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Summary: Research has examined the relationship between interoception and anxiety, depression, and psychosis; however, it is unclear which aspects of interoception have been systematically examined, what the combined findings are, and which areas require further research. To answer these questions, we systematically searched and narratively synthesised relevant reviews, meta-analyses, and theory papers (total n = 34). Existing systematic reviews and meta-analyses (anxiety n = 2; depression n = 2; psychosis n = 0), focus on cardiac interoceptive accuracy (heartbeat perception), and indicate that heartbeat perception is not systematically impaired in anxiety or depression. Heartbeat perception might be poorer in people with psychosis, but further evidence is needed. Other aspects of interoception, such as different body systems and processing levels, have been studied but not systematically reviewed. We highlight studies examining these alternative bodily domains and levels, review the efficacy of interoception-based psychological interventions, and make suggestions for future research. Funding: Wellcome Trust UK.

Motor sequence learning gradually quickens reaction time, suggesting that sequence learning alters motor preparation processes. Interestingly, evidence has shown that preparing sequence movements decreases short intracortical inhibition (SICI) in the contralateral motor cortex (M1), but also that sequence learning alters motor preparation processes in both the contralateral and ipsilateral M1s. Therefore, one possibility is that sequence learning alters the SICI decreases occurring during motor preparation in bilateral M1s. To examine this, two novel hypotheses were tested: unilateral sequence preparation would decrease SICI in bilateral M1s, and sequence learning would alter such bilateral SICI responses. Paired-pulse transcranial magnetic stimulation was delivered over the contralateral and ipsilateral M1s to assess SICI in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. In the absence of sequence learning, SICI decreased in both the contralateral and ipsilateral M1s during the preparation of sequences initiated by the right index finger, suggesting that SICI decreases in bilateral M1s during unilateral motor preparation. As sequence learning progressed, SICI decreased in the contralateral M1 whilst it increased in the ipsilateral M1. Moreover, these bilateral SICI responses were observed at the onset of motor preparation, suggesting that sequence learning altered baseline SICI levels rather than the SICI decreases occurring during motor preparation per se. Altogether, these results suggest that SICI responses in bilateral M1s reflect two motor processes: an acute decrease of inhibition during motor preparation, and a cooperative but bidirectional shift of baseline inhibition levels as sequence learning progresses.

Monetary rewards and punishments enhance motor performance and are associated with corticospinal excitability (CSE) increases within the motor cortex (M1) during movement preparation. However, such CSE changes have unclear origins. Based on converging evidence, one possibility is that they stem from increased glutamatergic (GLUTergic) facilitation and/or decreased type A gamma-aminobutyric acid (GABAA)-mediated inhibition within M1. To investigate this, paired-pulse transcranial magnetic stimulation was used over the left M1 to evaluate intracortical facilitation (ICF) and short intracortical inhibition (SICI), indirect assays of GLUTergic activity and GABAA-mediated inhibition, in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. Behaviourally, rewards and punishments enhanced both reaction and movement time. During movement preparation, regardless of rewards or punishments, ICF increased when the index finger initiated sequences, whereas SICI decreased when both the index and little fingers initiated sequences. This finding suggests that GLUTergic activity increases in a finger-specific manner whilst GABAA-mediated inhibition decreases in a finger-unspecific manner during preparation. In parallel, both rewards and punishments non-specifically increased ICF, but only rewards non-specifically decreased SICI as compared to neutral. This suggests that to enhance performance rewards both increase GLUTergic activity and decrease GABAA-mediated inhibition, whereas punishments selectively increase GLUTergic activity. A control experiment revealed that such changes were not observed post-movement as participants processed reward and punishment feedback, indicating they were selective to movement preparation. Collectively, these results map the intracortical excitability changes in M1 by which incentives enhance motor performance.

The spectroscopic quadrupole moment of the first 2+ state of 12C has been measured employing the Coulomb-excitation re-orientation technique. Our result of Qs(21+)=+9.3−3.8+3.5efm2 suggests a larger oblate deformation than previously reported. Combining this with the consistently re-analyzed adopted value, we present the most precise value to date of Qs(21+)=+9.5(18)efm2, which is consistent with a geometrical rotor description. This simple outcome is compared to state-of-the-art shell-model, mean-field, ab initio calculations, cluster-based and geometrical-like theories, which show varying degrees of emergent quadrupole collectivity.

Background: Transcranial direct current stimulation (TDCS) is typically applied before or during a task, for periods ranging from 5 to 30 min. Hypothesis: We hypothesise that briefer stimulation epochs synchronous with individual task actions may be more effective. Methods: In two separate experiments, we applied brief bursts of event-related anodal stimulation (erTDCS) to the cerebellum during a visuomotor adaptation task. Results: The first study demonstrated that 1 s duration erTDCS time-locked to the participants’ reaching actions enhanced adaptation significantly better than sham. A close replication in the second study demonstrated 0.5 s erTDCS synchronous with the reaching actions again resulted in better adaptation than standard TDCS, significantly better than sham. Stimulation either during the inter-trial intervals between movements or after movement, during assessment of visual feedback, had no significant effect. Because short duration stimulation with rapid onset and offset is more readily perceived by the participants, we additionally show that a non-electrical vibrotactile stimulation of the scalp, presented with the same timing as the erTDCS, had no significant effect. Conclusions: We conclude that short duration, event related, anodal TDCS targeting the cerebellum enhances motor adaptation compared to the standard model. We discuss possible mechanisms of action and speculate on neural learning processes that may be involved.

