High-density stable glasses formed on soft substrates.

Enabled by surface-mediated equilibration, physical vapour deposition can create high-density stable glasses comparable with liquid-quenched glasses aged for millions of years. Deposition is often performed at various rates and temperatures on rigid substrates to control the glass properties. Here we demonstrate that on soft, rubbery substrates, surface-mediated equilibration is enhanced up to 170 nm away from the interface, forming stable glasses with densities up to 2.5% higher than liquid-quenched glasses within 2.5 h of deposition. Gaining similar properties on rigid substrates would require 10 million times slower deposition, taking ~3,000 years. Controlling the modulus of the rubbery substrate provides control over the glass structure and density at constant deposition conditions. These results underscore the significance of substrate elasticity in manipulating the properties of the mobile surface layer and thus the glass structure and properties, allowing access to deeper states of the energy landscape without prohibitively slow deposition rates.

X-ray emission spectroscopy: an effective route to extract site occupation of cations.

Cation site occupation is an important determinant of materials properties, especially in a complex system with multiple cations such as in ternary spinels. Many methods for extracting the cation site information have been explored in the past, including analysis of spectra obtained through K-edge X-ray absorption spectroscopy (XAS). In this work, we measure the effectiveness of X-ray emission spectroscopy (XES) for determining the cation site occupation. As a test system we use spinel phase CoxMn3-xO4 nanoparticles contaminated with CoO phases because Co and Mn can occupy all cation sites and the impurity simulates typical products of oxide syntheses. We take advantage of the spin and oxidation state sensitive Kß1,3 peak obtained using XES and demonstrate that XES is a powerful and reliable technique for determining site occupation in ternary spinel systems. Comparison between the extended X-ray absorption fine structure (EXAFS) and XES techniques reveals that XES provides not only the site occupation information as EXAFS, but also additional information on the oxidation states of the cations at each site. We show that the error for EXAFS can be as high as 35% which makes the results obtained ambiguous for certain stoichiometries, whereas for XES, the error determined is consistently smaller than 10%. Thus, we conclude that XES is a superior and a far more accurate method than XAS in extracting cation site occupation in spinel crystal structures.

Dicer1 functions as a haploinsufficient tumor suppressor.

While the global down-regulation of microRNAs (miRNAs) is a common feature of human tumors, its genetic basis is largely undefined. To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 "floxed" or Dicer1(fl)) on several mouse models of cancer. Here we show Dicer1 functions as a haploinsufficient tumor suppressor gene. Deletion of a single copy of Dicer1 in tumors from Dicer1(fl/+) animals led to reduced survival compared with controls. These tumors exhibited impaired miRNA processing but failed to lose the wild-type Dicer1 allele. Moreover, tumors from Dicer1(fl/fl) animals always maintained one functional Dicer1 allele. Consistent with selection against full loss of Dicer1 expression, enforced Dicer1 deletion caused inhibition of tumorigenesis. Analysis of human cancer genome copy number data reveals frequent deletion of DICER1. Importantly, however, the gene has not been reported to undergo homozygous deletion, suggesting that DICER1 is haploinsufficient in human cancer. These findings suggest Dicer1 may be an important haploinsufficient tumor suppressor gene and, furthermore, that other factors controlling miRNA biogenesis may also function in this manner.

Combined Experimental and Computational Insight into the Role of Substrate in the Synthesis of Two-Dimensional WSe2.

Synthesis of large-area transition-metal dichalcogenides (TMDs) with controlled orientation is a significant challenge to their industrial applications. Substrate plays a vital role in determining the final quality of monolayer materials grown via the chemical vapor deposition process by controlling their orientation, crystal structure, and grain boundary. This study determined the binding energy and equilibrium distance for tungsten diselenide (WSe2) monolayers on crystalline and amorphous silicon dioxide and aluminum dioxide substrates. Differently oriented WSe2 monolayers are considered to investigate the role of the substrate in the orientation, binding strength, and equilibrium distance. This study can pave the way to synthesizing high-quality two-dimensional (2D) materials for electronic and chemical applications.

Tailoring amorphous boron nitride for high-performance two-dimensional electronics.

