“Take more laxatives was their answer to everything.”:A qualitative exploration of the patient, carer and healthcare professional experience of constipation in specialist palliative care

Constipation is a major problem for many older adults, more so for those who are receiving specialist palliative care. However, limited research reports the subjective experiences of constipation, despite evidenced differences between the healthcare professional and patient/carer perspective. The main aim of this study is to explore the experience of how constipation is assessed and managed within specialist palliative care from the patient, carer and healthcare professional perspective. Exploratory, qualitative design, utilising focus groups and interviews, and analysed using thematic analysis. Six focus groups with 27 healthcare professionals and semi-structured interviews with 13 patients and 5 family caregivers in specialist palliative care units across three regions of the United Kingdom. Constipation impacted physically, psychologically and socially on patients and families; however, they felt staff relegated it on the list of importance. Lifestyle modifications implemented at home were not incorporated into their specialist palliative care plan within the hospice. Comparatively, healthcare professionals saw constipation solely as a physical symptom. Assessment focused on the physical elements of constipation, and management was pharmacologically driven. Healthcare professionals reported patient embarrassment as a barrier to communicating about bowel care, whereas patients wanted staff to initiate communication and discuss constipation openly. Assessment and management of constipation may not yet reflect the holistic palliative care model. A focus on the pharmacological management may result in lifestyle modifications being underutilised. Healthcare professionals also need to be open to initiate communication on bowel care and consider non-pharmacological approaches. It is important that patients and families are supported in self-care management, alongside standardised guidelines for practice and for healthcare professionals to facilitate this

Cytosponge-trefoil factor 3 versus usual care to identify Barrett’s oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial

BACKGROUND: Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management. METHODS: This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed. FINDINGS: Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13 657 eligible patients who were sent an introductory letter with 14 days to opt out. 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 [95%]; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18·3 per 1000 person-years [95% CI 14·8-21·8]; rate ratio adjusted for cluster randomisation 10·6 [95% CI 6·0-18·8], p<0·0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants. INTERPRETATION: In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results. FUNDING: Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council.Funding The BEST3 study was primarily funded by Cancer Research UK (CRUK). National Institute for Health Research (NIHR) covered service support costs; NHS commissioners funded excess treatment costs; Medtronic funded Cytosponge devices and TFF3 antibodies. CRUK provide funding to The Cancer Prevention Trials Unit and the Medical Research Council to the MRC Cancer Unit

Barrett’s oESophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of oesophageal pre-cancer in primary care patients with chronic acid reflux

Abstract Background Early detection of oesophageal cancer improves outcomes; however, the optimal strategy for identifying patients at increased risk from the pre-cancerous lesion Barrett’s oesophagus (BE) is not clear. The Cytosponge, a novel non-endoscopic sponge device, combined with the biomarker Trefoil Factor 3 (TFF3) has been tested in four clinical studies. It was found to be safe, accurate and acceptable to patients. The aim of the BEST3 trial is to evaluate if the offer of a Cytosponge-TFF3 test in primary care for patients on long term acid suppressants leads to an increase in the number of patients diagnosed with BE. Methods The BEST3 trial is a pragmatic multi-site cluster-randomised controlled trial set in primary care in England. Approximately 120 practices will be randomised 1:1 to either the intervention arm, invitation to a Cytosponge-TFF3 test, or the control arm usual care. Inclusion criteria are men and women aged 50 or over with records of at least 6 months of prescriptions for acid-suppressants in the last year. Patients in the intervention arm will receive an invitation to have a Cytosponge-TFF3 test in their general practice. Patients with a positive TFF3 test will receive an invitation for an upper gastro-intestinal endoscopy at their local hospital-based endoscopy clinic to test for BE. The primary objective is to compare histologically confirmed BE diagnosis between the intervention and control arms to determine whether the offer of the Cytosponge-TFF3 test in primary care results in an increase in BE diagnosis within 12 months of study entry. Discussion The BEST3 trial is a well-powered pragmatic trial testing the use of the Cytosponge-TFF3 test in the same population that we envisage it being used in clinical practice. The data generated from this trial will enable NICE and other clinical bodies to decide whether this test is suitable for routine clinical use. Trial registration This trial was prospectively registered with the ISRCTN Registry on 19/01/2017, trial number ISRCTN68382401

Cytosponge-trefoil factor 3 versus usual care to identify Barrett’s oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial

BACKGROUND: Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management. METHODS: This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed. FINDINGS: Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13 657 eligible patients who were sent an introductory letter with 14 days to opt out. 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 [95%]; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18·3 per 1000 person-years [95% CI 14·8-21·8]; rate ratio adjusted for cluster randomisation 10·6 [95% CI 6·0-18·8], p<0·0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants. INTERPRETATION: In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results. FUNDING: Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council.Funding The BEST3 study was primarily funded by Cancer Research UK (CRUK). National Institute for Health Research (NIHR) covered service support costs; NHS commissioners funded excess treatment costs; Medtronic funded Cytosponge devices and TFF3 antibodies. CRUK provide funding to The Cancer Prevention Trials Unit and the Medical Research Council to the MRC Cancer Unit

Rectification of the Water Permeability in COS-7 Cells at 22, 10 and 0°C

The osmotic and permeability parameters of a cell membrane are essential physico-chemical properties of a cell and particularly important with respect to cell volume changes and the regulation thereof. Here, we report the hydraulic conductivity, Lp, the non-osmotic volume, Vb, and the Arrhenius activation energy, Ea, of mammalian COS-7 cells. The ratio of Vb to the isotonic cell volume, Vc iso, was 0.29. Ea, the activation energy required for the permeation of water through the cell membrane, was 10,700, and 12,000 cal/mol under hyper- and hypotonic conditions, respectively. Average values for Lp were calculated from swell/shrink curves by using an integrated equation for Lp. The curves represented the volume changes of 358 individually measured cells, placed into solutions of nonpermeating solutes of 157 or 602 mOsm/kg (at 0, 10 or 22°C) and imaged over time. Lp estimates for all six combinations of osmolality and temperature were calculated, resulting in values of 0.11, 0.21, and 0.10 µm/min/atm for exosmotic flow and 0.79, 1.73 and 1.87 µm/min/atm for endosmotic flow (at 0, 10 and 22°C, respectively). The unexpected finding of several fold higher Lp values for endosmotic flow indicates highly asymmetric membrane permeability for water in COS-7. This phenomenon is known as rectification and has mainly been reported for plant cell, but only rarely for animal cells. Although the mechanism underlying the strong rectification found in COS-7 cells is yet unknown, it is a phenomenon of biological interest and has important practical consequences, for instance, in the development of optimal cryopreservation

Change and Exchange: Economies of Literature and Knowledge in Early Modern Europe

The introductory essay outlines the way in which Change and Exchange places literature, and, in a wider sense, imaginative practice, at the centre of early modern economic knowledge. Probing the affinity between economic and metaphorical experience in terms of the transactional processes of change and exchange, it sets up the parameters within which the essays in the volume collectively forge a language to grasp early modern economic phenomena and their epistemic dimensions. It prepares the reader for the stimulating combination of materials that the book presents: the range of generic contexts engendered by emergent economic practices, structures of feeling and modes of knowing made available by new economic relations, and economies of transformation in discursive domains that are distinct from ‘economics’ as we understand it but cognate in their intuition of change and exchange as shaping agents

The effect of cartilage and bone density of mushroom-shaped, photooxidized, osteochondral transplants: an experimental study on graft performance in sheep using transplants originating from different species

BACKGROUND: Differences in overall performance of osteochondral photooxidized grafts were studied in accordance of their species origin and a new, more rigorous cleansing procedure using alcohol during preparation. METHODS: Photooxidized mushroom-shaped grafts of bovine, ovine, human and equine origin were implanted in the femoral condyles of 32 sheep (condyles: n = 64). No viable chondrocytes were present at the time of implantation. Grafts were evaluated at 6 months using plastic embedded sections of non-decalcified bone and cartilage specimens. Graft incorporation, the formation of cyst-like lesions at the base of the cartilage junction as well as cartilage morphology was studied qualitatively, semi-quantitatively using a score system and quantitatively by performing histomorphometrical measurements of percentage of bone and fibrous tissue of the original defects. For statistical analysis a factorial analysis of variance (ANOVA- test) was applied. RESULTS: Differences of graft performance were found according to species origin and cleansing process during graft preparation. According to the score system cartilage surface integrity was best for equine grafts, as well as dislocation or mechanical stability. The equine grafts showed the highest percentage for bone and lowest for fibrous tissue, resp. cystic lesions. The new, more rigorous cleansing process decreased cartilage persistence and overall graft performance. CONCLUSION: Performance of grafts from equine origin was better compared to bovine, ovine and human grafts. The exact reason for this difference was not proven in the current study, but could be related to differences in density of cartilage and subchondral bone between species