Co-receptor CD8-mediated modulation of T-cell receptor functional sensitivity and epitope recognition degeneracy

The interaction between T-cell receptors (TCRs) and peptide epitopes is highly degenerate: a TCR is capable of interacting productively with a wide range of different peptide ligands, involving not only cross-reactivity proper (similar epitopes elicit strong responses), but also polyspecificity (ligands with distinct physicochemical properties are capable of interacting with the TCR). Degeneracy does not gainsay the fact that TCR recognition is fundamentally specific: for the vast majority of ligands, the functional sensitivity of a given TCR is virtually null whereas this TCR has an appreciable functional sensitivity only for a minute fraction of all possible ligands. Degeneracy can be described mathematically as the probability that the functional sensitivity, of a given TCR to a randomly selected ligand, exceeds a set value. Variation of this value generates a statistical distribution that characterizes TCR degeneracy. This distribution can be modeled on the basis of a Gaussian distribution for the TCR/ligand dissociation energy. The kinetics of the TCR and the MHCI molecule can be used to transform this underlying Gaussian distribution into the observed distribution of functional sensitivity values. In the present paper, the model is extended by accounting explicitly for the kinetics of the interaction between the co-receptor and the MHCI molecule. We show that T-cells can modulate the level of degeneracy by varying the density of co-receptors on the cell surface. This could allow for an analog of avidity maturation during incipient T-cell responses

Regional analysis of UK primary care prescribing and adult service referrals for young people with attention-deficit hyperactivity disorder.

BACKGROUND: Approximately 20% of children with attention-deficit hyperactivity disorder (ADHD) experience clinical levels of impairment into adulthood. In the UK, there is a sharp reduction in ADHD drug prescribing over the period of transition from child to adult services, which is higher than expected given estimates of ADHD persistence, and may be linked to difficulties in accessing adult services. Little is currently known about geographical variations in prescribing and how this may relate to service access. AIMS: To analyse geographic variations in primary care prescribing of ADHD medications over the transition period (age 16-19 years) and adult mental health service (AMHS) referrals, and illustrate their relationship with UK adult ADHD service locations. METHOD: Using a Clinical Practice Research Datalink cohort of people with an ADHD diagnosis aged 10-20 in 2005 (study period 2005-2013; n = 9390, 99% diagnosed <18 years), regional data on ADHD prescribing over the transition period and AMHS referrals, were mapped against adult ADHD services identified in a linked mapping study. RESULTS: Differences were found by region in the mean age at cessation of ADHD prescribing, range 15.8-17.4 years (P<0.001), as well as in referral rates to AMHSs, range 4-21% (P<0.001). There was no obvious relationship between service provision and prescribing variation. CONCLUSIONS: Clear regional differences were found in primary care prescribing over the transition period and in referrals to AMHSs. Taken together with service mapping, this suggests inequitable provision and is important information for those who commission and deliver services for adults with ADHD

What paint can tell us: A fractal analysis of neurological changes in seven artists

Objective: The notion that artistic capability increases with dementia is both novel and largely unsupported by available literature. Recent research has suggested an emergence of artistic capabilities to be a by-product of involuntary behaviour seen with dementia, as opposed to a progression in original thinking (de Souza, et al., 2010). A far more complementary explanation comes from Hannemann (2006), who suggests that art offers an outlet for dementia patients to refine and sharpen their cognitive abilities. As dementia severely impedes linguistic skills, non-verbal therapeutic methods such as painting can permit dementia patients to express themselves in a way not possible verbally. Fractal analysis has been used to determine the authenticity of major works of art. Taylor et al., (1999) found that through a fractal analysis of Jackson Pollock’s paintings it was possible to distinguish authentic works from a large collection of fakes, demonstrating that when artists paint they instill within their work their own pattern of unique fractal behaviour. Can age-indexed variations in the fractal dimension of the works of artists anticipate specific cognitive deteriorations? Method: To answer this question we analysed age-related variations in the fractal dimension of a large corpus of digital images (n⫽2092) of work created by seven notable artists who experienced both normal ageing and neurodegenerative disorders. Results: The results of our analysis showed that patterns of change in the fractal dimension of the paintings differentiated artists who suffered neurological deterioration from those of normal aging controls. Conclusions: These findings are of importance for two reasons. Our work adds to studies that demonstrate that fractal analysis has the potential to determine the provenance of paintings. Secondly, our work suggests that may be possible to identify a-typical changes in the structure of an artist’s work; changes that may be early indicators of the onset of neurological deterioration

Impact of anthropogenic and natural environmental changes on Echinococcus transmission in Ningxia Hui Autonomous Region, the People’s Republic of China

