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1.  Associations of Mild Cognitive Impairment with Hospitalization and Readmission 
OBJECTIVES
To determine whether older adults with mild cognitive impairment (MCI), a condition not previously explored as a risk factor, experience increased hospitalizations and 30-day readmission compared to those with normal cognition. Frequent hospitalizations and unplanned readmissions are recognized as markers of poor quality care for older adults.
DESIGN
Post-hoc analysis of prospectively gathered data on incident hospitalization and readmission from the Ginkgo Evaluation of Memory Study (GEMS), a randomized double-blind placebo-controlled trial designed to assess the impact of Ginkgo biloba on incidence of dementia.
SETTING
GEMS was conducted in 5 academic medical centers in the United States.
PARTICIPANTS
2742 community-dwelling adults age 75 or older with normal cognition (n=2314) or MCI (n=428) at baseline cognitive testing.
MEASUREMENTS
Index hospitalization and 30-day hospital readmission, adjusted for age, sex, race, education, clinic site, trial assignment status, comorbidities, number of prescription medications, and living with an identified proxy.
RESULTS
MCI was associated with a 17% increase in the hazard of index hospitalization as compared with normal cognition (adjusted Hazard Ratio (HR)=1.17 (1.02 – 1.34)). In participants who lived with their proxy, MCI was associated with a 39% increased hazard of index hospitalization (adjusted HR=1.392 (1.169 – 1.657)). Baseline MCI was not associated with increased odds of 30-day hospital readmission (adjusted Odds Ratio=0.90 (0.60 – 1.36)).
CONCLUSION
MCI may represent a target condition for healthcare providers to coordinate support services in an effort to reduce hospitalization and subsequent disability.
doi:10.1111/jgs.13593
PMCID: PMC4809245  PMID: 26313420
rehospitalization; mild cognitive impairment (MCI); acute hospital utilization
2.  Effect of structured physical activity on prevention of serious fall injuries in adults aged 70-89: randomized clinical trial (LIFE Study) 
Objective To test whether a long term, structured physical activity program compared with a health education program reduces the risk of serious fall injuries among sedentary older people with functional limitations.
Design Multicenter, single blinded randomized trial (Lifestyle Interventions and Independence for Elders (LIFE) study).
Setting Eight centers across the United States, February 2010 to December 2011.
Participants 1635 sedentary adults aged 70-89 years with functional limitations, defined as a short physical performance battery score ≤9, but who were able to walk 400 m.
Interventions A permuted block algorithm stratified by field center and sex was used to allocate interventions. Participants were randomized to a structured, moderate intensity physical activity program (n=818) conducted in a center (twice a week) and at home (3-4 times a week) that included aerobic, strength, flexibility, and balance training activities, or to a health education program (n=817) consisting of workshops on topics relevant to older people and upper extremity stretching exercises.
Main outcome measures Serious fall injuries, defined as a fall that resulted in a clinical, non-vertebral fracture or that led to a hospital admission for another serious injury, was a prespecified secondary outcome in the LIFE Study. Outcomes were assessed every six months for up to 42 months by staff masked to intervention assignment. All participants were included in the analysis.
Results Over a median follow-up of 2.6 years, a serious fall injury was experienced by 75 (9.2%) participants in the physical activity group and 84 (10.3%) in the health education group (hazard ratio 0.90, 95% confidence interval 0.66 to 1.23; P=0.52). These results were consistent across several subgroups, including sex. However, in analyses that were not prespecified, sex specific differences were observed for rates of all serious fall injuries (rate ratio 0.54, 95% confidence interval 0.31 to 0.95 in men; 1.07, 0.75 to 1.53 in women; P=0.043 for interaction), fall related fractures (0.47, 0.25 to 0.86 in men; 1.12, 0.77 to 1.64 in women; P=0.017 for interaction), and fall related hospital admissions (0.41, 0.19 to 0.89 in men; 1.10, 0.65 to 1.88 in women; P=0.039 for interaction).
Conclusions In this trial, which was underpowered to detect small, but possibly important reductions in serious fall injuries, a structured physical activity program compared with a health education program did not reduce the risk of serious fall injuries among sedentary older people with functional limitations. These null results were accompanied by suggestive evidence that the physical activity program may reduce the rate of fall related fractures and hospital admissions in men.
Trial registration ClinicalsTrials.gov NCT01072500.
doi:10.1136/bmj.i245
PMCID: PMC4772786  PMID: 26842425
3.  A Physical Activity Intervention to Treat the Frailty Syndrome in Older Persons—Results From the LIFE-P Study 
Background.
The frailty syndrome is as a well-established condition of risk for disability. Aim of the study is to explore whether a physical activity (PA) intervention can reduce prevalence and severity of frailty in a community-dwelling elders at risk of disability.
Methods.
Exploratory analyses from the Lifestyle Interventions and Independence for Elders pilot, a randomized controlled trial enrolling 424 community-dwelling persons (mean age=76.8 years) with sedentary lifestyle and at risk of mobility disability. Participants were randomized to a 12-month PA intervention versus a successful aging education group. The frailty phenotype (ie, ≥3 of the following defining criteria: involuntary weight loss, exhaustion, sedentary behavior, slow gait speed, poor handgrip strength) was measured at baseline, 6 months, and 12 months. Repeated measures generalized linear models were conducted.
