Elucidating the Role of Hydrogen Bonding in the Optical Spectroscopy of the Solvated Green Fluorescent Protein Chromophore: Using Machine Learning to Establish the Importance of High-Level Electronic Structure.

Hydrogen bonding interactions with chromophores in chemical and biological environments play a key role in determining their electronic absorption and relaxation processes, which are manifested in their linear and multidimensional optical spectra. For chromophores in the condensed phase, the large number of atoms needed to simulate the environment has traditionally prohibited the use of high-level excited-state electronic structure methods. By leveraging transfer learning, we show how to construct machine-learned models to accurately predict the high-level excitation energies of a chromophore in solution from only 400 high-level calculations. We show that when the electronic excitations of the green fluorescent protein chromophore in water are treated using EOM-CCSD embedded in a DFT description of the solvent the optical spectrum is correctly captured and that this improvement arises from correctly treating the coupling of the electronic transition to electric fields, which leads to a larger response upon hydrogen bonding between the chromophore and water.

Effects of individual and neighborhood social risks on diabetes pay-for-performance program under a single-payer health system.

BACKGROUND: Enrollment in and adherence to a diabetes pay-for-performance (P4P) program can lead to desirable processes and outcomes of diabetes care. However, knowledge is limited on the potential exclusion of patients with individual or neighborhood social risks or interruption of services in the disease-specific P4P program without mandatory participation under a single-payer health system. OBJECTIVE: To investigate the impact of individual and neighborhood social risks on exclusion from and adherence to the diabetes P4P program of patients with type 2 diabetes (T2D) in Taiwan. METHODS: This study used data from Taiwan's 2009-2017 population-based National Health Insurance Research Database, 2010 Population and Housing Census, and 2010 Income Tax Statistics. A retrospective cohort study was conducted, and study populations were identified from 2012 to 2014. The first cohort comprised 183,806 patients with newly diagnosed T2D, who had undergone follow up for 1 year; the second cohort consisted of 78,602 P4P patients who had undergone follow up for 2 years after P4P enrollment. Binary logistic regression models were used to examine the associations of social risks with exclusion from and adherence to the diabetes P4P program. RESULTS: T2D patients with higher individual social risks were more likely to be excluded from the P4P program, but those with higher neighborhood-level social risks were slightly less likely to be excluded. T2D patients with the higher individual- or neighborhood-level social risks showed less likelihood of adhering to the program, and the person-level coefficient was stronger in magnitude than the neighborhood-level one. CONCLUSIONS: Our results indicate the importance of individual social risk adjustment and special financial incentives in disease-specific P4P programs. Strategies for improving program adherence should consider individual and neighborhood social risks.

Data-Efficient Machine Learning Potentials from Transfer Learning of Periodic Correlated Electronic Structure Methods: Liquid Water at AFQMC, CCSD, and CCSD(T) Accuracy.

Obtaining the atomistic structure and dynamics of disordered condensed-phase systems from first-principles remains one of the forefront challenges of chemical theory. Here we exploit recent advances in periodic electronic structure and provide a data-efficient approach to obtain machine-learned condensed-phase potential energy surfaces using AFQMC, CCSD, and CCSD(T) from a very small number (≤200) of energies by leveraging a transfer learning scheme starting from lower-tier electronic structure methods. We demonstrate the effectiveness of this approach for liquid water by performing both classical and path integral molecular dynamics simulations on these machine-learned potential energy surfaces. By doing this, we uncover the interplay of dynamical electron correlation and nuclear quantum effects across the entire liquid range of water while providing a general strategy for efficiently utilizing periodic correlated electronic structure methods to explore disordered condensed-phase systems.

Optically Induced Anisotropy in Time-Resolved Scattering: Imaging Molecular-Scale Structure and Dynamics in Disordered Media with Experiment and Theory.

Time-resolved scattering experiments enable imaging of materials at the molecular scale with femtosecond time resolution. However, in disordered media they provide access to just one radial dimension thus limiting the study of orientational structure and dynamics. Here we introduce a rigorous and practical theoretical framework for predicting and interpreting experiments combining optically induced anisotropy and time-resolved scattering. Using impulsive nuclear Raman and ultrafast x-ray scattering experiments of chloroform and simulations, we demonstrate that this framework can accurately predict and elucidate both the spatial and temporal features of these experiments.

