Elements of exogenous attentional cueing preserved during optokinetic motion of the visual scene.

Navigating through our environment raises challenges for perception by generating salient background visual motion and eliciting prominent eye movements to stabilise the retinal image. It remains unclear if exogenous spatial attentional orienting is possible during background motion and the eye movements it causes and whether this compromises the underlying neural processing. To test this, we combined exogenous orienting, visual scene motion, and electroencephalography (EEG). A total of 26 participants viewed a background of moving black and grey bars (optokinetic stimulation). We tested for effects of non-spatially predictive peripheral cueing on visual motion discrimination of a target dot, presented either at the same (valid) or opposite (invalid) location as the preceding cue. Valid cueing decreased reaction times not only when participants kept their gaze fixed on a central point (fixation blocks) but also even when there was no fixation point, so that participants performed intensive, repetitive tracking eye movements (eye movement blocks). Overall, manual response reaction times were slower during eye movements. Cueing also produced reliable effects on neural activity on either block, including within the first 120 ms of neural processing of the target. The key pattern with larger event-related potential (ERP) amplitudes on invalid versus valid trials showed that the neural substrate of exogenous cueing was highly similar during eye movements or fixation. Exogenous peripheral cueing and its neural correlates are robust against distraction from the moving visual scene, important for perceptual cognition during navigation.

An exploration of primary care healthcare professionals' understanding of pain and pain management following a brief pain science education.

BACKGROUND: Persistent pain is a leading cause of disability worldwide yet implementation of clinical guidelines that recommend a biopsychosocial approach remains a challenge in clinical practise. Limited pain understanding amongst clinicians may be partly responsible for this. PURPOSE OF THE STUDY: 1) Qualitatively explore the experience of receiving PSE, understanding of PSE and operationalisation of PSE-related principles in routine clinical practice. 2) Quantitatively explore pain knowledge, attitudes, and behaviours of general practitioners (GPs) and nurse practitioners (NPs) before and after pain science education (PSE). METHODS: An exploratory, single-site, mixed-methods study in north-east England. Fifteen NPs/GPs completed questionnaires and a case-vignette before and after a 70-min face-to-face PSE lecture. Qualitative data were thematically analysed from two focus groups after the intervention. RESULTS: Clinicians' relatively high prior levels of knowledge, attitudes, and behaviour were similar after PSE. Qualitative themes described facilitation of self-reflection on pain management behaviours, and difficulties in operationalising PSE principles in practise including: limited patient rapport; short appointment times; patients' passive and often oppositional biomedical treatment expectations; and clinicians' lack of readily understandable language to communicate with patients. CONCLUSION: The findings highlight the value of PSE perceived by these clinicians who were already favourably inclined towards biopsychosocial pain management. They sought more resources for their personal learning and for communication with patients. Even with such favourable disposition, the practicalities and environment of clinical practice impeded the operationalisation of PSE-related principles. TRIAL REGISTRATION: This study was prospectively registered at ClinicalTrials.Gov ( NCT04587596 ) in October 2020.

International, multi-disciplinary, cross-section study of pain knowledge and attitudes in nursing, midwifery and allied health professions students.

BACKGROUND: Persistent pain is a highly prevalent, global cause of disability. Research suggests that many healthcare professionals are not well equipped to manage pain, and this may be attributable at least in part to undergraduate education. The primary aim of this study was to quantify and compare first and final year nursing, midwifery and allied health professional (NMAHP) students' pain related knowledge and attitudes. The secondary aim was to explore what factors influence students' pain related knowledge and attitudes. METHODS: In this cross-sectional study, 1154 first and final year healthcare students, from 12 universities in five different countries completed the Revised Neurophysiology of Pain Quiz (RNPQ) [knowledge] and the Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS) [attitudes]. RESULTS: Physiotherapy was the only student group with statistically and clinically improved pain related knowledge [mean difference, 95% CI] (3.4, 3.0 to 3.9, p = 0.01) and attitudes (-17.2, -19.2 to 15.2, p = 0.01) between first and final year. Pain education teaching varied considerably from course to course (0 to 40 h), with greater levels of pain related knowledge and attitudes associated with higher volumes of pain specific teaching. CONCLUSIONS: There was little difference in pain knowledge and attitudes between all first and final year NMAHP students other than physiotherapy. This suggests that for most NMAHP disciplines, undergraduate teaching has little or no impact on students' understanding of pain. There is an urgent need to enhance pain education provision at the undergraduate level in NMAHPs. TRIAL REGISTRATION: The study protocol was prospectively registered at ClinicalTrials.Gov NCT03522857 .

The evolutionary origins of peroxynitrite signalling.

Peroxynitrite is a reactive intermediate formed in vivo through uncatalysed reaction of superoxide and nitric oxide radicals. Despite significant interest in detecting peroxynitrite in vivo and understanding its production, little attention has been given to the evolutionary origins of peroxynitrite signalling. Herein we focus on two enzymes that are key to the biosynthesis of superoxide and nitric oxide, NADPH oxidase 5 (NOX5) and endothelial nitric oxide synthase (eNOS), respectively. Multiple sequence alignments of both enzymes including homologues from all domains of life, coupled with a phylogenetic analysis of NOX5, suggest eNOS and NOX5 are present in animals as the result of horizontal gene transfer from ancestral cyanobacteria to ancestral eukaryotes. Therefore, biochemical studies from other laboratories on a NOX5 homologue in Cylindrospermum stagnale and an eNOS homologue in Synechococcus sp. PCC 7335 are likely to be of relevance to human NOX5 and eNOS and to the production of superoxide, nitric oxide and peroxynitrite in humans.

Right frontal eye field has perceptual and oculomotor functions during optokinetic stimulation and nystagmus.

The right frontal eye field (rFEF) is associated with visual perception and eye movements. rFEF is activated during optokinetic nystagmus (OKN), a reflex that moves the eye in response to visual motion (optokinetic stimulation, OKS). It remains unclear whether rFEF plays causal perceptual and/or oculomotor roles during OKS and OKN. To test this, participants viewed a leftward-moving visual scene of vertical bars and judged whether a flashed dot was moving. Single pulses of transcranial magnetic stimulation (TMS) were applied to rFEF on half of trials. In half of blocks, to explore oculomotor control, participants performed an OKN in response to the OKS. rFEF TMS, during OKN, made participants more accurate on trials when the dot was still, and it slowed eye movements. In separate blocks, participants fixated during OKS. This not only controlled for eye movements but also allowed the use of EEG to explore the FEF's role in visual motion discrimination. In these blocks, by contrast, leftward dot motion discrimination was impaired, associated with a disruption of the frontal-posterior balance in alpha-band oscillations. None of these effects occurred in a control site (M1) experiment. These results demonstrate multiple related yet dissociable causal roles of the right FEF during optokinetic stimulation.NEW & NOTEWORTHY This study demonstrates causal roles of the right frontal eye field (FEF) in motion discrimination and eye movement control during visual scene motion: previous work had only examined other stimuli and eye movements such as saccades. Using combined transcranial magnetic stimulation and EEG and a novel optokinetic stimulation motion-discrimination task, we find evidence for multiple related yet dissociable causal roles within the FEF: perceptual processing during optokinetic stimulation, generation of the optokinetic nystagmus, and the maintenance of alpha oscillations.

Shift in lateralization during illusory self-motion: EEG responses to visual flicker at 10 Hz and frequency-specific modulation by tACS.

Self-motion perception is a key aspect of higher vestibular processing, suggested to rely upon hemispheric lateralization and alpha-band oscillations. The first aim of this study was to test for any lateralization in the EEG alpha band during the illusory sense of self-movement (vection) induced by large optic flow stimuli. Visual stimuli flickered at alpha frequency (approx. 10 Hz) in order to produce steady state visually evoked potentials (SSVEPs), a robust EEG measure which allows probing the frequency-specific response of the cortex. The first main result was that differential lateralization of the alpha SSVEP response was found during vection compared with a matched random motion control condition, supporting the idea of lateralization of visual-vestibular function. Additionally, this effect was frequency-specific, not evident with lower frequency SSVEPs. The second aim of this study was to test for a causal role of the right hemisphere in producing this lateralization effect and to explore the possibility of selectively modulating the SSVEP response. Transcranial alternating current stimulation (tACS) was applied over the right hemisphere simultaneously with SSVEP recording, using a novel artefact removal strategy for combined tACS-EEG. The second main result was that tACS enhanced SSVEP amplitudes, and the effect of tACS was not confined to the right hemisphere. Subsequent control experiments showed the effect of tACS requires the flicker frequency and tACS frequency to be closely matched and tACS to be of sufficient intensity. Combined tACS-SSVEPs are a promising method for future investigation into the role of neural oscillations and for optimizing tACS.

A Case Study of Eukaryogenesis: The Evolution of Photoreception by Photolyase/Cryptochrome Proteins.

