Supportive and palliative care needs in advanced non-malignant liver disease: systematic review.

Advanced cirrhosis confers a significant symptom burden and has a 50% 2-year mortality rate in those with decompensated disease. There is increasing demand for supportive and palliative care (SAPC) for these patients, yet no consensus on the best model of delivery. It is necessary to identify the needs of such patients and their carers, and evaluate whether they are being met.A literature search was conducted using key words pertaining to adult patients with liver cirrhosis and their SAPC needs. Study quality was assessed and findings grouped by theme. 51 full texts were selected for inclusion, 8 qualitative studies, 33 quantitative studies, 7 systematic reviews, 2 mixed methods studies and 1 Delphi methods. Key findings were grouped into three main themes: SAPC needs, access to SAPC and models of care.Patients with cirrhosis have significant psychological and physical symptom burden with many unmet needs. These data failed to identify the best service model of care. The impact of specialist palliative care (SPC) referral was limited by small numbers and late referrals. With the majority of studies conducted in the USA, it is unclear how well these findings translate to other healthcare systems. Comparison between hepatology led services and SPC was limited by inconsistent outcome measures and prevented pooling of data sets. These data also had limited evaluation of patient-reported outcome measures. We propose the development of a core outcome set to ensure consistent and meaningful evaluation of the SAPC needs of patients with advanced non-malignant liver cirrhosis.

Additive manufacturing of patient specific bolus for radiotherapy: large scale production and quality assurance.

Bolus is commonly used to improve dose distributions in radiotherapy in particular if dose to skin must be optimised such as in breast or head and neck cancer. We are documenting four years of experience with 3D printed bolus at a large cancer centre. In addition to this we review the quality assurance (QA) program developed to support it. More than 2000 boluses were produced between Nov 2018 and Feb 2023 using fused deposition modelling (FDM) printing with polylactic acid (PLA) on up to five Raise 3D printers. Bolus is designed in the radiotherapy treatment planning system (Varian Eclipse), exported to an STL file followed by pre-processing. After checking each bolus with CT scanning initially we now produce standard quality control (QC) wedges every month and whenever a major change in printing processes occurs. A database records every bolus printed and manufacturing details. It takes about 3 days from designing the bolus in the planning system to delivering it to treatment. A 'premium' PLA material (Spidermaker) was found to be best in terms of homogeneity and CT number consistency (80 HU +/- 8HU). Most boluses were produced for photon beams (93.6%) with the rest used for electrons. We process about 120 kg of PLA per year with a typical bolus weighing less than 500 g and the majority of boluses 5 mm thick. Print times are proportional to bolus weight with about 24 h required for 500 g material deposited. 3D printing using FDM produces smooth and reproducible boluses. Quality control is essential but can be streamlined.

Techno-Economic and life cycle assessment of standalone Single-Stream material recovery facilities in the United states.

Material Recovery Facilities (MRFs) are crucial players in achieving a circular economy. MRFs receive complex waste streams and separate valuable recyclables from these mixtures. This study conducts techno-economic analysis (TEA) to estimate the net present value (NPV) and life cycle assessment (LCA) to estimate different environmental impacts of a commercial scale standalone, single-stream MRF to assess the economic feasibility and environmental impacts of recovering valuable recyclables from an MRF processing 120,000 tonnes per year (t/y). The TEA employs a discounted cash flow rate of return (DCFROR) analysis over a 20-year facility lifetime, along with a sensitivity analysis on the impact of different operating and economic parameters. Results show that the total fixed cost of building the MRF facility is $23 MM, and the operating cost is $45.48/tonne. The NPV of the MRF can vary from $3.57 MM to $60 MM, while 100-year global warming potential can range from 5.98 to 8.53 kg carbon dioxide equivalents (CO2-eq) per tonne of MSW. We have also found that MSW composition (arising from regional effects) significantly impacts costs, 100-year global warming potential, and other impact categories such as acidification potential, eutrophication potential, ecotoxicity, ozone depletion, photochemical oxidation, carcinogenic effects, and non-carcinogenic effects. Sensitivity and uncertainty analysis indicate that waste composition and market prices significantly impact the profitability of the MRF, and the waste composition mostly impacts global warming potential. Our analysis also indicates that facility capacity, fixed capital cost, and waste tipping fees are vital parameters that affect the economic viability of MRF operations.

Towards using 3D cellular cultures to model the activation and diverse functions of macrophages.