AENET-LAMMPS and AENET-TINKER: Interfaces for accurate and efficient molecular dynamics simulations with machine learning potentials.

Machine-learning potentials (MLPs) trained on data from quantum-mechanics based first-principles methods can approach the accuracy of the reference method at a fraction of the computational cost. To facilitate efficient MLP-based molecular dynamics and Monte Carlo simulations, an integration of the MLPs with sampling software is needed. Here, we develop two interfaces that link the atomic energy network (ænet) MLP package with the popular sampling packages TINKER and LAMMPS. The three packages, ænet, TINKER, and LAMMPS, are free and open-source software that enable, in combination, accurate simulations of large and complex systems with low computational cost that scales linearly with the number of atoms. Scaling tests show that the parallel efficiency of the ænet-TINKER interface is nearly optimal but is limited to shared-memory systems. The ænet-LAMMPS interface achieves excellent parallel efficiency on highly parallel distributed-memory systems and benefits from the highly optimized neighbor list implemented in LAMMPS. We demonstrate the utility of the two MLP interfaces for two relevant example applications: the investigation of diffusion phenomena in liquid water and the equilibration of nanostructured amorphous battery materials.

Social Determinants of Diabetes-Related Preventable Hospitalization in Taiwan: A Spatial Analysis.

Diabetes-Related Preventable Hospitalization (DRPH) has been identified as an important indicator of efficiency and quality of the health system and can be modified by social determinants. However, the spatial disparities, clustering, and relationships between DRPH and social determinants have rarely been investigated. Accordingly, this study examined the association of DRPH with area deprivation, densities of certificated diabetes health-promoting clinics (DHPC) and hospitals (DHPH), and the presence of elderly social services (ESS) using both statistical and spatial analyses. Data were obtained from the 2010-2016 National Health Insurance Research Database (NHIRD) and government open data. Township-level ordinary least squares (OSL) and geographically weighted regression (GWR) were conducted. DRPH rates were found to be negatively associated with densities of DHPC (ß = -66.36, p = 0.029; 40.3% of all townships) and ESS (ß = -1.85, p = 0.027; 28.4% of all townships) but positively associated with area deprivation (ß = 2.96, p = 0.002; 25.6% of all townships) in both OLS and GWR models. Significant relationships were found in varying areas in the GWR model. DRPH rates are high in townships of Taiwan that have lower DHPC densities, lower ESS densities, and greater socioeconomic deprivation. Spatial analysis could identify areas of concern for potential intervention.

A framework for automated structure elucidation from routine NMR spectra.

Methods to automate structure elucidation that can be applied broadly across chemical structure space have the potential to greatly accelerate chemical discovery. NMR spectroscopy is the most widely used and arguably the most powerful method for elucidating structures of organic molecules. Here we introduce a machine learning (ML) framework that provides a quantitative probabilistic ranking of the most likely structural connectivity of an unknown compound when given routine, experimental one dimensional 1H and/or 13C NMR spectra. In particular, our ML-based algorithm takes input NMR spectra and (i) predicts the presence of specific substructures out of hundreds of substructures it has learned to identify; (ii) annotates the spectrum to label peaks with predicted substructures; and (iii) uses the substructures to construct candidate constitutional isomers and assign to them a probabilistic ranking. Using experimental spectra and molecular formulae for molecules containing up to 10 non-hydrogen atoms, the correct constitutional isomer was the highest-ranking prediction made by our model in 67.4% of the cases and one of the top-ten predictions in 95.8% of the cases. This advance will aid in solving the structure of unknown compounds, and thus further the development of automated structure elucidation tools that could enable the creation of fully autonomous reaction discovery platforms.

Exploiting Machine Learning to Efficiently Predict Multidimensional Optical Spectra in Complex Environments.