Results.
A significant (p = .01) difference in frailty prevalence was observed at 12 months in the PA intervention group (10.0%; 95% confidence interval = 6.5%, 15.1%), relative to the successful aging group (19.1%; 95% confidence interval = 13.9%,15.6%). Over follow-up, in comparison to successful aging participants, the mean number of frailty criteria in the PA group was notably reduced for younger subjects, blacks, participants with frailty, and those with multimorbidity. Among the frailty criteria, the sedentary behavior was the one most affected by the intervention.
Conclusions.
Regular PA may reduce frailty, especially in individuals at higher risk of disability. Future studies should be aimed at testing the possible benefits produced by multidomain interventions on frailty.
doi:10.1093/gerona/glu099
PMCID: PMC4311184  PMID: 25387728
Frailty; Physical activity; Physical function; Successful aging; Clinical trials.
4.  Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial 
Diabetologia  2014;57(10):2030-2037.
Aims/hypothesis
We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes.
Methods
4119 ACCORD Trial participants randomized to target HbA1c <6.0% (42 mmol/mol) for 4.0±1.2 years were systematically transitioned to target HbA1c 7.0–7.9% (53–63 mmol/mol) and followed for an additional 1.1±0.2 years. Characteristics of participants with HbA1c <6.5% (48 mmol/mol) or ≥6.5% at transition were compared. Changes in BMI and glucose-lowering medications were compared between those ending with HbA1c <6.5% vs ≥6.5%. Poisson models were used to assess the independent effect of attaining HbA1c <6.5% before transition on ending with HbA1c <6.5%.
Results
Participants with pre-transition HbA1c <6.5% were older with shorter duration diabetes and took less insulin but more non-insulin glucose-lowering agents than those with higher HbA1c. A total of 823 participants achieved a final HbA1c <6.5%, and had greater post-transition reductions in BMI, insulin dose and secretagogue and acarbose use than those with higher HbA1c (p<0.0001). HbA1c <6.5% at transition predicted final HbA1c <6.5% (crude RR 4.9 [95% CI 4.0, 5.9]; RR 3.9 [95% CI 3.2, 4.8] adjusted for demographics, co-interventions, pre-intervention HbA1c, BMI and glucose-lowering medication, and post-transition change in both BMI and glucose-lowering medication). Progressively lower pre-transition HbA1c levels were associated with a greater likelihood of maintaining a final HbA1c of <6.5%. Follow-up duration was not associated with post-transition rise in HbA1c.
Conclusions/interpretation
Time-limited intensive glycaemic management using a combination of agents that achieves HbA1c levels below 6.5% in established diabetes is associated with glycaemic control more than 1 year after therapy is relaxed.
doi:10.1007/s00125-014-3318-5
PMCID: PMC4698982  PMID: 24985147
Intensive glucose lowering; Long-term glycaemic control; Post-intervention follow-up; Type 2 diabetes
5.  A preliminary comparison of myoelectric and cyclic control of an implanted neuroprosthesis to modulate gait speed in incomplete SCI 
Objective
Explore whether electromyography (EMG) control of electrical stimulation for walking after incomplete spinal cord injury (SCI) can affect ability to modulate speed and alter gait spatial-temporal parameters compared to cyclic repetition of pre-programmed stimulation.
Design
Single case study with subject acting as own concurrent control.
Setting
Hospital-based biomechanics laboratory.
Participants
Single subject with C6 AIS D SCI using an implanted neuroprosthesis for walking.
Interventions
Lower extremity muscle activation via an implanted system with two different control methods: (1) pre-programmed pattern of stimulation, and (2) EMG-controlled stimulation based on signals from the gastrocnemius and quadriceps.
Outcome measures
Gait speed, distance, and subjective rating of difficulty during 2-minute walks. Range of walking speeds and associated cadences, stride lengths, stride times, and double support times during quantitative gait analysis.
Results
EMG control resulted in statistically significant increases in both walking speed and distance (P < 0.001) over cyclic stimulation during 2-minute walks. Maximum walking speed with EMG control (0.48 m/second) was significantly (P < 0.001) faster than the fastest automatic pattern (0.39 m/second), with increased cadence and decreased stride and double support times (P < 0.000) but no change in stride length (z = −0.085; P = 0.932). The slowest walking with EMG control (0.25 m/second) was virtually indistinguishable from the slowest with automatic cycling (z = −0.239; P = 0.811).
Conclusion
EMG control can increase the ability to modulate comfortable walking speed over pre-programmed cyclic stimulation. While control methods did not differ at the lowest speed, EMG-triggered stimulation allowed significantly faster walking than cyclic stimulation. The expanded range of available walking speeds could permit users to better avoid obstacles and naturally adapt to various environments. Further research is required to definitively determine the robustness, generalizability, and functional implications of these results.
doi:10.1179/2045772314Y.0000000262
PMCID: PMC4293526  PMID: 25243532
Electromyography; Functional electrical stimulation; Gait training; Neural prosthesis; Rehabilitation; Spinal cord injury; Walking
6.  Assessing physical and cognitive function of older adults in continuing care retirement communities: Who are we recruiting? 
Contemporary clinical trials  2014;40:159-165.
Purpose
In partnership with six Continuing Care Retirement Communities (CCRCs), the current study focused on the feasibility of recruiting a representative sample of residents and then assessing their functional health.
Material and Methods
With our guidance, each of the six CCRCs recruited a volunteer (V-Group) and random (R-Group) sample of independent living residents. We provided face-to-face training and ongoing remote electronic support to the CCRC staff on the testing battery and the web-based data entry system. The testing battery was consisted of demographic, physical function, and psychosocial assessments.
Results
After training, CCRC staff were receptive to the study goals and successfully used the data entry website. In the V-Group (N=189), 76% were already participating in CCRC wellness programs. We attempted to recruit a random, unbiased (R-Group) sample of 20% (n=105) of eligible residents; however, only 30 consented to be tested and 70% of this group (21/30) was also already participating in a wellness program. Mean age of all participants was 82.9 years. The V-Group had a higher Short Physical Performance Battery (SPPB) total score (least squares mean[SE], 9.4[0.2] vs 8.2[0.4], p=0.014) and SPPB gait speed component score (3.5[0.1] vs 3.0[0.2], p=0.007) and spent more time doing moderate-to-vigorous physical activity (300[21] vs 163[49] min/week, p=0.013) compared to the R-Group.
Implications
While it is feasible to recruit, assess and transmit data on residents’ functional health in partnership with CCRCs, population validity was severely compromised. Attention needs to be given to the development of more effective methods to recruit less interested residents.
doi:10.1016/j.cct.2014.12.003
PMCID: PMC4314326  PMID: 25510892
Recruitment; Physical function assessment; Translational research; Older adults
7.  Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial 
Diabetes Care  2014;37(12):3279-3285.
OBJECTIVE
The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities.
RESEARCH DESIGN AND METHODS
We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease.
RESULTS
Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans.
CONCLUSIONS
Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
doi:10.2337/dc14-0973
PMCID: PMC4237972  PMID: 25267796
8.  The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial 
Diabetes Care  2014;37(12):3244-3252.
OBJECTIVE
Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later.
RESEARCH DESIGN AND METHODS
Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none, mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes.
RESULTS
Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm3 for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: −0.20, −0.57, and −0.42, respectively [P = 0.04]; DSST: −1.30, −1.84, and −2.89, respectively[P = 0.01]).
CONCLUSIONS
Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.
doi:10.2337/dc14-0502
PMCID: PMC4237980  PMID: 25193529
9.  Effect of Intensive Glycemic Control on Ischemic Heart Disease 
Lancet  2014;384(9958):1936-1941.
Background
The possibility that hyperglycemia accounts for the 2–3 fold higher risk of ischemic heart disease (IHD) in type 2 diabetes was explored by assessing the effect of intensive glucose lowering on IHD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Methods
10,251 people (mean age = 62) with type 2 diabetes (mean duration = 10 years, mean A1c = 8.3%) were allocated to intensive or standard glycemic control targeting an A1c <6% or 7–7.9% respectively. This intervention’s effect on IHD (fatal or non-fatal myocardial infarction, coronary revascularization, unstable angina, and new angina) was assessed during a mean active treatment period of 3.7 years followed by an additional 1.2 years.
Results
Fewer participants allocated to the intensive versus standard care group experienced a myocardial infarction during both active treatment (HR = 0.80; 95% CI 0.67 – 0.96; P = 0.015) and full (active and additional) follow-up (HR = 0.84; 95% CI 0.72 – 0.97; P = 0.02). Similar findings were observed for a composite IHD outcome of myocardial infarction, coronary revascularization or unstable angina (HR = 0.89; 95% CI 0.79–0.99 and HR = 0.87; 95% CI 0.79 – 0.96 during active treatment and full follow-up respectively)and for coronary revascularization (HR = 0.84; 95% CI 0.75–0.94), and unstable angina (HR = 0.81; 95% CI 0.67–0.97) during full follow-up. Adding A1C levels achieved during active treatment attenuated the significant hazard ratios to neutrality.
Conclusions
Glucose elevation is a modifiable risk factor for IHD in middle aged people with type 2 diabetes and other IHD risk factors.
doi:10.1016/S0140-6736(14)60611-5
PMCID: PMC4397008  PMID: 25088437
10.  Effects of Randomization to Intensive Glucose Control on Adverse Events, Cardiovascular Disease, and Mortality in Older Versus Younger Adults in the ACCORD Trial 
Diabetes Care  2014;37(3):634-643.
OBJECTIVE
We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
RESEARCH DESIGN AND METHODS
Participants with type 2 diabetes (n = 10,251) with a mean age of 62 years, a median duration of diabetes of 10 years, and a median A1C of 8.1% (65 mmol/mol) were randomized to treatment strategies targeting either A1C <6.0% (42 mmol/mol) or 7.0–7.9% (53–63 mmol/mol) and followed for a mean of 3.7 years. Outcomes were analyzed within subgroups defined by baseline age (<65 vs. ≥65 years).
RESULTS
Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences. Within the older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45% intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard).
