MICROBUBBLE INFUSED HYDROGELS FOR CARTILAGE TISSUE ENGINEERING
Andrew Mark
Columbia Univ New York Morningsidecity: New York country: United States (us)
Grant 3R21EB014382-01A1S1 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: In this potentially high-reward R21 proposal, we explore the novel application of lipid-shelled, gas-filled microbubbles (used clinically as ultrasound contrast agents) as a method for creating cell laden microporous hydogels for cartilage tissue engineering. Rather than classical techniques of porogen leaching (which are often toxic), microbubble dissolution can be triggered "on-demand" by applied hydrostatic pressure or ultrasound. The latter affords unique spatial control of micropore formation in the hydrogel, which we anticipate will promote culture development of mechanically functional, large (anatomically-shaped) engineered cartilage constructs to serve ultimately as clinical alternatives to large allografts or joint implants. The microbubble dissolution process generates micropores that are homogeneously distributed within the gels, while enabling the direct ab initio immobilization of cels within the gels. Importantly, preliminary data demonstrates a 2-fold increase in mechanical properties of chondrocyte-seeded hydrogels with microbubble- derived microporosity versus control gels. This effect is greater than we have observed with applied deformational loading using chondrogenic media. We also have evidence that microbubbles promote more homogeneous axial properties. The proposed research to fabricate patella constructs is guided by these Hypotheses (H) & Specific Aims (SA) H1 Microbubble-infused hydrogel scaffolds exhibit increasing solute permeability in a microbubble dose- dependent manner. SA1. Fabricate chondrocyte-seeded hydrogel constructs with microbubble concentrations yielding initially 25%, 50%, 100% greater permeability of transforming growth factor beta 3 (TGF-23), a critical chemical factor in engineering of functional cartilage, than the hydrogel without microbubbles (0%). Measure solute permeability (P) and material properties including Young´s modulus (EY) and dynamic modulus (G*). H2 Chondrocyte-seeded, hydrogel scaffolds incorporated with microbubbles will yield engineered tissues with properties closer to the native tissue compared to the same scaffolds without microbubbles. H2a. The properties of constructs with microbubbles are dependent on timing of microbubble dissolution. H2b. Application of applied dynamic deformational loading enhances the beneficial effects of microbubble-infused hydrogels. SA2a. Using microbubble conditions of SA1 (25%, 50%, 100% increase in TGF-23 permeability), culture constructs for 56 days with triggered dissolution of gas-filled microbubbles on day 0 or day 14. Measure material and biochemical properties, solute permeability, and perform histology on day 0, 14, 28 and 56. SA2b. Repeat SA2a using the best responding groups for microbubbles triggered on day 0 and day 14, but with application of daily dynamic deformational loading (10% deformation at 1 Hz, 3 hours/day)
Keywords: Age; Allografting; American; Anatomy; Arthritis; Biochemical; Boxing; Caliber; Cartilage; Cartilage injury; Cells; Chemicals; Chondrocytes; Clinical; Contrast Media; cost; Cues; Data; Defect; Degenerative polyarthritis; Development; Diffusion; Direct Costs; Dose; Drug Formulations; effective therapy; Engineering; Exhibits; Gases; Gel; high reward; Histology; Hour; Human; Hydrogels; Hydrostatic Pressure; Immobilization; Implant; Joint repair; Joints; Knee; Knee bone; Laboratories; Lipids; Measures; Mechanics; Medical; Methods; Microbubbles; novel; Nutrient; Peripheral; Permeability; Phenotype; Physiological; prevent; Process; Property; Proteoglycan; Relative (related person); Replacement Arthroplasty; Research; scaffold; Seeds; Sepharose; Shapes; solute; Staining method; Stains; Swelling; Techniques; Technology; Thick; Time; Tissue Engineering; Tissues; transforming growth factor beta3; Ultrasonography
Relevance: An estimated 27 million Americans age 25 and older have osteoarthritis (OA), with the total direct cost of OA is estimated at $28.6 billion dollars a year in related medical costs. Effective treatment of cartilage injuries using tissue engineering strategies may prevent the development of OA and may reduce the need for a total joint replacement. In this proposal, the novel application of microbubble technology as a means of fabricating cell seeded hydrogel scaffold constructs with microporosity for cartilage tissue engineering is investigated
Project start date: 2011-08-15
Project end date: 2013-07-31
Budget start date: 15-DEC-2011
Budget end date: 31-JUL-2012
3R21EB014382-01A1S1 (2012): $59753
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Andrew Mark
PREVENTION OF WEIGHT GAIN IN YOUNG ADULTS
Andrew Mark, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5U01HL090875-03 from National Heart, Lung, And Blood Institute
