Active Property-Structure Integrated Reconfiguration of Individual Resonant Nanoparticles.

Property-structure reconfigurable nanoparticles (NPs) provide additional flexibility for effectively and flexibly manipulating light at the nanoscale. This has facilitated the development of various multifunctional and high-performance nanophotonic devices. Resonant NPs based on dielectric active materials, especially phase change materials, are particularly promising for achieving reconfigurability. However, the on-demand control of the properties, especially the morphology, in individual dielectric resonant NP remains a significant challenge. In this study, we present an all-optical approach for one-step fabrication of Ge2Sb2Te5 (GST) hemispherical NPs, integrated active reversible phase-state switching, and morphology reshaping. Reversible optical switching is demonstrated, attributed to reversible phase-state changes, along with unidirectional modifications to their scattering intensity resulting from morphology reshaping. This novel technology allows the precise adjustment of each structural pixel without affecting the overall functionality of the switchable nanophotonic device. It is highly suitable for applications in single-pixel-addressable active optical devices, structural color displays, and information storage, among others.

Fractionated FLASH radiation in xenografted lung tumors induced FLASH effect at a split dose of 2 Gy.

PURPOSE: To explore the minimum split dose of FLASH radiotherapy (FLASH). MATERIAL AND METHODS: Lungs of nude mice were used to verify the capacity of normal tissue sparing of FLASH, while tumor-bearing nude mice were used to evaluate the curative power. Xenografted tumor models were established in Balb/c-nu mice using A549 cells at a concentration of 5×106/100 µL. With the same total dose (20 Gy), the dose rate of FLASH was 200 Gy/s when conventional radiotherapy(CONV) was 0.033 Gy/s. Two schemes of FLASH irradiations were applied: single pulse (FLASH1) and ten pulses (FLASH10). Then, according to the different tissue types and irradiation schemes, mice were divided into eight groups: Control-T, CONV-T, FLASH1-T, FLASH10-T (T for tumor) and Control-L, CONV-L, FLASH1-L, FLASH10-L (L for lung). Evaluation of FLASH effect was based on the changes in tumor volume and pathological analysis of tumor and lung tissues before and after irradiation. RESULTS: Compared to control group, the mean volume of tumors in nude mice increased slowly or decreased after irradiation with both FLASH and CONV (Control-T: 233.6±55.19 mm3, CONV-T: 146.1±50.62 mm3, FLASH1-T: 148±18.83 mm3, FLASH10-T: 119.1±50.62 mm3, p ≤ .05) . Tumor cells of irradiated groups had similar degrees of dissolution damage and inflammation, while the acute radiation pneumonia induced by FLASH was less severe. The pulmonary pathology of FLASH1-L and FLASH10-L were similar, and only a few neutrophils were observed. In addition to inflammatory cells, slight thickening of alveolar septum and obvious interstitial hemorrhage were also observed in the CONV-L group. CONCLUSION: The FLASH effect was successfully reproduced in both single and fractionated irradiation, with 2 Gy being the minimum split dose to achieve the FLASH effect in existing experiments. It is suggested that the transient oxygen depletion might not be the only mechanism behind the FLASH effect.

A Hybrid Spectral Library and Protein Sequence Database Search Strategy for Bottom-Up and Top-Down Proteomic Data Analysis.

Tandem mass spectrometry (MS/MS) is widely employed for the analysis of complex proteomic samples. While protein sequence database searching and spectral library searching are both well-established peptide identification methods, each has shortcomings. Protein sequence databases lack fragment peak intensity information, which can result in poor discrimination between correct and incorrect spectrum assignments. Spectral libraries usually contain fewer peptides than protein sequence databases, which limits the number of peptides that can be identified. Notably, few post-translationally modified peptides are represented in spectral libraries. This is because few search engines can both identify a broad spectrum of PTMs and create corresponding spectral libraries. Also, programs that generate spectral libraries using deep learning approaches are not yet able to accurately predict spectra for the vast majority of PTMs. Here, we address these limitations through use of a hybrid search strategy that combines protein sequence database and spectral library searches to improve identification success rates and sensitivity. This software uses Global PTM Discovery (G-PTM-D) to produce spectral libraries for a wide variety of different PTMs. These features, along with a new spectrum annotation and visualization tool, have been integrated into the freely available and open-source search engine MetaMorpheus.

