Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Racism and Nursing Leadership in Massachusetts: A Mixed-Methods Study.

BACKGROUND: Nursing in the United States has evolved within the same historical context that has reproduced and spread racism worldwide. Nurse administrators are integral to the quality of nurses' practice and play a key role in eliminating racial injustice in places of work. PURPOSE: Using a feminist and critical race feminist framework, this study examined Massachusetts nurses' experiences of racism in their places of work, focusing on nurse administrators' influence on the nonadministrator (staff nurse) experience of racism experiences before and after George Floyd's death. METHODS: An investigator-developed, electronic survey was sent to Massachusetts professional nursing organizations for distribution to their members in 2021. Two hundred nineteen nurse respondents completed Likert-scale and open-ended branching logic survey questions to yield the quantitative and qualitative data analyzed for this mixed-methods study. FINDINGS: Nurse administrators were: 1) more likely than staff nurses to state that policies and meetings to address racism and diversity, equity, and inclusion had taken place before and after George Floyd's murder; and 2) less likely than staff nurses to directly experience racism at the hands of a colleague or a superior. Nurse administrators influence staff nurses' experiences of racism.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis.

OBJECTIVES: Calcium pyrophosphate deposition (CPPD) disease, broadly defined, has been associated with increased risk of cardiovascular (CV) events. We investigated risk of CV events in patients with acute CPP crystal arthritis, the acute manifestation of CPPD. METHODS: Cohort study using Mass General Brigham electronic health record (EHR) data, 1991-2017. Patients with acute CPP crystal arthritis were identified using a published machine learning algorithm with positive predictive value 81%. Comparators were matched on year of EHR entry and index date of patients with acute CPP crystal arthritis (first positive synovial fluid CPP result or mention of 'pseudogout', or matched encounter). Major adverse cardiovascular event (MACE) was a composite of non-fatal CV event (myocardial infarction, acute coronary syndrome, coronary revascularisation, stroke) and death. We estimated incidence rates (IRs) and adjusted hazard ratios for MACE, non-fatal CV event and death, allowing for differential estimates during years 0-2 and 2-10. Sensitivity analyses included: (1) patients with acute CPP crystal arthritis diagnosed during outpatient visits, (2) patients with linked Medicare data, 2007-2016 and (3)patients matched on number of CV risk factors. RESULTS: We matched 1200 acute CPP crystal arthritis patients to 3810 comparators. IR for MACE in years 0-2 was 91/1000 person-years (p-y) in acute CPP crystal arthritis and 59/1000 p-y in comparators. In years 2-10, IR for MACE was 58/1000 p-y in acute CPP crystal arthritis and 53/1000 p-y in comparators. Acute CPP crystal arthritis was significantly associated with increased risk for MACE in years 0-2 (HR 1.32, 95% CI 1.01 to 1.73) and non-fatal CV event in years 0-2 (HR 1.92, 95% CI 1.12 to 3.28) and years 2-10 (HR 2.18, 95% CI 1.27 to 3.75), but not death. Results of sensitivity analyses were similar to the primary analysis; in the outpatient-only analysis, risk of non-fatal CVE was significantly elevated in years 2-10 but not in years 0-2. CONCLUSIONS: Acute CPP crystal arthritis was significantly associated with elevated short and long-term risk for non-fatal CV event.

Associations of the MUC5B promoter variant with timing of interstitial lung disease and rheumatoid arthritis onset.

OBJECTIVES: To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. METHODS: We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multihospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had CT imaging, lung biopsy or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual records review. We examined the associations of the MUC5B promoter variant (G>T at rs35705950) with RA-ILD, RA-ILD occurring before or within 2 years of RA diagnosis and RA diagnosis at age >55 years. We used multivariable logistic regression to estimate odds ratios (ORs) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. RESULTS: We identified 1005 RA patients with available genotype data for rs35705950 (mean age 45 years, 79% female, 81% European ancestry). The MUC5B promoter variant was present in 155 (15.4%) and was associated with RA-ILD [multivariable OR 3.34 (95% CI 1.97, 5.60)], RA-ILD before or within 2 years of RA diagnosis [OR 4.01 (95% CI 1.78, 8.80)] and RA onset after age 55 years [OR 1.52 (95% CI 1.08, 2.12)]. CONCLUSIONS: The common MUC5B promoter variant was associated with RA-ILD onset earlier in the RA disease course and older age of RA onset. These findings suggest that the MUC5B promoter variant may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.