Two-dimensional (2D) materials have garnered significant attention in recent years due to their atomically thin structure and unique electronic and optoelectronic properties. To harness their full potential for applications in next-generation electronics and photonics, precise control over the dielectric environment surrounding the 2D material is critical. The lack of nucleation sites on 2D surfaces to form thin, uniform dielectric layers often leads to interfacial defects that degrade the device performance, posing a major roadblock in the realization of 2D-based devices. Here, we demonstrate a wafer-scale, low-temperature process (<250 °C) using atomic layer deposition (ALD) for the synthesis of uniform, conformal amorphous boron nitride (aBN) thin films. ALD deposition temperatures between 125 and 250 °C result in stoichiometric films with high oxidative stability, yielding a dielectric strength of 8.2 MV/cm. Utilizing a seed-free ALD approach, we form uniform aBN dielectric layers on 2D surfaces and fabricate multiple quantum well structures of aBN/MoS2 and aBN-encapsulated double-gated monolayer (ML) MoS2 field-effect transistors to evaluate the impact of aBN dielectric environment on MoS2 optoelectronic and electronic properties. Our work in scalable aBN dielectric integration paves a way towards realizing the theoretical performance of 2D materials for next-generation electronics.

Economic Burden of HIV in a Commercially Insured Population in the United States.

Background: With advances in antiretroviral therapy (ART), people with HIV infection are living longer. Pre-exposure prophylaxis (PrEP) to reduce HIV infection risk continues to be underutilized in high-risk individuals. Recent data on economic burden for patients with newly diagnosed HIV-1 or initiated with PrEP are limited. Objectives: To assess characteristics, healthcare resource utilization (HRU), and costs among adults and adolescents either with newly diagnosed HIV-1 or initiated with PrEP. Methods: This retrospective observational study utilized data from the IBM MarketScan® Commercial Claims and Encounters database. Adults with newly diagnosed HIV-1 or those initiated with PrEP were included (index date was the first HIV diagnosis or PrEP prescription, respectively, between January 1, 2016, and April 30, 2021). Corresponding cohorts of adolescents were considered exploratory. Descriptive analyses were conducted to assess baseline demographics and clinical characteristics, and all-cause and HIV-related HRU and costs per patient per month (PPPM) during follow-up. Results: Data from 18 154 adults and 220 adolescents with newly diagnosed HIV and 34 123 adults and 175 adolescents initiated with PrEP were included. Approximately 70% of adolescents and 9% of adults receiving PrEP were female. Baseline depression/anxiety was present in 16.1% and 24.6% of adults and 14.5% and 45.1% of adolescents in the HIV and PrEP cohorts, respectively. Substance abuse in the HIV and PrEP cohorts, respectively, was reported in 10.1% and 7.0% of adults, and 2.7% and 17.7% of adolescents. During follow-up, among adults with newly diagnosed HIV, mean (SD) total all-cause and HIV-related PPPM costs were $2657 ($5954) and $1497 ($4463), respectively; pharmacy costs represented 47% of all-cause costs and 67% of HIV-related costs, but only 37% of patients had an HIV-related prescription. All-cause costs PPPM for adults with PrEP were $1761 ($1938), with pharmacy costs accounting for 71%. Conclusions: Despite advances in ART, patients with newly diagnosed HIV and at-risk patients receiving PrEP continue to incur HRU costs. The chronic nature of HIV warrants further exploration of factors contributing to disease burden and opportunities to improve prevention strategies.

Antiplatelet treatment patterns and outcomes of secondary stroke prevention in the United States.

Objective: Patients who have an ischemic stroke (IS) or transient ischemic attack (TIA) are at risk of having a secondary stroke. Single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) may be recommended for secondary stroke prevention (SSP), depending on severity and etiology. This study evaluated outpatient antiplatelet treatment patterns for SSP and outcomes after first hospitalization for IS/TIA among adults without atrial fibrillation in the United States. Materials and methods: This retrospective observational study utilized data from an adjudicated administrative health claims database. Eligible patients had an imputed National Institutes of Health Stroke Scale index event score ≤7. Over-the-counter medication use (eg, aspirin) was not captured. Results: Of 154,273 patients, 41,622 (27%) were prescribed antiplatelet therapy within 90 days of the event; 93.8% received SAPT, 6.1% received DAPT. The first line of antiplatelet therapy after discharge was started a mean of 17.0 days after the event; mean treatment duration was 61.9 days. The incidence rate for secondary IS was 5.53, 2.03, and 1.17 per person-year 90-days, 1-year, and 3-years following treatment initiation, respectively. Among patients matched for demographic and clinical characteristics, the risk of secondary IS was increased with DAPT versus SAPT (hazard ratio [95% CI]: 1.27 [1.20-1.34]; p < 0.0001). Conclusions: Many patients were not prescribed or discontinued antiplatelet therapy within 90 days of hospitalization for IS/TIA and, in most cases, prescriptions were not compliant with SSP consensus guidelines. Patients remained at risk for IS, which was highest within 90 days. More effective strategies for SSP are needed to improve outcomes in this patient population.

