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Objectives: Under the classification of multicategory survival outcomes of cancer patients, it is crucial to identify biomarkers that affect specific outcome categories. The classification of multicategory survival outcomes from transcriptomic data has been thoroughly investigated in computational biology. Nevertheless, several challenges must be addressed, including the ultra-high-dimensional feature space, feature contamination, and data imbalance, all of which contribute to the instability of the diagnostic model. Furthermore, although most methods achieve accurate predicted performance for binary classification with high-dimensional transcriptomic data, their extension to multi-class classification is not straightforward. Methods: We employ the One-versus-One strategy to transform multi-class classification into multiple binary classification, and utilize the overlapping group screening procedure with binary logistic regression to include pathway information for identifying important genes and gene-gene interactions for multicategory survival outcomes. Results: A series of simulation studies are conducted to compare the classification accuracy of our proposed approach with some existing machine learning methods. In practical data applications, we utilize the random oversampling procedure to tackle class imbalance issues. We then apply the proposed method to analyze transcriptomic data from various cancers in The Cancer Genome Atlas, such as kidney renal papillary cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Our aim is to establish an accurate microarray-based multicategory cancer diagnosis model. The numerical results illustrate that the new proposal effectively enhances cancer diagnosis compared to approaches that neglect pathway information. Conclusions: We showcase the effectiveness of the proposed method in terms of class prediction accuracy through evaluations on simulated synthetic datasets as well as real dataset applications. We also identified the cancer-related gene-gene interaction biomarkers and reported the corresponding network structure. According to the identified major genes and gene-gene interactions, we can predict for each patient the probabilities that he/she belongs to each of the survival outcome classes.

Objectives: This study analyzed the risk and impact of developing pneumogenic bacteremia in patients with CRAB nosocomial pneumonia in ICU. Methods: This is multicenter retrospective study. Clinical outcomes were compared between bacteremia and non-bacteremia group, and the risk factors for mortality and developing pneumogenic CRAB bacteremia were analyzed. Results: After patient recruitment, 164 cases were in the bacteremia group, and 519 cases were in the non-bacteremia group. The bacteremia group had 22.4 percentage of increase in-hospital mortality than the non-bacteremia group (68.3% vs 45.9%, P < 0.001). Multivariate analysis showed bacteremia was an independent risk factor for in-hospital mortality (aHR = 2.399, P < 0.001). A long time-interval between ICU admission and pneumonia onset was an independent risk factor for developing bacteremia (aOR = 1.040, P = < 0.001). Spearman's rank correlation analysis indicated a high correlation between the days from ICU admission to pneumonia onset and the days of ventilator use before pneumonia onset (correlation coefficient (ρ) = 0.777). Conclusions: In patients with CRAB nosocomial pneumonia, bacteremia increased the in-hospital mortality, and a longer interval from ICU admission to pneumonia onset was an independent risk factor for developing bacteremia, which was highly associated with the use of mechanical ventilation.

Abstract Background Vitamin D deficiency has been linked with several adverse maternal and fetal outcomes. Objective To summarize systematic reviews and meta-analyses evaluating the effects of vitamin D deficiency and of vitamin D supplementation in pregnancy on maternal and offspring health-related outcomes. Methods Prior to conducting this umbrella review, we registered the protocol in PROSPERO (CRD42022368003). We conducted searches in PubMed, Embase, and Cochrane Library for systematic reviews and meta-analyses on vitamin D in pregnancy, from database inception to October 2, 2023. All outcomes related to vitamin D in pregnancy obtained from the systematic reviews and meta-analyses were extracted. Data Extraction: Two reviewers independently chose studies and collected information on health outcomes. The quality of the included articles’ methodology was assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews–2). Results We identified 16 eligible systematic reviews and meta-analyses, which included 250,569 women. Our results demonstrated that vitamin D deficiency in pregnancy is associated with increased risk of preterm birth, small-for gestational age/low birth weight infants, recurrent miscarriage, bacterial vaginosis and gestational diabetes mellitus. Vitamin D supplementation in pregnancy increases birth weight, and reduces the risk of maternal pre-eclampsia, miscarriage, and vitamin D deficiency, fetal or neonatal mortality, as well as attention-deficit hyperactivity disorder, and autism spectrum disorder in childhood. In women with gestational diabetes mellitus, vitamin D supplementation in pregnancy can reduce the risk of maternal hyperbilirubinemia, polyhydramnios, macrosomia, fetal distress, and neonatal hospitalization. Conclusion Due to the association with adverse maternal and offspring health outcomes, we recommend the vitamin D status in pregnancy should be monitored, particularly in women at high risk of vitamin D deficiency. It is suggested that pregnant women take a dose of >400 IU/day of vitamin D supplementation during pregnancy to prevent certain adverse outcomes.

Background/Purpose: Newly developed temporary anchorage devices (TADs) serve a strong orthodontic anchorage to intrude molars for correction of anterior open bite (AOB). We measured cephalometric changes in skeletal open bite patients which developed subsequently to temporomandibular joint disorders with bilateral point contacts at terminal molars. Methods: We retrospectively recruited 32 patients who had been treated their TMD before orthodontic correction (overbite: −3.14 ± 1.86 mm). Partial orthodontic appliances were used to intrude posterior teeth using TADs until positive OB obtained (T1). Full fixed appliances were then used to achieve proper overjet and overbite (T2). We collected lateral cephalograms before (T0), during (T1) and after (T2) treatment, and at follow-ups (T3). Using ANOVA, we analyzed the differences among these time points to determine treatment changes and stability of orthodontic results. Results: In this group predominantly comprising young adult women, orthodontic treatment with TADs significantly reduced upper posterior dental heights (T2-T0:-1.84 ± 0.66 mm) and facilitated the retraction and uprighting upper incisors (T2-T0: −9.92 ± 1.72°), to achieve appropriate OJ (T2-T0: −3.21 ± 0.49 mm) and OB (T2-T0: 4.10 ± 0.28 mm) with p

