Mathematical models of granulopoiesis

Haemopoiesis (blood cell production) is a process subject to active physiological regulation. It constitutes one example of a biological process controlled through a hierarchy of feedback loops acting at a range of levels from the molecular to the macroscopic. The thesis describes mathematical studies of the more macroscopic (physiological) levels of the control of haemopoiesis, with special emphasis on granulopoiesis. Following review of pertinent background material in cybernetics, physiology and pathology, attention is focussed on the mathematical representation of cellular proliferation and maturation, and a representation formulated in tennis of experimental observables is proposed. This leads to the study of a non-linear transcendental equation of the form with the unknown quantity. An iterative method of solution is proposed for this equation, which permits kinetic analysis of a certain class of non-steady-state processes. The method is used for the analysis of maturation kinetics of embryonic erythroid cells. Attention is then turned to the causal basis of the control of haemopoiesis. It is pointed out that certain features of haemopoietic regulation lead to the expectation of oscillatory phenomena and th.at observation of such phenomena can be revealing. With this in mind, a simple model is advanced for the control of granulocyte production. The model comprises two feedback loops, one regulating 'de novo' granulopoiesis in accordance with marrow granulocyte numbers and one regulating release from the marrow in accordance with blood granu1ocyte numbers. The model is described by the system of delay-differential equations where Gm , GB are (respectively) the marrow granulocyte number and blood granulocyte number, both at time, and to are parameters, chosen to give maxim.um physiological realism. Since 'de novo' granulopoiesis is believed to constitute a drain on primitive 'stem, cells', regulation of stem cell number appears necessary. A model for stem cell mitotic autoregulation based on a diffusible inhibitor concept is proposed. This theory leads to the study of a pair of differential equations which, utilizing probable order-of-magnitude differences in relaxation times, may be reduced to the single equation which admits of a closed analytic solution. This equation exhibits both self-limiting and non-self-limiting modes of behaviour, the biological implications of which are discussed. With parameters selected for stability, the stem cell mitotic autoreguation loop may be adjoined to the granulopoiesis control system, previously considered, to obtain a composite model. However, the unstable and capricious behaviour of this multi-loop combination renders it physiologically unacceptable, Modifications which restore stability seem to imply heterogeneity of the stem cell population, representation of which lies outside the scope of the study described. In the following chapter, consideration is given to the physical, basis of regulation of 'de novo' granulopoiesis with emphasis on 'in vitro' evidence relating to 'colony stimulating factor' and the possible role of positive feedback in regulating granulocyte numbers in infection. By mathematical formulation of a. recently proposed pcsitive- feedback model it is shown that positive feedback systems can be stable in the absence of overt negative feedback loops provided passive damping elements (e.g, cell death) exist and satisfy'' certain criteria. It is shown, however, that the criteria concerned are incompa.tib3.e with known featu.res of the regulation of granulopoiesis in infection and the existence of additional, negatively-acting, loops is deduced. Some possibilities in this direction are proposed. The model studies may illuminate the pathogenesis of some disorders of the control of granulopoiesis, notably cyclical neutropenia and myeloid leukaemia

CT-derived measures of muscle quantity and quality predict poorer outcomes from elective colorectal surgery: a UK multicentre retrospective cohort study

Purpose To assess whether preoperative radiologically defined lean muscle measures are associated with adverse clinical outcomes in patients undergoing elective surgery for colorectal cancer. Methods This retrospective UK-based multicentre data collection study identified patients having had colorectal cancer resection with curative intent between January 2013 to December 2016. Preoperative computed-tomography (CT) scans were used to measure psoas muscle characteristics. Clinical records provided postoperative morbidity and mortality data. Results This study included 1122 patients. The cohort was separated into a combined group (patients with both sarcopenia and myosteatosis) and others group (either sarcopenia or myosteatosis, or neither). For the combined group, anastomotic leak was predicted on univariate (OR 4.1, 95% CI 1.43–11.79; p = 0.009) and multivariate analysis (OR 4.37, 95% CI 1.41–13.53; p = 0.01). Also for the combined group, mortality (up to 5 years postoperatively) was predicted on univariate (HR 2.41, 95% CI 1.64–3.52; p < 0.001) and multivariate analysis (HR 1.93, 95% CI 1.28–2.89; p = 0.002). A strong correlation exists between freehand-drawn region of interest-derived psoas density measurement and using the ellipse tool (R2 = 81%; p < 0.001). Conclusion Measures of lean muscle quality and quantity, which predict important clinical outcomes, can be quickly and easily taken from routine preoperative imaging in patients being considered for colorectal cancer surgery. As poor muscle mass and quality are again shown to predict poorer clinical outcomes, these should be proactively targeted within prehabilitation, perioperative and rehabilitation phases to minimise negative impact of these pathological states

