolation better than 21 dB. The transmitter exhibits a maximum output power of −0.04 dBm at 208 GHz with 3% efficiency and a phase noise of −84.9 dBc at 1-MHz offset. The transmitter and receiver achieve 7.5-Gb/s errorless [bit error rate (BER) < 1 × 10−12] data rate with 1.73 pJ/b energy efficiency and 9 Gb/s with 1 × 10−4 BER in loop-back test. The results of both the transmitter/receiver and standalone components show competitive performances at the frequency over 200 GHz among the designs in CMOS process.

Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27–single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. Results: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events ( P trend =0.005) and major coronary events ( P trend P =0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75–0.998], P =0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55–0.86], P =0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk ( P trend for HR=0.017, ARR P trend =0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Conclusion: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.

Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development., Kallman et al. showed the effect of Nrl in human PSC-derived retinal organoids. Using histological and single cell transcriptomics, they identified an intermediate “cod” subpopulation in the predominant S-opsin population. Their findings provide important insights for human retinal development and degeneration.

Virtual microscopy (VM) has been utilized to improve students' learning experience in microscope laboratory sessions, but minimal attention has been given to determining how to use VM more effectively. The study examined the influence of VM on academic performance and teacher and student perceptions and compared laboratory test scores before and after VM incorporation. A total of 662 third-year students studying histology and 651 fourth-year students studying pathology were divided into two groups. The light microscopy (LM) group used a light microscope in 2014 and 2015, while the LM + VM group used the VM platform and a light microscope in 2016 and 2017. Four factors positively predict laboratory scores (R square, 0.323; P < 0.001): (i) the pathology course and test-enhanced learning, (ii) the VM platform and experience, (iii) medical students and lecture scores, and (iv) female students. The LM + VM group exhibited less score variability on laboratory examinations relative to their mean than the LM group. The LM + VM group was also associated with fewer failing grades (F grade; odds ratio, 0.336; P < 0.001) and higher scores (A grade; odds ratio, 2.084; P < 0.001) after controlling for sex, school, course, and lecture grades. The positive effect of the VM platform on laboratory test grades was associated with prior experience using the VM platform and was synergistic with more interim tests. Both teachers and students agreed that the VM platform enhanced laboratory learning. The incorporation of the VM platform in the context of test-enhanced learning may help more students to master microscopic laboratory content.

PurposeThe purpose of this paper is to examine the relationships among choice of industry diversification, capabilities and business group performance, as well as to point out the potential concern about endogenous role of industry diversification.Design/methodology/approachUsing data from the top 100 business groups in Taiwan from TEJ database. This study uses Heckman’s two-step estimation procedure and contingency model to achieve unbiased results and examine our hypotheses.FindingsThe results of this study find that if business groups’ marketing or operational capabilities are strong they should adopt a high level of diversification strategy and if business groups’ R&D capability is strong they should adopt a low level one. The results of this study also show that the endogenous problem of industry diversification exists, and needs to be considered. Moreover, our finding confirms the importance of capability–strategy fit, which, in turn, can achieve better performance.Practical implicationsOn average, high industry diversification groups perform better than low industry diversification groups after controlling for endogeneity issues. Business groups can achieve better performance if their strategy choices match the capabilities they encounter. Managers should pay attention to strategy-capability fit issues. Specifically, they should review their organizational capabilities as well as check their strategies within firms.Originality/valueThis study is one of the first that attempts to explore the endogenous role of diversification strategy choices, and empirical examine strategy-capability fit on business group performance.

