Brain charts for the human lifespan.

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 trajectories2 of 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.

SyncMRT: a solution to image-guided synchrotron radiotherapy for quality assurance and pre-clinical trials.

In this work, a new image guidance system and protocols for delivering image-guided radiotherapy (IGRT) on the Imaging and Medical Beamline (IMBL) at the ANSTO Australian Synchrotron are introduced. The image guidance methods used and the resulting accuracy of tumour alignment in in vivo experiments are often under-reported. Image guidance tasks are often complex, time-consuming and prone to errors. If unchecked, they may result in potential mis-treatments. We introduce SyncMRT, a software package that provides a simple, image guidance tool-kit for aligning samples to the synchrotron beam. We have demonstrated sub-millimetre alignment using SyncMRT and the small-animal irradiation platform (the DynamicMRT system) on the IMBL. SyncMRT has become the standard for carrying out IGRT treatments on the IMBL and has been used in all pre-clinical radiotherapy experiments since 2017. Further, we introduce two quality assurance (QA) protocols to synchrotron radiotherapy on the IMBL: the Winston-Lutz test and hidden target test. It is shown that the presented QA tests are appropriate for picking up geometrical setup errors and assessing the end-to-end accuracy of the image guidance process. Together, these tools make image guidance easier and provide a mechanism for reporting the geometric accuracy of synchrotron-based IGRT treatments. Importantly, this work is scalable to other delivery systems, and is in continual development to support the upcoming veterinary radiotherapy trials on the IMBL.

Radiofrequency ablation for the treatment of haemorrhoidal disease: a minimally invasive and effective treatment modality.

BACKGROUND: Haemorrhoidal disease (HD) is a common colorectal condition that often requires surgical treatment. Less invasive procedures are usually more acceptable to patients. The aim of this study was to report the outcome of a novel and minimally invasive technique employing a radiofrequency ablation (RFA) energy (Rafaelo®) to treat HD. METHODS: A total number of 27 patients who had RFA for the treatment of HD were recruited to this study. The procedure was performed under deep sedation and local anaesthesia. Patients' demographics; haemorrhoid severity score (HSS); quality of life; pain and satisfaction scores; and recurrence rate were recorded. RESULTS: The mean age of the patients was 46 (SD 14) years, 18 (67%) males and 9 (33%) females. The mean body mass index was 25 (SD 4) kg/m2. The predominant symptom of all patients was per-rectal bleeding. HSS improved from 7.2 (SD 1.9) before the procedure to 1.6 (SD 1) after the procedure (p < 0.0001). Postoperative pain scores on a scale of 0-10 were 0, 2 (SD 2), 1 (SD 2), and 0 on immediate, day-1, day-3, and 2-month follow-up questionnaire. The mean satisfacion score was 9 (SD 1.5) out of 10 on 2-month follow-up. Mean time until patients returned to normal daily activity was 3 (SD 1) days following the procedure. Quality-of-life assessments including: visual analogue scale scores (before: mean 70, SD 23; after: mean 82, SD 16; p < 0.001) and EQ-5D-5L (before: mean 0.84, SD 0.15; after: mean 0.94, SD 0.13; p < 0.05) were significantly improved. The mean length of follow-up for recurrence of symptoms was 20 months (range 12-32 months). One patient (4%) reported the recurrence of rectal bleeding 12 months after the procedure. CONCLUSIONS: RFA for the treatment of HD is safe and effective in achieving symptomatic relief. It is associated with minimal postoperative pain and low incidence of recurrence.

Psychiatric gene discoveries shape evidence on ADHD's biology.

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.

FES assisted standing in people with incomplete spinal cord injury: a single case design series.

STUDY DESIGN: Single case cross-over design with multiple baselines. OBJECTIVE: To compare two functional electrical stimulation (FES) training protocols to assist sit-to-stand in people with incomplete spinal cord injury (SCI). SETTING: The study was conducted in Sydney, Australia. METHODS: Four subjects with incomplete SCI undertook nine sessions of FES supported cycling at either 100 or 35 Hz stimulus frequency repeated. Ground reaction force and rate of generation of vertical ground reaction force during standing from sitting were measured before and after each training series. RESULTS: Subjects improved their ability to generate greater support through the feet after training with 35 Hz stimulus paradigm but increased the rate of force production after training with 100 Hz stimulation. CONCLUSIONS: Different FES training paradigms appear to produce different responses; however the ability to stand up seems more responsive to training with 35 Hz FES stimulation.

Virtual reality in the rehabilitation of the arm after hemiplegic stroke: a randomized controlled pilot study.

