CONCLUSIONS Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective therapeutics for chronic myeloid leukemia (CML), patients often develop drug resistance due to ATP-site mutations that inhibit drug binding. TERN-701 is a potent and highly selective inhibitor of BCR::ABL1 that is designed to bind the allosteric myristoyl site on the kinase, circumventing resistance to active site mutations, with potential for synergistic combination with active site TKIs. Competition binding screens were used to assess the selectivity of TERN-701 on more than 450 targets spanning the human kinome. The potency of TERN-701 against the proliferation of wild type and mutant CML cell lines, as well as a panel of 102 cancer cell lines, was assessed using CellTiter-Glo®. Synergy between TERN-701 and active site TKIs was assessed in vitro with interactions quantified using Bliss, combination, and curve-shift analyses. Prospective mutagenesis experiments were conducted by treating BaF/3 cells engineered to overexpress the BCR::ABL1 kinase with various concentrations of both TERN-701 and the TKI imatinib, followed by observation of clonal outgrowth of treated cells over time. We have previously shown that TERN-701 is a potent inhibitor of native CML cell lines such as K562. Here, we show that TERN-701 inhibited cell proliferation in various clinically relevant mutant CML cell lines (including T315I) with IC 50s ranging from 5 to 26 nM and 70 to 1200 nM against active site and myristoyl site mutations, respectively. TERN-701 was highly selective for BCR::ABL1, with no appreciable activity (>50%) against >450 purified kinase targets. Against a panel of cancer cell lines, TERN-701 was more selective than the comparator allosteric BCR::ABL1 inhibitor asciminib while maintaining similar potency. In vitro combination studies previously revealed that TERN-701 works synergistically with multiple TKIs in the non-mutant K562 cell line. Here, expanded studies using KCL22-s and BCR::ABL1-T315I mutant cell lines identified strong synergistic interactions between TERN-701 and active site TKIs, including ponatinib and dasatinib. Furthermore, prospective mutagenesis studies showed that the combination of TERN-701 and imatinib resulted in greater inhibition of the outgrowth of resistant clones relative to either compound alone. TERN-701 is a potent and highly selective allosteric inhibitor of BCR::ABL1 that can act synergistically with active site TKIs in vitro, even against the T315I gatekeeper mutation that confers resistance to all approved active site TKIs except ponatinib, which has known safety liabilities. These data support the continued development of TERN-701 for the treatment of CML using both monotherapy and combination approaches.

Keywords: Patient preferences, Virtual consultations, Musculoskeletal Purpose: Videoconferencing (VC) has been cited as being able to reduce the number of face-to-face (F2F) outpatient appointments over the next 10 years. VC has been shown to be acceptable, however, face to face care is still seen as the ‘gold standard’. The COVID-19 pandemic has highlighted the potential for VC. The subject of this paper continues our previous research into patient preferences for VC in an orthopaedic rehabilitation setting. It is assumed that a patient will choose the option that they prefer (as iy provides the most utility). A Discrete Choice Experiment (DCE) was designed to investigate the factors influencing preference for VC among patients attending orthopaedic rehabilitation. Qualitative interviews were conducted with a small sample of participants to support theorisation into why the identified factors were important. The purpose of this research was to identify factors that influence patient preferences for video consultations in an orthopaedic rehabilitation setting. To explain why these factors influence preference. Methods: Previous research from the CONNECT Project informed DCE development. The design of the DCE took into account best practice guidance (ISPOR good practice for conjoint analysis) during its development. An efficient fractional factorial design with 16 choice scenarios was created that identified all main effects and partial two-way interactions. To reduce the impact of cognitive fatigue the design was blocked into two ‘blocks’ of eight scenarios each. Three pilots were undertaken to refine the questionnaire, to ensure comprehension. Quantitative analysis uses a binary logit regression models. A small number of participants strongly in favour of F2F and VC were sampled for qualitative interview using content analysis to provide additional insight into the results. Results: Two hundred and nineteen and 61 participants completed the ‘Block 1’ and ‘Block 2’ questionnaire, respectively. The study was terminated early due to COVID-19;as paired questionnaires from ‘Block 1’ and ‘Block 2’ were required for analysis, only 61 questionnaires (122 patients) were used. Duration of appointment, time of day, patient qualifications, access to equipment, difficulty with activities, multiple health issues, travel costs significant predictors to preference, were significant predictors of preference. A simplified conceptual model has been developed to explain how these factors interact to inform preference;these include contextual, structural and relationship factors. Eight participants who strongly preferred F2F and five participants who strongly preferred VC were interviewed. These interviews provided underlying rationale for choices. Conclusion(s): We have successfully designed and conducted a discrete choice experiment that investigated the trade-offs between pathway factors for patients attending orthopaedic rehabilitation appointments. A conceptual model was designed to focus attention towards the factors that influences preferences. Impact: An understanding of factors, such as those identified from this study, will enable clinicians to identify patients who prefer virtual consultations. The model developed from this study can inform the development of future technologies, trials and qualitative work to further explore the mechanisms that influence preference. Funding acknowledgements: Anthony Gilbert is funded by a Health Education England (HEE) and National Institute for Health Research (NIHR), Clinical Doctoral Research Fellowship for this research project (ICA-CDRF-2017-03-025).

