The measurement properties of the Lean-and-Release test in people with incomplete spinal cord injury or disease

Objective: To evaluate test-retest reliability, agreement, and convergent validity of the Lean-and-Release test for the assessment of reactive stepping among individuals with incomplete spinal cord injury or disease (iSCI/D). Design: Multi-center cross-sectional multiple test design. Setting: SCI/D rehabilitation hospital and biomechanics laboratory. Participants: Individuals with motor incomplete SCI/D (iSCI/D). Interventions: None. Outcome Measures: Twenty-six participants attended two sessions to complete the Lean-and-Release test and a battery of clinical tests. Behavioral (i.e. one-step, multi-step, loss of balance) and temporal (i.e. timing of foot off, foot contact, swing of reactive step) parameters were measured. Test-retest reliability was determined with intraclass correlation coefficients, and agreement was evaluated with Bland–Altman plots. Convergent validity was assessed through correlations with clinical tests. Results: The behavioral responses were reliable for the Lean-and-Release test (ICC = 0.76), but foot contact was the only reliable temporal parameter using data from a single site (ICC = 0.79). All variables showed agreement according to the Bland–Altman plots. The behavioral responses correlated with scores of lower extremity strength (0.54, P\u3c0.01) and balance confidence (0.55, P \u3c 0.01). Swing time of reactive stepping correlated with step time (0.73, P \u3c 0.01) and cadence (−0.73 P \u3c 0.01) of over ground walking. Conclusions: The behavioral response of the Lean-and-Release test is a reliable and valid measure for people with iSCI/D. Our findings support the use of the behavioral responses to evaluate reactive stepping for research and clinical purposes. Trial registration: ClinicalTrials.gov identifier: NCT02960178

Attention bias to emotional faces varies by IQ and anxiety in Williams syndrome

Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N=46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Spatiotemporal walking performance in different settings: effects of walking speed and sex

BackgroundUnderstanding the factors that influence walking is important as quantitative walking assessments have potential to inform health risk assessments. Wearable technology innovation has enabled quantitative walking assessments to be conducted in different settings. Understanding how different settings influence quantitative walking performance is required to better utilize the health-related potential of quantitative walking assessments.Research questionHow does spatiotemporal walking performance differ during walking in different settings at different speeds for young adults?MethodsForty-two young adults [21 male (23 ± 4 years), 21 female (24 ± 5 years)] walked in two laboratory settings (overground, treadmill) and three non-laboratory settings (hallway, indoor open, outdoor pathway) at three self-selected speeds (slow, preferred, fast) following verbal instructions. Six walking trials of each condition (10 m in laboratory overground, 20 m in other settings) were completed. Participants wore 17 inertial sensors (Xsens Awinda, Movella, Henderson, NV) and spatiotemporal parameters were computed from sensor-derived kinematics. Setting × speed × sex repeated measures analysis of variance were used for statistical analysis.ResultsRegardless of the speed condition, participants walked faster overground when compared to while on the treadmill and walked faster in the indoor open and outdoor pathway settings when compared to the laboratory overground setting. At slow speeds, participants also walked faster in the hallway when compared to the laboratory overground setting. Females had greater cadence when compared to males, independent of settings and speed conditions.SignificanceParticularly at slow speeds, spatiotemporal walking performance was different between the settings, suggesting that setting characteristics such as walkway boundary definition may significantly influence spatiotemporal walking performance

Modulation of the Hoffmann reflex in the tibialis anterior with a change in posture

Hoffmann (H-) reflex amplitudes in plantar flexor soleus muscle are modulated by posture, yet dorsiflexor tibialis anterior (TA) H-reflex parameters have sparingly been studied. The purpose was to investigate modulation of the TA H-reflex when postural demands are increased from sitting to standing. In this study, data from 18 participants (Age: 25 ± 4 years, Height: 170.9 ± 9.5 cm, Weight: 75.9 ± 17.2 kg) allowed comparison of two experimental conditions involving different postures (i.e. sitting and standing). Maximal amplitude of the TA H-reflex (Hmax) as a percent of the maximal M-wave amplitude (Mmax) (Hmax (% Mmax)) during sitting and standing was compared using ANOVA. Modulation of TA H-reflex amplitude was found: Eleven participants showed facilitation and seven showed no change of reflex amplitudes. Only participants in the facilitation group showed modulation related to changes in posture (sitting: 8.7 ± 2.9%; standing: 14.8 ± 6.7%, P = 0.005). These data provide evidence of the sensitivity to posture of TA H-reflexes. As with task-dependent changes in soleus H-reflexes, presynaptic regulation of Ia afferent transmission is a possible mechanism. Further investigations into causes of modulation are warranted

TGF-alpha can act as morphogen and/or mitogen in a colon-cancer cell line

Transforming growth factor alpha (TGF-alpha) has multifunctional biological effects on a variety of mesenchymal and epithelial cells. It is a potent mitogen for a number of normal and transformed cell types, regulates extracellular matrix (ECM) production and promotes breast, kidney and lung morphogenesis. To clarify the role of ECM proteins in the morphogenetic and mitogenic effects of TGF-alpha, we have used a human colon carcinoma cell line (SW1222) which expresses EGF receptor. Here we show that TGF-alpha at 1 ng/ml increases the proliferation of SW1222 cells, but only when they are cultured on plastic rather than collagen-coated plates. Higher concentrations of TGF-alpha (10 ng/ml) did not increase cell proliferation but significantly enhanced the crypt-like glandular differentiation when cells were grown in 3-dimensional collagen gel (p = 0.027). These effects were accompanied by increased expression of alpha 2 beta 1 and alpha 3 beta 1 integrin molecules, which are receptors for extracellular matrix proteins, and by a statistically significant increase in binding of SW1222 cells to type-1 collagen. The effects of TGF-alpha both on binding to type-1 collagen and on morphological differentiation in 3-dimensional collagen gel were inhibited by monoclonal antibodies recognizing the alpha 2 beta 1 integrin. These data indicate that the morphogenetic or mitogenic activities of TGF-alpha are critically dependent on cellular interactions with extracellular matrix proteins and are primarily mediated by the alpha 2 beta 1 integrin receptor. Inappropriate expression of this growth factor, seen in tumours whose cell-matrix interactions are greatly impaired, could have deleterious effects on the maintenance of normal tissue architecture and growth control