HIV-1 Nef Changes the Proteome of T Cells Extracellular Vesicles Depleting IFITMs and Other Antiviral Factors.

Extracellular vesicles (EVs) are biomolecule carriers for intercellular communication in health and disease. Nef is a HIV virulence factor that is released from cells within EVs and is present in plasma EVs of HIV-1 infected individuals. We performed a quantitative proteomic analysis to fully characterize the Nef-induced changes in protein composition of T cell-derived EVs and identify novel host targets of HIV. Several proteins with well-described roles in infection or not previously associated with HIV pathogenesis were specifically modulated by Nef in EVs. Among the downregulated proteins are the interferon-induced transmembrane 1, 2, and 3 (IFITM1-3) proteins, broad-spectrum antiviral factors known to be cell-to-cell transferable by EVs. We demonstrate that Nef depletes IFITM1-3 from EVs by excluding these proteins from the plasma membrane and lipid rafts, which are sites of EVs biogenesis in T cells. Our data establish Nef as a modulator of EVs' global protein content and as an HIV factor that antagonizes IFITMs.

Anatomical Registration of Implanted Sensors Improves Accuracy of Trunk Tilt Estimates with a Networked Neuroprosthesis.

For individuals with spinal cord injuries (SCIs) above the midthoracic level, a common complication is the partial or complete loss of trunk stability in the seated position. Functional neuromuscular stimulation (FNS) can restore seated posture and other motor functions after paralysis by applying small electrical currents to the peripheral motor nerves. In particular, the Networked Neuroprosthesis (NNP) is a fully implanted, modular FNS system that is also capable of capturing information from embedded accelerometers for measuring trunk tilt for feedback control of stimulation. The NNP modules containing the accelerometers are located in the body based on surgical constraints. As such, their exact orientations are generally unknown and cannot be easily assessed. In this study, a method for estimating trunk tilt that employed the Gram-Schmidt method to reorient acceleration signals to the anatomical axes of the body was developed and deployed in individuals with SCI using the implanted NNP system. An anatomically realistic model of a human trunk and five accelerometer sensors was developed to verify the accuracy of the reorientation algorithm. Correlation coefficients and root mean square errors (RMSEs) were calculated to compare target trunk tilt estimates and tilt estimates derived from simulated accelerometer signals under a variety of conditions. Simulated trunk tilt estimates with correlation coefficients above 0.92 and RMSEs below 5° were achieved. The algorithm was then applied to accelerometer signals from implanted sensors installed in three NNP recipients. Error analysis was performed by comparing the correlation coefficients and RMSEs derived from trunk tilt estimates calculated from implanted sensor signals to those calculated via motion capture data, which served as the gold standard. NNP-derived trunk tilt estimates exhibited correlation coefficients between 0.80 and 0.95 and RMSEs below 13° for both pitch and roll in most cases. These findings suggest that the algorithm is effective at estimating trunk tilt with the implanted sensors of the NNP system, which implies that the method may be appropriate for extracting feedback signals for control systems for seated stability with NNP technology for individuals who have reduced control of their trunk due to paralysis.

Implanted Pulse Generators in Lower Extremity Neuroprostheses: A 25-Year Review.

OBJECTIVES: Neuroprosthetic devices can improve quality of life by providing an alternative option for motor function lost after spinal cord injury, stroke, and other central nervous system disorders. The objective of this study is to analyze the outcomes of implanted pulse generators that our research group installed in volunteers with paralysis to assist with lower extremity function over a 25-year period, specifically, to determine survival rates and common modes of malfunction, reasons for removal or revision, and precipitating factors or external events that may have adversely influenced device performance. MATERIALS AND METHODS: Our implantable receiver-stimulator (IRS-8) and implantable stimulator-telemeter (IST-12 and IST-16) device histories were retrospectively reviewed through surgical notes, regulatory documentation, and manufacturing records from 1996 to 2021. RESULTS: Most of the 65 devices (64.6%) implanted in 43 volunteers remain implanted and operational. Seven underwent explantation owing to infection; seven had internal failures, and six were physically broken by external events. Of the 22 devices explanted, 15 were successfully replaced to restore recipients' enhanced functionality. There were no instances of sepsis or major health complications. The five infections that followed all 93 IRS and IST lower extremity research surgeries during this period indicate a pooled infection rate of 5.4%. The Kaplan-Meier analysis of technical malfunctions between the implant date and most recent follow-up shows five-, ten-, and 20-year device survival rates of 92%, 84%, and 71%, respectively. CONCLUSIONS: Incidence of malfunction is similar to, whereas infection rates are slightly higher than, other commonly implanted medical devices. Future investigations will focus on infection prevention, modifying techniques on the basis of recipient demographics, lifestyle factors, and education, and integrating similar experience of motor neuroprostheses used in other applications.

A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries.

BACKGROUND: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined. METHODS: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group. RESULTS: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups. CONCLUSIONS: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Long-Term Effects of Cognitive-Behavioral Therapy and Yoga for Worried Older Adults.

OBJECTIVES: Cognitive-behavioral therapy (CBT) and yoga decrease worry and anxiety. There are no long-term data comparing CBT and yoga for worry, anxiety, and sleep in older adults. The impact of preference and selection on these outcomes is unknown. In this secondary data analysis, we compared long-term effects of CBT by telephone and yoga on worry, anxiety, sleep, depressive symptoms, fatigue, physical function, social participation, and pain; and examined preference and selection effects. DESIGN: In this randomized preference trial, participants (N = 500) were randomized to a: 1) randomized controlled trial (RCT) of CBT or yoga (n = 250); or 2) preference trial (selected CBT or yoga; n = 250). Outcomes were measured at baseline and Week 37. SETTING: Community. PARTICIPANTS: Community-dwelling older adults (age 60+ years). INTERVENTIONS: CBT (by telephone) and yoga (in-person group classes). MEASUREMENTS: Penn State Worry Questionnaire - Abbreviated (worry);1,2 Insomnia Severity Index (sleep);3 PROMIS Anxiety Short Form v1.0 (anxiety);4,5 Generalized Anxiety Disorder Screener (generalized anxiety);6,7 and PROMIS-29 (depression, fatigue, physical function, social participation, pain).8,9 RESULTS: Six months after intervention completion, CBT and yoga RCT participants reported sustained improvements from baseline in worry, anxiety, sleep, depressive symptoms, fatigue, and social participation (no significant between-group differences). Using data combined from the randomized and preference trials, there were no significant preference or selection effects. Long-term intervention effects were observed at clinically meaningful levels for most of the study outcomes. CONCLUSIONS: CBT and yoga both demonstrated maintained improvements from baseline on multiple outcomes six months after intervention completion in a large sample of older adults. TRIAL REGISTRATION: www. CLINICALTRIALS: gov Identifier NCT02968238.

Man vs. Machine: Comparing Physician vs. Electronic Health Record-Based Model Predictions for 30-Day Hospital Readmissions.

BACKGROUND: Electronic health record (EHR)-based readmission risk prediction models can be automated in real-time but have modest discrimination and may be missing important readmission risk factors. Clinician predictions of readmissions may incorporate information unavailable in the EHR, but the comparative usefulness is unknown. We sought to compare clinicians versus a validated EHR-based prediction model in predicting 30-day hospital readmissions. METHODS: We conducted a prospective survey of internal medicine clinicians in an urban safety-net hospital. Clinicians prospectively predicted patients' 30-day readmission risk on 5-point Likert scales, subsequently dichotomized into low- vs. high-risk. We compared human with machine predictions using discrimination, net reclassification, and diagnostic test characteristics. Observed readmissions were ascertained from a regional hospitalization database. We also developed and assessed a "human-plus-machine" logistic regression model incorporating both human and machine predictions. RESULTS: We included 1183 hospitalizations from 106 clinicians, with a readmission rate of 20.8%. Both clinicians and the EHR model had similar discrimination (C-statistic 0.66 vs. 0.66, p = 0.91). Clinicians had higher specificity (79.0% vs. 48.9%, p < 0.001) but lower sensitivity (43.9 vs. 75.2%, p < 0.001) than EHR model predictions. Compared with machine, human was better at reclassifying non-readmissions (non-event NRI + 30.1%) but worse at reclassifying readmissions (event NRI - 31.3%). A human-plus-machine approach best optimized discrimination (C-statistic 0.70, 95% CI 0.67-0.74), sensitivity (65.5%), and specificity (66.7%). CONCLUSION: Clinicians had similar discrimination but higher specificity and lower sensitivity than EHR model predictions. Human-plus-machine was better than either alone. Readmission risk prediction strategies should incorporate clinician assessments to optimize the accuracy of readmission predictions.

Estimation of ascertainment bias and its effect on power in clinical trials with time-to-event outcomes.

While the gold standard for clinical trials is to blind all parties-participants, researchers, and evaluators-to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of postrandomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this article, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial vs changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed.

A case study of ascertainment bias for the primary outcome in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial.

BACKGROUND/AIM: In clinical trials, there is potential for bias from unblinded observers that may influence ascertainment of outcomes. This issue arose in the Strategies to Reduce Injuries and Develop Confidence in Elders trial, a cluster randomized trial to test a multicomponent intervention versus enhanced usual care (control) to prevent serious fall injuries, originally defined as a fall injury leading to medical attention. An unblinded nurse falls care manager administered the intervention, while the usual care arm did not involve contact with a falls care manager. Thus, there was an opportunity for falls care managers to refer participants reporting falls to seek medical attention. Since this type of observer bias could not occur in the usual care arm, there was potential for additional falls to be reported in the intervention arm, leading to dilution of the intervention effect and a reduction in study power. We describe the clinical basis for ascertainment bias, the statistical approach used to assess it, and its effect on study power. METHODS: The prespecified interim monitoring plan included a decision algorithm for assessing ascertainment bias and adapting (revising) the primary outcome definition, if necessary. The original definition categorized serious fall injuries requiring medical attention into Type 1 (fracture other than thoracic/lumbar vertebral, joint dislocation, cut requiring closure) and Type 2 (head injury, sprain or strain, bruising or swelling, other). The revised definition, proposed by the monitoring plan, excluded Type 2 injuries that did not necessarily require an overnight hospitalization since these would be most subject to bias. These injuries were categorized into those with (Type 2b) and without (Type 2c) medical attention. The remaining Type 2a injuries required medical attention and an overnight hospitalization. We used the ratio of 2b/(2b + 2c) in intervention versus control as a measure of ascertainment bias; ratios > 1 indicated the likelihood of falls care manager bias. We determined the effect of ascertainment bias on study power for the revised (Types 1 and 2a) versus original definition (Types 1, 2a, and 2b). RESULTS: The estimate of ascertainment bias was 1.14 (95% confidence interval: 0.98, 1.30), providing evidence of the likelihood of falls care manager bias. We estimated that this bias diluted the hazard ratio from the hypothesized 0.80 to 0.86 and reduced power to under 80% for the original primary outcome definition. In contrast, adapting the revised definition maintained study power at nearly 90%. CONCLUSION: There was evidence of ascertainment bias in the Strategies to Reduce Injuries and Develop Confidence in Elders trial. The decision to adapt the primary outcome definition reduced the likelihood of this bias while preserving the intervention effect and study power.

Comparison of cognitive-behavioral therapy and yoga for the treatment of late-life worry: A randomized preference trial.