Switzerland is a federal country with a liberal health system built on private mandatory health insurance where the government has three different roles (health protector, guarantor of the offered care and regulator). Health is mostly considered as a responsibility that lies with the individual person. Swiss health policies do not include the term “self-care”, although, the federal policy strategy established for this decade (Health2030) includes objectives and lines of action, some of which could be classified as self-care.Swiss policies do not specify the role of health professionals; therefore, it is up to each canton (the terminology used to describe a state of the Swiss Confederation), organization or enterprise to stipulate it. Regarding pharmacists, 1844 community pharmacies (CPs) take care of nearly 260,000 patients each day. The CPs play an important role in self-care that includes activities such as improving patients' health literacy, screening for different health problems, self-medication education or recommendation related to non-prescription medication. The government understands and emphasizes the importance of CPs' role in primary health care to overcome some of the health care system challenges, part of these actions related to self-care. However, there is scope for expansion regarding the role of the CPs in self-care. Nowadays the services and activities related are driven by health authorities (i.e., pharmacists' autonomous prescribing, vaccination, strategy for the prevention of non-communicable diseases or digitization of electronic patients' record), professional pharmacy associations (i.e., netCare® or screening tests), health foundations (i.e., prevention of addiction) and/or private stakeholders such as chain pharmacies (i.e., screening tests). The possibility of including some of these services related to self-care (even when no medication is supplied) as covered services for the mandatory health insurance is currently politically discussed. Long-term actions that also include remuneration, monitoring and quality assurance, or communication/information to public should be considered to support a broader implementation and the sustainability of CPs' services related to self-care.

Modelling population reference curves or normative modelling is increasingly used with the advent of large neuroimaging studies. In this paper we assess the performance of fitting methods from the perspective of clinical applications and investigate the influence of the sample size. Further, we evaluate linear and non-linear models for percentile curve estimation and highlight how the bias-variance trade-off manifests in typical neuroimaging data.We created plausible ground truth distributions of hippocampal volumes in the age range of 45 to 80 years, as an example application. Based on these distributions we repeatedly simulated samples for sizes between 50 and 50,000 data points, and for each simulated sample we fitted a range of normative models. We compared the fitted models and their variability across repetitions to the ground truth, with specific focus on the outer percentiles (1st, 5th, 10th) as these are the most clinically relevant.Our results quantify the expected decreasing trend in variance of the volume estimates with increasing sample size. However, bias in the volume estimates only decreases a modest amount, without much improvement at large sample sizes. The uncertainty of model performance is substantial for what would often be considered large samples in a neuroimaging context and rises dramatically at the ends of the age range, where fewer data points exist. Flexible models perform better across sample sizes, especially for non-linear ground truth.Surprisingly large samples of several thousand data points are needed to accurately capture outlying percentiles across the age range for applications in research and clinical settings. Performance evaluation methods should assess both bias and variance. Furthermore, caution is needed when attempting to go near the ends of the age range captured by the source data set and, as is a well known general principle, extrapolation beyond the age range should always be avoided. To help with such evaluations of normative models we have made our code available to guide researchers developing or utilising normative models.

Summary: Following positive social exchanges, the neural representation of interactive space around the body (peripersonal space; PPS) expands, whereas we also feel consciously more comfortable being closer to others (interpersonal distance; ID). However, it is unclear how relational traits, such as attachment styles, interact with the social malleability of our PPS and ID. A first, exploratory study (N=48) using a visuo-tactile, augmented reality task, found that PPS depended on the combined effects of social context and attachment anxiety. A follow-up preregistered study (N = 68), showed that those with high attachment anxiety demonstrated a sharper differentiation between peripersonal and extrapersonal space, even in a non-social context. A final, preregistered large-scale survey (N = 19,417) found that people scoring high in attachment anxiety prefer closer ID and differentiate their ID less based on feelings of social closeness. We conclude that attachment anxiety reduces the social malleability of both peripersonal and interpersonal space.

Background: Accurate registration between microscopy and MRI data is necessary for validating imaging biomarkers against neuropathology, and to disentangle complex signal dependencies in microstructural MRI. Existing registration methods often rely on serial histological sampling or significant manual input, providing limited scope to work with a large number of stand-alone histology sections. Here we present a customisable pipeline to assist the registration of stand-alone histology sections to whole-brain MRI data. Methods: Our pipeline registers stained histology sections to whole-brain post-mortem MRI in 4 stages, with the help of two photographic intermediaries: a block face image (to undistort histology sections) and coronal brain slab photographs (to insert them into MRI space). Each registration stage is implemented as a configurable stand-alone Python script using our novel platform, Tensor Image Registration Library (TIRL), which provides flexibility for wider adaptation. We report our experience of registering 87 PLP-stained histology sections from 14 subjects and perform various experiments to assess the accuracy and robustness of each stage of the pipeline. Results: All 87 histology sections were successfully registered to MRI. Histology-to-block registration (Stage 1) achieved 0.2–0.4 mm accuracy, better than commonly used existing methods. Block-to-slice matching (Stage 2) showed great robustness in automatically identifying and inserting small tissue blocks into whole brain slices with 0.2 mm accuracy. Simulations demonstrated sub-voxel level accuracy (0.13 mm) of the slice-to-volume registration (Stage 3) algorithm, which was observed in over 200 actual brain slice registrations, compensating 3D slice deformations up to 6.5 mm. Stage 4 combined the previous stages and generated refined pixelwise aligned multi-modal histology-MRI stacks. Conclusions: Our open-source pipeline provides robust automation tools for registering stand-alone histology sections to MRI data with sub-voxel level precision, and the underlying framework makes it readily adaptable to a diverse range of microscopy-MRI studies.

Hospital discharge is a key transition in a patient's care pathway, providing an effective point of intervention to address a patient's ongoing health and social care needs. Addressing these needs may prevent hospital readmissions. The hospital discharge process for people experiencing homelessness who have been admitted for medical conditions has not been well-characterized. To address this gap in knowledge, we interviewed hospital and shelter workers, and key informants, about their experiences when unhoused patients are discharged from hospitals to shelters. Using critical realism, we explored the organizational and service context of this process by looking at the relationship between structures and agency in the daily work of our participants. Our results indicate that the discharge process for unhoused patients was shaped by two systems failures, barriers to publicly funded systems including community resources, and silos and gaps between these systems, ultimately leading to failed transitions to the community. The most prominent manifestations of these systems failures were a) limited and inadequate access to post-discharge care and services, b) barriers to accessing shelters, c) inadequate service integration between healthcare and social service sectors, and, d) poor cross-sectoral knowledge between hospital and shelter workers. We characterize the discharge process for unhoused patients as a part of a larger systems failure in the care for unhoused patients and contend that improvements in hospital discharges requires changes to underlying structures that lead to inadequate discharges.

Background: The cerebellum and primary motor cortex (M1) are crucial to coordinated and accurate movements of the upper limbs. There is also appreciable evidence that these two structures exert somewhat divergent influences upon proximal versus distal upper limb control. Here, we aimed to differentially regulate the contribution of the cerebellum and M1 to proximal and distal effectors during motor adaptation, with transcranial direct current stimulation (tDCS). For this, we employed tasks that promote similar motor demands, but isolate whole arm from hand/finger movements, in order to functionally segregate the hierarchy of upper limb control. Methods: Both young and older adults took part in a visuomotor rotation task; where they adapted to a 60° visuomotor rotation using either a hand-held joystick (requiring finger/hand movements) or a 2D robotic manipulandum (requiring whole-arm reaching movements), while M1, cerebellar or sham tDCS was applied. Results: We found that cerebellar stimulation improved adaptation performance when arm movements were required to complete the task, while in contrast stimulation of M1 enhanced adaptation during hand and finger movements only. This double-dissociation was replicated in an independent group of older adults, demonstrating that the behaviour remains intact in ageing. Conclusions: These results suggest that stimulation of distinct motor areas can selectively improve motor adaptation in the proximal and distal upper limb. This also highlights new ways in which tDCS might be best applied to achieve reliable rehabilitation of upper limb motor deficits.

Summary: Background: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM. Methods: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation. Findings: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM. Interpretation: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM. Funding: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.

Background: The personal profile offers a potentially useful tool to support person-centred care of people living with dementia in hospital. To date, how profiles can be implemented into nurses’ work practices is not established. Objectives: The aim is to establish the feasibility of a Person-Centred Care package, including a personal profile and staff education program to enhance implementation. Design: Exploratory convergent mixed methods approach. Settings: Four units of a tertiary health service, two intervention units and two comparison units set in southeast Queensland, Australia. Participants: Person living with dementia and family carer dyads and staff. Methods: Practicality was determined using participation logs, audit and review of meeting minutes. Acceptability was determined using interviews with family carers and nursing staff. Efficacy was evaluated using pre-post comparison survey design, assessing staff knowledge using the Dementia Knowledge Assessment Scale and person-centred care using the Person-centredness of Older People with cognitive impairment in Acute Care-revised scale. Results: Practically, the personal profile was distributed to 95 and 73% of patients in the two intervention units. Of the 18 people living with dementia who consented to participate, only 6 (33%) had a This is Me form completed. The three-part education program was well attended (n = 190 participants). In terms of acceptability, carers’ (n = 5) experienced variable quality of engagement from nurses. In interviews, nurses (n = 18) experienced increased confidence to engage carers, in part attributed to local leadership, but attitudes towards care appeared to be influenced by perceived time constraints. For efficacy, completion of both surveys at all time points and in all units was 50% and higher. Dementia knowledge significantly improved in the intervention group (p

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise study sample differences contributing to differences in WMH variations across studies. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data.

Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure–activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series.

Increasingly large MRI neuroimaging datasets are becoming available, including many highly multi-site multi-scanner datasets. Combining the data from the different scanners is vital for increased statistical power; however, this leads to an increase in variance due to nonbiological factors such as the differences in acquisition protocols and hardware, which can mask signals of interest.We propose a deep learning based training scheme, inspired by domain adaptation techniques, which uses an iterative update approach to aim to create scanner-invariant features while simultaneously maintaining performance on the main task of interest, thus reducing the influence of scanner on network predictions. We demonstrate the framework for regression, classification and segmentation tasks with two different network architectures.We show that not only can the framework harmonise many-site datasets but it can also adapt to many data scenarios, including biased datasets and limited training labels. Finally, we show that the framework can be extended for the removal of other known confounds in addition to scanner. The overall framework is therefore flexible and should be applicable to a wide range of neuroimaging studies.

Both normal ageing and neurodegenerative diseases cause morphological changes to the brain. Age-related brain changes are subtle, nonlinear, and spatially and temporally heterogenous, both within a subject and across a population. Machine learning models are particularly suited to capture these patterns and can produce a model that is sensitive to changes of interest, despite the large variety in healthy brain appearance. In this paper, the power of convolutional neural networks (CNNs) and the rich UK Biobank dataset, the largest database currently available, are harnessed to address the problem of predicting brain age. We developed a 3D CNN architecture to predict chronological age, using a training dataset of 12,802 T1-weighted MRI images and a further 6,885 images for testing. The proposed method shows competitive performance on age prediction, but, most importantly, the CNN prediction errors ΔBrainAge=AgePredicted−AgeTrue correlated significantly with many clinical measurements from the UK Biobank in the female and male groups. In addition, having used images from only one imaging modality in this experiment, we examined the relationship between ΔBrainAge and the image-derived phenotypes (IDPs) from all other imaging modalities in the UK Biobank, showing correlations consistent with known patterns of ageing. Furthermore, we show that the use of nonlinearly registered images to train CNNs can lead to the network being driven by artefacts of the registration process and missing subtle indicators of ageing, limiting the clinical relevance. Due to the longitudinal aspect of the UK Biobank study, in the future it will be possible to explore whether the ΔBrainAge from models such as this network were predictive of any health outcomes.

Background: Preserved integrity of the corticospinal tract (CST) is a marker of good upper-limb behavior and recovery following stroke. However, there is less understanding of neural mechanisms that might help facilitate upper-limb motor recovery in stroke survivors with extensive CST damage. Objective: The purpose of this study was to investigate resting state functional connectivity in chronic stroke survivors with different levels of CST damage and to explore neural correlates of greater upper-limb motor performance in stroke survivors with compromised ipsilesional CST integrity. Methods: Thirty chronic stroke survivors (24 males, aged 64.7 ± 10.8 years) participated in this study. Three experimental sessions were conducted to: 1) obtain anatomical (T1, T2) structural (diffusion) and functional (resting state) MRI sequences, 2) determine CST integrity with transcranial magnetic stimulation (TMS) and conduct assessments of upper-limb behavior, and 3) reconfirm CST integrity status. Participants were divided into groups according to the extent of CST damage. Those in the extensive CST damage group did not show TMS evoked responses and had significantly lower ipsilesional fractional anisotropy. Results: Of the 30 chronic stroke survivors, 12 were categorized as having extensive CST damage. Stroke survivors with extensive CST damage had weaker functional connectivity in the ipsilesional sensorimotor network and greater functional connectivity in the ipsilesional fronto-parietal network compared to those with preserved CST integrity. For participants with extensive CST damage, improved motor performance was associated with greater functional connectivity of the ipsilesional fronto-parietal network and higher fractional anisotropy of the ipsilesional rostral superior longitudinal fasciculus. Conclusions: Stroke survivors with extensive CST damage have greater resting state functional connectivity of an ipsilesional fronto-parietal network that appears to be a behaviorally relevant neural mechanism that improves upper-limb motor performance.

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings: At 2–3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p

White matter hyperintensities (WMHs) on T2-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impairments. WMHs that appear as hypointense in T1-weighted images (T1w) may also indicate the most severe component of WMHs. We developed an automatic method that sub-classifies WMHs into four categories (periventricular/deep and T1w-hypointense/nonT1w-hypointense) using MRI data from 684 community-dwelling older adults from the Whitehall II study. To test if location and intensity information can impact cognition, we derived two general linear models using either overall or subdivided volumes. Results showed that periventricular T1w-hypointense WMHs were significantly associated with poorer performance in the trail making A (p = 0.011), digit symbol (p = 0.028) and digit coding (p = 0.009) tests. We found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in T1w reveals specific associations with cognitive performance.

