Validity of interpretation: A user validity perspective beyond the test score

This paper introduces the concept of user validity and provides a new perspective on the validity of interpretations from tests. Test interpretation is based on outputs such as test scores, profiles, reports, spreadsheets of multiple candidates' scores, etc. The user validity perspective focuses on the interpretations a test user makes given the purpose of the test and the information provided in the test output. This innovative perspective focuses on how user validity can be extended to content, criterion, and to some extent construct-related validity. It provides a basis for researching the validity of interpretations and an improved understanding of the appropriateness of different approaches to score interpretation, as well as how to design test outputs and assessments that are pragmatic and optimal

Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK

Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy

Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We now show that glutamine and glucose also fuel an indispensible dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of UDP-GlcNAc, a substrate for cellular glycosyltransferases. Immune activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-GlcNAc glycosyltransferase as compared to naïve cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation, via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation, and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology

Lived experience of work and long COVID in healthcare staff.

Healthcare workers (HCWs) had a greater occupational risk of exposure to coronavirus disease 2019 (COVID-19) and reported higher rates of long COVID (LC). This has implications for the provision of health care in already stretched health services. This study explored the impact of LC on a range of UK National Health Service (NHS) HCWs, their health and well-being, the effect on work patterns, and occupational support received. This research was conducted through a mixed-methods study, online survey and qualitative interviews. Participants self-reporting LC symptoms were recruited through social media and NHS channels. Interviews used maximum variation sampling of 50 HCWs including healthcare professionals, ancillary and administration staff. Thematic analysis was conducted using NVivo software. A total of 471 HCWs completed the online survey. Multiple LC symptoms were reported, revealing activity limitations for 90%. Two-thirds had taken sick leave, 18% were off-work and 33% reported changes in work duties. There were few differences in work practices by occupational group. Most participants were working but managing complex and dynamic symptoms, with periods of improvement and exacerbation. They engaged in a range of strategies: rest, pacing, planning and prioritizing, with work prioritized over other aspects of life. Symptom improvements were often linked to occupational medicine, managerial, colleague support and flexible workplace adjustments. The study concluded that LC has a significant impact on the lives of HCWs suffering prolonged symptoms. Due to the variability and dynamic nature of symptoms, workplace support and flexible policies are needed to help retain staff

Using shared goal setting to improve access and equity : a mixed methods study of the Good Goals intervention in children's occupational therapy

Peer reviewedPublisher PD

Myocardial active strain energy density and contractance: novel prognostic tools for left ventricular function and cardiovascular risk

Myocardial active strain energy density (MASED), also known as contractance, is a novel measure of myocardial contractile function, defined by the area within the stress-strain loop; it quantifies the energy per unit volume of myocardium used to perform work. MASED applies the principle of strain energy density, which is grounded in engineering science, to cardiac tissue. Using cardiovascular magnetic resonance imaging, we demonstrate that global longitudinal active strain energy density (GLASED), a subtype of MASED, provides superior predictive value compared to conventional metrics such as ejection fraction and global longitudinal strain in predicting mortality among patients with hypertensive heart disease, dilated cardiomyopathy, and amyloid heart disease (n = 183). In a large community-based cohort (n= 44 957), GLASED was the strongest independent predictor of all-cause mortality and major adverse cardiovascular events among 23 left ventricular structural and functional metrics. Echocardiographic assessment of GLASED further revealed significant associations with age and sex in healthy individuals. These findings indicate that MASED, and specifically GLASED, provide a more accurate and mechanistically grounded assessment of left ventricular performance and cardiovascular risk than established measures. In clinical practice, MASED has the potential to enhance risk stratification, guide heart failure management, and differentiate pathological from physiological hypertrophy. Prospective prognostic studies in wider disease populations are warranted to validate its clinical utility

The evolutionary significance of polyploidy

Polyploidy, or the duplication of entire genomes, has been observed in prokaryotic and eukaryotic organisms, and in somatic and germ cells. The consequences of polyploidization are complex and variable, and they differ greatly between systems (clonal or non-clonal) and species, but the process has often been considered to be an evolutionary 'dead end'. Here, we review the accumulating evidence that correlates polyploidization with environmental change or stress, and that has led to an increased recognition of its short-term adaptive potential. In addition, we discuss how, once polyploidy has been established, the unique retention profile of duplicated genes following whole-genome duplication might explain key longer-term evolutionary transitions and a general increase in biological complexity

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Associations between adolescent psychosocial factors and disengagement from education and employment in young adulthood among individuals with common mental health problems

Sumeyra Nur Tayfur - ORCID: 0000-0002-5151-850X https://orcid.org/0000-0002-5151-850XTransition to adulthood can be a challenging developmental task for adolescents with common mental health problems and is linked to adverse outcomes such as ‘not in education, employment or training’ (NEET). This study investigated longitudinal associations between adolescent psychosocial factors (e.g., self-esteem, aspirations, bullying, physical activity) and later NEET status among individuals with common mental health problems (i.e., depression and anxiety). A secondary data analysis of the Next Steps cohort study was completed using waves 2 and 8. Psychosocial factors, mental health, and background characteristics were captured when participants were aged 15–16 years (wave 2) while still in compulsory education. The 12-item General Health Questionnaire was used to identify adolescents with common mental health problems. The study population consisted of 2224 participants (females 66.8%) of which 1473 (66.2%) were aged 15 years and 751 (33.8%) were aged 16 years in wave 2. The outcome was NEET status at ages 25–26 years (wave 8). The results showed that after adjusting for background characteristics, adolescent self-esteem, locus of control, bullying, physical activity, job aspirations, and attitudes to school predicted NEET status. Educational aspirations, substance use, and behavioural problems were not significantly associated with NEET status. These findings provide new insights into the role of adolescent psychosocial factors in the context of education and employment outcomes for youth at risk and highlight the necessity of targeted mental health support to improve life chances.This study was funded by Lothian National Health Service, and Queen Margaret University, Edinburgh, Scotland through a Ph.D. bursary.https://doi.org/10.1007/s10964-022-01592-7pubpu

AMPK in Pathogens

During host–pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host–pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.CIHR -Canadian Institutes of Health Researc