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Electromagnetic (EM) instabilities and turbulence driven by the electron-temperature gradient are considered in a local slab model of a tokamak-like plasma. The model describes perturbations at scales both larger and smaller than the flux-freezing scale $d_e$, and so captures both electrostatic and EM regimes of turbulence. The well-known electrostatic instabilities -- slab and curvature-mediated ETG -- are recovered, and a new instability is found in the EM regime, called the Thermo-Alfv\'enic instability (TAI). It exists in both a slab version (sTAI, destabilising kinetic Alfv\'en waves) and a curvature-mediated version (cTAI), which is a cousin of the (electron-scale) kinetic ballooning mode (KBM). The cTAI turns out to be dominant at the largest scales covered by the model (greater than $d_e$ but smaller than $\rho_i$), its physical mechanism hinging on the fast equalisation of the total temperature along perturbed magnetic field lines (in contrast to KBM, which is pressure balanced). A turbulent cascade theory is then constructed, with two energy-injection scales: $d_e$, where the drivers are slab ETG and sTAI, and a larger (parallel system size dependent) scale, where the driver is cTAI. The latter dominates the turbulent transport if the temperature gradient is greater than a certain critical value, which scales inversely with the electron beta. The resulting heat flux scales more steeply with the temperature gradient than that due to electrostatic ETG turbulence, giving rise to stiffer transport. This can be viewed as a physical argument in favour of near-marginal steady-state in electron-transport-controlled plasmas (e.g., the pedestal). While the model is simplistic, the new physics that is revealed by it should be of interest to those attempting to model the effect of EM turbulence in tokamak-relevant configurations with high beta and large electron temperature gradients., Comment: 104 pages, 17 figures

Plasmas whose Coulomb-collision rates are very small may relax on shorter time scales to non-Maxwellian quasi-equilibria, which, nevertheless, have a universal form, with dependence on initial conditions retained only via an infinite set of Casimir invariants enforcing phase-volume conservation. These are distributions derived by Lynden-Bell (1967) via a statistical-mechanical entropy-maximisation procedure, assuming perfect mixing of phase-space elements. To show that these equilibria are reached dynamically, one must derive an effective `collisionless collision integral' for which they are fixed points -- unique and inevitable provided the integral has an appropriate H-theorem. We describe how such collision integrals are derived and what assumptions are required for them to have a closed form, how to prove the H-theorems for them, and why, for a system carrying sufficiently large electric-fluctuation energy, collisionless relaxation should be fast. It is suggested that collisionless dynamics may favour maximising entropy locally in phase space before converging to global maximum-entropy states. Relaxation due to interspecies interaction is examined, leading, inter alia, to spontaneous transient generation of electron currents. The formalism also allows efficient recovery of `true' collision integrals for both classical and quantum plasmas., Comment: 46 pages, 4 figures, submitted to JPP

Ion-gyroradius-scale microinstabilities typically have a frequency comparable to the ion transit frequency. Due to the small electron-to-ion mass ratio and the large electron transit frequency, it is conventionally assumed that passing electrons respond adiabatically in ion-gyroradius-scale modes. However, in gyrokinetic simulations of ion-gyroradius-scale modes in axisymmetric toroidal magnetic fields, the nonadiabatic response of passing electrons can drive the mode, and generate fluctuations with narrow radial layers, which may have consequences for turbulent transport in a variety of circumstances. In flux tube simulations, in the ballooning representation, these instabilities reveal themselves as modes with extended tails. The small electron-to-ion mass ratio limit of linear gyrokinetics for electrostatic instabilities is presented, in axisymmetric toroidal magnetic geometry, including the nonadiabatic response of passing electrons and associated narrow radial layers. This theory reveals the existence of ion-gyroradius-scale modes driven solely by the nonadiabatic passing electron response, and recovers the usual ion-gyroradius-scale modes driven by the response of ions and trapped electrons, where the nonadiabatic response of passing electrons is small. The collisionless and collisional limits of the theory are considered, demonstrating parallels in structure and physical processes to neoclassical transport theory. By examining initial-value simulations of fastest-growing eigenmodes, the predictions for mass-ratio scaling are tested and verified numerically for a range of collision frequencies. Insights from the small electron-to-ion mass ratio theory may lead to a computationally efficient treatment of extended modes., Comment: 75 pages, 23 figures