BACKGROUND: The purpose of this study was to compare the effects of cognitive-behavioral therapy (CBT) and yoga on late-life worry, anxiety, and sleep; and examine preference and selection effects on these outcomes. METHODS: A randomized preference trial of CBT and yoga was conducted in community-dwelling adults 60 years or older, who scored 26 or above on the Penn State Worry Questionnaire-Abbreviated (PSWQ-A). CBT consisted of 10 weekly telephone sessions. Yoga consisted of 20 biweekly group yoga classes. The primary outcome was worry (PSWQ-A); the secondary outcomes were anxiety (PROMIS-Anxiety) and sleep (Insomnia Severity Index [ISI]). We examined both preference effects (average effect for those who received their preferred intervention [regardless of whether it was CBT or yoga] minus the average for those who did not receive their preferred intervention [regardless of the intervention]) and selection effect (which addresses the question of whether there is a benefit to getting to select one intervention over the other, and measures the effect on outcomes of self-selection to a specific intervention). RESULTS: Five hundred older adults were randomized to the randomized trial (125 each in CBT and yoga) or the preference trial (120 chose CBT; 130 chose yoga). In the randomized trial, the intervention effect of yoga compared with CBT adjusted for baseline psychotropic medication use, gender, and race was 1.6 (-0.2, 3.3), p = .08 for the PSWQ-A. Similar results were observed with PROMIS-Anxiety (adjusted intervention effect: 0.3 [-1.5, 2.2], p = .71). Participants randomized to CBT experienced a greater reduction in the ISI compared with yoga (adjusted intervention effect: 2.4 [1.2, 3.7], p < .01]). Estimated in the combined data set (N = 500), the preference and selection effects were not significant for the PSWQ-A, PROMIS-Anxiety, and ISI. Of the 52 adverse events, only two were possibly related to the intervention. None of the 26 serious adverse events were related to the study interventions. CONCLUSIONS: CBT and yoga were both effective at reducing late-life worry and anxiety. However, a greater impact was seen for CBT compared with yoga for improving sleep. Neither preference nor selection effects was found.

Comparative effectiveness of long-term acute care hospital versus skilled nursing facility transfer.

BACKGROUND: Long-term acute care hospital (LTACH) use varies considerably across the U.S., which may reflect uncertainty about the effectiveness of LTACHs vs. skilled nursing facilities (SNF), the principal post-acute care alternative. Given that LTACHs provide more intensive care and thus receive over triple the reimbursement of SNFs for comparable diagnoses, we sought to compare outcomes and spending between LTACH versus SNF transfer. METHODS: Using Medicare claims linked to electronic health record (EHR) data from six Texas Hospitals between 2009 and 2010, we conducted a retrospective cohort study of patients hospitalized on a medicine service in a high-LTACH use region and discharged to either an LTACH or SNF and followed for one year. The primary outcomes included mortality, 60-day recovery without inpatient care, days at home, and healthcare spending RESULTS: Of 3503 patients, 18% were transferred to an LTACH. Patients transferred to LTACHs were younger (median 71 vs. 82 years), less likely to be female (50.5 vs 66.6%) and white (69.0 vs. 84.1%), but were sicker (24.3 vs. 14.2% for prolonged intensive care unit stay; median diagnosis resource intensity weight of 2.03 vs. 1.38). In unadjusted analyses, patients transferred to an LTACH vs. SNF were less likely to survive (59.1 vs. 65.0%) or recover (62.5 vs 66.0%), and spent fewer days at home (186 vs. 200). Adjusting for demographic and clinical confounders available in Medicare claims and EHR data, LTACH transfer was not significantly associated with differences in mortality (HR, 1.12, 95% CI, 0.94-1.33), recovery (SHR, 1.07, 0.93-1.23), and days spent at home (IRR, 0.96, 0.83-1.10), but was associated with greater Medicare spending ($16,689 for one year, 95% CI, $12,216-$21,162). CONCLUSION: LTACH transfer for Medicare beneficiaries is associated with similar clinical outcomes but with higher healthcare spending compared to SNF transfer. LTACH use should be reserved for patients who require complex inpatient care and cannot be cared for in SNFs.