Keywords: Patient preferences, Virtual consultations, Musculoskeletal Purpose: Videoconferencing (VC) technologies, such as Skype, Zoom, Attend Anywhere and MS Teams, have been received enthusiastically by healthcare policy makers as they provide a medium to improve access to care. Communication technologies such as videoconferencing is being used across many fields of healthcare and can offer advantages to patients. Previous research into Skype consultations in healthcare found that they were safe, effective and convenient for patients when healthcare professionals judged them clinically appropriate. Skype has been shown to be acceptable to half of patients in our previously published work. A preference is defined as an individualised 'total subjective comparative evaluation'. Put simply, an individual weighs up the state of affairs of the alternatives. Preference theory suggests that a person will prefer the outcome that yields increased utility, and therefore that patients would prefer a VC if they believe its benefits outweigh its burdens. To date, patient preferences for telemedicine have only been investigated at a general population level. To our knowledge, the factors underpinning patient preferences have not yet been investigated for virtual physiotherapy rehabilitation consultations. The purpose of this study was to identify characterize and explain factors that influence patient preferences for video consultations in an orthopaedic rehabilitation setting. Methods: This was a Qualitative study using semi-structured interviews and abductive analysis. Participants were: patients who were receiving orthopaedic rehabilitation for a musculoskeletal problem; Occupational therapists, physiotherapists or therapy technicians involved in the delivery of orthopaedic rehabilitation for patients with a musculoskeletal problem. All participants were recruited from a physiotherapy and occupational therapy department situated within a tertiary orthopaedic centre in the UK. Results: Twenty-two patients and 22 healthcare professionals were interviewed. The average interview length was 48 minutes. Four major factors were found to influence preference: the situation (the ways that patients understand and explain their clinical status, their treatment requirements, and the care pathway); the expectations of care (influenced by a patient's desire for contact, psychological status, previous care and perceived requirements); the demands (of care, of each patient's respective social situation and the consequences of choice); and the capacity (the patient's ability to allocate resources to care; these include financial, infrastructural, social and healthcare resources). These factors combined and competed with each other to influence preference. Conclusion(s): This study has identified key factors that appear to influence patient preference for video-conferenced consultations in orthopaedic rehabilitation. Sensitising questions have been developed to support the formation of preference for patients. A conceptual model of these factors, derived from empirical data, has been developed highlighting how they combine and compete. Impact: A better understanding of influencing mechanisms on patient preferences is needed to support the design of patient centered communication technology pathways. An understanding of factors, such as those identified from this study, will enable clinicians to identify patients who prefer virtual consultations. Funding acknowledgements: Anthony Gilbert is funded by a Health Education England (HEE) and National Institute for Health Research (NIHR), Clinical Doctoral Research Fellowship for this research project (ICA-CDRF-2017-03-025).

Background/Aims Physiotherapy consultations in an orthopaedic setting often require visualisation and a ‘hands on’ approach. There has been an increasing number of research studies exploring the effectiveness and acceptability of telephone and videoconferencing consultations within orthopaedics. Much of the drive behind this change has been to improve access to care and to link the clinic to the home environment. The introduction of communication technology consultations requires a shift in patient workload, which may impact on patient experience of accessing healthcare and managing their condition. The purpose of this research is to systematically review qualitative papers reporting communication technology consultations (phone and videoconference) in orthopaedics. Attention will be focused towards the effect of communication technology on the workload of being a patient. Methods The protocol for the systematic review was registered and is available to view on the PROSPERO database (CRD42018100896). MEDLINE, AMED, CINAHL, PsychINFO, SCOPUS databases were independently searched, using the search strategy, by two researchers to identify qualitative papers reporting communication technology use in an orthopaedics setting. Data from Introduction, Results and Discussion sections were extracted and an attribution of statements formulated. All statements were thematically analysed into families of themes surrounding patient workload. Results The search identified 1542 papers that were included for review and eight full texts met the inclusion criteria and were included for analysis. Two studies reported telephone consultations and six reported real time videoconferencing consultations. Six families of themes were identified: (1) skills; (2) clinical interactions; (3) environment; (4) processes; (5) impact on patient; (6) preferences. Conclusions Literature on the use of communication technologies in healthcare, such as videoconferencing and telephone consultations, is growing in orthopaedics. Qualitative papers highlight the benefits and challenges of communication technology consultations. This review synthesises the change in the workload that patient's face when using these technologies. These altered demands of communication technology consultations affect the patient's experience of accessing healthcare. Consideration of these factors and tailored individualised support for patients may enhance the patient experience and increase suitability of communication technology consultations for orthopaedic patients.