The advent of 3D cell culture technology promises to enhance understanding of cell biology within tissue microenvironments. Whilst traditional cell culturing methods have been a reliable tool for decades, they inadequately portray the complex environments in which cells inhabit in vivo. The need for better disease models has pushed the development of effective 3D cell models, providing more accurate drug screening assays. There has been great progress in developing 3D tissue models in fields such as cancer research and regenerative medicine, driven by desires to recreate the tumour microenvironment for the discovery of new chemotherapies, or development of artificial tissues or scaffolds for transplantation. Immunology is one field that lacks optimised 3D models and the biology of tissue resident immune cells such as macrophages has yet to be fully explored. This review aims to highlight the benefits of 3D cell culturing for greater understanding of macrophage biology. We review current knowledge of macrophage interactions with their tissue microenvironment and highlight the potential of 3D macrophage models in the development of more effective treatments for disease.

The effect of COVID-19 on orthopaedics in Aotearoa New Zealand-a survey of orthopaedic surgeons and training registrars.

AIM: This study aimed to assess the impact of COVID-19 on orthopaedic practice in New Zealand, with a focus on training and mental health. METHODS: An online survey was sent to the 385 consultant orthopaedic surgeons and registrars in New Zealand registered with the New Zealand Orthopaedic Association (NZOA). The survey consisted of 27 questions relating to demographics, the effects of COVID-19 on orthopaedic departments, on training, on mental health and the utilisation of telehealth and online teaching. RESULTS: In total, 189 of 385 NZOA members (49%) completed the survey. Of the 51 orthopaedic registrars surveyed, 55% felt that their training had been moderately affected, while 17% felt it had been significantly affected. Of those surveyed, 65% felt the pandemic had at least a mild effect on their mental health. Seven percent of registrars described a significant impact on their mental health compared to 2% of consultants (p=0.029). Overall, 46.5% felt they were more burnt out because of the pandemic, which was significantly higher in registrars compared to consultants (51% vs 44%, respectively; p=0.029). CONCLUSIONS: Despite the comparatively low number of COVID-19 cases, hospitalisations and deaths, the effects for orthopaedic surgeons and training registrars have been significant.

Initial United Kingdom experience of endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography.

Backgrounds/Aims: Gallstone disease is a recognized complication of bariatric surgery. Subsequent management of choledocholithiasis may be challenging due to altered anatomy which may include Roux-en-Y gastric bypass (RYGB). We conducted a retrospective service evaluation study to assess the safety and efficacy of endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) in patients with RYGB anatomy. Methods: All the patients who underwent EDGE for endoscopic retrograde cholangiopancreatography after RYGB at two tertiary care centers in the United Kingdom between January 2020 and October 2021 were included in the study. Clinical and demographic details were recorded for all patients. The primary outcome measures were technical and clinical success. Adverse events were recorded. Hot Axios lumen apposing metal stents measuring 20 mm in diameter and 10 mm in length were used in all the patients for creation of a gastro-gastric or gastro-jejunal fistula. Results: A total of 14 patients underwent EDGE during the study period. The majority of the patients were female (85.7%) and the mean age of patients was 65.8 ± 9.8 years. Technical success was achieved in all but one patient at the first attempt (92.8%) and clinical success was achieved in 100% of the patients. Complications arose in 3 patients with 1 patient experiencing persistent fistula and weight gain. Conclusions: In patients with RYGB anatomy, EDGE facilitated biliary access has a high rate of clinical success with an acceptable safety profile. Adverse events are uncommon and can be managed endoscopically.

Tetraspanin CD53 controls T cell immunity through regulation of CD45RO stability, mobility, and function.

T cells depend on the phosphatase CD45 to initiate T cell receptor signaling. Although the critical role of CD45 in T cells is established, the mechanisms controlling function and localization in the membrane are not well understood. Moreover, the regulation of specific CD45 isoforms in T cell signaling remains unresolved. By using unbiased mass spectrometry, we identify the tetraspanin CD53 as a partner of CD45 and show that CD53 controls CD45 function and T cell activation. CD53-negative T cells (Cd53-/-) exhibit substantial proliferation defects, and Cd53-/- mice show impaired tumor rejection and reduced IFNγ-producing T cells compared with wild-type mice. Investigation into the mechanism reveals that CD53 is required for CD45RO expression and mobility. In addition, CD53 is shown to stabilize CD45 on the membrane and is required for optimal phosphatase activity and subsequent Lck activation. Together, our findings reveal CD53 as a regulator of CD45 activity required for T cell immunity.

