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Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10−4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.

This paper describes how a charity — John Grooms — was able to achieve an uplift in revenue by using a values-based approach in a single supporter-based appeal. This involved a twofold approach. First, those individuals predicted, on the basis of their underlying values, to be most likely to donate to the charity were targeted. Secondly, these supporters were sent creative copy that contained appropriate values-based cues designed to appeal specifically to those targeted individuals. As a result of this, John Grooms achieved an uplift in revenue of 59 per cent when compared to an earlier campaign. This demonstrates how correct targeting and appropriately framed creative copy can be used in combination to increase revenue and hence the profitability of the appeal.

OBJECTIVE: To assess the effectiveness of physical therapy, given either as an individually attended treatment or in a small group format, in terms of pain, physical function, and health related quality of life for patients with osteoarthritis (OA) of the knee. METHODS: After 2 baseline assessments, 126 patients were randomized into one of 3 allocation arms: individual treatments (n = 43), small group format program (n = 40), and waiting list control (n = 43). After reassessment at 8 weeks, patients allocated to waiting list control were randomized into one of the 2 active treatment arms. Assessments included both self-report measures (WOMAC, SF-36) and objective measures of physical performance (gait analysis and muscle strength). RESULTS: Both physical therapy treatment allocations resulted in significant improvements in pain, physical function, and health related quality of life above the control group (standardized response mean 0.36 to 0.65). Improvements in the self-report measures were substantiated by significant correlated improvements in knee extensor strength and fast walking speed (rho 0.36-0.42). There were no significant differences in effectiveness between the 2 physical therapy allocations for any of the measured outcomes. Improvements gained were maintained for at least 2 months. Responsiveness to treatment was modified by loss of medial joint space width, the interaction being significant for physical function, gait, and knee extensor strength. CONCLUSION: Physical therapy, either as an individually delivered treatment or in a small group format, is an effective intervention for patients with knee OA. Responsiveness to this 8 week intervention was modified by loss of medial joint space width.

ObjectivesIncreased resistance to stretch of muscles after stroke may be the result of centrally mediated neural factors such as spasticity or local, peripheral factors such as muscle contracture or thixotropy. The aim was to investigate evidence for an abnormal thixotropic response and compare this with two other factors--contracture and spasticity--which could potentially contribute to muscle stiffness after stroke.MethodsThirty patients with stroke whose calf muscles were assessed clinically as stiff and 10 neurologically normal subjects were recruited. To measure thixotropy, their calf muscles were stretched through two cycles after two prestretch conditions: one in which the muscles were maintained in a shortened position and one in which they were maintained in a lengthened position. Spasticity was defined as the presence of tonic stretch reflexes in relaxed muscles. Contracture was defined as being present when maximum passive ankle dorsiflexion fell at least 2 SD below the mean value of the control subjects.ResultsBoth controls and patients with stroke exhibited a thixotropic response but this was no greater in the patients than the controls. About one third of the patients displayed muscle contracture and most exhibited spasticity. Contracture made a significant contribution (p=0.006) to the clinical measure of calf muscle stiffness while spasticity made a significant contribution (p=0.004) to the laboratory measure of calf muscle stiffness.ConclusionsMeasuring thixotropy at the level of joint movement was sufficiently sensitive to determine the thixotropic response in both neurologically normal subjects and patients impaired after stroke. The thixotropic response was not higher than normal after stroke, suggesting that whereas thixotropy may produce enough immediate resistance to impede movement in those who are very weak, it is not a substantial contributor to long term muscle stiffness. Contracture did significantly contribute to muscle stiffness, supporting the importance of prevention of contracture after stroke. Spasticity contributed to muscle stiffness only when the limb was moved quickly.

Nash's generalization of Gittins’ classic index result to so-called generalized bandit problems (GBPs) in which returns are dependent on the states of all arms (not only the one which is pulled) has proved important for applications. The index theory for special cases of this model in which all indices are positive is straightforward. However, this is not a natural restriction in practice. An earlier proposal for the general case did not yield satisfactory index-based suboptimality bounds for policies — a central feature of classical Gittins index theory. We develop such bounds via a notion of duality for GBPs which is of independent interest. The index which emerges naturally from this analysis is the reciprocal of the one proposed by Nash.

