PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.

Cost-Effectiveness Analysis of Digital Breast Tomosynthesis and Mammography in Breast Cancer Screening: A Markov Modeling Study.

BACKGROUND: Mammography (MG) has demonstrated its effectiveness in diminishing mortality and advanced-stage breast cancer incidences in breast screening initiatives. Notably, research has accentuated the superior diagnostic efficacy and cost-effectiveness of digital breast tomosynthesis (DBT). However, the scope of evidence validating the cost-effectiveness of DBT remains limited, prompting a requisite for more comprehensive investigation. The present study aimed to rigorously evaluate the cost-effectiveness of DBT plus MG (DBT-MG) compared to MG alone within the framework of Taiwan's National Health Insurance program. METHODS: All parameters for the Markov decision tree model, encompassing event probabilities, costs, and utilities (quality-adjusted life years, QALYs), were sourced from reputable literature, expert opinions, and official records. With 10,000 iterations, a 2-year cycle length, a 30-year time horizon, and a 2% annual discount rate, the analysis determined the incremental cost-effectiveness ratio (ICER) to compare the cost-effectiveness of the two screening methods. Probabilistic and one-way sensitivity analyses were also conducted to demonstrate the robustness of findings. RESULTS: The ICER of DBT-MG compared to MG was US$5971.5764/QALYs. At a willingness-to-pay (WTP) threshold of US$33,004 (Gross Domestic Product of Taiwan in 2021) per QALY, more than 98% of the probabilistic simulations favored adopting DBT-MG versus MG. The one-way sensitivity analysis also shows that the ICER depended heavily on recall rates, biopsy rates, and positive predictive value (PPV2). CONCLUSION: DBT-MG shows enhanced diagnostic efficacy, potentially diminishing recall costs. While exhibiting a higher biopsy rate, DBT-MG aids in the detection of early-stage breast cancers, reduces recall rates, and exhibits notably superior cost-effectiveness.

The combination of physical activity with fruit and vegetable intake associated with life satisfaction among middle-aged and older adults: a 16-year population-based cohort study.

BACKGROUND: Life satisfaction (LS) is part of a positive psychological feeling that protects individuals from a physical decline in old age. A healthy lifestyle, including physical activity (PA) and a healthy diet, such as the intake of fruits and vegetables (F&V), can lead to a better experience of LS in older adults. However, the association between PA and F&V intake habits when occurring together in older adults is still unclear for LS. The study aimed to investigate the combined association of PA and F&V intake on LS among a cohort of older Taiwanese adults. METHODS: Five waves of population-based data gathered by the Taiwan Longitudinal Survey on Aging between 1999 and 2015 were analyzed. The year 1999 was set as the baseline, and the number of respondents was 4,440. The independent variables included the frequency, duration, and intensity of PA and the frequency of F&V intake. LS was assessed by using the Life Satisfaction Index. We performed generalized estimating equations (GEE) analysis with adjustment for covariates of health behaviors and health indicators. RESULTS: After adjusting for confounders, model 1 showed that moderate and high-PA levels significantly correlated with LS (odds ratio [OR] = 1.41, 95% CI = 1.12-1.79) and OR = 1.74, 95% CI = 1.50-2.02). Moreover, high-F&V intake significantly correlated with LS (OR = 2.07, 95% CI = 1.69-2.53). Regarding the combined association shown in model 2, compared with both the low PA and F&V intake group, there were significantly higher LS in the both-high-group (OR = 4.69, 95% CI = 3.49-6.31), only-high-F&V intake (OR = 2.87, 95% CI = 2.14-3.85), only-high-PA (OR = 2.48, 95% CI = 1.74-3.52). CONCLUSIONS: Our findings show the significant combined association of PA and F&V intake on LS among older adults. In addition, older adults who engaged in higher frequency, duration, and intensity of daily PA combined more than seven times a week of F&V intake had significantly higher LS than those who only engaged in low PA or only intake less F&V. Adopting multiple healthy behaviors in daily life is a safe and effective approach to promote LS among older adults.

Lipid metabolism in the immune niche of tumor-prone liver microenvironment.

