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Background: Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients. Methods: The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools—a 3-minute video and 1-page checklist—delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to “make one positive change” in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period. Results: EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of β-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT ( P =0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups. Conclusions: A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03334188.

Background Heart failure with reduced ejection fraction (HFrEF) benefits from initiation and intensification of multiple pharmacotherapies. Unfortunately, there are major gaps in the routine use of these drugs. Without novel approaches to improve prescribing, the cumulative benefits of HFrEF treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients. Hypothesis Encouraging patients to engage providers in HFrEF prescribing decisions will improve the use of guideline-directed medical therapies. Design The Electronically delivered, Patient-activation tool for Intensification of Chronic medications for Heart Failure with reduced ejection fraction (EPIC-HF) trial randomizes patients with HFrEF to usual care versus patient-activation tools—a 3-minute video and 1-page checklist—delivered prior to cardiology clinic visits that encourage patients to work collaboratively with their clinicians to intensify HFrEF prescribing. The study assesses the effectiveness of the EPIC-HF intervention to improve guideline-directed medical therapy in the month after its delivery while using an implementation design to also understand the reach, adoption, implementation, and maintenance of this approach within the context of real-world care delivery. Study enrollment was completed in January 2020, with a total 305 patients. Baseline data revealed significant opportunities, with Summary The EPIC-HF trial assesses the implementation, effectiveness, and safety of patient engagement in HFrEF prescribing decisions. If successful, the tool can be easily disseminated and may inform similar interventions for other chronic conditions.

Introduction Guideline Directed Medical Therapy (GDMT) recommends a combined regimen of beta blockers, ACE-I/ARB/ARNI, and mineralocorticoid receptor agents for optimal treatment of patients with Heart Failure with Reduced Ejection Fraction (HFrEF). Unfortunately, data from numerous heart failure registries show that HFrEF patients by-and-large continue to remain on suboptimal therapy. Interventions to improve medication plans often target either patient adherence or provider prescribing methods, with mixed results. This suggests that a more novel approach—in which provider and patient are equally involved—may be necessary to incite change. Hypothesis Aspects of Direct-to-Consumer (DTC) methods and Shared Decision Making models can be harnessed to encourage patients to engage providers in HFrEF prescribing decisions. This in turn may improve use of guideline-directed medical therapies. Methods Using DTC and Shared Decision Making models as our framework (Figure 1), we developed a user-friendly patient activation intervention—a 3-minute video and a HFrEF medication checklist—to encourage patients to discuss with their provider “one thing” that can be done to improve their medication plan. Patients were enrolled across three medical centers within the UCHealth medical system, and randomized to either intervention or control arms. Data on HFrEF medication prescribing and dosing was collected at enrollment, at time of intervention, and at 1-and-6 months from intervention. Results 305 patients were enrolled in total. At time of enrollment, 8.5% were on GDMT at suboptimal doses; only one patient (.3%) was on GDMT at target doses. Conclusions Our baseline results highlight the clear need for effective interventions to improve HFrEF prescribing. If successful, our intervention is simple enough to be adapted and implemented across a multitude of settings.

Fingolimod (Gilenya; FTY720), a synthetic compound based on the fungal secondary metabolite myriocin (ISP-I), is a potent immunosuppressant that was approved (September 2010) by the U.S. FDA as a new treatment for multiple sclerosis (MS). Fingolimod was synthesized by the research group of Tetsuro Fujita at Kyoto University in 1992 while investigating structure-activity relationships of derivatives of the fungal metabolite ISP-I, isolated from Isaria sinclairii. Fingolimod becomes active in vivo following phosphorylation by sphingosine kinase 2 to form fingolimod-phosphate, which binds to extracellular G protein-coupled receptors, sphingosine 1-phosphates, and prevents the release of lymphocytes from lymphoid tissue. Fingolimod is orally active, which is unique among current first-line MS therapies, and it has the potential to be used in the treatment of organ transplants and cancer. This review highlights the discovery and development of fingolimod, from an isolated lead natural product, through synthetic analogues, to an approved drug.