Echinococcus transmission is known to be affected by various environmental factors, which may be modified by human influence or natural events including global warming. Considerable population growth in the last fifty years in Ningxia Hui Autonomous Region (NHAR), the People's Republic of China (PRC), has led to dramatic increases in deforestation and modified agricultural practices. In turn, this has resulted in many changes in the habitats for the definitive and intermediate hosts of both Echinococcus granulosus and E. multilocularis, which have increased the risks for transmission of both parasites, affecting echinococcosis prevalence and human disease. Ecological environmental changes due to anthropogenic activities and natural events drive Echinococcus transmission and NHAR provides a notable example illustrating how human activity can impact on a parasitic infection of major public health significance. It is very important to continually monitor these environmental (including climatic) factors that drive the distribution of Echinococcus spp. and their impact on transmission to humans because such information is necessary to formulate reliable future public health policy for echinococcosis control programs and to prevent disease spread.We acknowledge financial support by the National Health and Medical Research Council (NHMRC) of Australia (APP1009539) and the Natural Science Foundation of China (NSFC) (30960339) for our studies on echinococcosis. DJG is an Australian Research Council Fellow (DECRA); DPM is a NHMRC Senior Principal Research Fellow; ACAC is a NHMRC Career Development Fellow

Clinical audit of POM-V / POM prescriptions by remote consultation via a veterinary video telemedicine smartphone application

There is an erratum to this paper published in Veterinary Evidence Vol 7, Issue 2 (2022): 10.18849/VE.V7I2.627 Objective: To assess outcomes of a limited period (7 months) of remote video consultation with prescribing of prescription-only (POM) or prescription-only-veterinary (POM-V) medications by Royal College of Veterinary Surgeons (RCVS) registered veterinary surgeons to UK clients via a veterinary telemedicine smartphone application. Background: Objective evidence is needed to inform the veterinary profession on the impact that remote prescribing, without physical examination in person, has on animal health and welfare. During the COVID-19 pandemic, the RCVS allowed remote prescribing temporarily. Methods: Clinical records from all veterinary video consultations from 1 April–31 October 2020 were reviewed. Details were assessed pertaining to: signalment, body system / disease categories managed, referrals into practice, medication classes prescribed and outcomes following POM-V / POM medications. Records of adverse events and antimicrobial prescribing were reviewed. Results: 16.6% (3,541/21,383) of video consults had a POM-V / POM prescribed; with a (mild) adverse event rate of 0.8% (30/3541). Antibacterials were prescribed in 5.88% of all consultations (1,258/21,383), 99.3% (1249/1258) being first line. Follow-up on prescribing was available in 67.7% (2,399/3541) of cases. 89% (2135/2399) of all known treatment outcomes were complete or had an expected response to treatment. Dermatological disease was the most common body system / disease category seen and prescribed for. Conclusion: Low prescribing rates (including antibacterials) were recorded, treatments were efficacious and no harm was done by prescribing remotely via a veterinary video consult app. Application: Veterinary surgeons and governing bodies are invited to use the information provided in this clinical audit to inform decisions on the suitability of remote consultations and prescribing in veterinary medicine

Update to the effectiveness and cost-effectiveness of a mindfulness training programme in schools compared with normal school provision (MYRIAD): study protocol for a randomised controlled trial.

BACKGROUND: MYRIAD (My Resilience in Adolescence) is a superiority, parallel group, cluster randomised controlled trial designed to examine the effectiveness and cost-effectiveness of a mindfulness training (MT) programme, compared with normal social and emotional learning (SEL) school provision to enhance mental health, social-emotional-behavioural functioning and well-being in adolescence. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-017-1917-4 ). This included recruitment in two cohorts, enabling the learning from the smaller first cohort to be incorporated in the second cohort. Here we describe final amendments to the study protocol and discuss their underlying rationale. METHODS: Four major changes were introduced into the study protocol: (1) there were changes in eligibility criteria, including a clearer operational definition to assess the degree of SEL implementation in schools, and also new criteria to avoid experimental contamination; (2) the number of schools and pupils that had to be recruited was increased based on what we learned in the first cohort; (3) some changes were made to the secondary outcome measures to improve their validity and ability to measure constructs of interest and to reduce the burden on school staff; and (4) the current Coronavirus Disease 2019 (SARS-CoV-2 or COVID-19) pandemic both influences and makes it difficult to interpret the 2-year follow-up primary endpoint results, so we changed our primary endpoint to 1-year follow-up. DISCUSSION: These changes to the study protocol were approved by the Trial Management Group, Trial Steering Committee and Data and Ethics Monitoring Committees and improved the enrolment of participants and quality of measures. Furthermore, the change in the primary endpoint will give a more reliable answer to our primary question because it was collected prior to the COVID-19 pandemic in both cohort 1 and cohort 2. Nevertheless, the longer 2-year follow-up data will still be acquired, although this time-point will be now framed as a second major investigation to answer some new important questions presented by the combination of the pandemic and our study design. TRIAL REGISTRATION: International Standard Randomised Controlled Trials ISRCTN86619085 . Registered on 3 June 2016

Teachers "Finding Peace in a Frantic World": An Experimental Study of Self-Taught and Instructor-Led Mindfulness Program Formats on Acceptability, Effectiveness, and Mechanisms.

Mindfulness training (MT) is considered appropriate for school teachers and enhances well-being. Most research has investigated the efficacy of instructor-led MT. However, little is known about the benefits of using self-taught formats, nor what the key mechanisms of change are that contribute to enhanced teacher well-being. This study compared instructor-led and self-taught MT based on a book (Williams & Penman, 2011) in a sample of secondary school teachers. We assessed expectancy, the degree to which participants believed the intervention was effective, their program engagement, well-being and psychological distress, and evaluated whether mindfulness and self-compassion skills acted as mediators of outcomes. In total, 206 teachers from 43 schools were randomized by school to an instructor-led or self-taught course-77% female, mean age 39 years (SD = 9.0). Both MT formats showed similar rates of participant expectancy and engagement, but the instructor-led arm was perceived as more credible. Using linear mixed-effects models, we found the self-taught arm showed significant pre-post improvements in self-compassion and well-being, while the instructor-led arm showed such improvements in mindfulness, self-compassion, well-being, perceived stress, anxiety, depression, and burnout. Changes over time significantly differed between the groups in all these outcomes, favoring the instructor-led arm. The instructor-led arm, compared with the self-taught, indirectly improved teacher outcomes by enhancing mindfulness and self-compassion as mediating factors. Mindfulness practice frequency had indirect effects on teacher outcomes through mindfulness in both self-taught and instructor-led arms. Our results suggest both formats are considered reasonable, but the instructor-led is more effective than the self-taught. Trial registration: ISRCTN18013311

Estimating the prevalence of Echinococcus in domestic dogs in highly endemic for echinococcosis

Background: Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are highly endemic in Xiji County of Ningxia Hui Autonomous Region (NHAR) in China where the control campaign based on dog de-worming with praziquantel has been undertaken over preceding decades. This study is to determine the current prevalence of Echinococcus granulosus and E. multilocularis in domestic dogs and monitor the echinococcosis transmission dynamics. Methods: Study villages were selected using landscape patterns (Geographic Information System, GIS) for Echinococcus transmission "hot spots", combined with hospital records identifying risk areas for AE and CE. A survey of 750 domestic dogs, including copro-sampling and owner questionnaires, from 25 selected villages, was undertaken in 2012. A copro-multiplex PCR assay was used for the specific diagnosis of E. granulosus and E. multilocularis in the dogs. Data analysis, using IBM SPSS Statistics, was undertaken, to compare the prevalence of the two Echinococcus spp. in dogs between four geographical areas of Xiji by the χ 2 test. Univariate analysis of the combinations of outcomes from the questionnaire and copro-PCR assay data was carried out to determine the significant risk factors for dog infection. Results: The highest de-worming rate of 84.0% was found in the northwest area of Xiji County, and significant differences (P 0.05) in the prevalence of E. granulosus in dogs from the northwest, southwest, northeast, and southeast of Xiji, but there were significant differences (P< 0.05) between dogs infected with E. multilocularis from the four areas. None of the other independent variables was statistically significant. Conclusions: The results from this study indicate a high prevalence of both E. granulosus and E. muiltilocularis in dogs in Xiji County, NHAR. Transmission of E. multilocularis was more impacted by geographical risk-factors in Xiji County than that of E. granulosus. Dogs have the potential to maintain the transmission of both species of Echinococcus within local Xiji communities, and the current praziquantel dosing of dogs appears to be ineffective or poorly implemented in this area.This study was funded by the Science Fund for Gansu Provincial Key Science and Technology Projects (No. 1203NKDA039); Special Fund for Agro-scientific Research in the Public Interest (No. 200903036–07; 201303037); West China Top Class Discipline Project in Basic Medical Sciences, Ningxia Medical University; The National Natural Science Foundation of China (No. 30960339; 81460311) and the Australian National Health and Medical Research Council (NHMRC) (project grant No. APP 1009539)