SUMMARY. Optimal use of lumbar mobilisation requires a theoretical knowledge of the mechanical effects that occur. When a mobilisation force is applied the target vertebra will move with accompanying intervertebral displacements at many intervertebral joints. In addition, displacements and deformations of other tissues will contribute to the movement of the skin surface under the therapist's hands. The responses can be quantified in terms of the movements of the skin surface (described by the force-displacement relation), the absolute movement of the target vertebra, or the relative intervertebral movements. There are at least seven variables related to the manner of application of the mobilisation force that can be controlled by the therapist to alter the nature of the response. The patient's response is also determined by a number of variables related to the mechanical properties of the tissues of the spine, extra-spinal structures and the interaction between the patient and the treatment couch. Currently there is a moderate amount of information available about the effects of technique variations but there is very little data to directly link variations in the properties of specific anatomical structures with variations in either absolute or relative spinal movements or tissue loads.

Sixty-eight households from metropolitan Adelaide were sampled to determine the demand for psychological services, and respondents' willingness to pay a levy to receive a full rebate of psychological fees. Eighty-two percent of the sample were willing to pay such a levy. To assess the referral system, 9 general medical practitioners and 10 psychologists were presented with a list of 20 psychological problems, and asked whether they would treat, refer, or treat then refer for each problem. The psychologists reported that they would treat 12 problems, refer 4, and treat and refer 3. The G.P.'s reported that they would treat 6 problems, refer 7, and treat then refer 6.

Poor crop establishment and split seed associated with manganese (Mn) deficiency are major problems in the production of narrow-leafed lupins (Lupinus angustifolius L.) in Western Australia. A survey of Western Australian seed producers indicated that Mn concentrations in lupin seeds ranged from 8 to 62 mg kg-1, with the majority of the seed containing less than 20 mg kg-1. We studied seedling growth of lupins (cultivars Gungurru and Danja) in nutrient solution, from seed with Mn concentrations ranging from 8 (Seed8) to 223 (Seed 223) mg kg-1. Without added Mn, the final weight of plants grown from Seed8 was 39% for shoots and 30% for roots, compared to maximum growth (Seed62). With adequate external Mn supply, there was no effect of seed Mn on growth of plants grown from undamaged seedlings. Shoot weight of Gungurru lupins 42 days after imbibing increased with increasing seed Mn concentration up to about 55 mg kg-1 when grown without added Mn. Growth of Danja plants increased similarly with increasing seed Mn concentration.

Transgenic mice were produced from two 13 kb constructs containing the fetal (γ) globin genes. Each construct consisted of a Gγ globin gene linked to one of two alternative Aγ genes. The first construct contained a normal Gγ gene plus and Aγ gene with the −198T→C hereditary persistence of fetal haemoglobin (HPFH) mutation. In the second, a normal Gγ gene was linked to a Aγ gene with a−222 to −225 four base pair deletion in the promoter. This latter mutation has been associated with low Aγ expression in humans. Both Aγ genes in these constructs also contained the 3′ flanking enhancer. The two different constructs showed expression throughout gestation from day 11 yolk sac, through the fetal period and for a variable time during the first three postnatal weeks. Thereafter, no expression of any of the γ-globin genes was seen in adult erythroid tissues. Transcription from the normal Gγ and HPFH Aγ genes in the first construct paralleled each other in developmental timing, with a proportionate excess of Aγ more evident in later gestation. Gγ and Aγ mRNA transcripts from the normal Gγ+4 bp deletional Aγ construct were unable to be distinguished because of a 3′ Gγ-like conversion in the deletional Aγ gene. Combined γ-globin expression from the two genes in this second construct was detectable until just after birth, as seen with the individual genes in the first construct. Previous work has shown that when individual Gγ and Aγ transgenes are introduced into mice unlinked, without the locus control region (LCR), embryonic expression only is seen. In the present study, γ-globin expression was evident from both constructs throughout the fetal period of erythropoiesis. This suggests that the additional DNA sequences flanking the γ-globin genes included in these larger constructs are capable of supporting fetal recruitment of the γ-globin genes, independently of the LCR.

