Factors associated with pain intensity and analgesic use during inpatient rehabilitation for hip fracture.

PURPOSE: Effective pain management is vital for hip fracture recovery, yet the factors influencing pain reporting and pain medication use during inpatient rehabilitation for hip fractures are not well understood. This observational study aimed to (a) determine how cognitive abilities, expressive and receptive language abilities, and age are related to average daily pain intensity and analgesic use and (b) how average daily pain intensity and analgesic use are related to length of stay and functional outcomes in rehabilitation. DESIGN: Data were retrospectively obtained from 163 patients recovering from unilateral trochanteric fractures of the femur. RESULTS: During the first week of rehabilitation, patients received a daily average of 1,147.8 ± 978 mg of acetaminophen and a morphine milligram equivalent of 15.3 ± 18.2. Multivariable regression revealed independent relationships between more intact general cognitive abilities (B = -0.40, 95% CI [-0.70, -0.11]), and older age (B = -0.41, 95% CI [-0.70, -0.11]) with lower average daily pain intensity. Higher average daily pain intensity (B = 0.97, 95% CI [0.75, 1.20]) was independently related to greater opioid use. The length of stay was shorter among patients administered higher daily doses of acetaminophen (B = 0.03, 95% CI [-0.05, -0.01]). Average daily pain intensity and analgesic use were not related to functional outcomes in multivariable models. CONCLUSIONS: These findings inform the considerations for assessing and treating pain during inpatient rehabilitation. Supplemental strategies for assessing pain in older patients and alternative pain mitigation strategies for patients with impaired cognitive abilities should be considered. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Assessing Clinically Important Differences During Rehabilitation for Stroke: A Pilot Study Evaluating Anchor and Distribution Derived Estimates of Physical Function Change in Classically Summed and Rasch Models of Section GG of the Inpatient Rehabilitation Facility Patient Assessment Instrument.

OBJECTIVE: To determine clinically important differences (CIDs) on Section GG physical functioning scores on the Centers for Medicare and Medicaid Services (CMS) Inpatient Rehabilitation Facility Assessment Instrument (IRF-PAI) for patients with stroke, using anchor and distribution-based approaches. DESIGN: Pilot prospective observational cohort study. SETTING: Inpatient rehabilitation facility. PARTICIPANTS: Patients with stroke (N=208). INTERVENTIONS: Physicians assessed improvements during rehabilitation using the modified Rankin scale (mRS). Improvements (≥1 point) on the mRS were used as the anchor for establishing CIDs. MAIN OUTCOME MEASURES: Classically summed and Rasch transformed Section GG change scores associated with clinically important improvements on the mRS. RESULTS: A total of 166 patients (79.8%) improved ≥1 point on the mRS. Change scores of 27, 9, and 16 on Section GG total physical functioning (self-care + mobility), self-care, and mobility/walk scales, respectively, had high sensitivity (0.82-0.85) but low specificity (0.52-0.69) in identifying patients improving on the mRS. Positive predictive values ranged from 0.87 to 0.91, and negative predictive values ranged from 0.42 to 0.52. Total physical functioning and selfcare anchor-derived change scores were similar to the reliable change index (RCI [2.77 × SEM]), calculated as 28 and 10 points, respectively, whereas anchor-derived mobility/walk scale change scores were equivalent to 1.96 × SEM. Exploratory Rasch modeling identified 3 Section GG subscales (R-Self-Care, R-Mobility, and R-Walking). Improvements on the R-Walking subscale were most correlated with mRS improvements (ρ=-0.47); however, accuracy of CID estimates was not improved. CONCLUSIONS: Cut-off scores obtained using the mRS anchor aligned with more robust estimates of change, as estimated by distribution-based measures. While patients achieving anchor-derived cut-offs have a high probability of mRS improvement, change scores may fail to detect clinically meaningful improvements at these same thresholds. Alternative criteria for determining MCID/CIDs, should be explored. Rasch models require further validation.

Peer-Assisted Learning Is More Effective at Higher Task Complexity and Difficulty.

