Puget Sound Health Care System

Seattle, WA, United States

Puget Sound Health Care System

Seattle, WA, United States
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News Article | February 21, 2017
Site: www.eurekalert.org

PHILADELPHIA -- It is commonly known that testosterone levels decrease as men age, but until last year, little was known about the effects of testosterone treatment in older men with low testosterone. Today, in a group of papers published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine, researchers found that testosterone treatment improved bone density and anemia for men over 65 with unequivocally low testosterone. However, testosterone treatment did not improve cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries. A team of researchers from the Perelman School of Medicine at the University of Pennsylvania, and twelve other medical centers in the United States, in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. The first paper, which reported that testosterone treatment improved sexual function and mood, was published in February 2016. Today's publications of the Bone, Anemia, Cognition and Cardiovascular Trials conclude the primary results of the study. Researchers found that testosterone treatment improved bone density and estimated bone strength, as determined by quantitative computed tomography (CT). The treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "The paper reporting the results of the first three trials published last year was the first to show there were advantages to giving testosterone treatment to older men with low testosterone levels, and the bone and anemia trial results further support a benefit," said the principal investigator Peter J. Snyder, MD, a professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism. "However, the increase of plaque buildup in the coronary artery shows that this treatment may also have some risk" In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. However, Snyder added, "treating 788 men for one year is far too few to draw conclusions about the clinical significance of the increase in coronary artery plaque volume and the cardiovascular risk of testosterone treatment." The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said Snyder. The TTrials were conducted at 12 additional medical centers across the country including Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, Harbor-UCLA Medical Center, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health, and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


Harris A.H.S.,Center for Health Care Evaluation | Reeder R.,Center for Health Care Evaluation | Ellerbe L.,Center for Health Care Evaluation | Bradley K.A.,Puget Sound Health Care System | And 2 more authors.
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: The risks associated with preoperative alcohol misuse by patients before undergoing total joint arthroplasty are not well known, yet alcohol misuse by surgical patients is common and has been linked to an increased risk of complications after other procedures. The purpose of this study was to evaluate the association between a patient's preoperative standardized alcohol-misuse screening score and his or her risk of complications after total joint arthroplasty. Methods: The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) is an alcohol-misuse screening instrument administered annually to all patients receiving care through the Veterans Health Administration (VHA). The scores range from 0 to 12, with higher scores signifying greater and more frequent consumption. In a study of 185 male patients who had alcohol screening scores recorded in the year preceding surgery at a Palo Alto VHA facility, and who reported at least some alcohol use, we estimated the association between preoperative screening scores and the number of surgical complications in an age and comorbidity-adjusted regression analyses. Results: Of the 185 patients reporting at least some drinking in the year before their total joint replacement, 17% (thirty-two) had an alcohol screening score suggestive of alcohol misuse; six of those thirty-two patients had one complication, four had two complications, and two had three complications. The screening scores were significantly related to the number of complications in a negative binomial regression analysis (exp[b] = 1.29, p = 0.035), which demonstrated a 29% increase in the expected number of complications with every additional point of the screening score above 1, although with wide confidence intervals for the higher scores. Conclusions: Complications following total joint arthroplasty were significantly related to alcohol misuse in this group of male patients treated at a VHA facility. The AUDIT-C has three simple questions that can be incorporated into a preoperative evaluation and can alert the treatment team to patients with increased postoperative risk. Preoperative screening for alcohol misuse, and perhaps preoperative counseling or referral to treatment for heavy drinkers, may be indicated for patients who are to undergo total joint arthroplasty. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.