Antimicrobial resistance (AMR) has become a global health crisis in need of novel solutions. To this end, antibiotic combination therapies, which combine multiple antibiotics for treatment, have attracted significant attention as a potential approach for combating AMR. To facilitate advances in antibiotic combination therapies, most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however, there remains a need for automated high-throughput platforms that can create and examine antibiotic combinations on-demand, at scale, and with minimal reagent consumption. To address these challenges, we have developed a Robotic-Printed Combinatorial Droplet (RoboDrop) platform by integrating a programmable droplet microfluidic device that generates antibiotic combinations in nanoliter droplets in automation, a robotic arm that arranges the droplets in an array, and a camera that images the array of thousands of droplets in parallel. We further implement a resazurin-based bacterial viability assay to accelerate our antibiotic combination testing. As a demonstration, we use RoboDrop to corroborate two pairs of antibiotics with known interactions and subsequently identify a new synergistic combination of cefsulodin, penicillin, and oxacillin against a model E. coli strain. We therefore envision RoboDrop becoming a useful tool to efficiently identify new synergistic antibiotic combinations toward combating AMR.

For the 29.8 million people in the world living with HIV/AIDS and receiving antiretroviral therapy, it is crucial to monitor their HIV viral loads. To this end, rapid and portable diagnostic tools that can quantify HIV RNA are critically needed. We report herein a rapid and quantitative digital CRISPR-assisted HIV RNA detection assay that has been implemented within a portable smartphone-based device as a potential solution. Specifically, we first developed a fluorescence-based reverse transcription recombinase polymerase amplification (RT-RPA)-CRISPR assay that can efficiently detect HIV RNA at 42 °C. We then implemented this assay within a commercial stamp-sized digital chip, where RNA molecules were quantified as strongly fluorescent digital reaction wells. The isothermal reaction condition and the strong fluorescence in the digital chip simplified the design of thermal and optical modules, allowing us to engineer a palm-size device measuring 70 × 115 × 80 mm and weighing less than 0.6 kg. We also capitalized the smartphone by developing a custom app to control the device, perform the digital assay, and capture fluorescence images throughout the assay using the smartphone's camera. Moreover, we trained and verified a deep learning-based algorithm for analyzing fluorescence images and identifying positive digital reaction wells with high accuracy. Using our smartphone-enabled digital CRISPR device, we successfully detected as low as 75 copies of HIV RNA in just 15 min, showing its potential toward monitoring of HIV viral loads and aiding the global effort to combat the HIV/AIDS epidemic.

Abstract Recent advances in molecular analyses of ovarian cancer have revealed a wealth of promising tumour‐specific biomarkers, including protein, DNA mutations and methylation; however, reliably detecting such alterations at satisfactorily high sensitivity and specificity through low‐cost methods remains challenging, especially in early‐stage diseases. Here we present PapDREAM, a new approach that enables detection of rare, ovarian‐cancer‐specific aberrations of DNA methylation from routinely‐collected cervical Pap specimens. The PapDREAM approach employs a microfluidic platform that performs highly parallelized digital high‐resolution melt to analyze locus‐specific DNA methylation patterns on a molecule‐by‐molecule basis at or near single CpG‐site resolution at a fraction (

Abstract The continued spread of Candida auris in healthcare facilities has increased the demand for widely available screening to aid in containment and inform treatment options. Current methods of detection can be unreliable and require bulky and expensive instruments to lyse and identify fungal pathogens. Here, we present a quick, low-cost, instrument-free method for lysis of C. auris suitable for streamlined sample processing with polymerase chain reaction (PCR) detection. Chemical, thermal, and bead beating lysis techniques were evaluated for lysis performance and compatibility with nucleic acid extraction and downstream PCR reactions. Using only 10 s of manual shaking with glass beads, this method demonstrated a limit of detection (LOD) of C. auris at 500 colony forming units per mL, a 20-fold improvement compared to the LOD without manual shaking, and a 60-fold reduction in time compared to common fungal lysis kits, all while maintaining repeatability and reproducibility across multiple users. This work highlights a simple method for increasing sensitivity and reducing turnaround time of PCR-based C. auris detection and exhibits promise for integration into point-of-care platforms towards real-time triage of colonized patients.

AbstractBackground Although medical literature has highlighted the importance of role modelling, hardly any reveals how humanistic qualities and role modelling should be taught. This study aimed to determine whether the use of Bandura’s social cognitive learning for humanistic professional role modelling could elicit any positive effect on medical university students’ awareness of humanistic professionalism, caring behaviours, and school-to-work transitional anxiety.Methods We conducted a 16-week quasi-experimental study to examine whether the intervention could elicit any differences between the experimental group (BanduraSCLT – HPRM – Literature-and-Film Study; N = 34) and the control group (non-BanduraSCLT – HPRM – Literature-and-Film Study; N = 33), comprising of medical university students from the central part of Taiwan. The quantitative instruments included the Humanistic Professional Awareness Scale (HPAS-HSP), Caring Behaviour Scale (CBS-HSP) and School-to-Work Transitional Anxiety Scale (StWTA-HS). One-way MANOVA (multivariate analysis of variance) and one-way MANCOVA (multivariate analysis of covariance) were used for statistical analysis.Results The results revealed that students who received Bandura’s social cognitive learning for humanistic professional role modelling had significantly stronger humanistic professional awareness in terms of ‘personal integrity and accountability’, ‘sensitivity to others’ and ‘professional competence’. They also had more effective caring behaviour in terms of ‘support and attentiveness’, ‘professional knowledge and skills’, ‘gratifying needs and responsiveness’ and ‘confidentiality and trust’. In addition, they had less school-to-work transitional anxiety in terms of ‘inexperience in professional knowledge and skills’, ‘fear of death’, ‘fear of being infected’ and ‘interpersonal interactions.’Conclusion The findings suggest that using Bandura’s social cognitive learning for humanistic professional role modelling can have a positive impact on awareness of humanistic professionalism, caring behaviour and school-to-work transitional anxiety. Hence, it can be an effective teaching tool for medical education.