Introduction: Up to 40% of Parkinson’s disease patients taking dopamine agonist medication develop impulse control behaviors which can have severe negative consequences. The current study aimed to utilize dopamine genetics to identify patients most at risk of developing these behaviors. Methods: Demographic, clinical, and genetic data were obtained from the Parkinson’s Progression Markers Initiative for de novo patients (n = 327), patients taking dopamine agonists (n = 146), and healthy controls (n = 160). Impulsive behaviors were identified using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease. A dopamine genetic risk score was calculated for each patient according to polymorphisms in genes coding for dopamine D1, D2 and D3 receptors, and catechol-O-methyltransferase. A higher score reflected higher central dopamine neurotransmission. Results: Patients on agonists with a low dopamine genetic risk score were over 18 times more likely to have an impulsive behavior compared to higher scores (p = 0.04). The 38% of patients taking agonists who had at least one impulsive behavior were more likely to be male and report higher Unified Parkinson’s Disease Rating Scale I&II scores. With increasing time on dopamine agonists (range 92–2283 days, mean 798 ± 565 standard deviation), only patients with a high dopamine genetic risk score showed an increase in number of impulsive behaviors (p = 0.033). Predictive effects of the gene score were not present in de novo or healthy control. Conclusions: A dopamine genetic risk score can identify patients most at risk of developing impulsive behaviors on dopamine agonist medication and predict how these behaviors may worsen over time.

The developing Human Connectome Project (dHCP) aims to create a detailed 4-dimensional connectome of early life spanning 20–45 weeks post-menstrual age. This is being achieved through the acquisition of multi-modal MRI data from over 1000 in- and ex-utero subjects combined with the development of optimised pre-processing pipelines. In this paper we present an automated and robust pipeline to minimally pre-process highly confounded neonatal resting-state fMRI data, robustly, with low failure rates and high quality-assurance. The pipeline has been designed to specifically address the challenges that neonatal data presents including low and variable contrast and high levels of head motion. We provide a detailed description and evaluation of the pipeline which includes integrated slice-to-volume motion correction and dynamic susceptibility distortion correction, a robust multimodal registration approach, bespoke ICA-based denoising, and an automated QC framework. We assess these components on a large cohort of dHCP subjects and demonstrate that processing refinements integrated into the pipeline provide substantial reduction in movement related distortions, resulting in significant improvements in SNR, and detection of high quality RSNs from neonates.

Background: There is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution. Objective: Here we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task. Methods: Participants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (

The quantification of subcortical volume development from 3D fetal ultrasound can provide important diagnostic information during pregnancy monitoring. However, manual segmentation of subcortical structures in ultrasound volumes is time-consuming and challenging due to low soft tissue contrast, speckle and shadowing artifacts. For this reason, we developed a convolutional neural network (CNN) for the automated segmentation of the choroid plexus (CP), lateral posterior ventricle horns (LPVH), cavum septum pellucidum et vergae (CSPV), and cerebellum (CB) from 3D ultrasound. As ground-truth labels are scarce and expensive to obtain, we applied few-shot learning, in which only a small number of manual annotations (n = 9) are used to train a CNN. We compared training a CNN with only a few individually annotated volumes versus many weakly labelled volumes obtained from atlas-based segmentations. This showed that segmentation performance close to intra-observer variability can be obtained with only a handful of manual annotations. Finally, the trained models were applied to a large number (n = 278) of ultrasound image volumes of a diverse, healthy population, obtaining novel US-specific growth curves of the respective structures during the second trimester of gestation.

Background: Total knee arthroplasty (TKA) is one the most common elective procedures in the world. Post-operative infection is one of its most devastating complications, often necessitating multiple additional surgeries. We aimed to describe the relationship between surgical duration and risk of deep infection following primary elective TKA. Methods: In this cohort study we analyses primary TKAs done between 2009 and 2016 in Ontario, Canada. We utilized restricted cubic splines to identify a threshold of surgical duration that was associated with an increased risk for infection requiring surgery. Patients with a ‘short’ duration of surgery were matched to those with a ‘long’ duration on patient age (±3 years), patient sex, severe obesity (BMI > 40), the primary surgeon, the hospital and the type of anesthetic. Findings: In 92,343 primary TKAs, the median surgical duration was 106 min. We identified a cut-point of 100 min that was associated with an increased risk for infection. Subsequently, 17,815 TKA recipients with a ‘long’ procedure length were matched to those with a ‘short’ procedure length. ‘Long’ procedures had a higher rate of deep infection (1.1% versus 0.6%, p