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

There have been rapid advances in precision medicine since the Human Genome Project was completed in 2003, including several noteworthy advances in Women's Health. This includes significant advances in predicting individualized cancer risk based on hereditary cancer genetic testing, with the number of known cancer-predisposition genes extending well beyond BRCA1 and BRCA2. This has been coupled with gene-specific management guidelines for several gynecologic cancers. In addition, genetic testing can also inform therapy selection for women with gynecologic cancers. Here we address hereditary cancer and practical cancer genetics as it relates to the practicing Obstetrician/Gynecologist.

Study Objective To assess the safety and effectiveness of the Minerva Endometrial Ablation System for the treatment of heavy menstrual bleeding in premenopausal women. Design Multicenter, randomized, controlled, international study (Canadian Task Force classification I). Setting Thirteen academic and private medical centers. Patients Premenopausal women (n = 153) suffering from heavy menstrual bleeding (PALM-COEIN: E, O). Intervention Patients were treated using the Minerva Endometrial Ablation System or rollerball ablation. Measurements and Main Results At 1-year post-treatment, study success (alkaline hematin ≤80 mL) was observed in 93.1% of Minerva subjects and 80.4% of rollerball subjects with amenorrhea reported by 71.6% and 49% of subjects, respectively. The mean procedure times were 3.1 minutes for Minerva and 17.2 minutes for rollerball. There were no intraoperative adverse events and/or complications reported. Conclusion The results of this multicenter randomized controlled trial demonstrate that at the 12-month follow-up, the Minerva procedure produces statistically significantly higher rates of success, amenorrhea, and patient satisfaction as well as a shorter procedure time when compared with the historic criterion standard of rollerball ablation. Safety results were excellent and similar for both procedures.

Objective To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor. Methods This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up. Outcomes related to hereditary cancer assessment and testing were measured during an 8-week postintervention period. Patients and health care providers were surveyed about satisfaction with the process. Data also were collected during the 8 weeks before the intervention to assess the effects of screening process improvements. Results A total of 4,107 patients were seen during the postintervention period, and 92.8% (3,811) were assessed for hereditary cancer risk. Among those assessed, 906 of 3,811 (23.8%) women met National Comprehensive Cancer Network guidelines for genetic testing, and 813 of 906 (89.7%) eligible patients were offered genetic testing. A total of 165 of 4,107 (4.0%) women completed genetic testing and received a final test result. This represents a fourfold increase over genetic testing immediately before the intervention (1.1%) and an eightfold increase over the previous year (0.5%). Testing identified pathogenic variants in 9 of 165 (5.5%) tested women. All health care providers (15/15) reported that they will continue to use the established hereditary cancer risk assessment process. In addition, 98.8% (167/169) of patients who submitted a sample for genetic testing and completed a patient satisfaction survey stated that they were able to understand the information provided, and 97.6% (165/169) expressed satisfaction with the overall process. Conclusion It is feasible to incorporate hereditary cancer risk assessment, education, and testing into community obstetrics and gynecology practices. As a result, multigene panel testing identified significant cancer risks that otherwise would not have been recognized.

