Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.

Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov/ ), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.

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.

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.

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.

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.

Molecular size of surfactants affects their degree of enrichment in the sea spray aerosol formation.

Sea spray aerosol (SSA), the largest source of natural primary aerosol, plays an important role in atmospheric chemical processes and the earth radiation balance. Its formation process is controlled by many factors. In this study, ethylene glycol (EG) and polyethylene glycol (PEG) with three different molecular weights (200, 400, 600) were used to investigate the influence of molecular size on the properties of submicron SSA produced by plunging jet from an adjustable home-built SSA generator. Different parameters were tested to obtain the optimum experimental conditions. The addition of EG and PEG inhibited the production of SSA and increased the geometric mean diameter (GMD) between 10 and 35 nm. However, PEG with a molecular weight of 600 could promote the production of SSA at higher concentrations, which means that the molecular weight and concentration of the polymer would affect the production efficiency of SSA. Combining with the measurement of surface tension, we found no clear relationship between surface tension and the yield of SSA, due to the properties of the substances themselves. Transmission electron microscopy images show that the addition of EG and PEG could significantly change the structure of salt nuclei in SSA. PEG was significantly enriched in SSA (with enrichment factors within the range 92.9-133.4), and the enrichment was independent of the sampling time, while increasing with the increase of molecular weight. Our results highlight the influence of polymer molecular weight on the properties of SSA, and their importance to improve the accuracy of aerosol emission model parameters.

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.

Utilization of a styrene-derived pathway for 2-phenylethanol production in budding yeast.

2-Phenylethanol (2-PE) is an important flavor ingredient and is widely applied in the fields of food, cosmetics, and pharmaceuticals. Despite that Saccharomyces cerevisiae has the ability to naturally synthesize 2-PE via the Ehrlich pathway, de novo synthesis of 2-PE in high titer still remains a huge challenge. In this study, a non-native styrene degradation pathway was introduced into S. cerevisiae, which represents the first time to demonstrate the functional expression of "styrene-derived" 2-PE synthesis in yeast. Using a host strain engineered with L-phenylalanine (L-Phe) overproduction, the heterologous 2-PE pathway coupled with endogenous Ehrlich pathway produced 233 mg/L 2-PE under shake flasks. Additionally, we further engineered the permease transporters to improve the intracellular L-Phe availability, and further improved the 2-PE titer to 680 mg/L. Taken together, our work represents one of the pioneering reports to explore "styrene-derived" pathway in S. cerevisiae. The synthetic yeast described here might be used as a platform for the future development of next-generation high-yielding 2-PE yeast strains.Key Points• A styrene-derived pathway was established in yeast for 2-phenylethanol productions; membrane-associated styrene oxide isomerase was functional in yeast.• Transporter engineering to improve the L-phenylalanine importation with enhanced 2-phenylethanol productions.

Title: Expansion of a national differentiated service delivery model to support people living with HIV and other chronic conditions in South Africa: a descriptive analysis.

BACKGROUND: South Africa is home to 7.7 million people living with HIV and supports the largest antiretroviral therapy (ART) program worldwide. Despite global investment in HIV service delivery and the parallel challenge of non-communicable diseases (NCDs), there are few examples of integrated programs addressing both HIV and NCDs through differentiated service delivery. In 2014, the National Department of Health (NDoH) of South Africa launched the Central Chronic Medicines Dispensing and Distribution (CCMDD) program to provide patients who have chronic diseases, including HIV, with alternative access to medications via community-based pick-up points. This study describes the expansion of CCMDD toward national scale. METHODS: Yale monitors CCMDD expansion as part of its mixed methods evaluation of Project Last Mile, a national technical support partner for CCMDD since 2016. From March 2016 through October 2019, cumulative weekly data on CCMDD uptake [patients enrolled, facilities registered, pick-up points contracted], type of medication provided [ART only; NCD only; and ART-NCD] and collection sites preferred by patients [external pick-up points; adherence/outreach clubs; or facility-based fast lanes], were extracted for descriptive, longitudinal analysis. RESULTS: As of October 2019, 3,436 health facilities were registered with CCMDD across 46 health districts (88 % of South Africa's districts), and 2,037 external pick-up points had been contracted by the NDoH. A total of 2,069,039 patients were actively serviced through CCMDD, a significant increase since 2018 (p < 0.001), including 76 % collecting ART [64 % ART only, 12 % ART plus NCD/comorbidities] and 479,120 [24 %] collecting medications for chronic diseases only. Further, 734,005 (35 %) of patients were collecting from contracted, external pick-up points, a 73 % increase in patient volume from 2018. DISCUSSION: This longitudinal description of CCMDD provides an example of growth of a national differentiated service delivery model that integrates management of HIV and noncommunicable diseases. This study demonstrates the success of the program in engaging patients irrespective of their chronic condition, which bodes well for the potential of the program to address the rising burden of both HIV and NCDs in South Africa. CONCLUSIONS: The CCMDD program expansion signals the potential for a differentiated service delivery strategy in resource-limited settings that can be agnostic of the patients chronic disease condition.

