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.

Characterising group-level brain connectivity: A framework using Bayesian exponential random graph models.

The brain can be modelled as a network with nodes and edges derived from a range of imaging modalities: the nodes correspond to spatially distinct regions and the edges to the interactions between them. Whole-brain connectivity studies typically seek to determine how network properties change with a given categorical phenotype such as age-group, disease condition or mental state. To do so reliably, it is necessary to determine the features of the connectivity structure that are common across a group of brain scans. Given the complex interdependencies inherent in network data, this is not a straightforward task. Some studies construct a group-representative network (GRN), ignoring individual differences, while other studies analyse networks for each individual independently, ignoring information that is shared across individuals. We propose a Bayesian framework based on exponential random graph models (ERGM) extended to multiple networks to characterise the distribution of an entire population of networks. Using resting-state fMRI data from the Cam-CAN project, a study on healthy ageing, we demonstrate how our method can be used to characterise and compare the brain's functional connectivity structure across a group of young individuals and a group of old individuals.

Assessing dynamic functional connectivity in heterogeneous samples.

Several methods have been developed to measure dynamic functional connectivity (dFC) in fMRI data. These methods are often based on a sliding-window analysis, which aims to capture how the brain's functional organization varies over the course of a scan. The aim of many studies is to compare dFC across groups, such as younger versus older people. However, spurious group differences in measured dFC may be caused by other sources of heterogeneity between people. For example, the shape of the haemodynamic response function (HRF) and levels of measurement noise have been found to vary with age. We use a generic simulation framework for fMRI data to investigate the effect of such heterogeneity on estimates of dFC. Our findings show that, despite no differences in true dFC, individual differences in measured dFC can result from other (non-dynamic) features of the data, such as differences in neural autocorrelation, HRF shape, connectivity strength and measurement noise. We also find that common dFC methods such as k-means and multilayer modularity approaches can detect spurious group differences in dynamic connectivity due to inappropriate setting of their hyperparameters. fMRI studies therefore need to consider alternative sources of heterogeneity across individuals before concluding differences in dFC.

Prognostic models for identifying adults with intellectual disabilities and mealtime support needs who are at greatest risk of respiratory infection and emergency hospitalisation.

BACKGROUND: Among adults with intellectual disabilities (ID), problems with eating, drinking and swallowing (EDS), and an associated need for mealtime support, are common, with an estimated 15% of adults known to specialist ID services requiring mealtime support. We set out to identify which adults with ID who receive mealtime support are at an increased risk of respiratory infections and emergency hospitalisation related to EDS problems. METHOD: An exploratory, prospective cohort study was undertaken in the East of England. At baseline, structured interviews with the caregivers of 142 adults with ID and any type of mealtime support needs were used to gather information on health and support needs over the previous 12 months. These interviews were repeated at follow-up, 12 months later. The resulting dataset, covering a 24-month period, was analysed with logistic regression, using model averaging to perform sensitivity analysis, and backwards step-wise variable selection to identify the most important predictors. RESULTS: Individuals with a history of respiratory infections (in the first year of study), those who had epilepsy and those with caregiver-reported difficulty swallowing were most likely to have respiratory infections in the second year. Adults with increasing mealtime support needs, epilepsy and/or full mealtime support needs (fed mainly or entirely by a caregiver or enterally) were at increased risk of emergency hospitalisation for EDS-related problems. CONCLUSIONS: Our findings highlight the importance of carefully monitoring health issues experienced by adults with ID and EDS problems, as well as their eating, drinking and swallowing skills. However, the models developed in this exploratory research require validation through future studies addressing the EDS problems commonly experienced by adults with ID and their implications for health outcomes and quality of life. Further research into the relationship between epilepsy and EDS problems would provide much-needed insight into the complex relationship between the two areas.

One Hole in the Two-Leg t-J Ladder and Adiabatic Continuity to the Noninteracting Limit.

We carry out density-matrix-renormalization group (DMRG) calculations for the problem of one doped hole in a two-leg t-J ladder. Recent studies have concluded that exotic "Mott" physics-arising from the projection onto the space of no double-occupied sites-is manifest in this model system, leading to charge localization and a new mechanism for charge modulation. In contrast, we show that there is no localization and that the charge-density modulation arises when the minimum in the quasiparticle dispersion moves away from π. Although singular changes in the quasiparticle dispersion do occur as a function of model parameters, all of the DMRG results can be qualitatively understood from a noninteracting "band-structure" perspective.