Design and Synthesis of 56 Shape Diverse 3-D Fragments

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2-D molecules. Herein, we describe a workflow for the design and synthesis of 56 3-D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol -1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3-D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3-D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity

Cross-shell states in 15^{15}C: a test for p-sd interactions

The low-lying structure of $^{15}$C has been investigated via the neutron-removal $^{16}$C$(d,t)$ reaction. Along with bound neutron sd-shell hole states, unbound p-shell hole states have been firmly confirmed. The excitation energies and the deduced spectroscopic factors of the cross-shell states are an important measure of the $[(p)^{-1}(sd)^{2}]$ neutron configurations in $^{15}$C. Our results show a very good agreement with shell-model calculations using the SFO-tls interaction for $^{15}$C. However, a modification of the $p$-$sd$ and $sd$-$sd$ monopole terms was applied in order to reproduce the $N=9$ isotone $^{17}$O. In addition, the excitation energies and spectroscopic factors have been compared to the first calculations of $^{15}$C with the $ab~ initio$ self-consistent Green's function method employing the NNLO$_{sat}$ interaction. The results show the sensitivity to the size of the $N=8$ shell gap and highlight the need of going beyond the current truncation scheme in the theory

Identification of surgeon burnout via a single-item measure

Background Burnout is endemic in surgeons in the UK and linked with poor patient safety and quality of care, mental health problems, and workforce sustainability. Mechanisms are required to facilitate the efficient identification of burnout in this population. Multi-item measures of burnout may be unsuitable for this purpose owing to assessment burden, expertise required for analysis, and cost. Aims To determine whether surgeons in the UK reporting burnout on the 22-item Maslach Burnout Inventory (MBI) can be reliably identified by a single-item measure of burnout. Methods Consultant (n = 333) and trainee (n = 217) surgeons completed the MBI and a single-item measure of burnout. We applied tests of discriminatory power to assess whether a report of high burnout on the single-item measure correctly classified MBI cases and non-cases. Results The single-item measure demonstrated high discriminatory power on the emotional exhaustion burnout domain: the area under the curve was excellent for consultants and trainees (0.86 and 0.80), indicating high sensitivity and specificity. On the depersonalisation domain, discrimination was acceptable for consultants (0.76) and poor for trainees (0.69). In contrast, discrimination was acceptable for trainees (0.71) and poor for consultants (0.62) on the personal accomplishment domain. Conclusions A single-item measure of burnout is suitable for the efficient assessment of emotional exhaustion in consultant and trainee surgeons in the UK. Administered regularly, such a measure would facilitate the early identification of at-risk surgeons and swift intervention, as well as the monitoring of group-level temporal trends to inform resource allocation to coincide with peak periods

Low-lying single-particle structure of 17C and the N = 14 sub-shell closure

The first investigation of the single-particle structure of the bound states of 17C, via the C transfer reaction, has been undertaken. The measured angular distributions confirm the spin-parity assignments of and for the excited states located at 217 and 335 keV, respectively. The spectroscopic factors deduced for these states exhibit a marked single-particle character, in agreement with shell model and particle-core model calculations, and combined with their near degeneracy in energy provide clear evidence for the absence of the sub-shell closure. The very small spectroscopic factor found for the ground state is consistent with theoretical predictions and indicates that the strength is carried by unbound states. With a dominant valence neutron configuration and a very low separation energy, the excited state is a one-neutron halo candidate

Identification of Surgeon Burnout via a Single-Item Measure

BackgroundBurnout is endemic in surgeons in the UK and linked with poor patient safety and quality of care, mental health problems, and workforce sustainability. Mechanisms are required to facilitate the efficient identification of burnout in this population. Multi-item measures of burnout may be unsuitable for this purpose owing to assessment burden, expertise required for analysis, and cost.AimsTo determine whether surgeons in the UK reporting burnout on the 22-item Maslach Burnout Inventory (MBI) can be reliably identified by a single-item measure of burnout.MethodsConsultant (n = 333) and trainee (n = 217) surgeons completed the MBI and a single-item measure of burnout. We applied tests of discriminatory power to assess whether a report of high burnout on the single-item measure correctly classified MBI cases and non-cases.ResultsThe single-item measure demonstrated high discriminatory power on the emotional exhaustion burnout domain: the area under the curve was excellent for consultants and trainees (0.86 and 0.80), indicating high sensitivity and specificity. On the depersonalisation domain, discrimination was acceptable for consultants (0.76) and poor for trainees (0.69). In contrast, discrimination was acceptable for trainees (0.71) and poor for consultants (0.62) on the personal accomplishment domain.ConclusionsA single-item measure of burnout is suitable for the efficient assessment of emotional exhaustion in consultant and trainee surgeons in the UK. Administered regularly, such a measure would facilitate the early identification of at-risk surgeons and swift intervention, as well as the monitoring of group-level temporal trends to inform resource allocation to coincide with peak periods

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries