Establishment of clinical exercise physiology as a regulated healthcare profession in the UK:a progress report

In 2021, a 'call to action' was published to highlight the need for professional regulation of clinical exercise physiologists to be established within UK healthcare systems to ensure patient safety and align training and regulation with other health professions. This manuscript provides a progress report on the actions that Clinical Exercise Physiology UK (CEP-UK) has undertaken over the past 4 years, during which time clinical exercise physiologists have implemented regulation and gained formal recognition as healthcare professionals in the UK. An overview of the consultation process involved in creating a regulated health profession, notably the development of policies and procedures for both individual registration and institutional master's degree (MSc) accreditation is outlined. Additionally, the process for developing an industry-recognised scope of practice, a university MSc-level curriculum framework, the Academy for Healthcare Science Practitioner standards of proficiency and Continuing Professional Development opportunities is included. We outline the significant activities and milestones undertaken by CEP-UK and provide insight and clarity for other health professionals to understand the training and registration process for a clinical exercise physiologist in the UK. Finally, we include short, medium and long-term objectives for the future advocacy development of this workforce in the UK.</p

Measurements of 12C(&#8594;γ,pp) photon asymmetries for Eγ= 200–450 MeV

The 12C (&#8594;γ ,pp) reaction has been studied in the photon energy range 200-450 MeV at the Mainz microtron MAMI-C, where linearly polarised photons were energy-tagged using the Glasgow-Mainz Tagged Photon Spectrometer and protons were detected in the Crystal Ball detector. The photon asymmetry Σ has been measured over a wider Eγ range than previous measurements. The strongest asymmetries were found at low missing energies where direct emission of nucleon pairs is expected. Cuts on the difference in azimuthal angles of the two ejected protons increased the magnitude of the observed asymmetries. At low missing energies the Σ data exhibit a strong angular dependence, similar to deuteron photodisintegration

Quasi-free photoproduction of η-mesons off 3He nuclei

Quasi-free photoproduction of η-mesons has been measured off nucleons bound in 3He nuclei for incident photon energies from the threshold region up to 1.4 GeV. The experiment was performed at the tagged photon facility of the Mainz MAMI accelerator with an almost 4π covering electromagnetic calorimeter, combining the TAPS and Crystal Ball detectors. The η-mesons were detected in coincidence with the recoil nucleons. This allowed a comparison of the production cross section off quasi-free protons and quasi-free neutrons and a full kinematic reconstruction of the final state, eliminating effects from nuclear Fermi motion. In the S11(1535) resonance peak, the data agree with the neutron/proton cross section ratio extracted from measurements with deuteron targets. More importantly, the prominent structure observed in photoproduction off quasi-free neutrons bound in the deuteron is also clearly observed. Its parameters (width, strength) are consistent with the expectations from the deuteron results. On an absolute scale the cross sections for both quasi-free protons and neutrons are suppressed with respect to the deuteron target pointing to significant nuclear final-state interaction effects

APOΕ4 Lowers Energy Expenditure in Females and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer\u27s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a \u27Warburg like\u27 endophenotype that is observable in young females decades prior to clinically manifest AD

Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial

Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.</p> <p>Results</p> <p>Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented.</p> <p>Conclusions</p> <p>This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps.</p