This paper presents two studies in which a peer-assisted learning condition was compared to an individual learning condition. The first study used the paired-associates learning task and the second study used an incrementally more complex task-the remote associate test. Participants in the peer-assisted learning condition worked in groups of four. They had to solve a given problem individually and give a first answer before being able to request to see their peers' solutions; then, a second answer was issued. After six sessions of peer-assisted practice, a final individual test was administered. Peer interaction was found to benefit learning in both studies but the benefit transferred to the final test only in the second study. Fine-grained behavioral analyses and computational modeling suggested that the benefits of peer interaction were (partially) offset by its costs, particularly increased cognitive load and error exposure. Overall, the superiority of peer-assisted learning over individual learning was more pronounced in the more complex task and for the more difficult problems in that task.

Concurrent Validation of the Inpatient Rehabilitation Facility Patient Assessment Instrument Version 1.4; Sections GG, B, and C.

OBJECTIVE: To validate Sections GG (Self-Care and Mobility Assessment), B (Hearing, Speech, and Vision), and C (Cognitive Patterns) of the Centers for Medicare and Medicaid Services Inpatient Rehabilitation Facility Patient Assessment Instrument (CMS-IRF PAI) Version 1.4 in comparison with Functional Independence Measure (FIM) motor subscale (FIMm) and cognitive subscale (FIMc). DESIGN: Retrospective cohort. SETTING: Single inpatient rehabilitation facility. PARTICIPANTS: Cohort of 1296 patients admitted for rehabilitation after stroke, between October 1, 2016, and October 1, 2019. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sections GG, B, and C scores were compared with FIMm and FIMc using Spearman's and Bland-Altman Analyses. RESULTS: Sections GG and FIMm were highly correlated on admission (ρ=0.919, P<.001) and discharge (ρ=0.929, P<.001). Ceiling effects at discharge were more pronounced for Section GG (8.6%). Bland-Altman analyses revealed a bias toward higher scores on Section GG vs FIMm on admission (Bias=2.3%, P<.001), and discharge (Bias=6.2%, P<.001). Section GG showed bias toward greater gains in function (Bias=3.9%, P<.001), particularly in walking and stairs (bias=3.71%, P<.001). Comparable self-care items accounted for a smaller percentage of the Section GG gains compared with FIMm (bias=-7.5%, P<.001). The internal validity of a scale consisting of Section B and C (B+C scale) was good, (Cronbach's alpha=0.868) and was highly correlated with FIMc (ρ=0.745), but rated patients at a higher level of cognition (bias=20.0%, P<.001) and had a greater ceiling effect (20.4%) on admission compared with the FIMc (0.6%). CONCLUSION: The B+C scale and Section GG were correlated with FIMc and FIMm subscales but biased toward higher ratings of ability. Ceiling effects may limit discrimination at higher level of cognition/functional independence. The clinical acceptability of Section GG total scores as an outcome measure and predictor of long-term outcomes requires further study.

Predicting Falls in Rehabilitation: A Comparison of Three Instruments Including Hester Davis.

PURPOSE: The aim of this study was to evaluate the ability of the Hester Davis Scale (HDS), Section GG, and facility fall risk assessment scores to predict patients who fall during inpatient rehabilitation. DESIGN: This study was an observational quality improvement project. METHODS: Nurses administered the HDS in parallel to the facility's current fall risk assessment and Section GG of the Centers for Medicare & Medicaid Services Inpatient Rehabilitation Facility Patient Assessment Instrument. Receiver operating characteristic curves were compared in 1,645 patients. Relationships of individual scale items to falls were also assessed. RESULTS: The HDS (area under the curve [AUC] = .680, 95% CI [.626, .734]), facility fall risk assessment (AUC = .688, 95% CI [.637, .740]), and Section GG scores (AUC = .687, 95% CI [.638, .735]) adequately identified patients who fell. AUCs did not significantly differ between assessments. HDS scores of ≥13, facility scores of ≥14, and Section GG scores of ≤51 resulted in the highest sensitivity/specificity balance. CONCLUSIONS: HDS, facility fall risk assessment, and Section GG scores adequately and similarly identified patients of mixed diagnoses at risk of falling in inpatient rehabilitation. CLINICAL RELEVANCE TO THE PRACTICE OF REHABILITATION NURSING: Rehabilitation nurses have several options including the HDS and Section GG to identify patients at greatest risk of falling.

Characteristics and Outcomes of COVID-19 Survivors Requiring Inpatient Rehabilitation: A Comparison of Two Waves.

OBJECTIVE: Many survivors of severe or critical COVID-19 have required rehabilitation during the pandemic. The primary objective was to compare characteristics and outcomes of survivors of severe or critical COVID-19 admitted to the inpatient rehabilitation facility during the first two waves of the pandemic. Our secondary objective was to identify the factors contributing to functional dependence on admission, discharge, and length of stay. DESIGN: This is a retrospective cohort study of 138 patients admitted to an inpatient rehabilitation facility in two waves after hospitalization for severe or critical COVID-19 illness between April 1, 2020, and May 3, 2021. RESULTS: Inpatient rehabilitation facility patients in wave 2 had significantly greater functional independence (GG scores) on admission (52; interquartile range, 44-58 vs 41; interquartile range, 28-52), lower incidence of dysphagia and anemia. The patients in both waves experienced similar functional improvement efficiencies with a median GG score change of 3.6 per day and similar discharge GG scores. Neurological sequela (odds ratio, 0.12; P < 0.001) and anemia (odds ratio, 1.35; P < 0.002) were identified as independent predictors of functional independence on admission. CONCLUSIONS: Patients with functional deficits after COVID-19 should be considered for acute inpatient rehabilitation as both patient cohorts benefited from their inpatient rehabilitation facility stays with similar length of stays (11-12 days) and discharge to home rates (88%-90%).

Comparison of the Brief Interview for Mental Status (BIMS) and Montreal Cognitive Assessment (MoCA) for identifying cognitive impairments and predicting rehabilitation outcomes in an inpatient rehabilitation facility.

BACKGROUND: The Brief Interview for Mental Status (BIMS) is the Centers for Medicare and Medicaid Services' primary cognitive assessment for multiple health care settings. However, research suggests that the BIMS has low sensitivity in detecting mild cognitive impairment in community samples and nursing home residents. OBJECTIVE: To determine the sensitivity of the BIMS in identifying patients with mild or moderate cognitive impairments in an inpatient rehabilitation setting and the relationship of BIMS and Montreal Cognitive Assessment (MoCA) scores with rehabilitation outcomes. DESIGN: Retrospective cohort. SETTING: Inpatient rehabilitation facility. PATIENTS: A total of 2252 patients admitted for orthopedic or general rehabilitation. METHODS: The sensitivity and specificity of the BIMS for identification of cognitive impairments were determined using validated cutoff scores on the MoCA as criterion. Multivariable ordinal regression was employed to determine if MoCA and BIMS scores were independent predictors of rehabilitation outcomes. MAIN OUTCOME MEASUREMENTS: Functional independence at discharge (GG scores), rehabilitation efficiency (GG change per day), length of stay (LOS), and discharge destination. RESULTS: The BIMS had low sensitivity in identifying moderate (0.384) or mild (0.257) cognitive impairment. Patients classified as having moderate cognitive impairment on the MoCA had lower GG scores at discharge (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.30 to 0.46) and rehabilitation efficiency (OR 0.43, CI 0.34 to 0.53) compared to individuals identified as impaired on the BIMS (GG scores: OR 0.63, CI 0.52 to 0.78; efficiency: OR 0.71, CI 0.58 to 0.86). LOS (OR 1.49, CI 1.19 to 1.85) and discharge destination (OR 0.47, CI 0.28 to 0.77) were uniquely predicted in patients identified as moderately impaired on the MoCA but not the BIMS (LOS: OR 0.99, CI 0.80 to 1.21; discharge home: OR 0.93, CI 0.62 to 1.38). CONCLUSIONS: The BIMS had low sensitivity for detection of mild and moderate cognitive impairments. Compared to the MoCA, the BIMS was less effective at predicting rehabilitation outcomes.

Prism Adaptation Treatment of Spatial Neglect: Feasibility During Inpatient Rehabilitation and Identification of Patients Most Likely to Benefit.

Objective: Spatial Neglect is prevalent among stroke survivors, yet few treatments have evidence supporting efficacy. This study examines the feasibility of Prism Adaptation Treatment (PAT) within an inpatient rehabilitation facility and the degree by which PAT improves symptoms of spatial neglect and functional independence among sub-acute survivors of right hemispheric stroke. Design: In this retrospective cohort study, 37 right hemispheric stroke patients were identified as having received at least 4 PAT sessions during their inpatient stay. Spatial neglect and functional independence levels of patients in the PAT cohort were compared to a matched active control group comprised of rehabilitation patients receiving alternative therapies to address neglect admitted during the same time period. Results: Most patients received the full recommended 10 sessions of PAT (average sessions completed = 8.6). A higher percentage of severe neglect patients receiving PAT (69%) displayed clinically significant gains on FIM (≥22 points) compared to those receiving alternative treatments (6%). Patients with mild or moderate neglect in the PAT cohort did not exhibit greater benefit than controls. Conclusion: Provision of PAT for treatment of spatial neglect in right hemispheric stroke patients was feasible during the inpatient rehabilitation admission. Patients with severe neglect showed the most benefit from PAT. Clinical Trial Registration: This study was registered as a retrospective observational study on Itab Clinical Trials.gov. NCT04977219.

Functional outcomes and post-discharge care sought by patients with COVID-19 compared to matched controls after completing inpatient acute rehabilitation.

INTRODUCTION: A subset of patients with coronavirus disease 19 (COVID-19) can develop severe illness, resulting in significant functional and cognitive deficits that require acute inpatient rehabilitation. Guidelines following discharge from acute inpatient rehabilitation have not yet been established. This study seeks to establish outcomes of rehabilitation patients with COVID-19 and characterize their need for long-term care. OBJECTIVE: To determine the functional outcomes and utilization of follow-up medical care for patients with COVID-19 90 days following discharge from acute inpatient rehabilitation, as compared to rehabilitation impairment and age-matched controls. DESIGN: Prospective, single-center cohort study. SETTING: Inpatient rehabilitation facility (IRF). PATIENTS: Sixty-four patients recovering from COVID-19 and 64 age and impairment group category controls were identified to answer survey questions following discharge from inpatient rehabilitation. A total of 36 patients participated in the study (18 patients with COVID-19 and 18 controls). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Functional outcomes at discharge (GG Self-Care and Mobility Activities items of the IRF-PAI Version 3.0), hospital readmissions, and follow-up care sought by patients. RESULTS: The COVID-19 patient group had similar improvements in functional outcomes as compared to controls. Patients with COVID-19 required fewer 0-90 day readmissions than their matched controls (22.2% vs 61.1%, P < .05), but there were no differences in 0-90 day urgent care/emergency department visits, clinic visits and use of outpatient therapies. CONCLUSIONS: Patients with functional deficits as a result of COVID-19 who require multiple therapy disciplines should be considered for acute inpatient rehabilitation as this study demonstrates their ability to participate in and benefit from IRF level care.

How We Assess Spatial Neglect Matters: Prevalence of Spatial Neglect as Measured by the Catherine Bergego Scale and Impact on Rehabilitation Outcomes.

OBJECTIVE: The aim of this study was to determine the prevalence and functional impact of unilateral spatial neglect on right hemisphere stroke patients in an inpatient rehabilitation facility using a multidimensional, functionally based behavioral measure (Catherine Bergego Scale [CBS]). DESIGN: This was a retrospective cohort study of 742 consecutive admissions of patients with right hemispheric stroke to an inpatient rehabilitation facility. Spatial neglect was assessed using the CBS. Functional impact of neglect was measured by hospital length of stay, Functional Independence Measure change per day, discharge destination, and number of falls. RESULTS: As measured by the CBS, 86% of the right hemisphere stroke patients had symptoms of spatial neglect. Moderate and severe neglect was associated with less Functional Independence Measure change per day and lower rates of community discharge. The presence of neglect was not significantly associated with fall rate or length of hospital stay after controlling for admission Functional Independence Measure scores and age. The "difficulty looking left" CBS item had the strongest relationship with total CBS scores and effectively predicted Functional Independence Measure change per day and discharge destination. CONCLUSIONS: Using a sensitive measure, the CBS, rates of spatial neglect are extremely high in right hemisphere stroke patients entering inpatient rehabilitation. Both identification and determination of neglect severity are extremely important given their significant relationship to rehabilitation outcomes and discharge destinations. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. CME OBJECTIVES: Upon completion of this article, the reader should be able to (1) describe why carefully assessing spatial neglect in right hemisphere stroke patients is important; (2) identify multiple dimensions of spatial neglect assessed by the Catherine Bergego Scale and how this approach differs from traditional paper and pencil assessment methods; and (3) describe the relationship between spatial neglect as measured by the Catherine Bergego Scale and functional outcomes of right hemisphere stroke patients in inpatient rehabilitation settings. LEVEL: Advanced. ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Salinity Improves Performance and Alters Distribution of Soybean Aphids.

We know numerous abiotic factors strongly influence crop plants. Yet we often know much less about abiotic effects on closely interacting organisms including herbivorous insects. This lack of a whole-system perspective may lead to underestimating the threats from changing factors. High soil salinity is a specific example that we know threatens crop plants in many places, but we need to know much more about how other organisms are also affected. We investigated how salinity affects the soybean aphid (SBA; Aphis glycines Matsumura; Hemiptera: Aphididae) on soybean plants (Glycine max [L.] Merr.; Fabales: Fabaceae) grown across a range of saline conditions. We performed four complementary greenhouse experiments to understand different aspects of how salinity might affect SBA. We found that as salinity increased both population size and fecundity of SBA increased across electrical conductivity values ranging from 0.84 to 8.07 dS m-1. Tracking individual aphids we also found they lived longer and produced more offspring in high saline conditions compared to the control. Moreover, we found that salinity influenced aphid distribution such that when given the chance aphids accumulated more on high-salinity plants. These results suggest that SBA could become a larger problem in areas with higher salinity and that those aphids may exacerbate the negative effects of salinity for soybean production.

The effect of engineered nanotopography of electrospun microfibers on fiber rigidity and macrophage cytokine production.

Currently, it is unknown how the mechanical properties of electrospun fibers, and the presentation of surface nanotopography influence macrophage gene expression and protein production. By further elucidating how specific fiber properties (mechanical properties or surface properties) alter macrophage behavior, it may be possible to create electrospun fiber scaffolds capable of initiating unique cellular and tissue responses. In this study, we determined the elastic modulus and rigidity of fibers with varying topographies created by finely controlling humidity and including a non-solvent during electrospinning. In total,five fiber scaffold types were produced. Analysis of fiber physical properties demonstrated no change in fiber diameter amongst the five different fiber groups. However, the four different fibrous scaffolds with nanopits or divots each possessed different numbers of pits with different nanoscale dimensions. Unpolarized bone marrow derived murine macrophages (M0), macrophages polarized towards a pro-inflammatory phenotype (M1), or macrophages polarized towards anti-inflammatory phenotype (M2b) were placed onto each of the scaffolds and cytokine RNA expression and protein production were analyzed. Specific nanotopographies did not appreciably alter cytokine production from undifferentiated macrophages (M0) or anti-inflammatory macrophages (M2b), but a specific fiber (with many small pits) did increase IL-12 transcript and IL-12 protein production compared to fibers with small divots. When analyzing the mechanical properties between fibers with divots or with many small pits,divoted fibers possessed similar elastic moduli but different stiffness values. In total,we present techniques capable of creating unique electrospun fibers. These unique fibers have varying fiber mechanical characteristics and modestly modulate macrophage cytokine expression.

Supratherapeutic dose evaluation and effect of lesinurad on cardiac repolarization: a thorough QT/QTc study.