The Evolution of MXenes Conductivity and Optical Properties Upon Heating in Air.

MXenes, a family of 2D transition-metal carbides and nitrides, have excellent electrical conductivity and unique optical properties. However, MXenes oxidize in ambient conditions, which is accelerated upon heating. Intercalation of water also causes hydrolysis accelerating oxidation. Developing new tools to readily characterize MXenes' thermal stability can enable deeper insights into their structure-property relationships. Here, in situ spectroscopic ellipsometry (SE) is employed to characterize the optical properties of three types of MXenes (Ti3 C2 Tx , Mo2 TiC2 Tx , and Ti2 CTx ) with varied composition and atomistic structures to investigate their thermal degradation upon heating under ambient environment. It is demonstrated that changes in MXene extinction and optical conductivity in the visible and near-IR regions correlate well with the amount of intercalated water and hydroxyl termination groups and the degree of oxidation, measured using thermogravimetric analysis. Among the three MXenes, Ti3 C2 Tx and Ti2 CTx , respectively, have the highest and lowest thermal stability, indicating the role of transition-metal type, synthesis route, and the number of atomic layers in MXene flakes. These findings demonstrate the utility of SE as a powerful in situ technique for rapid structure-property relationship studies paving the way for the further design, fabrication, and property optimization of novel MXene materials.

Surface Immobilization of a Re(I) Tricarbonyl Phenanthroline Complex to Si(111) through Sonochemical Hydrosilylation.

A sonochemical-based hydrosilylation method was employed to covalently attach a rhenium tricarbonyl phenanthroline complex to silicon(111). fac-Re(5-(p-Styrene)-phen)(CO)3Cl (5-(p-styrene)-phen = 5-(4-vinylphenyl)-1,10-phenanthroline) was reacted with hydrogen-terminated silicon(111) in an ultrasonic bath to generate a hybrid photoelectrode. Subsequent reaction with 1-hexene enabled functionalization of remaining atop Si sites. Attenuated total reflectance-Fourier transform infrared spectroscopy confirms attachment of the organometallic complex to silicon without degradation of the organometallic core, supporting hydrosilylation as a strategy for installing coordination complexes that retain their molecular integrity. Detection of Re(I) and nitrogen by X-ray photoelectron spectroscopy (XPS) further support immobilization of fac-Re(5-(p-styrene)-phen)(CO)3Cl. Cyclic voltammetry and electrochemical impedance spectroscopy under white light illumination indicate that fac-Re(5-(p-styrene)-phen)(CO)3Cl undergoes two electron reductions. Mott-Schottky analysis indicates that the flat band potential is 239 mV more positive for p-Si(111) co-functionalized with both fac-Re(5-(p-styrene)-phen)(CO)3Cl and 1-hexene than when functionalized with 1-hexene alone. XPS, ultraviolet photoelectron spectroscopy, and Mott-Schottky analysis show that functionalization with fac-Re(5-(p-styrene)-phen)(CO)3Cl and 1-hexene introduces a negative interfacial dipole, facilitating reductive photoelectrochemistry.

Global Implications for COVID-19 Vaccine Series Completion: Insights from Real-World Data from the United States.