Motivation In gene expression and genome-wide association studies, the identification of interaction effects is an important and challenging issue owing to its ultrahigh-dimensional nature. In particular, contaminated data and right-censored survival outcome make the associated feature screening even challenging. Results In this article, we propose an inverse probability-of-censoring weighted Kendall’s tau statistic to measure association of a survival trait with biomarkers, as well as a Kendall’s partial correlation statistic to measure the relationship of a survival trait with an interaction variable conditional on the main effects. The Kendall’s partial correlation is then used to conduct interaction screening. Simulation studies under various scenarios are performed to compare the performance of our proposal with some commonly available methods. In the real data application, we utilize our proposed method to identify epistasis associated with the clinical survival outcomes of non-small-cell lung cancer, diffuse large B-cell lymphoma and lung adenocarcinoma patients. Both simulation and real data studies demonstrate that our method performs well and outperforms existing methods in identifying main and interaction biomarkers. Availability and implementation R-package ‘IPCWK’ is available to implement this method, together with a reference manual describing how to perform the ‘IPCWK’ package. Supplementary information Supplementary data are available at Bioinformatics online.

Background: Sjogren's syndrome (SS) is a chronic autoimmune disease with lymphocytic exocrine gland infiltration causing dry mouth and eyes. The disease can develop alone (primary SS, PSS) or with other autoimmune diseases (secondary SS, SSS). PSS has been suggested to increase the acute pancreatitis risk. However, whether all patients with SS share this higher risk remains uncertain. This nationwide population-based cohort study aimed to detect associations between SS and acute pancreatitis. Methods: We identified 11,922 individuals with SS cohort and 47,688 individuals without SS (non-SS cohort) between 2000 and 2010 from the Taiwan National Health Insurance database. We matched the individuals between the SS and non-SS cohorts according to age, gender, and index year at a 1:4 ratio. We used a Cox multivariable proportional-hazards model to determine the effects of SS on the acute pancreatitis risk. Results: The SS cohort had a higher acute pancreatitis risk than the non-SS cohort after covariate adjustments (adjusted hazard ratio [HR], 3.374; 95% confidence interval [CI], 2.869–3.969). Patients with PSS exhibited a 2.872-fold risk (95% CI, 2.611–3.901) and patients with SSS a 4.121-fold risk (95% CI, 3.752–5.124) for acute pancreatitis. Our subgroup analyses revealed that patients with SS and systemic lupus erythematosus (adjusted HR, 3.85; 95% CI, 3.259–4.999), rheumatoid arthritis (adjusted HR, 4.298; 95% CI, 3.862–5.286), systemic sclerosis (adjusted HR, 2.765; 95% CI, 2.26–3.68), or polymyositis (adjusted HR, 2.641; 95% CI,1.847–3.101) and dermatomyositis (adjusted HR, 3.77; 95% CI, 2.894–4.502) had higher acute pancreatitis risk. Conclusions: Patients with SS presented increased acute pancreatitis risks than patients without SS, and patients with SSS had higher acute pancreatitis risks than patients with PSS. Physicians should be aware of this increased risk in patients with SS.

Infection is a possible cause of rhabdomyolysis. We describe the case of a 63-year-old male with malaise and erythematous papules on the right C5–C7 dermatomes, consistent with herpes zoster. Serum antibody and Tzanck tests of the skin lesion were positive. Increased serum creatine kinase (CK) and myoglobin levels and cola-colored urine indicated the development of rhabdomyolysis. Acute kidney injury was also observed. After excluding other possible predisposing factors, the patient was diagnosed with varicella-zoster virus (VZV)-induced rhabdomyolysis. Extracellular volume with alkalized fluids and topical acyclovir was administered. While CK levels declined to normal by day 13, the renal function was not restored. The skin lesion crusted by day 8 and scaled off gradually by day 13. Our case and literature review highlighted the necessity for systemic antiviral treatment and that poor VZV infection control could lead to irreversible kidney injury. In addition, systemic acyclovir should be administered carefully due to its complication of nephrotoxicity.

Embolotherapy using particle embolics is normally performed with exogenous contrast to assist in visualization. However, the exact location of the embolics cannot be identified after contrast washout. We developed a novel, pseudo-check valve-integrated microfluidic device, that partitions barium- impregnated alginate from crosslinking solution, thereby preventing nozzle failure. This enables rapid and continuous generation of inherently X-ray-visible embolic microspheres (XEMs) with uniform size. The XEMs are visible under clinical X-ray and cone beam CT both in vitro and in vivo. In particular, we demonstrated the embolization properties of these XEMs in large animals, performing direct intra- and post-procedural assessment of embolic delivery. The persistent radiopacity of these XEMs enables real-time evaluation of embolization precision and offers great promise for non-invasive follow-up examination without exogenous contrast. We also demonstrated that bariatric arterial embolization with XEMs significantly suppresses weight gain in swine, as an example of a non-oncological application of embolotherapy.

