CASTELO: clustered atom subtypes aided lead optimization-a combined machine learning and molecular modeling method.

BACKGROUND: Drug discovery is a multi-stage process that comprises two costly major steps: pre-clinical research and clinical trials. Among its stages, lead optimization easily consumes more than half of the pre-clinical budget. We propose a combined machine learning and molecular modeling approach that partially automates lead optimization workflow in silico, providing suggestions for modification hot spots. RESULTS: The initial data collection is achieved with physics-based molecular dynamics simulation. Contact matrices are calculated as the preliminary features extracted from the simulations. To take advantage of the temporal information from the simulations, we enhanced contact matrices data with temporal dynamism representation, which are then modeled with unsupervised convolutional variational autoencoder (CVAE). Finally, conventional and CVAE-based clustering methods are compared with metrics to rank the submolecular structures and propose potential candidates for lead optimization. CONCLUSION: With no need for extensive structure-activity data, our method provides new hints for drug modification hotspots which can be used to improve drug potency and reduce the lead optimization time. It can potentially become a valuable tool for medicinal chemists.

In Situ TEM Investigation of the Electrochemical Behavior in CNTs/MnO2-Based Energy Storage Devices.

Transition metal oxides have attracted much interest owing to their ability to provide high power density in lithium batteries; therefore, it is important to understand the electrochemical behavior and mechanism of lithiation-delithiation processes. In this study, we successfully and directly observed the structural evolution of CNTs/MnO2 during the lithiation process using transmission electron microscopy (TEM). CNTs/MnO2 were selected due to their high surface area and capacitance effect, and the lithiation mechanism of the CNT wall expansion was systematically analyzed. Interestingly, the wall spacings of CNTs/MnO2 and CNTs were obviously expanded by 10.92% and 2.59%, respectively. The MnO2 layer caused structural defects on the CNTs surface that could allow penetration of Li+ and Mn4+ through the tube wall and hence improve the ionic transportation speed. This study provided direct evidence for understanding the role of CNTs/MnO2 in the lithiation process used in lithium ion batteries and also offers potential benefits for applications and development of supercapacitors.

Characterization of young infants with fecal carriage of multidrug-resistant Escherichia coli in Southern Taiwan.

BACKGROUND: The accelerating prevalence of extended-spectrum ß-lactamase (ESBL)-producing and multidrug-resistance (MDR) Escherichia coli(E. coli) become a public health challenge worldwide. This study aimed to discuss the prevalence of drug-resistant E. coli colonization and analyze its risk factors and clinical characteristics among young infants in Southern Taiwan. METHODS: Stool samples were collected from young infants, aged less than three months, within three days of their hospitalization from September to December 2019 in a tertiary hospital. A questionnaire was designed for parents to complete. E. coli colonies were selected and analyzed for antimicrobial susceptibility. PCR-based multilocus sequence typing was to detect the presence of sequence type ST131 and blaCTX-M genes. RESULTS: Among 100 enrolled infants, 36% had fecal carriage of E. coli isolates, of which twenty nine (80.5%) were MDR, thirteen (36.1%) were ESBL-producing isolates and five (13.8%) and ten (27.7%) were ST131 and strains carrying CTX-M-14 gene, respectively. Compared to non-ST131 and non-CTX-M-14 gene carrier, isolates of ST131 and CTX-M-14 gene carrier showed a significantly higher resistance rate to cefixime, ceftriaxone, and gentamycin, with p value all <0.05. CONCLUSION: The prevalence of ESBL-producing and MDR E. coli fecal carriage were both high in young infants. The most common sequence type is ST131, of which all are strains carrying CTX-M-14. Further surveillance and investigation to control for the high prevalence of antimicrobial-resistant E. coli fecal carriage among infants in Taiwan are warranted.

SSII cancellation in an EAM-based OFDM-IMDD transmission system employing a novel dynamic chirp model.