The transfection efficiency and stability of the delivery vehicles of plasmid DNA (pDNA) are critical metrics to ensure high-quality and high-yield production of viral vectors. We previously identified that the optimal size of pDNA/poly(ethylenimine) (PEI) transfection particles is 400–500 nm and developed a bottom-up assembly method to construct stable 400-nm pDNA/PEI particles and benchmarked their transfection efficiency in producing lentiviral vectors (LVVs). Here, we report scale-up production protocols for such transfection particles. Using a two-inlet confined impinging jet (CIJ) mixer with a dual syringe pump set-up, we produced a 1-L batch at a flow rate of 100 mL/min, and further scaled up this process with a larger CIJ mixer and a dual peristaltic pump array, allowing for continuous production at a flow rate of 1 L/min without a lot size limit. We demonstrated the scalability of this process with a 5-L lot and validated the quality of these 400-nm transfection particles against the target product profile, including physical properties, shelf and on-bench stability, transfection efficiency, and LVV production yield in both 15-mL bench culture and 2-L bioreactor runs. These results confirm the potential of this particle assembly process as a scalable manufacturing platform for viral vector production.

The complexity of cancer development involves intricate interactions among multiple biomarkers, such as gene-environment interactions. Utilizing microarray gene expression profile data for cancer classification is anticipated to be effective, thus drawing considerable interest in the fields of bioinformatics and computational biology. Due to the characteristics of genomic data, problems of high-dimensional interactions and noise interference do exist during the analysis process. When building cancer diagnosis models, we often face the dilemma of model adaptation errors due to an imbalance of data types. To mitigate the issues, we apply the SMOTE-Tomek procedure to rectify the imbalance problem. Following this, we utilize the overlapping group screening method alongside a binary logistic regression model to integrate gene pathway information, facilitating the identification of significant biomarkers associated with clinically imbalanced cancer or normal outcomes. Simulation studies across different imbalanced rates and gene structures validate our proposed method’s effectiveness, surpassing common machine learning techniques in terms of classification prediction accuracy. We also demonstrate that prediction performance improves with SMOTE-Tomek treatment compared to no imbalance treatment and SMOTE treatment across various imbalance rates. In the real-world application, we integrate clinical and gene expression data with prior pathway information. We employ SMOTE-Tomek and our proposed methods to identify critical biomarkers and gene-environment interactions linked to the imbalanced binary outcomes (cancer or normal) in patients from the Cancer Genome Atlas datasets of lung adenocarcinoma and breast invasive carcinoma. Our proposed method consistently achieves satisfactory classification accuracy. Additionally, we have identified biomarkers indicative of gene-environment interactions relevant to cancer and have provided corresponding estimates of odds ratios. Moreover, in high-dimensional imbalanced data, for achieving good prediction results, we recommend considering the order of balancing processing and feature screening.

Analyzing treatment or exposure effect is a major research theme in scientific studies. In the current big-data era where multiple sources of data are available, it is of interest to perform a synthesized analysis of treatment effects by integrating information from different data sources or studies. However, studies may contain heterogeneous and incomplete covariate sets, and individual data therein may not be accessible. We apply and extend the generalized meta-analysis method to integrate summary results (e.g., regression coefficients) of outcome and treatment (propensity score, PS) regression analyses across different datasets that may contain heterogeneous covariate sets. The proposed integrated analysis utilizes a reference dataset, which contains data on the complete set of covariates. The asymptotic distribution for the proposed integrated estimator is established. Simulations reveal that the proposed estimator performs well. We apply the proposed method to obtain the causal effect of waist circumference on hypertension by integrating two existing outcomes and PS regression analyses with different sets of covariates.

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a key pathogen associated with ventilator-associated pneumonia (VAP). Research on treatment outcomes, especially ventilator dependence, in patients with VAP caused by CRAB remains limited. Methods: This retrospective multicenter study included ICU-admitted patients with VAP caused by CRAB. The original cohort was included as the mortality evaluation cohort. The ventilator dependence evaluation cohort included cases that survived more than 21 days after VAP and without prolonged ventilation before VAP onset. The mortality rate, ventilator dependence rate, clinical factors associated with treatment outcomes, and treatment outcome differences with various VAP onset times were investigated. Results: In total, 401 patients with VAP caused by CRAB were analyzed. The 21-day all-cause mortality rate was 25.2%, and the 21-day ventilator dependence rate was 48.8%. Clinical factors associated with 21-day mortality included lower body mass index, higher sequential organ failure assessment score, vasopressors usage, CRAB persistence, and VAP onset time > seven days. Clinical factors associated with 21-day ventilator dependence included older age, vasopressors usage, and VAP onset time > seven days. Conclusions: ICU-admitted patients with CRAB-related VAP had high mortality and ventilator dependence rates. Older age, vasopressor usage, and longer VAP onset time were independent factors associated with ventilator dependence.

ABSTRACTBackground Narrative medicine can serve as a tool to empathize with human beings’ predicament and suffering. The research intended to examine whether the use of narrative medicine to form an empathetic connection could bring any positive impacts on health professions students.Methods A two-group quasi-experimental design was adopted to examine whether the intervention of narrative medicine to form an empathetic connection could demonstrate differences between the experimental group (35 students) and the control group (32 students) with regard to professional identity, self-reflection, emotional catharsis, and reflective writing competency. These 67 participants were health professions students in a medical university (mean age = 20.02; SD = 0.23), with varied majors in health disciplines. The 16-week intervention was the use of narrative medicine to form an empathetic connection with those suffering, via the three stages of narrative medicine: attention → representation → affiliation. The quantitative instruments included a professional identity scale (PIS-HSP), a reflective thinking scale (RTS-HSP), and an emotional catharsis scale (ECS-IN), as well as an analytic reflective writing scoring rubric (ARWSR-HSP). To triangulate the quantitative results, the study also used the student interviews. The SPSS software was used to analyze the data.Results The quantitative results demonstrated that the narrative medicine-based intervention could bring positive effects on the health professions students. After going through the intervention, the students in the experimental group had stronger professional identity, a higher reflective thinking level, more emotional catharsis, and greater improvement in reflective writing competency than those not receiving the intervention, though some subscales not reaching statistical significance.Conclusion This research results proved that the use of narrative medicine to form an empathetic connection could bring positive impacts on health professions students regarding professional identity, self-reflection, emotional catharsis, and self-reflective writing competency.