Increasing evidence shows that maternal touch may promote emotion regulation in infants, however less is known about how parental higher-order social cognition abilities are translated into tactile, affect-regulatory behaviours towards their infants. During 10 min book-reading, mother-infant sessions when infants were 12 months old (N = 45), we investigated maternal mind-mindedness (MM), the social cognitive ability to understand an infant’s mental state, by coding the contingency of maternal verbal statements towards the infants’ needs and desires. We also rated spontaneous tactile interactions in terms of their emotional contingency. We found that frequent non-attuned mind-related comments were associated with touch behaviours that were not contingent with the infant’s emotions; ultimately discouraging affective tactile responses from the infant. However, comments that were more appropriate to infant’s mental states did not necessarily predict more emotionally-contingent tactile behaviours. These findings suggest that when parental high-order social cognitive abilities are compromised, they are also likely to translate into inappropriate, tactile attempts to regulate infant’s emotions. Keywords: Mind-mindedness, Mother-infant interaction, Maternal touch, Infant touch, Contingency

Objective: To determine whether brain imaging markers of tissue microstructure can detect the effect of disease progression across the preclinical stages of Huntington's disease. Methods: Longitudinal microstructural changes in diffusion imaging metrics (mean diffusivity and fractional anisotropy) were investigated in participants with presymptomatic Huntington's disease (N = 35) stratified into three preclinical subgroups according to their estimated time until onset of symptoms, compared with age- and gender-matched healthy controls (N = 19) over a 1y period. Results: Significant differences were found over the four groups in change of mean diffusivity in the posterior basal ganglia and the splenium of the corpus callosum. This overall effect was driven by significant differences between the group far-from-onset (FAR) of symptoms and the groups midway- (MID) and near-the-onset (NEAR) of symptoms. In particular, an initial decrease of mean diffusivity in the FAR group was followed by a subsequent increase in groups closer to onset of symptoms. The seemingly counter-intuitive decrease of mean diffusivity in the group furthest from onset of symptoms might be an early indicator of neuroinflammatory process preceding the neurodegenerative phase. In contrast, the only clinical measure that was able to capture a difference in 1y changes between the preclinical stages was the UHDRS confidence in motor score. Conclusions: With sensitivity to longitudinal changes in brain microstructure within and between preclinical stages, and potential differential response to distinct pathophysiological mechanisms, diffusion imaging is a promising state marker for monitoring treatment response and identifying the optimal therapeutic window of opportunity in preclinical Huntington's disease. Keywords: Preclinical Huntington's disease, Longitudinal, Microstructure, Corpus callosum, Basal ganglia, Diffusion imaging

The data presented is related to the research article “Analysis of multiple vitamin D metabolites by ultra performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS)” (Jenkinson et al., 2018) [1]. This article will include data obtained from method development, optimization and analysis of multiple vitamin D metabolites on an ultra performance supercritical fluid chromatography tandem-mass spectrometry (UPSFC-MS/MS). This includes chromatograms from column screening to confirm the most suitable column for analyte separation. Additionally, further chromatograms and figures compare separation and analyte signal strength during the optimization of other UPSFC parameters. Mass spectra will demonstrate the optimization of MS conditions for the UPSFC-MS/MS method. Chromatogram data from UHPLC vitamin D analysis is also presented in order to compare the separation and elution of vitamin D metabolites using UPSFC and UHPLC. This data will highlight the outputs that aid in method development and identifying the separation technique suited for vitamin D quantitation. Keywords: Vitamin D, Method development, UPSFC-MS/MS, LC-MS/MS

Carotid Intima-media thickness (CIMT) and plaque are well established markers of subclinical atherosclerosis and are widely used for identifying subclinical atherosclerotic disease. We performed association analyses using Metabochip array to identify genetic variants that influence variation in CIMT and plaque, measured using B-mode ultrasonography, in rheumatoid arthritis (RA) patients. Data on genetic associations of common variants associated with both CIMT and plaque in RA subjects involving Mexican Americans (MA) and European Americans (EA) populations are presented in this article. Strong associations were observed after adjusting for covariate effects including baseline clinical characteristics and statin use. Susceptibility loci and genes and/or nearest genes associated with CIMT in MAs and EAs with RA are presented. In addition, common susceptibility loci influencing CIMT and plaque in both MAs and EAs have been presented. Polygenic Risk Score (PRS) plots showing complementary evidence for the observed CIMT and plaque association signals are also shown in this article. For further interpretation and details, please see the research article titled “A Genetic Association Study of Carotid Intima-Media Thickness (CIMT) and Plaque in Mexican Americans and European Americans with Rheumatoid Arthritis” which is being published in Atherosclerosis (Arya et al., 2018) [1].(Arya et al., in press) Thus, common variants in several genes exhibited significant associations with CIMT and plaque in both MAs and EAs as presented in this article. These findings may help understand the genetic architecture of subclinical atherosclerosis in RA populations.

Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology.Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region – and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract.The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI.These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.