First Demonstration of Novel Vertical Gate-All-Around Field-Effect-Transistors Featured by Self-Aligned and Replaced High-κ Metal Gates.

A novel n-type nanowire/nanosheet (NW/NS) vertical sandwich gate-all-around field-effect-transistor (nVSAFET) with self-aligned and replaced high-κ metal gates (HKMGs) is presented for the first time, aiming at a 3 nm technology node and beyond. The nVSAFETs were fabricated by an integration flow of Si/SiGe epitaxy, quasi-atomic layer etching (qALE) of SiGe selective to Si, formation of SiGe/Si core/shell NS/NW structure, building of nitride dummy gate, and replacement of the dummy gate. This fabrication method is complementary metal oxide semiconductor (CMOS)-compatible, simple, and reproducible, and NWs with a diameter of 17 nm and NSs with a thickness of 20 nm were obtained. Excellent control of short-channel-effects was presented. The device performance was also investigated and discussed. The proposed integration scheme has great potential for applications in chip manufacturing, especially with vertical channel devices.

SP1-mediated transcriptional activation of PTTG1 regulates the migration and phenotypic switching of aortic vascular smooth muscle cells in aortic dissection through MAPK signaling.

Pituitary tumor-transforming gene 1 (PTTG1) has been found to be associated with the process of cell proliferation and invasion, and is highly expressed in aortic dissection (AD). However, its potential role and underlying mechanism in AD remain uncertain. This study aims at elucidating the roles of specificity protein 1 (SP1) and PTTG1 in the migration and phenotypic switching of aortic vascular smooth muscle cells (VSMCs) in AD. Aortic samples were collected from 35 patients with AD for examination of PTTG1 expression in the tissues by qPCR, western blot and immunofluorescence. Human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with platelet-derived growth factor-BB (PDGF-BB) to establish the cellular model of AD. PTTG1 expression in VSMCs was also examined by qPCR and western blot. Cell viability was detected by CCK-8, cell proliferation by EdU staining and cell migration by wound healing and transwell. Western blot was then performed to assay migration-related proteins. After interference with PTTG1, the levels of smooth muscle pthenotypic switch markers smooth muscle protein 22 alpha (SM22-α) and osteopontin (OPN) were detected by qPCR, western blot and immunofluorescence. The binding of SP1 and PTTG1 was verified with dual-luciferase reporter assay and chromatin immunoprecipitation assay (ChIP). PTTG1 overexpression was found in AD patients. Interference with PTTG1 attenuated the proliferation and migration of PDGF-BB-stimulated HAVSMCs, in addition to their switching from contractile phenotype to synthetic phenotype. Transcription factor SP1 was up-regulated in PDGF-BB-stimulated HAVSMCs, combined with PTTG1 promoter sequence and regulated PTTG1 expression, whose overexpression reversed the effects of PTTG1 interference on cell proliferation, migration and phenotypic switching. SP1 transcriptional activation of PTTG1 activated MAPK/ERK signaling pathway. In conclusion, SP1 transcriptional activation of PTTG1 regulates the migration and phenotypic transformation of HAVSMCs in AD by MAPK Signaling.

Follow-up vascular ultrasounds in patients with giant cell arteritis.

