Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1.

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1-deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1-deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.

γδ Thymocyte Maturation and Emigration in Adult Mice.

Several unique waves of γδ T cells are generated solely in the fetal/neonatal thymus, whereas additional γδ T cell subsets are generated in adults. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived γδ thymocytes in mice. In the Rag2pGFP model, immature (CD24+) γδ thymocytes expressed high levels of GFP whereas only a minority of mature (CD24-) γδ thymocytes were GFP+ Similarly, most peripheral GFP+ γδ T cells were immature. Analysis of γδ recent thymic emigrants (RTEs) indicated that most γδ T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature γδ thymocytes can mature outside the thymus. Mature γδ T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature γδ thymocytes that produced IFN-γ or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of γδ T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident γδ thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the γδ T cell compartment in adult mice.

Management of haematoma after thyroid surgery: systematic review and multidisciplinary consensus guidelines from the Difficult Airway Society, the British Association of Endocrine and Thyroid Surgeons and the British Association of Otorhinolaryngology, Head and Neck Surgery.

Haematoma after thyroid surgery can lead to airway obstruction and death. We therefore developed guidelines to improve the safety of peri-operative care of patients undergoing thyroid surgery. We conducted a systematic review to inform recommendations, with expert consensus used in the absence of high-quality evidence, and a Delphi study was used to ratify recommendations. We highlight the importance of multidisciplinary team management and make recommendations in key areas including: monitoring; recognition; post-thyroid surgery emergency box; management of suspected haematoma following thyroid surgery; cognitive aids; post-haematoma evacuation care; day-case thyroid surgery; training; consent and pre-operative communication; postoperative communication; and institutional policies. The guidelines support a multidisciplinary approach to the management of suspected haematoma following thyroid surgery through oxygenation and evaluation; haematoma evacuation; and tracheal intubation. They have been produced with materials to support implementation. While these guidelines are specific to thyroid surgery, the principles may apply to other forms of neck surgery. These guidelines and recommendations provided are the first in this area and it is hoped they will support multidisciplinary team working, improving care and outcomes for patients having thyroid surgery.

Measuring antimicrobial use on dairy farms: A method comparison cohort study.

Antimicrobial use on UK dairy farms is measured for surveillance purposes, with veterinary sales data as a proxy for use. Two other methods of recording use have been used commonly on-farm: medicine waste bins and farm medicine records. However, none of these methods has been validated to measure antimicrobial use. The objective of this research was to assess agreement between the 3 most common methods for measuring on-farm antimicrobial use with a predetermined reference method on UK dairy farms. Antimicrobial use was measured prospectively on 26 UK dairy farms using medicine waste bins into which participants placed all discarded medicine packaging for a 12-mo period. At the end of 12 mo, farm medicine records and veterinary sales data were obtained retrospectively for participating farms. The reference method used was based on pre- and poststudy inventories combined with veterinary sales data. We investigated the systematic difference between the mean on-farm antimicrobial use measured by each of the 3 methods and a reference method, using one-way repeated-measures ANOVA models. Reliability and clinical relevance of the agreement between each pair of methods was quantified using the concordance correlation coefficient (CCC) and the Bland-Altman method, respectively. When compared with the reference method, veterinary sales data had excellent reliability for injectable antimicrobials and intramammary antimicrobials [95% confidence interval (CI) of CCC > 0.90] and moderate to excellent reliability for other antimicrobials (95% CI of CCC: 0.68-0.97). Medicine waste bins had good to excellent reliability for injectable (95% CI of CCC: 0.84-0.99), and intramammary products (95% CI of CCC: 0.78-0.94) and no agreement for other forms of antimicrobial. Farm medicine records did not agree for any form of antimicrobial when compared with the reference method. The use of veterinary sales data as a proxy for on-farm antimicrobial use in the UK represented excellent statistical reliability and offered clinically good agreement with the reference method when used to measure injectable antimicrobials. This study applies to the UK context and included a relatively small number of farms. However, these results have research and policy implications, both nationally and internationally, and are essential in accurately quantifying agricultural antimicrobial use to inform both animal and human health.