Objectives This study mainly uses machine learning (ML) to make predictions by inputting features during training and inference. The method of feature selection is an important factor affecting the accuracy of ML models, and the process includes data extraction, which is the collection of all data required for ML. It also needs to import the concept of feature engineering, namely, this study needs to label the raw data of the cardiac ultrasound dataset with one or more meaningful and informative labels so that the ML model can learn from it and predict more accurate target values. Therefore, this study will enhance the strategies of feature selection methods from the raw dataset, as well as the issue of data scrubbing. Methods In this study, the ultrasound dataset was cleaned and critical features were selected through data standardization, normalization, and missing features imputation in the field of feature engineering. The aim of data scrubbing was to retain and select critical features of the echocardiogram dataset while making the prediction of the ML algorithm more accurate. Results This paper mainly utilizes commonly used methods in feature engineering and finally selects four important feature values. With the ML algorithms available on the Azure platform, namely, Random Forest and CatBoost, a Voting Ensemble method is used as the training algorithm, and this study also uses visual tools to gain a clearer understanding of the raw data and to improve the accuracy of the predictive model. Conclusion This paper emphasizes feature engineering, specifically on the cleaning and analysis of missing values in the raw dataset of echocardiography and the identification of important critical features in the raw dataset. The Azure platform is used to predict patients with a history of heart disease (individuals who have been under surveillance in the past three years and those who haven’t). Through data scrubbing and preprocessing methods in feature engineering, the model can more accurately predict the future occurrence of heart disease in patients.

Abstract Background Tigecycline has in vitro bacteriostatic activity against a broad spectrum of bacteria, including carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the role of tigecycline in treatment of nosocomial pneumonia caused by CR-GNB remains controversial and clinical evidences are limited. We aimed to investigate the clinical benefits of tigecycline as part of the combination treatment of nosocomial CR-GNB pneumonia in intensive care unit (ICU). Methods This multi-centre cohort study retrospectively enrolled ICU-admitted patients with nosocomial pneumonia caused by CR-GNB. Patients were categorized based on whether add-on tigecycline was used in combination with at least one anti-CR-GNB antibiotic. Clinical outcomes and all-cause mortality between patients with and without tigecycline were compared in the original and propensity score (PS)-matched cohorts. A subgroup analysis was also performed to explore the differences of clinical efficacies of add-on tigecycline treatment when combined with various anti-CR-GNB agents. Results We analysed 395 patients with CR-GNB nosocomial pneumonia, of whom 148 received tigecycline and 247 did not. More than 80% of the enrolled patients were infected by CR-Acinetobacter baumannii (CRAB). A trend of lower all-cause mortality on day 28 was noted in tigecycline group in the original cohort (27.7% vs. 36.0%, p = 0.088). In PS-matched cohort (102 patient pairs), patients with tigecycline had significantly lower clinical failure (46.1% vs. 62.7%, p = 0.017) and mortality rates (28.4% vs. 52.9%, p

Abstract Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are both associated with significant morbidity and mortality in daily clinical practice, as well as in a critical care setting. It is unclear whether colistin susceptible-only Acinetobacter baumannii (CSO AB) is a unique phenotype separate from or a subset of CRAB-associated pneumonia. The aim of this study is to investigate the prevalence of CSO AB pneumonia and compare the presentation and outcome between CSO AB and CRAB-associated pneumonia in critically ill patients. This multicenter retrospective cohort study initially recruited 955 patients with CR-GNB pneumonia. After exclusion, 575 patients left who were ICU-admitted and had CRAB nosocomial pneumonia remained. Among them, 79 patients had CSO AB pneumonia, classified as the CSO AB group. The other 496 patients were classified as the CRAB group. We compared demographic characteristics, disease severity, and treatment outcomes between the two groups. The prevalence of CSO AB among all cases of CRAB pneumonia was 13.74% (79/575). The CSO AB and CRAB groups had similar demographic characteristics and disease severities at initial presentation. The in-hospital mortality rate was 45.6% and 46.4% for CSO AB and CRAB groups, respectively (p = 0.991). The CSO AB group had significantly better clinical outcomes at day 7 (65.8% vs 52.4%, p = 0.036) but longer length of ICU stay (27 days vs 19 days, p = 0.043) compared to the CRAB group. However, other treatment outcomes, including clinical outcomes at day 14 and 28, mortality, microbiological eradication, ventilator weaning, and newly onset dialysis, were similar. In conclusion, CSO AB accounted for 13.74% of all cases of CRAB pneumonia, and the clinical presentation and treatment outcomes of CSO AB and CRAB pneumonia were similar.

Lipid nanoparticles (LNPs) are effective vehicles to deliver mRNA vaccines and therapeutics but assessing the mRNA packaging characteristics in LNPs is challenging. Here, the authors report that mRNA and lipid contents in LNP formulations can be quantitatively examined by multi-laser cylindrical illumination confocal spectroscopy at the single-nanoparticle level.

Abstract There remains tremendous interest in developing liquid biopsy assays for detection of cancer‐specific alterations, such as mutations and DNA methylation, in cell‐free DNA (cfDNA) obtained through noninvasive blood draws. However, liquid biopsy analysis is often challenging due to exceedingly low fractions of circulating tumor DNA (ctDNA), necessitating the use of extended tumor biomarker panels. While multiplexed PCR strategies provide advantages such as higher throughput, their implementation is often hindered by challenges such as primer‐dimers and PCR competition. Alternatively, digital PCR (dPCR) approaches generally offer superior performance, but with constrained multiplexing capability. This paper describes development and validation of the first multiplex digital methylation‐specific PCR (mdMSP) platform for simultaneous analysis of four methylation biomarkers for liquid‐biopsy‐based detection of non‐small cell lung cancer (NSCLC). mdMSP employs a microfluidic device containing four independent, but identical modules, housing a total of 40 160 nanowells. Analytical validation of the mdMSP platform demonstrates multiplex detection at analytical specificities as low as 0.0005%. The clinical utility of mdMSP is also demonstrated in a cohort of 72 clinical samples of low‐volume liquid biopsy specimens from patients with computed tomography (CT)‐scan indeterminant pulmonary nodules, exhibiting superior clinical performance when compared to traditional MSP assays for noninvasive detection of early‐stage NSCLC.