OBJECTIVES: Literature describing follow-up vascular ultrasound (VUS) in giant cell arteritis (GCA) is limited. We report our experience with follow-up VUS obtained in clinical care of patients with GCA. METHODS: We retrospectively identified GCA patients with an abnormal initial VUS, defined as circumferential hypoechoic wall thickening ("halo sign"), or circumferential hyperechoic wall thickening without evidence of arteriosclerosis or arteritis, who subsequently underwent follow-up VUS during 2013-2018. Studies were interpreted as active arteritis, hyperechoic wall thickening without active arteritis, or no arteritis. We compared clinical and laboratory characteristics at time of initial VUS among patients with active arteritis vs. hyperechoic wall thickening without active arteritis. We described whether and how VUS interpretation changed from initial to follow-up VUS. Among individual vessels, we tested whether abnormal findings (e.g. halo sign) persisted at follow-up VUS using McNemar's test. RESULTS: 42 patients fulfilled study criteria. Median time between initial and follow-up VUS was 5.1 (IQR 2.6-7.9) months. Characteristics at initial VUS did not differ according to VUS interpretation. Among 36 patients with active arteritis on initial VUS, follow-up VUS showed active arteritis in 25.0%, hyperechoic wall thickening in 33.3% and no arteritis in 41.7%. Among 6 patients with hyperechoic wall thickening on initial VUS, half had no arteritis on follow-up VUS. Sonographic findings tended to persist in axillary arteries and were more likely to change in the superficial temporal arteries. CONCLUSIONS: Among 42 GCA patients, the majority had a change in VUS interpretation between initial and follow-up VUS. Sonographic findings in the temporal circulation more frequently changed than findings in axillary arteries.

New Indole Glycosides from Aesculus chinensis var. chekiangensis and Their Neuroprotective Activities.

The dried seeds of Aesculus chinensis Bge. var. chekiangensis (Hu et Fang) Fang, called "Suo Luo Zi", have been used in traditional Chinese medicine. Nevertheless, most studies have been focused on components of less polarity fractions. In this research, twelve indoles, including six new indole glycosides (1-6) as well as six known analogs were isolated from the polar portion which has been seldom studied. This is the first description of N-glucosylated indoles obtained from the genus of Aesculus. Structures of the new compounds (1-6) were elucidated based on comprehensive interpretation of HRESIMS, 1D and 2D NMR. Additionally, the neuroprotective activities of the N-glucosylated indoles were evaluated for the first time indicating that compounds 1-5 and 9-10 exhibited moderate neuroprotective activities. Further cytotoxicity tests of isolates 1-10 on three human tumor cell lines suggested that none of these compounds were cytotoxic (IC50 > 50 µM).

[Induction of robust senescence-associated secretory phenotype in mouse NIH-3T3 cells by mitomycin C].

Senescence-associated secretory phenotype (SASP) is often a concomitant result of cell senescence, embodied by the enhanced function of secretion. The SASP factors secreted by senescent cells include cytokines, proteases and chemokines, etc, which can exert great influence on local as well as systemic environment and participate in the process of cell senescence, immunoregulation, angiogenesis, cell proliferation and tumor invasion, etc. Relative to the abundance of SASP models in human cells, the in vitro SASP model derived from mouse cells is scarce at present. Therefore, the study aimed to establish a mouse SASP model to facilitate the research in the field. With this objective, we treated the INK4a-deficient mouse NIH-3T3 cells and the wildtype mouse embryonic fibroblasts (MEF) respectively with mitomycin C (MMC), an anticarcinoma drug which could induce DNA damage. The occurring of cell senescence was evaluated by cell morphology, ß-gal staining, integration ratio of EdU and Western blot. Quantitative RT-PCR and ELISA were used to detect the expression and secretion of SASP factors, respectively. The results showed that, 8 days after the treatment of NIH-3T3 cells with MMC (1 µg/mL) for 12 h or 24 h, the cells became enlarged and the ratios of ß-gal-positive (blue-stained) cells significantly increased, up to 77.4% and 90.4%, respectively. Meanwhile, the expression of P21 protein increased and the integration ratios of EdU significantly decreased (P < 0.01). Quantitative RT-PCR detection showed that the mRNA levels of several SASP genes, including IL-6, TNF-α, IL-1α and IL-1ß increased evidently. ELISA detection further observed an enhanced secretion of IL-6 (P < 0.01). On the contrary, although wildtype MEF could also be induced into senescence by MMC treatment for 12 h or 24 h, embodied by the enlarged cell volume, increased ratios of ß-gal-positive cells (up to 71.7% and 80.2%, respectively) and enhanced expression of P21 protein, the secretion of IL-6 displayed no significant change. Our study indicated that, although MMC could induce senescence in both mouse NIH-3T3 cells and wildtype MEF, only senescent NIH-3T3 cells displayed the canonical SASP phenomena. Current study suggested that senescent NIH-3T3 cells might be an appropriate in vitro SASP model of mouse cells.

Electrochemiluminescence Resonance Energy Transfer System: Mechanism and Application in Ratiometric Aptasensor for Lead Ion.