Diagnostic Value of Carcinoembryonic Antigen Combined with Multi-Inflammatory Cell Ratios in Colorectal Cancer.

Purpose: To evaluate the diagnostic value of carcinoembryonic antigen (CEA) combined with inflammatory cell ratios in colorectal cancer (CRC). Methods: This retrospective study compared the data of CRC patients with healthy controls. The CEA levels were measured, and the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated. The receiver-operating characteristic (ROC) curve was used to assess the diagnostic value of each marker and combined detection. Spearman's rank correlation test was used to analyze the correlation between CEA and NLR, d-NLR, and PLR. Results: Inflammatory cell ratios and CEA were significantly higher in the CRC group. ROC curve analysis showed that NLR, d-NLR, and PLR had good diagnostic efficacy. The threshold showed that NLR, d-NLR, and PLR were all related to TNM stage, not to age, gender, tumor location, and degree of differentiation. CEA combined with NLR, d-NLR, and PLR (CNDNP) had a significant diagnostic value in CRC. Correlation studies showed that CEA was positively correlated with NLR and d-NLR but not with PLR. Conclusion: The combination of CEA with CNDNP might be a valuable indicator for CRC diagnosis.

Carbon nanotube filter functionalized with MIL-101(Fe) for enhanced flow-through electro-Fenton.

Herein, an electrochemical carbon nanotubes (CNT) filter modified with MIL-101(Fe) has been designed for the electro-Fenton applications by serving as a functional flow-through electrode. Under an electric field, the hybrid filter enabled the in situ generation of H2O2via the two-electron oxygen reduction reaction, which promoted the production of HO by the accelerated Fe2+/Fe3+ cycling of MIL-101(Fe). It was observed that 93.2 ± 1.2% tetracycline and 69.0 ± 0.8% total organic carbon (TOC) were removed in 2 h under the optimized conditions. The electron paramagnetic resonance (EPR) analysis and radical scavenging experiments revealed that HO predominated the tetracycline degradation. As compared to the batch reactor, the performance of the proposed system was improved by 5.6 times owing to the convection-enhanced mass transport. The plausible working mechanism and degradation pathway were also subsequently proposed. The findings reported in this study provide a promising insight for the environmental remediation by integrating nanotechnology and Fenton chemistry.

Trends in Recurrent Coronary Heart Disease After Myocardial Infarction Among US Women and Men Between 2008 and 2017.

BACKGROUND: Rates for recurrent coronary heart disease (CHD) events have declined in the United States. However, few studies have assessed whether this decline has been similar among women and men. METHODS: Data were used from 770 408 US women and 700 477 US men <65 years of age with commercial health insurance through MarketScan and ≥66 years of age with government health insurance through Medicare who had a myocardial infarction (MI) hospitalization between 2008 and 2017. Women and men were followed up for recurrent MI, recurrent CHD events (ie, recurrent MI or coronary revascularization), heart failure hospitalization, and all-cause mortality (Medicare only) in the 365 days after MI. RESULTS: From 2008 to 2017, age-standardized recurrent MI rates per 1000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men (multivariable-adjusted P interaction by sex <0.001). Recurrent CHD event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men (P interaction <0.001). Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men (P interaction=0.001). All-cause mortality rates decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men (P interaction=0.82). In 2017, the multivariable-adjusted rate ratios comparing women with men were 0.90 (95% CI, 0.86-0.93) for recurrent MI, 0.80 (95% CI, 0.78-0.82) for recurrent CHD events, 0.99 (95% CI, 0.96-1.01) for heart failure hospitalization, and 0.82 (95% CI, 0.80-0.83) for all-cause mortality. CONCLUSIONS: Rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high, and rates of recurrent MI, recurrent CHD events, and death continue to be higher among men than women.

Adaptive support ventilation attenuates postpneumonectomy acute lung injury in a porcine model.

OBJECTIVES: An optimal ventilation strategy that causes as little mechanical stress and inflammation as possible is critical for patients undergoing pneumonectomy. The aim of this study was to determine whether adaptive support ventilation (ASV) can provide protective ventilation to the remaining lung after pneumonectomy with minimal mechanical stress and less inflammation than volume-control ventilation (VCV). METHODS: In this study, 15 pigs were randomly allocated to 3 groups (n = 5 for each group): the control group, the VCV group and the ASV group. After left pneumonectomy, the VCV group was treated with the volume-control set to 20 ml/kg, and the ASV group with the mode set to achieve 60% of the minute ventilation of 2 lungs. RESULTS: The ASV group had lower alveolar strain than the VCV group. The ASV group exhibited less lung injury and greater alveolar fluid clearance than the VCV group (13.3% vs -17.8%; P ≤ 0.018). Ventilator-induced lung injury was associated with changes in the cytokine levels in the exhaled breath condensate, differential changes in plasma and changes in the cytokines in the bronchoalveolar lavage fluid. Expression of 3 microRNAs (miR449b-3p, P ≤ 0.001; miR451-5p, P = 0.027; and miR144-5p, P = 0.008) was increased in the VCV group compared with the ASV group. CONCLUSIONS: The ASV mode was capable of supporting rapid, shallow breathing patterns to exert lung-protective effects in a porcine postpneumonectomy model. Further investigation of microRNAs as biomarkers of ventilator-induced lung injury is warranted.

Atherosclerotic Risk and Statin Use Among Patients With Peripheral Artery Disease.

BACKGROUND: Peripheral artery disease (PAD) is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD) events. OBJECTIVES: The goal of this study was to compare the risk for ASCVD events and the use of statins among patients with PAD versus those with coronary heart disease (CHD) or cerebrovascular disease. METHODS: The authors conducted a retrospective cohort study of adults age ≥19 years with commercial or Medicare health insurance who had a history of PAD, CHD, or cerebrovascular disease on December 31, 2014. Patients were followed for ASCVD events comprising CHD, cerebrovascular disease, and PAD events until December 31, 2017. RESULTS: Among 943,232 patients included in the analysis, the age-standardized ASCVD event rate per 1,000 person-years for those with a history of 1, 2, and 3 conditions including PAD, CHD, and cerebrovascular disease was 40.8 (95% confidence interval [CI]: 40.3 to 41.3), 68.9 (95% CI: 67.9 to 70.0), and 119.5 (95% CI: 117.0 to 122.0), respectively. The ASCVD event rate among patients with PAD only, CHD only, and cerebrovascular disease only was 34.7 (95% CI: 33.2 to 36.2), 42.2 (95% CI: 41.5 to 42.8), and 38.9 (95% CI: 37.6 to 40.1), respectively. Among patients with PAD and CHD, with PAD and cerebrovascular disease, and with CHD and cerebrovascular disease, the ASCVD event rate was 72.8 (95% CI: 71.0 to 74.7), 63.9 (95% CI: 60.6 to 67.4), and 67.9 (95% CI: 66.4 to 69.3), respectively. Statin use was lower in patients with PAD only (33.9%) versus those with cerebrovascular disease only (43.0%) or CHD only (51.7%). CONCLUSIONS: Despite having high risk for ASCVD events, patients with PAD were less likely to be taking a statin versus those with CHD or cerebrovascular disease. ASCVD risk-reduction interventions including statin therapy in patients with PAD are warranted.

Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia.

A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.

Agreement of claims-based methods for identifying sepsis with clinical criteria in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Claims-based algorithms are commonly used to identify sepsis in health services research because the laboratory features required to define clinical criteria may not be available in administrative data. METHODS: We evaluated claims-based sepsis algorithms among adults in the US aged ≥65 years with Medicare health insurance enrolled in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Suspected infections from baseline (2003-2007) through December 31, 2012 were analyzed. Two claims-based algorithms were evaluated: (1) infection plus organ dysfunction diagnoses or sepsis diagnoses (Medicare-Implicit/Explicit) and (2) Centers for Medicare and Medicaid Services Severe Sepsis/Septic Shock Measure diagnoses (Medicare-CMS). Three classifications based on clinical criteria were used as standards for comparison: (1) the sepsis-related organ failure assessment (SOFA) score (REGARDS-SOFA), (2) "quick" SOFA (REGARDS-qSOFA), and (3) Centers for Disease Control and Prevention electronic health record criteria (REGARDS-EHR). RESULTS: There were 2217 suspected infections among 9522 participants included in the current study. The total number of suspected infections classified as sepsis was 468 for Medicare-Implicit/Explicit, 249 for Medicare-CMS, 541 for REGARDS-SOFA, 185 for REGARDS-qSOFA, and 331 for REGARDS-EHR. The overall agreement between Medicare-Implicit/Explicit and REGARDS-SOFA, REGARDS-qSOFA, and REGARDS-EHR was 77, 79, and 81%, respectively, sensitivity was 46, 53, and 57%, and specificity was 87, 82, and 85%. Comparing Medicare-CMS and REGARDS-SOFA, REGARDS-qSOFA, and REGARDS-EHR, agreement was 77, 87, and 85%, respectively, sensitivity was 27, 41, and 36%, and specificity was 94, 92, and 93%. Events meeting the REGARDS-SOFA classification had a lower 90-day mortality rate (140.7 per 100 person-years) compared with the Medicare-CMS (296.1 per 100 person-years), REGARDS-qSOFA (238.6 per 100 person-years), Medicare-Implicit/Explicit (219.4 per 100 person-years), and REGARDS-EHR classifications (201.8 per 100 person-years). CONCLUSION: Claims-based sepsis algorithms have high agreement and specificity but low sensitivity when compared with clinical criteria. Both claims-based algorithms identified a patient population with similar 90-day mortality rates as compared with classifications based on qSOFA and EHR criteria but higher mortality relative to SOFA criteria.

Adaptive Support Ventilation Attenuates Ventilator Induced Lung Injury: Human and Animal Study.

Adaptive support ventilation (ASV) is a closed-loop ventilation, which can make automatic adjustments in tidal volume (VT) and respiratory rate based on the minimal work of breathing. The purpose of this research was to study whether ASV can provide a protective ventilation pattern to decrease the risk of ventilator-induced lung injury in patients of acute respiratory distress syndrome (ARDS). In the clinical study, 15 ARDS patients were randomly allocated to an ASV group or a pressure-control ventilation (PCV) group. There was no significant difference in the mortality rate and respiratory parameters between these two groups, suggesting the feasible use of ASV in ARDS. In animal experiments of 18 piglets, the ASV group had a lower alveolar strain compared with the volume-control ventilation (VCV) group. The ASV group exhibited less lung injury and greater alveolar fluid clearance compared with the VCV group. Tissue analysis showed lower expression of matrix metalloproteinase 9 and higher expression of claudin-4 and occludin in the ASV group than in the VCV group. In conclusion, the ASV mode is capable of providing ventilation pattern fitting into the lung-protecting strategy; this study suggests that ASV mode may effectively reduce the risk or severity of ventilator-associated lung injury in animal models.

The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation.

The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.

Association of Region and Hospital and Patient Characteristics With Use of High-Intensity Statins After Myocardial Infarction Among Medicare Beneficiaries.

Importance: High-intensity statin use after myocardial infarction (MI) varies by patient characteristics, but little is known about differences in use by hospital or region. Objective: To explore the relative strength of associations of region and hospital and patient characteristics with high-intensity statin use after MI. Design, Setting, and Participants: This retrospective cohort analysis used Medicare administrative claims and enrollment data to evaluate fee-for-service Medicare beneficiaries 66 years or older who were hospitalized for MI from January 1, 2011, through June 30, 2015, with a statin prescription claim within 30 days of discharge. Data were analyzed from January 4, 2017, through May 12, 2019. Exposures: Beneficiary characteristics were abstracted from Medicare data. Hospital characteristics were obtained from the 2014 American Hospital Association Survey and Hospital Compare quality metrics. Nine regions were defined according to the US Census. Main Outcomes and Measures: Intensity of the first statin claim after discharge characterized as high (atorvastatin calcium, 40-80 mg, or rosuvastatin calcium, 20-40 mg/d) vs low to moderate (all other statin types and doses). Trends in high-intensity statins were examined from 2011 through 2015. Associations of region and beneficiary and hospital characteristics with high-intensity statin use from January 1, 2014, to June 15, 2015, were examined using Poisson distribution mixed models. Results: Among the 139 643 fee-for-service beneficiaries included (69 968 men [50.1%] and 69 675 women [49.9%]; mean [SD] age, 76.7 [7.5] years), high-intensity statin use overall increased from 23.4% in 2011 to 55.6% in 2015, but treatment gaps persisted across regions. In models considering region and beneficiary and hospital characteristics, region was the strongest correlate of high-intensity statin use, with 66% higher use in New England than in the West South Central region (risk ratio [RR], 1.66; 95% CI, 1.47-1.87). Hospital size of at least 500 beds (RR, 1.15; 95% CI, 1.07-1.23), medical school affiliation (RR, 1.11; 95% CI, 1.05-1.17), male sex (RR, 1.10; 95% CI, 1.07-1.13), and patient receipt of a stent (RR, 1.35; 95% CI, 1.31-1.39) were associated with greater high-intensity statin use. For-profit hospital ownership, patient age older than 75 years, prior coronary disease, and other comorbidities were associated with lower use. Conclusions and Relevance: This study's findings suggest that geographic region is the strongest correlate of high-intensity statin use after MI, leading to large treatment disparities.

Adherence to Statin Therapy Among US Adults Between 2007 and 2014.

Background Prior studies suggest that persistence with and adherence to statin therapy is low. Interventions to improve statin persistence and adherence have been developed over the past decade. Methods and Results This was a retrospective cohort study of adults aged ≥21 y with commercial or government health insurance in the MarketScan (Truven Health Analytics) and Medicare databases who initiated statins in 2007-2014 and (1) started treatment after a myocardial infarction (n=201 573), (2) had diabetes mellitus but without coronary heart disease (CHD; n=610 049), or (3) did not have CHD or diabetes mellitus (n=2 244 868). Persistence with (ie, not discontinuing treatment) and high adherence to statin therapy were assessed using pharmacy fills in the year following treatment initiation. In 2007 and 2014, the proportions of patients persistent with statin therapy were 78.1% and 79.1%, respectively, among those initiating treatment following myocardial infarction; 66.5% and 67.3%, respectively, for those with diabetes mellitus but without CHD; and 64.3% and 63.9%, respectively, for those without CHD or diabetes mellitus. Between 2007 and 2014, high adherence to statin therapy increased from 57.9% to 63.8% among patients initiating treatment following myocardial infarction and from 34.9% to 37.6% among those with diabetes mellitus but without CHD (each Ptrend<0.001). Among patients without CHD or diabetes mellitus, high adherence did not improve between 2007 (35.7%) and 2014 (36.8%; Ptrend=0.14). In 2014, statin adherence was lower among younger, black, and Hispanic patients versus white patients and those initiating a high-intensity statin dosage. Statin adherence was higher among men and patients with cardiologist care following treatment initiation. Conclusions Persistence with and adherence to statin therapy remain low, particularly among those without CHD.

Validation of the REGARDS Severe Sepsis Risk Score.

There are no validated systems for characterizing long-term risk of severe sepsis in community-dwelling adults. We tested the ability of the REasons for Geographic and Racial Differences in Stroke-Severe Sepsis Risk Score (REGARDS-SSRS) to predict 10-year severe sepsis risk in separate cohorts of community-dwelling adults. We internally tested the REGARDS-SSRS on the REGARDS-Medicare subcohort. We then externally validated the REGARDS-SSRS using (1) the Cardiovascular Health Study (CHS) and (2) the Atherosclerosis Risk in Communities (ARIC) cohorts. Participants included community-dwelling adults: REGARDS-Medicare, age ≥65 years, n = 9522; CHS, age ≥65 years, n = 5888; ARIC, age 45⁻64 years, n = 11,584. The primary exposure was 10-year severe sepsis risk, predicted by the REGARDS-SSRS from participant sociodemographics, health behaviors, chronic medical conditions and select biomarkers. The primary outcome was first severe sepsis hospitalizations, defined as the concurrent presence of ICD-9 discharge diagnoses for a serious infection and organ dysfunction. Median SSRS in the cohorts were: REGARDS-Medicare 11 points (IQR 7⁻16), CHS 10 (IQR 6⁻15), ARIC 7 (IQR 5⁻10). Severe sepsis incidence rates were: REGARDS-Medicare 30.7 per 1000 person-years (95% CI: 29.2⁻32.2); CHS 11.9 (10.9⁻12.9); ARIC 6.8 (6.3⁻7.3). SSRS discrimination for first severe sepsis events were: REGARDS-Medicare C-statistic 0.704 (95% CI: 0.691⁻0.718), CHS 0.696 (0.675⁻0.716), ARIC 0.697 (0.677⁻0.716). The REGARDS-SRSS may potentially play a role in identifying community-dwelling adults at high severe sepsis risk.

Regulation of the terminal maturation of iNKT cells by mediator complex subunit 23.