Poor compliance documenting informed consent in trauma patients with distal radius fractures compared to elective total knee arthroplasty.

BACKGROUND: The purpose of this study was (1) to evaluate the adequacy of informed consent documentation in the trauma setting for distal radius fracture surgery compared with the elective setting for total knee arthroplasty (TKA) at a large public hospital and (2) to explore the relevant guidelines in New Zealand relating to consent documentation. METHODS: Consecutive adult patients (≥16 years) undergoing operations for distal radius fractures and elective TKA over a 12-month period in a single-centre were retrospectively identified. All medical records were reviewed for the risks and complications recorded. The consent form was analysed using the Flesch Reading Ease Score (FRES) and the Simple Measure of Gobbledygook (SMOG) index readability scores. RESULTS: A total of 133 patients undergoing 134 operations for 135 distal radius fractures and 239 patients undergoing 247 TKA were included. Specific risks of surgery were recorded significantly less frequently for distal radius fractures than TKA (43.3% versus 78.5%, P < 0.001). Significantly fewer risks were recorded in the trauma setting compared to the elective (2.35 ± 2.98 versus 4.95 ± 3.33, P < 0.001). The readability of the consent form was 40.5 using the FRES and 10.9 using the SMOG index, indicating a university undergraduate level of reading. CONCLUSIONS: This study has shown poor compliance in documenting risks of surgery during the informed consent process in an acute trauma setting compared to elective arthroplasty. Institutions must prioritize improving documentation of informed consent for orthopaedic trauma patients to ensure a patient-centred approach to healthcare.

Discordance in STING-Induced Activation and Cell Death Between Mouse and Human Dendritic Cell Populations.

Stimulator of Interferon Genes (STING) is a cytosolic sensor of cyclic dinucleotides (CDNs). The activation of dendritic cells (DC) via the STING pathway, and their subsequent production of type I interferon (IFN) is considered central to eradicating tumours in mouse models. However, this contribution of STING in preclinical murine studies has not translated into positive outcomes of STING agonists in phase I & II clinical trials. We therefore questioned whether a difference in human DC responses could be critical to the lack of STING agonist efficacy in human settings. This study sought to directly compare mouse and human plasmacytoid DCs and conventional DC subset responses upon STING activation. We found all mouse and human DC subsets were potently activated by STING stimulation. As expected, Type I IFNs were produced by both mouse and human plasmacytoid DCs. However, mouse and human plasmacytoid and conventional DCs all produced type III IFNs (i.e., IFN-λs) in response to STING activation. Of particular interest, all human DCs produced large amounts of IFN-λ1, not expressed in the mouse genome. Furthermore, we also found differential cell death responses upon STING activation, observing rapid ablation of mouse, but not human, plasmacytoid DCs. STING-induced cell death in murine plasmacytoid DCs occurred in a cell-intrinsic manner and involved intrinsic apoptosis. These data highlight discordance between STING IFN and cell death responses in mouse and human DCs and caution against extrapolating STING-mediated events in mouse models to equivalent human outcomes.

Tarsoconjunctival 'Hughes' flap for repair of globe perforation: A modified technique in the management of severe scleral necrosis.

We report an unusual case of scleral and lid necrosis from suspected self-harm and the management of the resultant scleral perforation with a tarsoconjunctival 'Hughes' flap. To our knowledge, no previous literature describes such a technique in the repair of toxic scleral melts. Our case describes an alternative use for a Hughes flap in providing tectonic support and helping to restore the integrity of the globe in a complex case where conventional methods of 'patching' had failed.

Attitudes to radiation safety and cholangiogram interpretation in endoscopic retrograde cholangiopancreatography (ERCP): a UK survey.

