Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Contextualizing the revised Patient Perception of Patient-Centeredness (PPPC-R) scale in primary healthcare settings: a validity and reliability evaluation study.

BACKGROUND: An English version of the Patient Perception of Patient-Centeredness (PPPC) scale was recently revised, and it is necessary to test this instrument in different primary care populations. AIM: This study aimed to assess the validity and reliability of a Chinese version of the PPPC scale. DESIGN: A mixed method was used in this study. The Delphi method was used to collect qualitative and quantitative data to address the content validity of the PPPC scale by calculating the Content Validity Index, Content Validity Ratio, the adjusted Kappa, and the Item Impact Score. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were used to assess the construct validity of the PPPC scale through a cross-sectional survey. The internal consistency was also assessed. SETTING/PARTICIPANTS: In the Delphi consultation, seven experts were consulted through a questionnaire sent by email. The cross-sectional survey interviewed 188 outpatients in Guangzhou city and 108 outpatients in Hohhot City from community health service centers or stations face-to-face. RESULTS: The 21 items in the scale were relevant to their component. The Item-level Content Validity Index for each item was higher than 0.79, and the average Scale-level content validity index was 0.97 in each evaluation round. The initial proposed 4-factor CFA model did not fit adequately. Still, we found a 3-factor solution based on our EFA model and the validation via the CFA model (model fit: [Formula: see text], P < 0.001, RMSEA = 0.044, CFI = 0.981; factor loadings: 0.553 to 0.888). Cronbach's α also indicated good internal consistency reliability: The overall Cronbach's α was 0.922, and the Cronbach's α for each factor was 0.851, 0.872, and 0.717, respectively. CONCLUSIONS: The Chinese version of the PPPC scale provides a valuable tool for evaluating patient-centered medical service quality.

UCP2 promotes NSCLC proliferation and glycolysis via the mTOR/HIF-1α signaling.

BACKGROUND: Metabolic disturbance is a hallmark of cancers. Targeting key metabolic pathways and metabolism-related molecular could be a potential therapeutic approach. Uncoupling protein 2 (UCP2) plays a pivotal part in the malignancy of cancer and its capacity to develop resistance to pharmaceutical interventions. However, it is unclear about the mechanism of how UCP2 acts in the tumor growth and metabolic reprogramming process in non-small cell lung cancer (NSCLC). METHODS: Here, we conducted qRT-PCR to investigate the expression of UCP2 in both NSCLC tissues and cell lines. Subsequent functional studies including colony formation assay, CCK-8 assay, and glycolysis assay were conducted to investigate the functions of UCP2 in NSCLC. The regulatory mechanism of UCP2 toward the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1 alpha (HIF-1α) signaling in NSCLC was confirmed through western blotting. RESULTS: We observed a significant upregulation of UCP2 in both NSCLC tissues and cell lines. The increased expression of UCP2 has a strong association with a worse outlook. Silencing UCP2 remarkably dampened NSCLC cell proliferation and glycolysis capacities. Mechanically, UCP2 promoted NSCLC tumorigenesis partially via regulating the mTOR/HIF-1α axis. CONCLUSION: Taken together, we explored the functions as well as the mechanisms of the UCP2/mTOR/HIF-1α axis in NSCLC progression, uncovering potential biological signatures and targets for NSCLC treatment.

Tumor-derived Exosomal ENO2 Modulates Polarization of Tumor-associated Macrophages through Reprogramming Glycolysis to Promote Progression of Diffuse Large B-cell Lymphoma.