We develop a novel subcarrier-to-subcarrier intermixing interference (SSII) cancellation technique to estimate and eliminate SSII. For the first time, the SSII cancellation technique is experimentally demonstrated in an electro-absorption modulator- (EAM-) based intensity-modulation-direct-detection (IMDD) multi-band OFDM transmission system. Since the characteristics of SSII are seriously affected by the chirp parameter, a simple constant chirp model, we found, cannot effectively remove the SSII. Therefore, assuming that the chirp parameter linearly depends on the optical power, a novel dynamic chirp model is developed to obtain better estimation and cancellation of SSII. Compared with 23.6% SSII cancellation by the constant chirp model, our experimental results show that incorporating the dynamic chirp model into the SSII cancellation technique can achieve up to 74.4% SSII cancellation and 2.8-dB sensitivity improvement in a 32.25-Gbps OFDM system over 100-km uncompensated standard single-mode fiber.

Characteristics and prognosis in patients with false-positive ST-elevation myocardial infarction in the ED.

BACKGROUND: There are several causes of ST-segment elevation (STE) besides acute myocardial infarction (MI). OBJECTIVES: We design this study to determine the prevalence, etiology, clinical manifestation, electrocardiographic characteristics, and outcome in patients with false-positive STEMI. METHODS: This is a retrospective case-control study design. At our emergency department, 297 patients who underwent emergent coronary angiography for suspected STEMI were enrolled from January 2004 to December 2010. RESULTS: Of the 297 patients who underwent coronary angiography, 31 patients (10.4%) did not have a clear culprit coronary lesion and were classified as false-positive STEMI. False-positive STEMI patients had a lower incidence of typical chest pain or chest tightness (58.1% vs 87.6%, P < .001). Inferior STE occurred significantly more often in the patients with true-positive STEMI (49.6% vs 25.8%, P = .012), and diffuse STE, more often in the patients with false-positive STEMI (19.4% vs 0.38%, P = .001). Total height of STE was lower in false-positive STEMI patients (7.5 ± 4.9 vs 10.9 ± 7.9 mm, P = .002) if excluding 5 patients of marked STE just after cardiopulmonary resuscitation. Concave STE and no reciprocal ST-segment depression occurred more often in false-positive STEMI patients (51.6% vs 24.1%, P = .001; 64.5% vs 19.2%, P < .001). There was no significant difference of in-hospital major adverse events in the patients with false-positive and true-positive STEMI. CONCLUSIONS: The diagnosis of false-positive STEMI is not uncommon. Detailed clinical evaluation and electrocardiogram interpretation may avoid partly unnecessary catheterization laboratory activation.

Effects of early aminophylline therapy on clinical outcomes in premature infants.

BACKGROUND: Aminophylline use and the association between clinical outcomes and therapy timing have been less investigated. The objective of this study was to determine the efficacy of early aminophylline use (within the first two days of life) in premature infants. METHOD: A retrospective observational cohort of infants weighing <1500 g and <30 weeks of gestational age at Kaohsiung Veterans General Hospital received aminophylline either within the first two days of life (EA, early aminophylline group), after the third day of life (LA, late aminophylline group), or without aminophylline during the first month of life (WA, without aminophylline group). Demographic data and neonatal clinical outcomes were compared among the three groups. RESULTS: This study included 89 preterm infants (EA = 33, LA = 38, WA = 18). The EA group had a lower incidence of bronchopulmonary dysplasia (BPD) than the WA group (adjusted odds ratio [aOR] = 8.86(1.56-59.32); P = 0.024). Although there was no significant difference in BPD incidence between the EA and LA groups (aOR = 2.66(0.51-13.81), P = 0.244), a trend remained. Birth body weight less than 1000 g was also a significant risk factor for BPD (aOR = 8.86(1.32-47.41), P = 0.014). The duration of mechanical ventilation was shorter in the infants in the EA group compared to the WA group (estimated beta = -11.344(-19.57-3.12); P = 0.008). CONCLUSION: Early aminophylline administration may be associated with a decreased incidence of BPD in preterm infants. However, the clinical benefits of aminophylline treatment require further investigation. In addition, a birth body weight of less than 1000 g was a crucial risk factor for BPD.

A nomogram for predicting the development of serious bacterial infections in febrile term neonates: A single medical center experience in Southern Taiwan.