Background: The efficacy of cardiac screening programs for individuals in competitive athletics and high-risk occupations such as commercial and military aviation continues to be highly debated. For the past 12 yr, all United States Air Force (USAF) pilot applicants have undergone screening echocardiography. Methods: All available studies were reviewed for disqualifying (DQ) diagnoses. Findings were analyzed and compared to current USAF waiver policy. Results: Between inception in March 1994 and 01 September 2006, there were 20,208 screening echocardiograms performed. Of these, 294 (1.45%) were initially read as disqualifying. The most common diagnoses were bicuspid aortic valves with mild or less aortic insufficiency (N = 154, 0.76%), mitral valve prolapse with mild or less mitral regurgitation (N = 51, 0.25%), and trileaflet aortic valve with mild aortic insufficiency (N = 58, 0.29%). Evolution of USAF waiver policy has now rendered these diagnoses waiverable for entry into pilot training. Under current policy, 285/294 would be eligible for an unrestricted waiver, leaving only 9 individuals "DQ/no-waiver" (0.0445%). There were no cases of hypertrophic cardiomyopathy. Although the number of USAF pilot applicants has increased in recent years, the DQ/no-waiver rate has actually decreased, with only a single DQ/no-waiver finding since 2004 (N = 5802 studies; 0.0172%). Discussion: The infrequency of positive findings in this large cohort of screening echocardiography raises questions about the appropriateness of such programs. Under current USAF policy, it is not efficacious to perform screening echocardiography on all pilot applicants.

The efficacy of cardiac screening programs for individuals in competitive athletics and high-risk occupations such as commercial and military aviation continues to be highly debated. Prior to 2008, all United States Air Force (USAF) pilot applicants underwent screening echocardiography and some form

Although drizzle was a relatively infrequent occurrence during the Monterey Area Ship Track study, diverse measurements from several sources produced data signals consistent with a reduction in drizzle drops in stratus clouds affected by ship effluents. Concurrent increases in liquid water in the cloud droplet size range, due to redistribution from the drizzle mode, were not always observed, possibly because of the relatively small and often negligible amounts of water in the drizzle mode. Significant changes in cloud droplet size distribution, as well as reductions in drizzle flux and concentrations of drops >50-μm radius, were observed in ship tracks when drizzle was more uniformly present in the ambient cloud. Radiometric measurements showed that increased droplet concentrations in ship tracks, which resulted in reduced droplet sizes, can significantly alter the liquid water path. Radar observations indicated that the reduced reflectivities of ship tracks compared with ambient clouds may be du...

Emissions of particles, gases, heat, and water vapor from ships are discussed with respect to their potential for changing the microstructure of marine stratiform clouds and producing the phenomenon known as "ship tracks." Airborne measurements are used to derive emission factors of SO_2 and NO from diesel-powered and steam turbine-powered ships, burning low-grade marine fuel oil (MFO); they were ~15–89 and ~2–25 g kg^(-1) of fuel burned, respectively. By contrast a steam turbine–powered ship burning high-grade navy distillate fuel had an SO_2 emission factor of ~6 g kg^(-1). Various types of ships, burning both MFO and navy distillate fuel, emitted from ~4 x 10^(15) to 2 x 10^(16) total particles per kilogram of fuel burned (~4 x 10^(15)–1.5 x 10^(16) particles per second). However, diesel-powered ships burning MFO emitted particles with a larger mode radius (~0.03–0.05 µm) and larger maximum sizes than those powered by steam turbines burning navy distillate fuel (mode radius ~0.02 µm). Consequently, if the particles have similar chemical compositions, those emitted by diesel ships burning MFO will serve as cloud condensation nuclei (CCN) at lower supersaturations (and will therefore be more likely to produce ship tracks) than the particles emitted by steam turbine ships burning distillate fuel. Since steam turbine–powered ships fueled by MFO emit particles with a mode radius similar to that of diesel-powered ships fueled by MFO, it appears that, for given ambient conditions, the type of fuel burned by a ship is more important than the type of ship engine in determining whether or not a ship will produce a ship track. However, more measurements are needed to test this hypothesis. The particles emitted from ships appear to be primarily organics, possibly combined with sulfuric acid produced by gas-to-particle conversion of SO_2. Comparison of model results with measurements in ship tracks suggests that the particles from ships contain only about 10% water-soluble materials. Measurements of the total particles entering marine stratiform clouds from diesel-powered ships fueled by MFO, and increases in droplet concentrations produced by these particles, show that only about 12% of the particles serve as CCN. The fluxes of heat and water vapor from ships are estimated to be ~2–22 MW and ~0.5–1.5 kg s^(-1), respectively. These emissions rarely produced measurable temperature perturbations, and never produced detectable perturbations in water vapor, in the plumes from ships. Nuclear-powered ships, which emit heat but negligible particles, do not produce ship tracks. Therefore, it is concluded that heat and water vapor emissions do not play a significant role in ship track formation and that particle emissions, particularly from those burning low-grade fuel oil, are responsible for ship track formation. Subsequent papers in this special issue discuss and test these hypotheses.