OBJECTIVE: To assess the feasibility of a trial to investigate the effectiveness of virtual reality-mediated therapy compared to conventional physiotherapy in the motor rehabilitation of the arm following stroke, and to provide data for a power analysis to determine numbers for a future main trial. DESIGN: Pilot randomized controlled trial. SETTING: Clinical research facility. PARTICIPANTS: Eighteen people with a first stroke, 10 males and 8 females, 7 right and 2 left side most affected. Mean time since stroke 10.8 months. INTERVENTIONS: Participants were randomized to a virtual reality group or a conventional arm therapy group for nine sessions over three weeks. MAIN MEASURES: The upper limb Motricity Index and the Action Research Arm Test were completed at baseline, post intervention and six weeks follow-up. RESULTS: Outcome data were obtained from 95% of participants at the end of treatment and at follow-up: one participant withdrew. Compliance was high; only two people reported side-effects from virtual reality exposure. Both groups demonstrated small (7-8 points on upper limb Motricity Index and 4 points on the Action Research Arm Test), but non-significant, changes to their arm impairment and activity levels. CONCLUSION: A randomized controlled trial of virtual reality-mediated therapy comparable to conventional therapy would be feasible, with some suggested improvements in recruitment and outcome measures. Seventy-eight participants (39 per group) would be required for a main trial.

A commercial treatment planning system with a hybrid dose calculation algorithm for synchrotron radiotherapy trials.

Synchrotron Radiotherapy (SyncRT) is a preclinical radiation treatment which delivers synchrotron x-rays to cancer targets. SyncRT allows for novel treatments such as Microbeam Radiotherapy, which has been shown to have exceptional healthy tissue sparing capabilities while maintaining good tumour control. Veterinary trials in SyncRT are anticipated to take place in the near future at the Australian Synchrotron's Imaging and Medical Beamline (IMBL). However, before veterinary trials can commence, a computerised treatment planning system (TPS) is required, which can quickly and accurately calculate the synchrotron x-ray dose through patient CT images. Furthermore, SyncRT TPS's must be familiar and intuitive to radiotherapy planners in order to alleviate necessary training and reduce user error. We have paired an accurate and fast Monte Carlo (MC) based SyncRT dose calculation algorithm with EclipseTM, the most widely implemented commercial TPS in the clinic. Using EclipseTM, we have performed preliminary SyncRT trials on dog cadavers at the IMBL, and verified calculated doses against dosimetric measurement to within 5% for heterogeneous tissue-equivalent phantoms. We have also performed a validation of the TPS against a full MC simulation for constructed heterogeneous phantoms in EclipseTM, and showed good agreement for a range of water-like tissues to within 5%-8%. Our custom EclipseTM TPS for SyncRT is ready to perform live veterinary trials at the IMBL.

Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

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.

A Monte Carlo model of synchrotron radiotherapy shows good agreement with experimental dosimetry measurements: Data from the imaging and medical beamline at the Australian Synchrotron.

Experimental measurement of Synchrotron Radiotherapy (SyncRT) doses is challenging, especially for Microbeam Radiotherapy (MRT), which is characterised by very high dynamic ranges with spatial resolutions on the micrometer scale. Monte Carlo (MC) simulation is considered a gold standard for accurate dose calculation in radiotherapy, and is therefore routinely relied upon to produce verification data. We present a MC model for Australian Synchrotron's Imaging and Medical Beamline (IMBL), which is capable of generating accurate dosimetry data to inform and/or verify SyncRT experiments. Our MC model showed excellent agreement with dosimetric measurement for Synchrotron Broadbeam Radiotherapy (SBBR). Our MC model is also the first to achieve validation for MRT, using two methods of dosimetry, to within clinical tolerances of 5% for a 20×20 mm2 field size, except for surface measurements at 5 mm depth, which remained to within good agreement of 7.5%. Our experimental methodology has allowed us to control measurement uncertainties for MRT doses to within 5-6%, which has also not been previously achieved, and provides a confidence which until now has been lacking in MRT validation studies. The MC model is suitable for SyncRT dose calculation of clinically relevant field sizes at the IMBL, and can be extended to include medical beamlines at other Synchrotron facilities as well. The presented MC model will be used as a validation tool for treatment planning dose calculation algorithms, and is an important step towards veterinary SyncRT trials at the Australian Synchrotron.

Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen.

Self-tolerance to a transgene-encoded protein, hen egg lysozyme, was examined in the T and B cell repertoires of a series of lines of transgenic mice that expressed different serum concentrations of soluble lysozyme. T cells were tolerant in all lines in which lysozyme was expressed irrespective of the antigen concentration, whereas B cell tolerance did not occur when the serum lysozyme concentration was less than 1.5 nanograms per milliliter (0.1 nM). Induction of elevated transgene expression could restore B cell tolerance. These findings support the hypothesis that autoimmune disease may in some instances arise through a bypass of T cell tolerance.

Intra-cavitary dosimetry for IMRT head and neck treatment using thermoluminescent dosimeters in a naso-oesophageal tube.