A Comparison of Random Forest Variable Selection Methods for Classification Prediction Modeling.

Random forest classification is a popular machine learning method for developing prediction models in many research settings. Often in prediction modeling, a goal is to reduce the number of variables needed to obtain a prediction in order to reduce the burden of data collection and improve efficiency. Several variable selection methods exist for the setting of random forest classification; however, there is a paucity of literature to guide users as to which method may be preferable for different types of datasets. Using 311 classification datasets freely available online, we evaluate the prediction error rates, number of variables, computation times and area under the receiver operating curve for many random forest variable selection methods. We compare random forest variable selection methods for different types of datasets (datasets with binary outcomes, datasets with many predictors, and datasets with imbalanced outcomes) and for different types of methods (standard random forest versus conditional random forest methods and test based versus performance based methods). Based on our study, the best variable selection methods for most datasets are Jiang's method and the method implemented in the VSURF R package. For datasets with many predictors, the methods implemented in the R packages varSelRF and Boruta are preferable due to computational efficiency. A significant contribution of this study is the ability to assess different variable selection techniques in the setting of random forest classification in order to identify preferable methods based on applications in expert and intelligent systems.

Long-Term Performance and User Satisfaction With Implanted Neuroprostheses for Upright Mobility After Paraplegia: 2- to 14-Year Follow-Up.

OBJECTIVE: To quantify the long-term (>2y) effects of lower extremity (LE) neuroprostheses (NPs) for standing, transfers, stepping, and seated stability after spinal cord injury. DESIGN: Single-subject design case series with participants acting as their own concurrent controls, including retrospective data review. SETTING: Hospital-based clinical biomechanics laboratory with experienced (>20y in the field) research biomedical engineers, a physical therapist, and medical monitoring review. PARTICIPANTS: Long-term (6.2±2.7y) at-home users (N=22; 19 men, 3 women) of implanted NPs for trunk and LE function with chronic (14.4±7.1y) spinal cord injury resulting in full or partial paralysis. INTERVENTIONS: Technical and clinical performance measurements, along with user satisfaction surveys. MAIN OUTCOME MEASURES: Knee extension moment, maximum standing time, body weight supported by lower extremities, 3 functional standing tasks, 2 satisfaction surveys, NP usage, and stability of implanted components. RESULTS: Stimulated knee extension strength and functional capabilities were maintained, with 94% of implant recipients reporting being very or moderately satisfied with their system. More than half (60%) of the participants were still using their implanted NPs for exercise and function for >10min/d on nearly half or more of the days monitored; however, maximum standing times and percentage body weight through LEs decreased slightly over the follow-up interval. Stimulus thresholds were uniformly stable. Six-year survival rates for the first-generation implanted pulse generator (IPG) and epimysial electrodes were close to 90%, whereas those for the second-generation IPG along with the intramuscular and nerve cuff electrodes were >98%. CONCLUSIONS: Objective and subjective measures of the technical and clinical performances of implanted LE NPs generally remained consistent for 22 participants after an average of 6 years of unsupervised use at home. These findings suggest that implanted LE NPs can provide lasting benefits that recipients value.

Oxidation of tartrazine with ultraviolet light emitting diodes: pH and duty cycles effects.

The presence of tartrazine (TAR) in the water cycle poses serious threats to human health. This study investigated the used of light emitting diodes (LEDs) in the advanced oxidation of TAR under different pH and duty cycle (DC) conditions. The first order reaction rate constant for TAR oxidation was positively correlated with DC, negatively correlated with pH, and typically greatest at pH 6. Chemical byproduct analysis indicated that OH addition, H abstraction, and electron transfer without molecule transfer were among the relevant reaction mechanisms for TAR degradation. Six byproducts were identified, four were reported for the first time, and two demonstrated that TAR rings were cleaved. This research is the first to determine the optimal pH for UVLED-driven oxidation of TAR and the first to identify new TAR-related byproducts from UVLED-based water treatment.

ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial.

AIMS/HYPOTHESIS: The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a double 2x2 factorial parallel-group randomised clinical trial, tested whether intensive compared with standard management of hyperglycaemia, BP or lipid levels reduced cognitive decline and brain atrophy in 2977 people with type 2 diabetes. We describe the results of the observational extension study, ACCORDION MIND (ClinicalTrials.gov registration no. NCT00182910), which aimed to measure the long-term effects of the three ACCORD interventions on cognitive and brain structure outcomes approximately 4 years after the trial ended. METHODS: Participants (mean diabetes duration 10 years; mean age 62 years at baseline) received a fourth cognitive assessment and a third brain MRI, targeted at 80 months post-randomisation. Primary outcomes were performance on the Digit Symbol Substitution Test (DSST) and total brain volume (TBV). The contrast of primary interest compared glycaemic intervention groups at the ACCORDION visit; secondary contrasts were the BP and lipid interventions. RESULTS: Of the surviving ACCORD participants eligible for ACCORDION MIND, 1328 (68%) were re-examined at the ACCORDION follow-up visit, approximately 47 months after the intensive glycaemia intervention was stopped. The significant differences in therapeutic targets for each of the three interventions (glycaemic, BP and lipid) were not sustained. We found no significant difference in 80 month mean change from baseline in DSST scores or in TBV between the glycaemic intervention groups, or the BP and lipid interventions. Sensitivity analyses of the sites with ≥70% participation at 80 months revealed consistent results. CONCLUSIONS/INTERPRETATION: The ACCORD interventions did not result in long-term beneficial or adverse effects on cognitive or brain MRI outcomes at approximately 80 months follow-up. Loss of separation in therapeutic targets between treatment arms and loss to follow-up may have contributed to the lack of detectable long-term effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00182910.

The effect of intervening hospitalizations on the benefit of structured physical activity in promoting independent mobility among community-living older persons: secondary analysis of a randomized controlled trial.

BACKGROUND: Among older persons, disability is often precipitated by intervening illnesses and injuries leading to hospitalization. In the Lifestyle Interventions and Independence for Elders (LIFE) Study, a structured moderate-intensity physical activity program, compared with a health education program, was shown to significantly reduce the amount of time spent with major mobility disability (MMD) over the course of 3.5 years. We aimed to determine whether the benefit of the physical activity program in promoting independent mobility was diminished in the setting of intervening hospitalizations. METHODS: We analyzed data from a single-blinded, parallel group randomized trial (ClinicalTrials.gov: NCT01072500). In this trial, 1635 sedentary persons, aged 70-89 years, who had functional limitations but were able to walk 400 m, were randomized from eight US centers between February 2010 and December 2013: 818 to physical activity (800 received intervention) and 817 to health education (805 received intervention). Intervening hospitalizations and MMD, defined as the inability to walk 400 m, were assessed every 6 months for up to 3.5 years. RESULTS: For both the physical activity and health education groups, intervening hospitalizations were strongly associated with the initial onset of MMD and inversely associated with recovery from MMD, defined as a transition from initial MMD onset to no MMD. The benefit of the physical activity intervention did not differ significantly based on hospital exposure. For onset of MMD, the hazard ratios (HR) were 0.79 (95% confidence interval [CI] 0.58-1.1) and 0.77 (0.62-0.95) in the presence and absence of intervening hospitalizations, respectively (P-interaction, 0.903). For recovery of MMD, the magnitude of effect was modestly greater among participants who were hospitalized (HR 1.5, 95% CI 0.71-3.0) than in those who were not hospitalized (HR 1.2, 95% CI 0.88-1.7), but this difference did not achieve statistical significance (P-interaction, 0.670). CONCLUSIONS: Intervening hospitalizations had strong deleterious effects on the onset of MMD and recovery from MMD, but did not diminish the beneficial effect of the LIFE physical activity intervention in promoting independent mobility. To achieve sustained benefits over time, structured physical activity programs should be designed to accommodate acute illnesses and injuries leading to hospitalizations given their high frequency in older persons with functional limitations. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01072500 .

Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus.

BACKGROUND: Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM). STUDY DESIGN: Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM. SETTING & PARTICIPANTS: African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American-Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies. PREDICTORS: eGFR (CKD-EPI creatinine equation), spot UACR. MEASUREMENTS: MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A1c concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed. RESULTS: Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A1c concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m2; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests. LIMITATIONS: Cross-sectional; single UACR measurement. CONCLUSIONS: In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.

Long-Term Effects of Telephone-Delivered Psychotherapy for Late-Life GAD.

OBJECTIVE: To examine the long-term effects of telephone-delivered cognitive-behavioral therapy (CBT-T) compared with nondirective supportive therapy (NST-T) in rural older adults with generalized anxiety disorder (GAD). METHODS: 141 adults aged 60 years and older with a principal/co-principal diagnosis of GAD were randomized to either CBT-T or NST-T. CBT-T consisted of up to 11 sessions (9 were required) focused on recognition of anxiety symptoms, relaxation, cognitive restructuring and use of coping statements, problem-solving, worry control, behavioral activation, exposure therapy, and relapse prevention, with optional chapters on sleep and pain. NST-T consisted of 10 sessions focused on providing a supportive atmosphere in which participants could share and discuss their feelings and did not provide any direct suggestions. Primary outcomes included interviewer-rated anxiety severity and self-report worry severity measured at 9 months and 15 months after randomization. Mood-specific secondary outcomes included self-report GAD symptoms and depressive symptoms. RESULTS: At 15 months, after adjustment for multiple testing, there was a significantly greater decline in general anxiety symptoms (difference in improvement: 3.31; 95% CI: 0.45-6.17; t = 2.29; df = 136; p = 0.024) and worry (difference in improvement: 3.13; 95% CI: 0.59-5.68; t = 2.43; df = 136; p = 0.016) among participants in CBT-T compared with those in the NST-T group. There were no significant differences between the conditions in terms of depressive symptoms (difference in improvement: 2.88; 95% CI: 0.17-5.60; t = 2.10; df = 136; p = 0.0376) and GAD symptoms (difference in improvement: 1.65; 95% CI: -0.20 to 3.50; t = 1.76; df = 136; p = 0.080). CONCLUSIONS: CBT-T is superior to NST-T in reducing worry and anxiety symptoms 1 year after completing treatment.

Effect of Structured Physical Activity on Overall Burden and Transitions Between States of Major Mobility Disability in Older Persons: Secondary Analysis of a Randomized Trial.

Background: The total time a patient is disabled likely has a greater influence on his or her quality of life than the initial occurrence of disability alone. Objective: To compare the effect of a long-term, structured physical activity program with that of a health education intervention on the proportion of patient assessments indicating major mobility disability (MMD) (that is, MMD burden) and on the risk for transitions into and out of MMD. Design: Single-blinded, parallel-group, randomized trial. (ClinicalTrials.gov: NCT01072500). Setting: 8 U.S. centers between February 2010 and December 2013. Participants: 1635 sedentary persons, aged 70 to 89 years, who had functional limitations but could walk 400 m. Intervention: Physical activity (n = 818) and health education (n = 817). Measurements: MMD, defined as the inability to walk 400 m, was assessed every 6 months for up to 3.5 years. Results: During a median follow-up of 2.7 years, the proportion of assessments showing MMD was substantially lower in the physical activity (0.13 [95% CI, 0.11 to 0.15]) than the health education (0.17 [CI, 0.15 to 0.19]) group, yielding a risk ratio of 0.75 (CI, 0.64 to 0.89). In a multistate model, the hazard ratios for comparisons of physical activity with health education were 0.87 (CI, 0.73 to 1.03) for the transition from no MMD to MMD; 0.52 (CI, 0.10 to 2.67) for no MMD to death; 1.33 (CI, 0.99 to 1.77) for MMD to no MMD; and 1.92 (CI, 1.15 to 3.20) for MMD to death. Limitation: The intention-to-treat principle was maintained for MMD burden and first transition out of no MMD, but not for subsequent transitions. Conclusion: A structured physical activity program reduced the MMD burden for an extended period, in part through enhanced recovery after the onset of disability and diminished risk for subsequent disability episodes. Primary Funding Source: National Institute on Aging, National Institutes of Health.

