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1.  Prediction of Graft Patency and Mortality after Distal Revascularization and Interval Ligation for Hemodialysis Access Related Hand Ischemia 
Journal of vascular surgery  2012;57(2):451-458.
The treatment goals for access related hand ischemia (ARHI) are to reverse symptoms and salvage the access. Many procedures have been described, but the optimal treatment strategy remains unresolved. In an effort to guide clinical decision making, this study was undertaken to document our outcomes for distal revascularization and interval ligation (DRIL) and identify predictors of bypass patency and patient mortality.
A retrospective review was performed of all patients who underwent DRIL at the University of Florida from 2002–2011. Diagnosis of ARHI was based primarily upon clinical symptoms with non-invasive studies used to corroborate in equivocal cases. Patient demographics, procedure-outcome variables and re-interventions were recorded. Bypass patency and mortality were estimated using cumulative incidence and Kaplan-Meier methodology, respectively. Cumulative incidence and Cox regression analysis were performed to determine predictors of bypass patency and mortality, respectively.
134 DRILs were performed in 126 patients (age 57±12yrs (mean±SD)) following brachial artery-based access. The post-operative complication rate was 27% (19%-wound), and 30-day mortality was 2%. The wrist/brachial (WBI) and digital/brachial (DBI) indices increased 0.31±0.25 and 0.25±0.29, respectively. Symptoms resolved in 82% of patients, and 85% continued to use their access. Cumulative incidences of loss of primary and primary-assisted patency rates were 5±2%, 4±2% and 22±5%, 18±5% at 1 and 5 years, respectively with a mean follow-up of 14.8 months. Univariate predictors of primary patency failure were DRIL complications (3.3; 1.2–8.9, p=0.02), configuration other than brachiobasilic/brachiocephalic autogenous access (3.4; 1.4–8.3, p=0.009), and ≥2 prior access attempts (4.1; 1.6–10.4, p=0.004). Brachiocephalic access configuration (0.2; 0.04–0.8, p =0.02), and autogenous vein conduit (0.2; 0.06–0.58, p=0.004) were predictors of improved bypass patency. All-cause mortality was 28% and 79% at 1 and 5 years, respectively. Multi-variable predictors of mortality were age > 40 (8.3; 2.5–33.3, p =0.0004), grade 3 ischemia (2.6; 1.5–4.6, p=0.0008), complication from DRIL (2.4; 1.3–4.5, p=0.004), and smoking history (2.2; 1.3–4, p=0.007). Patients with no prior access attempts had lower predicted mortality (0.5; 0.3–0.9, p=0.02).
The DRIL procedure effectively improves distal perfusion and reverses the symptoms of ARHI while salvaging the access, but the long-term survival of these patients is poor. Given the poor survival, pre-operative risk stratification is critical. Patients at high risk for DRIL failure and mortality may be best served with alternate remedial procedures.
PMCID: PMC4135397  PMID: 23244784
2.  Hindlimb Muscle Morphology and Function in a New Atrophy Model Combining Spinal Cord Injury and Cast Immobilization 
Journal of Neurotrauma  2013;30(3):227-235.
Contusion spinal cord injury (SCI) animal models are used to study loss of muscle function and mass. However, parallels to the human condition typically have been confounded by spontaneous recovery observed within the first few post-injury weeks, partly because of free cage activity. We implemented a new rat model combining SCI with cast immobilization (IMM) to more closely reproduce the unloading conditions experienced by SCI patients. Magnetic resonance imaging was used to monitor hindlimb muscles' cross-sectional area (CSA) after SCI, IMM alone, SCI combined with IMM (SCI+IMM), and in controls (CTR) over a period of 21 days. Soleus muscle tetanic force was measured in situ on day 21, and hindlimb muscles were harvested for histology. IMM alone produced a decrease in triceps surae CSA to 63.9±4.9% of baseline values within 14 days. In SCI, CSA decreased to 75.0±10.5% after 7 days, and recovered to 77.9±10.7% by day 21. SCI+IMM showed the greatest amount of atrophy (56.9±9.9% on day 21). In all groups, muscle mass and soleus tetanic force decreased in parallel, such that specific force was maintained. Extensor digitorum longus (EDL) and soleus fiber size decreased in all groups, particularly in SCI+IMM. We observed a significant degree of asymmetry in muscle CSA in SCI but not IMM. This effect increased between day 7 and 21 in SCI, but also in SCI+IMM, suggesting a minor dependence on muscle activity. SCI+IMM offers a clinically relevant model of SCI to investigate the mechanistic basis for skeletal muscle adaptations after SCI and develop therapeutic approaches.
PMCID: PMC3565549  PMID: 22985272
atrophy; immobilization; magnetic resonance imaging; SCI; skeletal muscle
3.  Estimating the Causal Effect of Low Tidal Volume Ventilation on Survival in Patients with Acute Lung Injury† 
Acute lung injury (ALI) is a condition characterized by acute onset of severe hypoxemia and bilateral pulmonary infiltrates. ALI patients typically require mechanical ventilation in an intensive care unit. Low tidal volume ventilation (LTVV), a time-varying dynamic treatment regime, has been recommended as an effective ventilation strategy. This recommendation was based on the results of the ARMA study, a randomized clinical trial designed to compare low vs. high tidal volume strategies (The Acute Respiratory Distress Syndrome Network, 2000) . After publication of the trial, some critics focused on the high non-adherence rates in the LTVV arm suggesting that non-adherence occurred because treating physicians felt that deviating from the prescribed regime would improve patient outcomes. In this paper, we seek to address this controversy by estimating the survival distribution in the counterfactual setting where all patients assigned to LTVV followed the regime. Inference is based on a fully Bayesian implementation of Robins’ (1986) G-computation formula. In addition to re-analyzing data from the ARMA trial, we also apply our methodology to data from a subsequent trial (ALVEOLI), which implemented the LTVV regime in both of its study arms and also suffered from non-adherence.
PMCID: PMC3197806  PMID: 22025809
Bayesian inference; Causal inference; Dynamic treatment regime; G-computation formula
5.  Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats 
Age  2010;33(2):167-183.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
PMCID: PMC3127467  PMID: 21153712
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
6.  Influence of Calorie Restriction on Measures of Age-Related Cognitive Decline: Role of Increased Physical Activity 
Controversy exists as to whether lifelong 40% calorie restriction (CR) enhances, has no effect on, or disrupts cognitive function during aging. Here, we report the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway × Fisher344 rats across a range of ages (8–38 months), using two tasks that are differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). All ages performed equally in object recognition, whereas, as a group, CR rats were impaired. In contrast, there was an age-related impairment in the MWM that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Finally, CR resulted in an overall increase in physical activity, one of several behavioral confounders to consider in the interpretation of cognitive outcomes in both tasks.
PMCID: PMC2709546  PMID: 19420296
Morris water maze; Object recognition; Animal models of aging; Calorie restriction
8.  Methods of time sampling: A reappraisal of momentary time sampling and partial interval recording 
We compared the accuracy of momentary time sampling (MTS) and partial interval recording (PIR) in estimating both absolute behavioral levels and relative change. A computer randomly generated runs of pseudobehavior varying in duration and rate and simulated MTS and PIR of each run. Results indicated that when estimating absolute behavioral levels, duration rather than rate should be used as the dependent measure, and MTS is more accurate than PIR. In contrast, PIR is the more sensitive method for detecting relative changes in behavioral levels, although, at high rates, PIR tends to underestimate the degree of change.
PMCID: PMC1308042  PMID: 16795692
observation methods; momentary time sampling; partial interval recording; measurement error

Results 1-8 (8)