The effect of voluntary lateral trunk bending on balance recovery following multi-directional stance perturbations

Stabilising shifts of the centre of mass (COM) are observed during balance recovery when subjects simultaneously execute voluntary unilateral knee flexion or unilateral arm raising. Here, we examined whether voluntary lateral trunk bending provided more beneficial stabilising effects, and how motor programs of balance corrections are combined with those of the focal voluntary action. The upright balance of 24 healthy young subjects (19-33years of age) was perturbed using multi-directional rotations of the support-surface. The perturbations consisted of combined pitch and roll rotations (7.5° and 60°/s) presented randomly in six different directions. Three conditions were tested: perturbation of stance only (PO); combined balance perturbation and cued uphill bending of the trunk (CONT); and combined perturbation and cued downhill bending of the trunk (IPS). For comparison, subjects were required to perform trunk bending alone (TO). Outcome measures were biomechanical responses and surface EMG activity of several muscles. Calculated predicted outcomes (PO+TO) were compared with combined measures (CONT or IPS). CONT trunk bending uphill showed two phases of benefit in balance recovery for laterally but, in contrast to voluntary knee bending, not for posterior directed components of the perturbations. IPS trunk bending had negative effects on balance. Early balance correcting muscle responses were marginally greater than PO responses. Prominent secondary balance correcting responses, having a similar timing as voluntary responses observed under TO conditions, were seen under CONT only in trunk muscles. These, and later stabilising, responses had amplitudes as expected from PO+TO conditions being significantly greater than PO responses. The ability with which different muscle synergies for balance corrections and voluntary trunk bending were integrated into one indicates a flexible adjustment of the CNS programs to the demands of both task

Control of roll and pitch motion during multi-directional balance perturbations

Does the central nervous system (CNS) independently control roll and pitch movements of the human body during balance corrections? To help provide an answer to this question, we perturbed the balance of 16 young healthy subjects using multi-directional rotations of the support surface. All rotations had pitch and roll components, for which either the roll (DR) or the pitch (DP) component were delayed by 150ms or not at all (ND). The outcome measures were the biomechanical responses of the body and surface EMG activity of several muscles. Across all perturbation directions, DR caused equally delayed shifts (150ms) in peak lateral centre of mass (COM) velocity. Across directions, DP did not cause equally delayed shifts in anterior-posterior COM velocity. After 300ms however, the vector direction of COM velocity was similar to the ND directions. Trunk, arm and knee joint rotations followed this roll compared to pitch pattern, but were different from ND rotation synergies after 300ms, suggesting an intersegmental compensation for the delay effects. Balance correcting responses of muscles demonstrated both roll and pitch directed components regardless of axial alignment. We categorised muscles into three groups: pitch oriented, roll oriented and mixed based on their responses to DR and DP. Lower leg muscles were pitch oriented, trunk muscles were roll oriented, and knee and arm muscles were mixed. The results of this study suggest that roll, but not pitch components, of balance correcting movement strategies and muscle synergies are separately programmed by the CNS. Reliance on differentially activated arm and knee muscles to correct roll perturbations reveals a dependence of the pitch response on that of roll, possibly due to biomechanical constraints, and accounts for the failure of DP to be transmitted equally in time across all limbs segments. Thus it appears the CNS preferentially programs the roll response of the body and then adjusts the pitch response accordingl

Citizen engagement in spatial planning, shaping places together

This paper explores the roles and practices of collective citizen engagement in spatial planning. Drawing on a selection of core articles in planning scholarship, it investigates how citizens (re-)shape urban places by responding to perceived flaws in how spatial planning addresses societal challenges. Formal planning interventions are often spatially and socially selective, ineffective, or even non-existent due to a lack of institutional capacities and resources. Consequently, citizens take on roles that they consider as missing, underperformed or ineffective. The paper shows that this results in a variety of practices complementary to, independent from, or opposing formal planning actors and interventions. Five dilemmas citizens face are identified, highlighting the tensions that surface on exclusion, participation, and governmental responsibilities when citizens claim their role in urban governance