Microencapsulation of gallium-indium (Ga-In) liquid metal for self-healing applications.

Microcapsules containing a liquid metal alloy core of gallium-indium (Ga-In) are prepared via in situ urea-formaldehyde (UF) microencapsulation. The capsule size, shape, thermal properties, and shell wall thickness are investigated. We prepare ellipsoidal capsules with major and minor diameter aspect ratios ranging from 1.64 to 1.08 and with major diameters ranging from 245 µm to 3 µm. We observe that as the capsule major diameter decreases, the aspect ratio approaches 1. The thermal properties of the prepared microcapsules are investigated by thermogravimetric (TGA) and differential scanning calorimetry (DSC). Microcapsules are shown to survive incorporation into an epoxy matrix and to trigger via mechanical damage to the cured matrix. Microcapsules containing liquid metal cores may have diverse applications ranging from self-healing to contrast enhancement or the demonstration of mechano-adaptive circuitry.

Access to and perceived unmet need for mental health services and support in a community sample of UK adolescents with and without experience of childhood adversity.

AIMS: Children and adolescents with a history of adverse childhood experiences (ACEs) are more likely than their peers to develop mental health difficulties, but not enough is known about their help-seeking behaviours and preferences. We aimed to determine whether ACEs are associated with access to and perceived unmet need for mental health services and support amongst secondary school students. METHODS: We used multi-level logistic regression with data from the 2020 OxWell Student Survey to assess whether ACEs were associated with (1) prior access to mental health support and (2) perceived unmet need for mental health services in a community sample of English secondary school students. We assessed ACEs as a cumulative score from the Center for Youth Wellness Adverse Childhood Experiences Questionnaire: Teen Self-Report version and accounted for current mental health difficulties as measured by the 25-item Revised Children's Anxiety and Depression Scale (RCADS). RESULTS: Our analysis included 2018 students across 64 schools, of whom 29.9% (598/2002) reported prior access to mental health support. Of those not reporting prior access, 34.1% (469/1377) reported a perceived unmet need for services. In the unadjusted models, cumulative ACE scores were significantly positively associated with both prior access to mental health support (odds ratio (OR) = 1.36; 95% confidence interval (CI): 1.29-1.43) and perceived unmet need for mental health services (OR = 1.47; 95% CI: 1.37-1.59), meaning that students who had experienced adversity had a greater chance of having previously accessed support as well as perceiving an unmet need for services. After adjusting for mental health difficulties and other sociodemographic variables, cumulative ACE scores were positively associated with prior access (adjusted OR (aOR) = 1.25; 95% CI: 1.17-1.34 with a significant interaction between RCADS and ACE scores, aOR = 0.88; 95% CI: 0.84-0.93) as well as perceived unmet need (aOR = 1.32; 95% CI: 1.21-1.43 with a significant interaction between RCADS and ACE scores, aOR = 0.85; 95% CI: 0.78-0.91). CONCLUSIONS: Although it is encouraging that adolescents with experience of adversity are more likely than their peers with similar levels of depression and anxiety symptoms to have accessed mental health support, there remains a concern that those who have not accessed support are more likely to perceive an as-yet unmet need for it. Mental health support must be available, accessible and acceptable to all who need it, especially for those groups that traditionally have not accessed services, including the more marginalised and vulnerable populations.

Human leucocyte antigen-G: expression and function in airway allergic disease.

Human leucocyte antigen-G (HLA-G) is a non-classical HLA class I molecule demonstrated originally in placental trophoblast cells. Recognition of the importance of HLA-G to the maternal immune accommodation of the semi-allogeneic fetus has led to investigations of its role in the suppression of immune responses and induction of tolerance. More recently, HLA-G has been shown to have increased expression in several immunological diseases including asthma and allergic rhinitis. The focus of this review is the potential role of HLA-G in immunological airway diseases.

Regulation of human eosinophil degranulation and activation by endogenous phospholipase A2.