CONCLUSIONS
Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants, whereas it had a neutral effect in older participants. The intensive to standard relative risk of severe hypoglycemia was similar in both age subgroups, with higher absolute rates in older participants within both treatment arms.
doi:10.2337/dc13-1545
PMCID: PMC3931381  PMID: 24170759
11.  Physical Activity in Prefrail Older Adults: Confidence and Satisfaction Related to Physical Function 
We examined the hypothesis that physical activity will have favorable effects on measures of self-efficacy for a 400-m walk and satisfaction with physical functioning in older adults 70+ years of age who have deficits in mobility. We randomized a total of 412 adults aged 70–89 years at elevated risk for mobility disability to either a physical activity or a successful aging educational control intervention for 12 months. Participants in the physical activity intervention had more favorable changes in both outcomes as a result of treatment than those in the successful aging intervention. Gender, age, and scores on a short physical performance battery did not moderate these effects. Physical activity is an effective means of intervening on self-efficacy and satisfaction with physical function in older adults with impaired lower extremity functioning. This is an important finding in light of the importance of these process variables in behavior change and quality of life.
PMCID: PMC4509632  PMID: 18332190
Self-efficacy; Aging; Disability; Mobility; Quality of life
12.  Sleep-Wake Disturbances in Sedentary Community-Dwelling Elders With Functional Limitations 
OBJECTIVES
To evaluate sleep-wake disturbances in sedentary community-dwelling elders with functional limitations.
DESIGN
Cross-sectional.
SETTING
Lifestyle Interventions and Independence in Elder (LIFE) Study.
PARTICIPANTS
1635 community-dwelling persons, mean age 78.9, who spent <20 minutes/week in the past month of regular physical activity and <125 minutes/week of moderate physical activity, and had a Short Physical Performance Battery (SPPB) score <10.
MEASUREMENTS
Mobility was evaluated by the 400-meter walk time (slow gait speed defined as <0.8 m/s) and SPPB score (≤7 defined moderate-to-severe mobility impairment). Physical inactivity was defined by sedentary time, as percent of accelerometry wear time with activity <100 counts/min); top quartile established high sedentary time. Sleep-wake disturbances were evaluated by the Insomnia Severity Index (ISI) (range 0–28; ≥8 defined insomnia), Epworth Sleepiness Scale (ESS) (range 0–24; ≥10 defined daytime drowsiness), Pittsburgh Sleep Quality Index (PSQI) (range 0–21; >5 defined poor sleep quality), and Berlin Questionnaire (high risk of sleep apnea).
RESULTS
Prevalence rates were 43.5% for slow gait speed and 44.7% for moderate-to-severe mobility impairment, with 77.0% of accelerometry wear time spent as sedentary time. Prevalence rates were 33.0% for insomnia, 18.1% for daytime drowsiness, 47.8% for poor sleep quality, and 32.9% for high risk of sleep apnea. Participants with insomnia, daytime drowsiness, and poor sleep quality had mean values of 12.1 for ISI, 12.5 for ESS, and 9.2 for PSQI, respectively. In adjusted models, measures of mobility and physical inactivity were generally not associated with sleep-wake disturbances, using continuous or categorical variables.
CONCLUSION
In a large sample of sedentary community-dwelling elders with functional limitations, sleep-wake disturbances were prevalent but only mildly severe, and were generally not associated with mobility impairment or physical inactivity.
doi:10.1111/jgs.12845
PMCID: PMC4057978  PMID: 24889836
mobility impairment; physical inactivity; sleep-wake disturbances
13.  Obesity Influences Transitional States of Disability in Older Adults With Knee Pain 
Objectives
This study employed relatively new statistical methods to understand how many states are needed to describe disability in older adults with knee pain, describe the relative probability of transitioning between states over time, and examine whether obesity influences the probability of transitioning between states.
Design
Prospective epidemiologic study of older adults with knee pain.
Setting
Community.
Participants
The participants, 245 women and 235 men, were 65 years or older, had chronic knee pain on most days, and had difficulty with at least 1 mobility-related activity caused by knee pain.
Interventions
Not applicable.
Main Outcome Measure
The primary instrument, the Pepper Assessment Tool for Disability, evaluated self-reported difficulty with mobility, basic activities of daily living (ADLs), and instrumental activities of daily living (IADLs).
Results
The Hidden Markov Model yielded 6 states reflecting changes in mobility, ADLs, and IADLs. There is evidence that loss in more demanding mobility-related activities such as stair climbing is an early sign for the onset of disability and that functional deficits in the lower extremities are critical to the early loss of ADLs. Overall the trend is for older adults to experience greater progression than regression and for obesity to be important in understanding severe states of disability.
Conclusions
These data provide a strong rationale for characterizing disability on a continuum and underscore the fluid nature of disability in older adults. As expected, lower-extremity function plays a key role in the disablement process; obesity is also particularly relevant to understanding severe states of disability.
doi:10.1016/j.apmr.2008.05.013
PMCID: PMC4427514  PMID: 18996238
Aged; Obesity; Rehabilitation
14.  Cognitive Function and Brain Structure in Persons With Type 2 Diabetes Mellitus After Intensive Lowering of Blood Pressure and Lipid Levels 
JAMA internal medicine  2014;174(3):324-333.
IMPORTANCE
Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown.
OBJECTIVE
To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM.