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

A class of simple kinetic systems is considered, described by the 1D Vlasov-Landau equation with Poisson or Boltzmann electrostatic response and an energy source. Assuming a stochastic electric field, a solvable model is constructed for the phase-space turbulence of the particle distribution. The model is a kinetic analog of the Kraichnan-Batchelor model of chaotic advection. The solution of the model is found in Fourier-Hermite space and shows that the free-energy flux from low to high Hermite moments is suppressed, with phase mixing cancelled on average by anti-phase-mixing (stochastic plasma echo). This implies that Landau damping is an ineffective route to dissipation (i.e., to thermalisation of electric energy via velocity space). The full Fourier-Hermite spectrum is derived. Its asymptotics are $m^{-3/2}$ at low wave numbers and high Hermite moments ($m$) and $m^{-1/2}k^{-2}$ at low Hermite moments and high wave numbers ($k$). These conclusions hold at wave numbers below a certain cut off (analog of Kolmogorov scale), which increases with the amplitude of the stochastic electric field and scales as inverse square of the collision rate. The energy distribution and flows in phase space are a simple and, therefore, useful example of competition between phase mixing and nonlinear dynamics in kinetic turbulence, reminiscent of more realistic but more complicated multi-dimensional systems that have not so far been amenable to complete analytical solution., Comment: 35 pages, minor edits, final version accepted by JPP

Star polymer architectures were developed as multimodal imaging systems as fluorescence and magnetic resonance imaging (MRI) agents. Acrylate star polymers in hydrodynamic diameters of 10 ± 2 nm comprising fluorene derivatives as core units were modified with dopamine derivatives in adjustable quantities to chelate lanthanides such as Gd3+ and Eu3+. Ionic relaxivity values of 84 mM−1s−1 in an applied magnetic field of 0.5T at 37 °C confirmed the rapid water exchange of the highly hydrated star polymer. The utility is extended by the consecutive modification with allyl groups to perform thiol-ene reactions to conjugate thiol modified targeting units such as (cRGD) and dendritic molecular transporter as cell penetrating units. Cell uptake experiments in NIH 3T3 cells showed a rapid uptake of the star polymer independently of the presence of molecular transporter unit as it was detected through both the blue fluorescence of the fluorine core and the red fluorescence of the complexed Eu3+ to the linear polymer arms. In vivo mouse models confirmed the star polymer imaging reagent altered the image contrast significantly. In this work, we have adapted macromolecules as imaging agents for fluorescence microscopy and magnetic resonance imaging in conjunction with intracellular delivery and targeting.

We present the synthesis of polymeric nanoparticles from single ABA type block copolymers in an intramolecular-chain process to result 3-D architectures that confine a single chain of conducting copolymers. ABA triblock copolymers were prepared from conducting polymers such as fluorene homopolymers and fluorene/thiophene copolymers designed as telechelic macroinitiators to facilitate nitroxide-mediated living free radical polymerization methods. The polymerization with styrene and vinylbenzosulfone cross-linking units led to the desired ABA triblock copolymers with 8:1:8 and 5:1:5 ratios of the polymer copolymer blocks under living free radical polymerization conditions. In an intramolecular chain collapse process the ABA triblock copolymers form well-defined single chain nanoparticles with the confined semiconducting polymer block as core unit via a controlled cross-linking of the benzosulfone unit in the A block copolymer. The photoluminescence measurements illustrate the influence of the molecular weig...

The electrophoretic deposition of polystyrene/divinylbenzene (PS/DVB) star polymer-europium sulphide (EuS) nanocomposite films from a colloidal suspension is reported. Liquid suspension, containing both the PS/DVB star polymer and EuS nanocrystals were prepared by separately injecting dichloromethane (DCM) based solutions of EuS nanocrystals and of the star polymers, respectively, into a stratified liquid combination of hexane and DCM. Scanning electron microscopy illustrates images of the dependence of surface morphology on nanocrystal concentration of the PS/DVB-EuS star polymer film. These polymer-encased nanocrystal films may be a more practical option for the fabrication of magneto-optical thin film devices, such as optical switches, optical isolators, and optical memories.