The unique granular proteins of eosinophils may have a pathogenetic role in asthma and in the defense against parasitic infestations. However, the mechanisms regulating eosinophil degranulation are largely unknown. We examined the hypothesis that release of these proteins is regulated by endogenous activation of phospholipase A2. Human eosinophils (HE) were isolated from the peripheral blood of 42 subjects either by Percoll density separation or by negative-selection immunomagnetic fractionation. Eosinophil activation was initiated in vitro with 10(-6) M FMLP and 5 micrograms/ml cytochalasin B and was assessed by measurement of eosinophil peroxidase (EPO), leukotriene C4 (LTC4) and superoxide radical (.O2-) secretion. Treatment of HE with 100 microM mepacrine before activation blocked EPO release (2.0 +/- 0.2 vs 10.2 +/- 2.1% cell content for activated HE, P < 0.004, n = 9), .O2- generation (2.6 +/- 0.9 vs 44.2 +/- 10.8 nmol/ml per 10(6) HE, P < 0.002, n = 5), and LTC4 secretion (68.2 +/- 32.2 vs 1,125.2 +/- 526.8 pg/ml per 10(6) HE, P < 0.04, n = 8). Pretreatment of HE with 100 microM 4-bromophenacyl bromide before activation similarly blocked EPO release, .O2- generation and LTC4 secretion. Addition of AA to HE after treatment with 100 microM mepacrine and before subsequent activation reversed the inhibition of both EPO (10.4 +/- 2.2% with 1 microM AA vs 2.0 +/- 0.2% for mepacrine, n = 5, P < 0.02) and LTC4 secretion (695.1 +/- 412.9 with 10 microM AA vs 68.2 +/- 32.2 pg/ml per 10(6) HE for mepacrine, n = 8, P < 0.04), but did not reverse inhibition of .O2- generation by mepacrine. We demonstrate that secretion of preformed cytotoxic proteins and .O2- by eosinophils is regulated endogenously by phospholipase A2.

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Isocapnic dry gas hyperventilation provokes hyperpnea-induced bronchoconstriction in guinea pigs by releasing tachykinins from airway sensory C-fiber neurons. It is unknown whether dry gas hyperpnea directly stimulates C-fibers to release tachykinins, or whether this physical stimulus initiates a mediator cascade that indirectly stimulates C-fiber tachykinin release. We tested the hypotheses that mucosal hypothermia and/or hyperosmolarity--physical consequences of airway heat and water loss imposed by dry gas hyperpnea--can directly stimulate C-fiber tachykinin release. Neurons isolated from neonatal rat dorsal root ganglia were maintained in primary culture for 1 wk. Cells were then exposed for 30 min at 37 degrees C to graded concentrations of NaCl, mannitol, sucrose, or glycerol (0-600 mOsm) added to isotonic medium, or to isotonic medium at 25 degrees C without or with 462 mOsm mannitol added. Fractional release of substance P (SP) was calculated from supernatant and intracellular SP contents following exposure. Hyperosmolar solutions containing excess NaCl, mannitol, or sucrose all increased fractional SP release equivalently, in an osmolarity-dependent fashion. In marked contrast, hypothermia had no effect on fractional SP release under isotonic or hypertonic conditions. Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers. The lack of effect of glycerol, a solute which quickly crosses cell membranes, suggests that neuronal volume change represents the physical stimulus transduced by C-fibers during hyperosmolar exposure.

Life extension of self-healing polymers with rapidly growing fatigue cracks.

Self-healing polymers, based on microencapsulated dicyclopentadiene and Grubbs' catalyst embedded in the polymer matrix, are capable of responding to propagating fatigue cracks by autonomic processes that lead to higher endurance limits and life extension, or even the complete arrest of the crack growth. The amount of fatigue-life extension depends on the relative magnitude of the mechanical kinetics of crack propagation and the chemical kinetics of healing. As the healing kinetics are accelerated, greater fatigue life extension is achieved. The use of wax-protected, recrystallized Grubbs' catalyst leads to a fourfold increase in the rate of polymerization of bulk dicyclopentadiene and extends the fatigue life of a polymer specimen over 30 times longer than a comparable non-healing specimen. The fatigue life of polymers under extremely fast fatigue crack growth can be extended through the incorporation of periodic rest periods, effectively training the self-healing polymeric material to achieve higher endurance limits.

Colonoscopy first for iron-deficiency anaemia: a Numbers Needed to Investigate approach.