BACKGROUND: Serious bacterial infections (SBIs) could lead to mortality or severe long-term sequelae in neonates and infants aged <3 months. Accordingly, the aim of this study was to develop a quantitative and accurate assessment tool for predicting the risk of SBIs in febrile neonates. METHODS: This retrospective study enrolled 131 febrile term neonates (aged <30 days) who were hospitalized at Kaohsiung Veterans General Hospital between January 2005 and December 2020. These neonates were classified into SBI and nonbacterial infection (NBI) groups on the basis of microbiological laboratory reports. The clinical characteristics and routine blood tests of both groups at the time of admission were analyzed. Stepwise logistic regression was applied to create and validate the nomogram for SBI prediction. RESULTS: Among the 131 febrile neonates, 38 and 93 developed SBIs and NBIs, respectively. At the time of admission, ill clinical appearance, serum myelocyte/metamyelocyte presence, C-reactive protein (CRP) > 2.5 mg/dL, and pyuria were associated with an increased risk of SBIs. Accordingly, these four factors were used to develop a nomogram for SBI prediction, which exhibited significantly high performance (area under curve = 0.848, p < 0.001) in predicting SBI risk. CONCLUSION: We developed a nomogram combining clinical appearance, serum myelocyte/metamyelocyte presence, CRP, and pyuria for predicting SBI risk in febrile neonates. This tool can assist clinicians in making early diagnoses and delivering the appropriate treatment.

Long-term medical utilization following ventilator-associated pneumonia in acute stroke and traumatic brain injury patients: a case-control study.

BACKGROUND: The economic burden of ventilator-associated pneumonia (VAP) during the index hospitalization has been confirmed in previous studies. However, the long-term economic impact is still unclear. The aim of this study is to examine the effect of VAP on medical utilization in the long term. METHODS: This is a retrospective case-control study. Study subjects were patients experiencing their first traumatic brain injury, acute hemorrhagic stroke, or acute ischemic stroke during 2004. All subjects underwent endotracheal intubation in the emergency room (ER) on the day of admission or the day before admission, were transferred to the intensive care unit (ICU) and were mechanically ventilated for 48 hours or more. A total of 943 patients who developed VAP were included as the case group, and each was matched with two control patients without VAP by age ( ± 2 years), gender, diagnosis, date of admission ( ± 1 month) and hospital size, resulting in a total of 2,802 patients in the study. Using robust regression and Poisson regression models we examined the effect of VAP on medical utilization including hospitalization expenses, outpatient expenses, total medical expenses, number of ER visits, number of readmissions, number of hospitalization days and number of ICU days, during the index hospitalization and during the following 2-year period. RESULTS: Patients in the VAP group had higher hospitalization expenses, longer length of stay in hospital and in ICU, and a greater number of readmissions than the control group patients. CONCLUSIONS: VAP has a significant impact on medical expenses and utilization, both during the index hospitalization during which VAP developed and in the longer term.

Online Machine Learning for Accelerating Molecular Dynamics Modeling of Cells.

We developed a biomechanics-informed online learning framework to learn the dynamics with ground truth generated with multiscale modeling simulation. It was built on Summit-like supercomputers, which were also used to benchmark and validate our framework on one physiologically significant modeling of deformable biological cells. We generalized the century-old equation of Jeffery orbits to a new equation of motion with additional parameters to account for the flow conditions and the cell deformability. Using simulation data at particle-based resolutions for flowing cells and the learned parameters from our framework, we validated the new equation by the motions, mostly rotations, of a human platelet in shear blood flow at various shear stresses and platelet deformability. Our online framework, which surrogates redundant computations in the conventional multiscale modeling by solutions of our learned equation, accelerates the conventional modeling by three orders of magnitude without visible loss of accuracy.

Dynamics-Based Peptide-MHC Binding Optimization by a Convolutional Variational Autoencoder: A Use-Case Model for CASTELO.