Eukaryogenesis, the origin of the eukaryotes, is still poorly understood. Herein, we show how a detailed all-kingdom phylogenetic analysis overlaid with a map of key biochemical features can provide valuable clues. The photolyase/cryptochrome family of proteins are well known to repair DNA in response to potentially harmful effects of sunlight and to entrain circadian rhythms. Phylogenetic analysis of photolyase/cryptochrome protein sequences from a wide range of prokaryotes and eukaryotes points to a number of horizontal gene transfer events between ancestral bacteria and ancestral eukaryotes. Previous experimental research has characterised patterns of tryptophan residues in these proteins that are important for photoreception, specifically a tryptophan dyad, a canonical tryptophan triad, an alternative tryptophan triad, a tryptophan tetrad and an alternative tetrad. Our results suggest that the spread of the different triad and tetrad motifs across the kingdoms of life accompanied the putative horizontal gene transfers and is consistent with multiple bacterial contributions to eukaryogenesis.

Taking Attention Out of Context: Frontopolar Transcranial Magnetic Stimulation Abolishes the Formation of New Context Memories in Visual Search.

This study investigates the causal contribution of the left frontopolar cortex (FPC) to the processing of violated expectations from learned target-distractor spatial contingencies during visual search. The experiment consisted of two phases: learning and test. Participants searched for targets presented either among repeated or nonrepeated target-distractor configurations. Prior research showed that repeated encounters of identically arranged displays lead to memory about these arrays, which then can come to guide search (contextual cueing effect). The crucial manipulation was a change of the target location, in a nevertheless constant distractor layout, at the transition from learning to test. In addition to this change, we applied repetitive transcranial magnetic stimulation (rTMS) over the left lateral FPC, over a posterior control site, or no rTMS at all (baseline; between-group manipulation) to see how FPC rTMS influences the ability of observers to adapt context-based memories acquired in the training phase. The learning phase showed expedited search in repeated relative to nonrepeated displays, with this context-based facilitation being comparable across all experimental groups. For the test phase, the recovery of cueing was critically dependent on the stimulation site: Although there was evidence of context adaptation toward the end of the experiment in the occipital and no-rTMS conditions, observers with FPC rTMS showed no evidence of relearning at all after target location changes. This finding shows that FPC plays an important role in the regulation of prediction errors in statistical context learning, thus contributing to an update of the spatial target-distractor contingencies after target position changes in learned spatial arrays.

Identification of a cyanobacterial aldehyde dehydrogenase that produces retinoic acid in vitro.

Retinoic acid signalling is generally considered to be of animal origin. Recently, retinoic acid has been identified in cyanobacteria, yet no mechanism for its production has been identified. Here, we characterise for the first time a cyanobacterial aldehyde dehydrogenase that produces retinoic acid in vitro. Our computational studies suggest that the cyanobacterial aldehyde dehydrogenase resembles an ancestor of both eukaryotic aldehyde dehydrogenase 1 and aldehyde dehydrogenase 2. The Chlorogloeopsis fritschii aldehyde dehydrogenase described here may find applications in synthetic production of retinoic acid as well as contributing to our understanding of retinoid synthesis in cyanobacteria.

Subthalamic stimulation, oscillatory activity and connectivity reveal functional role of STN and network mechanisms during decision making under conflict.

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards.

The role of the dorsal medial frontal cortex in central processing limitation: a transcranial magnetic stimulation study.

When humans perform two tasks simultaneously, responses to the second task are increasingly delayed as the interval between the two tasks decreases (psychological refractory period). This delay of the second task is thought to reflect a central processing limitation at the response selection stage. However, the neural mechanisms underlying this central processing limitation remain unclear. Using transcranial magnetic stimulation (TMS), we examined the role of the dorsal medial frontal cortex (dMFC) in a dual-task paradigm in which participants performed an auditory task 1 and a visual task 2. We found that dMFC TMS, relative to control conditions, reduced the psychological refractory period for task 2 processing, whereas we observed no dMFC TMS effects on task 1 processing. This suggests a causal role of the dMFC in coordinating response selection processes at the central bottleneck.

Occipital TMS at phosphene detection threshold captures attention automatically.

Strong stimuli may capture attention automatically, suggesting that attentional selection is determined primarily by physical stimulus properties. The mechanisms underlying capture remain controversial, in particular, whether feedforward subcortical processes are its main source. Also, it remains unclear whether only physical stimulus properties determine capture strength. Here, we demonstrate strong capture in the absence of feedforward input to subcortical structures such as the superior colliculus, by using transcranial magnetic stimulation (TMS) over occipital visual cortex as an attention cue. This implies that the feedforward sweep through subcortex is not necessary for capture to occur but rather provides an additional source of capture. Furthermore, seen cues captured attention more strongly than (physically identical) unseen cues, suggesting that the momentary state of the nervous system modulates attentional selection. In summary, we demonstrate the existence of several sources of attentional capture, and that both physical stimulus properties and the state of the nervous system influence capture.