DESIGN, SETTING, AND PARTICIPANTS
A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c (HbA1c) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009.
MAIN OUTCOME MEASURES
Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health.
RESULTS
Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, −4.4 [95% CI, −7.8 to −1.1] cm3; P = .01). Fibrate therapy had no effect on TBV compared with placebo.
CONCLUSIONS AND RELEVANCE
In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00000620
doi:10.1001/jamainternmed.2013.13656
PMCID: PMC4423790  PMID: 24493100
15.  The effects of strength and power training on single-step balance recovery in older adults: a preliminary study 
Improving muscle strength and power may mitigate the effects of sarcopenia, but it is unknown if this improves an older adult’s ability to recover from a large postural perturbation. Forward tripping is prevalent in older adults and lateral falls are important due to risk of hip fracture. We used a forward and a lateral single-step balance recovery task to examine the effects of strength training (ST) or power (PT) training on single-step balance recovery in older adults. Twenty older adults (70.8±4.4 years, eleven male) were randomly assigned to either a 6-week (three times/week) lower extremity ST or PT intervention. Maximum forward (FLeanmax) and lateral (LLeanmax) lean angle and strength and power in knee extension and leg press were assessed at baseline and follow-up. Fifteen participants completed the study (ST =7, PT =8). Least squares means (95% CI) for ΔFLeanmax (ST: +4.1° [0.7, 7.5]; PT: +0.6° [−2.5, 3.8]) and ΔLLeanmax (ST: +2.2° [0.4, 4.1]; PT: +2.6° [0.9, 4.4]) indicated no differences between groups following training. In exploratory post hoc analyses collapsed by group, ΔFLeanmax was +2.4° (0.1, 4.7) and ΔLLeanmax was +2.4° (1.2, 3.6). These improvements on the balance recovery tasks ranged from ~15%–30%. The results of this preliminary study suggest that resistance training may improve balance recovery performance, and that, in this small sample, PT did not lead to larger improvements in single-step balance recovery compared to ST.
doi:10.2147/CIA.S59310
PMCID: PMC4000185  PMID: 24790422
resistance exercise; falls; muscle strength; muscle power; exercise intervention; randomized trial
16.  Effect of Diabetes on Brain structure 
Radiology  2014;272(1):210-216.
Purpose
To investigate the association of characteristics of type 2 diabetes mellitus (duration and biochemical severity of diabetes) to brain structure measured on magnetic resonance (MR) images, specifically testing whether more severity in metrics of diabetes is inversely correlated with brain volumes and positively correlated with ischemic lesion volumes.
Materials and Methods
This study protocol was approved by the institutional review board of each center and participants provided written informed consent. Baseline severity of diabetes was evaluated by testing fasting plasma glucose levels, hemoglobin A1c levels, and duration of diabetes. MR imaging was performed with fluid-attenuated inversion recovery, proton-density, T2-weighted, and T1-weighted sequences, which were postprocessed with an automated computer algorithm that classified brain tissue as gray or white matter and as normal or ischemic. Separate linear regression models adjusted for potential confounding factors were used to investigate the relationship of the diabetes measures to MR imaging outcomes in 614 participants (mean age, 62 years; mean duration of type 2 diabetes mellitus, 9.9 years).
Results
The mean volumes of total gray matter (463.9 cm3) and total white matter (463.6 cm3) were similar. The mean volume of abnormal tissue was 2.5 cm3, mostly in the white matter (81% white matter, 5% gray matter, 14% deep gray and white matter). Longer duration of diabetes and higher fasting plasma glucose level were associated with lower normal (β = −0.431 and −0.053, respectively; P < .01) and total gray matter volumes (β = −0.428 and −0.053, respectively; P < .01). Fasting plasma glucose was also inversely correlated with ischemic lesion volume (β = −0.006; P < .04). Hemoglobin A1c level was not associated with any MR imaging measure.
Conclusion
Longer duration of diabetes is associated with brain volume loss, particularly in the gray matter, possibly reflecting direct neurologic insult; biochemical measures of glycemia were less consistently related to MR imaging changes. Contrary to common clinical belief, in this sample of patients with type 2 diabetes mellitus, there was no association of diabetes characteristics with small vessel ischemic disease in the brain.
doi:10.1148/radiol.14131494
PMCID: PMC4263658  PMID: 24779562
17.  Novel pegylated silver coated carbon nanotubes kill Salmonella but they are non-toxic to eukaryotic cells 
Background
Resistance of food borne pathogens such as Salmonella to existing antibiotics is of grave concern. Silver coated single walled carbon nanotubes (SWCNTs-Ag) have broad-spectrum antibacterial activity and may be a good treatment alternative. However, toxicity to human cells due to their physico-chemical properties is a serious public health concern. Although pegylation is commonly used to reduce metal nanoparticle toxicity, SWCNTs-Ag have not been pegylated as yet, and the effect of pegylation of SWCNTs-Ag on their anti-bacterial activity and cell cytotoxicity remains to be studied. Further, there are no molecular studies on the anti-bacterial mechanism of SWCNTs-Ag or their functionalized nanocomposites.