Abstract Droplet microfluidics has in recent years found a wide range of analytical and bioanalytical applications. In droplet microfluidics, the samples that are discretized into droplets within the devices are predominantly loaded through tubings, but such tubing-based sample loading has drawbacks such as limited scalability for processing many samples, difficulty for automation, and sample wastage. While advances in autosamplers have alleviated some of these drawbacks, sample loading that can instead obviate tubings offers a potentially promising alternative but has been underexplored. To fill the gap, we introduce herein a droplet device that features a new Tubing Eliminated Sample Loading Interface (TESLI). TESLI integrates a network of programmable pneumatic microvalves that regulate vacuum and pressure sources so that successive sub-microliter samples can be directly spotted onto the open-to-atmosphere TESLI inlet, vacuumed into the device, and pressurized into nanoliter droplets within the device with minimal wastage. The same vacuum and pressure regulation also endows TESLI with cleaning and sample switching capabilities, thus enabling scalable processing of many samples in succession. Moreover, we implement a pair of TESLIs in our device to parallelize and alternate their operation as means to minimizing idle time. For demonstration, we use our device to successively process 44 samples into droplets—a number that can further scale. Our results demonstrate the feasibility of tubing-free sample loading and a promising approach for advancing droplet microfluidics.

Variation in methylcytosine is perhaps the most well-studied epigenetic mechanism of gene regulation. Methods that have been developed and implemented for assessing DNA methylation require sample DNA to be extracted, purified and chemically-processed through bisulfite conversion before downstream analysis. While some automated solutions exist for each of these individual process steps, a fully integrated solution for accomplishing the entire process in a high-throughput manner has yet to be demonstrated. Thus, sample processing methods still require numerous manual steps that may reduce sample throughput and precision, while increasing the risk of contamination and human error. In this work, we present an integrated, automated solution for performing the entire sample preparation process, including DNA extraction, purification, bisulfite conversion and PCR plate preparation within in an enclosed environment. The method employs silica-coated magnetic particles that eliminate the need for a centrifuge or vacuum manifold, thereby reducing the complexity and cost of the required automation platform. Toward this end, we also compare commercial DNA extraction and bisulfite conversion kits to identify a protocol suitable for automation to significantly improve genomic and bisulfite-treated DNA yields over manufacturer protocols. Overall, this research demonstrated development of an automated protocol that offers the ability to generate high-quality, bisulfite-treated DNA samples in a high-throughput and clean environment with minimal user intervention and comparable yields to manual processing.

Abstract Tracking kinematic details of motor behaviors is a foundation to study the neuronal mechanism and biology of motor control. However, most of the physiological motor behaviors and movement disorders, such as gait, balance, tremor, dystonia, and myoclonus, are highly dependent on the overall momentum of the whole‐body movements. Therefore, tracking the targeted movement and overall momentum simultaneously is critical for motor control research, but it remains an unmet need. Here, we introduce the intrinsic oscillatory property (IOP), a fundamental mechanical principle of physics, as a method for motion tracking in a force plate. The overall kinetic energy of animal motions can be transformed into the oscillatory amplitudes at the designed IOP frequency of the force plate, while the target movement has its own frequency features and can be tracked simultaneously. Using action tremor as an example, we reported that force plate‐based IOP approach has superior performance and reliability in detecting both tremor severity and tremor frequency, showing a lower level of coefficient of variation (CV) compared with video‐ and accelerometer‐based motion tracking methods and their combination. Under the locomotor suppression effect of medications, therapeutic effects on tremor severity can still be quantified by dynamically adjusting the overall locomotor activity detected by IOP. We further validated IOP method in optogenetic‐induced movements and natural movements, confirming that IOP can represent the intensity of general rhythmic and nonrhythmic movements, thus it can be generalized as a common approach to study kinematics.

Abstract Background In the context of biomedical and epidemiological research, gene-environment (G-E) interaction is of great significance to the etiology and progression of many complex diseases. In high-dimensional genetic data, two general models, marginal and joint models, are proposed to identify important interaction factors. Most existing approaches for identifying G-E interactions are limited owing to the lack of robustness to outliers/contamination in response and predictor data. In particular, right-censored survival outcomes make the associated feature screening even challenging. In this article, we utilize the overlapping group screening (OGS) approach to select important G-E interactions related to clinical survival outcomes by incorporating the gene pathway information under a joint modeling framework. Results Simulation studies under various scenarios are carried out to compare the performances of our proposed method with some commonly used methods. In the real data applications, we use our proposed method to identify G-E interactions related to the clinical survival outcomes of patients with head and neck squamous cell carcinoma, and esophageal carcinoma in The Cancer Genome Atlas clinical survival genetic data, and further establish corresponding survival prediction models. Both simulation and real data studies show that our method performs well and outperforms existing methods in the G-E interaction selection, effect estimation, and survival prediction accuracy. Conclusions The OGS approach is useful for selecting important environmental factors, genes and G-E interactions in the ultra-high dimensional feature space. The prediction ability of OGS with the Lasso penalty is better than existing methods. The same idea of the OGS approach can apply to other outcome models, such as the proportional odds survival time model, the logistic regression model for binary outcomes, and the multinomial logistic regression model for multi-class outcomes.

Abstract Nosocomial pneumonia caused by carbapenem-resistant gram-negative bacteria (CRGNB) is a growing threat due to the limited therapeutic choices and high mortality rate. The aim of this study was to evaluate the prognostic factors for mortality in patients with nosocomial pneumonia caused by CRGNB and the impact of colistin-based therapy on the outcomes of intensive care unit (ICU) patients. We conducted a retrospective study of the ICUs in five tertiary teaching hospitals in Taiwan. Patients with nosocomial pneumonia caused by CRGNB from January 2016 to December 2016 were included. Prognostic factors for mortality were analyzed using multivariate logistic regression. The influence of colistin-based therapy on mortality and clinical and microbiological outcomes were evaluated in subgroups using different severity stratification criteria. A total of 690 patients were enrolled in the study, with an in-hospital mortality of 46.1%. The most common CRGNB pathogens were Acinetobacter baumannii (78.7%) and Pseudomonas aeruginosa (13.0%). Significant predictors (odds ratio and 95% confidence interval) of mortality from multivariate analysis were a length of hospital stay (LOS) prior to pneumonia of longer than 9 days (2.18, 1.53–3.10), a sequential organ failure assessment (SOFA) score of more than 7 (2.36, 1.65–3.37), supportive care with vasopressor therapy (3.21, 2.26–4.56), and escalation of antimicrobial therapy (0.71, 0.50–0.99). There were no significant differences between the colistin-based therapy in the deceased and survival groups (42.1% vs. 42.7%, p = 0.873). In the subgroup analysis, patients with multiple organ involvement (> 2 organs) or higher SOFA score (> 7) receiving colistin-based therapy had better survival outcomes. Prolonged LOS prior to pneumonia onset, high SOFA score, vasopressor requirement, and timely escalation of antimicrobial therapy were predictors for mortality in critically ill patients with nosocomial CRGNB pneumonia. Colistin-based therapy was associated with better survival outcomes in subgroups of patients with a SOFA score of more than 7 and multiple organ involvement.

Abstract Objectives Prompt diagnosis and treatment of sexually transmitted infections (STIs) are essential to combat the STI epidemic in resource-limited settings. We characterized the burden of 5 curable STIs chlamydia, gonorrhea, trichomoniasis, Mycoplasma genitalium, syphilis, and HIV infection in Ugandan men with urethritis. Methods Participants were recruited from a gonococcal surveillance program in Kampala, Uganda. Questionnaires, penile swabs were collected and tested by nucleic acid amplification. Gonococcal isolates were tested for antimicrobial sensitivity. Sequential point-of-care tests on blood samples were used to screen for syphilis and HIV. Bivariable and multivariable multinomial logistic regression models were used to estimate odds ratios for preselected factors likely to be associated with STIs. Adherence to STI treatment guidelines were analyzed. Results From October 2019 to November 2020, positivity (95% CI) for gonorrhea, chlamydia, trichomoniasis, and Mycoplasma genitalium, were 66.4% (60.1%, 72.2%), 21.7% (16.8%, 27.4%), 2.0% (0.7%, 4.9%), and 12.4% (8.7%, 17.3%) respectively. All Neisseria gonorrhoeae isolates were resistant to ciprofloxacin, penicillin, and tetracycline, but susceptible to extended spectrum cephalosporins and azithromycin. HIV and syphilis prevalence was 20.0% (50/250) and 10.0% (25/250), and the proportion unaware of their infection was 4.0% and 80.0% respectively. Most participants were treated per national guidelines. Multivariable analysis demonstrated significant associations between curable STI coinfections and younger age, transactional sex, but not HIV status, nor condom or alcohol use. Conclusions STI coinfections including HIV their associated risk factors, and gonococcal AMR were common in this population. The majority with syphilis were unaware of their infection and were untreated. Transactional sex was associated with STI coinfections, and > 80% of participants received appropriate treatment.

Abstract Background The importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB. Methods This was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67). Results The loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan–Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups. Conclusions The administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

Various traditional Chinese herbs and complex formulas have been suggested to exhibit lifespan extension properties. Here, the authors isolated the flavonoid corylin from Psoralea corylifolia and demonstrated its longevity properties in yeast, human cells and mouse.

Persons in the stage of adolescence are eager to know who they are. They are curious about their unique characteristics and identities and how they can start to bring about the self-realization that provides a gateway to adulthood by exploring those characteristics and identities. In this process of self-exploration, adolescents who receive encouragement as they search for an authentic identity, though they sometimes have conflicts with parents and others, are likely to develop a secure ego-identity and a strong sense of independence and self-control. By contrast, adolescents who fail to receive encouragement during the process of identity exploration, for whatever reason, may remain unsure about who they are, and hence feel insecure and confused about themselves as well as their future. The present study uses the fictional character Harry Potter to explore these issues in greater depth, mainly focusing on his early adolescent years—that is, when he is 11-13 years old. The study demonstrates that Harry Potter can manage to resolve conflicting ideas and thereby lay the foundations for a healthy ego-identity despite difficult circumstances. The study uses Erikson’s and other psychologists’ understanding of the importance of self-exploration in adolescence as an interpretive lens to examine the dynamics of trauma, love, and self-realization in Rowling’s Harry Potter and the Prisoner of Azkaban. More specifically, it considers how family love (or the lack thereof), mentorship, and friendship in adolescence impact Harry’s mental and physical behaviors and influence the development of his identity.

Antimicrobial resistance (AMR) is a global threat fueled by incorrect (and overuse) of antibiotic drugs, giving rise to the evolution of multi- and extreme drug-resistant bacterial strains. The longer time to antibiotic administration (TTA) associated with the gold standard bacterial culture method has been responsible for the empirical usage of antibiotics and is a key factor in the rise of AMR. While polymerase chain reaction (PCR) and other nucleic acid amplification methods are rapidly replacing traditional culture methods, their scope has been restricted mainly to detect genotypic determinants of resistance and provide little to no information on phenotypic susceptibility to antibiotics. The work presented here aims to provide phenotypic antimicrobial susceptibility testing (AST) information by pairing short growth periods (~3–4 h) with downstream PCR assays to ultimately predict minimum inhibitory concentration (MIC) values of antibiotic treatment. To further simplify the dual workflows of the AST and PCR assays, these reactions are carried out in a single-vessel format (PCR tube) using novel lyophilized reagent beads (LRBs), which store dried PCR reagents along with primers and enzymes, and antibiotic drugs separately. The two reactions are separated in space and time using a melting paraffin wax seal, thus eliminating the need to transfer reagents across different consumables and minimizing user interactions. Finally, these two-step single-vessel reactions are multiplexed by using a microfluidic manifold that allows simultaneous testing of an unknown bacterial sample against different antibiotics at varying concentrations. The LRBs used in the microfluidic system showed no interference with the bacterial growth and PCR assays and provided an innovative platform for rapid point-of-care diagnostics (POC-Dx).