Complex intensity-modulated radiation therapy (IMRT) treatment plans require rigorous quality assurance tests. The aim of this study was to independently verify the delivered dose inside the patient in the region of the treatment site. A flexible naso-gastric tube containing thermoluminescent dosimeters (TLDs) was inserted into the oesophagus via the sinus cavity before the patient's first treatment. Lead markers were also inserted into the tube in order that the TLD positions could be accurately determined from the lateral and anterior-posterior electronic portal images taken prior to treatment. The measured dose was corrected for both daily linac output variations and the estimated dose received from the portal images. The predicted dose for each TLD was determined from the treatment planning system and compared to the measured TLD doses. The results comprise 431 TLD measurements on 43 patients. The mean measured-to-predicted dose ratio was 0.988 +/- 0.011 (95% confidence interval) for measured doses above 0.2 Gy. There was a variation in this ratio when the measurements were separated into low dose (0.2-1.0 Gy), medium dose (1.0-1.8 Gy) and high dose (>1.8 Gy) measurements. The TLD-loaded, naso-oesophageal tube for in vivo dose verification is straightforward to implement, and well tolerated by patients. It provides independent reassurance of the delivered dose for head and neck IMRT.

A method of dosimetry for synchrotron microbeam radiation therapy using radiochromic films of different sensitivity.

This paper describes a method of film dosimetry used to measure the peak-to-valley dose ratios for synchrotron microbeam radiation therapy (MRT). Two types of radiochromic film (manufactured by International Specialty Products, NJ, USA) were irradiated in a phantom and also flush against a microbeam collimator (beam width 25 microm, centre-to-centre spacing 200 microm) on beamline BL28 B2 at the SPring-8 synchrotron. Four experiments are reported: (1) the HD-810 and EBT varieties of radiochromic film were used to record 'peak' dose and 'valley' (regions in between peaks) dose, respectively; (2) a stack of HD-810 film sheets was microbeam-irradiated and analysed to investigate a possible dose build-up effect; (3) a very high MRT dose was delivered to HD-810 film to elicit a measurable valley dose to compare with the result obtained using broad beam radiation; (4) the half value layer of the beam with and without the microbeam collimator was measured to investigate the effect of the collimator on the beam quality. The valley dose obtained for films placed flush against the collimator was approximately 0.2% of the peak dose. Within the water phantom, the valley dose had increased to between 0.7 and 1.8% of the peak dose, depending on the depth in the phantom. We also demonstrated, experimentally and by Monte Carlo simulation, that the dose is not maximal on the surface and that there is a dose build-up effect. The microbeam collimator did not make an appreciable difference to the beam quality. The values of the peak-to-valley ratio reported in this paper are higher than those predicted by previously published Monte Carlo simulation papers.

In-vivo dosimetry from total body irradiation patients (2000-2006): results and analysis.

In-vivo dosimetry is an important technique to ensure accuracy of delivered dose during total body irradiation (TBI). We present an analysis of semiconductor diode dosimetry, constituting seven years of dosimetry data from eighty-six patients who underwent total body irradiation. For lateral field irradiation, the mean exit dose, averaged over five anatomical sites (head, sternal notch, chest, abdomen and pelvis) and as a percentage of the planned dose was 95.7% (SD 7.8%). For AP/PA irradiation, the mean exit dose averaged over five anatomical sites and as a percentage of the planned dose was 95.5% (SD 9.8%). We propose a number of possible reasons for these differences, including patient setup variations, movement of the patient and diodes during treatment, imprecise placement of planned bolus material, inaccurate inhomogeneity corrections and modelling by the treatment planning system.

Characterization of Diffuse Intrinsic Pontine Glioma Radiosensitivity using Synchrotron Microbeam Radiotherapy and Conventional Radiation Therapy In Vitro.

Synchrotron microbeam radiation therapy is a promising preclinical radiotherapy modality that has been proposed as an alternative to conventional radiation therapy for diseases such as diffuse intrinsic pontine glioma (DIPG), a devastating pediatric tumor of the brainstem. The primary goal of this study was to characterize and compare the radiosensitivity of two DIPG cell lines (SF7761 and JHH-DIPG-1) to microbeam and conventional radiation. We hypothesized that these DIPG cell lines would exhibit differential responses to each radiation modality. Single cell suspensions were exposed to microbeam (112, 250, 560, 1,180 Gy peak dose) or conventional (2, 4, 6 and 8 Gy) radiation to produce clonogenic cell-survival curves. Apoptosis induction and the cell cycle were also analyzed five days postirradiation using flow cytometry. JHH-DIPG-1 cells displayed greater radioresistance than SF7761 to both microbeam and conventional radiation, with higher colony formation and increased accumulation of G2/M-phase cells. Apoptosis was significantly increased in SF7761 cells compared to JHH-DIPG-1 after microbeam irradiation, demonstrating cell-line specific differential radiosensitivity to microbeam radiation. Additionally, biologically equivalent doses to microbeam and conventional radiation were calculated based on clonogenic survival, furthering our understanding of the response of cancer cells to these two radiotherapy modalities.