Materials and methods
In this study we created novel pegylated SWCNTS-Ag (pSWCNTs-Ag), and employed 3 eukaryotic cell lines to evaluate their cytotoxicity as compared to plain SWCNTS-Ag. Simultaneously, we evaluated their antibacterial activity on Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) by the MIC and growth curve assays. In order to understand the possible mechanisms of action of both SWCNTs-Ag and pSWCNTs-Ag, we used electron microscopy (EM) and molecular studies (qRT-PCR).
Results
pSWCNTs-Ag inhibited Salmonella Typhimurium at 62.5 μg/mL, while remaining non-toxic to human cells. By comparison, plain SWCNTs-Ag were toxic to human cells at 62.5 μg/mL. EM analysis revealed that bacteria internalized either of these nanocomposites after the outer cell membranes were damaged, resulting in cell lysis or expulsion of cytoplasmic contents, leaving empty ghosts. The expression of genes regulating the membrane associated metabolic transporter system (artP, dppA, and livJ), amino acid biosynthesis (trp and argC) and outer membrane integrity (ompF) protiens, was significantly down regulated in Salmonella treated with both pSWCNTs-Ag and SWCNTs-Ag. Although EM analysis of bacteria treated with either SWCNTs-Ag or pSWCNTs-Ag revealed relatively similar morphological changes, the expression of genes regulating the normal physiological processes of bacteria (ybeF), quorum sensing (sdiA), outer membrane structure (safC), invasion (ychP) and virulence (safC, ychP, sseA and sseG) were exclusively down regulated several fold in pSWCNTs-Ag treated bacteria.
Conclusions
Altogether, the present data shows that our novel pSWCNTs-Ag are non-toxic to human cells at their bactericidal concentration, as compared to plain SWCNTS-Ag. Therefore, pSWCNTs-Ag may be safe alternative antimicrobials to treat foodborne pathogens.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0085-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12951-015-0085-5
PMCID: PMC4377206  PMID: 25888864
Pegylation; Silver coated carbon nanotubes; Toxicity; Gene regulation; Food borne
18.  Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials 
PLoS ONE  2015;10(3):e0121993.
Background
Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.
Methods
2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.
Results
Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30–46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73–1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71–0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72–1.00).
Conclusions
In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.
doi:10.1371/journal.pone.0121993
PMCID: PMC4368053  PMID: 25794148
19.  Effect of Diabetes on Brain Structure: The Action to Control Cardiovascular Risk in Diabetes MR Imaging Baseline Data 
Radiology  2014;272(1):210-216.
The results of this study show that measures of longer duration of diabetes or biochemical severity correlated primarily with brain atrophy, but not with white matter lesion volume, which is the major MR imaging marker of small vessel ischemic disease.
Purpose
To investigate the association of characteristics of type 2 diabetes mellitus (duration and biochemical severity of diabetes) to brain structure measured on magnetic resonance (MR) images, specifically testing whether more severity in metrics of diabetes is inversely correlated with brain volumes and positively correlated with ischemic lesion volumes.
Materials and Methods
This study protocol was approved by the institutional review board of each center and participants provided written informed consent. Baseline severity of diabetes was evaluated by testing fasting plasma glucose levels, hemoglobin A1c levels, and duration of diabetes. MR imaging was performed with fluid-attenuated inversion recovery, proton-density, T2-weighted, and T1-weighted sequences, which were postprocessed with an automated computer algorithm that classified brain tissue as gray or white matter and as normal or ischemic. Separate linear regression models adjusted for potential confounding factors were used to investigate the relationship of the diabetes measures to MR imaging outcomes in 614 participants (mean age, 62 years; mean duration of type 2 diabetes mellitus, 9.9 years).
Results
The mean volumes of total gray matter (463.9 cm3) and total white matter (463.6 cm3) were similar. The mean volume of abnormal tissue was 2.5 cm3, mostly in the white matter (81% white matter, 5% gray matter, 14% deep gray and white matter). Longer duration of diabetes and higher fasting plasma glucose level were associated with lower normal (β = −0.431 and −0.053, respectively; P < .01) and total gray matter volumes (β = −0.428 and −0.053, respectively; P < .01). Fasting plasma glucose was also inversely correlated with ischemic lesion volume (β = −0.006; P < .04). Hemoglobin A1c level was not associated with any MR imaging measure.
Conclusion
Longer duration of diabetes is associated with brain volume loss, particularly in the gray matter, possibly reflecting direct neurologic insult; biochemical measures of glycemia were less consistently related to MR imaging changes. Contrary to common clinical belief, in this sample of patients with type 2 diabetes mellitus, there was no association of diabetes characteristics with small vessel ischemic disease in the brain.
© RSNA, 2014
Clinical trial registration no. NCT00182910
Online supplemental material is available for this article.
doi:10.1148/radiol.14131494
PMCID: PMC4263658  PMID: 24779562
20.  Lower Extremity Muscle Function After Strength or Power Training in Older Adults 
It is unclear whether strength training (ST) or power training (PT) is the more effective intervention at improving muscle strength and power and physical function in older adults. The authors compared the effects of lower extremity PT with those of ST on muscle strength and power in 45 older adults (74.8 ± 5.7 yr) with self-reported difficulty in common daily activities. Participants were randomized to 1 of 3 treatment groups: PT, ST, or wait-list control. PT and ST trained 3 times/wk for 12 wk using knee-extension (KE) and leg-press (LP) machines at ~70% of 1-repetition maximum (1RM). For PT, the concentric phase of the KE and LP was completed “as fast as possible,” whereas for ST the concentric phase was 2–3 s. Both PT and ST paused briefly at the midpoint of the movement and completed the eccentric phase of the movement in 2–3 s. PT and ST groups showed significant improvements in KE and LP 1RM compared with the control group. Maximum KE and LP power increased approximately twofold in PT compared with ST. At 12 wk, compared with control, maximum KE and LP power were significantly increased for the PT group but not for the ST group. In older adults with compromised function, PT leads to similar increases in strength and larger increases in power than ST.