The liver is a common primary site not only for tumorigenesis, but also for cancer metastasis. Advanced cancer patients with liver metastases also show reduced response rates and survival benefits when treated with immune checkpoint inhibitors. Accumulating evidence has highlighted the importance of the liver immune microenvironment in determining tumorigenesis, metastasis-organotropism, and immunotherapy resistance. Various immune cells such as T cells, natural killer and natural killer T cells, macrophages and dendritic cells, and stromal cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes are implicated in contributing to the immune niche of tumor-prone liver microenvironment. In parallel, as the major organ for lipid metabolism, the increased abundance of lipids and their metabolites is linked to processes crucial for nonalcoholic fatty liver disease and related liver cancer development. Furthermore, the proliferation, differentiation, and functions of hepatic immune and stromal cells are also reported to be regulated by lipid metabolism. Therefore, targeting lipid metabolism may hold great potential to reprogram the immunosuppressive liver microenvironment and synergistically enhance the immunotherapy efficacy in the circumstance of liver metastasis. In this review, we describe how the hepatic microenvironment adapts to the lipid metabolic alterations in pathologic conditions like nonalcoholic fatty liver disease. We also illustrate how these immunometabolic alterations promote the development of liver cancers and immunotherapy resistance. Finally, we discuss the current therapeutic options and hypothetic combination immunotherapies for the treatment of advanced liver cancers.

Simulation of vertical dispersion and pollution impact of artificial light at night in urban environment.

The use of artificial light at night (ALAN) enables social and commercial activities for urban living. However, the excessive usage of lighting causes nuisance and waste of energy. Light is provided to illuminate target areas on the street level where activities take place, yet light can also cause trespass to residents at the floors above. While regulations are beginning to cover light design, simulation tools for the outdoor environment have also become more popular for assessing the design condition. Simulation tools allow visualisation of the impact of the selected light sources on those who are affected. However, this cause-and-effect relationship is not easy to determine in the complex urban environment. The current work offers a simple methodology that takes site survey results and correlates them with the simulation model to determine lighting impact on the investigated area in 3D. Four buildings in two mixed commercial and residential streets in Hong Kong were studied. Data collection from each residential building requires lengthy work and permission from each household. Therefore, a valid lighting simulation model could help determine the light pollution impact in the area. A light model using DIALux is developed and calibrated by correlating the simulated data with the actual measured data. The correlation value R2 achieved ranged from 0.95 to 0.99, verifying the accuracy of this model and matched from 340 lx to 46 lx for the lower to higher floors of one building and 10 lx to 4 lx for floors of another building. This model can also be applied to human health research, by providing light-level data on residential windows in an area or determining the environmental impact of a development project.

Effect of Hand Hygiene Intervention in Community Kindergartens: A Quasi-Experimental Study.

This study aimed to evaluate the effect of hand hygiene interventions on the overall hand hygiene (HH) status of teaching instruction of hand hygiene in kindergartens, given the vulnerability of kindergarten children and their high risk due to infectious diseases and the current COVID-19 epidemic. We investigated the HH status of teachers from two kindergartens in the same community. The participants were recruited from 28 classes in both kindergartens. After completing the baseline survey, the intervention program consisted of three components: lectures on infectious diseases, lectures on HH, and seven-step hand washing techniques conducted in two kindergartens. The intervention program effectively increased teachers' perceived disease susceptibility (p < 0.05), reduced the total bacterial colonization of children's hands (p < 0.001), and improved the HH environment (p < 0.01). We recommend that health authorities or kindergartens adopt this HH intervention program to effectively improve the HH status in kindergartens and allow for preventive responses to the COVID-19 epidemic or other emerging infectious diseases.

Bioaugmentation of Methanosarcina thermophila grown on biochar particles during semi-continuous thermophilic food waste anaerobic digestion under two different bioaugmentation regimes.

This study presents the effect of bioaugmentation of thermophilic anaerobic digestion of food waste with Methanosarcina thermophila grown on a wood-derived biochar. Two different supplementation regimes were tested, namely a single bioaugmentation (SBABC) in which 10% v/v of the microbes grown on biochar (1 g/L) is added at setup of the reactors, versus a routine bioaugmentation (RBABC) wherein the same amount of supplements were added over 10 feeding cycles. The optimally performing 'R' and 'S' reactors had increased methane yields by 37% and 32% over their respective controls while reactors SBABC 2 and 3 produced 21.89% and 56.09% higher average methane yield than RBABC 2 and 3, respectively. It appears that a single dose bioaugmentation is advantageous for improving AD as analysed in terms of average methane yield and VFA production. This study provides the basis for understanding how biochar and bioaugmentation can be used for engineering sustainable pilot-scale AD processes.

The combined effect of physical activity and fruit and vegetable intake on decreasing cognitive decline in older Taiwanese adults.

