Medicaid Eligibility Loss Among Dual-Eligible Beneficiaries Before and During COVID-19 Public Health Emergency.

Importance: Medicaid coverage loss can substantially compromise access to and affordability of health care for dual-eligible beneficiaries. The extent to which this population lost Medicaid coverage before and during the COVID-19 public health emergency (PHE) and the characteristics of beneficiaries more at risk for coverage loss are currently not well known. Objective: To assess the loss of Medicaid coverage among dual-eligible beneficiaries before and during the first year of the PHE, and to examine beneficiary-level and plan-level factors associated with heightened likelihood of losing Medicaid. Design, Setting, and Participants: This repeated cross-sectional study used national Medicare data to estimate annual rates of Medicaid loss among dual-eligible beneficiaries before (2015 to 2019) and during the PHE (2020). Individuals who were dual eligible for Medicare and Medicaid at the beginning of a given year and who continuously received low-income subsidies for Medicare Part D prescription drug coverage were included in the sample. Multivariable regression models were used to examine beneficiary-level and plan-level factors associated with Medicaid loss. Data analyses were conducted between March 2023 and October 2023. Exposure: Onset of PHE. Main Outcomes and Measures: Loss of Medicaid for at least 1 month within a year. Results: Sample included 56 172 736 dual-eligible beneficiary-years between 2015 and 2020. In 2020, most dual-eligible beneficiaries were aged over 65 years (5 984 420 [61.1%]), female (5 868 866 [59.9%]), non-Hispanic White (4 928 035 [50.3%]), full-benefit eligible (6 837 815 [69.8%]), and enrolled in traditional Medicare (5 343 537 [54.6%]). The adjusted proportion of dual-eligible beneficiaries losing Medicaid for at least 1 month increased from 6.6% in 2015 to 7.3% in 2019 and then dropped to 2.3% in 2020. Between 2015 and 2019, dual-eligible beneficiaries who were older (ages 55-64 years: -1.4%; 95% CI, -1.8% to -1.0%; ages 65-74 years: -2.0%; 95% CI, -2.5% to -1.5%; ages 75 and older: -4.5%; 95% CI, -5.0% to -4.0%), disabled (-0.8%; 95% CI, -1.1% to -0.6%), and in integrated care programs were less likely to lose Medicaid. In 2020, the disparities within each of these demographic groups narrowed significantly. Notably, while Black (0.6%; 95% CI, 0.2% to 0.9%) and Hispanic (0.7%; 95% CI, 0.3% to 1.2%) dual-eligible beneficiaries were more likely to lose Medicaid than their non-Hispanic White counterparts between 2015 and 2019, such gap was eliminated for Black beneficiaries and narrowed for Hispanic beneficiaries in 2020. Conclusions and Relevance: During the PHE, Medicaid coverage loss declined significantly among dual-eligible beneficiaries, and disparities were mitigated across subgroups. As the PHE unwinds, it is crucial for policymakers to implement strategies to minimize Medicaid coverage disruptions and racial and ethnic disparities, especially given that loss of Medicaid was slightly increasing over time before the PHE.

Microbial and metabolic profiles unveil mutualistic microbe-microbe interaction in obesity-related colorectal cancer.

Obesity is a risk factor for colorectal cancer (CRC), and the involvement of gut microbiota in the pathogenesis of obesity and CRC is widely recognized. However, the landscape of fecal microbiome and metabolome distinguishing patients with obesity-related CRC from obesity remains unknown. Here, we utilize metagenomic sequencing and metabolomics from 522 patients with CRC and healthy controls to identify the characteristics of obese CRC. Our integrated analysis reveals that obesity-related CRC is characterized by elevated Peptostreptococcus stomatis, dysregulated fatty acids and phospholipids, and altered Kyoto Encyclopedia of Genes and Genomes pathways involving glycerophospholipid metabolism and lipopolysaccharide synthesis. Correlation analysis unveils microbial interactions in obesity, where the probiotic Faecalibacterium prausnitzii and the tumor-promoting species P. stomatis may engage in cross-feeding, thereby promoting tumorigenesis. In vitro experiments affirm enhanced growth under cross-feeding conditions. The mutualistic microbe-microbe interaction may contribute to the association between obesity and elevated CRC risk. Additionally, diagnostic models incorporating BMI-specific microbial biomarkers display promise for precise CRC screening.

Preferences for risks and benefits of treatment outcomes for chronic low back pain: Choice-based conjoint measure development and discrete choice experiment.