We report the synthesis of star polymers with site-isolated chromophores obtained by nitroxide-mediated polymerization and reversible addition−fragmentation chain transfer techniques through the “arm first” method. Linear polymer precursors such as α-alkoxyamine-terminated polystyrene (PS) and thioester-terminated poly(acrylic acid) (PAA) were prepared followed by the addition of fluorescent divinyl cross-linkers derived from the fluorene and thiophene families. We first synthesized organic soluble star polymers containing hexyl-functionalized fluorene and thiophene cross-linkers with PS. Second, ethylene oxide (EO)-functionalized fluorene cross-linkers were incorporated into PAA linear precursors to give water-soluble star polymers with site-isolated chromophore core units. The photoluminescence increased significantly while the emitting wavelength corresponded with highly dilute, nonconjugated chromophores in solution. This effect is indicative for a highly localized concentration of chomophores in the ...

Summary: The development of suitable delivery systems for intracellular delivery of proteins, peptides and other bioactive materials opens the possibility to establish refined strategies for small drug delivery, gene delivery and vaccination. We present the assembly of advanced drug delivery systems from tailored building blocks to scaffolds and bioactive cargos to afford targeting and transport across biological barriers. In particular, the utilization of novel molecular transporter will advance the bioavailability of small and macromolecular drugs that show targeted intracellular delivery.

Planar wire array plasmas created by a 1 MA current discharge provide a novel method to investigate dense plasma dynamics, heating mechanism and radiation properties. This is a strongly inhomogeneous on small scale plasma, which has high resistivity with density and magnetic field dependence. The planar array dynamics leads to generation of a plasma with a chain of hot spots in a dense, high-opacity column. The single planar array consists of a number of wires with inter-wire separation of ≤1 mm in a linear row. It has been shown that a strongly inhomogeneous on small scale planar wire array plasma can radiate much more energy than the kinetic energy of imploding plasma. The results of recent experiments on scaling of radiation yields and powers with array masses, materials, inter-wire gaps and array width at 1 MA, 1.5 TW power Z-pinch Zebra generator at University of Nevada at Reno are presented. Radiation properties of planar arrays were compared with low-number cylindrical arrays and compact cylindrical array loads. Data on the generation of the hot spots during implosion of planar array plasma and its impact on the radiation pulse are reported.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

The transition between dormant and active Mycobacterium tuberculosis infection requires reorganization of its lipid metabolism and activation of a battery of serine hydrolase enzymes. Among these serine hydrolases, Rv0045c is a mycobacterial-specific serine hydrolase with limited sequence homology outside mycobacteria but structural homology to divergent bacterial hydrolase families. Herein, we determined the global substrate specificity of Rv0045c against a library of fluorogenic hydrolase substrates, constructed a combined experimental and computational model for its binding pocket, and performed comprehensive substitutional analysis to develop a structural map of its binding pocket. Rv0045c showed strong substrate selectivity toward short, straight chain alkyl esters with the highest activity toward four atom chains. This strong substrate preference was maintained through the combined action of residues in a flexible loop connecting the cap and α/β hydrolase domains and in residues close to the catalytic triad. Two residues bracketing the substrate-binding pocket (Gly90 and His187) were essential to maintaining the narrow substrate selectivity of Rv0045c toward various acyl ester substituents, as independent conversion of these residues significantly increased its catalytic activity and broadened its substrate specificity. Focused saturation mutagenesis of position 187 implicated this residue, as the differentiation point between the substrate specificity of Rv0045c and the structurally homologous ybfF hydrolase family. Insertion of the analogous tyrosine residue from ybfF hydrolases into Rv0045c increased the catalytic activity of Rv0045 by over 20-fold toward diverse ester substrates. The unique binding pocket structure and selectivity of Rv0045c provide molecular indications of its biological role and evidence for expanded substrate diversity in serine hydrolases from M. tuberculosis.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Tularemia is a deadly, febrile disease caused by infection by the Gram-negative bacterium, Francisella tularensis. Members of the ubiquitous serine hydrolase protein family are among current targets to treat diverse bacterial infections. Herein we present a structural and functional study of a novel bacterial carboxylesterase (FTT258) from F. tularensis, a homologue of human acyl protein thioesterase (hAPT1). The structure of FTT258 has been determined in multiple forms, and unexpectedly large conformational changes of a peripheral flexible loop occur in the presence of a mechanistic cyclobutanone ligand. The concomitant changes in this hydrophobic loop and the newly exposed hydrophobic substrate binding pocket suggest that the observed structural changes are essential to the biological function and catalytic activity of FTT258. Using diverse substrate libraries, site-directed mutagenesis, and liposome binding assays, we determined the importance of these structural changes to the catalytic activity and membrane binding activity of FTT258. Residues within the newly exposed hydrophobic binding pocket and within the peripheral flexible loop proved essential to the hydrolytic activity of FTT258, indicating that structural rearrangement is required for catalytic activity. Both FTT258 and hAPT1 also showed significant association with liposomes designed to mimic bacterial or human membranes, respectively, even though similar structural rearrangements for hAPT1 have not been reported. The necessity for acyl protein thioesterases to have maximal catalytic activity near the membrane surface suggests that these conformational changes in the protein may dually regulate catalytic activity and membrane association in bacterial and human homologues.