The factors associated with cognitive decline among older adults include physical activity and fruit and vegetable intake. However, the long-term effects of concomitant physical activity and fruit and vegetable intake are unknown. This 16-year longitudinal study explored the joint effect of mitigating cognitive decline in a cohort of older Taiwanese individuals. Five population-based surveys (Taiwan Longitudinal Survey on Aging [1999-2015]) involving 4440 respondents over 53 years old in 1999 were conducted. Cognitive function was assessed using the Short Portable Mental Status Questionnaire (SPMSQ). The demographic, socioeconomic, health-related, behavioral, and disease status covariates were adjusted in the regression analysis. Trends in cognitive decline were observed over 16 years. The risk of cognitive decline decreased by 63% when high physical activity and high fruit and vegetable intake were combined (odds ratio 0.37; 95% confidence interval 0.23-0.59), indicating a potential combined effect of physical activity and fruit and vegetable intake on mitigating cognitive decline. These personal actions are safe, effective, and economical approaches to health promotion and disease prevention.

A Proposed Multi-Criteria Optimization Approach to Enhance Clinical Outcomes Evaluation for Diabetes Care: A Commentary.

There are several challenges in diabetes care management including optimizing the currently used therapies, educating patients on selfmanagement, and improving patient lifestyle and systematic healthcare barriers. The purpose of performing a systems approach to implementation science aided by artificial intelligence techniques in diabetes care is two-fold: 1) to explicate the systems approach to formulate predictive analytics that will simultaneously consider multiple input and output variables to generate an ideal decision-making solution for an optimal outcome; and 2) to incorporate contextual and ecological variations in practicing diabetes care coupled with specific health educational interventions as exogenous variables in prediction. A similar taxonomy of modeling approaches proposed by Brennon et al (2006) is formulated to examining the determinants of diabetes care outcomes in program evaluation. The discipline-free methods used in implementation science research, applied to efficiency and quality-of-care analysis are presented. Finally, we illustrate a logically formulated predictive analytics with efficiency and quality criteria included for evaluation of behavioralchange intervention programs, with the time effect included, in diabetes care and research.

Assessing Patient Safety Culture in United States Hospitals.

A positive patient safety culture plays a major role in reducing medical errors and increasing productivity among healthcare staff. Furthermore, understanding staff perceptions of patient safety culture and effective patient safety factors is a first step toward enhancing quality of care and patient safety. The objectives of this study were to assess patient safety culture in hospitals in the United States and to investigate the effects of hospital and respondent characteristics on perceived patient safety culture. An analysis of 67,010 respondents in the 2018 Agency for Healthcare Research and Quality (AHRQ) comparative database was conducted with partial least squares structural equation modeling (PLS-SEM). The results revealed that perceptions of patient safety culture had a positive influence on the overall perceptions of patient safety and frequency of event reporting. Moreover, staff position, teaching status, and geographic region were found to have varying influence on the patient safety culture, overall perceptions of patient safety, and frequency of event reporting.

Predictive Analytics for the KMAP-O Model in Design and Evaluation of Diabetes Care Management Research.

This is a commentary on methodological challenges and analytical requirements in designing an evaluation of the knowledge, motivation, attitude, preventive practice-outcome (KMAP-O) model for selfcare management of diabetes. Critical issues pertaining to an investigation of the dose-response relationship between the intervention program and outcomes, the comparative effectiveness evaluation, and the lengths of observation were noted. Although numerous publications on factors influencing diabetes care and control were systematically reviewed and documented in the literature, scientific results on artificial intelligence research remain to be uncovered. To optimizing the knowledge and clinical practice in selfcare management, specific methodological approaches to predictive analytics are suggested for future clinical studies, using a comprehensive behavioral system such as the KMAP-O model.

Inherent Bias in Artificial Intelligence-Based Decision Support Systems for Healthcare.

The objective of this article is to discuss the inherent bias involved with artificial intelligence-based decision support systems for healthcare. In this article, the authors describe some relevant work published in this area. A proposed overview of solutions is also presented. The authors believe that the information presented in this article will enhance the readers' understanding of this inherent bias and add to the discussion on this topic. Finally, the authors discuss an overview of the need to implement transdisciplinary solutions that can be used to mitigate this bias.

ER Use among Older Adult RHC Medicare Beneficiaries in the Southeastern United States.

PURPOSE: This study analyzed individual factors of race and dual eligibility on emergency room (ER) utilization of older adult Medicare patients treated by RHCs in CMS Region 4. METHODOLOGY/APPROACH: A prospective, longitudinal design was employed to analyze health disparities that potentially exist among RHC Medicare beneficiary patients (+65) in terms of ER use. The years of investigation were 2010 through 2012, using mixed multilevel, binary logistic regression. FINDINGS: This study found that dual eligible RHC patients utilized ER services at higher rates than non-dual eligible, Medicare only RHC patients at: 77%, 80%, and 66%, in 2010, 2011, and 2012, respectively; and above the White reference group, Black RHC Medicare patients utilized ER services at higher rates of: 18%, 20%, and 34%, in 2010, 2011, and 2012, respectively. RESEARCH LIMITATIONS/IMPLICATIONS: Regarding limitations, cohort data observations within the window of 3 years were only analyzed; regarding generalizability, in different CMS regions, results will likely vary; and linking other variables together in the study was limited by the accessible data. Future research should consider these limitations, and attempt to refine. The findings support that dual Medicare and Medicaid eligibility, as a proxy measure of socio-economic status, and race continue to influence higher rates of ER utilization in CMS Region 4. ORIGINALITY/VALUE: In terms of ER utilization disparities, persistently, as recent as 2012, Black, dual eligible RHC Medicare beneficiary patients age 65 and over may be twice as likely to utilize ER services for care than their counterparts in the Southeastern United States.

Emotional Labor in Health Care: The Moderating Roles of Personality and the Mediating Role of Sleep on Job Performance and Satisfaction.

The objective of this study is to investigate the effects of emotional labor on job performance and satisfaction, as well as to examine the mediating effect of sleep problems and the moderating effects of personality traits. A time-lagged study was conducted on 864 health professionals. Scales for emotional labor, sleep, personality traits, and job satisfaction were used and job performance data was obtained from records maintained by human resources. Structural equation modeling was performed to investigate the relations. Sleep problems only partially mediated the relationship between surface acting and job satisfaction but completely mediated the relationship between surface acting and job performance. Several personality traits were shown to moderate the relationship between surface acting and sleep problems. The effects were stronger for people with low agreeableness and high neuroticism. The relationship between high levels of deep acting and low levels of sleep problems was more pronounced in individuals with low extraversion. Supervisors should be conscious of emotional labor in the work context and provide necessary deep acting training to facilitate emotional regulation.

A Longitudinal Analysis of Total Pain Scores for a Panel of Patients Treated by Pain Clinics.

BACKGROUND: There is a critical necessity to identify psychometric properties of the total pain score as a measurement of pain management effectiveness in the clinic. PURPOSE: In this article, we perform the analysis of the global pain scores from a panel of patients treated by 10 pain management physicians in a single group practice. BASIC PROCEDURES: The pain measurement consists of 4 pain subscales, namely physical pain, emotions, clinical outcome, and activities. A panel of 130 patients with 4 pain measurements is available to perform longitudinal analysis of the total pain scores. The analysis includes the following: (1) confirmatory factor analysis of the global pain scores with 4 related dimensions, (2) the stability of the pain scores between 2 clinical visits, (3) the change trajectories of pain scores in 4 waves of the pain measurement, and (4) the detection of physician variability in patients' treatment outcomes measured by the reduction of total pain scores. MAIN FINDINGS: The global pain scores were relatively stable between time 1 and time 2 clinical visits. The analysis indicated that there was a decrease in pain with longitudinal advancement in treatment. It also indicated that there was no significant change in this improvement with respect to difference in physicians involved in providing treatment. PRINCIPAL CONCLUSION: While the results indicated a decrease in pain with an alleviation in treatment provided to the patient, the article delineates a well-thought scientific approach to the targeted problem.

Factors Influencing Variations in Hospitalization for Diabetes with Hypoglycemia.

Many studies have explored risk factors associated with Hypoglycemia (HG) and examined the variation in healthcare utilization among HG patients. However, most of these studies failed to integrate a comprehensive list of personal risk factors in their investigations. This empirical study employed the Behavioral Model (BM) of health care utilization as a framework to investigate diabetes' hospitalizations with HG. The national inpatient sample with all non-pregnant adult patients admitted to hospitals' emergency departments and diagnosed with HG from 2012 to 2014 was used. Personal factors were grouped as predictors of the length of stay and the total charges incurred for hospitalization. High-risk profiles of hospitalized HG patients were identified. The analysis shows the need for care factors are the most influential predictors for lengthy hospitalization. The predisposing factors have a limited influence, while enabling factors influence the variation in hospital total charges. The presence of renal disease and diabetes mellitus (DM) complications played a key role in predicting hospital utilization. Furthermore, age, socio-economic status (SES), and the geographical location of the patients were also found to be vital factors in determining the variability in utilization among HG patients. Findings provide practical applications for targeting the high-risk HG patients for interventions.

Challenges in implementing mHealth interventions: a technical perspective.

Over the years, the healthcare community has witnessed many improvements in methods and technologies used in healthcare delivery, including mHealth as an emerging area of healthcare applications to improve access to health services. However, challenges involved in implementing mHealth to optimal advantage do exist. In this article, we identify some of the most important challenges and propose feasible solutions.

KMAP-O framework for care management research of patients with type 2 diabetes.

AIM: To review impacts of interventions involving self-management education, health coaching, and motivational interviewing for type 2 diabetes. METHODS: A thorough review of the scientific literature on diabetes care and management was executed by a research team. RESULTS: This article summarizes important findings in regard to the validity of developing a comprehensive behavioral system as a framework for empirical investigation. The behavioral system framework consists of patients' knowledge (K), motivation (M), attitude (A), and practice (P) as predictor variables for diabetes care outcomes (O). Care management strategies or health education programs serve as the intervention variable that directly influences K, M, A, and P and then indirectly affects the variability in patient care outcomes of patients with type 2 diabetes. CONCLUSION: This review contributes to the understanding of the KMAP-O framework and how it can guide the care management of patients with type 2 diabetes. It will allow the tailoring of interventions to be more effective through knowledge enhancement, increased motivation, attitudinal changes, and improved preventive practice to reduce the progression of type 2 diabetes and comorbidities. Furthermore, the use of health information technology for enhancing changes in KMAP and communications is advocated in health promotion and development.

Strategies to Modify the Risk of Heart Failure Readmission: A Systematic Review and Meta-Analysis.

BACKGROUND: Human factors play an important role in health-care outcomes of heart failure (HF) patients. A systematic review and meta-analysis of clinical trial studies on HF hospitalization may yield positive proofs of the beneficial effect of specific care management strategies. PURPOSE: To investigate how the 8 guiding principles of choice, rest, environment, activity, trust, interpersonal relationships, outlook, and nutrition reduce HF readmissions. BASIC PROCEDURES: Appropriate keywords were identified related to the (1) independent variable of hospitalization and treatment, (2) the moderating variable of care management principles, (3) the dependent variable of readmission, and (4) the disease of HF to conduct searches in 9 databases. Databases searched included CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ERIC, MEDLINE, PubMed, PsycInfo, Science Direct, and Web of Science. Only prospective studies associated with HF hospitalization and readmissions, published in English, Chinese, Spanish, and German journals between January 1, 1990, and August 31, 2015, were included in the systematic review. In the meta-analysis, data were collected from studies that measured HF readmission for individual patients. MAIN FINDINGS: The results indicate that an intervention involving any human factor principles may nearly double an individual's probability of not being readmitted. Participants in interventions that incorporated single or combined principles were 1.4 to 6.8 times less likely to be readmitted. PRINCIPAL CONCLUSIONS: Interventions with human factor principles reduce readmissions among HF patients. Overall, this review may help reconfigure the design, implementation, and evaluation of clinical practice for reducing HF readmissions in the future.

Variations in Influenza and Pneumonia Immunizations for Medicare Beneficiaries Served by Rural Health Clinics.

The availability of a rural health clinic (RHC) database over the period of 6 years (2008-2013) offers a unique opportunity to examine the trends and patterns of disparities in immunization for influenza and pneumonia among Medicare beneficiaries in the southeastern states. The purpose of this exploratory study was twofold. First, it examined the rural trends and patterns of immunization rates before (2008-2009) and after (2010-2013) the Affordable Care Act (ACA) enactment by state and year. Second, it investigated how contextual, organizational, and aggregate patient characteristics may influence the variations in immunization for influenza and pneumonia of Medicare beneficiaries served by RHCs. Four data sources from federal agencies were merged to perform a longitudinal analysis of the influences of contextual, organizational, and aggregate patient characteristics on the disparities in immunization rates of rural Medicare beneficiaries for influenza and pneumonia. We included both time-varying and time-constant predictors in a multivariate analysis using Generalized Estimating Equation. This study revealed the increased immunization rates for both influenza and pneumonia over a period of 6 years. The ACA had a positive effect on increased immunization rates for pneumonia, but not for influenza, in rural Medicare beneficiaries in the eight states. The RHCs that served more dually-eligible patients had higher immunization rates. For influenza immunization, provider-based RHCs had a higher rate than the independent RHCs. For pneumonia immunization, no organizational variables were relevant in the explanation of the variability. The results also showed that no single dominant factor influenced health care disparities. This investigation suggested further improvements in preventive care are needed to target poor and isolated rural beneficiaries. Furthermore, the integration of immunization data from multiple sources is critically needed for understanding health disparities.