Abstract: Young adults, age 20-35, experience the greatest rate of weight gain, averaging 1 to 2 pounds per year. This weight gain is associated with a worsening in cardiovascular risk factors and an increase in the prevalence of metabolic syndrome. Given the difficulties in producing sustained weight loss later in life, preventing weight gain from occurring during young adulthood is critical to curbing the obesity epidemic. This project involves two linked R01 applications--a Clinical Coordinating Center application submitted by Dr. Rena Wing, The Miriam Hospital, and a Data Coordinating Center, submitted by Dr. Mark Espeland, Wake Forest University School of Medicine. The purpose of the project is to test two interventions to prevent weight gain in young adults. Both interventions are based on a self-regulation approach that we have shown can help prevent weight regain in recent weight losers. Key aspects of this self-regulation include daily self-weighing, use of the information from the scale to know when adjustments in eating and activity are needed, behavioral skills to modify these behaviors, and small reinforcements for successful prevention of weight gain. One self-regulation intervention is focused on making small consistent changes in eating and exercise behavior to prevent weight gain; the other emphasizes periodic larger changes in eating and exercise behavior that result in small weight losses. These interventions will be compared to each other and to a control condition in a 3-armed randomized controlled clinical trial. The study will involve 600 adults (300 at the Miriam Hospital clinical site and 300 at the University of North Carolina clinical site), aged 18-35 with a BMI of 23-30, who are randomly assigned to 1) control; 2) self-regulation intervention with small behavior changes or 3) self-regulation with large behavior changes. Participants will be recruited over 18 months and will be followed from randomization until the end of the grant, resulting in 24-48 months of follow-up (mean=3 years). The primary hypothesis is that the magnitude of weight gain across an average planned follow-up of 3 years will differ among the three groups (a priori hypothesis is that weight gain will be greatest in control, intermediate in small changes, and least in the large change condition). Secondary hypotheses will compare the three groups on the proportion gaining weight (defined as > 1lb over baseline), changes in cardiovascular risk factors, and changes in the process measures (such as diet, physical activity, and dietary restraint). This project focuses on weight gain in young adults-a critical time for the prevention of obesity-and tests innovative approaches based on self-regulation of body eight. This approach shows promise for reducing weight gain and thereby improving long-term cardiovascular health. (End of )
Keywords: ing; Accountability; Adherence (attribute); Adult; African American; Age; age group; aged; Americas; Area; arm; base; Behavior; behavior change; Behavioral; Blood Pressure; Body Weight; Body Weight Changes; Body Weight decreased; cardiovascular risk factor; Cardiovascular system; Clinical; clinical research site; Clinical Trials; Collaborations; comparative efficacy; Control Groups; Data; Data Coordinating Center; design; Development; Diet; Eating; Eating Behavior; Educational process of instructing; Enrollment; Environmental Risk Factor; Epidemic; Equipment and supply inventories; Ethnicity aspects; Exercise; experience; follow-up; forest; Goals; Grant; group intervention; Health; Health Sciences; high risk; Hospitals; improved; Informal Social Control; innovation; insulin sensitivity; Intake; Intervention; intervention effect; Lead; Life; Life Style; Link; Lipids; Maintenance; Measures; Mediator of activation protein; medical schools; meetings; Menopause; Mental Depression; Metabolic; Metabolic syndrome; North Carolina; Obesity; obesity in children; obesity prevention; Participant; Physical activity; Pilot Projects; Population Study; preference; Prevalence; prevent; Prevention program; Preventive Intervention; Process Measure; programs; psychologic; Psychological reinforcement; psychosocial; public health medicine (field); Randomized; Randomized Controlled Clinical Trials; Recommendation; Recording of previous events; Recruitment Activity; Reporting; Research; Research Priority; restraint; Risk Factors; satisfaction; Self Efficacy; Site; skills; Strategic Planning; System; Testing; Text; therapy design; Time; Translating; trial comparing; United States National Institutes of Health; Universities; waist circumference; Weight; Weight Gain; weight gain prevention; Weight maintenance regimen; Wing; Woman; Work; young adult
Project start date: 2009-08-18
Project end date: 2014-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5U01HL090875-03 (2011): $375472
WEBSMART: EFFICACY OF WEB-BASED PAIN SELF-MANAGEMENT FOR ADOLESCENTS WITH JIA
Andrew Mark, Director, Pain Psychology
Children´s Mercy Hosp (kansas City, Mo)city: Kansas City country: United States (us)
Grant 1R01AR061513-01 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: There is a critical gap in the contemporary treatment of Juvenile Idiopathic Arthritis (JIA) wherein a majority of adolescent patients still experience ongoing pain and reduced health-related quality of life even with advances in medical management of the disease. Despite the pervasiveness of problems with pain and quality of life impairments in adolescents with JIA, most patients receive no training in the strategies that can help empower them to reduce pain and disability before transitioning into adulthood. The Internet offers a unique opportunity to reach adolescents with JIA and provide the training in pain self-management strategies that otherwise may not occur due to treatment access and resource obstacles. The objective in this application is to conduct a definitive empirical test of an investigator-developed online coping skills training program for English- and