Health gains and financial risk protection afforded by public financing of selected malaria interventions in Ethiopia: an extended cost-effectiveness analysis.

BACKGROUND: Malaria is a public health burden and a major cause for morbidity and mortality in Ethiopia. Malaria also places a substantial financial burden on families and Ethiopia's national economy. Economic evaluations, with evidence on equity and financial risk protection (FRP), are therefore essential to support decision-making for policymakers to identify best buys amongst possible malaria interventions. The aim of this study is to estimate the expected health and FRP benefits of universal public financing of key malaria interventions in Ethiopia. METHODS: Using extended cost-effectiveness analysis (ECEA), the potential health and FRP benefits were estimated, and their distributions across socio-economic groups, of publicly financing a 10% coverage increase in artemisinin-based combination therapy (ACT), long-lasting insecticide-treated bed nets (LLIN), indoor residual spraying (IRS), and malaria vaccine (hypothetical). RESULTS: ACT, LLIN, IRS, and vaccine would avert 358, 188, 107 and 38 deaths, respectively, each year at a net government cost of $5.7, 16.5, 32.6, and 5.1 million, respectively. The annual cost of implementing IRS would be two times higher than that of the LLIN interventions, and would be the main driver of the total costs. The averted deaths would be mainly concentrated in the poorest two income quintiles. The four interventions would eliminate about $4,627,800 of private health expenditures, and the poorest income quintiles would see the greatest FRP benefits. ACT and LLINs would have the largest impact on malaria-related deaths averted and FRP benefits. CONCLUSIONS: ACT, LLIN, IRS, and vaccine interventions would bring large health and financial benefits to the poorest households in Ethiopia.

General practice for the poor and specialist services for the rich: inequality evidence from a cross-sectional survey on Hangzhou residents, China.

BACKGROUND: Inequalities in health care services are becoming an increasing concern in the world including in China. This study measured the income-related inequalities of residents in Hangzhou of China in access to general practice and specialist care and identified socioeconomic factors associated with such inequalities. METHODS: A cross-sectional questionnaire survey was conducted on 1048 residents in ten urban communities in Hangzhou, China. The percentage and frequency of respondents visiting general practice (GP) and hospital specialist clinics over the past four weeks prior to the survey were estimated. Income-related inequalities in access to these services were measured by the concentration index. Logistic regression and Poisson regression models were established to decompose the contributions of socioeconomic factors (residency, income, education, marital status, and social health insurance) to the inequalities in the probability and frequency of accessing these services, respectively, after adjustment for the needs factors (age, sex and illness conditions). RESULTS: The GP services were in favor of the poor, with a concentration index of - 0.0464 and - 0.1346 for the probability and frequency of GP visits, respectively. In contrast, the specialist services were in favor of the rich, with a concentration index of 0.1258 and 0.1279 for the probability and frequency of specialist visits, respectively. Income is the biggest contributor to the inequalities, except for the frequency of visits to specialists in which education played the greatest role. CONCLUSIONS: Income-related inequalities in GP and specialist care are evident in China. Policy interventions should pay increasing attention to the emergence of a two-tier system, potentially enlarging socioeconomic disparities in health care services.

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.

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.

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.

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.

CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression.

Circular RNAs (circRNAs) have been recognized as pivotal regulators in tumorigenesis, yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma (HCC) remain elusive. We sought to unveil the expression profile and biological role of circMYBL2 in HCC. Initial microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells, and qRT‒PCR analysis was then performed in HCC cell lines and tissues, revealing significant upregulation of circMYBL2. Subsequent experiments were conducted to evaluate the biological function of circMYBL2 in HCC progression. Furthermore, bioinformatics analysis, qRT‒PCR analysis, luciferase reporter assays, and western blot analysis were employed to investigate the interplay among circMYBL2, miR-1205, and E2F1. CircMYBL2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell lines. Elevated expression of circMYBL2 increased the proliferation and migration of HCC cells, whereas circMYBL2 knockdown elicited contrasting effects. Mechanistically, our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging miR-1205. Our findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis, suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.

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.

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.

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.