INTRODUCTION: Understanding individual patient preferences for chronic low back pain (cLBP) outcomes is essential for targeting available therapeutic options; yet tools to elicit patient outcome preferences are limited. OBJECTIVE: To develop and test a choice-based conjoint (CBC) measure, commonly used in behavioral economics research, to elicit what outcomes patients with cLBP want to achieve and avoid. DESIGN: We developed a survey-based CBC measure to allow patients to make risk/benefit trade-off choices between possible treatment outcomes. After extensive literature, clinician, and patient input, our measure included seven attributes: fatigue, anxiety/depression, difficulty thinking/making decisions, pain intensity, physical abilities, change in pain, and ability to enjoy life despite pain. Random-parameters logit models were used to estimate strength of preferences, and latent class analysis was used to identify patient characteristics associated with distinct preference. SETTING: Online study using the Sawtooth web-based platform. PARTICIPANTS: Two hundred eleven individuals with cLBP recruited from online advertising as well as at clinical sites across multiple academic and private institutions. INTERVENTIONS: Not applicable. RESULTS: The most valued outcome was the highest level of physical activity (ß = 1.6-1.98; p < .001), followed by avoiding cognitive difficulties (ß = -1.48; p < .001). Avoidance of severe pain was comparable to avoiding constant fatigue and near-constant depression/anxiety (ß = -0.99, -1.02); p < .001). There was an association between preferences and current pain/disability status; patients with higher pain had a stronger preference to avoid severe pain, whereas those with higher disability have stronger preferences for achieving physical activity. The latent class analysis identified two distinct groups: (1) more risk-seeking and willing to accept worse outcomes (56%); and (2) more risk-averse with a stronger preference for achieving maximum benefits (44%). CONCLUSIONS: Our study illuminated cLBP patient preferences for treatment outcomes and heterogeneity in these preferences. Patients stressed the importance of reaching high physical activity and avoiding cognitive declines, even over a desire to avoid pain. More work is needed to understand patient preferences to aid informed, shared decisions.

CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression.

BACKGROUND: UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear. METHODS: Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses. RESULTS: Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression. CONCLUSIONS: In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.

Shuangshen Ningxin capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy: network pharmacology and experiments in vivo.

BACKGROUND: Myocardial ischemia/reperfusion injury (MI/RI) is involved in a variety of pathological states for which there is no effective treatment exists. Shuangshen Ningxin (SSNX) capsule which is developed by Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine has been demonstrated to alleviate MI/RI, but its mechanism remains to be further elucidated. METHODS: The MI/RI miniature pigs model was constructed to assess the pharmacodynamics of SSNX by blocking the proximal blood flow of the left anterior descending branch of the cardiac coronary artery through an interventional balloon. The principal chemical compounds and potential targets of SSNX were screened by HPLC-MS and SwissTargetPrediction. The targets of MI/RI were identified based on Online Mendelian Inheritance in Man (OMIM) and GeneCards. Cytoscape 3.9.0 was applied to construct a protein-protein interaction (PPI) network, and Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using metascape. To further validate the mechanism of SSNX, Molecular docking, Transmission electron microscopy, and Western blot analysis were used to test the effectiveness of targets in related pathways. RESULTS: Our results indicated that SSNX significantly improved cardiac function, attenuated myocardial I/R injury. Through network analysis, a total of 15 active components and 201 targets were obtained from SSNX, 75 of which are potential targets for the treatment of MI/RI. KEGG and MCODE analysis showed that SSNX is involved in the mitophagy signaling pathway, and ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb2 are key components associated with the mitophagy. Further experimental results proved that SSNX protected mitochondrial structure and function, and significantly reduced the expression of mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1), Parkin, FUN14 domain containing 1 (FUNDC1) and Bcl-2/E1B-19 kDa interacting protein 3 (BNIP3) in MI/RI miniature pigs. CONCLUSION: In our study, the integration of network pharmacology and experiments in vivo demonstrated that SSNX interfered with MI/RI by inhibiting mitophagy.

Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers.