Early cancer detection requires identification of cellular changes resulting from oncogenesis. Abnormal DNA methylation patterns occurring early in tumor development have been widely identified as early biomarkers for multiple types of cancer tumors. Methylation-Specific PCR (MSP) has permitted highly sensitive detection of these methylation changes at known biomarker locations. MSP requires multiple sample preparation steps including protein digestion, DNA isolation, and bisulfite conversion prior to detection. In this work, we present a streamlined assay platform and instrumentation for integration of all sample processing steps required to obtain quantitative MSP signal from raw biological samples through the use of droplet magnetofluidic principles. In conjunction with this platform, we present a streamlined protocol for solid-phase DNA extraction from cells and bisulfite conversion of genomic DNA, minimizing the processing steps and reagent volume for implementation on a compact assay platform.

BACKGROUND Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.

Fibrinogen-like-protein 1 (FGL1) is a novel hepatokine that plays an important role in hepatic steatosis and insulin resistance. Although FGL1 expression can be detected in adipose tissues, the functions of FGL1 in adipose tissues are still unknown. In this study, 356 participants with (body mass index (BMI) ≥25 kg/m2 ; n = 134) or without obesity (BMI

Antimicrobial resistance is a global threat that if left unchecked could lead to 10 million annual mortalities by 2050. One factor contributing to the rise of multi-drug resistant (MDR) pathogens is the reliance on traditional culture-based pathogen identification (ID) and antimicrobial susceptibility testing (AST) that typically takes several days. This delay of objective pathogen ID and AST information to inform clinical-decision making results in clinicians treating patients empirically often using first-line, broad-spectrum antibiotics, contributing to the misuse/overuse of antibiotics. To combat the rise in MDR pathogens, there is a critical demand for rapid ID and AST technologies. Among the advances in ID and AST technologies in the past decade, single-cell diagnostic technologies powered by droplet microfluidics offer great promise due to their potential for high-sensitivity detection and rapid turnaround time. Our lab has been at the forefront of developing such technologies and applying them toward diagnosing urinary tract infections (UTIs) – one of the most common infections and a frequent reason for prescription of antimicrobials. For pathogen ID, we first demonstrated highly sensitive, amplification-free detection of single bacterial cells by confining them into picoliter-scale droplets and detection with fluorogenic peptide nucleic acid (PNA) probes that target their 16S ribosomal RNA (rRNA), a well-characterized marker for phylogenic classification. We subsequently improved the PNA probe design and enhanced detection sensitivity. For single-cell AST, we first employed a growth indicator dye and engineered an integrated device that allows us to detect growth from single bacterial cells under antibiotic exposure within 1 hour – equivalent to 2 to 3 bacterial replications. To expand beyond testing a single antibiotic condition per device – a common limitation for droplet microfluidics – we developed an integrated programmable droplet microfluidic device for scalable single-cell AST. Using the scalable single-cell AST platform, we demonstrated the generation of up to 32 droplet groups in a single device with custom antibiotic titers, the capacity to scale up single-cell AST and provide reliable pathogen categories beyond a binary call embodies a critical advance. Finally, we developed an integrated ID and AST platform. To this end, we developed a PNA probe panel that can identify nearly 90% of uropathogens and showed quantitative detection of 16S rRNA from single bacterial cells in droplets-enabled AST after as little as 10-min antibiotic exposure. This platform achieved both ID and AST from minimally-processed urine samples in 30 min, representing one of the fastest turnaround time to date. In addition to tracing the development of our technologies, we compare them with contemporary research advances and offer our perspectives for future development, with the vision that single-cell ID and AST technologies powered by droplet microfluidics can indeed become a useful diagnostic tool for combating antimicrobial resistance. [Image: see text]