This retrospective cohort analysis leveraged vaccination data for BNT162b2, mRNA-1273, and Ad26.COV2.S in the United States from the Komodo Healthcare Map database, the TriNetX Dataworks USA Network, and Cerner Real-World EHR (electronic health record) Data to evaluate rates of adherence to and completion of COVID-19 vaccination series (November 2020 through June 2021). Individuals were indexed on the date they received the first dose of a COVID-19 vaccine, with an adherence follow-up window of 42 days. Adherence/completion rates were calculated in the overall cohort of each database and by month of initiation and stratified by age, race/ethnicity, and urban/rural status. Overall adherence and completion to 2-dose COVID-19 mRNA vaccine schedules ranged from 79.4% to 87.4% and 81.0% to 89.2%, respectively. In TriNetX and Cerner, mRNA-1273 recipients were generally less adherent compared with BNT162b2 across sociodemographic groups. In Komodo, rates of adherence/completion between mRNA-1273 and BNT162b2 were similar. Adherence/completion were generally lower in younger (<65 years) versus older recipients (≥65 years), particularly for mRNA-1273. No other sociodemographic-based gaps in vaccine adherence/completion were identified. These data demonstrate high but incomplete adherence to/completion of multidose COVID-19 vaccines during initial vaccine rollout in the United States. Multidose schedules may contribute to challenges associated with successful global vaccination.

Suppression of non-small cell lung tumor development by the let-7 microRNA family.

Many microRNAs (miRNAs) target mRNAs involved in processes aberrant in tumorigenesis, such as proliferation, survival, and differentiation. In particular, the let-7 miRNA family has been proposed to function in tumor suppression, because reduced expression of let-7 family members is common in non-small cell lung cancer (NSCLC). Here, we show that let-7 functionally inhibits non-small cell tumor development. Ectopic expression of let-7g in K-Ras(G12D)-expressing murine lung cancer cells induced both cell cycle arrest and cell death. In tumor xenografts, we observed significant growth reduction of both murine and human non-small cell lung tumors when overexpression of let-7g was induced from lentiviral vectors. In let-7g expressing tumors, reductions in Ras family and HMGA2 protein levels were detected. Importantly, let-7g-mediated tumor suppression was more potent in lung cancer cell lines harboring oncogenic K-Ras mutations than in lines with other mutations. Ectopic expression of K-Ras(G12D) largely rescued let-7g mediated tumor suppression, whereas ectopic expression of HMGA2 was less effective. Finally, in an autochthonous model of NSCLC in the mouse, let-7g expression substantially reduced lung tumor burden.

Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation.

OBJECTIVE: Endothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumour necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: (1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin and (2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects. METHODS: E-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for 4 weeks. Changes in E-selectin were compared between treatment groups. RESULTS: Obese subjects had higher E-selectin than non-obese controls (47.4 [32.7-58.8] vs. 27.2 [20.3-42.1] ng/ml, obese vs. non-obese, P < 0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumour necrosis factor receptors 1 (P = 0.03) and 2 (P = 0.02). In multivariate modelling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (-5.7+/- 8.7 vs. 0.5+/- 6.0 ng/ml, etanercept vs. placebo, P = 0.005). CONCLUSIONS: E-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity.

Regenerative potentials of the murine thyroid in experimental autoimmune thyroiditis: role of CD24.

Hashimoto thyroiditis can be partially reproduced in mice by immunization with thyroglobulin or, more recently, thyroperoxidase. This experimental autoimmune thyroiditis (EAT) model has been extensively characterized during early disease phases (up to d 35 after immunization). By extending the analysis of EAT to 100 d after immunization, we noted a remarkable regenerative capacity of the thyroid and the expression of Oct-4, suggesting in vivo the existence of adult thyroid stem cells. After an almost complete destruction of the follicular architecture, occurring between d 21 and 28, the thyroid was capable of restoring its follicles and reducing the mononuclear infiltration, so that by d 100 after immunization, it regained its normal morphology and function. During this regeneration process, thyrocytes expressed high levels of CD24. We therefore assessed the role of CD24 in thyroid regeneration by inducing EAT in mice lacking CD24. Regeneration was faster in the absence of CD24, likely a consequence of the effect of CD24 on the infiltrating lymphocytes. The study suggests that the EAT model can also be used as a tool to investigate adult thyroid stem cells.

Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men.