Macrophages can be polarized into functional classically activated (M1) or alternatively activated (M2) phenotype. Tumor-associated macrophages (TAMs) mainly exhibit M2 phenotype. Previous works determined that up-regulation of enolase 2 (ENO2) in diffuse large B-cell lymphoma (DLBCL) cells can promote macrophages to an M2-like phenotype, thereby consequently promoting the progression of DLBCL. Exosomes are a subset of extracellular vesicles, carrying various bioactive molecules, mediate signals transduction and regulate immune cells. In our study, we investigated the role and related mechanisms of DLBCL-derived exosomal ENO2 in regulating macrophage polarization during DLBCL progression via bioinformatics analysis and a series of experiments. The results of bioinformatics analysis indicated that high expression of ENO2 was positively correlated with DLBCL progression and macrophages M2/M1 ratio. ENO2 protein levels were increased in the exosomes of the sera of DLBCL patients and DLBCL cells. Moreover, the DLBCL-derived exosomes were assimilated by macrophages and then regulated macrophage polarization. The results of in vitro and in vivo experiments showed that DLBCL-derived exosomal ENO2 modulated macrophages polarization (increased M2 phenotype and decreased M1 phenotype), thereby promoting DLBCL proliferation, migration, and invasion. We then revealed that the modulation of macrophages polarization by DLBCL-derived exosomal ENO2 depended on glycolysis and was promoted through GSK3ß/ß-catenin/c-Myc signaling pathway. These findings suggested that DLBCL-derived exosomal ENO2 accelerated glycolysis via GSK3ß/ß-catenin/c-Myc signaling pathway to ultimately promote macrophages to an M2-like phenotype, which can promote the proliferation, migration and invasion of DLBCL, suggesting that exosomal ENO2 may be a promising therapeutic target and prognostic biomarker for DLBCL.

A Pragmatic Approach to Identifying and Profiling Primary Care Clinicians and Primary Care Practices in the USA.

BACKGROUND: There are no consistent data on US primary care clinicians and primary care practices owing to the lack of standard methods to identify them, hampering efforts in primary care improvement. METHODS: We develop a pragmatic framework that identifies primary care clinicians and practices in the context of the US healthcare system, and applied the framework to the IQVIA OneKey Healthcare Professional database to identify and profile primary care clinicians and practices in the USA. RESULTS: Our framework prescribes sequential steps to identify primary care clinicians by cross-examining clinician specialties and organizational affiliations, and then identify primary care practices based on organization types and presence of primary care clinicians. Applying this framework to the 2021 IQVIA data, we identified 365,751 physicians with a primary specialty in primary care, and after excluding those who further specialized (24%), served as hospitalists (5%), or worked in non-primary care settings (41%), we determined that 179,369 (49%) of them were actually practicing primary care. We identified 287,506 nurse practitioners and 134,083 physician assistants and determined that 88,574 (31%) and 29,781 (22%), respectively, were delivering primary care. We identified 94,489 primary care practices, and found that 45% of them were with one primary care physician, 15% had two physicians, 12% employed nurse practitioners or physician assistants only, and 19% employed both primary care physicians and specialists. CONCLUSIONS: Our approach offers a pragmatic and consistent alternative to the diverse methods currently used to identify and profile primary care workforce and organizations in the USA.

A novel axis of circKIF4A-miR-637-STAT3 promotes brain metastasis in triple-negative breast cancer.

Among patients with triple-negative breast cancer (TNBC), distant metastasis is the leading cause of death. Our previous studies have shown that TNBC progression is greatly facilitated by circKIF4A, but uncertainty remains regarding its role in TNBC brain metastasis and the molecular mechanism. In this study, we found notable upregulation of circKIF4A in TNBC cell lines and brain metastases. Inhibition of circKIF4A impaired the ability of TNBC to proliferate, migrate, and cause brain metastasis. Luciferase reporter assays confirmed that circKIF4A competed for binding to miR-637 with STAT3 3' UTR. Western blot analysis revealed that inhibition of circKIF4A decreased STAT3 and p62 expression, while increased the LC3B-II/LC3B-I ratio and the expression of Beclin, indicating that downregulation of circKIF4A induced autophagy by competing with STAT3 for binding to miR-637. By employing a competitive endogenous RNA (ceRNA) mechanism, the circKIF4A-miR-637-STAT3 axis coordinates brain metastasis in TNBC. circKIF4A can therefore be used as a prognostic biomarker for brain metastasis in TNBC and as a therapeutic target.

Adoption of Electronic Health Record Among Substance Use Disorder Treatment Programs: Nationwide Cross-Sectional Survey Study.