Dissociable networks control conflict during perception and response selection: a transcranial magnetic stimulation Study.

Current models of conflict processing propose that cognitive control resolves conflict in the flanker task by enhancing task-relevant stimulus processing at a perceptual level. However, because conflicts occur at both a perceptual and a response selection level in that task, we tested the hypothesis of conflict-specific control networks for perceptual and response selection conflicts using transcranial magnetic stimulation (TMS). TMS of the presupplementary motor area selectively disrupted the processing of response selection conflict, whereas TMS of the posterior intraparietal sulcus/inferior parietal lobule interfered with perceptual conflict processing. In more detail, the presupplementary motor area seems to resolve response selection conflict mainly when no conflicts have occurred in the previous trial. In contrast, the posterior intraparietal sulcus/inferior parietal lobule may resolve perceptual conflicts selectively when a conflict has occurred in the previous trial. The current data show the need for revising models of cognitive control by providing evidence for the existence of conflict-specific control networks resolving conflict at different processing levels.

Oxidation of tertiary amine-derivatized surfaces to control protein adhesion.

Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques.

A paradoxical role for inhibition in initiation.

Subliminal stimuli, of which subjects are unaware, affect movements made to subsequent visible cues. Sumner and colleagues in this issue of Neuron show that restricted supplementary motor and eye field lesions compromise voluntary control of action because they disrupt the normal unconscious and automatic inhibition of alternative movements partially activated by subliminal stimuli.

TMS of the right angular gyrus modulates priming of pop-out in visual search: combined TMS-ERP evidence.

During priming of pop-out, performance at discriminating a pop-out feature target in visual search is affected by whether the target on the previous trial was defined by the same feature as on the upcoming trial. Recent studies suggest that priming of pop-out relies on attentional processes. With the use of simultaneous, combined transcranial magnetic stimulation and event-related potential recording (TMS-ERP), we tested for any critical role of the right angular gyrus (rANG) and left and right frontal eye fields (FEFs)-key attentional sites-in modulating both performance and the ERPs evoked by such visual events. Intertrial TMS trains were applied while participants discriminated the orientation of a color pop-out element in a visual search array. rANG TMS disrupted priming of pop-out, reducing reaction time costs on switch trials and speeding responses when the color of the pop-out target switched. rANG TMS caused a negativity in the ERP elicited in response to the visual stimulus array, starting 210 ms after stimulus onset. Both behavioral and ERP effects were apparent only after rANG TMS, on switch trials, and when the target in the visual search array was presented in the left visual field, with no effects after left or right FEF TMS. These results provide evidence for an attentional reorienting mechanism, which originates in the rANG and is modulated by the implicit memory of the previous trial. The rANG plays a causal role on switch trials during priming of pop-out by interacting with visual processing, particularly in the ipsilateral hemisphere representing the contralateral hemifield.

Investigation of optimal cues to instruction for pelvic floor muscle contraction: a pilot study using 2D ultrasound imaging in pre-menopausal, nulliparous, continent women.

AIMS: Optimal urethrovesical positioning (UVP) may be important for continence. Pelvic floor muscle contraction (PFMC) influences UVP. PFMC instruction cues vary and often encourage anterior PFM recruitment that may result in sub-maximal posterior facilitation. STUDY HYPOTHESIS: posterior or combined cues are more influential in optimizing UVP during PFMC following a brief practice period than anterior cue. METHODS: Seventeen pre-menopausal, nulliparous, continent women were taught selective PFMC using different cues: anterior; posterior; anterior and posterior combined. Perineal ultrasound images of three PFMC for each cue were captured in supine and standing twice, 5 min apart. For reliability two raters measured data using angle of urethral inclination (AUI). Data analysis was undertaken using a customized General Linear Model ANOVA testing for interactions between all variables; subject, cue, posture, and test. Post hoc Bonferroni correction was used with a significance level of 0.05. RESULTS: The ANOVA showed significant differences between variables (P = 0.000). Post hoc analysis indicated significant differences between posterior and anterior cues 4.240° (P = 0.003); combined and anterior 3.756° (P = 0.009) but not between posterior and combined cues -0.484° (P = 1.00). Mean difference in AUI between supine and standing was 9.496° (P = 0.000); however, the interaction of cues and postures was not significant. CONCLUSIONS: AUI was significantly more acute/optimal when PFMC instruction included a posterior cue. This may be due to optimal recruitment of puborectalis and other posterior regional muscles which may be sub-maximally recruited with anterior cue. Investigation of the potential impact of these findings and possible usefulness of standardized instructions in PFM training is required.

