A penalized Cox proportional hazards model with multiple time-varying exposures

In recent pharmacoepidemiology research, the increasing use of electronic medication dispensing data provides an unprecedented opportunity to examine various health outcomes associated with long-term medication usage. Often, patients may take multiple types of medications intended for the same medical condition and the medication exposure status and intensity may vary over time, posing challenges to the statistical modeling of such data. In this article, we propose a penalized Cox proportional hazards (PH) model with multiple functional covariates and potential interaction effects. We also consider constrained coefficient functions to ensure a diminishing medication effect over time. Hypothesis testing of interaction effect and main effect was discussed under the penalized Cox PH model setting. Our simulation studies demonstrate the adequate performance of the proposed methods for both parameter estimation and hypothesis testing. Application to a primary care depression cohort study was also illustrated to examine the effects of two common types of antidepressants on the risk of coronary artery disease

Flexible models of time-varying exposures

Indiana University-Purdue University Indianapolis (IUPUI)With the availability of electronic medical records, medication dispensing data offers an unprecedented opportunity for researchers to explore complex relationships among longterm medication use, disease progression and potential side-effects in large patient populations. However, these data also pose challenges to existing statistical models because both medication exposure status and its intensity vary over time. This dissertation focused on flexible models to investigate the association between time-varying exposures and different types of outcomes. First, a penalized functional regression model was developed to estimate the effect of time-varying exposures on multivariate longitudinal outcomes. Second, for survival outcomes, a regression spline based model was proposed in the Cox proportional hazards (PH) framework to compare disease risk among different types of time-varying exposures. Finally, a penalized spline based Cox PH model with functional interaction terms was developed to estimate interaction effect between multiple medication classes. Data from a primary care patient cohort are used to illustrate the proposed approaches in determining the association between antidepressant use and various outcomes.NIH grants, R01 AG019181 and P30 AG10133

Antidepressant Use in the Elderly Is Associated With an Increased Risk of Dementia

A retrospective cohort study was conducted including 3688 patients age 60 years or older without dementia enrolled in a depression screening study in primary care clinics. Information on antidepressant use and incident dementia during follow-up was retrieved from electronic medical records. The Cox proportional hazard models were used to compare the risk for incident dementia among 5 participant groups: selective serotonin re-uptake inhibitors (SSRI) only, non-SSRI only (non-SSRI), mixed group of SSRI and non-SSRI, not on antidepressants but depressed, and not on antidepressants and not depressed. SSRI and non-SSRI users had significantly higher dementia risk than the nondepressed nonusers (hazard ratio [HR]=1.83, P=0.0025 for SSRI users and HR=1.50, P=0.004 for non-SSRI users). In addition, SSRIs users had significantly higher dementia risk than non-users with severe depression (HR=2.26, P=0.0005). Future research is needed to confirm our results in other populations and to explore potential mechanism underlying the observed association

Direct synthesis and chemical vapor deposition of 2D carbide and nitride MXenes

Two-dimensional (2D) transition metal carbides and nitrides (MXenes) are a large family of materials actively studied for various applications, especially in the field of energy storage. MXenes are commonly synthesized by etching the layered ternary compounds, MAX phases. We demonstrate a direct synthetic route for scalable and atom-economic synthesis of MXenes, including phases that have not been synthesized from MAX phases, by the reactions of metals and metal halides with graphite, methane, or nitrogen. The direct synthesis enables chemical vapor deposition (CVD) growth of MXene carpets and complex spherulite-like morphologies that form through buckling and release of MXene carpet to expose fresh surface for further reaction. The directly synthesized MXenes showed excellent energy storage capacity for Li-ion intercalation.Comment: 9 pages, 4 figure

Redefined blood pressure variability measure and its association with mortality in elderly primary care patients

Visit-to-visit blood pressure (BP) variability has received considerable attention recently. The objective of our study is to define a variability measure that is independent of change over time and determine the association between longitudinal summary measures of BP measurements and mortality risk. Data for the study came from a prospective cohort of 2906 adults, aged ≥60 years, in an urban primary care system with ≤15 years of follow-up. Dates of death for deceased participants were retrieved from the National Death Index. Systolic and diastolic BP measurements from outpatient clinic visits were extracted from the Regenstrief Medical Record System. For each patient, the intercept, regression slope, and root mean square error for visit-to-visit variability were derived using linear regression models and used as independent variables in Cox proportional hazards models for both all-cause mortality and mortality attributable to coronary heart disease or stroke. Rate of change was associated with mortality risk in a U-shaped relationship and that participants with little or no change in BP had the lowest mortality risk. BP variability was not an independent predictor of mortality risk. By separating change over time from visit-to-visit variability in studies with relatively long follow-up, we demonstrated in this elderly primary care patient population that BP changes over time, not variability, were associated with greater mortality risk. Future research is needed to confirm our findings in other populations