BACKGROUND: Fluoroscopy during endoscopic retrograde cholangiopancreatography (ERCP) exposes staff and patients to potentially harmful ionizing radiation. We performed a UK survey to explore trainee and trainer attitudes to radiation protection and cholangiogram interpretation in ERCP. METHODS: An electronic 10-point survey was prospectively distributed to endoscopy unit leads, training programme directors between October and November 2019. Only UK-based ERCP trainees and trainers with hands-on procedural exposure were eligible for the survey. RESULTS: The survey was completed by 107 respondents (58 trainees and 49 trainers), with an estimated overall response rate of 46%. Overall, 49% of respondents were up to date with their radiation protection course, 38% were aware of European Basic safety standards directive (BSSD), 38% wore radiation protection goggles, and 40% were aware of the average radiation screening dose per ERCP procedure. Compared with trainers, trainees were less likely to routinely wear thyroid protection shields (76% vs 92%; p=0.028), have awareness of the BSSD (20% vs 49%; p=0.037) or know their average procedural radiation dosages (21% vs 63%; p<0.001). With regard to cholangiogram interpretation, only 26% had received formal training, with 97% of trainees expressing a desire for further training. CONCLUSION: This survey highlights a relative complacency in safety attitudes to radiation protection during ERCP. These data provide impetus to improve training and quality assurance in radiation protection, which should be regarded as a mandatory safety aspect prior to commencing hands-on ERCP training.

Management of infected post-pancreatic resection fluid collections under endoscopic ultrasound guidance using lumen apposing metal stent: A case series and review of the literature.

BACKGROUNDS/AIMS: Post-operative pancreatic fistulas (POPF) and fluid collections (POPFC) remain significant sources of morbidity and mortality after pancreatic resections. There remains a paucity of literature describing endoscopic ultrasound (EUS) guided drainage of POPFC using a Hot AXIOS™ lumen apposing metal stent (LAMS). METHODS: We conducted a retrospective study, encompassing all consecutive patients with POPFC managed using Hot AXIOS™ LAMS at our institution between January 2017 and December 2019. Primary outcome measures were technical and clinical success. Secondary outcome measures were adverse events and recurrence rates. RESULTS: Five patients underwent EUS guided drainage using Hot AXIOS™ LAMS during the study period. Mean age of patients was 67.8 ± 2.16 years. The majority (60.0%) of patients were males. Median duration of symptom onset after surgery was 9 days. All patients presented with abdominal pain. Median size of the collection measured on computed tomography was 91 mm. Median interval time between symptom onset and EUS drainage was 30 days. Two patients required percutaneous drainage prior to EUS guided drainage. Technical and clinical success were achieved for all patients. No adverse events were observed. Median duration of follow-up was 90 days. No recurrence of collection occurred during the follow-up period. CONCLUSIONS: EUS guided drainage of POPFC using Hot AXIOS™ LAMS is a safe and effective treatment modality with technical and clinical success rates of 100% in our experience.

Time domain principal component analysis for rapid, real-time 2D MRI reconstruction from undersampled data.

PURPOSE: A rapid real-time 2D accelerated method was developed for magnetic resonance imaging (MRI) using principal component analysis (PCA) in the temporal domain. This method employs a moving window of previous dynamic frames to reconstruct the current, real-time frame within this window. This technique could be particularly useful in real-time tracking applications such as in MR-guided radiotherapy, where low latency real-time reconstructions are essential. METHODS: The method was tested retrospectively on 15 fully-sampled data sets of lung patient data acquired on a 3T Philips Achieva system. High frequency data are incoherently undersampled, while the central low-frequency data are always acquired to characterize the temporal fluctuations through PCA. The undersampling pattern is derived in such a way that all of k-space is acquired within a pre-determined number of frames. The missing data in the current frame are then filled in by fitting the temporal characterizations to the acquired undersampled data, using a pre-determined number of PCs. A subset of six patients was used to test the contour ability of the images. Various accelerations between 3x and 8x were tested along with the optimal number of PCs for fitting. A comparison was also performed with previous work from our group proposed by Dietz et al. as well as with a standard low resolution acquisition. In order to determine how the method would perform at lower signal to noise ratio (SNR), noise levels of 2×, 4×, and 6× were added to the 3T data. Metrics such as normalised mean square error and Dice coefficient were used to measure the reconstruction image quality and contour ability. RESULTS: The proposed method demonstrated good temporal robustness as consistent metrics were detected for the duration of the imaging session. It was found that the optimal number of PCs for temporal fitting was dependent on the acceleration rate. For the data tested, five PCs were found to be optimal at the acceleration rates of 3× and 4×. This number decreases to three at accelerations of 5× and 6× and further decreases to two at an acceleration rate of 8×, likely due to greater instability with fewer acquired data points. The use of too many PCs for fitting increased the chances of noisy reconstruction which affected contourability. CONCLUSIONS: The proposed 2D real-time MR acceleration method demonstrated greater robustness in the metrics over time when compared with previous real-time PCA methods using metrics such as normalised mean squared error, peak SNR and structural similarity up to an acceleration of 8x. Improved temporal robustness of image structure contourability and accurate definition was also demonstrated using several metrics including the Dice coefficient. Reconstruction of raw acquired data can be performed at approximately 50 ms per frame using an Intel core i5 CPU. The method has the advantage of being very flexible in terms of hardware requirements as it can operate successfully on a single coil channel and does not require specialized computing power to implement in real-time.

DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model.

Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.

The diagnostic and prognostic significance of liver histology in alcoholic hepatitis.

BACKGROUND: Liver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial. AIM: To assess the utility of liver biopsy in the assessment of clinically severe AH METHODS: The histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores. RESULTS: The STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty-one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol-related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28-day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score. CONCLUSION: Liver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis. Clinical trial registration EudraCT reference number: 2009-013897-42. ISRCTN reference number: 88782125. MREC number: 09/MRE09/59. UKCRIN ID: 9143.

Incidence and Survival for Common Cancers Are Lower in New Mexico and Along the US-Mexico Border Than Elsewhere in the United States.

Background Few in-depth reports on cancer epidemiology in New Mexico or the United States-Mexico border region exist. We aim to quantify cancer incidence and survival in New Mexico and the United States-Mexico border region in New Mexico. Methods Incidence and survival were obtained using SEER*Stat 8.3. The data were divided into either New Mexico, or SEER 18 (comprised of the 17 remaining regions) and then further divided by county in New Mexico and by time period. Incidence rates were age-standardized to the 2000 US census. Five-year survival was calculated for each cancer type. Kaplan-Meier survival plots were produced, and significance was determined using log-rank analysis. Results Analysis demonstrated that cancers in New Mexico are diagnosed at a lower rate with the exception of thyroid, liver, and ovarian. Survival is generally lower in New Mexico with 10 of the 14 cancers having worse survival in New Mexico. Only uterine cancer had improved survival in New Mexico (77.9% vs 74.9%, P < .001). Additionally, breast (82.2%), prostate (83.3%), lung and bronchus (13.7%), colorectal (53.7%), melanoma (80.1%), kidney and renal pelvis (61.2%), uterine (78.5%), and ovarian (41.6%) all had lower survival in the border counties. Conclusion Comparing New Mexico to the other regions in the SEER 18 database, both cancer incidence and survival are consistently lower; these findings could be explained by lower access to healthcare, which can result in underreporting and delays in diagnosis.

One becomes two: second species of the Euwallacea fornicatus (Coleoptera: Curculionidae: Scolytinae) species complex is established on two Hawaiian Islands.

The cryptic species that make up the Euwallacea fornicatus species complex can be readily distinguished via their DNA sequences. Until recently, it was believed that the Hawaiian Islands had been invaded by only one of these cryptic species, E. perbrevis (tea shot hole borer; TSHB). However, following the 2016 deposition of a DNA sequence in the public repository GenBank, it became evident that another species, E. fornicatus (polyphagous shot hole borer; PSHB), had been detected in macadamia orchards on Hawai'i Island (the Big Island). We surveyed the two most-populous islands of Hawai'i, Big Island and O'ahu, and herein confirm that populations of TSHB and PSHB are established on both. Beetles were collected using a variety of techniques in macadamia orchards and natural areas. Individual specimens were identified to species using a high-resolution melt assay, described herein and validated by subsequent sequencing of specimens. It remains unclear how long each species has been present in the state, and while neither is currently recognized as causing serious economic or ecological damage in Hawai'i, the similarity of the newly-confirmed PSHB population to other damaging invasive PSHB populations around the world is discussed. Although the invasive PSHB populations in Hawai'i and California likely have different geographic origins within the beetle's native range, they share identical Fusarium and Graphium fungal symbionts, neither of which have been isolated from PSHB in that native range.

Randomised clinical trial: palliative long-term abdominal drains vs large-volume paracentesis in refractory ascites due to cirrhosis.