Clinical and Psychosocial Factors Influencing Retinal Screening Uptake Among Young Adults with Type 2 Diabetes.

PURPOSE OF REVIEW: Young adults with type 2 diabetes (T2D, 18-39 years) experience early-onset and rapid progression of diabetic retinopathy (DR), the leading cause of vision loss for working age adults. Despite this, uptake of retinal screening, the crucial first step in preventing vision loss from DR, is low. The aim of this review is to summarize the clinical and psychosocial factors affecting uptake of retinal screening. RECENT FINDINGS: Barriers include lack of diabetes-related symptoms, low personal DR risk perception, high rates of depression and diabetes-related distress, fatalism about inevitability of complications, time and financial constraints, disengagement with existing diabetes self-management services, and perceived stigma due to having a condition associated with older adults. Young adults with T2D are an under-researched population who face an accumulation of barriers to retinal screening. Tailored interventions that address the needs, characteristics, and priorities of young adults with T2D are warranted.

Dynamic causal modelling of lateral interactions in the visual cortex.

This paper presents a dynamic causal model based upon neural field models of the Amari type. We consider the application of these models to non-invasive data, with a special focus on the mapping from source activity on the cortical surface to a single channel. We introduce a neural field model based upon the canonical microcircuit (CMC), in which neuronal populations are assigned to different cortical layers. We show that DCM can disambiguate between alternative (neural mass and field) models of cortical activity. However, unlike neural mass models, DCM with neural fields can address questions about neuronal microcircuitry and lateral interactions. This is because they are equipped with interlaminar connections and horizontal intra-laminar connections that are patchy in nature. These horizontal or lateral connections can be regarded as connecting macrocolumns with similar feature selectivity. Crucially, the spatial parameters governing horizontal connectivity determine the separation (width) of cortical macrocolumns. Thus we can estimate the width of macro columns, using non-invasive electromagnetic signals. We illustrate this estimation using dynamic causal models of steady-state or ongoing spectral activity measured using magnetoencephalography (MEG) in human visual cortex. Specifically, we revisit the hypothesis that the size of a macrocolumn is a key determinant of neuronal dynamics, particularly the peak gamma frequency. We are able to show a correlation, over subjects, between columnar size and peak gamma frequency - that fits comfortably with established correlations between peak gamma frequency and the size of visual cortex defined retinotopically. We also considered cortical excitability and assessed its relative influence on observed gamma activity. This example highlights the potential utility of dynamic causal modelling and neural fields in providing quantitative characterisations of spatially extended dynamics on the cortical surface - that are parameterised in terms of horizontal connections, implicit in the cortical micro-architecture and its synaptic parameters.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer.

BACKGROUND: Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS: A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS: The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS: This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.

Feedback of personal retinal images appears to have a motivational impact in people with non-proliferative diabetic retinopathy and suboptimal HbA1c: findings of a pilot study.

AIM: To conduct a pilot study to explore the potential impact of visual feedback of personal retinal images on diabetes outcomes. METHODS: Twenty-five participants with non-proliferative diabetic retinopathy and suboptimal HbA(1c) (> 53 mmol/mol; > 7%) were randomized to receive visual feedback of their own retinal images or to a control group. At baseline and 3-month follow-up, HbA(1c), standard measures of beliefs, diabetes-related distress and self-care activities were assessed. RESULTS: In unadjusted models, relative to controls, the intervention group showed significantly greater improvement in HbA(1c) at 3-month follow-up (-0.6% vs. +0.3%, P < 0.01), as well as enhanced motivation to improve blood glucose management (P < 0.05). CONCLUSIONS: This small pilot study provides preliminary evidence that visual feedback of personal retinal images may offer a practical educational strategy for clinicians in eye care services to improve diabetes outcomes in non-target compliant patients. A fully powered randomized controlled trial is required to confirm these findings and determine the optimal use of feedback to produce sustained effects.

The effect of monoalkyl phosphates and fluoride on dissolution of hydroxyapatite, and interactions with saliva.

The aims were to investigate the effect of monoalkyl phosphates (MAPs) and fluoride on dissolution rate of native and saliva-coated hydroxyapatite (HA). Fluoride at 300 mg/l (as NaF) inhibited dissolution of native HA by 12%, while potassium and sodium dodecyl phosphates (PDP, SDP), at 0.1% or higher, inhibited dissolution by 26-34%. MAPs, but not fluoride, also showed persistence of action. MAPs at 0.5% and fluoride at 300 mg/l were then tested separately against HA pre-treated with human saliva for 2 or 18 h. Agents were applied with brushing to half the specimens, and without brushing to the other half. In control (water-treated) specimens, pre-treatment of HA with human saliva reduced dissolution rate on average by 41% (2 h) and 63% (18 h). Brushing did not have a statistically significant effect on dissolution rate of saliva-coated specimens. In brushed specimens, fluoride significantly increased the inhibition due to 2- or 18-hour saliva pre-treatment. It is hypothesised that brushing partially removes the salivary film and allows KOH-soluble calcium fluoride formation at the surfaces of HA particles. Inhibition was reduced by PDP in 2-hour/non-brushed specimens and in 18-hour/brushed specimens. PDP did not affect dissolution rates in the remaining groups and SDP did not affect dissolution rate in any group. Possible reasons for these variable results are discussed. The experiments show that pre-treatment with saliva can significantly modify results of tests on potential anti-erosive agents and it is recommended that saliva pre-treatment should be a routine part of testing such agents.

The influence of spontaneous activity on stimulus processing in primary visual cortex.

Spontaneous activity in the resting human brain has been studied extensively; however, how such activity affects the local processing of a sensory stimulus is relatively unknown. Here, we examined the impact of spontaneous activity in primary visual cortex on neuronal and behavioural responses to a simple visual stimulus, using functional MRI. Stimulus-evoked responses remained essentially unchanged by spontaneous fluctuations, combining with them in a largely linear fashion (i.e., with little evidence for an interaction). However, interactions between spontaneous fluctuations and stimulus-evoked responses were evident behaviourally; high levels of spontaneous activity tended to be associated with increased stimulus detection at perceptual threshold. Our results extend those found in studies of spontaneous fluctuations in motor cortex and higher order visual areas, and suggest a fundamental role for spontaneous activity in stimulus processing.

Online social network size is reflected in human brain structure.

The increasing ubiquity of web-based social networking services is a striking feature of modern human society. The degree to which individuals participate in these networks varies substantially for reasons that are unclear. Here, we show a biological basis for such variability by demonstrating that quantitative variation in the number of friends an individual declares on a web-based social networking service reliably predicted grey matter density in the right superior temporal sulcus, left middle temporal gyrus and entorhinal cortex. Such regions have been previously implicated in social perception and associative memory, respectively. We further show that variability in the size of such online friendship networks was significantly correlated with the size of more intimate real-world social groups. However, the brain regions we identified were specifically associated with online social network size, whereas the grey matter density of the amygdala was correlated both with online and real-world social network sizes. Taken together, our findings demonstrate that the size of an individual's online social network is closely linked to focal brain structure implicated in social cognition.

Republished article: The impact of diabetic retinopathy: understanding the patient's perspective.

Understanding the impact of a condition from the patient's perspective is important, and different types of patient-reported outcomes or instruments are available to help with this. This review article summarises the current evidence on the impact of diabetic retinopathy (DR) and its associated vision impairment on patient-reported outcomes. We have included research that has used a range of outcome measures to assess the impact of DR on generic health-related quality of life, utility, vision-functioning and vision-specific quality of life. This review also offers clarification on frequently misused psychometric terminologies to help clinicians and researchers better understand the literature associated with patient-reported outcome research. Overall, the evidence suggests that DR, particularly in its vision-threatening stages, has a substantial, negative impact on the patient. However, our understanding of the impact of DR is currently restricted due to limitations inherent in currently available patient-reported outcome measures. We conclude by discussing potential directions for future research in this area, such as item banking and computer adaptive testing.

The validity and reliability of weight and height measurements and body mass index calculations in early pregnancy.

BACKGROUND: Obesity is increasing in the UK and this is having an impact on the health of pregnant women and their infants. It is recommended that all pregnant women have their height and weight measured and their body mass index (BMI, kg m(-) ²) calculated and recorded in the midwifery notes. The aim of the present audit was to determine the extent of compliance with this recommendation. METHODS: An audit was undertaken in a large district general hospital in the South West of England. A convenience sample of the midwifery notes was accessed retrospectively on the post-natal wards. Data collected from the notes included weight, height, BMI and gestational age when first recorded. RESULTS: A total of 486 maternal notes were audited; of these, 9% did not have the BMI recorded. In total, 53.8% of the sample had either height or weight not recorded; however, 90.9% of the sample had a BMI recorded. In addition, 39.7% (n = 126) of heights and 16.0% (n = 63) of weights were recorded in imperial format. There was a high prevalence overweight (26.2%) and obesity (21.3%) amongst the sample. CONCLUSIONS: Recommendations for measurement of height, weight and calculation of BMI were not always followed. Where BMI was recorded, many notes had either height or weight missing or had measurements recorded in imperial units. This raises the question of how BMI was calculated and its accuracy. Inaccuracies in BMI could lead to individuals being overlooked as high risk and may not be referred for appropriate care including dietetic care. Accurate anthropometric measurements are important for dietary management and monitoring of weight gain.

An exercise protocol that replicates soccer match-play.

This study compared the demands of a soccer match simulation (SMS) incorporating 90 min of soccer-specific movement with passing, dribbling and shooting skills with those of competitive match-play (match). 10 elite youth soccer players participated in SMS and match-play while ingesting fluid-electrolyte beverages. No differences existed between trials for mean HR (SMS, match: 158 ± 4 beats·min (-1), 160 ± 3 beats·min (-1); P = 0.587), peak HR (SMS, match: 197 ± 3 beats·min (-1), 197 ± 4 beats·min (-1); P = 0.935) and blood glucose concentrations (SMS, match: 4.5 ± 0.1 mmol·L (-1), 4.6 ± 0.2 mmol·L (-1); P = 0.170). Inter-trial coefficient of variation (with Bland and Altman limits of agreement) were 2.6% (-19.4-15.4 beats·min (-1)), 1.6% (-14.3-14.7 beats·min (-1)) and 5.0% (-0.9-0.7 mmol·L (-1)) for mean HR, peak HR and blood glucose concentrations. Although the pattern of blood lactate response was similar between trials, blood lactate concentrations were higher at 15 min in SMS when compared to match. Notably, blood glucose concentrations were depressed by 17 ± 4% and 19 ± 5% at 15 min after half-time during match-play and SMS, respectively. Time spent completing low-intensity, moderate-intensity and high-intensity activities were similar between trials ( P > 0.05). In conclusion, the SMS replicates the physiological demands of match-play while including technical actions.

Unexpected difficult tracheal intubation secondary to subglottic stenosis leading to emergency front-of-neck airway.

A 26-year-old woman presenting for an elective day case procedure under general anaesthesia had undiagnosed subglottic stenosis leading to a life threatening airway emergency requiring emergency front-of-neck airway. We outline the case and discuss key anaesthetic considerations in subglottic stenosis, including concerning features of a medical/anaesthetic history and the potential for rapid deterioration of a stenotic airway following manipulation. We also consider the effect of anaesthesia on the calibre of subglottic stenosis and the effects of positive pressure ventilation. Subglottic stenosis is a rare condition with congenital, acquired and idiopathic origins; however, iatrogenic trauma is the most common cause. We are aware of a small number of published case reports of previously undiagnosed subglottic stenosis in adults discovered after induction of anaesthesia; situational deterioration to 'cannot intubate, cannot oxygenate' scenarios appear even rarer.

Rewarding feedback after correct visual discriminations has both general and specific influences on visual cortex.

Reward can influence visual performance, but the neural basis of this effect remains poorly understood. Here we used functional magnetic resonance imaging to investigate how rewarding feedback affected activity in distinct areas of human visual cortex, separating rewarding feedback events after correct performance from preceding visual events. Participants discriminated oriented gratings in either hemifield, receiving auditory feedback at trial end that signaled financial reward after correct performance. Greater rewards improved performance for all but the most difficult trials. Rewarding feedback increased blood-oxygen-level-dependent (BOLD) signals in striatum and orbitofrontal cortex. It also increased BOLD signals in visual areas beyond retinotopic cortex, but not in primary visual cortex representing the judged stimuli. These modulations were seen at a time point in which no visual stimuli were presented or expected, demonstrating a novel type of activity change in visual cortex that cannot reflect modulation of response to incoming or anticipated visual stimuli. Rewarded trials led on the next trial to improved performance and enhanced visual activity contralateral to the judged stimulus, for retinotopic representations of the judged visual stimuli in V1. Our findings distinguish general effects in nonretinotopic visual cortex when receiving rewarding feedback after correct performance from consequences of reward for spatially specific responses in V1.

Differing causal roles for lateral occipital cortex and occipital face area in invariant shape recognition.

The human extrastriate visual cortex contains functionally distinct regions where neuronal populations exhibit signals that are selective for objects. How such regions might play a causal role in underpinning our ability to recognize objects across different viewpoints remains uncertain. Here, we tested whether two extrastriate areas, the lateral occipital (LO) region and occipital face area (OFA), contained neuronal populations that play a causal role in recognizing two-dimensional shapes across different rotations. We used visual priming to modulate the rotation-sensitive activity of neuronal populations in these areas. State-dependent transcranial magnetic stimulation (TMS) was applied after the presentation of a shape and immediately before a subsequent probe shape to which participants had to respond. We found that TMS applied to both the LO region and OFA modulated rotation-invariant shape priming but, whereas the LO region was modulated by TMS for small rotations, the OFA was modulated for larger rotations. Importantly, our results demonstrate that a node in the face-sensitive network, the OFA, participates in causally relevant encoding of non-face stimuli.

Overlapping functional anatomy for working memory and visual search.

Recent behavioural findings using dual-task paradigms demonstrate the importance of both spatial and non-spatial working memory processes in inefficient visual search (Anderson et al. in Exp Psychol 55:301-312, 2008). Here, using functional magnetic resonance imaging (fMRI), we sought to determine whether brain areas recruited during visual search are also involved in working memory. Using visually matched spatial and non-spatial working memory tasks, we confirmed previous behavioural findings that show significant dual-task interference effects occur when inefficient visual search is performed concurrently with either working memory task. Furthermore, we find considerable overlap in the cortical network activated by inefficient search and both working memory tasks. Our findings suggest that the interference effects observed behaviourally may have arisen from competition for cortical processes subserved by these overlapping regions. Drawing on previous findings (Anderson et al. in Exp Brain Res 180:289-302, 2007), we propose that the most likely anatomical locus for these interference effects is the inferior and middle frontal cortex of the right hemisphere. These areas are associated with attentional selection from memory as well as manipulation of information in memory, and we propose that the visual search and working memory tasks used here compete for common processing resources underlying these mechanisms.

The emergence of magnetic ordering at complex oxide interfaces tuned by defects.

Complex oxides show extreme sensitivity to structural distortions and defects, and the intricate balance of competing interactions which emerge at atomically defined interfaces may give rise to unexpected physics. In the interfaces of non-magnetic complex oxides, one of the most intriguing properties is the emergence of magnetism which is sensitive to chemical defects. Particularly, it is unclear which defects are responsible for the emergent magnetic interfaces. Here, we show direct and clear experimental evidence, supported by theoretical explanation, that the B-site cation stoichiometry is crucial for the creation and control of magnetism at the interface between non-magnetic ABO3-perovskite oxides, LaAlO3 and SrTiO3. We find that consecutive defect formation, driven by atomic charge compensation, establishes the formation of robust perpendicular magnetic moments at the interface. Our observations propose a route to tune these emerging magnetoelectric structures, which are strongly coupled at the polar-nonpolar complex oxide interfaces.