The excited-state dynamics of chromophores in complex environments determine a range of vital biological and energy capture processes. Time-resolved, multidimensional optical spectroscopies provide a key tool to investigate these processes. Although theory has the potential to decode these spectra in terms of the electronic and atomistic dynamics, the need for large numbers of excited-state electronic structure calculations severely limits first-principles predictions of multidimensional optical spectra for chromophores in the condensed phase. Here, we leverage the locality of chromophore excitations to develop machine learning models to predict the excited-state energy gap of chromophores in complex environments for efficiently constructing linear and multidimensional optical spectra. By analyzing the performance of these models, which span a hierarchy of physical approximations, across a range of chromophore-environment interaction strengths, we provide strategies for the construction of machine learning models that greatly accelerate the calculation of multidimensional optical spectra from first principles.

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1'-O-isopropyl ether Shows Improved Selectivity Against the Epstein-Barr Virus Lytic Cycle.

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4'-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1'-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.

Development and Validation of a Self-Assessment Tool for an Integrative Model of Health Promotion in Hospitals: Taiwan's Experience.

The Health Promotion Administration of Taiwan launched an integrative certification initiative in 2016 to streamline a plural system of certifications of health promotion in hospitals. It endeavored to replace original certifications, thereby establishing the proposal of a self-assessment instrument to aid in this integration. This study aimed to verify the robustness of this self-assessment tool by conducting exploratory factor analyses through stratification, reliability tests, content and construct validity tests, and specialist evaluations, which were convened to judge the comprehensibility, applicability, and importance of the standards and measures of this tool. A stratified random sampling of 46 hospitals was performed to confirm the validity of this tool. The tool rendered a floor effect of 0% and a ceiling effect of 13%. A valid factor structure and internal consistency (α ranged from 0.88 to 0.96) in each standard were verified. Hospitals with previous certificates or with 300+ beds achieved high compliance scores. A majority of experts agreed that the sub-standards were comprehensible (≥80%), applicable (≥70%), and important (≥70%). Finally, we conclude that the self-assessment tool is valid and can serve as a reference for other countries with hospitals committed to health promotion in hospital settings.

NHI-PharmaCloud in Taiwan--A preliminary evaluation using the RE-AIM framework and lessons learned.

OBJECTIVES: The aim of this article is to present the preliminary impact of a medication monitoring program, PharmaCloud, in Taiwan and analyze the embedded factors that have contributed to the performance thereof. This article also compared PharmaCloud with similar international programs in order to draw lessons learned. METHODS: The five domains of the RE-AIM framework - reach, effectiveness, adoption, implementation, and maintenance - were examined using qualitative and quantitative data. A difference-in-differences model was applied to analyze the quantitative impact of PharmaCloud on drug utilization and drug expenses. The qualitative impact was evaluated by document analysis based on field reports from the participating medical institutions. RESULTS: Reach and adoption: although all of the major hospitals adopted PharmaCloud and some of the hospitals had high inquiry rates, more time and incentives are needed to raise the overall inquiry rate. Effectiveness: during the study period of 3 months, the number of medications per prescription declined in the intervention group was 0.15 more than that of the general population, and the drug expense per person declined in the intervention group was NT $567 (US $18.9) more than that of the general population. The potential savings could be between 2% and 5% of the total pharmaceutical expenditure. Medication duplication was found to have decreased more in the intervention group. IMPLEMENTATION: a variety of innovations in care delivery are being developed in which the pharmacists play a more significant role. Maintenance: the embedded National Health Insurance would lend strong support for PharmaCloud to grow and thrive. CONCLUSION: PharmaCloud owes its effectiveness to the embedded National Health Insurance (NHI) program, which is universal and provides a comprehensive benefit package including more than 16,000 prescription drugs. An effective medication program is one that operates under the principle of universality and comprehensiveness, facilitates innovations, and has a substantial level of interoperability with the intra-hospital health information systems.

Strengthening health promotion in hospitals with capacity building: a Taiwanese case study.

Organizational capacity building for health promotion (HP) is beneficial to the effective implementation of HP in organizational settings. The World Health Organization (WHO) Health Promoting Hospitals' (HPHs) initiative encourages hospitals to promote the health of their stakeholders by developing organizational capacity. This study analyzes an application case of one hospital of the HPH initiative in Taiwan, characterizes actions aiming at building organizational support to strengthen health gains and identifies facilitators of and barriers to the implementation of the HP in this hospital. Case study methodology was used with a triangulation of various sources; thematic analysis was used to analyze qualitative information. This study found a positive impact of the HPH initiative on the case hospital, such as more support from leadership, a fine-tuned HP mission and strategy, cultivated pro-HP habits of physical activities, a supportive intramural structure, an HP-inclusive system, improved management practices and enhanced staff participation. Transformational and transactional enablers are of equal importance in implementing HPH. However, it was also found that the case hospital encountered more transactional barriers than transformational ones. This hospital was hindered by insufficient support from external environments, leadership with limited autonomy and authority, a preference for ideals over professionalism, insufficient participation by physicians, a lack of manpower and time, a merit system with limited stimulating effect, ineffective management practices in weak central project management, a lack of integration, insufficient communication and an inability to inculcate the staff on the importance of HP, and inadequate staff participation. Several implications for other hospitals are suggested.

Self-reported changes in the implementation of hospital-based health promotion in Taiwan.

PURPOSE: To evaluate the pattern of perceived changes in the implementation of the Health Promoting Hospital (HPH) Initiative. DESIGN: This was a cross-sectional study with a self-administered questionnaire, asking the correspondents what changes they perceived before and after adopting the HPH initiative. SETTING: This study was conducted with 55 hospitals committed to the HPH in Taiwan, and 52 completed the questionnaire. SUBJECTS: One coordinator in each of the 55 hospitals served as subject. INTERVENTION: HPH seeks to improve health gains for its stakeholders by developing structure, cultures, decisions, and process conducive to health promotion. MEASURES: Perceived changes were measured in the areas of more resource inputs, changing work models, realigned implementation strategies, more programs, higher service volume, and improved quality control. Regarding realigned strategies, emphasizing the impact of healthy public policies, supportive environments, staff participation, individual knowledge and skills, and reorienting health services were measured. ANALYSIS: Descriptive analysis was used to examine the pattern of "prevalence of changes." RESULTS: Changes were more prevalent in the domains of patients and community (both with averaged ranks = 1.8); "realigning strategies" was the area in which more changes were perceived (average rank = 1). Emphases on healthy public policies and reorienting health services were the leading changes (both averaged ranks = 2.4) regarding realigning strategies. CONCLUSION: The HPH initiative appeared to be an effective approach to build organizational capacity for health promotion.

Barriers to and facilitators of the implementation of health promoting hospitals in Taiwan: a top-down movement in need of ground support.

This study investigates barriers to and facilitators of health promoting hospitals (HPH) in Taiwan. The findings are based on a cross-sectional questionnaire survey involving 55 hospitals committed to health promotion (HP) as of the end of 2009, and 52 of them completed the questionnaire. The five most reported barriers are inadequate national health insurance coverage of HP, staff detachment, incoherence of government policies, weak inter-sectoral link and resistance to change. The five most reported facilitators are support from hospital superintendents, support from unit/department directors, HP-inclusive hospital development mission and goals, funding from the government, founding of HP-related committees, resources and healthy policies. The study also found that organizational capacity building (OCB) had a significantly negative association with the number of barriers and a positive association with the number of facilitators. Stepwise linear regressions further found that OCB in structure was a significant predictor of the fewer number of barriers and that in-staff participation was a significant predictor of the more perceived facilitators. It also confirmed the significant role of organizational capacity building and that of coordinators in the effective implementation of HPH. The transformational factors as well as transactional factors are very much at work as facilitators, but the transactional factors are trapped in a less-than-friendly environment. Comprehensive support from transformational factors as well as transactional factors is essential and further support for daily routine operations and staff participation are required to sustain the implementation of HPH in Taiwan.

Achieving organizational change: findings from a case study of health promoting hospitals in Taiwan.

The Taiwanese Network of Health Promoting Hospitals (HPH) has been in place since 2006 and developing rapidly. The criticism of inadequate evaluation of the HPH approach taken elsewhere also holds true for the Taiwan HPH Network. Organizational change is a key to sustainable and effective health promotion, and it is also an important aspect in the European HPH movement. Therefore, this study aims to evaluate changes in organizational capacity for the implementation of HPH in Taiwan. All 55 HPH coordinators were invited to participate in the study, and 52 of them completed the questionnaires. The survey covered seven dimensions of HPH organizational capacity, and a total score of each dimension was calculated and converted to a figure on a scale of 10. This study has shown that HPH made a positive impact on HP hospitals in Taiwan regarding organizational change in capacity building for HPH. Leadership, organization culture and mission and strategy received the top three highest mean scores (8.19 ± 1.25, 8.08 ± 1.39, 7.99 ± 1.42), while staff participation received the lowest score (7.62 ± 1.26). The high level of organizational change was associated with the high satisfaction levels of organizational support from the viewpoint of the HPH coordinators. Based on a cluster analysis, a majority of the HP hospitals in Taiwan seemed to have adopted the addition model in putting the HPH initiative into practice; a few hospitals appeared to have accepted HPH initiative well through the integration model. These results presented evidence that HPH contributed to organizational capacity building of hospitals for health promotion.

Between professional dignity and economic interests--evidence based on a survey of Taiwan's primary care physicians.

OBJECTIVE: If the entirety of professional autonomy must be compromised in the face of a state-run social insurance, physicians may choose to preserve only certain dimensions of their professional autonomy. This study tests the relative importance of the target-income hypothesis versus the professional allegiance hypothesis in explaining physicians' behavior by collating economic interests against professional dignity. DATA AND METHOD: A self-administered questionnaire was used to collect the response data from the 1244 physicians who practiced as office-based providers under the contract with the National Health Insurance (NHI) in the South Region of Taiwan and had experienced a change in the utilization review system; 394 (31%) physicians completed the questionnaire. Chi-squared analysis, logistical ordered regression, and odds-ratio analysis were conducted to test the effects of the physicians' experience with the utilization review system on their satisfaction with the NHI program. RESULT: The ordered logistical regression verified the hypotheses of physicians' experiences on the satisfaction of the professional-controlled review system, and the odds-ratio analysis suggested that the physicians might give considerable value to their professional dignity. This effect was strong enough to balance out that of the loss in economic interests as the odds ratio was 0.5667 with the 95% confidence interval being (0.1014, 3.1682), which includes the odds ratio of 1. CONCLUSION: Economic incentives should not always take center stage if the policy makers are to co-opt physicians. The professional allegiance hypothesis is at work as strongly as the target-income hypothesis.

The health promoting hospital movement in Taiwan: recent development and gaps in workplace.

OBJECTIVE: To examine the development in healthcare workplace health promotion (WHP) in Taiwan through the Health Promoting Hospital (HPH) initiative. METHODS: A cross-sectional survey was conducted with a self-administered questionnaire, involving all 55 hospitals committed to the HPH approach (HP hospitals) as of the end of 2009; 52 completed the questionnaire. RESULTS: Fifty of 52 hospitals perceived a change in organizational capacity which mainly occurred in the areas of re-aligning strategies (96 %) and more resources (71 %). Regarding re-aligning strategies, 85 % of the hospitals engaged in increased staff participation, 66 % in staff-oriented health services. CONCLUSIONS: The HPH initiative has led to new developments in capacity building of WHP among HP hospitals in Taiwan, and this study has mapped a pattern of such developments.

Relation of polymorphisms in five genes to long-term aortocoronary saphenous vein graft patency.

Saphenous veins grafts (SVGs) continue to be used as conduits for coronary bypass surgery in nearly 350,000 patients annually in the United States. A possible genetic contribution to SVG longevity has not been well studied. We analyzed 168 single nucleotide polymorphisms from 150 candidate genes in 155 patients (2.1 SVGs/patient) followed for 10 +/- 4 years who underwent coronary angiography for clinical indications. Age at coronary bypass was 54 +/- 8 years, 61% were men, and 39% had diabetes mellitus. At the time of study entry, 76% were on statins. SVG patency (<70% diameter stenosis, no intervention), the primary study end point, was 60% at 5 years and 19% at 10 years. After adjustment for other factors associated with SVG patency (male gender, p = 0.007; low low-density lipoprotein, p = 0.016), 7 polymorphisms in 5 genes were associated with SVG patency (p <0.01). In conclusion, these data represent an initial step toward the use of a personalized genetic approach to coronary revascularization.