INTRODUCTION: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization. METHODS: The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve) was determined at doses of 800 mg, 1,200 mg, and 1,600 mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600 mg (supratherapeutic dose), lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI). RESULTS: The upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI) was <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, confirming assay sensitivity. CONCLUSION: Lesinurad, at supratherapeutic doses, does not have a significant effect on the QT interval in healthy male or female subjects.

Summer-to-Winter Phenotypic Flexibility of Fatty Acid Transport and Catabolism in Skeletal Muscle and Heart of Small Birds.

Prolonged shivering in birds is mainly fueled by lipids. Consequently, lipid transport and catabolism are vital for thermogenic performance and could be upregulated along with thermogenic capacity as part of the winter phenotype. We investigated summer-to-winter variation in lipid transport and catabolism by measuring mRNA expression, protein levels, and enzyme activities for several key steps of lipid transport and catabolic pathways in pectoralis muscle and heart in two small temperate-zone resident birds, American goldfinches (Spinus tristis) and black-capped chickadees (Poecile atricapillus). Cytosolic fatty acid binding protein (FABPc; a key component of intramyocyte lipid transport) mRNA and/or protein levels were generally higher in winter for pectoralis muscle and heart for both species. However, seasonal variation in plasma membrane lipid transporters, fatty acyl translocase, and plasma membrane fatty acid binding protein in pectoralis and heart differed between the two species, with winter increases for chickadees and seasonal stability or summer increases for goldfinches. Catabolic enzyme activities generally showed limited seasonal differences for both tissues and both species. These data suggest that FABPc is an important target of upregulation for the winter phenotype in pectoralis and heart of both species. Plasma membrane lipid transporters and lipid catabolic capacity were also elevated in winter for chickadees but not for goldfinches. Because the two species show differential regulation of distinct aspects of lipid transport and catabolism, these data are consistent with other recent studies documenting that different bird species or populations employ a variety of strategies to promote elevated winter thermogenic capacity.

EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4.

Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor ß1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF.

Migration-induced variation of fatty acid transporters and cellular metabolic intensity in passerine birds.

Because lipids are the main fuel supporting avian endurance activity, lipid transport and oxidation capacities may increase during migration. We measured enzyme activities, mRNA expression and protein levels in pectoralis and heart for several key steps of lipid transport and catabolism pathways to investigate whether these pathways were upregulated during migration. We used yellow-rumped (Setophaga coronata) and yellow (S. petechia) warblers and warbling vireos (Vireo gilvus) as study species because they all show migration-induced increases in organismal metabolic capacities. For yellow-rumped warblers, ß-hydroxyacyl CoA-dehydrogenase (HOAD) activities and fatty acid transporter mRNA and/or protein levels were higher during spring than fall in pectoralis and heart, except that fatty acid translocase (FAT/CD36) protein levels showed the opposite pattern in heart. Lipid transporter protein levels, but not mRNA expression, in pectoralis and heart of warbling vireos were higher either during spring or fall than summer, but this was not true for HOAD activities. For yellow warblers, pectoralis, but not heart, protein levels of lipid transporters were upregulated during migration relative to summer, but this pattern was not evident for mRNA expression or HOAD activity. Finally, muscle and heart citrate synthase and carnitine palmitoyl transferase activities showed little seasonal variation for any species. These data suggest that pectoralis and heart lipid transport and catabolism capacities are often, but not universally, important correlates of elevated organismal metabolic capacity during migration. In contrast, migration-induced variation in cellular metabolic intensity and mitochondrial membrane transport are apparently not common correlates of the migratory phenotype in passerines.

Reduced Atherosclerosis in apoE-inhibitory FcγRIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages.