INTRODUCTION:Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. METHODS AND ANALYSIS:The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for 18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. ETHICS AND DISSEMINATION:Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals. TRIAL REGISTRATION NUMBER:ISRCTN30784948; Pre-results.

Background: Idiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease that generally affects people over 60 years old. The main symptoms are shortness of breath and cough, and as the disease progresses there is a considerable impact on day-to-day life. Few treatments are currently available. Objectives: To conduct a systematic review of clinical effectiveness and an analysis of cost-effectiveness of treatments for IPF based on an economic model informed by systematic reviews of cost-effectiveness and quality of life. Data sources: Eleven electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, and The Cochrane Library and the Centre for Reviews and Dissemination databases, were searched from database inception to July 2013. Reference lists of relevant publications were also checked and experts consulted. Methods: Two reviewers independently screened references for the systematic reviews, extracted and checked data from the included studies and appraised their risk of bias. An advisory group was consulted about the choice of interventions until consensus was reached about eligibility. A narrative review with meta-analysis was undertaken, and a network meta-analysis (NMA) was performed. A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Parameter values were obtained from NMA and systematic reviews. Univariate and probabilistic sensitivity analyses were undertaken. The model perspective is NHS and Personal Social Services, and discount rate is 3.5% for costs and health benefits. Results: Fourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, three N-acetylcysteine (NAC) (alone or in combination), four pirfenidone, one BIBF 1120, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good, with a low risk of bias. The current evidence suggests that some treatments appear to be clinically effective. The model base-case results show increased survival for five pharmacological treatments, compared with best supportive care, at increased cost. General recommendations cannot be made of their cost-effectiveness owing to limitations in the evidence base. Limitations: Few direct comparisons of treatments were identified. An indirect comparison through a NMA was performed; however, caution is recommended in the interpretation of these results. In relation to the economic model, there is an assumption that pharmacological treatments have a constant effect on the relative rate of per cent predicted forced vital capacity decline. Conclusions: Few interventions have any statistically significant effect on IPF and a lack of studies on palliative care approaches was identified. Research is required into the effects of symptom control interventions, in particular pulmonary rehabilitation and thalidomide. Other research priorities include a well-conducted randomised controlled trial on inhaled NAC therapy and an updated evidence synthesis once the results of ongoing studies are reported. Study registration: This study is registered as PROSPERO CRD42012002116. Funding: The National Institute for Health Research Health Technology Assessment programme.

Rationale: Severe sepsis and septic shock are associated with high morbidity and mortality. Our institution initiated an interdisciplinary approach towards identifying and managing sepsis that included a sepsis screening tool to be used by nursing staff to assist in rapidly identifying intensive care unit (ICU) patients with severe sepsis and septic shock. The objective of this study was to determine the percentage of patients ultimately diagnosed with severe sepsis or septic shock who were first identified by the ICU sepsis screening tool. Methods: In July 2012, we implemented a bedside screening tool utilized by nurses once each shift designed for the prompt identification of patients with sepsis. The tool begins by identifying any criteria for the systemic inflammatory response syndrome (SIRS). In the presence of two or more SIRS criteria, the nursing staff is directed to notify providers. The screening instrument was made in a “stop” and “go” fashion that transitioned between SIRS to septic shock. The tool was used by nurses in the medical intensive care unit (MICU) and cardiac intensive care unit (CICU). After four weeks, patients who were admitted to the ICUs with at least one completed sepsis screening tool were reviewed to determine if the tool allowed an earlier diagnosis of severe sepsis or septic shock in any of the patients. Results: A total number of 522 sepsis screening sheets were collected in four weeks from 188 patients who were admitted to the CICU and 65 ± 14 and 43% were female. The 36 (19%) ICU patients diagnosed with severe sepsis or septic shock had MICU. The average age was average SOFA II scores of 5.5 ± 4.9. Of those, 23 (64%) entered the ICU with a diagnosis of severe sepsis or septic shock whereas the remaining 13 (36%) were first diagnosed with severe sepsis by the sepsis screening tool. These latter patients were initially admitted with other diagnoses (e.g. medication overdose, diabetic ketoacidosis, gastrointestinal bleeding). Conclusion: These data suggest that the implementation of a nursing-driven sepsis screening tool resulted in an earlier identification of severe sepsis and septic shock in more than one third of patients admitted to the ICU with these critical diagnoses. If this translates into a more rapid implementation of appropriate therapy, the use of this screening tool could improve survival in patients with severe sepsis or septic shock.