Whey protein-derived exosomes increase protein synthesis and hypertrophy in C2-C12 myotubes.

We sought to examine potential amino acid independent mechanisms whereby hydrolyzed whey protein (WP) affects muscle protein synthesis (MPS) and anabolism in vitro. Specifically, we tested (1) whether 3-h and 6-h treatments of WP, essential amino acids, or l-leucine (Leu) affected MPS, and whether 6-h treatments with low-, medium-, or high doses of WP versus Leu affected MPS; (2) whether knockdown of the primary Leu transporter affected WP- and Leu-mediated changes in MPS, mammalian target of rapamycin (mTOR) signaling responses, or both, following 6-h treatments; (3) whether exosomes isolated from WP (WP-EXO) affected MPS, mTOR signaling responses, or both, compared with untreated (control) myotubes, following 6-h, 12-h, and 24-h treatments, and whether they affected myotube diameter following 24-h and 48-h treatments. For all treatments, 7-d post-differentiated C2C12 myotubes were examined. In experiment 1, 6-h WP treatments increased MPS compared with control (+46%), Leu (+24%), and essential amino acids (+25%). Moreover, the 6-h low-, medium-, and high WP treatments increased MPS by approximately 40 to 50% more than corresponding Leu treatments. In experiment 2 (LAT short hairpin RNA-transfected myotubes), 6-h WP treatments increased MPS compared with control (+18%) and Leu (+19%). In experiment 3, WP-EXO treatments increased MPS over controls at 12h (+18%) and 24h (+45%), and myotube diameters increased with 24-h (+24%) and 48-h (+40%) WP-EXO treatments compared with controls. The WP-EXO treatments did not appear to operate through mTOR signaling; instead, they increased mRNA and protein levels o eukaryotic initiation factor 4A. Bovine-specific microRNA following 24-h WP-EXO treatments were enriched in myotubes (chiefly miR-149-3p, miR-2881), but were not related to hypertrophic gene targets. To summarize, hydrolyzed WP-EXO increased skeletal MPS and anabolism in vitro, and this may be related to an unknown mechanism that increases translation initiation factors rather than enhancing mTOR signaling or the involvement of bovine-specific microRNA.

Advanced Oxidation of Tartrazine and Brilliant Blue with Pulsed Ultraviolet Light Emitting Diodes.

This study investigated the effect of ultraviolet light-emitting diodes (UVLEDs) coupled with hydrogen peroxide as an advanced oxidation process (AOP) for the degradation of two test chemicals. Brilliant Blue FCF consistently exhibited greater degradation than tartrazine, with 83% degradation after 300 minutes at the 100% duty cycle compared with only 17% degradation of tartrazine under the same conditions. These differences are attributable to the structural properties of the compounds. Duty cycle was positively correlated with the first-order rate constants (k) for both chemicals but, interestingly, negatively correlated with the normalized first-order rate constants (k/duty cycle). Synergistic effects of both hydraulic mixing and LED duty cycle were manifested as novel oscillations in the effluent contaminant concentration. Further, LED output and efficiency were dependent upon duty cycle and less efficient over time perhaps due to heating effects on semiconductor performance.