Serine hydrolases have diverse intracellular substrates, biological functions, and structural plasticity, and are thus important for biocatalyst design. Amongst serine hydrolases, the recently described ybfF enzyme family are promising novel biocatalysts with an unusual bifurcated substrate-binding cleft and the ability to recognize commercially relevant substrates. We characterized in detail the substrate selectivity of a novel ybfF enzyme from Vibrio cholerae (Vc-ybfF) by using a 21-member library of fluorogenic ester substrates. We assigned the roles of the two substrate-binding clefts in controlling the substrate selectivity and folded stability of Vc-ybfF by comprehensive substitution analysis. The overall substrate preference of Vc-ybfF was for short polar chains, but it retained significant activity with a range of cyclic and extended esters. This broad substrate specificity combined with the substitutional analysis demonstrates that the larger binding cleft controls the substrate specificity of Vc-ybfF. Key selectivity residues (Tyr116, Arg120, Tyr209) are also located at the larger binding pocket and control the substrate specificity profile. In the structure of ybfF the narrower binding cleft contains water molecules prepositioned for hydrolysis, but based on substitution this cleft showed only minimal contribution to catalysis. Instead, the residues surrounding the narrow binding cleft and at the entrance to the binding pocket contributed significantly to the folded stability of Vc-ybfF. The relative contributions of each cleft of the binding pocket to the catalytic activity and folded stability of Vc-ybfF provide a valuable map for designing future biocatalysts based on the ybfF scaffold.

Study Objective To assess adverse events associated with radiofrequency endometrial ablation in treatment of heavy menstrual bleeding in patients with a history of low transverse cesarean delivery (C-section group) and patients who delivered vaginally (vaginal delivery group). Design Retrospective cohort study (Canadian Task Force classification II-2). Setting Community-based gynecology practice in the United States. Patients The study included 194 patients (100 in the C-section group and 94 in the vaginal delivery group), aged 21 to 55 years, with a history of heavy menstrual bleeding. Interventions NovaSure endometrial ablation procedures were performed from April 2004 through December 2010. Measurements and Main Results Demographic characteristics, gynecologic and pregnancy history, and procedure setting were compared between groups. Intraoperative and postoperative adverse events that occurred within 72 hours of the procedure were summarized. The C-section and vaginal delivery groups were similar for demographic characteristics with the exception of age (mean [SD], 40.6 [5.0] years vs 42.5 [5.3] years, respectively; p = .01). Parity was significantly higher in the C-section group compared with the vaginal delivery group (2.4 [0.9] vs 2.1 [0.7]; p = .006). Adverse events commonly associated with endometrial ablation occurred in 3 patients in the C-section group and 5 patients in the vaginal delivery group (p = .68). In addition, 1 patient failed the pre-ablation cavity integrity assessment; therefore, ablation was not performed. All events resolved without sequelae. No uterine perforation or bowel or bladder injury occurred in any patient. Conclusion Radiofrequency endometrial ablation performed in a community practice was well tolerated in patients with a history of low transverse cesarean delivery.

Acetyl esterases from carbohydrate esterase family 7 exhibit unusual substrate specificity. These proteins catalyze the cleavage of disparate acetate esters with high efficiency, but are unreactive to larger acyl groups. The structural basis for this distinct selectivity profile is unknown. Here, we investigate a thermostable acetyl esterase (TM0077) from Thermotoga maritima using evolutionary relationships, structural information, fluorescent kinetic measurements, and site directed mutagenesis. We measured the kinetic and structural determinants for this specificity using a diverse series of small molecule enzyme substrates, including novel fluorogenic esters. These experiments identified two hydrophobic plasticity residues (Pro228, and Ile276) surrounding the nucleophilic serine that impart this specificity of TM0077 for small, straight-chain esters. Substitution of these residues with alanine imparts broader specificity to TM0077 for the hydrolysis of longer and bulkier esters. Our results suggest the specificity of acetyl esterases have been finely tuned by evolution to catalyze the removal of acetate groups from diverse substrates, but can be modified by focused amino acid substitutions to yield enzymes capable of cleaving larger ester functionalities.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

The controlled electrophoretic deposition of polystyrene/divinylbenzene (PS/DVB) star polymer films from a colloidal suspension is reported. Liquid suspensions, containing the PS/DVB star polymer, were prepared by injecting a dichloromethane (DCM) solution of the star polymer into a stratified liquid combination of hexane and DCM. A variety of hexane/DCM volume ratios were examined to identify the optimal solution conditions for electrophoretic deposition; thin films were produced from both unmixed and well-mixed hexane/DCM suspensions. Unmixed suspensions yielded spatially separated thin films, deposited in a controlled fashion, that were dependent on the polarity of the corresponding electrode. Films on the positive electrode differed in thickness, microstructure, and appearance from those formed on the negative electrode. In contrast, films produced from well-mixed hexane/DCM suspensions deposited uniformly across only the negative electrode. Atomic force microscopy studies revealed nanostructured surface morphologies that were unique to each of these films. Additionally, these microscopy studies shed light on the possible conformations of star polymers adsorbed on a surface. By controlling the composition and the mixing state of the solution and by controlling the bias of electrodes, we achieved controlled deposition of star polymer films with a specific nanostructure. These nanostructured films may have broad use in optical and biological device applications.

This MBA Project applies economic principles to assess changes affecting the automobile insurance industry, Pay-as-You-Drive (PAYD) and Pay-at-the-Pump (PATP). These changes could affect DoD in the future. The Project also applies economic principles to Basic Allowance for Housing (BAH) and the Military Housing Privatization Initiative (MHPI) currently affecting DoD. Each program is explained; then selected economic principles are applied that may influence decision-making of major stakeholders. Both PAYD and PATP automobile insurance provide consumers with the option to pay an amount for insurance directly related to actual miles driven. The shift from a fixed to a variable cost for automobile insurance creates an incentive for consumers to drive less, thus saving on the total cost of automobile insurance. BAH and MHPI together represent a shift in how DoD calculates and pays for housing of military service members. Congress and DoD are challenged with rebuilding military housing after decades of neglect.

We evaluated a program for prevention of preterm birth involving early detection and aggressive intervention with subcutaneous terbutaline pump therapy in a high-risk, private patient population. Risk factor screening, frequent cervical examinations, and intensive patient education were used to detect preterm labor before it progressed to an advanced stage. Home terbutaline pump therapy was prescribed for patients with uterine contractions associated with progressive cervical change, after stabilization with IV magnesium sulfate. In this study of 51 patients, home terbutaline pump therapy was successful in 98% of the cases, prolonging pregnancy an average of 6.6 weeks. Mean gestational age at delivery was 37 +/- 1.4 weeks, and infant birth weight averaged 3 kg. Only 22% of infants required admission to the neonatal intensive care unit, with a mean length of stay of 7.25 days. Population factors in this compliant, well-educated patient group may have contributed to the positive outcomes achieved.