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Interventions for the prevention and treatment of pes cavus.

BACKGROUND: People with pes cavus frequently suffer foot pain, which can lead to significant disability. Despite anecdotal reports, rigorous scientific investigation of this condition and how best to manage it is lacking. OBJECTIVES: To assess the effects of interventions for the prevention and treatment of pes cavus. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (April 2007), MEDLINE (January 1966 to April 2007), EMBASE (January 1980 to April 2007), CINAHL (January 1982 to April 2007), AMED (January 1985 to April 2007), all EBM Reviews (January 1991 to April 2007), SPORTdiscuss (January 1830 to April 2007) and reference lists of articles. We also contacted known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials of interventions for the treatment of pes cavus. We also included trials aimed at preventing or correcting the cavus foot deformity. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Only one trial (custom-made foot orthoses) fully met the inclusion criteria. Two additional cross-over trials (off-the-shelf foot orthoses and footwear) were also included. Both studies assessed secondary biomechanical outcomes less than three-months after randomisation. Data used in the three studies could not be pooled due to heterogeneity of diagnostic groups and outcome measures. The one trial that fully met the inclusion criteria investigated the treatment of cavus foot pain in 154 adults over a three month period. The trial showed a significant reduction in the level of foot pain, measured using the validated 100-point Foot Health Status Questionnaire, with custom-made foot orthoses versus sham orthoses (WMD 10.90; 95% CI 3.21 to 18.59). Furthermore, a significant improvement in foot function measured with the same questionnaire was reported with custom-made foot orthoses (WMD 11.00; 95% CI 3.35 to 18.65). There was also an increase in physical functioning of the Medical Outcomes Short Form - 36 (WMD 9.50; 95% CI 4.07 to 14.93). There was no difference in reported adverse events following the allocation of custom-made (9%) or sham foot orthoses (15%) (RR 0.61; 95% CI 0.26 to 1.48). AUTHORS' CONCLUSIONS: In one randomised controlled trial, custom-made foot orthoses were significantly more beneficial than sham orthoses for treating chronic musculoskeletal foot pain associated with pes cavus in a variety of clinical populations. There is no evidence for any other type of intervention for the treatment or prevention of foot pain in people with a cavus foot type.

Virtual reality in stroke rehabilitation: still more virtual than real.

PURPOSE: To assess the utility of virtual reality (VR) in stroke rehabilitation. METHOD: The Medline, Proquest, AMED, CINAHL, EMBASE and PsychInfo databases were electronically searched from inception/1980 to February 2005, using the keywords: Virtual reality, rehabilitation, stroke, physiotherapy/physical therapy and hemiplegia. Articles that met the study's inclusion criteria were required to: (i) be published in an English language peer reviewed journal, (ii) involve the use of VR in a stroke rehabilitation setting; and (iii) report impairment and/or activity oriented outcome measures. Two assessors independently assessed each study's quality using the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) grading system. RESULTS: Eleven papers met the inclusion criteria: Five addressed upper limb rehabilitation, three gait and balance, two cognitive interventions, and one both upper and lower limb rehabilitation. Three were judged to be AACPDM Level I/Weak, two Level III/Weak, three Level IV/Weak and three Level V quality of evidence. All articles involved before and after interventions; three randomized controlled trials obtained statistical significance, the remaining eight studies found VR-based therapy to be beneficial. None of the studies reported any significant adverse effects. CONCLUSION: VR is a potentially exciting and safe tool for stroke rehabilitation but its evidence base is too limited by design and power issues to permit a definitive assessment of its value. Thus, while the findings of this review are generally positive, the level of evidence is still weak to moderate, in terms of research quality. Further study in the form of rigorous controlled studies is warranted.

Pattern of recovery after open reduction and internal fixation of proximal phalangeal fractures in the finger: a prospective longitudinal study.

The purpose of this study was to determine the pattern of recovery after open reduction and internal fixation of proximal phalangeal fractures. A prospective longitudinal study of 66 patients who started rehabilitation within 1 week of fixation was undertaken. Measures of the level of impairment (range of motion, pain, strength), activity limitation (hand use) and return to work were collected at Weeks 1, 6, 12 and 26 after operation. Before starting rehabilitation, although pain was minimal, the range of motion was severely restricted and there was considerable restriction in ability to work. Most of the recovery in range of motion, pain, strength, hand use and work participation occurred by Week 6, with smaller gains by Week 12 and Week 26. LEVEL OF EVIDENCE: III.