BACKGROUND: Palliative care remains suboptimal in end-stage liver disease. AIM: To inform a definitive study, we assessed palliative long-term abdominal drains in end-stage liver disease to determine recruitment, attrition, safety/potential effectiveness, questionnaires/interview uptake/completion and make a preliminary cost comparison. METHODS: A 12-week feasibility nonblinded randomised controlled trial comparing large-volume paracentesis vs long-term abdominal drains in refractory ascites due to end-stage liver disease with fortnightly home visits for clinical/questionnaire-based assessments. Study success criteria were attrition not >50%, <10% long-term abdominal drain removal due to complications, the long-term abdominal drain group to spend <50% ascites-related study time in hospital vs large-volume paracentesis group and 80% questionnaire/interview uptake/completion. RESULTS: Of 59 eligible patients, 36 (61%) were randomised, 17 to long-term abdominal drain and 19 to large-volume paracentesis. Following randomisation, median number (IQR) of hospital ascitic drains (long-term abdominal drain group vs large-volume paracentesis group) were 0 (0-1) vs 4 (3-7); week 12 serum albumin (g/L) and serum creatinine (µmol/L) were 29 (26.5-32.5) vs 30 (25-35) and 104.5 (81-115.5) vs 127 (63-158) respectively. Total attrition was 42% (long-term abdominal drain group 47%, large-volume paracentesis group 37%). Median (IQR) fortnightly community/hospital/social care ascites-related costs and percentage study time in hospital were lower in the long-term abdominal drain group, £329 (253-580) vs £843 (603-1060) and 0% (0-0.74) vs 2.75% (2.35-3.84) respectively. Self-limiting cellulitis/leakage occurred in 41% (7/17) in the long-term abdominal drain group vs 11% (2/19) in the large-volume paracentesis group; peritonitis incidence was 6% (1/17) vs 11% (2/19) respectively. Questionnaires/interview uptake/completion were ≥80%; interviews indicated that long-term abdominal drains could transform the care pathway. CONCLUSIONS: The REDUCe study demonstrates feasibility with preliminary evidence of long-term abdominal drain acceptability/effectiveness/safety and reduction in health resource utilisation. TRIAL REGISTRATION: ISRCTN30697116, date assigned: 07/10/2015.

Leukocyte Tetraspanin CD53 Restrains α3 Integrin Mobilization and Facilitates Cytoskeletal Remodeling and Transmigration in Mice.

The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53-/- mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53-/- neutrophils revealed no alteration in expression of ß2 integrins, whereas L-selectin was almost completely absent from Cd53-/- neutrophils. In addition, Cd53-/- neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53-/- mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.

Application of the optimized carbon monoxide rebreathing method for the measurement of total haemoglobin mass in chronic liver disease.

BACKGROUND: Anemia is common in liver cirrhosis. This generally infers a fall in total hemoglobin mass (tHb-mass). However, hemoglobin concentration ([Hb]) may fall due to an expansion in plasma volume (PV). The "optimized carbon monoxide rebreathing method" (oCOR) measures tHb-mass directly and PV (indirectly using hematocrit). It relies upon carboxyhemoglobin (COHb) distribution throughout the entire circulation. In healthy subjects, such distribution is complete within 6-8 min. Given the altered circulatory dynamics in cirrhosis, we sought in this pilot study, to assess whether this was true in cirrhosis. The primary aim was to ascertain if the standard timings for the oCOR were applicable to patients with chronic liver disease and cirrhosis. The secondary aim was to explore the applicability of standard CO dosing methodologies to this patient population. METHODS: Sixteen patients with chronic liver parenchymal disease were studied. However, tHb-mass was determined using the standard oCOR technique before elective paracentesis. Three subjects had an inadequate COHb% rise. In the remaining 13 (11 male), mean ± standard deviation (SD) age was 52 ± 13.8 years, body mass 79.1 ± 11.4 kg, height 175 ± 6.8 cm. To these, mean ± SD dose of carbon monoxide (CO) gas administered was 0.73 ± 0.13 ml/kg COHb values at baseline, 6 and 8 min (and "7-min value") were compared to those at 10, 12, 15 and 20 min after CO rebreathing. RESULTS: The "7-min value" for median COHb% (IQR) of 6.30% (6.21%-7.47%) did not differ significantly from those at subsequent time points (8 min: 6.30% (6.21%-7.47%), 10 min: 6.33% (6.00%-7.50%), 12 min: 6.33% (5.90%-7.40%), 15 min: 6.37% (5.80%-7.33%), 20 min: 6.27% (5.70%-7.20%)). Mean difference in calculated tHb-mass between minute 7 and minute 20 was only 4.1 g, or 0.6%, p = .68. No subjects reported any adverse effects. CONCLUSIONS: The oCOR method can be safely used to measure tHb-mass in patients with chronic liver disease and ascites, without adjustment of blood sample timings. Further work might refine and validate appropriate dosing regimens.