Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

Inflammation causes debilitating human conditions and older treatments rely on global immunosuppression that non‐specifically alleviates symptoms. Currently, several monoclonal antibodies (mAbs) are available that specifically block pro‐inflammatory cytokines. These include mAbs specific to tumour necrosis factor (TNF), interleukin (IL)‐1β, IL‐6, IL‐17 and IL‐12/IL‐23. The chapter summarises the key elements in human inflammatory disease conditions, including various forms of arthritis, psoriasis, Crohn\u27s disease and ulcerative colitis, plus pyrin‐associated inflammatory syndromes and periodic fevers, to explain the benefit of cytokine neutralisation through mAb‐type reagents. The chapter reviews the efficacy and safety of the current repertoire of anti‐cytokine/cytokine receptor mAbs. It also discusses the known side effects and adverse events that are sometimes associated with systemic blockade of cytokines in vivo, and concludes that the accumulating knowledge of treatment failures can reveal unappreciated aspects of cytokine biology and even new treatment opportunities. The chapter includes mention of the rapidly expanding cohort of biosimilar mAbs and the mAbs to IL‐4, IL‐5 and IL‐13 that are now emerging, in addition to the need for treatments for disorders that remain refractory to the current repertoire of anti‐cytokine mAbs and conventional treatments. Thus, here we summarise the current status of anti‐cytokine mAbs for human inflammatory diseases

Understanding and Affecting Student Reasoning About Sound Waves

Student learning of sound waves can be helped through the creation of group-learning classroom materials whose development and design rely on explicit investigations into student understanding. We describe reasoning in terms of sets of resources, i.e. grouped building blocks of thinking that are commonly used in many different settings. Students in our university physics classes often used sets of resources that were different from the ones we wish them to use. By designing curriculum materials that ask students to think about the physics from a different view, we bring about improvement in student understanding of sound waves. Our curriculum modifications are specific to our own classes, but our description of student learning is more generally useful for teachers. We describe how students can use multiple sets of resources in their thinking, and raise questions that should be considered by both instructors and researchers.Comment: 23 pages, 4 figures, 3 tables, 28 references, 7 notes. Accepted for publication in the International Journal of Science Educatio

Durability of Benefits From Supervised Treadmill Exercise in People With Peripheral Artery Disease.

Background It is currently unknown whether 6 months of supervised treadmill exercise has a durable benefit on 6-minute walk performance, even after exercise is completed, in people with peripheral artery disease. Methods and Results A total of 156 participants with peripheral artery disease were randomized to 1 of 3 groups: supervised treadmill exercise, supervised resistance training, or attention control. Participants received supervised sessions during months 1 to 6 and telephone contact during months 6 to 12. Primary outcomes were change in 6-minute walk distance and short physical performance battery at 6-month follow-up and have been reported previously. Secondary outcomes were change in 6-minute walk and short physical performance battery at 12-month follow-up and are reported here. A group of 134 participants (86%) completed the 12-month follow-up. At 6-month follow-up, compared with control, 6-minute walk distance improved in the treadmill exercise group (+36.1 m, 95% CI =13.9-58.3, P=0.001). Between 6- and 12-month follow-up, 6-minute walk distance significantly declined (-28.6 m, 95% CI=-52.6 to -4.5, P=0.020) and physical activity declined -272 activity units (95% CI =-546 to +2, P=0.052) in the treadmill exercise group compared with controls. At 12-month follow-up, 6 months after completing supervised treadmill exercise, change in 6-minute walk distance was not different between the treadmill exercise and control groups (+7.5, 95% CI =-17.5 to +32.6, P=0.56). There were no differences in short physical performance battery change between either exercise group and control at 6-month or 12-month follow-up. Conclusions A 6-month supervised treadmill exercise intervention that improved 6-minute walk distance at 6-month follow-up did not have persistent benefit at 12-month follow-up. These results do not support a durable benefit of supervised treadmill exercise in peripheral artery disease. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Identifier: NCT 00106327

Associations of Weight Change With Changes in Calf Muscle Characteristics and Functional Decline in Peripheral Artery Disease.

Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle-brachial index <0.90 were identified from Chicago-area hospitals in 2002-2004. Weight and 6-minute walk distance were measured annually. Weight change categories were weight loss or gain (≥5 pounds/year at ≥1 visit) or stable (weight change <5 pounds at each visit). Participants reported whether weight loss was "intentional" or "unintentional." Calf muscle area was measured with computed tomography every 2 years. Associations of weight change with changes in calf muscle area and 6-minute walk distance were analyzed using mixed-effects models and adjusted for age, body mass index, ankle-brachial index, physical activity, and other confounders. Among 389 participants, mean ankle-brachial index was 0.63±0.16, mean age was 74.5±7.8, and mean body mass index was 28.1±5.1 kg/m2. Over 3.23±1.37 years, muscle area declined more in adults with intentional weight loss versus stable or gain (pair-wise comparisons, P<0.001). Intentional weight loss was associated with less annual decline in 6-minute walk distance than weight gain (intentional loss, 3.7 m; stable, -14.0 m; gain, -28.5 m; unintentional loss, -20.8 m; pair-wise comparison intentional loss versus gain, P=0.003). Conclusions Despite a greater loss of calf muscle area, adults with peripheral artery disease who intentionally lost ≥5 pounds experienced less functional decline than those who gained weight. A randomized trial is needed to establish whether benefits of weight loss in peripheral artery disease outweigh potential adverse effects

Racial Differences in the Effect of Granulocyte Macrophage Colony-Stimulating Factor on Improved Walking Distance in Peripheral Artery Disease: The PROPEL Randomized Clinical Trial.

Background The effects of race on response to medical therapy in people with peripheral artery disease ( PAD ) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6 months: supervised treadmill exercise+granulocyte-macrophage colony-stimulating factor ( GM - CSF ) (Group 1), exercise+placebo (Group 2), attention control+ GM - CSF (Group 3), or attention control+placebo (Group 4). Change in 6-minute walk distance was measured at 12- and 26-week follow-up. In these exploratory analyses, groups receiving GM - CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM - CSF improved 6-minute walk distance by +22.0 m (95% CI : -4.5, +48.5, P=0.103) at 12 weeks and +44.4 m (95% CI : +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM - CSF on 6-minute walk distance at 12-week ( P=0.26) or 26-week (-5.0 m [-27.5, +17.5, P=0.66]) follow-up, compared with placebo. There was an interaction of race on the effect of GM - CSF on 6-minute walk change at 26-week follow-up ( P=0.018). Exercise improved 6-minute walk distance in black ( P=0.006) and white ( P=0.034) participants without interaction. Conclusions GM - CSF improved 6-minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM - CSF efficacy in PAD . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01408901

Preschool children perceived by mothers as irregular eaters: physical and psychosocial predictors from a Birth Cohort Study

Objective: Parents often report their children display irregular eating patterns. Our aim is to describe the stability of maternal-perceived irregular eating of their offspring from 6 months to 2-4 years of age and to investigate factors that are associated with maternal perceived irregular eating of their 2-4 year old offspring. Methods: A longitudinal mother-child linked analysis was carried out using 5 year follow-up data from a population-based prospective birth cohort of 5122 mothers who were participants in the Mater-University Study of Pregnancy, Brisbane. Measures included responses to standardized questionnaires, pediatrician review and standardized measures such as the Peabody Picture Vocabulary Test-Revised and the Child Behavior Checklist. Results: 20.2% and 7.6% of mothers respectively stated their 2-4 year old was sometimes or often an irregular eater. Continuity of feeding difficulties from age 6 months was prominent: 48% of 6 month Olds with a feeding problem were 'sometimes' or 'often' irregular eaters at age 2-4 years. From a multivariable analysis, both child-intrinsic factors (chronic physical morbidity, sleeplessness and anxiety-depressive symptoms) and factors that impinge upon the child (poor maternal health and maternal depression and anxiety) independently contributed to irregular eating status at age 2-4 years. Conclusions: We conclude that approximately one third of mothers had some concern with their child's irregular eating, 7.6% of mothers were often concerned. irregular eating children were usually physically well, more likely to have persisting feeding problems, sleeplessness, behavioral problems and lived with mothers with perceived poor physical and mental health. Ontervention strategies should be family orientated and include child, mother and mother-child psychosocial approaches

Momentum-space entanglement and renormalization in quantum field theory

The degrees of freedom of any interacting quantum field theory are entangled in momentum space. Thus, in the vacuum state, the infrared degrees of freedom are described by a density matrix with an entanglement entropy. We derive a relation between this density matrix and the conventional Wilsonian effective action. We argue that the entanglement entropy of and mutual information between subsets of field theoretic degrees of freedom at different momentum scales are natural observables in quantum field theory and demonstrate how to compute these in perturbation theory. The results may be understood heuristically based on the scale-dependence of the coupling strength and number of degrees of freedom. We measure the rate at which entanglement between degrees of freedom declines as their scales separate and suggest that this decay is related to the property of decoupling in quantum field theory.Comment: 31 pages, LaTeX, 6 figure