Long-term follow-up of respiratory function in facioscapulohumeral muscular dystrophy

OBJECTIVE: To evaluate the 5-year change in respiratory function in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Genetically confirmed patients with FSHD aged ≥ 18 years were examined twice over five years. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured using hand-held spirometry with a face mask. Several clinical outcome measures were correlated to respiratory function. RESULTS: Ninety-two patients were included (57% male, age 18–75 years). At baseline, the spirometry outcomes of 41 patients showed a restrictive ventilatory pattern (FVC  10% predicted. The subgroup of 15 patients was more severely affected at baseline (p = 0.002 for FSHD clinical score and 0.007 for Ricci score). They developed more frequently spinal and thorax deformities (p < 0.001 for kyphoscoliosis and 0.012 for pectus excavatum) and had a larger decline in axial muscle function (p = 0.020). Only weak correlations were found between the change in FVC% predicted and the change in clinical scores between baseline and follow-up. INTERPRETATION: Respiratory function remained stable in most patients with FSHD, but a subgroup of patients showed a pronounced deterioration. They showed more severe muscle weakness including the leg muscles at baseline (Ricci score ≥ 6), had spinal and thorax deformities and a relatively fast decline in axial muscle function at follow-up

What Future for LEADER as a Catalyst of Social Innovation?

The LEADER Approach was initially designed to promote innovation in European rural areas by sustaining a bottom-up approach to local development. Nowadays the LEADER Approach includes elements that are generally considered to support social innovation. Classical features of the LEADER Approach \u2013 for example, area-based development strategies and cooperation and networking \u2013 are considered catalysts of social innovation as well. By drawing on key elements which support social innovation, the chapter discusses the future role of the LEADER Approach and Local Action Groups, and debates the challenges and potentials of the new rural development policy within emerging social, environmental and economic needs

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.</p

Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.

Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes. Some of these genes may have important roles in influencing clinical outcome, and could represent genetic dependencies in ERBB2+ve cancers and therefore potential therapeutic targets. Here, we describe an integrated genomic, gene expression and functional analysis to determine whether the genes present within amplicons are critical for the survival of ERBB2+ve breast tumour cells. We show that only a fraction of the ERBB2-amplified breast tumour lines are truly addicted to the ERBB2 oncogene at the mRNA level and display a heterogeneous set of additional genetic dependencies. These include an addiction to the transcription factor gene TFAP2C when it is amplified and overexpressed, suggesting that TFAP2C represents a genetic dependency in some ERBB2+ve breast cancer cell

Relational knowledge leadership and local economic development

This paper concerns the role of spatial leadership in the development of the knowledge-based economy. It is argued within academic and practitioner circles that leadership of knowledge networks requires a particular non-hierarchical style that is required to establish an ambience conducive to networking and knowledge sharing across boundaries. In this paper, we explore this hypothesis at both theoretical and empirical levels. Theoretically, we propose a conceptualization of relational knowledge leadership, which is ‘nomadic’ in its capacity to travel across multiple scales and cross sectoral, thematic and geographical boundaries. We have operationalized this type of relational knowledge leadership along four key features, derived from literatures on regional learning, organizational leadership and place leadership. Two empirical case studies are then presented, one from Birmingham in the UK and one from Eindhoven in the Netherlands, exploring how these features are expressed on the sub-national level. Also conclusions are drawn regarding the status of relational knowledge leadership. It is argued that the concept of relational knowledge leadership as viewed through our analytical lens does accord with the experience of leadership in the two cases presented. The cases also show that this style of leadership is confronted with three types of tensions that play through knowledge networking. Furthermore, it is argued that the cases exhibit this style of leadership to different degrees, reflecting their different cultural and political context

Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Background: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Methods: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. Results: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infilt