The capillary isotachophoresis (cITP) separation of the isomers of the tricyclic antidepressant doxepin using β-cyclodextrin (β-CD) as a buffer additive is investigated by online microcoil NMR detection. Capillary electrophoresis (CE) is also used to determine the binding constant between the doxepin E and Z geometric isomers and β-CD. Although the doxepin isomers could be easily baseline resolved by CE, their separation by cITP was more challenging due in part to the high concentration of doxepin after cITP-focusing. The use of online (1)H NMR detection allows observation of changes in doxepin dynamics due to formation of the β-CD inclusion complex, changes in the fraction complexed and the intracapillary pH. It also provides novel experimental evidence that a weak complex between β-CD and acetate contributes to its active transport from the leading electrolyte through the sample band to the trailing electrolyte in this cationic cITP separation. The results of these cITP-NMR experiments provide new mechanistic details about the interactions of the buffer counterion acetate with various components of the separation system and have important implications for other analyses based on formation of cyclodextrin inclusion complexes.

Diffusion NMR is a useful method for the analysis of mixtures, providing information about the number of components as well as insight into their relative sizes. This work explores the use of diffusion-edited NMR measurements for the identification of the glycosaminoglycan impurities dermatan sulfate (DS), chondroitin sulfate (CS), and oversulfated chondroitin sulfate (OSCS) in solutions of heparin subjected to enzymatic digestion. Enzymatic digestion significantly improves the resolution of the biopolymer impurities in diffusion-edited H-1 NMR spectra facilitating identification of high molecular weight contaminants.

Glycosaminoglycans (GAGs) are a class of biopolymers that include chondrotin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, heparin, and heparan sulfate. The GAGs are linear polysaccharides that are microheterogeneous in composition and polydisperse in size. Because they have the most complex structures, this article is aimed at describing a step-by-step procedure for processing and analyzing heparin and heparan sulfate-derived oligosaccharides, although the basic protocols and procedures apply equally well to other members of the GAG family. The methods described in this manuscript include the preparation of oligosaccharides through enzymatic depolymerization, size fractionation by preparative scale size-exclusion chromatography (SEC), and disaccharide isomer analysis by reverse-phase ion-pair high-performance liquid chromatography (RPIP-HPLC) and capillary electrophoresis (CE).

Reverse-phase ion-pair high-performance liquid chromatography (RPIP-HPLC) is an increasingly popular chromatographic technique for the separation of charged compounds, including oligosaccharides derived from the glycosaminoglycans (GAGs) heparin and heparan sulfate (HS). This family of heparin disaccharides has been shown to be useful compounds to probe the details of the RPIP-HPLC separation mechanism, the aspects of which are still being debated. In this manuscript, the effects of ion-pairing reagent (IPR) concentration, counterion, and mobile phase pH on the quality of the RPIP-UPLC separation were examined with particular emphasis on how these factors impact the separation of the disaccharide anomers. These results highlight the role of the IPR counterion and demonstrate that the resolution of the disaccharide anomers can be minimized by conducting the separation at low pH, simplifying chromatographic analysis and improving resolution. The results presented herein can also provide insights into strategies for developing more sensitive and efficient reverse-phase separations for other charged analytes including larger GAG oligosaccharides.

The structural complexity and microheterogeneity of the glycosaminoglycans heparin and heparan sulfate make their characterization a daunting task. The methodology described herein utilizes a combination of enzymatic digestion, size-exclusion chromatography, strong anion-exchange HPLC, reverse-phase ion-pair ultrahigh performance liquid chromatography–mass spectrometry, and microcoil NMR for the efficient sequencing of heparin-derived tetrasaccharides. The high mass sensitivity of microcoil NMR makes this technique well suited for the characterization of mass-limited samples removing a bottleneck in the analysis workflow and permitting structural characterization of minor components isolated from a heparin enzymatic digestion. Complete characterization of one tetrasulfonated, five pentasulfonated isomers and two hexasulfonated tetrasaccharide sequences is described. To our knowledge, two of the identified minor tetrasaccharides are unique, and have not been previously reported: IdoA(2S)-GlcNS(6S)-IdoA(2S)-GlcNS(6S) and ΔUA(2S)-GlcNS(6S)-IdoA-GlcNS(6S).