Impact of Oncology Drug Review Times on Public Funding Recommendations.

New oncology drugs undergo detailed review prior to public funding in a single-payer healthcare system. The aim of this study was to assess how cancer drug review times impact funding recommendations. Drugs reviewed by the pan-Canadian Oncology Drug Review (pCODR) between the years 2012 and 2020 were included. Data were collected including Health Canada approval dates, initial and final funding recommendations, treatment intent, drug class, clinical indications, and incremental cost-effectiveness ratios (ICER). Univariable and multivariable analyses were used to determine the association between funding recommendations and review times. Of the 164 applications submitted, 130 received a positive final recommendation. Median time from Health Canada (HC) approval to final recommendation was longer for drugs indicated for the treatment of gastrointestinal (GI) and lung cancer compared to breast, genitourinary (GU), and other tumours (205 vs. 198 vs. 111 vs. 129 vs. 181 days, respectively; Kruskal-Wallis p = 0.0312). Drugs with longer review times were more likely to receive a negative pCODR recommendation, even when adjusting for tumour type, drug class, and intent of therapy (157 vs. 298 days; Wilcoxon p = 0.0003, OR 1.002 95% CI [1.000-1.004].). There was no association between funding recommendation and tumour type or class of drug. The exploration of factors associated with variance in review times will be important in ensuring timely patient access to cancer drugs.

Using the Standing and Walking Assessment Tool at Discharge Predicts Community Outdoor Walking Capacity in Persons With Traumatic Spinal Cord Injury.

OBJECTIVE: The Standing and Walking Assessment Tool (SWAT) standardizes the timing and content of walking assessments during inpatient rehabilitation by combining 12 stages ranging from lowest to highest function (0, 0.5, 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C, and 4) with 5 standard measures: the Berg Balance Scale, the modified Timed "Up & Go" test, the Activities-specific Balance Confidence Scale, the modified 6-Minute Walk Test, and the 10-Meter Walk Test (10MWT). This study aimed to determine if the SWAT at rehabilitation discharge could predict outdoor walking capacity 1-year after discharge in people with traumatic spinal cord injury. METHODS: This retrospective study used data obtained from the Rick Hansen Spinal Cord Injury Registry from 2014 to 2020. Community outdoor walking capacity was measured using the Spinal Cord Independence Measure III (SCIM III) outdoor mobility score obtained 12 (±4) months after discharge. Of 206 study participants, 90 were community nonwalkers (ie, SCIM III score 0-3), 41 were community walkers with aids (ie, SCIM III score 4-6), and 75 were independent community walkers (ie, SCIM III score 7-8). Bivariate, multivariable regression, and an area under the receiver operating characteristic curve analyses were performed. RESULTS: At rehabilitation discharge, 3 significant SWAT associations were confirmed: 0-3A with community nonwalkers, 3B/higher with community walkers with and without an aid, and 4 with independent community walkers. Moreover, at discharge, a higher (Berg Balance Scale, Activities-specific Balance Confidence Scale), faster (modified Timed "Up & Go," 10MWT), or further (10MWT) SWAT measure was significantly associated with independent community walking. Multivariable analysis indicated that all SWAT measures, except the 10MWT were significant predictors of independent community walking. Furthermore, the Activities-Specific Balance Confidence Scale had the highest area under the receiver operating characteristic score (0.91), demonstrating an excellent ability to distinguish community walkers with aids from independent community walkers. CONCLUSION: The SWAT stage and measures at discharge can predict community outdoor walking capacity in persons with traumatic spinal cord injury. Notably, a patient's confidence in performing activities plays an important part in achieving walking ability in the community. IMPACT: The discharge SWAT is useful to optimize discharge planning.

Frailty Among Sexual and Gender Minority Older Adults: The All of Us Database.

BACKGROUND: Despite known disparities in health status among older sexual and gender minority adults (OSGM), the prevalence of frailty is unknown. The aim of this study was to develop and validate a deficit-accumulation frailty index (AoU-FI) for the All of Us database to describe and compare frailty between OSGM and non-OSGM participants. METHODS: Developed using a standardized approach, the AoU-FI consists of 33 deficits from baseline survey responses of adults aged 50+. OSGM were self-reported as "not straight" or as having discordant gender and sex assigned at birth. Descriptive statistics characterized the AoU-FI. Regression was used to assess the association between frailty, age, and gender. Validation of the AoU-FI used Cox proportional hazard models to test the association between frailty categories (robust <0.15, 0.15 ≤ pre-frail ≤ 0.25, frail >0.25) and mortality. RESULTS: There were 9 110 OSGM and 67 420 non-OSGM with sufficient data to calculate AoU-FI; 41% OSGM versus 50% non-OSGM were robust, whereas 34% versus 32% were pre-frail, and 26% versus 19% were frail. Mean AoU-FI was 0.19 (95% confidence interval [CI]: 0.187, 0.191) for OSGM and 0.168 (95% CI: 0.167, 0.169) for non-OSGM. Compared to robust, odds of mortality were higher among frail OSGM (odds ratio [OR] 6.40; 95% CI: 1.84, 22.23) and non-OSGM (OR 3.96; 95% CI: 2.96, 5.29). CONCLUSIONS: The AoU-FI identified a higher burden of frailty, increased risk of mortality, and an attenuated impact of age on frailty among OSGM compared to non-OSGM. Future work is needed to understand how frailty affects the OSGM population.

Communicating Standing and Walking Data after Spinal Cord Injury: A Patient-Engaged, Qualitative Study.

Background: The Standing and Walking Assessment Tool has been implemented by physical therapists across Canada, but there is no standardized communication tool to inform inpatients living with spinal cord injury (SCI) about their standing and walking ability. Objectives: To identify how inpatients with SCI are currently receiving feedback on their standing and walking ability, and to determine if and how they would like to receive information on their standing and walking. Methods: Ontario's Patient Engagement Framework informed study protocol development. Inpatients with SCI were recruited from a rehabilitation centre in Canada. Purposeful sampling considering severity of SCI and sex was adopted. Three to four months following discharge from inpatient rehabilitation, a semi-structured interview was conducted to explore participants'experiences and preferences regarding feedback on standing and walking ability during inpatient SCI rehabilitation. Interviews were audio-recorded and transcribed verbatim. A conventional content analysis was completed. Results: Fifteen individuals with SCI (5 female, 10 male) participated. Four themes emerged from the transcripts: (1) motivation for standing and walking, (2) current standing and walking practice, (3) participant preferences for feedback on standing and walking ability, and (4) perceptions of preexisting tools. Conclusion: Information on standing and walking ability was shared with inpatients with SCI in a variety of ways. Participants identified various preferences for the nature, format, and frequency of feedback concerning standing and walking ability during inpatient rehabilitation, which suggests the need for an individualized approach to communicating this information.

Pharmacological Prevention and Management of Skeletal-Related Events and Bone Loss in Individuals with Cancer.

OBJECTIVE: To provide a literature review of the clinical efficacy and safety data of various pharmacological agents used to manage bone health in people affected by cancer. DATA SOURCES: Peer-reviewed articles and research publications identified from PubMed and relevant clinical guidelines were used in this evidence synthesis. CONCLUSION: Individuals with cancers such as breast and prostate cancers, multiple myeloma, and other malignancies are at a high risk of developing skeletal-related events such as bone fracture, bone metastasis, and osteoporosis. Pharmacologic agents such as bisphosphonates and RANK-L inhibitor (denosumab) are the mainstay therapy options for managing bone health in this population. IMPLICATIONS FOR NURSING PRACTICE: Nurses and nurse practitioners should be aware of the efficacy data of bisphosphonates and denosumab but also should be well-versed in the appropriate administration of these agents, potential side effect profiles, timely assessment, and interventions to optimize quality of life.

Impact of Value Frameworks on the Magnitude of Clinical Benefit: Evaluating a Decade of Randomized Trials for Systemic Therapy in Solid Malignancies.

In the era of rapid development of new, expensive cancer therapies, value frameworks have been developed to quantify clinical benefit (CB). We assessed the evolution of CB since the 2015 introduction of The American Society of Clinical Oncology and The European Society of Medical Oncology value frameworks. Randomized clinical trials (RCTs) assessing systemic therapies for solid malignancies from 2010 to 2020 were evaluated and CB (Δ) in 2010-2014 (pre-value frameworks (PRE)) were compared to 2015-2020 (POST) for overall survival (OS), progression-free survival (PFS), response rate (RR), and quality of life (QoL). In the 485 studies analyzed (12% PRE and 88% POST), the most common primary endpoint was PFS (49%), followed by OS (20%), RR (12%), and QoL (6%), with a significant increase in OS and decrease in RR as primary endpoints in the POST era (p = 0.011). Multivariable analyses revealed significant improvement in ΔOS POST (OR 2.86, 95% CI 0.46 to 5.26, p = 0.02) while controlling for other variables. After the development of value frameworks, median ΔOS improved minimally. The impact of value frameworks has yet to be fully realized in RCTs. Efforts to include endpoints shown to impact value, such as QoL, into clinical trials are warranted.

VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis.

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.

A Multidisciplinary Consultation-Liaison Team Approach to Reduce Enhanced Observer Usage.

BACKGROUND: There are few evidence-informed guidelines and findings to show that the use of sitters improves patient safety; overall, it is a costly intervention to address patients with disruptive behaviors. OBJECTIVE: The purpose of this article is to demonstrate that the creation of a multidisciplinary consultation-liaison (C-L) team, integrated with a psychiatric C-L team, together can decrease sitter use and improve outcomes using nonpharmacologic interventions. METHODS: This retrospective study describes the planning, implementation, and data collection using in creating an multidisciplinary C-L team to collaborate with the psychiatric C-L team and outcomes to support the approach. The multidisciplinary C-L team was composed of advanced practice registered nurses and creative art therapists. The teams worked closely with the medical units to develop and monitor criteria for sitter use. The key outcomes of the intervention improved patient safety and reduced overall cost. RESULTS: In the first year of implementation of a multidisciplinary C-L approach, sitter use decreased by 72%. Nonpharmacologic interventions improved patient outcomes by providing education to medical staff that enhanced the assessment and implementation of enhanced observer use across all the medical units. Subsequent data also reflect a sustained reduction in cost over the next 2-year period, saving the institution nearly $70K a month. CONCLUSION: An multidisciplinary C-L and psychiatric C-L team collaborated on the need for psychiatric medications, or nonpharmacologic interventions to address behaviors and decrease the need for an enhanced observer. The teams worked together to make policy revisions and algorithms and provide education, the result of which was significant financial savings and improved patient safety.

Characteristics and Outcomes of Patients in Rehabilitation with Hip Fracture: A Retrospective Chart Review.

ABSTRACTHip fracture rehabilitation has two streams: high tolerance short duration (HTSD) and low tolerance long duration (LTLD). This study examined patient characteristics and outcomes in HTSD and LTLD associated with length of stay (LOS) and discharge destination. We retrospectively examined patients' medical charts following hip fracture surgery and collected demographic, functional, and health characteristics. A statistical analysis was done to describe the differences between HTSD (n = 73) and LTLD (n = 57) patient characteristics and their relationship with LOS and discharge destination. Those in LTLD were significantly older, less independent with prefracture bathing and instrumental activities of daily living, had lower Functional Independence Measure (FIM) admission scores, and more co-morbidities. Higher FIM motor score on admission in HTSD and greater change in FIM total score in LTLD was significantly correlated with discharge home. Diabetes in LTLD and lower total admission FIM in HTSD was significantly associated with increased LOS.