The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI) < 9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of 16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These novel data on SSRI daily dose in pregnancy parallels the extant literature with tricyclic antidepressants (TCA). Further work to determine the predictors of dose adjustments will provide guidelines for minimizing fetal exposure to both medication and maternal mental illness.

A web-based Statics course is being developed by the authors as part of the Open Learning Initiative (OLI) at Carnegie Mellon University. OLI seeks to create and sustain freely available, cognitively informed learning tools designed to provide a substantial amount of instruction through the digital learning environment. This paper highlights the potential opportunities of online learning materials to enhance a traditional lecture-based course. We also identify the challenges that online materials face in promoting learning in an engineering course in which problem solving is intimately tied with drawing, and with writing and solving equations. Examples that illustrate the potential benefits of online materials, and that address the challenges associated with learning engineering courses, are presented. Finally, user studies and initial experience in blending these materials into an ongoing Statics course are summarized.

This paper focuses on an experimental program, "Engineering Education Scholars Workshops", funded by the National Science Foundation's Engineering Directorate. The authors report on the work in progress in developing, providing and evaluating faculty development workshops for emerging engineering faculty.

The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI)9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of 16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These novel data on SSRI daily dose in pregnancy parallels the extant literature with tricyclic antidepressants (TCA). Further work to determine the predictors of dose adjustments will provide guidelines for minimizing fetal exposure to both medication and maternal mental illness.

The introduction of lithium salts almost a century ago and the subsequent approval of lithium carbonate for the treatment of patients with bipolar disorder represent one of the cornerstones of modern psychopharmacology. The onset of bipolar disorder in women often occurs during the childbearing years, which complicates the treatment decisions secondary to the possibility of conception while taking medication. The establishment of the lithium registry for fetal teratogenesis in the late 1960s ushered in a heightened level of concern for the use of lithium during the reproductive years; although, in the years to come, it has become apparent that alternative pharmacologic treatments for bipolar disorder may exceed the teratogenic risk of lithium monotherapy. In this paper, the available data on the use of antimanic medications during pregnancy and lactation are reviewed with an emphasis on providing a realistic risk/benefit assessment for medication selection and management of these patients. Treatment strategies are discussed for (1) women who are contemplating pregnancy (2) women who inadvertently conceive while taking medications (3) women who choose to become pregnant while taking medication, and (4) women who intend to breastfeed while taking medications.

The ability of the systemic circulation to maintain cardiac output during decreases in arterial pressure was evaluated in conscious dogs with intact reflexes (n = 8) and during pharmacological blockade of the autonomic nervous system, angiotensin II formation, and arginine vasopressin (n = 6). Cardiac output was measured electromagnetically, and aortic pressure was controlled via a gravity reservoir connected to a carotid artery. When aortic pressure was decreased in either small steps to approximately 60% of control, or decreased in a single square-wave step to 75% of control and maintained for 2 h, cardiac output decreased to the same or a greater extent in both control and areflexic dogs. Thus total peripheral resistance did not decrease, and autoregulation of the cardiac output did not occur in response to short-term (less than or equal to 2 h) decreases in arterial pressure, even in the absence of the major pressor systems. After long-term (greater than 8 h) decreases in arterial pressure to 75% of control in five dogs with all reflexes intact, significant autoregulation of the cardiac output occurred. The relationship between the gain of blood flow autoregulation and the corresponding values of mixed venous oxygen tension suggests that whole body autoregulation results when oxygen extraction reserve becomes limited.