An unsolved challenge in the development of antigen-specific immunotherapies is determining the optimal antigens to target. Comprehension of antigen-major histocompatibility complex (MHC) binding is paramount toward achieving this goal. Here, we apply CASTELO, a combined machine learning-molecular dynamics (ML-MD) approach, to identify per-residue antigen binding contributions and then design novel antigens of increased MHC-II binding affinity for a type 1 diabetes-implicated system. We build upon a small-molecule lead optimization algorithm by training a convolutional variational autoencoder (CVAE) on MD trajectories of 48 different systems across four antigens and four HLA serotypes. We develop several new machine learning metrics including a structure-based anchor residue classification model as well as cluster comparison scores. ML-MD predictions agree well with experimental binding results and free energy perturbation-predicted binding affinities. Moreover, ML-MD metrics are independent of traditional MD stability metrics such as contact area and root-mean-square fluctuations (RMSF), which do not reflect binding affinity data. Our work supports the role of structure-based deep learning techniques in antigen-specific immunotherapy design.

The occurrence of delayed neuropsychologic sequelae in acute carbon monoxide poisoning patients after treatment with hyperbaric or normobaric oxygen therapy.

ABSTRACT: This study aimed at assessing which one of the 2 therapies is better for treating carbon monoxide (CO) poisoning from the perspective of reducing delayed neuropsychologic sequelae (DNS).We used Taiwan's National Health Insurance Research Database (NHIRD) to conduct a nationwide population-based cohort study to assess which therapy is better for CO poisoning patients. To accurately identify patients with DNS, the definition of DNS is included neurological sequelae, and cognitive and psychological sequele. The independent variable was therapy and the dependent variable was DNS occurred within 1 year after discharge from a medical institution. The control variables were age, gender, the severity of CO poisoning, and comorbidities present before CO poisoning admission.The risk of developing DNS in patients treated with Hyperbaric Oxygen (HBO) was 1.87-fold (P < .001) than normobaric oxygen (NBO) therapy. The severity of CO poisoning and comorbidities were also found to have significant influences on the risk of developing DNS.HBO may be a risk therapy for treating CO poisoning.

Effect of Postoperative Adverse Events on Hospitalization Expenditures and Length of Stay Among Surgery Patients in Taiwan: A Nationwide Population-Based Case-Control Study.

Background: The current study sought to determine the incidence of postoperative adverse events (AEs) based on data from the 2006 Taiwan National Health Insurance Research Database (NHIRD). Methods: This retrospective case-control study included patients who experienced postoperative AEs in 387 hospitals throughout Taiwan in 2006. The independent variable was the presence or absence of 10 possible postoperative AEs, as identified by patient safety indicators (PSIs). Results: A total of 17,517 postoperative AEs were identified during the study year. PSI incidence ranged from 0.1/1,000 admissions (obstetric trauma-cesarean section) to 132.6/1,000 admissions (obstetric trauma with instrument). Length of stay (LOS) associated with postoperative AEs ranged from 0.10 days (obstetric trauma with instrument) to 14.06 days (postoperative respiratory failure). Total hospitalization expenditures (THEs) ranged from 363.7 New Taiwan Dollars (obstetric trauma without instrument) to 263,732 NTD (postoperative respiratory failure). Compared to patients without AEs, we determined that the THEs were 2.13 times in cases of postoperative AE and LOS was 1.72 times higher. Conclusions: AEs that occur during hospitalization have a major impact on THEs and LOS.

Role of precursors mixing sequence on the properties of CoMn2O4 cathode materials and their application in pseudocapacitor.

In this study, the effect of oxygen vacancy in the CoMn2O4 on pseudocapacitive characteristics was examined, and two tetragonal CoMn2O4 spinel compounds with different oxygen vacancy concentrations and morphologies were synthesized by controlling the mixing sequence of the Co and Mn precursors. The mixing sequence was changed; thus, morphologies were changed from spherical nanoparticles to nanoflakes and oxygen vacancies were increased. Electrochemical studies have revealed that tetragonal CoMn2O4 spinels with a higher number of oxygen vacancies exhibit a higher specific capacitance of 1709 F g-1 than those with a lower number of oxygen vacancies, which have a higher specific capacitance of 990 F g-1. Oxygen vacancies create an active site for oxygen ion intercalation. Therefore, oxidation-reduction reactions occur because of the diffusion of oxygen ions at octahedral/tetrahedral crystal edges. The solid-state asymmetric pseudocapacitor exhibits a maximum energy density of 32 Wh-kg-1 and an excellent cyclic stability of nearly 100%.