OBJECTIVES The potential of DNA methylation alterations in early pancreatic cancer (PC) detection among pancreatic tissue cell-free DNA seems promising. This study investigates the diagnostic capacity of the 4-gene methylation biomarker panel, which included ADAMTS1, BNC1, LRFN5, and PXDN genes, in a case-control study. METHODS A genome-wide pharmacoepigenetic approach identified ADAMTS1, BNC1, LRFN5, and PXDN genes as putative targets. Tissue samples including stage I-IV PC (n = 44), pancreatic intraepithelial neoplasia (n = 15), intraductal papillary mucinous neoplasms (n = 24), and normal pancreas (n = 8), and cell-free DNA, which was acquired through methylation on beads technology from PC (n = 22) and control patients (n = 10), were included. The 2-∆ct was the outcome of interest and underwent receiver operating characteristic analysis to determine the diagnostic accuracy of the panel. RESULTS Receiver operating characteristic analysis revealed an area under the curve of 0.93 among ADAMTS1, 0.76 among BNC1, 0.75 among PXDN, and 0.69 among LRFN5 gene. The combination gene methylation panel (ADAMTS1, BNC1, LRFN5, and PXDN) had an area under the curve of 0.94, with a sensitivity of 100% and specificity of 90%. CONCLUSIONS This methylation-based biomarker panel had promising accuracy for PC detection and warranted further validation in prospective PC surveillance trials.

There remains an unmet need for a simple microfluidic platform that can perform multi-step and multi-reagent biochemical assays in parallel for high-throughput detection and analysis of single molecules and single cells. In response, we report herein a PDMS-based vacuum-driven microfluidic array that is capable of multi-step sample loading and digitalization. The array features multi-level bifurcation microchannels connecting to 4096 dead-end microchambers for partitioning liquid reagents/samples. To realize multi-step repetitive liquid sample loading, we attach an external vacuum onto the chip to create internal negative pressure for a continuous liquid driving force. We demonstrated a high uniformity of our device for three sequential liquid loadings. To further improve its utility, we developed a thermosetting-oil covering method to prevent evaporation for assays that require high temperatures. We successfully performed digital PCR assays on our device, demonstrating the efficient multi-step reagent handling and the effective anti-evaporation design for thermal cycling. Furthermore, we performed a digital PCR detection for single-cell methicillin-resistant Staphylococcus aureus using a three-step loading approach and achieved accurate single-cell quantification. Taken together, we have demonstrated that our vacuum-driven microfluidic array is capable of multi-step sample digitalization at high throughput for single-molecule and single-cell analyses.

Background The high costs of chronic conditions call for new treatment approaches that reduce costs while ensuring desirable health outcomes. There has been a growing transformation of care delivery models from conventional referral systems to integrated care models. This study seeks to evaluate the cost-saving impact of integrated care delivery model under pay-for-performance (P4P) scheme with continuity of care at institution level (ICOC). Methods We analyzed the Taiwan National Health Insurance claim data of 21,725 diabetic patients who visited clinics and/or hospitals at least four times a year for 8 years. Using average local provider P4P participation rate (for each accreditation level) as an instrumental variable in two-stage least squares (2SLS) regressions, we have estimated consistent estimates of the ICOC elasticities for all-cause inpatient and outpatient costs. Results Our results show that ICOC significantly reduced inpatient costs but increased outpatient costs with the elasticity for treatment costs of -11.6 and 1.03, respectively. The decrease in inpatient costs offset the increase in outpatient costs and the resulting total cost saving showed significant association with ICOC. The saving effect of ICOC is especially robust among patients who used clinics as their principal source of care. Conclusions Institutional continuity of care has a substantial impact on the treatment costs of diabetes patients. In the context where inpatient care costs are significantly higher than that of the outpatient care, ICOC would lead to a meaningful cost-saving effect. For new diabetes patients, care by clinics demonstrated the strongest saving effect.