We report the successful growth of ZnSe and ZnSe/ZnS superlattices on GaAs by pulsed laser deposition. An XeCl excimer laser operated at 308 nm was used to ablate/evaporate II‐VI bulk targets in an ultra high vacuum chamber. These superlattices are important optoelectronic materials that have major applications in the field of blue light emitting diodes and semiconductor lasers. For typical growth temperatures in the range 350–450 °C we obtained epitaxial layers with excellent optical properties. The laser power and fluence were varied to produce growth rates in the range 0.1–1 A/pulse. The layer thicknesses were determined by optical reflection spectroscopy. the photoluminescence of the pulsed laser deposited ZnSe layers showed dominant bound and free exciton features. The superlattice samples showed large blue shifts (∼400 meV) in the photoluminescence as the layer thicknesses were varied. These results are consistent with strong quantum confinement of the heavy holes in the ZnSe layers (valence band of...

An improved flow sheet for recording vital signs and fluid balance on a medical oncology unit was developed and tested using quality-assurance techniques. The new form, which replaced three separate forms, measurably improved documentation on all quality-assurance monitors tested. Additional benefits include cost-savings and decreased time expenditures by nursing staff.

We previously reported an X-linked combined immunode-ficiency disease (CID) characterized by immune deficiencies and complicating infections that were more moderate than those found in severe CID (SCID). Since other unstudied males in the family died in infancy, we questioned whether this T cell defect was more profound in early life. Subsequently, the development of blood T cells in an affected new-born male was examined. T cells were virtually undetectable at 48 hr. Over the next several months, CD4+ T cells (principally CD45RO+) rose to levels similar to those found in older affected males, but CD8+ T cells developed more slowly and never attained levels found in other affected males. Thus, this disease in early life mimics SCID and may pose a higher risk of fatal infections to affected individuals during that period. Finally, we speculate that the genetic defect may disrupt intrathymic development or selection of T cells.

We report the successful growth of ZnSe and ZnSe/ZnS superlattices on GaAs by pulsed laser deposition. An XeCl excimer laser operated at 308 nm was used to ablate/evaporate Il-VI bulk targets in an ultra high vacuum enclosure. For typical growth temperatures in the range 350°–450°C we obtained epitaxial layers with excellent optical properties. The laser power and fluence were varied to produce growth rates in the range 0.1–1 Å/pulse. The photoluminescence of the pulsed laser deposited ZnSe layers showed dominant bound and free exciton features. The superlattice samples showed large blue shifts (∼400 meV) in the photoluminescence as the layer thicknesses were varied. These results are consistent with strong quantum confinement of the heavy holes in the ZnSe layers (valence band offset for ZnSe/ZnS ∼ 850±100 meV), while the electrons are not confined to either layer because of very small conduction band offsets Strong exciton photoluminescence exhibited by our samples indicates that pulsed laser deposition is a promising growth technique for the fabrication of iI-VI epitaxial layers and strained layer superlattices for visible light emitter applications.

Four pediatricians introduced a portable cholesterol analyzer into their group practice. Their experience is described on the basis of 12 months of screening in 1665 children and adolescents. The overall 50th and 90th percentile values for a subgroup of 1406 routinely screened children were 156 and 197 mg/dL, respectively, but there was marked variation in these values among specific age and sex groups. Cholesterol levels decreased by age group during the early teenage years and increased thereafter, these changes occurring at ages approximately 2 years younger for girls than for boys. Further analysis of screening results for 398 sibling pairs demonstrated significant concordance between paired cholesterol levels when classified by the respective age- and sex-specific 90th percentile values for each member of the pair. Sibling pairs in which both members' cholesterol values exceeded their 90th percentile value were identified 2.4 times as frequently as expected (confidence interval 1.1 to 4.5, P = .029). The observations reported here indicate that office-based cholesterol screening in a pediatric practice may be both practical and useful, although further consideration of screening criteria is needed. Age- and sex-specific reference values for cholesterol levels during childhood could improve screening results. Special emphasis should be directed toward screening siblings of children in whom high cholesterol levels have been detected.