OBJECTIVE: Fcγ receptors (FcγRs) are classified as activating (FcγRI, III, and IV) and inhibitory (FcγRII) receptors. We have reported that deletion of activating FcγRs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory FcγRIIb exacerbates atherosclerosis. APPROACH AND RESULTS: ApoE-FcγRIIb double knockout mice, congenic to the C57BL/6 (apoE-FcγRIIbB6 (-/-)), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-FcγRIIbB6 (-/-) male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-FcγRIIbB6 (-/-) marrow into apoE single knockout mice also developed reduced lesions. CD4(+) T cells from apoE-FcγRIIbB6 (-/-) mice produced higher levels of interleukin-10 and transforming growth factor-ß than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-FcγRIIb129/B6 (-/-) mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from FcγRIIb129/B6 (-/-) mice on a mixed genetic background produced more interleukin-1ß and MCP-1 (monocyte chemoattractant protein-1) in response to immune complexes, whereas congenic FcγRIIbB6 (-/-) mice generated more interleukin-10 and significantly less interleukin-1ß. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed FcγRIIb129/B6 (-/-) mice. CONCLUSIONS: Our findings demonstrate a detrimental role for FcγRIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-FcγRIIbB6 (-/-) mice. As 129/sv genome-derived lupus-associated genes have been implicated in lupus phenotype in FcγRIIb129/B6 (-/-) mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions.

Phenotypic flexibility of skeletal muscle and heart masses and expression of myostatin and tolloid-like proteinases in migrating passerine birds.

Migrant birds require large flight muscles and hearts to enhance aerobic capacity and support sustained flight. A potential mechanism for increasing muscle and heart masses during migration in birds is the muscle growth inhibitor myostatin and its metalloproteinase activators, tolloid-like proteinases (TLL-1 and TLL-2). We hypothesized that myostatin, TLL-1 and TLL-2 are downregulated during migration in pectoralis and hearts of migratory passerines to promote hypertrophy. We measured seasonal variation of tissue masses, mRNA expression of myostatin, TLL-1, and TLL-2, and myostatin protein levels in pectoralis muscle and heart for yellow warblers (Setophaga petechia), warbling vireos (Vireo gilvus), and yellow-rumped warblers (Setophaga coronata). Pectoralis mass was greatest in spring for warbling vireos and yellow warblers, but was stable between spring and fall for yellow-rumped warblers. Heart mass was higher in spring than in fall for yellow-rumped warblers, lowest in fall for warbling vireos, and seasonally stable for yellow warblers. Pectoralis and heart mRNA expression of myostatin and the TLLs did not differ significantly for any of the three species, offering little support for our hypothesis for a prominent role for myostatin in regulating migration-induced variation in pectoralis and heart masses. In contrast, pectoralis myostatin protein levels were lowest in spring for all three species, consistent with our hypothesis. Myostatin protein levels in heart, however, were seasonally stable for warbling vireos and yellow warblers, and increased in spring relative to fall for yellow-rumped warblers. These data offer mixed support for our hypothesis for the pectoralis, but suggest that myostatin is not a prominent regulator of migration-induced heart hypertrophy. Moreover, the different seasonal patterns for pectoralis mRNA and protein expression suggest that post-transcriptional modification of myostatin may contribute to pectoralis mass regulation during migration.

Anti-inflammatory immune skewing is atheroprotective: Apoe−/−FcγRIIb−/− mice develop fibrous carotid plaques.

BACKGROUND: Stroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcγR) expression than their stable counterparts, how FcγR expression impacts plaque histology is unknown. We investigated the role of FcγRIIb in carotid plaque development and stability in apolipoprotein (Apo)e−/− and Apoe−/−FcγRIIb−/− double knockout (DKO) animals. METHODS AND RESULTS: Plaques were induced by implantation of a shear stress­modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe−/− mice were foam­cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg­1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)­10, immune complexes, and regulatory T cells (Tregs) and lower IL­12, IL­1ß, and tumor necrosis factor alpha (TNF­α) in DKO mice. Similarly, in vitro stimulation produced higher IL­10 and Arg­1 and lower iNOS, IL­1ß, and TNF­α in DKO versus Apoe−/− macrophages. These results define a systemic anti­inflammatory phenotype. CONCLUSIONS: We hypothesized that removal of FcγRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcγRIIb on a congenic C57BL/6 background induces an anti­inflammatory Treg/M2 polarization that is atheroprotective.