Hybrid organic-inorganic two-dimensional metal carbide MXenes with amido- and imido-terminated surfaces

Two-dimensional (2D) transition-metal carbides and nitrides (MXenes) show impressive performance in applications, such as supercapacitors, batteries, electromagnetic interference shielding, or electrocatalysis. These materials combine the electronic and mechanical properties of 2D inorganic crystals with chemically modifiable surfaces, and surface-engineered MXenes represent an ideal platform for fundamental and applied studies of interfaces in 2D functional materials. A natural step in structural engineering of MXene compounds is the development and understanding of MXenes with various organic functional groups covalently bound to inorganic 2D sheets. Such hybrid structures have the potential to unite the tailorability of organic molecules with the unique electronic properties of inorganic 2D solids. Here, we introduce a new family of hybrid MXenes (h-MXenes) with amido- and imido-bonding between organic and inorganic parts. The description of h-MXene structure requires an intricate mix of concepts from the fields of coordination chemistry, self-assembled monolayers (SAMs) and surface science. The optical properties of h-MXenes reveal coherent coupling between the organic and inorganic components. h-MXenes also show superior stability against hydrolysis in aqueous solutions.Comment: 10 pages, 4 figure

OsbZIP18, a Positive Regulator of Serotonin Biosynthesis, Negatively Controls the UV-B Tolerance in Rice

Serotonin (5-hydroxytryptamine) plays an important role in many developmental processes and biotic/abiotic stress responses in plants. Although serotonin biosynthetic pathways in plants have been uncovered, knowledge of the mechanisms of serotonin accumulation is still limited, and no regulators have been identified to date. Here, we identified the basic leucine zipper transcription factor OsbZIP18 as a positive regulator of serotonin biosynthesis in rice. Overexpression of OsbZIP18 strongly induced the levels of serotonin and its early precursors (tryptophan and tryptamine), resulting in stunted growth and dark-brown phenotypes. A function analysis showed that OsbZIP18 activated serotonin biosynthesis genes (including tryptophan decarboxylase 1 (OsTDC1), tryptophan decarboxylase 3 (OsTDC3), and tryptamine 5-hydroxylase (OsT5H)) by directly binding to the ACE-containing or G-box cis-elements in their promoters. Furthermore, we demonstrated that OsbZIP18 is induced by UV-B stress, and experiments using UV-B radiation showed that transgenic plants overexpressing OsbZIP18 exhibited UV-B stress-sensitive phenotypes. Besides, exogenous serotonin significantly exacerbates UV-B stress of OsbZIP18_OE plants, suggesting that the excessive accumulation of serotonin may be responsible for the sensitivity of OsbZIP18_OE plants to UV-B stress. Overall, we identified a positive regulator of serotonin biosynthesis and demonstrated that UV-B-stress induced serotonin accumulation, partly in an OsbZIP18-dependent manner

Radio Frequency Switch Design with Interference Suppression and Electrostatic Discharge for 5th Generation of Mobile Network

In the next few years, the 5th generation of mobile network employing the massive multiple input multiple output (MIMO), beam-forming, mm-wave frequency bands and carrier aggregation techniques will further increase the data rate to enrich the growing of mobile devices at the price of more complex multi-band, multi-frequency front end module (FEM). As an indispensable part of radio-frequency front end (RFFE), antenna switch circuit needs more restrict performance not only the basic insertion loss, isolation and power handling capability, but the requirements from higher data rate, low interference and better reliability of 5G application. To achieve those additional requirements for 5G RF switch with 45nm silicon-on-insulator (SOI) CMOS technology, this dissertation presents a novel multi-bands switch array structure to analysis the interference between switches in a single chip. The comprehensive study of switch array reveals that existing noise isolation techniques are insufficient and calls for novel in-die interference elimination. To reduce this in-die crosstalk, an above-silicon through back-end-of-line (BEOL) metal wall is developed as a practical solution with about 18.5dB (~98.6%) suppression. To reach a higher data rate with available frequency bands, millimeter wave (mm-wave) switches (28GHz/38GHz) has been demonstrated with the consideration of reliability issue of electrostatic discharge (ESD) which will introduce severe parasitic effects under this frequency level and degrade the performance of RFICs. The insertion loss and isolation together with ESD protection capability have been compared which shows the importance of ESD-RFIC co-design. Considering the necessity of accurate estimation for ESD performance, a novel methodology for both human body model (HBM) and charged device model (CDM) ESD protections using combined TCAD simulation and TLP/VFTLP measurements is depicted. To improve the accuracy of parasitic capacitance extraction, this dissertation introduces an enhanced de-embedded method with the help of HFSS simulation which reduces one third of the testchip size and gives a better reference for co-design