News Article | February 21, 2017
Site: www.eurekalert.org

LOS ANGELES -- Research published today found testosterone treatment improved bone density and anemia for men over 65 with low testosterone. But the treatment didn't improve patients' cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries, according to four studies published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine. A team of researchers from LA BioMed and 12 other medical centers in the U.S., in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. Four of those studies were published today. "While we have long known that testosterone levels decrease as men age, very little was known about the effects of testosterone treatment in older men with low testosterone until last year," said Ronald S. Swerdloff, MD, an LA BioMed researcher and co-author of the four studies. "Our first published research last year found benefits to testosterone treatment, and this latest series of studies finds further benefits in terms of improving bone density and anemia. However, the cardiovascular study showed that the testosterone treatment group had increased plaque buildup in coronary arteries, suggesting a possible risk factor." In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. "We want to emphasize that this study was exploratory and emphasizes the need for a large-scale, well-controlled, long-term safety trial to determine if there is an increased risk of heart damage or death," Dr. Swerdloff said. "As with all medications the physician and patient need to balance the benefits and risks of treatment." Dr. Christina Wang, an LA BioMed researcher and co-author of the four studies, noted that the researchers also found that testosterone treatment improved bone density and estimated bone strength, as determined by CT. "After one year of treatment, older men with low testosterone significantly increased bone density and estimated bone strength compared to those on placebo," said Dr. Wang. "A larger and longer trial would be needed to determine if testosterone treatment reduces fracture risk." Testosterone treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "As a result of these findings, physicians may wish to consider measuring testosterone in men age 65 and older who have unexplained anemia and symptoms suggestive of low testosterone levels," said Dr. Swerdloff. The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said principal investigator Peter J. Snyder, MD, University of Pennsylvania Perelman School of Medicine professor of medicine in the Division of Endocrinology, Diabetes and Metabolism. In addition to LA BioMed and University of Pennsylvania, the TTrials were conducted at Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.


News Article | February 21, 2017
Site: www.eurekalert.org

New Haven, Conn.-- Older men with low testosterone levels showed improved bone density and strength, as well as reduced anemia, after one year of testosterone therapy, according to a new study conducted at Yale and other sites. The therapy had no impact on cognitive function, however, and may worsen plaque in coronary arteries, said the researchers. The results of the four trials were published online Feb. 21 in two journals, JAMA and JAMA Internal Medicine. The studies, known as the TTrials, are the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due to age. At 12 study sites across the country, 790 participants were given testosterone gel or a placebo applied daily to the skin. Over a year, investigators measured the effects of testosterone on four areas: anemia, bone density and strength, cardiovascular health, and cognitive function. The findings are the second set of results from the long-term TTrials, which demonstrated the benefit of testosterone therapy on sexual function in older men with low testosterone in a report published last year. "Looking globally at testosterone therapy, the strongest evidence is for sexual function," said Thomas Gill, M.D., the Humana Foundation Professor of Medicine and a lead author. The latest studies demonstrate that if a man with low serum testosterone is going to be prescribed testosterone for diminished sexual function, he may have some additional benefits on hemoglobin levels and bone density, Gill noted. While the outcome of the cardiovascular trial raises concern, he said, a larger and longer study would be needed to determine the clinical significance of the findings. The TTrials were conducted at 12 additional medical centers, including Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, Harbor-UCLA Medical Center, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pennsylvania, and University of Pittsburgh School of Public Health. The studies were funded primarily by the National Institute on Aging, part of the National Institutes of Health (NIH). Additional funding came from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all part of NIH. Additional funding, and the study drug and placebo, were provided by AbbVie Pharmaceuticals.


Wyman S.K.,Fred Hutchinson Cancer Research Center | Knouf E.C.,Fred Hutchinson Cancer Research Center | Knouf E.C.,University of Washington | Parkin R.K.,Fred Hutchinson Cancer Research Center | And 10 more authors.
Genome Research | Year: 2011

Modification of microRNA sequences by the 3′ addition of nucleotides to generate so-called "isomiRs" adds to the complexity of miRNA function, with recent reports showing that 3′ modifications can influence miRNA stability and efficiency of target repression. Here, we show that the 3′ modification of miRNAs is a physiological and common posttranscriptional event that shows selectivity for specific miRNAs and is observed across species ranging from C. elegans to human. The modifications result predominantly from adenylation and uridylation and are seen across tissue types, disease states, and developmental stages. To quantitatively profile 3′ nucleotide additions, we developed and validated a novel assay based on NanoString Technologies' nCounter platform. For certain miRNAs, the frequency of modification was altered by processes such as cell differentiation, indicating that 3′ modification is a biologically regulated process. To investigate the mechanism of 3′ nucleotide additions, we used RNA interference to screen a panel of eight candidate miRNA nucleotidyl transferases for 3′ miRNA modification activity in human cells. Multiple enzymes, including MTPAP, PAPD4, PAPD5, ZCCHC6, ZCCHC11, and TUT1, were found to govern 3′ nucleotide addition to miRNAs in a miRNA-specific manner. Three of these enzymes-MTPAP, ZCCHC6, and TUT1-have not previously been known to modify miRNAs. Collectively, our results indicate that 3′ modification observed in next-generation small RNA sequencing data is a biologically relevant process, and identify enzymatic mechanisms that may lead to new approaches for modulating miRNA activity in vivo. © 2011 by Cold Spring Harbor Laboratory Press.