Summary: Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR. : Elhassan et al. show that oral nicotinamide riboside increases the NAD+ metabolome in aged human skeletal muscle, without apparently altering mitochondrial bioenergetics. Measures of muscle and whole-body metabolism are also unchanged. Nicotinamide riboside reduces the levels of circulating inflammatory cytokines. Studies in relevant human disease models are warranted. Keywords: nicotinamide adenine dinucleotide, metabolism, aging, inflammation, cell adhesion

Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimer's disease (AD). For example, an objective evaluation of a patient's hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patient's hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individual's hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution. Keywords: Atrophy, Brain ageing, MRI, Normative values, Sex differences

Type 2 diabetes (T2D) is a common, multifactorial disease that is influenced by genetic and environmental factors and their interactions. However, common variants identified by genome wide association studies (GWAS) explain only about 10% of the total trait variance for T2D and less than 5% of the variance for obesity, indicating that a large proportion of heritability is still unexplained. The transcriptomic approach described here uses quantitative gene expression and disease-related physiological data (deep phenotyping) to measure the direct correlation between the expression of specific genes and physiological traits. Transcriptomic analysis bridges the gulf between GWAS and physiological studies. Recent GWAS studies have utilized very large population samples, numbering in the tens of thousands (or even hundreds of thousands) of individuals, yet establishing causal functional relationships between strongly associated genetic variants and disease remains elusive. In light of the findings described below, it is appropriate to consider how and why transcriptomic approaches in small samples might be capable of identifying complex disease-related genes which are not apparent using GWAS in large samples.

Background: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy., Methods: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020)., Results: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up., Conclusion: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify., Competing Interests: Conflict of interest Lauranne Derikx has served on an advisory board for Sandoz and as a speaker for Janssen. Spyros Siakavellas has received speaker fees from Pfizer and Janssen. Nikolas Plevris has served as a speaker for Janssen, Takeda and Pfizer. Beatriz Gros has served as a speaker for Abbvie and Galapagos. Colin Noble has served on an advisory board for Galapagos. Gareth-Rhys Jones has served as a speaker for Takeda, Janssen, Abbvie and Ferring. Charlie Lees has acted as a consultant to Abbvie, Janssen, Takeda, Pfizer, Galapagos, BMS, Pharmacosmos, GSK, Gilead, Topivert, Vifor Pharma, Celltrion, Dr Falk, Oshi Health, Trellus Health and Iterative Scopes; he has received speaking fees and travel support from Pfizer, Janssen, Abbvie, Galapagos, Fresnius Kabi, Takeda, Shire, Ferring, and Dr Falk. None of the other authors reported any conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Metribuzin is a herbicide that inhibits photosynthesis and has been used for over 40 years. Its main target organ is the liver and to some extent the kidney in rats, dogs, and rabbits. Metribuzin shows a specific thyroxine (T4) profile in rat studies with T4 increases at low doses and T4 decreases at higher doses. Only the T4 decreases occur together with histopathological changes in the thyroid and weight changes of liver and thyroid. A set of experiments was conducted to investigate metribuzin's endocrine disruptor potential according to European guidance and regulations. The results indicate that a liver enzyme modulation, i.e. of the uridine 5'-diphospho-glucuronosyltransferase (UDPGT, UGT), is most likely responsible for both increased and decreased plasma thyroxine level and for thyroid histopathological observations. Animals with high T4 levels show low UGT activity, while animals with low T4 levels show high UGT activity. A causal relationship was inferred, since other potentially human-relevant mode of action (MOA) pathways were excluded in dedicated studies, i.e. inhibition of deiodinases (DIO), inhibition of thyroid peroxidase (TPO) or of the sodium importer system (NIS). This liver metabolism-associated MOA is considered not relevant for human hazard assessment, due to species differences in thyroid homeostasis between humans and rats and, more importantly, based on experimental data showing that metribuzin affects UGT activity in rat but not in human hepatocytes. Further, we discuss whether or not increased T4 levels in the rat, in the absence of histopathological changes, should be considered as adverse and therefore used as an appropriate hazard model for humans. Based on a weight of evidence approach, metribuzin should not be classified as an endocrine disruptor with regard to the thyroid modality., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microorganisms are able to colonise a wide range of extreme environments, including nuclear facilities. In this study, the First Generation Magnox Storage Pond (FGMSP) a high pH, legacy spent nuclear fuel pond (SNFP) situated at Sellafield, Cumbria, UK, was studied. Despite the inhospitable conditions in the FGMSP, microorganisms can cause "blooms" within the facility which to date have not been studied. These microbial blooms significantly reduce visibility in the engineered facility, disrupting fuel retrieval operations and slowing decommissioning. The microbial community colonising the pond during two microbial bloom periods was determined by using physiological measurements and high throughput next generation sequencing techniques. In situ probes within the ponds targeting photosynthetic pigments indicated a cyanobacterial bloom event. Analysis of the 16S rRNA gene data suggested that a single cyanobacterial genus was dominant during the bloom events, which was most closely related to Pseudanabaena sp. Comparisons between the microbial community of FGMSP and an adjacent SNFP that is periodically purged into the FGMSP, showed different community profiles. Data confirm the onset of the microbial blooms occurred when the pond purge rate was reduced, and blooms could be controlled by re-establishing the purging regime. The presence of Pseudanabaena sp. that can colonise the pond and dominate during bloom periods is notable since they have received little attention for their role in cyanobacterial bloom formation. This work also informs bioremediation efforts to treat waters contaminated with radionuclides, which could benefit from the use of cyanobacteria able to tolerate extreme environments and accumulate priority radionuclides., Competing Interests: Declaration of competing interest The authors declare that this study received funding from Sellafield Ltd. The funder had no role in study design and analysis, decision to publish, or preparation of the manuscript. Sellafield Ltd. did provide the pond water samples and detailed pond data collected as part of routine operations. All authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Testing (IWGT), comprised of experts from Japan, Europe and the United States, met on September 9, 2005, in San Francisco, CA, USA. This meeting of the MLA Workgroup was devoted to reaching a consensus on issues involved with 24-h treatment. Recommendations were made concerning the acceptable values for the negative/solvent control (mutant frequency, cloning efficiency and suspension growth) and the criteria to define an acceptable positive control response. Consensus was also reached concerning the use of the global evaluation factor (GEF) and appropriate statistical trend analysis to define positive and negative responses for the 24-h treatment. The Workgroup agreed to continue their support of the International Committee on Harmonization (ICH) recommendation that the MLA assay should include a 24-h treatment (without S-9) in those situations where the short treatment (3-4 h) gives negative results.