BACKGROUND: Electronic health record (EHR) systems have been shown to be associated with improvements in care processes, quality of care, and patient outcomes. EHR also has a crucial role in the delivery of substance use disorder (SUD) treatment and is considered important for addressing SUD crises, including the opioid epidemic. However, little is known about the adoption of EHR in SUD treatment programs or the organizational-level factors associated with the adoption of EHR in SUD treatment. OBJECTIVE: We examined the adoption of EHR in SUD programs, with a focus on changes in adoption from 2014 to 2017, and identified organizational-level factors associated with EHR adoption. METHODS: We used data from the 2014 and 2017 National Drug Abuse Treatment System Surveys. Our analysis included 1027 SUD programs (531 in 2014 and 496 in 2017). We used chi-square and Mann-Whitney U tests for categorical and continuous variables, respectively, to assess changes in EHR adoption, technology use, program, and client characteristics. We also investigated differences in characteristics and barriers to adoption by EHR adoption status (adopted EHR vs had not adopted or were planning to adopt EHR). We then conducted multivariate logistic regressions to examine internal and external factors associated with EHR adoption. RESULTS: The adoption of EHR increased significantly from 57.6% (306/531) in 2014 to 69.2% (343/496) in 2017 (P<.001), showing that nearly one-third (153/496, 30.8%) of SUD programs had not yet adopted an EHR system by 2017. We identified a significant increase in technology use and ownership by a parent company (P=.01 and P<.001) and a decrease in the percentage of uninsured patients in 2017 (P<.001), compared to 2014. Our analysis further showed significant differences by adoption status for three major barriers to adoption: (1) start-up costs, (2) ongoing financial costs, and (3) privacy or security concerns (P<.001). Programs that used computerized scheduling (adjusted odds ratio [AOR] 3.02, 95% CI 2.23-4.09) and billing systems (AOR 2.29, 95% CI 1.62-3.25) were more likely to adopt EHR. Similarly, ownership type, such as private nonprofit (AOR 1.86, 95% CI 1.31-2.65) and public (AOR 2.14, 95% CI 1.27-3.67), or interest in participating in a patient-centered medical home (AOR 1.93, 95% CI 1.29-2.92), were associated with an increased likelihood to adopt EHR. Overall, SUD programs were more likely to adopt an EHR system in 2017 compared to 2014 (AOR 1.44, 95% CI 1.07-1.94). CONCLUSIONS: Our findings highlighted that SUD programs may be on track to achieve widespread EHR adoption. However, there is a need for focused strategies, resources, and policies explicitly designed to systematically address barriers and tackle obstacles to expanding the adoption of EHR systems. These efforts must be holistic and address factors at multiple organizational levels.

Conditions for successful implementation of couple-based collaborative management model of diabetes among community-dwelling older Chinese: a qualitative comparative analysis.

BACKGROUND: Diabetes mellitus is a prevalent and potentially devastating chronic illness affecting many older adults. Given spousal involvement in many aspects of diabetes management, coping with their partners is increasingly seen as a potential solution to make up for limited resources. This study aimed to identify the key conditions for optimal implementation of couple-based collaborative management model (CCMM) among Chinese older couples with type 2 diabetes mellitus. METHODS: Older couples and community healthcare practitioners were selected according to couples' joint intervention attendance rate and community's average attendance rate. This mixed methods research consisted of a qualitative phase and a quantitative phase. In the qualitative phase, in-depth interviews were conducted among 12 pairs of couples in the intervention group and 4 corresponding practitioners, in the follow-up period of the multicentered RCT from January to April 2022. Qualitative comparative analysis (QCA) in the quantitative phase to identify conditions influencing CCMM's implementation and to explore necessary and sufficient combinations of conditions (i.e., solutions) for improving patients' glycated hemoglobin (HbA1c) control (outcome). RESULTS: Key conditions included implementation process, couple's role in diabetes management, their belief and perception of CCMM, as well as objective obstacles and subjective initiative for behavior change. Accordingly, major barriers in CCMM's implementation were patients' strong autonomy (particularly among husbands), misbelief and misperception about diabetes management as a result of low literacy, and mistrust of the practitioners. QCA further revealed that no single condition was necessary for effective HbA1c control, while three types of their combinations would be sufficient. Solution 1 and 2 both comprised the presence of spousal willingness to help, plus correct belief and perception of diabetes management, well embodying the utility of couple collaborative management in supporting patients' HbA1c control. On the other hand, solution 3 indicated that high-quality implementation even without spousal support, can promote the patient's subjective initiative to overcome objective obstacles, suggesting enhanced self-management for HbA1c control. CONCLUSIONS: Tailored CCMM should be implemented in reference to older couple's preferences and literacy levels, to ensure intervention fidelity, and establish correct understanding of collaborative management among them.

circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis.