Fey N.P.,University of Texas at Austin | Klute G.K.,Puget Sound Health Care System | Neptune R.R.,University of Texas at Austin
Clinical Biomechanics | Year: 2011

Background: Below-knee amputees commonly experience asymmetrical gait patterns and develop comorbidities in their intact and residual legs. Carbon fiber prosthetic feet have been developed to minimize these asymmetries by utilizing elastic energy storage and return to provide body support, forward propulsion and leg swing initiation. However, how prosthetic foot stiffness influences walking characteristics is not well-understood. The purpose of this study was to identify the influence of foot stiffness on kinematics, kinetics, muscle activity, prosthetic energy storage and return, and mechanical efficiency during amputee walking. Methods: A comprehensive biomechanical analysis was performed on 12 unilateral below-knee amputees. Subjects walked overground at 1.2 m/s with three prosthetic feet of varying keel and heel stiffness levels, which were created using additive manufacturing. Findings: As stiffness decreased, peak residual and intact leg ankle angles and residual leg knee flexion angle increased. The residual and intact leg braking ground reaction forces and knee extensor moments, residual leg vastus and gluteus medius activity, and intact leg vastus and rectus femoris activity also increased. The second vertical ground reaction force peak and hamstring activity in the residual leg and first vertical ground reaction force peak in the intact leg decreased. In addition, prosthetic energy storage and return increased and mechanical efficiency decreased as stiffness decreased. Interpretation: Decreasing foot stiffness can increase prosthesis range of motion, mid-stance energy storage and late-stance energy return, but the net contributions to forward propulsion and swing initiation may be limited as additional muscle activity to provide body support becomes necessary. © 2011 Elsevier Ltd. All rights reserved.


Ventura J.D.,Gordon College | Segal A.D.,Puget Sound Health Care System | Klute G.K.,Puget Sound Health Care System | Neptune R.R.,University of Texas at Austin
Gait and Posture | Year: 2011

Turning plays a prominent role in daily living activities and requires the modulation of the ground reaction forces to accelerate the body's center-of-mass along the path of the turn. With the ankle plantarflexors being prominent contributors to the propulsive ground reaction forces, it is not clear how transtibial amputees perform turning tasks without these important muscles. The purpose of this study was to identify the compensatory mechanisms used by transtibial amputees during a simple turning task by analyzing the radial and anterior-posterior ground reaction impulses and sagittal, transverse and coronal joint work of the residual and intact legs. These quantities were analyzed with the residual leg on both the inside and outside of the turn and compared to non-amputees. The analysis showed that amputees and non-amputees use different joint strategies to turn. Amputees rely primarily on sagittal plane hip joint work to turn while non-amputees rely primarily on ankle work in the sagittal plane and hip joint work in the coronal plane. Differences in strategies are most likely due to the minimal power output provided by the passive prosthetic feet used by amputees and perhaps a desire to minimize the risk of falling. Understanding these differences in turning strategies will aid in developing effective rehabilitation therapies and prosthetic devices that improve amputee mobility. © 2011 Elsevier B.V.