Modern microelectronics technology holds the promise of high level, computer-aided design of very complex systems on a single silicon chip. The freedom to create non-standard architectures within this context has stimulated widespread interest in the development of computing structures that offer increased processing speed relative to the von Neumann architecture. This paper describes two architectures that are especially well suited for large scale integration because of their concurrent structure and their use of primarily local data flows. The first architecture is designed to implement the QR matrix decomposition and it can be used to reliably solve the least squares and eigenvalue problems of linear algebra. The second architecture is based on an elementary building block approach to the realization of FIR and IIR lattice digital filters. An especially important issue that is sometimes overlooked in the system level design of an architecture is the impact of the particular scheme for implementing the fundamental operations such as multiplication, rotation, etc., on the performance of the highly parallel computing structure. It is argued that if one can imbed pipelined operations within the concurrent computing structure, then often the resulting system will not only provide substantial processing gain but it can be implemented in such a way that efficient use of chip real estate is achieved.

Hindlimb vascular bed pressure-flow relationships were evaluated in seven conscious dogs using a newly developed controlled-flow perfusion technique. For controlled-flow perfusion, blood was diverted from a common carotid artery to a roller pump for perfusion of the left hindlimb vascular bed via an artificial vascular graft anastomosed to the left external iliac artery. An occlusion cuff positioned around the external iliac artery proximal to the graft arrested normal hindlimb blood flow during perfusion. Collateral flow was minimized by ligating all other major arteries supplying the left hindlimb. Hindlimb perfusion pressure, measured via the left deep femoral artery, decreased to a plateau value of 19.7 +/- 3.4 mmHg when pump flow was zero. Pressure-flow relationships were evaluated while the dogs were at rest by changing flow in small “square-wave” steps for 3 min each and measuring the steady-state perfusion pressure at each step. The hindlimb was perfused over a wide range of flows (25–450 ml/min) that resulted in perfusion pressures ranging from 40 to 175 mmHg. The hindlimb pressure-flow relationship obtained was indicative of net passive vascular behavior. That is, resistance to flow decreased with increases in flow, such that a curvilinear pressure-flow relationship occurred that was convex to the pressure axis. We conclude that the hindlimb circulation of resting conscious dogs can be perfused using controlled-flow perfusion techniques. These techniques can also be applied to other vascular beds and should be useful for evaluating peripheral vascular responses to drugs and reflexogenic alterations.

Normalized multidimensional Newton-Raphson method eliminating initial guess, using two- transformation technique

Stimulated production of reactive oxygen species (ROS) by plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidases (Nox) in non-phagocytic cells regulates a number of biological processes including growth, vessel tone, and oxygen sensing. The purpose of this study was to investigate H(2)O(2)-stimulated ROS production in primary adult cardiac fibroblasts (CF). Results demonstrate that CF express an H(2)O(2)-inducible oxidant generating system that is inhibitable by diphenylene iodonium (DPI) and sensitive to antioxidants. In addition to H(2)O(2), generation of ROS was stimulated potently by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and arachidonic acid (AA) in a protein kinase C-independent manner. Pretreatment with arachidonyl trifluoromethyl ketone was nearly as effective as DPI at reducing H(2)O(2)- and OAG-stimulated oxidant generation indicating a central role for phospholipase A(2) (PLA(2)) in this signaling pathway. Co-stimulation with H(2)O(2) and OAG did not increase ROS generation as compared to OAG alone suggesting both agonists signal through a shared, rate-limited enzymatic pathway involving PLA(2). Co-stimulation with H(2)O(2) and AA had additive effects indicating these two agonists stimulate oxidant production through a parallel activation pathway. Reverse transcriptase-coupled polymerase chain reaction and Western blotting demonstrate primary cardiac fibroblasts express transcripts and protein for Nox4, p22, p47, and p67 phox. Transfections with Nox4 small inhibitory ribonucleic acid oligonucleotides or p22 phox antisense oligonucleotides significantly downregulated stimulated Nox activity. Inhibitors of nitric oxide synthases were without effect. We conclude adult CF express Nox4/p22 phox-containing oxidant generating complex activated by H(2)O(2), OAG, and AA through a pathway that requires activation of PLA(2).