This study intended to develop and assess the psychometric properties of a caring behavior scale on healthcare students and providers (CBS-HSP) in a Taiwanese population. After a literature review was conducted and an expert panel was consulted for item generation, 104 items for the CBS-HSP scale were derived on a nine-point Likert scale, with 9 indicating ‘extremely important’ and 1 indicating ‘extremely unimportant.’ A pilot study was then conducted with seven hundred forty-eight healthcare students and providers in Taiwan for further data analysis. The statistic software used in the study was SPSS for the exploratory factor analysis (EFA) and AMOS for the confirmatory factor analysis (CFA). Also, to examine the psychometric properties of the scale, internal consistency, convergent validities, discriminant validities, and model fit indices were calculated in the study. The EFA results derived 31 items in four factors, with 65.742% of the total variance explained: ‘support and attentiveness’ (11 items; 48.714% of the variance explained), ‘professional knowledge and skills’ (8 items; 8.226% of the variance explained), ‘gratifying needs and responsiveness’ (7 items; 5.236% of the variance explained), and ‘confidentiality and trust’ (5 items; 3.566% of the variance explained). The Cronbach’s alphas for the four subscales and the overall scale ranged from 0.894 to 0.964. The CFA results yielded the same 31 items, with the same four factors. The CFA results demonstrated good to excellent model fit in the χ2/df ratio (1.242), GFI (0.988), CFI (0.988), TFI (0.985), and RMSEA (0.031). The Cronbach’s alphas ranged between 0.866 and 0.971; the composite alphas ranged between 0.854 and 0.964. The convergent and discriminant validities also proved the stability of the CBS-HSP scale. The research results indicated that the developed CBS-HSP appeared to be a reliable instrument to measure healthcare students’ and providers’ caring behaviors.

Abstract 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.

This study intended to use the film Mona Lisa Smile (1993) as an example to examine how women in the traditional generation of 1950 were gender stereotyped and used to trade themselves off through marriage in consideration of a cost-and-benefit analysis. However, as the change of women’s gender consciousness from the conservative to the feminist in the USA of 1950, women began to realize their potential and subjectivity, hence questing for liberal spirit and autonomy to choose their career and husbands based on love. The researchers used the qualitative method, with both the primary and secondary data, to facilitate a latent-content analysis. After conducting a content analysis of the film and the script of Mona Lisa Smile, the researchers took notes regarding gender stereotyping and conventional gender norms in social interactions and conducted a literature review of Becker’s side bet theory and Homan’s social exchange theory to investigate how women in America in the 1950s were disciplined to meet the expectation of social norms to fit the notion of conventional matrimony, and how people, both men and women, while choosing their mates, seek the maximum interest and minimum cost. The film Mona Lisa Smile lets readers have a chance to see the transformation of a marital relationship from the old days to modern ones. With raised gender consciousness, women may now subject their choices to their own will and, hence, apply a different definition to the word “marriage.”

Some antituberculosis agents may cause hypothyroidism, and thyroid hormones play a vital role in Mycobacterium tuberculosis infection. However, the relationship between tuberculosis (TB) and hypothyroidism has not been clearly established. Therefore, this retrospective, longitudinal cohort study aimed to investigate the association between these two diseases using the 2000–2017 data from the Taiwan's National Health Insurance Research Database. The hypothyroidism and TB cohorts were matched with the control group in a 1:4 ratio. Adjusted hazard ratios (aHRs) were assessed using Cox proportional hazards regression analysis in each cohort. In total, 3,976 individuals with hypothyroidism and 35 120 individuals with TB were included in this study. The risk of developing TB in patients with hypothyroidism was 2.91 times higher than that in those without hypothyroidism (95% confidence interval [CI], 1.50–3.65). The subgroup of thyroxine replacement therapy (TRT) had a 2.40 times higher risk (95% CI, 1.26–3.01), whereas the subgroup of non-TRT had a 3.62 times higher risk of developing TB than those without hypothyroidism (95% CI, 2.19–4.84). On the other hand, the risk of developing hypothyroidism in patients with TB was 2.01 times higher than that in those without TB (95% CI, 1.41–2.38). Our findings provide evidence that TB and hypothyroidism are interrelated. Thus, clinicians and public health authorities should monitor the association between these two diseases to reduce the relevant disease burden.

Abstract We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI‐high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI‐high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21‐day cycle. A total of 6 patients with CHFR‐methylated, MSI‐high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression‐free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof‐of‐concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker‐selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.

Abstract Background Atherogenic dyslipidemia (AD), characterized by increased concentrations of apolipoprotein B (ApoB)-containing particles, is often present in individuals with type 2 diabetes mellitus (T2DM). Non-high-density lipoprotein cholesterol (non-HDL-C), cholesterol transported by apolipoprotein B (ApoB)-containing particles), and total apoB are considered secondary goals of lipid-lowering therapy to guide treatment of residual cardiovascular risk. The BANTING and BERSON studies demonstrated that evolocumab added to statin therapy reduced atherogenic lipid and lipoproteins concentrations in patients with T2DM. Methods This post-hoc analysis combined data from two randomized, placebo-controlled trials, BANTING and BERSON, to investigate the effect of evolocumab (140 mg every two weeks [Q2W] or 420 mg monthly [QM]) on atherogenic lipid (LDL-C, non-HDL-C, VLDL-C, remnant cholesterol) and lipoproteins (ApoB, lipoprotein(a) (Lp[a])), and achievement of 2019 European Society of Cardiology/European Atherosclerosis Society lipid treatment goals in individuals with and without AD. Results In individuals with high TGs with (n = 389) and without (n = 196) AD receiving background statin therapy, evolocumab, compared with placebo, substantially reduced the cholesterol levels from all ApoB atherogenic lipoproteins (least squares (LS) mean LDL-C by 66.7% to 74.3%, non-HDL-C by 53.4% to 65.8%, median remnant cholesterol by 28.9% to 34.2%, VLDL-C by 16.1% to 19.6%) and median TGs levels (by 17.5% to 19.6%) at the mean of weeks 10 and 12. LS mean ApoB was significantly reduced by 41.5% to 56.6% at week 12. Results were consistent in diabetic individuals with normal TGs (n = 519). Evolocumab was also associated with a significant reduction in median Lp(a) by 35.0% to 53.9% at the mean of weeks 10 and 12. A majority (74.7% to 79.8%) of evolocumab-treated individuals achieved the goal of both an LDL-C 75% achieved non-HDL-C 67% achieved ApoB