Ventura J.D.,University of Texas at Austin | Klute G.K.,Puget Sound Health Care System | Neptune R.R.,University of Texas at Austin
Clinical Biomechanics | Year: 2011

Background: Prosthetic devices are intended to return lower limb amputees to their pre-amputation functional status. However, prosthetic devices designed for unilateral below-knee amputees have yet to completely restore the biomechanical functions normally provided by the ankle muscles, leading to gait asymmetries and increased reliance on their intact leg. In an effort to improve amputee gait, energy storage and return feet have been developed that store mechanical energy in elastic structures in early to mid-stance and return it in late stance. However, little is known regarding how ankle compliance and the level of energy return influences walking mechanics. The purpose of this study was to identify the influence of prosthetic ankle dorsiflexion and energy storage and return on leg loading during steady-state walking. Methods: Compliant ankles with different stiffness levels were attached to a Seattle Lightfoot2 in different orientations (forward- and reverse-facing). Findings: The ankles decreased residual leg vertical ground reaction forces in late stance, increased residual leg propulsive ground reaction force impulses and increased residual leg knee joint extensor moments. The reverse-facing ankles increased residual leg vertical ground reaction forces in early stance, and the compliant forward-facing ankle increased residual leg braking impulses. In contrast to previous studies, increased energy storage and return from compliant ankles did not decrease hip joint powers or the intact leg vertical ground reaction forces. Interpretation: These results provide insight into the relationships between ankle dorsiflexion, energy storage and return, and leg loading, which may lead to more effective prosthetic devices to improve amputee gait. © 2010 Elsevier Ltd.


Ventura J.D.,University of Texas at Austin | Klute G.K.,Puget Sound Health Care System | Neptune R.R.,University of Texas at Austin
Gait and Posture | Year: 2011

In an effort to improve amputee gait, energy storage and return (ESAR) prosthetic feet have been developed to provide enhanced function by storing and returning mechanical energy through elastic structures. However, the effect of ESAR feet on muscle activity in amputee walking is not well understood. Previous studies have analyzed commercial prosthetic feet with a wide range of material properties and geometries, making it difficult to associate specific ESAR properties with changes in muscle activity. In contrast, prosthetic ankles offer a systematic way to manipulate ESAR properties while keeping the prosthetic heel and keel geometry intact. In the present study, ESAR ankles were added to a Seattle Lightfoot2 to carefully control the energy storage and return by altering the ankle stiffness and orientation in order to identify its effect on lower extremity muscle activity during below-knee amputee walking. A total of five foot conditions were analyzed: solid ankle (SA), stiff forward-facing ankle (FA), compliant FA, stiff reverse-facing ankle (RA) and compliant RA. The ESAR ankles decreased the activity of muscles that contribute to body forward propulsion and increased the activity of muscles that provide body support. The compliant ankles generally caused a greater change in muscle activity than the stiff ankles, but without a corresponding increase in energy return. Ankle orientation also had an effect, with RA generally causing a lower change in muscle activity than FA. These results highlight the influence of ESAR stiffness on muscle activity and the importance of prescribing appropriate prosthetic foot stiffness to improve rehabilitation outcomes. © 2010 Elsevier B.V.


Fey N.P.,University of Texas at Austin | Klute G.K.,Puget Sound Health Care System | Neptune R.R.,University of Texas at Austin
Journal of Biomechanics | Year: 2013

Most prosthetic feet are designed to improve amputee gait by storing and releasing elastic energy during stance. However, how prosthetic foot stiffness influences muscle and foot function is unclear. Identifying these relationships would provide quantitative rationale for prosthetic foot prescription that may lead to improved amputee gait. The purpose of this study was to identify the influence of altered prosthetic foot stiffness on muscle and foot function using forward dynamics simulations of amputee walking. Three 2D muscle-actuated forward dynamics simulations of unilateral below-knee amputee walking with a range of foot stiffness levels were generated, and muscle and prosthetic foot contributions to body support and propulsion and residual leg swing were quantified. As stiffness decreased, the prosthetic keel provided increased support and braking (negative propulsion) during the first half of stance while the heel contribution to support decreased. During the second half of stance, the keel provided decreased propulsion and increased support. In addition, the keel absorbed less power from the leg, contributing more to swing initiation. Thus, several muscle compensations were necessary. During the first half of stance, the residual leg hamstrings provided decreased support and increased propulsion. During the second half of stance, the intact leg vasti provided increased support and the residual leg rectus femoris transferred increased energy from the leg to the trunk for propulsion. These results highlight the influence prosthetic foot stiffness has on muscle and foot function throughout the gait cycle and may aid in prescribing feet of appropriate stiffness. © 2012 Elsevier Ltd.

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