Fabrication of integrated circuits or systems that span an entire wafer or a significant part of a wafer have held the interest of a number of semiconductor researchers [1]. The expected benefits of smaller size, increased reliability, reduced cost, shorter signal delays, and simpler packaging are significant. Unfortunately, most of the previously reported attempts have been surpassed by increased density, improved circuitry, and better packaging of conventional integrated circuits.

A highly concurrent architecture for a high-speed digital signal processing engine is described. Initially, a repetitive structure of identical processing elements which realizes a one-dimensional state variable filter is defined. This structure uses primarily local communication with topologically simple interconnections among the processing elements. It is then shown that these relatively simple processing engines can be combined, again in a regular manner, to solve two-dimensional filter problems. Application of this basic filter structure to provide high-speed solutions for other standard signal processing transforms such as the Discrete Fourier Transform , the Chirp Z Transform, and the Running Discrete Discrete Transform is also presented.

ABSTRACT The collapse of Texas Tower Number 4 radar platform offshore from New Jersey in 1961 with the loss of 28 lives and the destruction of 22 offshore platforms in the northern Gulf of Mexico during the passage of Hurricanes Hilda (1964) and Betsy (1965) emphasize the importance of sound dynamic analyses of offshore installations subject to environmental extremes. This paper presents an analysis of the dynamic response of a Cook Inlet monopod structure subject to severe tidal current-driven ice loads. Dynamic analyses of several offshore structures in the northern Gulf are also presented. Basic dynamic analysis methods are discussed with an emphasis on their range of applicability and limitations. Measurement techniques utilized in gathering pertinent vibration at a from offshore platforms are discussed. Comparisons of measured and computed dynamic response data are presented to establish the validity of the analysis techniques utilized. The importance of developing sound analytical and measured dynamic response data for offshore installations is outlined. INTRODUCTION More than 16 per cent of the free world's petroleum is currently being produced from the continental shelves offshore from some 60 countries. While much of the early development has been concentrated in shallow water areas (under 100 feet), more and more of this production is being developed in water depths greater than 100 feet. Problems associated with the drilling and production of oil in these deeper water areas end to increase exponentially with increase in water depth. This is particularly true with regard to the dynamic response of offshore structures to high wind and wave forces created by environmental extremes such as exist during the passage of a major storm or hurricane. In the early stages, offshore structures installed in shallow water depths were designed with little consideration for the dynamic response of these structures. So long as the structure was composed of a large deck are supported by relatively short piles, the inherent stiffness of the structure resulted in a high natural frequency of response with low amplitude oscillations due to severe win and wave loads. With fixed platforms now installed in mean water depths as great as 340 feet, platform dynamic response has become a major consideration for the safety of these structures which are exposed to high storm induced environmental forces. The devastating effects of hurricane winds, waves, tides, and currents are clearly demonstrated by the destruction of 22 and severe damage to 10 other offshore structures during the passage of hurricanes Hilda (1964) and Betsy (1965) across the Gulf of Mexico and the Louisiana coast (Reference 1). Although 4 of these structures were old, 3 of them had been designed for a "maximum 100-yearstorm". Most structural failures during the passage of hurricanes HiIda and Betsy were probably quite similar to the collapse of the Eugene Island Block 276-A platform shown in Figure (Reference 2). In this artist's drawing (based on divers' reports) it may be noted that the platform jacket and the platform deck section were found essentially intact.