In this paper, a novel electrochemiluminescence resonance energy transfer (ECL-RET) system from O2/S2O8(2-) to a kind of amino-terminated perylene derivative (PTC-NH2) was demonstrated for the first time, which was then applied to construct a ratiometric aptasensor for lead ion (Pb(2+)) detection. First, gold-nanoparticles-functionalized fullerene nanocomposites (AuNPs@nano-C60) were coated on a glassy carbon electrode (GCE), and then thiol-modified assistant probes (APs) were attached on AuNPs@nano-C60/GCE. Then the resultant electrode was hybridized with capture probes (the aptamer of the Pb(2+), abbreviated as CPs) to generate DNA duplexes, which could induce PTC-NH2 to be intercalated into the dsDNA grooves by the electrostatic adsorption. Herein, ECL dual peaks at -0.7 V (vs Ag/AgCl) and -2.0 V (vs Ag/AgCl) were obtained when the prepared aptasensor was detected in air-saturated S2O8(2-) solution, which could be attributed to the emission of excited dimmers (π-excimers) ((1)(NH2-PTC)2*) and (1)(O2)2*, respectively. In the presence of Pb(2+), the dsDNA was unwound, and Pb(2+) G-quadruplex structure was generated because of the highly specific affinity between Pb(2+) and CPs, which made the PTC-NH2 release from the electrode surface. As a result, the ECL signal at -0.7 V was decreased, and the ECL signal around -2.0 V was increased. By measuring the ratio of ECL intensities at two excitation potentials, the developed aptasensor exhibited the linear response range from 1.0 × 10(-12) M to 1.0 × 10(-7) M with a detection limit of 3.5 × 10(-13) M (S/N = 3) for Pb(2+), which could offer an alternative analytical method with excellent properties of high selectivity, accuracy, and sensitivity.

Transcriptome Analysis of Differentially Expressed Genes and Molecular Pathways Involved in C2C12 Cells Myogenic Differentiation.

Muscles are essential tissues responsible for movement, stability, and metabolism, playing a crucial role in human health and well-being. A comprehensive understanding of muscle differentiation processes is imperative for combating muscle degenerative diseases such as muscular dystrophy. In this study, C2C12 cells were induced to differentiate into myotubes in vitro. Phenotypic changes were observed utilizing Gimsa and immunofluorescent staining techniques. RNA sequencing was conducted at distinct time points (0, 2, 4, and 7 days) during the differentiation process. To elucidate the underlying molecular mechanisms, differential expression analysis, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA) were performed. Soft clustering of time series gene expression was employed to establish the expression patterns of differentially expressed genes (DEGs) at various time points during myogenesis. Additionally, quantitative reverse transcription PCR was utilized to validate gene expression from RNA-seq data at the mRNA level. Throughout the myogenic differentiation of C2C12 cells, notable morphological changes were observed, with myoblasts forming multinucleated myotubes by day 4 and plump elongated structures by day 7. Gene expression analysis revealed a substantial increase in DEGs as differentiation progressed, with a significant rise in DEGs from day 0 to day 7. Enrichment analysis highlighted key biological processes and pathways involved, including signal transduction and immune system processes, as well as pathways like chemokine and calcium signaling. Noise-robust soft clustering identified distinct temporal gene expression patterns, categorizing genes into upregulated, downregulated, and biphasic response clusters. The MYH family exhibited diverse expression changes, with Myh3, Myh13, Myh6, Myh7, Myh2, Myh8, Myh14, Myh7b, Myh1, and Myh4 upregulated, Myh10, Myh9, and Myh12 downregulated. Key transcription factors displayed dynamic expression patterns, which was crucial for the regulation of myoblast differentiation. A comprehensive and dynamic transcriptomic analysis of the C2C12 myoblast differentiation process has significantly enhanced our understanding of the key genes and biological pathways involved in myogenesis.

[Study of apoptosis related factors regulatory mechanism of resveratrol to human skin squamous cell carcinoma A431 xenograft in nude mice].

OBJECTIVE: To explore the anti-tumor effects of resveratrol (Res) upon human skin squamous cell carcinoma A431 xenograft in nude mice and elucidate the regulatory mechanisms of survivin and caspase-3. METHODS: The model of human skin squamous cell carcinoma (A431) xenograft in nude mice was established. And the animals were randomly divided into saline-negative control, cyclophosphamide (CTX) positive control, Res high-, medium- and low-dosage and blank control groups (n = 10 each). After drug intervention, tumor-bearing mice were sacrificed. The tumor growth curve was plotted and the Res inhibition rate calculated by terminal tumor weight. The morphological changes of tumor cell among groups were observed by hematoxylin and eosin staining; cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL; the impact of Res upon the protein expressions of survivin and caspase-3 in tumor issues was observed by Western blot. Analysis of variance and Pearson's correlation were employed for statistical analyses. RESULTS: (1) By the end of treatment, the tumor volume of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups were (1154 ± 255), (1002 ± 115), (1207 ± 176), (1342 ± 211), (1642 ± 226), (1564 ± 156) mm(3) respectively, and tumor weight of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups (1.84 ± 0.30), (1.72 ± 0.39), (1.96 ± 0.40), (2.67 ± 0.73), (3.16 ± 0.52), (3.33 ± 0.59) g respectively. Through analysis of variance, the tumor volume and weight of Res high-, medium-, low-dosage groups were smaller than those of saline-negative control and blank control groups (all P < 0.05). The inhibition rate of Res high-, medium- and low-dosage groups were 45.57%, 37.97% and 15.51% respectively. (2) The apoptosis index of the above groups were 36.79% ± 8.86%, 33.15% ± 6.00%, 18.09% ± 3.92%, 10.53% ± 4.20%, 3.87% ± 1.63%, 2.73% ± 1.61%. Through analysis of variance, the apoptosis index of Res groups were higher than those of saline-negative control and blank control groups (all P < 0.05). (3) The protein expression of survivin/ß-actin of each group were 0.48 ± 0.20, 0.19 ± 0.11, 0.22 ± 0.12, 0.28 ± 0.24, 0.98 ± 0.41, 0.85 ± 0.34. The protein expression of caspase-3/ß-actin of each group were 0.42 ± 0.09, 0.31 ± 0.10, 0.31 ± 0.07, 0.22 ± 0.08, 0.14 ± 0.04, 0.13 ± 0.05 respectively. Through analysis of variance, the protein expression of survivin of Res groups was lower than those of the saline-negative control and blank control groups (all P < 0.05). And the protein expression of caspase-3 of Res groups were higher than those of the saline-negative control and blank control group (all P < 0.05). Through Pearson's analysis, the protein expression of survivin and caspase-3 had no correlation (r = -0.279, P > 0.05). CONCLUSIONS: Res inhibits the growth of human skin squamous cell carcinoma A431 xenograft in nude mice. And its mechanism may be associated with the apoptosis of tumor cell through the depression of survivin and the activation of caspase-3.

E prostanoid receptor-3 promotes oxidized low-density lipoprotein-induced human aortic smooth muscle cells inflammation.

AIM: The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor-3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis. METHODS AND RESULTS: ApoE-/- mice were used to construct in vivo model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low-density lipoprotein (ox-LDL) to construct in vitro model of atherosclerosis. mRNA expressions were assessed by qRT-PCR, and western blot was applied to assess the protein levels. CCK-8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme-linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis. In vivo experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L-798106 (EP3 inhibitor) significantly inhibited the levels of pro-inflammatory cytokines in atherosclerosis in vivo. EP3 inhibitor (L-798106) significantly reversed ox-LDL-caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (P < 0.05). The levels of interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) in HASMCs were elevated by ox-LDL, whereas L-798106 or knockdown of cyclic AMP (cAMP) response element-binding protein (CREB) notably restored this phenomenon (P < 0.05). EP3 overexpression further aggravated ox-LDL-induced inflammation in HASMCs, and EP3 up-regulated the levels of IL-17 and ICAM-1 in ox-LDL-treated HASMCs (P < 0.05). EP3 up-regulation promoted the inflammatory responses in ox-LDL-treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL-17/ICAM-1 axis (P < 0.05). CONCLUSIONS: EP3 inhibitor alleviates ox-LDL-induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL-17/ICAM-1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.