Invariant natural killer T cells (iNKT cells) are a specific subset of T cells that recognize glycolipid antigens and upon activation rapidly exert effector functions. This unique function is established during iNKT cell development; the detailed mechanisms of this process, however, remain to be elucidated. Here the authors show that deletion of the mediator subunit Med23 in CD4+CD8+ double positive (DP) thymocytes completely blocks iNKT cell development at stage 2. This dysregulation is accompanied by a bias in the expression of genes related to the regulation of transcription and metabolism, and functional impairment of the cells including the loss of NK cell characteristics, reduced ability to secrete cytokines and attenuated recruitment capacity upon activation. Moreover, Med23-deficient iNKT cells exhibit impaired anti-tumor activity. Our study identifies Med23 as an essential transcriptional regulator that controls iNKT cell differentiation and terminal maturation.

Med23 serves as a gatekeeper of the myeloid potential of hematopoietic stem cells.

In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23-deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physiological stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.

Titration to High-Intensity Statin Therapy Following Acute Myocardial Infarction in Patients With and Without Diabetes Mellitus.

BACKGROUND: Patients with diabetes mellitus (DM) have a high risk for cardiovascular disease (CVD) events after an acute myocardial infarction (AMI). High-intensity statins reduce CVD risk following AMI among patients with and without DM. METHODS: We determined the proportion of Medicare beneficiaries 66 to 75 years of age taking a low/moderate-intensity statin with (n = 6718) and without (n = 6414) DM who titrated to a high-intensity statin dosage (i.e., atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) following an AMI hospitalization in 2014-2015. All patients had a pharmacy claim for a statin fill within 365 days prior to, and within 30 days after their AMI hospitalization. We excluded beneficiaries without Medicare fee-for-service coverage including pharmacy benefits during the study period and those with a pharmacy claim for a high-intensity statin prior to their AMI. RESULTS: The first statin fill following hospital discharge was for a high-intensity dosage among 37.7% and 44.4% of patients with and without DM, respectively. After multivariable adjustment, the risk ratio (RR) for titrating to a high-intensity statin comparing patients with versus without DM was 1.01 (95% CI 0.96, 1.06). Among patients whose first statin fill post-AMI was for a low/moderate-intensity dosage, 7.5% of those with DM titrated to a high-intensity statin within 182 days, compared with 9.2% of those without DM (multivariable-adjusted RR 0.90 [95% CI 0.75, 1.08]). CONCLUSIONS: Most patients taking a low/moderate-intensity statin were not titrated to a high-intensity dosage following AMI irrespective of their diabetes status, potentially leaving substantial residual risk for recurrent CVD events.

Sex Differences in High-Intensity Statin Use Following Myocardial Infarction in the United States.

BACKGROUND: Historically, women have been less likely than men to receive guideline-recommended statin therapy for the secondary prevention of myocardial infarction (MI). OBJECTIVES: The authors examined contemporary sex differences in prescription fills for high-intensity statin therapy following an MI, overall and across population subgroups, and assessed whether sex differences were attenuated following recent efforts to reduce sex disparities in the use of cardiovascular disease preventive therapies. METHODS: The authors studied 16,898 (26% women) U.S. adults <65 years of age with commercial health insurance in the MarketScan database, and 71,358 (49% women) U.S. adults ≥66 years of age with government health insurance through Medicare who filled statin prescriptions within 30 days after hospital discharge for MI in 2014 to 2015. The authors calculated adjusted women-to-men risk ratios and 95% confidence intervals (CIs) for filling a high-intensity statin prescription (i.e., atorvastatin 40 to 80 mg, and rosuvastatin 20 to 40 mg) following hospital discharge for MI. RESULTS: In 2014 to 2015, 56% of men and 47% of women filled a high-intensity statin following hospital discharge for MI. Adjusted risk ratios for filling a high-intensity statin comparing women with men were 0.91 (95% CI: 0.90 to 0.92) in the total population, 0.91 (95% CI: 0.89 to 0.92) among those with no prior statin use, and 0.87 (95% CI: 0.85 to 0.90) and 0.98 (95% CI: 0.97 to 1.00) for those taking low/moderate-intensity and high-intensity statins prior to their MI, respectively. Women were less likely than men to fill high-intensity statins within all subgroups analyzed, and the disparity was largest in the youngest and oldest adults and for those without prevalent comorbid conditions. CONCLUSIONS: Despite recent efforts to reduce sex differences in guideline-recommended therapy, women continue to be less likely than men to fill a prescription for high-intensity statins following hospitalization for MI.