Flexible solid-like electrolytes with ultrahigh conductivity and their applications in all-solid-state supercapacitors.

All-solid-state supercapacitors (ASSS) with solid-state electrolytes (SSEs) can be used to overcome the liquid leakage problem in devices. However, ionic conduction in solid electrolytes is one of the barriers to further improvements in ASSS. This paper describes the fabrication of a flexible SSE composed of poly(vinylidene fluoride-co-hexafluoropropylene), 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, and ethylene carbonate, which demonstrates an ultrahigh conductivity of 8.52 mS cm-1 and a wide 5 V operation voltage window of -2 to +3 V. Electrodes composed of active carbon, multiwall carbon nanotubes, and polyvinylidene fluoride were used as both anode and cathode to assemble a symmetrical supercapacitor. The resultant supercapacitor exhibits a maximum power density of 3747 W kg-1 at an energy density of 7.71 W h kg-1 and a maximum energy density 17.1 W h kg-1 at a power density of 630 W kg-1. It displays excellent cycling stability with 91.3% of the initial specific capacitance after 3000 charging/discharging cycles. This flexible SSE in this study demonstrates a high potential for use in energy storage, conversion, and wearable device applications.

Maternal pregnancy-induced hypertension increases subsequent neonatal necrotizing enterocolitis risk: A nationwide population-based retrospective cohort study in Taiwan.

The utero-placental ischemia induced by pregnancy-induced hypertension (PIH) could lead to fetal hypoxia and proinflammatory cytokine release, which are associated with the development of neonatal necrotizing enterocolitis (NEC). However, a few studies have investigated the relationship between PIH and neonatal NEC and have produced controversial results. Therefore, we attempted to assess the relationship between PIH and the subsequent neonatal NEC risk and identify predictive risk factors.Patients with newly diagnosed PIH were recruited from the Taiwan National Health Insurance Research Database (NHIRD). For each participant, 4 age- and delivery-year-matched participants without PIH were randomly selected. A multivariable logistic regression was performed for the identification of the predictive risk factors for neonatal NEC.Among the 23.3 million individuals registered in the NHIRD, 29,013 patients with PIH and 116,052 matched controls were identified. For the multivariable analysis, maternal PIH was associated with an increased risk of subsequent neonatal NEC development (odds ratio [OR] 1.86, 95% confidence interval [CI] 1.08-3.21, P = .026). Furthermore, single parity (OR 2.06, 95% CI 1.12-3.77, P = .019), preterm birth (OR 5.97, 95% CI 3.49-10.20, P < .001), multiple gestations (OR 2.25, 95% CI 1.22-4.14, P = .010), and intrauterine growth restriction (IUGR) (OR 3.59, 95% CI 2.06-6.24, P < .001) were independent risk factors for the development of subsequent neonatal NEC.Maternal PIH increases the risk for developing neonatal NEC. Furthermore, primiparity, preterm birth, multiple gestations, and IUGR were independent risk factors for neonatal NEC.

Coronary Artery Calcium Score Compared with Cardio-Ankle Vascular Index in the Prediction of Cardiovascular Events in Asymptomatic Patients with Type 2 Diabetes.