CONTEXT AND OBJECTIVE: Strategies to augment pulsatile GH may be beneficial in patients with excess visceral adiposity, in whom GH secretion is reduced. The objective of this study was to determine the effects of a novel GHRH (GHRH(1-44)) analog, tesamorelin, on endogenous GH pulsatility and insulin sensitivity in healthy men. DESIGN, PARTICIPANTS, AND INTERVENTION: Thirteen males (mean age 45 ± 3 yr and body mass index 27.3 ± 1.2 kg/m(2)) received tesamorelin 2 mg sc once daily for 2 wk, with assessment made at baseline, after 2 wk of treatment, and after 2 wk of withdrawal. OUTCOME MEASURES: The primary end point was change in mean overnight GH as determined by overnight frequent sampling. Secondary end points included insulin-stimulated glucose uptake as measured by euglycemic hyperinsulinemic clamp; IGF-I; and GH secretion parameters, including pulse area, pulse frequency, and basal secretion. RESULTS: Tesamorelin treatment increased mean overnight GH (change +0.5 ± 0.1 µg/liter, P = 0.004), average log(10) GH peak area (change +0.4 ± 0.1 log(10) µg/liter, P = 0.001), and basal GH secretion (change +0.008 ± 0.003 µg/liter · min, P = 0.008). IGF-I increased by 181 ± 22 µg/liter (P < 0.0001). Neither fasting glucose (P = 0.93) nor insulin-stimulated glucose uptake (P = 0.61) was significantly affected by tesamorelin. CONCLUSIONS: Once-daily short-term treatment with a GHRH(1-44) analog, tesamorelin, augments basal and pulsatile GH secretion. Moreover, although tesamorelin significantly increases IGF-I, peripheral insulin-stimulated glucose uptake appears to be preserved.

Influence of signal transducer and activator of transcription-1 signaling on thyroid morphology and function.

Interferon (IFN)-gamma has been involved in the pathogenesis of Hashimoto thyroiditis. It is a cytokine released by infiltrating mononuclear cells that mediates its actions mainly through signal transducer and activator of transcription-1 (STAT1) but also through other transcription factors. To dissect the effect of IFN gamma on thyroid morphology and function, we crossed transgenic mice that express IFN gamma specifically in the thyroid gland to mice deficient in STAT1. Lack of STAT1 ameliorated the abnormal thyroid morphology and the primary hypothyroidism typical of IFN gamma transgenic mice but not the suppressed iodine accumulation. Interestingly, lack of STAT1 alone decreased iodine accumulation, seemingly through expression of TGFbeta. These results indicate that STAT1 is required to mediate some but not all of the phenotypic changes induced by IFN gamma and that it also regulates iodine accumulation via TGFbeta signaling.

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

BACKGROUND: Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE: In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.

Effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake and visceral fat in HIV-infected patients.

OBJECTIVE: To determine the effects of switching from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) on muscle glucose uptake, glucose homeostasis, lipids, and body composition. METHODS: Fifteen HIV-infected men and women on a regimen containing LPV/r and with evidence of hyperinsulinemia and/or dyslipidemia were randomized to continue LPV/r or to switch to ATV/r (ATV 300 mg and ritonavir 100 mg daily) for 6 months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography. Secondary endpoints included abdominal visceral adipose tissue, fasting lipids, and safety parameters. The difference over time between treatment groups (treatment effect of ATV/r relative to LPV/r) was determined by repeated measures ANCOVA. RESULTS: After 6 months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 +/- 5.9 micromol/kg per min, ATV/r vs. LPV/r, P = 0.035), and visceral adipose tissue area decreased significantly in individuals who switched to ATV/r (treatment effect -31 +/- 11 cm, ATV/r vs. LPV/r, P = 0.047). Switching to ATV/r significantly decreased triglyceride (treatment effect -182 +/- 64 mg/dl, ATV/r vs. LPV/r, P = 0.02) and total cholesterol (treatment effect -23 +/- 8 mg/dl, ATV/r vs. LPV/r, P = 0.01), whereas high-density lipoprotein and low-density lipoprotein did not change significantly. Fasting glucose also decreased significantly following switch to ATV/r (treatment effect -15 +/- 4 mg/dl, ATV/r vs. LPV/r, P = 0.002). CONCLUSION: Switching from LPV/r to ATV/r significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters, and decreases fasting glucose over 6 months.