The Mouse Lymphoma Assay (MLA) Workgroup of the International Workshop on Genotoxicity Tests (IWGT) met on June 28th and 29th, 2002, in Plymouth, England. This meeting of the MLA group was devoted to discussing the criteria for assay acceptance and appropriate approaches to data evaluation. Prior to the meeting, the group conducted an extensive analysis of data from both the microwell and soft agar versions of the assay. For the establishment of criteria for assay acceptance, 10 laboratories (6 using the microwell method and 4 using soft agar) provided data on their background mutant frequencies, plating efficiencies of the negative/vehicle control, cell suspension growth, and positive control mutant frequencies. Using the distribution curves generated from this data, the Workgroup reached consensus on the range of values that should be used to determine whether an individual experiment is acceptable. In order to establish appropriate approaches for data evaluation, the group used a number of statistical methods to evaluate approximately 400 experimental data sets from 10 laboratories entered into a database created for the earlier MLA Workshop held in New Orleans [Environ. Mol. Mutagen. 40 (2002) 292]. While the Workgroup could not, during this meeting, make a final recommendation for the evaluation of data, a general strategy was developed and the Workgroup members agreed to evaluate this new proposed approach using their own laboratory data. This evaluation should lead to a consensus global approach for data evaluation in the near future.

Confidence in the measurement of positive effects determined by monitoring of environmentally or occupationally exposed individuals can be enhanced by a knowledge of the normal variability in these endpoints in the general population. Confounding effects can be determined and study interpretation improved by correlation of this variability with various lifestyle factors such as sex and age of donor, smoking and drinking habits, viral infections, exposure to diagnostic X-rays, etc. 8 blood samples were taken from each of 24 male and 24 female volunteers over a period of 2 years. Questionnaires pertaining to lifestyle were completed at the time of each sampling. Whole blood was cultured and slides prepared for CA or SCE analysis. Separated mononuclear cells were cultured with a range of phytohaemagglutinin concentrations and the maximum level of mitogen-induced blastogenesis was determined by measurements of [3H]thymidine uptake. There was a significant effect of both year and season of sampling for all 3 endpoints. No significant effects in any of the 3 endpoints were found with respect to sex or age of donor nor any of the other lifestyle factors, although SCE frequency and mitogen-induced blastogenesis were nearly always higher in females than males. These results point to the need for concurrent sampling of controls with exposed populations.

Adult offspring aged 52-104 weeks, from male Sprague-Dawley rats treated chronically with cyclophosphamide (CP) were examined for tumours and gross abnormalities. Litter size at birth and at weaning was found to be greatly reduced as a result of paternal CP treatment. No unusual abnormalities were found at post-mortem examination but there was an increase in the incidence of hydronephrosis in offspring from CP-treated males compared with offspring from control males. This increase could have been indirectly caused by CP-treatment through reduced litter size. Histological examination of 26 tumours showed a variety of tumour types in the offspring of CP-treated and control males. Two of the four uterine tumours in offspring from CP-treated males were examined histologically; one was a sarcoma and the other an adenocarcinoma. Although no uterine tumours were found in offspring from control males, it is not clear whether this difference in frequency was treatment-related. The most common tumour site in female offspring from both CP-treated and control males was the mammary gland, and all six of these tumours which were examined histologically were adenofibromas. Abnormal karyotypes were observed in 2 out of 21 offspring showing abnormalities from CP-treated males and none out of 2 offspring with abnormalities from control males. These were not associated with tumours. It was concluded from this limited study that there was no clear evidence of increased tumour incidence in the offspring from CP-treated males. There was an indication that abnormal karyotypes may have been caused by the paternal CP treatment and these abnormalities persisted into adulthood.