Self-initiation Inhibits the Postural and Electrophysiological Responses to Optic Flow and Button Pressing.

As we move through our environment, our visual system is presented with optic flow, a potentially important cue for perception, navigation and postural control. How does the brain anticipate the optic flow that arises as a consequence of our own movement? Converging evidence suggests that stimuli are processed differently by the brain if occurring as a consequence of self-initiated actions, compared to when externally generated. However, this has mainly been demonstrated with auditory stimuli. It is not clear how this occurs with optic flow. We measured behavioural, neurophysiological and head motion responses of 29 healthy participants to radially expanding, vection-inducing optic flow stimuli, simulating forward transitional motion, which were either initiated by the participant's own button-press ("self-initiated flow") or by the computer ("passive flow"). Self-initiation led to a prominent and left-lateralized inhibition of the flow-evoked posterior event-related alpha desynchronization (ERD), and a stabilisation of postural responses. Neither effect was present in control button-press-only trials, without optic flow. Additionally, self-initiation also produced a large event-related potential (ERP) negativity between 130-170 ms after optic flow onset. Furthermore, participants' visual induced motion sickness (VIMS) and vection intensity ratings correlated positively across the group - although many participants felt vection in the absence of any VIMS, none reported the opposite combination. Finally, we found that the simple act of making a button press leads to a detectable head movement even when using a chin rest. Taken together, our results indicate that the visual system is capable of predicting optic flow when self-initiated, to affect behaviour.

The influence of TMS of the rTPJ on attentional control and mentalizing.

Mentalizing is the powerful cognitive ability to understand others. By attributing mental states to others, we become able to explain and predict their behavior. The right temporoparietal junction (rTPJ) plays a key role in processing models of mental states. Yet, a different line of research suggests that the rTPJ is crucially involved in attentional control, prompting debates on its cognitive function. In this pre-registered neuro-navigated event-related TMS study, we tested for the rTPJ's specificity in mentalizing and attentional control. We interfered with its activity in a recently developed spatial cueing paradigm in which another's mental states were apparently task-relevant, allowing direct comparison of TMS effects on attention and mentalizing. We contrasted effects with a nearby control TMS site. Our confirmatory analysis showed no evidence for an involvement of the rTPJ in mentalizing or attentional control, presumably due to an observed large inter-individual variability of TMS effects on context and validity. To follow up this finding, we conducted exploratory analyses which revealed that rTPJ TMS had an influence on both attentional control and mentalizing. TMS effects on attention and mentalizing co-varied across participants: participants responding most to rTPJ TMS on mentalizing were also those for whom rTPJ TMS increased the attentional effect the most. This provides further evidence against total absolute segregation between mentalizing and attention within the rTPJ. Rather, our results suggest a common cognitive mechanism in both domains for which the rTPJ is necessary, paving the way for future research to cross-validate and extend these findings.

Operational Modeling with Health Economics to Support Decision Making for COPD Patients.

OBJECTIVE: To assess the impact of interventions for improving the management of chronic obstructive pulmonary disease (COPD), specifically increased use of pulmonary rehabilitation (PR) on patient outcomes and cost-benefit analysis. DATA SOURCES: We used the national Hospital Episode Statistics (HES) datasets in England, local data and experts from the hospital setting, National Prices and National Tariffs, reports and the literature around the effectiveness of PR programs. STUDY DESIGN: The COPD pathway was modeled using discrete event simulation (DES) to capture the patient pathway to an adequate level of detail as well as randomness in the real world. DES was further enhanced by the integration of a health economic model to calculate the net benefit and cost of treating COPD patients based on key sets of interventions. DATA COLLECTION/EXTRACTION METHODS: A total of 150 input parameters and 75 distributions were established to power the model using the HES dataset, outpatient activity data from the hospital and community services, and the literature. PRINCIPAL FINDINGS: The simulation model showed that increasing referral to PR (by 10%, 20%, or 30%) would be cost-effective (with a benefit-cost ratio of 5.81, 5.95, and 5.91, respectively) by having a positive impact on patient outcomes and operational metrics. Number of deaths, admissions, and bed days decreased (ie, by 3.56 patients, 4.90 admissions, and 137.31 bed days for a 30% increase in PR referrals) as well as quality of life increased (ie, by 5.53 QALY among 1540 patients for the 30% increase). CONCLUSIONS: No operational model, either statistical or simulation, has previously been developed to capture the COPD patient pathway within a hospital setting. To date, no model has investigated the impact of PR on COPD services, such as operations, key performance, patient outcomes, and cost-benefit analysis. The study will support policies around extending availability of PR as a major intervention.