Spanish- speaking adolescents with JIA. Based on data from the investigators´ preliminary work, the central hypothesis is that use of an online coping skills training program will produce superior improvements in pain and health-related quality of life outcomes for adolescents with JIA relative to outcomes attained with additional attention to coping efforts and review of extant online educational information about JIA (control condition). Specific aims for the proposed work include (a) determining the extent to which an online coping skills training program for English- and Spanish-speaking adolescents with JIA produces improvements in key health outcomes that currently do not optimally respond to only contemporary medical management (pain and health-related quality of life); and (b) determining predictors of change in pain and health-related quality of life indices in English- and Spanish- speaking adolescents with JIA and establishing the extent to which online coping skills training influences health outcomes via these predictors. The aims will be achieved through the approach of using a multi-center randomized controlled trial in which a sample of 360 consenting English- and Spanish-speaking adolescents aged 12-18 years with JIA will be enrolled and randomized into one of two groups (a) an experimental group consisting of a 12-week interactive online multi-component treatment protocol including targeted disease education, training in empirically supported cognitive-behavioral coping skills, and social support augmented by monthly telephone contact with a nurse; or (b) a control group consisting of 12 weeks of guided access to extant online resources for disease education and additional attention to own best efforts at managing JIA via monthly telephone contact with a nurse. Outcome data will be collected from both groups prior to treatment, immediately following the intervention, and at 6- and 12-month follow-up assessments. Successful completion of this project is expected to establish to what extent and how an innovative online self-management program produces change in clinically relevant health outcomes in both English- and Spanish-speaking adolescents with JIA. The proposed study therefore can be expected to have a significant positive impact in the healthcare of teens with JIA and in identifying treatment targets for other youth self-management interventions. The proposed research is relevant to public health because without research to determine efficacious and accessible programs for managing pain in youth with arthritis, significant unnecessary long-term disability and costs to the healthcare system and family will continue to ensue. The project is therefore relevant to parts of NIH´s mission that pertain to developing fundamental knowledge and innovative strategies that can help protect and improve citizens´ health and enhance the Nation´s economic well-being
Keywords: Adolescent; Adult; Affect; aged; Arthritis; Attention; base; Behavioral; Child; Childhood; Chronic Childhood Arthritis; Chronic Disease; clinically relevant; Cognitive; Consent; Control Groups; coping; Coping Skills; cost; cost effective; Data; Deformity; Development; disability; Disease; Disease Management; Economics; Educational aspects; Effectiveness; Elements; Emotional; empowered; Enrollment; expectation; experience; Family; follow-up; Frequencies (time pattern); Goals; Growth; Health; health related quality of life; Health Services Accessibility; Healthcare; Healthcare Systems; Impairment; improved; indexing; innovation; Instruction; interactive multimedia; Internet; Intervention; Joints; Knowledge; Learning; Long-Term Effects; Longevity; Medical; Mission; Nurses; Online Systems; Outcome; Pain; Pain management; Patients; peer; Persistent pain; Personal Satisfaction; programs; public health medicine (field); Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Relative (related person); Research; Research Personnel; Resources; Rheumatology; Sampling; Self Efficacy; Self Management; skills training; social; Social support; standard care; Teenagers; Telephone; Testing; Time; Training; Training and Education; Training Programs; Treatment Protocols; United States; Work; Youth
Relevance: The proposed research is relevant to public health because without research to determine efficacious and accessible programs for managing pain in youth with arthritis, significant unnecessary long-term disability and costs to the healthcare system and family will continue to ensue. The project is therefore relevant to parts of NIH´s mission that pertain to developing fundamental knowledge and innovative strategies that can help protect and improve citizens´ health and enhance the Nation´s economic well-being
Project start date: 2011-09-15
Project end date: 2015-06-30
Budget start date: 15-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-006
1R01AR061513-01 (2011): $573408
SENIORS HEALTH AND ACTIVITY RESEARCH PROGRAM PILOT (SHARP-P)
Andrew Mark, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5R01AG029285-02 from National Institute On Aging