Abstract The metabolically healthy obese (MHO) characterized by the absence of metabolic syndrome have shown superior cardiorespiratory fitness (CRF) and similar muscular strength as compared with the metabolically unhealthy obese (MUO). However, this finding might be biased by the baseline sedentary behavior in the general population. This study utilized 3669 physically active military males aged 18–50 years in Taiwan. Obesity and metabolically unhealthy were respectively defined as body mass index ≥ 27.5 kg/m2 and presence of at least two major components of the metabolic syndrome, according to the International Diabetes Federation criteria for Asian male adults. Four groups were accordingly classified as the metabolically healthy lean (MHL, n = 2510), metabolically unhealthy lean (MUL, n = 331), MHO (n = 181) and MUO (n = 647). CRF was evaluated by time for a 3-km run, and muscular strengths were separately assessed by numbers of push-up and sit-up within 2 min. Analysis of covariance was utilized to compare the difference in each exercise performance between groups adjusting for age, service specialty, smoking, alcohol intake and physical activity. The metabolic syndrome prevalence in MUL and MUO was 49.8% and 47.6%, respectively. The performance of CRF did not differ between MHO and MUO (892.3 ± 5.4 s and 892.6 ± 3.0 s, p = 0.97) which were both inferior to MUL and MHL (875.2 ± 4.0 s and 848.6 ± 1.3 s, all p values

The article presents the High-Pull Palatal Gear (HPPG) technique as an alternative to orthognathic surgery for treating hyperdivergent Class II malocclusions. The technique involves using miniscrews to intrude the maxillary dentition and correct the occlusal plane. By carefully controlling forces and miniscrew placement, the HPPG technique can improve facial profile and smile aesthetics. The article provides a case report and cephalometric analysis to support the effectiveness of the technique. [Extracted from the article]

Brain myelinating oligodendrocytes are rare and difficult to isolate, which has limited data on their development. Here the authors develop a reporter for scalable purification of human pluripotent stem cell derived oligodendrocyte lineage cells, and use this to map differentiation using single cell RNA-sequencing,

This study analyzes how the characters in Lee Unkrich and Adrian Molina’s animated film Coco, mainly Mamá Imelda, Héctor, and Miguel, manage their emotional responses when they are facing loss, bereavement, or other significant changes in their lives. The study uses Elisabeth Kübler-Ross’s five-stage model of grief to analyze how these characters go through the grieving process. Moreover, in order to suggest how those who are grieving can enter into positive states of mind, the study expands on Kübler-Ross’s original model by incorporating a positive mindset of hope. In dialogue with Unkrich and Molina’s film, the study uses Kübler-Ross’s ideas to explore coping mechanisms that can help manage difficult times in life, while also suggesting the benefits of maintaining a positive mindset through hope.

Background In high-dimensional survival genomic data, identifying cancer-related genes is a challenging and important subject in the field of bioinformatics. In recent years, many feature screening approaches for survival outcomes with high-dimensional survival genomic data have been developed; however, few studies have systematically compared these methods. The primary purpose of this article is to conduct a series of simulation studies for systematic comparison; the second purpose of this article is to use these feature screening methods to further establish a more accurate prediction model for patient survival based on the survival genomic datasets of The Cancer Genome Atlas (TCGA). Results Simulation studies prove that network-adjusted feature screening measurement performs well and outperforms existing popular univariate independent feature screening methods. In the application of real data, we show that the proposed network-adjusted feature screening approach leads to more accurate survival prediction than alternative methods that do not account for gene-gene dependency information. We also use TCGA clinical survival genetic data to identify biomarkers associated with clinical survival outcomes in patients with various cancers including esophageal, pancreatic, head and neck squamous cell, lung, and breast invasive carcinomas. Conclusions These applications reveal advantages of the new proposed network-adjusted feature selection method over alternative methods that do not consider gene-gene dependency information. We also identify cancer-related genes that are almost detected in the literature. As a result, the network-based screening method is reliable and credible.

Candida auris is an emerging multidrug-resistant fungal pathogen that can cause severe and deadly infections. To date, C. auris has spurred outbreaks in healthcare settings in thirty-three countries across five continents. To control and potentially prevent its spread, there is an urgent need for point-of-care (POC) diagnostics that can rapidly screen patients, close patient contacts, and surveil environmental sources. Droplet magnetofluidics (DM), which leverages nucleic acid-binding magnetic beads for realizing POC-amenable nucleic acid detection platforms, offers a promising solution. Herein, we report the first DM device—coined POC.auris—for POC detection of C. auris. As part of POC.auris, we have incorporated a handheld cell lysis module that lyses C. auris cells with 2 min hands-on time. Subsequently, within the palm-sized and automated DM device, C. auris and control DNA are magnetically extracted and purified by a motorized magnetic arm and finally amplified via a duplex real-time quantitative PCR assay by a miniaturized rapid PCR module and a miniaturized fluorescence detector—all in ≤30 min. For demonstration, we use POC.auris to detect C. auris isolates from 3 major clades, with no cross reactivity against other Candida species and a limit of detection of ∼300 colony forming units per mL. Taken together, POC.auris presents a potentially useful tool for combating C. auris.

All human beings seek certain identities in order to understand their existence and position in society, the groups to which they belong, and the unique characteristics they have. This paper examines how, in Jane Eyre, Charlotte Bronte examines socially constructed institutionalism in Victorian England. This paper also explores how the protagonist, Jane Eyre, oppressed due to her social class and gender, struggles to live with equality, dignity, and freedom, and finally reaches independence and self-fulfillment. Jane successfully completes the stages of identity development, and, after acquiring a sense of competence, achieves happiness and intimacy in an equal partnership with her true love, Mr. Rochester.

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.