PMCID: PMC4318571  PMID: 19940322
aging; resistance training; disability; physical function
21.  A neuroprosthesis for control of seated balance after spinal cord injury 
Background
A major desire of individuals with spinal cord injury (SCI) is the ability to maintain a stable trunk while in a seated position. Such stability is invaluable during many activities of daily living (ADL) such as regular work in the home and office environments, wheelchair propulsion and driving a vehicle. Functional neuromuscular stimulation (FNS) has the ability to restore function to paralyzed muscles by application of measured low-level currents to the nerves serving those muscles.
Methods
A feedback control system for maintaining seated balance under external perturbations was designed and tested in individuals with thoracic and cervical level spinal cord injuries. The control system relied on a signal related to the tilt of the trunk from the vertical position (which varied between 1.0 ≡ erect posture and 0.0 ≡ most forward flexed posture) derived from a sensor fixed to the sternum to activate the user’s own hip and trunk extensor muscles via an implanted neuroprosthesis. A proportional-derivative controller modulated stimulation between trunk tilt values indicating deviation from the erect posture and maximum desired forward flexion. Tests were carried out with external perturbation forces set at 35%, 40% and 45% body-weight (BW) and maximal forward trunk tilt flexion thresholds set at 0.85, 0.75 and 0.70.
Results
Preliminary tests in a case series of five subjects show that the controller could maintain trunk stability in the sagittal plane for perturbations up to 45% of body weight and for flexion thresholds as low as 0.7. The mean settling time varied across subjects from 0.5(±0.4) and 2.0 (±1.1) seconds. Mean response time of the feedback control system varied from 393(±38) ms and 536(±84) ms across the cohort.
Conclusions
The results show the high potential for robust control of seated balance against nominal perturbations in individuals with spinal cord injury and indicates that trunk control with FNS is a promising intervention for individuals with SCI.
doi:10.1186/1743-0003-12-8
PMCID: PMC4326199  PMID: 25608888
Trunk control; Seated balance; Functional Neuromuscular Stimulation (FNS); Spinal cord injury; Feedback control; Rehabilitation
22.  Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE Study randomized clinical trial 
JAMA  2014;311(23):2387-2396.
SUMMARY
Importance
In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining if physical activity prevents or delays mobility disability.
Objective
To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability.
Design, Setting, and Participants
The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban and rural communities at 8 field centers throughout the US. We randomized a volunteer sample of 1,635 sedentary men and women aged 70–89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m.
Interventions
Participants were randomized to a structured moderate intensity physical activity program (n=818) done in a center and at home that included including aerobic, resistance and flexibility training activities or to a health education program (n=817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises.
Main Outcomes and Measures
The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m.
Results
Incident major mobility disability occurred in 30.1% (n=246/818) of physical activity and 35.5% (n=290/817) of health education participants (HR=0.82, 95%CI=0.69–0.98, p=0.03). Persistent mobility disability was experienced by 120/818 (14.7%) physical activity and 162/817 (19.8%) health education participants (HR=0.72; 95%CI=0.57–0.91; p=0.006). Serious adverse events were reported by 404/818 (49.4%) of the physical activity and 373/817 (45.7%) of the health education participants (Risk Ratio=1.08; 95%CI=0.98–1.20).
Conclusions and Relevance
A structured moderate intensity physical activity program, compared with a health education program, reduced major mobility disability over 2.6 years among older adults at risk of disability. These findings suggest mobility benefit from such a program in vulnerable older adults.
Registration
ClinicalsTrials.gov identifier NCT01072500.
doi:10.1001/jama.2014.5616
PMCID: PMC4266388  PMID: 24866862
23.  A Randomized Controlled Trial of Telephone-Delivered Cognitive-Behavioral Therapy for Late-life Anxiety Disorders 
Objectives
Older adults face a number of barriers to receiving psychotherapy, such as a lack of transportation and access to providers. One way to overcome such barriers is to provide treatment by telephone. The purpose of this study was to examine the effects of cognitive behavioral therapy delivered by telephone (CBT-T) to older adults diagnosed with an anxiety disorder.
Design
Randomized controlled trial.
Setting
Participants' homes.
Participants
Sixty participants ≥ 60 years of age with a diagnosis of Generalized Anxiety Disorder, Panic Disorder, or Anxiety Disorder Not Otherwise Specified.
Intervention
CBT-T vs. information-only comparison.