Simple response time (SRT) and discrimination response time (DRT) were measured in a population of females aged between 20 and 80 years. The investigation involved comparison of foot and hand response times and comparison of response time of the various decades. Foot response time was slower (P<0.001) than hand response time although the correlation was high (r = 0.8555). The only decade to differ significantly in response time was the eighth (P<0.05). DRT did not add any additional information to the SRT measurement for this study group. Clinical implications are discussed.

The first aim of this study was to measure the contributions of muscle and tendon to the total compliance of resting muscle-tendon units. A second aim was to determine whether the decrease in muscle-tendon unit rest length produced by prolonged immobilisation in a shortened position is mediated primarily by adaptations of the muscle or tendon. One ankle joint from each of five rabbits was immobilised in a plantarflexed position for 14 days. The passive length-tension properties of soleus muscle fascicles and tendons from both hindlimbs were measured using a video-based tensile-testing system. In non-immobilised muscles, muscle fascicle strains exceeded tendon strains by up to four times. However, because the rest length of tendon was much greater than that of muscle fascicles, changes in tendon length accounted for nearly half of the total change in muscle-tendon unit length. The rest length of immobilised muscle-tendon units was less than that of non-immobilised muscle-tendon units from contralateral limbs. Most of this difference was attributable to a change in the rest length of the tendon; there was little change in the rest length of muscle fascicles. It is concluded that the tendon is responsible for a large part of the compliance of rabbit soleus muscle-tendon units at physiological resting tensions, and that adaptation of tendon rest length is the primary mechanism by which the rabbit soleus shortens in response to immobilisation at short lengths.

Objectives Clinically, it is assumed that spasticity of the calf muscles interferes with walking after stroke. The aim was to examine this assumption by evaluating the contribution of spasticity in the gastrocnemius muscle to walking dysfunction in an ambulant stroke population several months after stroke. Methods Fourteen stroke patients who were able to walk independently and 15 neurologically normal control subjects were recruited. Both resting and action stretch reflexes of the gastrocnemius muscle were investigated under conditions that simulated walking. Resting tonic stretch reflexes were measured to assess spasticity whereas action tonic stretch reflexes were measured to assess the possible contribution of spasticity to gait dysfunction. Results Two thirds of the stroke patients exhibited resting tonic stretch reflexes which indicate spasticity, whereas none of the control subjects did. However, the stroke patients exhibited action tonic stretch reflexes that were of similar magnitude to the control subjects, suggesting that their reflex activity during walking was not different from that of control subjects. Furthermore, there was no evidence that the action stretch reflex in the stroke patients contributed a higher resistance to stretch than the control subjects. Conclusions Whereas most of the stroke patients exhibited spasticity when measured both clinically and physiologically, they did not exhibit an increase in resistance to dorsiflexion due to exaggerated action tonic stretch reflexes. It is concluded that it is unlikely that spasticity causes problems in walking after stroke in ambulant patients. Therefore, it seems inappropriate to routinely reduce or inhibit the reflex response to improve functional movement in stroke rehabilitation. Factors other than spasticity should be considered when analysing walking after stroke, so that appropriate treatment is provided to patients.

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

SUMMARY. Optimal use of lumbar mobilisation requires a theoretical knowledge of the mechanical effects that occur. When a mobilisation force is applied the target vertebra will move with accompanying intervertebral displacements at many intervertebral joints. In addition, displacements and deformations of other tissues will contribute to the movement of the skin surface under the therapist's hands. The responses can be quantified in terms of the movements of the skin surface (described by the force-displacement relation), the absolute movement of the target vertebra, or the relative intervertebral movements. There are at least seven variables related to the manner of application of the mobilisation force that can be controlled by the therapist to alter the nature of the response. The patient's response is also determined by a number of variables related to the mechanical properties of the tissues of the spine, extra-spinal structures and the interaction between the patient and the treatment couch. Currently there is a moderate amount of information available about the effects of technique variations but there is very little data to directly link variations in the properties of specific anatomical structures with variations in either absolute or relative spinal movements or tissue loads. Copyright 1996 Harcourt Publishers Ltd

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