Abstract: The incidence of age-associated cognitive impairment is increasing rapidly and looms as a major clinical and public health issue. Drugs have been developed to treat dementia and compounds have been tested as preventive agents, and while some progress has been made, non-pharmacologic interventions also require study. Evidence from small or uncontrolled studies indicates that physical exercise and cognitive training have considerable promise as prevention strategies, to the extent that they are often recommended, however their efficacy has not been established by an adequately powered randomized clinical trial (RCT). Our goal is to develop and conduct such a well-designed trial to assess whether a multi-factorial intervention involving physical activity and cognitive training reduces the risk of significant cognitive decline in older individuals. We propose in this application to prepare ourselves for this by conducting a pilot study, which will provide the experience and data to assess whether physical activity and cognitive training separately improve executive function and episodic memory over 6 months, to determine whether a combination intervention holds promise beyond individual interventions without compromising adherence, and to design a well-organized and efficient full scale, multi-center RCT. A composite measure based on executive function and episodic memory is chosen as the primary outcome these components are important markers of cognitive aging and may be most responsive to our interventions. Participants (N=120) will be aged 70-85 yrs. In an effort to identify an at-risk yet not cognitively impaired population we have will select a ´normal´ population with mild deficits in Modified Mini-Mental State exam scores who may be appropriate candidates for the full scale RCT. We will screen out individuals with mild cognitive impairment, a pre-dementia transitional state. Participants will be randomly assigned to one of four conditions an educational control condition, moderate-intensity physical activity training, repetition lag cognitive training, or both physical activity and repetitive lag training. Secondary outcomes will be measures of other cognitive domains, perceived cognitive functioning problems, quality of life, adherence, satisfaction, and fitness. This resubmission represents the collaboration of a team of investigators with extensive expertise in the underlying sciences and technology. To reduce costs, the pilot will be conducted at a single site. The results of a full-scale RCT will answer whether non-pharmacological approaches are effective in preventing significant cognitive decline, fill an important gap in knowledge for practicing evidence-based geriatric medicine, and provide critical context for evaluating future trials of pharmacologic agents
Keywords: acetylcholineesterase inhibition; acetylcholineesterase inhibitor; Acetylcholinesterase Inhibitors; Active Follow-up; Activities of Daily Living; Activities of everyday life; Address; Adherence; Adherence (attribute); adjudicate; advanced age; Aerobic; Affect; Age; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Ammon Horn; Amyloid; Amyloid Substance; Animals; Anti-Inflammatories; Anti-inflammatory; Anti-Inflammatory Agents; Antiinflammatories; Antiinflammatory Agents; Arm; Attention; base; Biologic Products; Biological Agent; Biological Products; biopharmaceutical; biotherapeutic agent; Brain; Cerebrum; Clinical; clinical investigation; Clinical Research; clinical significance; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; clinically significant; Cognition Disorders; Cognitive; Cognitive aging; Cognitive decline; cognitive disease; cognitive disorder; Cognitive Disturbance; cognitive dysfunction; cognitive function; Cognitive function abnormal; Cognitive Impairment; cognitive loss; cognitively impaired; Cohort Studies; Collaborations; Comb animal structure; Combs; Communication; Concurrent Studies; Condition; Control Groups; Cornu Ammonis; cost; daily living functionality; Data; Data Collection; Dementia; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deposit; Deposition; design; designing; disability; Disadvantaged; Disturbance in cognition; Dose; Drops; drug/agent; Drugs; early detection; Early Diagnosis; Education for Intervention; Educational Intervention; effect of intervention; Effectiveness; Effectiveness of Interventions; Elderly; Elderly, over 65; elders; Encephalon; Encephalons; Environment; Episodic memory; Episodic memory, function; Estrogenic Agents; Estrogenic Compounds; Estrogens; Evidence based practice; executive control; executive function; Exercise; Exercise, Physical; experience; Fatigue; fitness; follow-up; functional ability; functional capacity; Future; geriatric; geriatric medicine; Geriatrics; Gerontology / Geriatrics; Goals; Health; health care service utilization; Health Care Utilization; Health education; Health Instruction; health related quality of life; health services utilization; Health Training; Health Tutoring; healthcare service utilization; healthcare utilization; healthy aging; hippocampal; Hippocampus; Hippocampus (Brain); Human; Human Experimentation; Human, General; IADL; Impaired cognition; improved; Incidence; Individual; Infrastructure; Inhibitors, Acetylcholinesterase; Institutionalization; Institutionalizations; Instruction Intervention; instructional intervention; instrumental activity of daily living; interest; Intervention; Intervention Strategies; Intervention Studies; interventional strategy; Investigators; Knowledge; Lack of Energy; language translation; late life; later life; Leadership; Learning; Life; life style intervention; lifestyle intervention; Mammals, Mice; Man (Taxonomy); Man, Modern; Manuals; Measurable; Measurement; Measures; Medication; Memory; mental; Methods; Mice; mild cognitive disorder; mild cognitive impairment; mild neurocognitive disorder; Mind; Monitor; Moods; Murine; Mus; Nervous System, Brain; Neural Growth; neural mechanism; neurogenesis; neuromechanism; Neuronal Growth; Numbers; older adult; older person; On-Line Systems; online computer; Online Systems; Outcome; Outcome Measure; Pain; Painful; Participant; Patients; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Physical activity; Pilot Projects; pilot study; Population; Populations at Risk; Position; Positioning Attribute; pre-clinical; preclinical; prevent; preventing; Prevention strategy; Preventive; Preventive strategy; primary degenerative dementia; Primary Senile Degenerative Dementia; Principal Investigator; Procedures; Process Measure; processing speed; programs; Programs (PT); Programs [Publication Type]; Psyche structure; Public Health; public health medicine (field); QOL; Quality Control; Quality of life; randomisation; randomization; Randomized; Randomized Clinical Trials; randomly assigned; Range; Rate; recruit; Recruitment Activity; Relative; Relative (related person); Reporting; Research; Research Activity; Research Infrastructure; Research Personnel; Researchers; response; Risk; Role; Safety; Sample Size; satisfaction; Science; Score; senile dementia of the Alzheimer type; senior citizen; Site; size; skills; Sleep; social; social role; Standards; Standards of Weights and Measures; Structure; Synapses; Synaptic; Syndrome; System; System, LOINC Axis 4; Target Populations; Technology; Testing; Therapeutic Estrogen; Time; Training; Training Intervention; Training Programs; Translating; Translatings; treatment utilization; Uncontrolled Study; Upper arm; visual spatial; Visuospatial; Vitamin E; web based; Work
Project start date: 2007-09-30
Project end date: 2011-05-31
Budget start date: 1-JUN-2008
Budget end date: 31-MAY-2011
PFA/PA: PAR-05-021
5R01AG029285-02 (2008): $464500
ACTION FOR HEALTH IN DIABETES BRAIN MAGNETIC RESONANCE IMAGING ANCILLARY STUDY
Andrew Mark, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 1R01DK092237-01 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Preservation of brain health is a critical goal in the care of adults with type 2 diabetes mellitus, who are at increased risk for atrophy, cerebrovascular disease, and cognitive impairment. Weight loss and increased physical activity hold promise as potentially effective strategies for this purpose, but are currently unproven in any population. Because unintended weight loss often precedes declines in later life brain health, a randomized controlled clinical trial is necessary, which must feature an effective behavioral intervention that is sustained over a long period of time in a large well characterized cohort. Mounting such a program de novo would be very expensive. Instead, we propose to make use of the ongoing and very successful Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, adding cross-sectional magnetic resonance imaging (MRI) to its extensive data collection protocol. This is feasible participants in clinical trials have been repeatedly shown to be willing to join brain imaging studies and we have developed successful protocols for maintaining safety, confidentiality, and quality. This is novel Look AHEAD and the state-of-the-art MRI protocols that we propose provide an unprecedented opportunity to assess the long-term effectiveness of mid-life behavioral changes on brain structure and function and to advance understanding of brain health in diabetes. We address an important public health priority for a rapidly growing and under-studied segment of the US population in a cost-effective manner, leveraging the extensive research resources available from Look AHEAD. We respond to PAR-09-247, which targets ancillary study applications to major NIDDK clinical trials, including Look AHEAD. We will enroll 496 participants, ages 55-85 years with type 2 diabetes, from 3 Look AHEAD clinics. They will have been randomly assigned 10 years ago when they were obese or overweight, with equal probability, to either an ongoing intensive lifestyle intervention that has induced sustained weight loss and increased physical activity or control condition (diabetes support and education) that has fostered excellent retention. A proven protocol for standardized structural MRI will provide regional brain and ischemic lesion volumes; functional MRI will provide assessments of functional activation, resting state connectivity, and cerebral blood flow. A tested cognitive battery and physical activity assessment will be administered. A comprehensive analysis of these data will make use of established statistical approaches and novel machine-learning methods. Look AHEAD provides extensive 10-year characterizations of participant´s health and behavior, their medical care and its cost, and the trial´s interventions; state-of-the art data management systems; and provisions for developing public access databases. Our research team includes established and productive experts in brain imaging, diabetes research, behavioral medicine, data and image analysis, neuroepidemiology, and collaboration. The goal of this project is the care of adults with type 2 diabetes mellitus, who are at increased risk for atrophy, cerebrovascular disease, and cognitive impairment. NOTE The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers´ commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion
Keywords: Address; Adult; Affect; Age; aged; Ancillary Study; Area; Atrophic; Behavior Therapy; Behavioral; Behavioral Medicine; Biological Preservation; Body Weight decreased; Brain; Brain imaging; brain volume; Caring; cerebral atrophy; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinic; Clinical; clinical care; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; cognitive function; cohort; Collaborations; Comorbidity; Conduct Clinical Trials; Confidentiality; cost; cost effective; Cost Savings; Critiques; Data; Data Analyses; Data Collection; data management; Databases; Dementia; Diabetes Mellitus; Dyslipidemias; Educational aspects; Effectiveness; Elderly; Enrollment; Event; Face; Fostering; Functional Magnetic Resonance Imaging; Glucose; Goals; Health; Health behavior; Hippocampus (Brain); Hypertension; Hypoglycemia; Image; Image Analysis; Impaired cognition; Individual; Insulin; Insulin Resistance; interest; intervention effect; Intervention Trial; ischemic lesion; Lead; Life; Life Style; lifestyle intervention; Link; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Medical Care Costs; meetings; Memory; Metabolism; Methods; middle age; Mission; Motivation; multidisciplinary; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; novel; novel strategies; Obesity; Outcome; Overweight; Participant; Physical activity; Population; Positioning Attribute; prevent; Prevention strategy; primary outcome; Probability; programs; Protocols documentation; public health medicine (field); public health priorities; Published Comment; Quality of life; Randomized; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Reporting; Research; research study; Resources; Rest; Risk; Risk Factors; Safety; secondary outcome; Structure; System; Testing; Time; Weight; Weight Gain
Relevance: The goal of this project is the care of adults with type 2 diabetes mellitus, who are at increased risk for atrophy, cerebrovascular disease, and cognitive impairment. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers´ commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion
Project start date: 2011-09-15
Project end date: 2015-08-31
Budget start date: 15-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PAR-09-247
1R01DK092237-01 (2011): $790366
LOOK AHEAD: ACTION FOR HEALTH IN DIABETES
Andrew Mark, Professor
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5U01DK057136-13 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Look AHEAD is randomized clinical trial examining the long-term health effects of an intensive weight loss intervention in approximately 5,145 overweight volunteers with type 2 diabetes. Participants are randomized to an intensive lifestyle intervention designed to achieve and maintain weight loss by decreased caloric intake and increased physical activity, or to a control program of diabetes support and education. The primary outcome of Look AHEAD is the aggregate occurrence of severe cardiovascular events (fatal and non-fatal Ml and stroke and cardiovascular deaths) over a planed follow-up of 11.5 years. The original grant application provided funding for the first 7 years of the study (1 year for study design and 6 for execution of the trial). The present grant application is for an additional 7 years of funding to complete the Look AHEAD trial. All aspects of the study have proceeded extremely well - the sample of 5,145 was recruited on time; retention has been excellent and the intervention has been effective in producing initial weight loss and maintaining it over time. All 16 clinical sites have been successful in recruitment, retention, and delivery of the intervention and the DSMB has been very positive about the execution of the trial. The present application reviews the overall design of Look AHEAD, progress to date, and plans for the future. Specific Aims are to retain the cohort over time, continue to complete annual in-person visits and semi-annual telephone interviews for outcome assessments and continue to administer the lifestyle intervention. These procedures will enable us to analyze the effects of the intervention on serious cardiovascular- related factors and complications, and cost-effectiveness of the intervention
Keywords: Adherence (attribute); Adult; Affect; Angioplasty; Applications Grants; arm; base; Body mass index; Body Weight decreased; Bypass; Cardiovascular Diseases; cardiovascular disorder risk; Cardiovascular system; Carotid Endarterectomy; Cessation of life; Clinical; clinical research site; cohort; Community Health Centers; Congestive Heart Failure; Control Groups; coronary angioplasty; Coronary Artery Bypass; cost effectiveness; Country; Data; design; Diabetes Mellitus; Diet; Direct Costs; Disease; Educational aspects; Effectiveness of Interventions; Energy Intake; Epidemic; Event; Facilities and Administrative Costs; follow-up; Funding; Future; Goals; Grant; hazard; Health; Hospitalization; Incidence; Intention; Intervention; intervention effect; intervention program; lifestyle intervention; Long-Term Effects; Longitudinal Studies; Measures; Mediating; Metabolic; Minority; Morbidity - disease rate; Mortality Vital Statistics; Multi-Institutional Clinical Trial; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; obesity risk; Outcome; Outcome Assessment (Health Care); Overweight; Participant; Peripheral Vascular Diseases; Persons; Physical activity; Population; primary outcome; Principal Investigator; Procedures; Process; programs; Protocols documentation; public health medicine (field); Randomized; Randomized Clinical Trials; Recruitment Activity; Research Design; Risk Factors; Sampling; secondary outcome; stroke; Telephone Interviews; Testing; therapy design; Time; United States; United States National Institutes of Health; Visit; volunteer; Weight; Weight Gain; weight loss intervention
Project start date: 1999-09-30
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-DK-05-504
5U01DK057136-13 (2011): $2502070
3U01DK057136-11S2 (2009): $155882
PSYCHOSOCIAL PAIN MANAGEMENT DURING ADDICTIONS TREATMENT TO IMPROVE OUTCOMES
Andrew Mark, Assistant Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 1R01DA029587-01A1 from National Institute On Drug Abuse
Abstract: Chronic pain among individuals with Substance Use Disorders (SUDs) is a common and critically important problem that is rarely managed appropriately. The estimated rates of chronic pain in patients who are in SUD treatment are as high as 60 percent, with many patients reporting long-lasting and significant pain during treatment. The treatment of pain is complicated in those with SUDs because of the potential for abuse and diversion of many prescription pain medications. Furthermore, recent evidence suggests that untreated pain may undermine the effectiveness of standard treatments for SUDs. An important potential strategy is the use of cognitive behavioral therapy (CBT) to both manage pain and decrease substance use/misuse. Psychosocial interventions such as CBT have demonstrated efficacy for reducing pain and improving functioning in persons with a broad spectrum of pain-related problems, but have not been evaluated in those with SUDs. Thus, SUD treatment providers are left without successful and empirically-supported methods for treating the large number of patients with chronic pain who also have SUDs. The proposed study is a randomized controlled efficacy trial of a group-based intervention that integrates CBT for pain and SUDs compared to a Supportive Psychoeducation Control (SPC) group in a sample of patients in SUD treatment with co-occurring chronic pain. A total of 452 patients (226 male and 226 female) with current pain rated as moderate or greater will be recruited from a large residential SUD treatment facility. These participants will be randomly assigned to either a 4-week (8-session) group of integrated CBT for pain and SUDs or a 4-week (8-session) SPC group. All participants will be re-assessed immediately post-intervention completion (around 1-month) and at 3-, 6-, and 12- months after the intervention. The primary specific aims will focus on pain (level, tolerance and pain-related disability) and substance use (frequency of drug, alcohol and opioid medication misuse) outcomes. Secondary analyses will explore 1) whether change in pain during the intervention mediates the effect of CBT on subsequent substance use/misuse; 2) other hypothesized mechanisms of action for the CBT intervention; and 3) the impact of the intervention on HIV risk behaviors and depressive symptoms. Mixed model regression analyses will be used for all primary aims, within each gender, to estimate between-group differences in changes in outcomes over time. Currently, treatment providers lack evidence-based interventions to address pain in individuals with SUDs. Improving the treatment of pain in patients with SUDs could have a wide-ranging impact not only on individuals´ pain, but also on their substance use and quality of life. Knowledge generated in the proposed study is likely to have broad implications for the care of patients with pain and SUDs in many different healthcare settings. The proposed project will determine the efficacy of a cognitive-behavioral pain management intervention targeting individuals with co-occurring pain and substance use disorders who will be recruited at the start of a residential treatment episode. This proposed efficacy study will provide crucial data on a brief, innovative method designed to improve outcomes in the large numbers of individuals with both substance use disorders and chronic pain
Keywords: addiction; Address; Aftercare; Alcohol consumption; Alcohol or Other Drugs use; alcohol use disorder; Alcohols; Analgesics; base; Behavioral; chronic pain; Cognitive; Cognitive Therapy; Control Groups; coping; Data; depressive symptoms; design; disability; Drug abuser; Drug usage; effective intervention; Effectiveness; Effectiveness of Interventions; efficacy testing; efficacy trial; evidence base; Evidence based intervention; Female; follow-up; Frequencies (time pattern); Gender; Goals; Health; Health Personnel; Healthcare; HIV; Illicit Drugs; improved; improved functioning; Individual; innovation; Intervention; intervention effect; Knowledge; Left; male; Mediating; men; Mental Depression; Methods; Modeling; Motivation; Opiates; Opioid; Outcome; Pain; Pain management; Pain Threshold; Participant; Patient Care; patient population; Patients; Persons; Pharmaceutical Preparations; Population; post intervention; Protocols documentation; psychoeducation; psychosocial; Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Regression Analysis; Reporting; Residential Treatment; Risk Behaviors; Sampling; Self Efficacy; Staging; standard care; Substance Use Disorder; Testing; Time; treatment effect; treatment program; Woman
Relevance: The proposed project will determine the efficacy of a cognitive-behavioral pain management intervention targeting individuals with co-occurring pain and substance use disorders who will be recruited at the start of a residential treatment episode. This proposed efficacy study will provide crucial data on a brief, innovative method designed to improve outcomes in the large numbers of individuals with both substance use disorders and chronic pain