Background and aim: As non-coding RNAs, circular RNAs (circRNAs) contribute to the progression of malignancies by regulating various biological processes. In prostate cancer, however, there is still a lack of understanding regarding the potential molecular pathways and roles of circRNAs. Methods: Loss-off function experiments were performed to investigate the potential biological function of circRNA in the progression of prostate cancer. Western blot, qRT-PCR, and IHC assay were used to examine the expression level of different genes or circRNAs. Further molecular biology experiments were conducted to uncover the molecular mechanism underlying circRNA in prostate cancer using dual luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: A novel circRNA (hsa_circ_0124696, named circROBO1) was identified as a significantly upregulated circRNA in both prostate cancer cells and tissues. Suppression of circROBO1 significantly attenuated the proliferation of prostate cancer cells. In addition, we found that the knockdown of circROBO1 remarkably increased the sensitivity of prostate cancer to enzalutamide treatment. A deceleration in glycolysis rate was observed after inhibition of circROBO1, which could suppress prostate cancer growth and overcome resistance to enzalutamide. Our results revealed that circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis. Conclusion: Our study identified the biological role of the circROBO1-miR-556-5p-PGK1 axis in the growth and enzalutamide resistance of prostate cancer, which is the potential therapeutic target of prostate cancer.

Enabling System Functionalities of Primary Care Practices for Team Dynamics in Transformation to Team-Based Care: A Qualitative Comparative Analysis (QCA).

Team-based primary care has been shown to be an important initiative for transforming primary care to achieve whole-person care, enhance health equity, and reduce provider burnout. Organizational approaches have been explored to better implement team-based care but a thorough understanding of the role of system functions is lacking. We aimed to identify the combinations of system functionalities in primary care practices that most enable effective teamwork. We used a novel method, qualitative comparative analysis (QCA), to identify cross-case patterns in 19 primary care practices in the Harvard Academic Innovations Collaborative (AIC), an initiative for transforming primary care practices by establishing teams and implementing team-based care. QCA findings identified that primary care practices with strong team dynamics exhibited strengths in three operational care process functionalities, including management of abnormal test results, cancer screening and medication management for high-priority patients, care transitions, and in health information technology (HIT) functionality. HIT functionality alone was not sufficient to achieve the desired outcomes. System functionalities in a primary care practice that support physicians and their teams in identifying patients with urgent and complex acute illnesses requiring immediate response and care and overcoming barriers to collaboration within and across institutional settings, may be essential for sustaining strong team-based primary care.

Transgenic soybean of GsMYB10 shapes rhizosphere microbes to promote resistance to aluminum (Al) toxicity.

Plant resistance genes could affect rhizosphere microbiota, which in turn enhanced plant resistance to stresses. Our previous study found that overexpression of the GsMYB10 gene led to enhanced tolerance of soybean plants to aluminum (Al) toxicity. However, whether GsMYB10 gene could regulate rhizosphere microbiota to mitigate Al toxicity remains unclear. Here, we analyzed the rhizosphere microbiomes of HC6 soybean (WT) and transgenic soybean (trans-GsMYB10) at three Al concentrations, and constructed three different synthetic microbial communities (SynComs), including bacterial, fungal and cross-kingdom (bacteria and fungi) SynComs to verify their role in improving Al tolerance of soybean. Trans-GsMYB10 shaped the rhizosphere microbial communities and harbored some beneficial microbes, such as Bacillus, Aspergillus and Talaromyces under Al toxicity. Fungal and cross-kingdom SynComs showed a more effective role than the bacterial one in resistance to Al stress, and these SynComs helped soybean resist Al toxicity via affecting some functional genes that involved cell wall biosynthesis and organic acid transport etc. Overall, this study reveals the mechanism of soybean functional genes regulating the synergistic resistance of rhizosphere microbiota and plants to Al toxicity, and also highlights the possibility of focusing on the rhizobial microbial community as a potential molecular breeding target to produce crops.

Copper-inducible expression system for metabolic engineering of Escherichia coli.

AIMS: The inducible expression system plays an important role in engineering Escherichia coli for chemical production. However, it still heavily relies on expensive chemical inducers, like IPTG. There is a pressing need to develop alternative expression systems with more affordable inducers. MATERIALS AND RESULTS: We herein report a copper-inducible expression system in E. coli based on the two-component Cus system and T7 RNA polymerase (RNAP). By integrating the gene encoding T7 RNAP at the CusC locus, we managed to program eGFP expression under the T7 promoter in response to different concentrations of Cu2+ (0-20 µM). Subsequently, we demonstrated that the copper-inducible expression system was suitable for the metabolic engineering of E. coli toward protocatechuic acid overproduction, and the resulting strain with combined manipulation of the central metabolism via CRISPRi produced 4.12 g L-1 PCA under the optimal copper concentration and induction time. CONCLUSIONS: We have established a copper-inducible T7 RNAP expression system in E. coli. The copper-inducible expression system could rationally control metabolic pathways in a temporal and dose-dependent manner. The gradient expression system based on copper inducer could be widely used in E. coli cell factories, and the design principle reported here would also be applicable in other prokaryotes.

Can higher spending on primary healthcare mitigate the impact of ageing and non-communicable diseases on health expenditure?

INTRODUCTION: Financing healthcare for ageing populations has become an increasingly urgent policy concern. Primary healthcare (PHC) has been viewed as the cornerstone of health systems. While most research has examined the effects of PHC on population health, there is still a relative paucity of analysis on the effects of PHC on health expenditures, particularly, in low-income and middle-income countries. Knowledge on PHC's potential role in mitigating the impact of ageing and non-communicable diseases (NCDs) on health expenditure remains limited. METHODS: Using publicly accessible secondary data at country level, this paper examines the impact of ageing and the NCD burden on health expenditures. Regression with the interaction terms is used to explore whether greater expenditures on PHC can mitigate the growing fiscal pressure from ageing and the NCD burden. RESULTS: The empirical evidence shows that a higher share of PHC spending is correlated with lower per capita non-PHC spending, after controlling for population aged 60 and over and NCD burden, and gross domestic product per capita. However, the mitigating effects of PHC spending to reduce non-PHC expenditure caused by ageing and NCDs are not significant. CONCLUSIONS: The findings suggest that more PHC spending can potentially lower total health expenditure. However, higher primary health spending cannot fulfil that potential without scrupulous attention to the way it is delivered. More spending on PHC, together with changes in PHC service delivery, highlighting its coordination and referring roles, will put nations on a pathway to achieving universal health coverage more sustainably.

Measuring Organizational Culture in Ethiopia's Primary Care System: Validation of a Practical Survey Tool for Managers.

BACKGROUND: Organizational culture has been widely recognized as predictive of health system performance and improved outcomes across various healthcare settings. Research on organizational culture in healthcare has been largely conducted in high-income settings, and validated scales to measure this concept in primary healthcare systems in low- and middle-income country (LMIC) settings are lacking. Our study aimed to validate a tool to measure organizational culture in the context of the Ethiopian Primary Healthcare Transformation Initiative (PTI), a collaborative of the Federal Ministry of Health (FMoH) and the Yale Global Health Leadership Initiative to strengthen primary healthcare system performance in Ethiopia. METHODS: Following established survey development and adaptation guidelines, we adapted a 31-item US-based organizational culture scale using (1) cognitive interviewing, (2) testing with 1176 district and zonal health officials from four regions in Ethiopia, and (3) exploratory factor analysis (EFA). RESULTS: Based on the results of cognitive interviewing, an adapted 30-item survey was piloted. The factor analyses of 1034 complete surveys (88% complete responses) identified five constructs of the scale which demonstrated strong validity and internal consistency: learning and problem solving, psychological safety, resistance to change, time for improvement, and commitment to the organization. Of the 30 a priori items, 26 items loaded well on the five constructs (loading values 0.40-0.86), and 4 items failed to load. Cronbach alpha coefficients were 0.86 for the scale as a whole and ranged from 0.65 to 0.90 for the subscales. The five-factor solution accounted for 62% of total variance in culture scores across respondents. CONCLUSION: Through validation and factor analyses, we generated a 26-item scale for measuring organizational culture in public primary healthcare systems in LMIC settings. This validated tool can be useful for managers, implementers, policy-makers, and researchers to assess and improve organizational culture in support of improved primary healthcare system performance.

Enrichment of short-chain organic acids transferred to submicron sea spray aerosols.

Organic acids, considered to be a substantial component of the marine carbon cycle, can enter the atmosphere through sea spray aerosol (SSA) and further affect the climate. Despite their importance, the distribution and mixing state of organic acids in SSA over the marine boundary layer are poorly understood and therefore need more investigation. Here, we have used ion chromatography (IC) in anion mode to measure short-chain organic acids concentrations in SSA collected throughout a custom-made SSA simulation chamber. The enrichment behavior and morphology of monocarboxylic acids (MAs, C1-8) and dicarboxylic acids (DAs) in submicron SSA were studied in seawater. We found that with MAs addition, the number concentration and mass concentration of SSA particles decreased gradually for C5-8 MAs, whereas they weakly varied with DAs addition due to the fact that carboxyl groups at both ends of DAs increased the surface tension of seawater. Moreover, the target compounds in submicron SSA displayed a surface activity-dependent enrichment behavior, where seawater with stronger surface activity, such as that containing MAs with >5 carbons, was more enriched in SSA in comparison to seawater with weaker surface activity. MAs with chain length <5 carbons were slightly enriched in SSA, whereas the enrichment factor (EF) of C5-8 MAs further increased with increasing chain length. These findings are of utmost importance in further understanding and quantifying the contribution of organic matter to SSA, which is crucial for assessing the atmosphere feedback of the marine carbon cycle. MAIN FINDING OF THE WORK: Surface tension of seawater is the key factor affecting the enrichment of short-chain organic acids in SSA.

Plants and rhizospheric environment: Affected by zinc oxide nanoparticles (ZnO NPs). A review.

Nowadays, there are many critical concerns in the agricultural sector, including reduced productivity of plants due to various environmental factors. Hence, a continuous innovation of existing technologies is necessary. Among the available technologies for sustainable agriculture, nanotechnology is one of the more promising technologies and has a great scope for development in agriculture. Zinc oxide nanoparticles (ZnO NPs) have attracted much attention due to their good properties and can be put into agriculture as nano-fertilizers, nano-growth regulators and nano-pesticides, although much remains to be explored about their mechanisms. Here, we review the literature on the interaction of ZnO NPs with plants through (i) uptake and transport pathways of ZnO NPs in plants. (ii) The mechanisms involved in improving growth, development and resistance. (iii) their effects on the rhizospheric environment. (iv) The toxic effects and mechanisms in plants. Our major conclusions are as follows: (1) they can be absorbed by the plant through the roots and leaves, with subsequent transformation. (2) moderate application can promote plant growth and mitigate stress, while excessive application can produce toxic effects. (3) the effects of them on the rhizospheric environment cannot be ignored. This study may provide a reference for the safe and effective use of ZnO NPs in agricultural production.

Exploring system features of primary care practices that promote better providers' clinical work satisfaction: A qualitative comparative analysis.

BACKGROUND: Health care delivery system features can have a profound effect on how frontline physicians and other clinical personnel in primary care practices (primary care providers [PCPs]) view the quality and safety of what they deliver and, ultimately, their clinical work satisfaction. PURPOSE: The aim of this study was to investigate the combinations of system features (i.e., team dynamics, provider-perceived safety culture, and patient care coordination between PCPs) that are most conducive to positively enhancing PCPs' clinical work satisfaction. APPROACH: Nineteen Harvard-affiliated primary care practice sites participated in the Academic Innovations Collaborative 2012-2016, which aimed to establish team-based care and improve patient safety. An All-Staff Survey was administered to 854 PCPs in 2015. The survey measured provider experience of team dynamics, provider-perceived safety culture, patient care coordination between PCPs, and providers' clinical work satisfaction. We performed a qualitative comparative analysis to identify "recipes," that is, combinations of conditions necessary and sufficient for enhancing PCPs' clinical work satisfaction. RESULTS: Strong provider-perceived safety culture and effective team dynamics constitute sufficient conditions that, when present in practices, could best support PCPs to achieve greater clinical work satisfaction. CONCLUSIONS: Our findings suggest the importance of creating and sustaining a strong safety culture and of establishing and implementing highly functioning teams in primary care practices for enhancing PCPs' clinical work satisfaction. PRACTICE IMPLICATIONS: Conducting the qualitative comparative analysis provides a new perspective for informing primary care and encouraging primary care practices to pursue strategic priorities for enhancing PCPs' clinical work satisfaction and providing safe, high-quality care.

An Analysis of Zonal Health Management Capacity and Health System Performance: Ethiopia Primary Healthcare Transformation Initiative.

BACKGROUND: District management is emerging as a lynchpin for primary healthcare system performance. However, delivery of district-level interventions at scale is challenging, and overlooks the potential role of management at other subnational levels. From 2015-2019, Ethiopia's Primary Healthcare Transformation Initiative (PTI), aimed to build a culture of performance management and accountability at the zonal level. This paper aims to evaluate the longitudinal change in management practice and performance in the 19 zones participating in PTI, which included 315 districts and 1617 health centers. METHODS: Using data from PTI intervention (2018 to 2019), we employed quantitative measures of management capacity at health center, district, and zonal levels, and quantified primary healthcare service performance using a summary score based on antenatal care coverage, contraception use, skilled birth attendance, infant immunization, and availability of essential medications. We used multiple generalized linear regression models accounting for clustering of health centers within zones to quantify (1) change in management and performance during the two-year intervention, (2) associations between the changes in management capacity at the zonal, district, and health facility level. RESULTS: Adherence to management standards at the zonal, district, and health facility level improved significantly over two years (37%, P<.001; 18%, P<.001; 18%, P<.001; respectively), as did the performance summary score (14%, P<.001). Adherence at the zonal level in year one was associated with district level adherence in year one (P=.04), and, over the two-year period (P=.002), and district management mediated the relationship between management practice at zonal and health center levels (P<.001). CONCLUSION: Improvements in zonal-level management practice were associated with significant improvements in district-level management and performance in PTI sites. Investments in managerial practices at the zonal level may provide an immediate way to energize primary healthcare system performance at scale in low-income country settings.

Engineering a Synthetic Pathway for Tyrosol Synthesis in Escherichia coli.

Tyrosol is an aromatic compound with great value that is widely used in the food and pharmaceutical industry. In this study, we reported a synthetic pathway for converting p-coumaric acid (p-CA) into tyrosol in Escherichia coli. We found that the enzyme cascade comprising ferulic acid decarboxylase (FDC1) from Saccharomyces cerevisiae, styrene monooxygenase (SMO), styrene oxide isomerase (SOI) from Pseudomonas putida, and phenylacetaldehyde reductase (PAR) from Solanum lycopersicum could efficiently synthesize tyrosol from p-CA with a conversion rate over 90%. To further expand the range of substrates, we also introduced tyrosine ammonia-lyase (TAL) from Flavobacterium johnsoniae to connect the synthetic pathway with the endogenous l-tyrosine metabolism. We found that tyrosol could be efficiently produced from glycerol, reaching 545.51 mg/L tyrosol in a tyrosine-overproducing strain under shake flasks. In summary, we have established alternative routes for tyrosol synthesis from p-CA (a potential lignin-derived biomass), glucose, and glycerol.

District-Level Health Management and Health System Performance: The Ethiopia Primary Healthcare Transformation Initiative.

BACKGROUND: Despite a wide range of interventions to improve district health management capacity in low-income settings, evidence of the impact of these investments on system-wide management capacity and primary healthcare systems performance is limited. To address this gap, we conducted a longitudinal study of the 36 rural districts (woredas), including 229 health centers, participating in the Primary Healthcare Transformation Initiative (PTI) in Ethiopia. METHODS: Between 2015 and 2017, we collected quantitative measures of management capacity at the district and health center levels and a primary healthcare key performance indicator (KPI) summary score based on antenatal care (ANC) coverage, contraception use, skilled birth attendance, infant immunization, and availability of essential medications. We conducted repeated measures analysis of variance (ANOVA) to assess (1) changes in management capacities at the district health office level and health center level, (2) changes in health systems performance, and (3) the differential effects of more vs less intensive intervention models. RESULTS: Adherence to management standards at both district and health center levels improved during the intervention, and the most prominent improvement was achieved during district managers' exposure to intensive mentorship and education. We did not observe similar patterns of change in KPI summary score. CONCLUSION: The district health office is a valuable entry point for primary healthcare reform, and district- and facility-level management capacity can be measured and improved in a relatively short period of time. A combination of intensive mentorship and structured team-based education can serve as both an accelerator for change and a mechanism to inform broader reform efforts.