BACKGROUND: British Society of Gastroenterology guidelines recommend that gastrointestinal investigations should be considered in males and post-menopausal women presenting with iron-deficiency anaemia (IDA). AIM: To compare the diagnostic yields and clinical effectiveness of upper and lower gastrointestinal (GI) investigation in detecting malignancy among patients presenting with IDA. DESIGN: Retrospective review of case notes, endoscopy records and radiology reports. METHODS: We reviewed the results of 3798 investigations in 2600 patients presenting to our hospital with IDA from October 1995 to December 2003. The findings of the 2318 gastroscopies were compared with those of the 896 colonoscopies and the 584 barium enemas. Patients diagnosed with GI malignancy were identified and their outcomes determined. RESULTS: Gastroscopy identified 44 patients with newly-diagnosed upper GI cancer (18 oesophageal, 26 gastric). Thus for patients being gastroscoped for IDA, the Numbers Needed to Investigate (NNI) to detect each cancer was 53. Five-year survival for these 44 patients was 10%, so the NNI to identify each curable upper GI malignancy was 527. Colonoscopy or barium enema identified 111 (7.5%) patients with newly diagnosed colorectal cancer, giving a NNI of 13. Their 5-year survival was 35%, giving a NNI to identify each curable colorectal cancer patient of 38. DISCUSSION: Potentially curable gastrointestinal malignancy was diagnosed over 13 times more commonly using colonoscopy or barium enema vs. gastroscopy. For patients presenting with IDA, our findings favour investigating the lower GI tract first, or performing both gastroscopy and colonoscopy during the same endoscopy list.

Signal amplification system for DNA hybridization assays based on in vitro expression of a DNA label encoding apoaequorin.

The development of hybridization assays based on an apoaequorin-encoding DNA label is reported. The constructed label contains the T7 RNA polymerase promoter, the apoaequorin coding sequence and a downstream (dA/dT)(30). In the captured target configuration, biotinylated target DNA (233 bp) was captured on streptavidin-coated microtiter wells and hybridized to a poly(dT)-tailed detection probe. In the sandwich-type assay, the target DNA was hybridized simultaneously with an immobilized capture probe (through biotin/streptavidin) and a poly(dT)-tailed detection probe. In both configurations, the hybrids were reacted with poly(dA)-tailed apoaequorin DNA. The DNA label was subjected to in vitro transcription/translation to produce apoaequorin, which was converted to active aequorin in the reaction mixture. Generated aequorin was determined by its characteristic Ca(2+)-triggered bioluminescence. Each DNA label was estimated to produce 156 aequorin molecules. As low as 0.25 and 0.5 amol of target DNA were detected with the sandwich-type and captured target hybridization assays, respectively, with a linear range spanning four orders of magnitude. In comparison, captured target hybridization assays using photoprotein aequorin or firefly luciferase-encoding DNA labels were able to detect 25 and 20.5 amol of target DNA, respectively. The dramatic improvement in sensitivity observed with the proposed systems is attributed to amplification introduced by in vitro expression of apoaequorin DNA into multiple active aequorin molecules.

The effects of methylenedioxymethamphetamine (MDMA, "Ecstasy") on monoaminergic neurotransmission in the central nervous system.

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a popular recreationally used drug among young people in Europe and North America. The recent surge in use of MDMA and increasing concerns about possible toxic effects of the drug have inspired a great deal of research into the mechanisms by which the drug may affect the central nervous system. This paper reviews studies on the neurochemical, behavioral and neurophysiological effects of MDMA, with emphasis on MDMA effects in regions of the brain that have been implicated in reward. Experiments in awake, behaving laboratory animals have demonstrated that single injections of MDMA increase extracellular levels of the neurotransmitters dopamine (DA) and serotonin (5HT) in the nucleus accumbens and in several other brain regions that are important for reward. Most of the behavioral and electrophysiological changes that have been reported to date for single doses of MDMA appear to be mediated by this MDMA-induced increase in extracellular DA and 5HT. As an example, MDMA-induced hyperthermia and locomotor hyperactivity in laboratory animals can be blocked by administering drugs that prevent MDMA-induced 5HT release and can be attenuated by administering 5HT receptor antagonists, whereas effects of MDMA on delayed reinforcement tasks appear to be mediated by MDMA-induced increases in extracellular DA. Similarly, the effects of MDMA on neuronal excitability in the nucleus accumbens and in several other brain regions can be prevented by administering drugs that block MDMA-induced 5HT release and can be attenuated by depleting brain DA levels or by administering either DA D1 receptor antagonists or 5HT receptor antagonists. In addition to the acute effects of MDMA, it is now well established that repeated or high-dose administration of MDMA is neurotoxic to a subpopulation of 5HT-containing axons that project to the forebrain in laboratory animals. Recent studies have shown that this neurotoxic effect of MDMA is associated with long-duration changes in both DA and 5HT neurotransmission in the nucleus accumbens. Whether these long-duration changes in neurotransmission might be related to reports of depression and other psychopathologies by some frequent users of MDMA remains to be determined. Methylene-dioxymethamphetamine has been found to increase extracellular levels of norepinephrine and to alter brain levels of several neuropeptides as well as altering levels of DA and 5HT. Much additional research is required to understand the multiple ways in which this complex drug may alter neurotransmission in the brain, both acutely and in the long term.