BACKGROUND: Accumulating evidence has indicated the role of gut microbiota in remodeling host immune signatures, but various interplays underlying colorectal cancers (CRC) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) remain poorly understood. This study aims to decipher the gut microbiome-host immune interactions between dMMR and pMMR CRC. METHOD: We performed metagenomic sequencing and metabolomic analysis of fecal samples from a cohort encompassing 455 participants, including 21 dMMR CRC, 207 pMMR CRC, and 227 healthy controls. Among them, 50 tumor samples collected from 5 dMMR CRC and 45 pMMR CRC were conducted bulk RNA sequencing. RESULTS: Pronounced microbiota and metabolic heterogeneity were identified with 211 dMMR-enriched species, such as Fusobacterium nucleatum and Akkermansia muciniphila, 2 dMMR-depleted species, such as Flavonifractor plautii, 13 dMMR-enriched metabolites, such as retinoic acid, and 77 dMMR-depleted metabolites, such as lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid. F. plautii was enriched in pMMR CRC and it was positively associated with fatty acid degradation, which might account for the accumulation of dMMR-depleted metabolites classified as short chain organic acid (lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid) in pMMR CRC. The microbial-metabolic association analysis revealed the characterization of pMMR CRC as the accumulation of lactate induced by the depletion of specific gut microbiota which was negatively associated with antitumor immune, whereas the nucleotide metabolism and peptide degradation mediated by dMMR-enriched species characterized dMMR CRC. MMR-specific metabolic landscapes were related to distinctive immune features, such as CD8+ T cells, dendritic cells and M2-like macrophages. CONCLUSIONS: Our mutiomics results delineate a heterogeneous landscape of microbiome-host immune interactions within dMMR and pMMR CRC from aspects of bacterial communities, metabolic features, and correlation with immunocyte compartment, which infers the underlying mechanism of heterogeneous immune responses.

Rapid Enrollment Growth In 'Look-Alike' Dual-Eligible Special Needs Plans: A Threat To Integrated Care.

Policy makers are increasingly investing in efforts to better integrate Medicare and Medicaid services for people who are eligible for both programs, including expanding Dual-Eligible Special Needs Plans (D-SNPs). In recent years, however, a potential threat to integration has emerged in the form of D-SNP "look-alike" plans, which are conventional Medicare Advantage plans that are marketed toward and primarily enroll dual eligibles but are not subject to federal regulations requiring integrated Medicaid services. To date, limited evidence exists documenting national enrollment trends in look-alike plans or the characteristics of dual eligibles in these plans. We found that look-alike plans experienced rapid enrollment growth among dual eligibles during the period 2013-20, increasing from 20,900 dual eligibles across four states to 220,860 dual eligibles across seventeen states, for an elevenfold increase. Nearly one-third of dual eligibles in look-alike plans were previously in integrated care programs. Compared with D-SNPs, look-alike plans were more likely to enroll dual eligibles who were older, Hispanic, and from disadvantaged communities. Our findings suggest that look-alike plans have the potential to compromise national efforts to integrate care delivery for dual eligibles, including vulnerable subgroups who may benefit the most from integrated coverage.

Decoding the microbiome: advances in genetic manipulation for gut bacteria.

Studies of the gut microbiota have revealed associations between specific bacterial species or community compositions with health and disease, yet the causal mechanisms underlying microbiota gene-host interactions remain poorly understood. This is partly due to limited genetic manipulation (GM) tools for gut bacteria. Here, we review current advances and challenges in the development of GM approaches, including clustered regularly interspaced short palindromic repeats (CRISPR)-Cas and transposase-based systems in either model or non-model gut bacteria. By overcoming barriers to 'taming' the gut microbiome, GM tools allow molecular understanding of host-microbiome associations and accelerate microbiome engineering for clinical treatment of cancer and metabolic disorders. Finally, we provide perspectives on the future development of GM for gut microbiome species, where more effort should be placed on assembling a generalized GM pipeline to accelerate the application of groundbreaking GM tools in non-model gut bacteria towards both basic understanding and clinical translation.

Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.

CAPER: patient preferences to inform nonsurgical treatment of chronic low back pain: a discrete-choice experiment.

OBJECTIVE: We developed and used a discrete-choice measure to study patient preferences with regard to the risks and benefits of nonsurgical treatments when they are making treatment selections for chronic low back pain. METHODS: "CAPER TREATMENT" (Leslie Wilson) was developed with standard choice-based conjoint procedures (discrete-choice methodology that mimics an individual's decision-making process). After expert input and pilot testing, our final measure had 7 attributes (chance of pain relief, duration of relief, physical activity changes, treatment method, treatment type, treatment time burden, and risks of treatment) with 3-4 levels each. Using Sawtooth software (Sawtooth Software, Inc., Provo, UT, USA), we created a random, full-profile, balanced-overlap experimental design. Respondents (n = 211) were recruited via an emailed online link and completed 14 choice-based conjoint choice pairs; 2 fixed questions; and demographic, clinical, and quality-of-life questions. Analysis was performed with random-parameters multinomial logit with 1000 Halton draws. RESULTS: Patients cared most about the chance of pain relief, followed closely by improving physical activity, even more than duration of pain relief. There was comparatively less concern about time commitment and risks. Gender and socioeconomic status influenced preferences, especially with relation to strength of expectations for outcomes. Patients experiencing a low level of pain (Pain, Enjoyment, and General Activity Scale [PEG], question 1, numeric rating scale score<4) had a stronger desire for maximally improved physical activity, whereas those in a high level of pain (PEG, question 1, numeric rating scale score>6) preferred both maximum and more limited activity. Highly disabled patients (Oswestry Disability Index score>40) demonstrated distinctly different preferences, placing more weight on achieving pain control and less on improving physical activity. CONCLUSIONS: Individuals with chronic low back pain were willing to trade risks and inconveniences for better pain control and physical activity. Additionally, different preference phenotypes exist, which suggests a need for clinicians to target treatments to particular patients.

Dysbiosis of the stool DNA and RNA virome in Crohn's disease.

Pathogenesis of Crohn's disease (CD) relates to gut microbiome dysbiosis. However, less is known about the viral microbiome, consisting of bacteriophages and eukaryotic viruses, in CD. Here, we profiled the stool virome, viral functions, and viral-bacterial correlations that involved in CD pathogenesis. Metagenomics and metaviromics with novel viral identification and data analysis workflow were performed on stool of non-CD household controls, CD flare and remission patients. Both bacteriome and DNA/RNA virome alterations were characterized and correlated with disease status. There was a decreased diversity and extreme heterogeneity in both DNA and RNA virome in CD. We observed CD-specific dysbiosis in virome, particularly the prominent DNA eukaryotic Torque teno virus (TTV), disease-associated Faecalibacterium phage and Escherichia phage, and RNA tomato diet-related virus in CD, while some diverse prokaryotic viruses were more abundant in healthy subjects. Compared with the remission, inflammation-associated eukaryotic TTV and prokaryotic Staphylococcus phages were predominated in the flare, and displayed a link with complications and multiple therapeutic approaches. Multiple viral functions, particularly functions of viral DNA replication, integration and modification as well as the eukaryotic TTV-related capsid protein, were markedly enriched in CD. Furthermore, the virus-bacteria interactions became more specialized in CD, and the combination of bacteriome and virome composition provided better classification between CD and health. Our study presents a global view of the comprehensive viral component change in the CD patients' gut microbiome, and highlights the great potential of virome biomarkers in pathogenesis and accurate diagnostics of CD risk and disease status.

Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer.

OBJECTIVE: The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC. DESIGN: We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. RESULTS: Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome-metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls. CONCLUSION: Our large-sample multiomics data suggest that altered microbiome-metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

Applications of human organoids in the personalized treatment for digestive diseases.

Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

State Mandatory Paid Sick Leave Associated With A Decline In Emergency Department Use In The US, 2011-19.

Paid sick leave provides workers with job-protected paid time off to address short-term illnesses or seek preventive care for themselves and their family members. We studied the impact of mandatory paid sick leave at the state level on emergency department (ED) visit rates, using all-payer, longitudinal ED data from the Healthcare Cost and Utilization Project for the period 2011-19. We found that state implementation of paid sick leave mandates was associated with a 5.6 percent reduction in the total ED visit rate relative to the baseline, equivalent to 23 fewer visits per 1,000 population per year. The reduction was concentrated in Medicaid patients. Some of the largest reductions were ED visits related to adult dental conditions, adult mental health or substance use disorders, and pediatric asthma. Mandatory paid sick leave may be an effective policy lever to reduce excess ED use and costs.

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism.

BACKGROUND: Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. METHODS: The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid ß-oxidation. RESULTS: PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild-type mice, PTPRO-knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl-CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

Preferences for Risks and Benefits of Islet Cell Transplantation for Persons With Type 1 Diabetes With History of Episodes of Severe Hypoglycemia: A Discrete-Choice Experiment to Inform Regulatory Decisions.

BACKGROUND: The advisory panel for US Food and Drug Administration (FDA) recently endorsed pancreatic islet cell transplantation (ICT) therapy for suboptimally controlled type 1 diabetes (T1D), and FDA approval is under consideration. An important part of regulatory approval includes the patient perspective, through discrete choice. We developed a discrete-choice instrument and used it to determine how 90 people with T1D weigh the risks and benefits of ICT to inform regulatory decisions. METHODS: Sawtooth software created a random, full-profile, balanced-overlap experimental design for a measure with 8 attributes of ICT risks/benefits, each with 3 to 5 levels. We asked 18 random task pairs, sociodemographics, diabetes management, and hypoglycemia questions. Analysis was performed using random parameters logistic regression technique. RESULTS: The strongest preference was for avoiding the highest chance (15%) of serious procedure-related complications (ß = -2.03, P < 0.001). The strongest positive preference was for gaining 5-y insulin independence (ß = 1.75, P < 0.001). The desire for 5-y HbA1C-defined clinical treatment success was also strong (ß = 1.39, P < 0.001). Subgroup analysis suggested strong gender differences with women showing much higher preferences for all benefits (68% higher for 5-y insulin independence), and men were generally more risk averse than women. Those with high versus low diabetes distress showed 3 times stronger preference for 5-y insulin independence but also twice preference to avoid risks of serious complications. CONCLUSIONS: Despite showing the most preference for avoiding serious ICT complications, people with T1D had a strong preference for achieving ICT benefits, especially insulin independence. We identified important attributes of ICT and demonstrated that patients are willing to make these trade-offs, showing support for the introduction of ICT.

Effects of the Affordable Care Act Medicaid Expansion on the Compensation of New Primary Care Physicians.

BACKGROUND: It is well-documented that the Affordable Care Act Medicaid expansion increased health care utilization by low-income Americans. Emerging studies also found that the expansion changed the geographical distribution of new physicians. However, the effect of the expansion on physician compensation has not been studied. OBJECTIVES: We aimed to assess how the Medicaid expansion affected the compensation of new primary care physicians (PCPs) and whether the effect differed by specialty, gender, and geography. RESEARCH DESIGN: We used a quasiexperimental difference-in-differences design to assess changes in compensation for new PCPs from before to after the Medicaid expansion in states that expanded Medicaid compared with states that did not expand. SUBJECTS: Our study included 2003 new PCPs who responded to the Survey of Residents Completing Training in New York between 2009 and 2018. MEASURES: Our primary outcome was respondents' self-reported starting salary for their first year of practice. Our secondary outcomes were respondents' self-reported additional anticipated income and incentives they received for accepting the job offer. RESULTS: We found that starting salaries for new PCPs, especially new general internists and family physicians, grew faster in expansion states than in nonexpansion states. In addition, we found that the expansion was associated with a statistically significant increase in receiving additional anticipated income as part of the compensation package for new PCPs practicing in rural areas.

The Affordable Care Act Medicaid Expansion, Social Disadvantage, and the Practice Location Choices of New General Internists.

BACKGROUND: A recent study found that states that expanded Medicaid under the Affordable Care Act (ACA) gained new general internists who were establishing their first practices, whereas nonexpansion states lost them. OBJECTIVE: The objective of this study was to examine the level of social disadvantage of the areas of expansion states that gained new physicians and the areas of nonexpansion states that lost them. RESEARCH DESIGN: We used American Community Survey data to classify commuting zones as high, medium, or low social disadvantage. Using 2009-2019 data from the AMA Physician Masterfile and information on states' Medicaid expansion status, we estimated conditional logit models to compare where new physicians located during the 6 years following the expansion to where they located during the 5 years preceding the expansion. SUBJECTS: A total of 32,102 new general internists. RESULTS: Compared with preexpansion patterns, new general internists were more likely to locate in expansion states after the expansion, a finding that held for high, medium, and low disadvantage areas. We estimated that, between 2014 and 2019, nonexpansion states lost 371 new general internists (95% confidence interval, 203-540) to expansion states. However, 62.5% of the physicians lost by nonexpansion states were lost from high disadvantage areas even though these areas only accounted for 17.9% of the population of nonexpansion states. CONCLUSIONS: States that opted not to expand Medicaid lost new general internists to expansion states. A highly disproportionate share of the physicians lost by nonexpansion states were lost from high disadvantage areas, potentially compromising access for all residents irrespective of insurance coverage.

Dysbiosis of human gut microbiome in young-onset colorectal cancer.

The incidence of sporadic young-onset colorectal cancer (yCRC) is increasing. A significant knowledge gap exists in the gut microbiota and its diagnostic value for yCRC patients. Through 16S rRNA gene sequencing, 728 samples are collected to identify microbial markers, and an independent cohort of 310 samples is used to validate the results. Furthermore, species-level and functional analysis are performed by metagenome sequencing using 200 samples. Gut microbial diversity is increased in yCRC. Flavonifractor plautii is an important bacterial species in yCRC, while genus Streptococcus contains the key phylotype in the old-onset colorectal cancer. Functional analysis reveals that yCRC has unique characteristics of bacterial metabolism characterized by the dominance of DNA binding and RNA-dependent DNA biosynthetic process. The random forest classifier model achieves a powerful classification potential. This study highlights the potential of the gut microbiota biomarkers as a promising non-invasive tool for the accurate detection and distinction of individuals with yCRC.

Fusobacterium Nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling.

Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial-mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. SIGNIFICANCE: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13-EpOME axis in Fn-infected patients.