Project start date: 2011-04-01
Project end date: 2016-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-067
1R01DA029587-01A1 (2011): $467682
GNRH SIGNALING MECHANISMS IN THE PITUITARY GONADOTROPE
Andrew Mark, Associate Professor-ir
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01HD037568-11 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Activation of the gonadotropin-releasing hormone (GnRH) receptor initiates a number of complex signaling cascades in pituitary gonadotropes. The rhythmic stimulation of gonadotropes by pulsatile GnRH underlies the differential control of luteinizing hormone and follicle-stimulating hormone production, and ultimately the control of reproduction. GnRH receptor signaling cascades regulate gonadotropin secretion, gene transcription and cell differentiation. We have shown that GnRH regulates protein synthesis and activates the unfolded protein response (UPR), a protective response to modulate stressful demands of protein synthesis. The UPR also activated by inflammatory and metabolic stress signals. The regulatory schemes utilized by the GnRH receptor are essential to maintain cell homeostasis and sensitivity to recurring GnRH pulses. To maintain pulse sensitivity and hormone synthesis, gonadotropes must resolve the intracellular alterations induced by secretion, increase protein synthesis to continue to meet these demands, and resolve the signaling events activated by the previous pulse to allow full response to the next. We have identified the UPR and control of translation as central elements maintaining gonadotrope sensitivity to GnRH and biosynthetic capacity. We propose to examine these components in vitro to determine their mechanism of regulation and in experimental mouse models to determine their physiological role in reproduction. The UPR may provide a direct link between physiological stress and reproductive function. Specific Aim 1 The Unfolded Protein Response in gonadotrope function. We will determine the role of the three main regulators of the unfolded protein response, EIF2AK3 and ERN1, in normal gonadotrope cell function Specific Aim 2 Mechanisms of mRNA redistribution in response to GnRH We have demonstrated that GnRH causes a redistribution of mRNA in gonadotropes. We will determine the specificity of redistribution and the factors determining susceptibility to redistribution. Specific Aim 3 Physiological consequences of an impaired stress response in mice We will examine the role of the unfolded protein response in normal gonadotrope cell function by examining the reproductive impact of pituitary-specific knockout of critical UPR regulatory factors. To preserve normal reproductive hormone production and to respond correctly to environmental cues, pituitary cells must minimize cellular stress and adapt to the demand of continued hormone production. We are investigating the mechanisms cells use to adapt to stress and preserve normal cell function. These regulatory pathways are essential to assure proper reproductive hormone synthesis and reproductive success
Keywords: activating transcription factor; Address; Anterior Pituitary Gland; Apoptosis; Area; base; biological adaptation to stress; Cell Death; Cell Differentiation process; cell growth; Cell physiology; Cells; Cellular Stress; Complex; Cues; Diet; Elements; Endoplasmic Reticulum; endoplasmic reticulum stress; Event; Fatty acid glycerol esters; Feedback; Follicle Stimulating Hormone; Frequencies (time pattern); Gene Expression; Genes; Genetic Transcription; Glycoproteins; Gonadotrope Cell; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Homeostasis; hormone sensitivity; Hormones; Hypothalamic structure; In Vitro; Inflammatory; Knock-out; Knockout Mice; Lead; Link; Luteinizing Hormone; Mediating; Mediator of activation protein; meetings; Messenger RNA; Metabolic stress; Monitor; mouse model; Mus; Neuraxis; Normal Cell; novel; Ovulation; Phosphotransferases; Physiologic pulse; Physiological; Pituitary Gland; Polyribosomes; Post-Transcriptional Regulation; Predisposition; Production; Protein Biosynthesis; Proteins; public health relevance; Receptor Signaling; Regulation; Regulatory Pathway; Reproduction; reproductive; reproductive function; reproductive hormone; reproductive success; response; Ribonucleoproteins; RNA Binding; Role; Scheme; Signal Transduction; Specificity; Stress; stress management; Structure; System; Testing; Translation Initiation; Translations; Vertebrates
Relevance: Narrative To preserve normal reproductive hormone production and to respond correctly to environmental cues, pituitary cells must minimize cellular stress and adapt to the demand of continued hormone production. We are investigating the mechanisms cells use to adapt to stress and preserve normal cell function. These regulatory pathways are essential to assure proper reproductive hormone synthesis and reproductive success
Project start date: 2000-03-20
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01HD037568-11 (2011): $311472
TEMPERATURE FLUCTUATION AND PATHOGEN SURVIVAL ON FRESH PRODUCE DURING TRANSIT
Andrew Mark, Professor
University Of Georgia (uga)city: Athens country: United States (us)
Project start date: 2009-06-22
Project end date: 2011-11-21
Budget start date: 22-JUN-2009
Budget end date: 21-NOV-2011
PFA/PA: RFA-FD-08-005
1R01FD003677-01 (2009): $0