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat.

This study examined whether peripheral inflammatory injury increases the levels or changes the disposition of substance P (SubP) in the rostral ventromedial medulla (RVM), which serves as a central relay in bulbospinal pathways of pain modulation. Enzyme immunoassay and reverse transcriptase quantitative polymerase chain reaction were used to measure SubP protein and transcript, respectively, in tissue homogenates prepared from the RVM and the periaqueductal gray (PAG) and cuneiform nuclei of rats that had received an intraplantar injection of saline or complete Freund's adjuvant (CFA). Matrix-Assisted Laser Desorption/Ionization Time of Flight analysis confirmed that the RVM does not contain hemokinin-1 (HK-1), which can confound measurements of SubP because it is recognized equally well by commercial antibodies for SubP. Levels of SubP protein in the RVM were unchanged four hours, four days and two weeks after injection of CFA. Tac1 transcripts were similarly unchanged in the RVM four days or two weeks after CFA. In contrast, the density of SubP immunoreactive processes in the RVM increased 2-fold within four hours and 2.7-fold four days after CFA injection; it was unchanged at two weeks. SubP-immunoreactive processes in the RVM include axon terminals of neurons located in the PAG and cuneiform nucleus. SubP content in homogenates of the PAG and cuneiform nucleus was significantly increased four days after CFA, but not at four hours or two weeks. Tac1 transcripts in homogenates of these nuclei were unchanged four days and two weeks after CFA. These findings suggest that there is an increased mobilization of SubP within processes in the RVM shortly after injury accompanied by an increased synthesis of SubP in neurons that project to the RVM. These findings are consonant with the hypothesis that an increase in SubP release in the RVM contributes to the hyperalgesia that develops after peripheral inflammatory injury.

Isoproterenol induced myocardial necrosis is associated with stress protein synthesis in rat heart and thoracic aorta.

Large doses of isoproterenol, which produced macroscopically visible myocardial necrosis, induced the synthesis and accumulation of a 71,000 dalton protein (SP71) in the heart, aorta, and salivary gland of adult male rats. This protein was identical to a protein that has previously been found to be synthesised in the heart in response to heat shock and tissue slicing. Detectable amounts of SP71 were no longer seen five days after the isoproterenol injection, suggesting that this protein accumulates as part of a cellular response to stress and then degrades during tissue repair.

Piecewise Approximate Bayesian Computation: fast inference for discretely observed Markov models using a factorised posterior distribution.

Many modern statistical applications involve inference for complicated stochastic models for which the likelihood function is difficult or even impossible to calculate, and hence conventional likelihood-based inferential techniques cannot be used. In such settings, Bayesian inference can be performed using Approximate Bayesian Computation (ABC). However, in spite of many recent developments to ABC methodology, in many applications the computational cost of ABC necessitates the choice of summary statistics and tolerances that can potentially severely bias the estimate of the posterior. We propose a new "piecewise" ABC approach suitable for discretely observed Markov models that involves writing the posterior density of the parameters as a product of factors, each a function of only a subset of the data, and then using ABC within each factor. The approach has the advantage of side-stepping the need to choose a summary statistic and it enables a stringent tolerance to be set, making the posterior "less approximate". We investigate two methods for estimating the posterior density based on ABC samples for each of the factors: the first is to use a Gaussian approximation for each factor, and the second is to use a kernel density estimate. Both methods have their merits. The Gaussian approximation is simple, fast, and probably adequate for many applications. On the other hand, using instead a kernel density estimate has the benefit of consistently estimating the true piecewise ABC posterior as the number of ABC samples tends to infinity. We illustrate the piecewise ABC approach with four examples; in each case, the approach offers fast and accurate inference.

Anticonvulsant withdrawal-emergent psychopathology.

We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.