AIM: Coronary artery calcium (CAC) score has a role in stratifying cardiovascular risk in patients with diabetes. Cardio-ankle vascular index (CAVI) is also a useful method to detect coronary artery calcification. This study compares CAC score with CAVI in the prediction of cardiovascular events in patients with diabetes. METHODS: From August 2006 to June 2008, a total of 626 patients with diabetes who received CAC score assessment with concomitant tests of ankle-brachial index and CAVI were included in this study. RESULTS: During 4 years of follow-up, 98 participants developed cardiovascular events. There is an increased incidence of coronary revascularization and total cardiovascular events with higher categories of CAC score (P ＜ 0.05 when CAC score ≥ 100). The logistic regression analyses revealed pooled odd ratios for coronary revascularization, and total cardiovascular events were 1.25 [95% confidence interval (CI) 1.03- 1.51, P =0.021] and 1.23 (95% CI 1.07-1.42, P = 0.005), respectively, for high versus low CAVI (CAVI ≥ 9.0 vs CAVI ＜ 9.0). The logistic regression model revealed that a CACscore of ≥ 1000 rather than a CAVI of ≥ 9.0 had a higher predictive value for total cardiovascular events. CONCLUSIONS: A CAC score of ≥ 100 or a CAVI of ≥ 9.0 predicts future total cardiovascular events in asymptomatic patients with type 2 diabetes. Considering the advantages of CAVI, it can be used as one of the screening tools to reflect coronary atherosclerosis in these patients.

Percutaneous dilatational tracheostomy versus open tracheostomy--a prospective, randomized, controlled trial.

BACKGROUND: Percutaneous dilatational tracheostomy has gained popularity, but its superiority to open tracheostomy is unclear. The object of this study was to compare procedure time, complication, safety and cost-effect between the percutaneous dilatational tracheostomy (PDT) and the conventional open tracheotomy (OT). METHODS: A prospective randomized clinic trial was conducted in a general Intensive Care Unit of an University-based hospital. Eighty-three consecutive patients who needed elective tracheostomies were selected for this study. PDT was performed using the Ciaglia method with OT as control group. Age, gender, operative data, complications and mortality were recorded for analysis. RESULTS: The procedure time was 22.0 +/- 12.1 minutes in PDT group, and 41.5 +/- 5.9 minutes in OT group, with significant statistical difference (p < 0.001). The incidences of complications were not different between both groups. Ages, gender or days of pre-tracheostomy intubation showed no difference between two groups. CONCLUSIONS: The PDT appears to be a simple, safe and time-saving bedside procedure. It can be recommended when an elective tracheostomy is needed in a critical patient.

Selecting representative affective dimensions using Procrustes analysis: an application to mobile phone design.

Collecting affective responses (ARs) from consumers is crucial to designers aspiring to produce an appealing product. Adjectives are frequently used by researchers as an affective means by which consumers can describe their subjective feelings regarding a specific product design. This study proposes a Kansei engineering (KE) approach for selecting representative affective dimensions using factor analysis (FA) and Procrustes analysis (PA). A semantic differential (SD) experiment is used to examine consumers' ARs toward a set of representative product samples. FA is employed to extract the underlying latent factors using an initial set of affective dimensions. A backward elimination process based on PA is used to determine the relative significance of adjectives in each step according to the calculated residual sum of squared differences (RSSDs) to finally obtain the ranking of the initial set of adjectives. Additionally, the results of the proposed approach are compared to the method that combines FA and two-stage cluster analysis (CA). A case study of mobile phone design is provided to demonstrate the analysis results.

Alcohol intoxication increases morbidity in drivers involved in motor vehicle accidents.

We prospectively examined the correlation of alcohol intoxication with injury severity, morbidity, and mortality in drivers involved in motor vehicle accidents in a prospective cohort study. The study enrolled 923 injured patients, of whom 421 were legally intoxicated (blood alcohol concentration [BAC] > or = 50 mg/dL) and 502 were not intoxicated (BAC < 50 mg/dL). The intoxicated drivers had a significantly higher injury severity score (ISS), lower Glasgow Coma Score, lower systolic blood pressure; higher rate in old age, male sex, greater rate of habitual drinking, greater lack of use of safety gear, and greater accident-related morbidity. After logistic regression analysis, alcohol intoxication was not associated with severe injury (ISS > or = 9); however, alcohol intoxication analyzed either as a preinjury or postinjury risk factor, was one of the predictors for morbidity. Severe head injury was the only predictor of mortality. In conclusion, although alcohol intoxication is not associated with an increased incidence of severe injury or mortality in drivers involved in motor vehicle crashes, it is one of the significant predictors for morbidity after injury.