Measurements
Co-primary outcomes included worry (Penn State Worry Questionnaire) and general anxiety (State Trait Anxiety Inventory). Secondary outcomes included clinician-rated anxiety (Hamilton Anxiety Rating Scale), anxiety sensitivity (Anxiety Sensitivity Index), depressive symptoms (Beck Depression Inventory), quality of life (SF-36), and sleep (Insomnia Severity Index). Assessments were completed prior to randomization, immediately upon completion of treatment, and 6 months after completing treatment.
Results
CBT-T was superior to information-only in reducing general anxiety (ES = 0.71), worry (ES = 0.61), anxiety sensitivity (ES = 0.85), and insomnia (ES = 0.82) at the post-treatment assessment; however, only the reductions in worry were maintained by the 6 month follow-up assessment (ES = 0.80).
Conclusions
These results suggest that CBT-T may be efficacious in reducing anxiety and worry in older adults, but additional sessions may be needed to maintain these effects.
doi:10.1097/JGP.0b013e31822ccd3e
PMCID: PMC3407971  PMID: 22828172
anxiety; cognitive-behavioral therapy; elderly; Generalized Anxiety Disorder; Panic Disorder; telephone-delivered psychotherapy
24.  Depression is associated with accelerated cognitive decline among patients with Type 2 diabetes in the ACCORD-MIND trial 
JAMA psychiatry  2013;70(10):1041-1047.
Context
Depression has been identified as a risk factor for dementia among patients with Type 2 diabetes mellitus but the cognitive domains and patient groups most affected have not been identified.
Objective
To determine whether comorbid depression in patients with type 2 diabetes accelerates cognitive decline.
Design
A 40-month cohort study of participants in the ACCORD-MIND trial
Setting
52 clinics organized into 6 clinical networks across the US and Canada.
Participants
2977 participants with Type 2 diabetes at high-risk for cardiovascular events
Main Outcome Measures
The Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and the modified Stroop test were used to assess cognition. The Physician’s Health Questionnaire-9 (PHQ-9) was used to assess depression. Mixed effects statistical models were used to analyze these cognitive outcomes incorporating depression as a time-dependent covariate.
Results
Participants with scores indicative of depression (PHQ-9 > 10) showed greater cognitive decline during 40-months follow-up on all tests, with the following differences in estimated least squares means: DSST 0.72 (95%CI 0.25, 1.19, p=0.0029), RAVLT 0.18 (95%CI 0.07, 0.29, p=0.0009), Stroop Interference −1.06 (95%CI −1.93, −0.18, p=0.0179). This effect of depression on risk of cognitive decline did not differ according to: previous cardiovascular disease, baseline cognition or age, intensive vs. standard treatment of glucose, blood pressure treatment, lipid treatment, or insulin use. Addition of demographic and clinical covariates to models did not significantly change the cognitive decline associated with depression.
Conclusions
Depression in patients with Type 2 diabetes was associated with greater cognitive decline in all domains, across all treatment arms, and in all participant subgroups assessed.
doi:10.1001/jamapsychiatry.2013.1965
PMCID: PMC4212406  PMID: 23945905
25.  Effects of Intramuscular Trunk Stimulation on Manual Wheelchair Propulsion Mechanics in Six Subjects with Spinal Cord Injury 
Objective
To quantify the effects of stabilizing the paralyzed trunk and pelvis with electrical stimulation on manual wheelchair propulsion.
Design
Single-subject design case series with subjects acting as their own concurrent controls.
Setting
Hospital-based clinical biomechanics laboratory.
Participants
Six (4M, 2F age 46±10.8yrs) long-time users (6.1±3.9yrs) of implanted neuroprostheses for lower extremity function with chronic (8.6±2.8yrs) mid-cervical or thoracic level injuries (C6-T10).
Interventions
Continuous low level stimulation to the hip (gluteus maximus, posterior adductor or hamstrings) and trunk extensor (lumbar erector spinae and/or quadratus lumborum) muscles with implanted intramuscular electrodes.
Main Outcome Measure(s)
Pushrim kinetics (peak resultant force, fraction effective force), kinematics (cadence, stroke length and maximum forward lean), and peak shoulder moment at preferred speed over 10m level surface; speed, pushrim kinetics and subjective ratings of effort for level 100m sprints and up a 30.5m ramp of approximately 5% grade.
Results
Three out of five subjects demonstrated reduced peak resultant pushrim forces (p≤0.014) and improved efficiency, (p≤0.048) with stimulation during self-paced level propulsion. Peak sagittal shoulder moment remained unchanged in three subjects and increased in two others (p<0.001). Maximal forward trunk lean also increased by 19-26% (p<0.001) with stimulation in these three subjects. Stroke lengths were unchanged by stimulation in all subjects, and two showed extremely small (5%) but statistically significant increases in cadence (p≤0.021). Performance measures for sprints and inclines were generally unchanged with stimulation, however subjects consistently rated propulsion with stimulation to be easier for both surfaces.
Conclusions
Stabilizing the pelvis and trunk with low levels of continuous electrical stimulation to the lumbar trunk and hip extensors can positively impact the mechanics of manual wheelchair propulsion and reduce both perceived and physical measures of effort.
doi:10.1016/j.apmr.2013.04.010
PMCID: PMC4103696  PMID: 23628377
Neural Prostheses; Spinal Cord Injuries; Posture; Electrical Stimulation; Torso

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