Immunity to Murine Sarcoma Virus Induced Tumors. III. Analysis of the Cell Populations Involved in Protection from Lethal Tumour Progression of Sublethally Irradiated, MSV Inoculated, Mice

A comparison was made between the cells responsible for demonstrable activity against MSV antigens, using both in vivo and in vitro assays. Similar cells (in terms of size and sensitivity to anti-theta serum) were detected in both assays. However, while lymphoid cells from animals at all stages post-MSV infection were active in protecting irradiated mice from the lethal effect of induction of MSV sarcomata, cells from animals at early stages post-MSV infection (when the tumour was in a progressive phase of growth) were not active in the in vitro assay. By manipulation of the in vivo assay conditions a situation was observed in which cells from “progressor animals” were able to suppress both the in vitro and in vivo activity of regressor lymphoid cells. The potential physiological role of this cell type is disussed

Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/β, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis

The Effectiveness of Pharmacological and Non-Pharmacological Interventions for Improving Glycaemic Control in Adults with Severe Mental Illness: A Systematic Review and Meta-Analysis

People with severe mental illness (SMI) have reduced life expectancy compared with the general population, which can be explained partly by their increased risk of diabetes. We conducted a meta-analysis to determine the clinical effectiveness of pharmacological and non-pharmacological interventions for improving glycaemic control in people with SMI (PROSPERO registration: CRD42015015558). A systematic literature search was performed on 30/10/2015 to identify randomised controlled trials (RCTs) in adults with SMI, with or without a diagnosis of diabetes that measured fasting blood glucose or glycated haemoglobin (HbA1c). Screening and data extraction were carried out independently by two reviewers. We used random effects meta-analysis to estimate effectiveness, and subgroup analysis and univariate meta-regression to explore heterogeneity. The Cochrane Collaboration’s tool was used to assess risk of bias. We found 54 eligible RCTs in 4,392 adults (40 pharmacological, 13 behavioural, one mixed intervention). Data for meta-analysis were available from 48 RCTs (n = 4052). Both pharmacological (mean difference (MD), -0.11mmol/L; 95% confidence interval (CI), [-0.19, -0.02], p = 0.02, n = 2536) and behavioural interventions (MD, -0.28mmol//L; 95% CI, [-0.43, -0.12], p<0.001, n = 956) were effective in lowering fasting glucose, but not HbA1c (pharmacological MD, -0.03%; 95% CI, [-0.12, 0.06], p = 0.52, n = 1515; behavioural MD, 0.18%; 95% CI, [-0.07, 0.42], p = 0.16, n = 140) compared with usual care or placebo. In subgroup analysis of pharmacological interventions, metformin and antipsychotic switching strategies improved HbA1c. Behavioural interventions of longer duration and those including repeated physical activity had greater effects on fasting glucose than those without these characteristics. Baseline levels of fasting glucose explained some of the heterogeneity in behavioural interventions but not in pharmacological interventions. Although the strength of the evidence is limited by inadequate trial design and reporting and significant heterogeneity, there is some evidence that behavioural interventions, antipsychotic switching, and metformin can lead to clinically important improvements in glycaemic measurements in adults with SMI

Toward Facilitating the Collection and Utilization of Patient-reported Outcomes in the Military Health System: Lessons Learned from a Pragmatic Clinical Trial on Physical Therapy Management for Low Back Pain

In pursuit of delivering \u27the right care to the right patient at the right time,\u27 the Military Health System (MHS) advocates for collecting and using patient-reported outcomes (PROs) to help demonstrate value-based care.1 PROs identify patients’ perceptions of their health, function, and well-being, which can enhance patient-centered communication and guide data-driven healthcare. 2 The MHS recognizes the value of incorporating PRO data into clinical decision-making and has established a number of platforms for PRO collection across health conditions (eg, behavioral health, traumatic brain injury, musculoskeletal injuries). The Military Orthopedics Tracking Injuries and Outcomes Network (MOTION)3 was started as a research endeavor specific to collecting PROs relevant to postsurgical conditions, which later expanded to cover rehabilitation settings and all musculoskeletal injuries. In MHS physical therapy clinics, the Defense Health Agency’s Clinical Assessment Management Portal (CAMP), a digital PRO collection platform, enables point-of-care capture of MOTION-recommended PROs

Microvascular Endothelial Cells Exhibit Optimal Aspect Ratio for Minimizing Flow Resistance

A recent analytical solution of the three-dimensional Stokes flow through a bumpy tube predicts that for a given bump area, there exists an optimal circumferential wavenumber which minimizes flow resistance. This study uses measurements of microvessel endothelial cell morphology to test whether this prediction holds in the microvasculature. Endothelial cell (EC) morphology was measured in blood perfused in situ microvessels in anesthetized mice using confocal intravital microscopy. EC borders were identified by immunofluorescently labeling the EC surface molecule ICAM-1 which is expressed on the surface but not in the EC border regions. Comparison of this theory with extensive in situ measurements of microvascular EC geometry in mouse cremaster muscle using intravital microscopy reveals that the spacing of EC nuclei in venules ranging from 27 to 106 μm in diameter indeed lies quite close to this predicted optimal configuration. Interestingly, arteriolar ECs are configured to minimize flow resistance not in the resting state, but at the dilated vessel diameter. These results raise the question of whether less organized circulatory systems, such as that found in newly formed solid tumors or in the developing embryo, may deviate from the optimal bump spacing predicted to minimize flow resistance

Device-based 24-hour movement behaviours in adult phase III cardiac rehabilitation service-users during the COVID-19 pandemic: a mixed-methods prospective observational study

Purpose To examine changes in device-based 24-hour movement behaviours (MB), and facilitators and barriers to physical activity (PA) and exercise, during remotely-delivered cardiac rehabilitation (RDCR). Materials and methods This prospective observational study used wrist-worn GENEActiv accelerometers to assess MB of 10 service-users (63 ± 10 years) at the start, middle, and end of three-months of RDCR. Barriers and facilitators to PA and exercise were explored through self-report diaries and analysed using content analysis. Results At start, service-users were sedentary for 12.6 ± 0.7 h ⋅ day−1 and accumulated most PA at a light-intensity (133.52 ± 28.57 min ⋅ day−1) – neither changed significantly during RDCR. Sleep efficiency significantly reduced from start (88.80 ± 4.2%) to the end (86.1 ± 4.76%) of CR, with values meeting health-based recommendations (≥85%). Barriers to RDCR exercise included exertional discomfort and cardiac symptoms, and reduced confidence when exercising alone. Setting meaningful PA goals, self-monitoring health targets, and having social support, facilitated PA and exercise during RDCR. Conclusions Our RDCR programme failed to elicit significant changes in MB or sleep. To increase the likelihood of successful RDCR, it is important to promote a variety of exercise and PA options, target sedentary time, and apply theory to RDCR design, delivery, and support strategies. IMPLICATIONS FOR REHABILITATION Practitioners should work with service-users to understand how best to support them to maximise the benefit(s) of remotely/hybrid delivered services. Facilitating easy (and regular) access to health professionals during remotely/hybrid delivered cardiac rehabilitation (CR) will support the development of service-users’ physical activity (PA) and exercise self-efficacy (i.e., confidence). Remotely/hybrid delivered CR should be informed by theory and/or behaviour change techniques to support increased PA, reduced sedentary time and improved sleep during and after CR. It is important to include strategies to reduce sedentary time in addition to targeting PA and exercise in remotely-delivered CR

Landscape-level human disturbance results in loss and contraction of mammalian populations in tropical forests

Tropical forests hold most of Earth's biodiversity and a higher concentration of threatened mammals than other biomes. As a result, some mammal species persist almost exclusively in protected areas, often within extensively transformed and heavily populated landscapes. Other species depend on remaining remote forested areas with sparse human populations. However, it remains unclear how mammalian communities in tropical forests respond to anthropogenic pressures in the broader landscape in which they are embedded. As governments commit to increasing the extent of global protected areas to prevent further biodiversity loss, identifying the landscape-level conditions supporting wildlife has become essential. Here, we assessed the relationship between mammal communities and anthropogenic threats in the broader landscape. We simultaneously modeled species richness and community occupancy as complementary metrics of community structure, using a state-of-the-art community model parameterized with a standardized pan-tropical data set of 239 mammal species from 37 forests across 3 continents. Forest loss and fragmentation within a 50-km buffer were associated with reduced occupancy in monitored communities, while species richness was unaffected by them. In contrast, landscape-scale human density was associated with reduced mammal richness but not occupancy, suggesting that sensitive species have been extirpated, while remaining taxa are relatively unaffected. Taken together, these results provide evidence of extinction filtering within tropical forests triggered by anthropogenic pressure occurring in the broader landscape. Therefore, existing and new reserves may not achieve the desired biodiversity outcomes without concurrent investment in addressing landscape-scale threats

Saturation sampling for spatial variation in multiple air pollutants across an inversion-prone metropolitan area of complex terrain

Background: Characterizing intra-urban variation in air quality is important for epidemiological investigation of health outcomes and disparities. To date, however, few studies have been designed to capture spatial variation during select hours of the day, or to examine the roles of meteorology and complex terrain in shaping intra-urban exposure gradients. Methods: We designed a spatial saturation monitoring study to target local air pollution sources, and to understand the role of topography and temperature inversions on fine-scale pollution variation by systematically allocating sampling locations across gradients in emissions sources (vehicle traffic, industrial facilities) and topography (elevation) in the Pittsburgh area. Street-level integrated samples of fine particulate matter (PM2.5), black carbon (BC), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3) were collected during morning rush and probable inversion hours (6-11 AM), during summer and winter. We hypothesized that pollution concentrations would be: 1) higher under inversion conditions, 2) exacerbated in lower-elevation areas, and 3) vary by season. Results: During July-August 2011 and January-March 2012, we observed wide spatial and seasonal variability in pollution concentrations, exceeding the range measured at regulatory monitors. We identified elevated concentrations of multiple pollutants at lower-elevation sites, and a positive association between inversion frequency and NO2 concentration. We examined temporal adjustment methods for deriving seasonal concentration estimates, and found that the appropriate reference temporal trend differs between pollutants. Conclusions: Our time-stratified spatial saturation approach found some evidence for modification of inversion-concentration relationships by topography, and provided useful insights for refining and interpreting GIS-based pollution source indicators for Land Use Regression modeling

Protein Design Using Continuous Rotamers

Optimizing amino acid conformation and identity is a central problem in computational protein design. Protein design algorithms must allow realistic protein flexibility to occur during this optimization, or they may fail to find the best sequence with the lowest energy. Most design algorithms implement side-chain flexibility by allowing the side chains to move between a small set of discrete, low-energy states, which we call rigid rotamers. In this work we show that allowing continuous side-chain flexibility (which we call continuous rotamers) greatly improves protein flexibility modeling. We present a large-scale study that compares the sequences and best energy conformations in 69 protein-core redesigns using a rigid-rotamer model versus a continuous-rotamer model. We show that in nearly all of our redesigns the sequence found by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover, the sequences found by the continuous-rotamer model are more similar to the native sequences. We then show that the seemingly easy solution of sampling more rigid rotamers within the continuous region is not a practical alternative to a continuous-rotamer model: at computationally feasible resolutions, using more rigid rotamers was never better than a continuous-rotamer model and almost always resulted in higher energies. Finally, we present a new protein design algorithm based on the dead-end elimination (DEE) algorithm, which we call iMinDEE, that makes the use of continuous rotamers feasible in larger systems. iMinDEE guarantees finding the optimal answer while pruning the search space with close to the same efficiency of DEE. Availability: Software is available under the Lesser GNU Public License v3. Contact the authors for source code