Confirming Prior and Identifying Novel Correlates of Acute Calcium Pyrophosphate Crystal Arthritis.

OBJECTIVE: To investigate previously identified and novel correlates of acute calcium pyrophosphate (CPP) crystal arthritis among well-characterized cases. METHODS: In this case-control study, we identified cases of acute CPP crystal arthritis using a validated algorithm (positive predictive value 81%) applied in the Partners HealthCare electronic health record (EHR). Cases were matched to general patient controls on the year of first EHR encounter and index date. Prespecified potential correlates included sex, race, and comorbidities and medications previously associated with CPP deposition/acute CPP crystal arthritis in the literature. We estimated odds ratios (ORs) and 95% confidence intervals using conditional logistic regression models adjusted for demographic characteristics, comorbidities, medications prescribed in the past 90 days, health care utilization, and multimorbidity score. RESULTS: We identified 1,697 cases matched to 6,503 controls. Mean ± SD age was 73.7 ± 11.8 years, 56.7% were female, 80.8% were White, and 10.3% were Black. All prespecified covariates were more common in cases than controls. Osteoarthritis (OR 3.08), male sex (OR 1.35), rheumatoid arthritis (OR 2.09), gout (OR 2.83), proton pump inhibitors (OR 1.94), loop diuretics (OR 1.60), and thiazides (OR 1.46) were significantly associated with acute CPP crystal arthritis after full adjustment. Black race was associated with lower odds for acute CPP crystal arthritis compared to White race (OR 0.47). CONCLUSION: Using a validated algorithm to identify nearly 1,700 patients with acute CPP crystal arthritis, we confirmed important correlates of this acute manifestation of CPP deposition. This is the first study to report higher odds for acute CPP crystal arthritis among males.

Demonstration of Germanium Vertical Gate-All-Around Field-Effect Transistors Featured by Self-Aligned High-κ Metal Gates with Record High Performance.

A special Ge nanowire/nanosheet (NW/NS) p-type vertical sandwich gate-all-around (GAA) field-effect transistor (FET) (Ge NW/NS pVSAFET) with self-aligned high-κ metal gates (HKMGs) is proposed. The Ge pVSAFETs were fabricated by high-quality GeSi/Ge epitaxy, an exclusively developed self-limiting isotropic quasi atomic layer etching (qALE) of Ge selective to both GeSi and the (111) plane, top-drain implantation, and ozone postoxidation (OPO) channel passivation. The Ge pVSAFETs, which have hourglass-shaped (111) channels with the smallest size range from 5 to 20 nm formed by qALE, have reached a record high Ion of ∼291 µA/µm and exhibited good short channel effects (SCEs) control. The integration flow is compatible with mainstream CMOS processes, and Ge pVSAFETs with precise control of gate lengths/channel sizes were obtained.

Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: A nested case-control study.

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods: This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and rheumatoid factor status. A multiplex assay measured ACPA and anti-native protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD. Findings: We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity antibodies that were associated with RA-ILD. The antibody isotypes and targeted proteins were: IgA2 to citrullinated histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22), IgA2 to citrullinated histone 2A (OR 4.03, 95% CI 2.03-8.00), IgG to cyclic citrullinated filaggrin (OR 3.47, 95% CI 1.71-7.01), IgA2 to native cyclic histone 2A (OR 5.52, 95% CI 2.38-12.78), IgA2 to native histone 2A (OR 4.60, 95% CI 2.18-9.74), and IgG to native cyclic filaggrin (OR 2.53, 95% CI 1.47-4.34). These six antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these antibodies with the clinical factors (smoking, disease activity, glucocorticoid use, obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9) biomarkers achieved specificity ≥93% for RA-ILD. Interpretation: Specific ACPA and anti-native protein antibodies improve RA-ILD prediction. These findings implicate synovial protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies. Funding: National Institutes of Health.

Dynamic Frequency-Temperature Characteristic Modeling for Quartz Crystal Resonator Based on Improved Echo State Network.

Quartz crystal resonators are the key component of various kinds of electronic systems because they provide the reference frequency source of the system running clocks. However, the frequency stability is often affected by the temperature. Therefore, the frequency-temperature ( f-T ) characteristic modeling has been an important research topic in the frequency control field. The classic f-T modeling method omits the system dynamics and may lead to a large frequency compensation error in the case of rapid temperature changing. To deal with this issue, this article proposes a dynamic f-T modeling method based on improved echo state network (ESN), called residual scaled ESN (RSESN). In the proposed method, the residual modeling framework is designed for purposes of good physical understandability and high prediction precision. This framework uses the static polynomial f-T model to depict the approximated data relationship and applies the complicated network model to compensate the detailed dynamic error. To estimate the dynamic errors, one effective dynamic modeling tool, ESN, is introduced to build the dynamic compensation model for f-T characteristic of quartz crystal resonators. For a better fitting performance, the ESN activation limitations are analyzed and the scaled echo states are constructed in the improved ESN model. The modeling and testing results on the real experiment data show that the proposed method can capture the dynamic information effectively and provide better frequency deviation predictions.

Timing of sinusitis and other respiratory tract diseases and risk of rheumatoid arthritis.

OBJECTIVE: To investigate the association between timing of respiratory tract diseases and risk of rheumatoid arthritis (RA). METHODS: This case-control study using the Mass General Brigham Biobank matched incident RA cases, confirmed by ACR/EULAR criteria, with at least seven years preceding electronic health record (EHR) data to three controls on age, sex, and EHR history from RA diagnosis (index date). We ascertained timing (>0-5 years/>5-10 years/>10 years) of the first documented respiratory tract disease prior to index date using diagnosis codes. We estimated odds ratios (OR) with 95% confidence intervals (CI) for RA for each respiratory exposure using logistic regression models, adjusting for potential confounders. We also conducted a stratified analysis by serostatus and smoking. RESULTS: We identified 625 incident RA cases (median 56 years, 75% female, 57% seropositive) and 1,875 controls. Acute sinusitis was associated with RA only in the >5 to 10 years before RA (OR 3.90, 95% CI:1.90,8.01). In contrast, pneumonia was associated with RA only in the >0 to 5 years before RA (OR 1.73, 95% CI:1.00,3.00), and chronic respiratory tract diseases only >10 years before RA (OR 1.43, 95% CI:1.00,2.05). All respiratory tract diseases tended to show a stronger association with seronegative RA than seropositive RA, although the interaction was statistically significant only for chronic sinusitis (p=0.04). Respiratory diseases showed a nonsignificantly stronger association among smokers than nonsmokers. CONCLUSION: Sinusitis and other respiratory diseases are associated with increased risk of RA, especially 5 years before RA onset. RA may begin many years before clinical onset.

The Impact of an Integrated Care Management Program on Acute Care Use and Outpatient Appointment Attendance Among High-Risk Patients With Lupus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) often struggle with high acute care use (emergency department [ED] visits and hospitalizations) and missed appointments. A nurse-led integrated care management program (iCMP) at our multihospital system coordinates care for patients at high risk for frequent acute care use due to comorbidities, demographics, and prior use patterns. We studied whether iCMP enrollment was associated with decreased acute care use and missed appointment rates among patients with SLE. METHODS: We used a validated electronic health record (EHR) machine learning algorithm to identify adults with SLE and then determined which patients were enrolled in the iCMP from January 2012 to February 2019. We then used EHR data linked to insurance claims to compare the incidence rates of ED visits, hospitalizations, potentially avoidable ED visits and hospitalizations, and missed appointments during iCMP enrollment versus the 12 months prior to iCMP enrollment. We used Poisson regression to compare incidence rate ratios (IRRs) during the iCMP versus pre-iCMP for each use measure, adjusted for age, sex, race and ethnicity, number of comorbidities, and calendar year, accounting for within-patient clustering. RESULTS: We identified 67 iCMP enrollees with SLE and linked EHR claims data. In adjusted analyses, iCMP enrollment was associated with reduced rates of ED visits (IRR 0.63, 95% confidence interval [CI] 0.47-0.85), avoidable ED visits (IRR 0.50, 95% CI 0.28-0.88), and avoidable hospitalizations (IRR 0.37, 95% CI 0.21-0.65). CONCLUSION: A nurse-led iCMP was effective at decreasing the rate of all ED visits and potentially avoidable ED visits and hospitalizations among high-risk patients with SLE. Further studies are needed to confirm these findings in other patient populations.