Radio Frequency Switch Design with Interference Suppression and Electrostatic Discharge for 5th Generation of Mobile Network

In the next few years, the 5th generation of mobile network employing the massive multiple input multiple output (MIMO), beam-forming, mm-wave frequency bands and carrier aggregation techniques will further increase the data rate to enrich the growing of mobile devices at the price of more complex multi-band, multi-frequency front end module (FEM). As an indispensable part of radio-frequency front end (RFFE), antenna switch circuit needs more restrict performance not only the basic insertion loss, isolation and power handling capability, but the requirements from higher data rate, low interference and better reliability of 5G application. To achieve those additional requirements for 5G RF switch with 45nm silicon-on-insulator (SOI) CMOS technology, this dissertation presents a novel multi-bands switch array structure to analysis the interference between switches in a single chip. The comprehensive study of switch array reveals that existing noise isolation techniques are insufficient and calls for novel in-die interference elimination. To reduce this in-die crosstalk, an above-silicon through back-end-of-line (BEOL) metal wall is developed as a practical solution with about 18.5dB (~98.6%) suppression. To reach a higher data rate with available frequency bands, millimeter wave (mm-wave) switches (28GHz/38GHz) has been demonstrated with the consideration of reliability issue of electrostatic discharge (ESD) which will introduce severe parasitic effects under this frequency level and degrade the performance of RFICs. The insertion loss and isolation together with ESD protection capability have been compared which shows the importance of ESD-RFIC co-design. Considering the necessity of accurate estimation for ESD performance, a novel methodology for both human body model (HBM) and charged device model (CDM) ESD protections using combined TCAD simulation and TLP/VFTLP measurements is depicted. To improve the accuracy of parasitic capacitance extraction, this dissertation introduces an enhanced de-embedded method with the help of HFSS simulation which reduces one third of the testchip size and gives a better reference for co-design

Comparison of matrix frequency-doubling technology perimetry and standard automated perimetry in monitoring the development of visual field defects for glaucoma suspect eyes.

Perimetry is indispensable for the clinical management of glaucoma suspects. Our goal is to compare the performance of standard automated perimetry (SAP) and Matrix frequency-doubling technology (FDT) perimetry in monitoring the development of visual field (VF) defects in glaucoma suspect eyes.Longitudinal data of paired SAP and FDT from 221 eyes of 155 glaucoma suspects enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. All eyes had glaucomatous optic neuropathy or ocular hypertension, but normal SAP and FDT results at baseline. The development of glaucomatous VF defects was defined as the presence of a cluster of ≥ 3 (less conservative) or ≥ 4 (more conservative) locations confirmed on ≥ 2 additional consecutive tests. Risk factors for the development of VF defects were analyzed by COX proportional hazard models. After conversion into common logarithmic units, the rates of change of global VF indices were fitted with linear mixed models.FDT detected more eyes that developed VF defects than SAP using the less conservative criterion, and no significant difference was observed using the more conservative criterion. For those eyes detected by both SAP and FDT, FDT detected the development of VF defects either earlier than SAP or simultaneously in most cases. Baseline structural measurements were not significantly associated with an increased risk for the development of glaucomatous VF defects on either SAP or FDT. Older age was significantly associated with the development of VF defects on FDT but not on SAP. Both SAP and FDT detected a progressing worsening trend of pattern standard deviation over time with a similar rate of change between these test types.Matrix FDT would be useful to monitor the onset of VF defects in glaucoma suspects and may outperform SAP in the early stage of glaucomatous VF damage