Brain Network Modularity Predicts Exercise-Related Executive Function Gains in Older Adults.

Recent work suggests that the brain can be conceptualized as a network comprised of groups of sub-networks or modules. The extent of segregation between modules can be quantified with a modularity metric, where networks with high modularity have dense connections within modules and sparser connections between modules. Previous work has shown that higher modularity predicts greater improvements after cognitive training in patients with traumatic brain injury and in healthy older and young adults. It is not known, however, whether modularity can also predict cognitive gains after a physical exercise intervention. Here, we quantified modularity in older adults (N = 128, mean age = 64.74) who underwent one of the following interventions for 6 months (NCT01472744 on ClinicalTrials.gov): (1) aerobic exercise in the form of brisk walking (Walk), (2) aerobic exercise in the form of brisk walking plus nutritional supplement (Walk+), (3) stretching, strengthening and stability (SSS), or (4) dance instruction. After the intervention, the Walk, Walk+ and SSS groups showed gains in cardiorespiratory fitness (CRF), with larger effects in both walking groups compared to the SSS and Dance groups. The Walk, Walk+ and SSS groups also improved in executive function (EF) as measured by reasoning, working memory, and task-switching tests. In the Walk, Walk+, and SSS groups that improved in EF, higher baseline modularity was positively related to EF gains, even after controlling for age, in-scanner motion and baseline EF. No relationship between modularity and EF gains was observed in the Dance group, which did not show training-related gains in CRF or EF control. These results are consistent with previous studies demonstrating that individuals with a more modular brain network organization are more responsive to cognitive training. These findings suggest that the predictive power of modularity may be generalizable across interventions aimed to enhance aspects of cognition and that, especially in low-performing individuals, global network properties can capture individual differences in neuroplasticity.

Magnetic susceptibility-induced echo-time shifts: Is there a bias in age-related fMRI studies?

PURPOSE: To evaluate the potential for bias in functional magnetic resonance imaging (fMRI) aging studies resulting from age-related differences in magnetic field distributions that can impact echo time and functional contrast. MATERIALS AND METHODS: Magnetic field maps were taken on 31 younger adults (age: 22 ± 2.9 years) and 46 older adults (age: 66 ± 4.5 years) on a 3T scanner. Using the spatial gradients of the magnetic field map for each participant, an echo planar imaging (EPI) trajectory was simulated. The effective echo time, time at which the k-space trajectory is the closest to the center of k-space, was calculated. This was used to examine both within-subject and across-age-group differences in the effective echo time maps. The blood oxygenation level-dependent (BOLD) percent signal change resulting from those echo time shifts was also calculated to determine their impact on fMRI aging studies. RESULTS: For a single subject, the effective echo time varied as much as ±5 msec across the brain. An unpaired t-test between the effective echo time across age groups resulted in significant differences in several regions of the brain (P < 0.01). The difference in echo time was only ∼1 msec, however, which is not expected to have an important impact on BOLD fMRI percent signal change (<4%). CONCLUSION: Susceptibility-induced magnetic field gradients induce local echo-time shifts in gradient echo fMRI images, which can cause variable BOLD sensitivity across the brain. However, the age-related differences in BOLD signal are expected to be small for an fMRI study at 3T. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:207-214.

White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults.

White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.

Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging.

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the default mode network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks.

Brain activation during dual-task processing is associated with cardiorespiratory fitness and performance in older adults.

Higher cardiorespiratory fitness is associated with better cognitive performance and enhanced brain activation. Yet, the extent to which cardiorespiratory fitness-related brain activation is associated with better cognitive performance is not well understood. In this cross-sectional study, we examined whether the association between cardiorespiratory fitness and executive function was mediated by greater prefrontal cortex activation in healthy older adults. Brain activation was measured during dual-task performance with functional magnetic resonance imaging in a sample of 128 healthy older adults (59-80 years). Higher cardiorespiratory fitness was associated with greater activation during dual-task processing in several brain areas including the anterior cingulate and supplementary motor cortex (ACC/SMA), thalamus and basal ganglia, right motor/somatosensory cortex and middle frontal gyrus, and left somatosensory cortex, controlling for age, sex, education, and gray matter volume. Of these regions, greater ACC/SMA activation mediated the association between cardiorespiratory fitness and dual-task performance. We provide novel evidence that cardiorespiratory fitness may support cognitive performance by facilitating brain activation in a core region critical for executive function.

Physical Activity Is Linked to Greater Moment-To-Moment Variability in Spontaneous Brain Activity in Older Adults.

Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age are associated with greater brain structural and functional integrity, and higher cognitive functioning. However, it is not known how different aspects of lifestyle such as sedentariness, light PA (LI-PA), or moderate-to-vigorous physical activity (MV-PA) relate to neural activity in aging. In addition, it is not known whether the effects of PA on brain function differ or overlap with those of CRF. Here, we objectively measured CRF as oxygen consumption during a maximal exercise test and measured PA with an accelerometer worn for 7 days in 100 healthy but low active older adults (aged 60-80 years). We modeled the relationships between CRF, PA, and brain functional integrity using multivariate partial least squares analysis. As an index of functional brain integrity we used spontaneous moment-to-moment variability in the blood oxygenation level-dependent signal (SDBOLD), known to be associated with better cognitive functioning in aging. We found that older adults who engaged more in LI-PA and MV-PA had greater SDBOLD in brain regions that play a role in integrating segregated functional domains in the brain and benefit from greater CRF or PA, such as precuneus, hippocampus, medial and lateral prefrontal, and temporal cortices. Our results suggest that engaging in higher intensity PA may have protective effects on neural processing in aging. Finally, we demonstrated that older adults with greater overall WM microstructure were those showing more LI-PA and MV-PA and greater SDBOLD. We conclude that SDBOLD is a promising correlate of functional brain health in aging. Future analyses will evaluate whether SDBOLD is modifiable with interventions aimed to increase PA and CRF in older adults.

Robust neuroprosthetic control from the stroke perilesional cortex.

Intracortical brain-machine interfaces (BMIs) may eventually restore function in those with motor disability after stroke. However, current research into the development of intracortical BMIs has focused on subjects with largely intact cortical structures, such as those with spinal cord injury. Although the stroke perilesional cortex (PLC) has been hypothesized as a potential site for a BMI, it remains unclear whether the injured motor cortical network can support neuroprosthetic control directly. Using chronic electrophysiological recordings in a rat stroke model, we demonstrate here the PLC's capacity for neuroprosthetic control and physiological plasticity. We initially found that the perilesional network demonstrated abnormally increased slow oscillations that also modulated neural firing. Despite these striking abnormalities, neurons in the perilesional network could be modulated volitionally to learn neuroprosthetic control. The rate of learning was surprisingly similar regardless of the electrode distance from the stroke site and was not significantly different from intact animals. Moreover, neurons achieved similar task-related modulation and, as an ensemble, formed cell assemblies with learning. Such control was even achieved in animals with poor motor recovery, suggesting that neuroprosthetic control is possible even in the absence of motor recovery. Interestingly, achieving successful control also reduced locking to abnormal oscillations significantly. Our results thus suggest that, despite the disrupted connectivity in the PLC, it may serve as an effective target for neuroprosthetic control in those with poor motor recovery after stroke.

White matter integrity supports BOLD signal variability and cognitive performance in the aging human brain.

Decline in cognitive performance in old age is linked to both suboptimal neural processing in grey matter (GM) and reduced integrity of white matter (WM), but the whole-brain structure-function-cognition associations remain poorly understood. Here we apply a novel measure of GM processing-moment-to-moment variability in the blood oxygenation level-dependent signal (SDBOLD)-to study the associations between GM function during resting state, performance on four main cognitive domains (i.e., fluid intelligence, perceptual speed, episodic memory, vocabulary), and WM microstructural integrity in 91 healthy older adults (aged 60-80 years). We modeled the relations between whole-GM SDBOLD with cognitive performance using multivariate partial least squares analysis. We found that greater SDBOLD was associated with better fluid abilities and memory. Most of regions showing behaviorally relevant SDBOLD (e.g., precuneus and insula) were localized to inter- or intra-network "hubs" that connect and integrate segregated functional domains in the brain. Our results suggest that optimal dynamic range of neural processing in hub regions may support cognitive operations that specifically rely on the most flexible neural processing and complex cross-talk between different brain networks. Finally, we demonstrated that older adults with greater WM integrity in all major WM tracts had also greater SDBOLD and better performance on tests of memory and fluid abilities. We conclude that SDBOLD is a promising functional neural correlate of individual differences in cognition in healthy older adults and is supported by overall WM integrity.

An automated behavioral box to assess forelimb function in rats.

BACKGROUND: Rodent forelimb reaching behaviors are commonly assessed using a single-pellet reach-to-grasp task. While the task is widely recognized as a very sensitive measure of distal limb function, it is also known to be very labor-intensive, both for initial training and the daily assessment of function. NEW METHOD: Using components developed by open-source electronics platforms, we have designed and tested a low-cost automated behavioral box to measure forelimb function in rats. Our apparatus, made primarily of acrylic, was equipped with multiple sensors to control the duration and difficulty of the task, detect reach outcomes, and dispense pellets. Our control software, developed in MATLAB, was also used to control a camera in order to capture and process video during reaches. Importantly, such processing could monitor task performance in near real-time. RESULTS: We further demonstrate that the automated apparatus can be used to expedite skill acquisition, thereby increasing throughput as well as facilitating studies of early versus late motor learning. The setup is also readily compatible with chronic electrophysiological monitoring. COMPARISON WITH EXISTING METHODS: Compared to a previous version of this task, our setup provides a more efficient method to train and test rodents for studies of motor learning and recovery of function after stroke. The unbiased delivery of behavioral cues and outcomes also facilitates electrophysiological studies. CONCLUSIONS: In summary, our automated behavioral box will allow high-throughput and efficient monitoring of rat forelimb function in both healthy and injured animals.

The inflammasome adaptor ASC contributes to multiple innate immune processes in the resolution of otitis media.

This study was designed to understand the contribution of the inflammasome and IL-1ß activation in otitis media (OM). We examined the middle ear (ME) response to non-typeable Haemophilus influenzae (NTHi) in wild type (WT) mice using gene microarrays and a murine model of acute OM. Expression of members of the NOD domain-like receptor family of inflammasome genes was significantly up-regulated early in NTHi infection of the ME, potentially activating specific downstream regulatory cascades that contribute to the proliferative inflammatory response observed during OM. Expression of the pro-forms of the inflammasome targets IL-1ß and IL-18 were also up-regulated. To evaluate the role of inflammasome-mediated cytokine maturation, NTHi-induced OM was examined in Asc(-/-)-deficient mice and compared with that seen in WT mice. Mice lacking the Asc gene showed near absence of IL-1ß maturation in the ME and a reduction in leukocyte recruitment and infiltration to the cavity, and their macrophages exhibited reduced phagocytosis of NTHi. These inflammatory defects were linked to an increase in the degree and duration of mucosal epithelial hyperplasia in the ME of Asc(-/-) mice, as well as a delay in bacterial clearance from their MEs. These data demonstrate an important role for the inflammasome and cytokine processing in the course and resolution of OM.

Physical activity and cardiorespiratory fitness are beneficial for white matter in low-fit older adults.

Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60-78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle.