A practical approach to implementing incremental haemodialysis.

The majority of end-stage kidney disease patients are treated with haemodialysis (HD). Starting HD can pose physical, social, and psychological challenges to patients, and mortality rates within the first 6 months are disproportionately high, with intensive HD regimens implicated as a potential factor. Starting HD with an incremental approach, taking residual kidney function (RKF) into account, potentially allows for a gentle start with reduced dialysis intensity. Dialysis intensity (session time or frequency) can then be proportionally increased as RKF reduces. This approach to starting HD has been reported in observational studies to result in better patient self-reported health quality of life and reduced costs, and now several definitive randomised controlled trials are underway comparing an incremental approach to the conventional thrice weekly paradigm. Physician concerns over the risk of inadequate dialysis, with consequent increased emergency admissions, and practical challenges of how to estimate RKF and implement incremental dialysis have impeded widespread adoption. Addressing these challenges is paramount to increasing the uptake of incremental HD. Careful patient selection lies at the heart of a successful incremental HD programme. Generally, patients with a residual urea clearance of > 3 ml/min/1.73 m2 can be considered suitable for starting with incremental HD provided they comply with fluid intake, salt and other dietary recommendations. Calculating RKF from regular interdialytic urine collections and appropriately adjusting sessional HD clearance targets are practical and conceptual challenges. In this report we aim to disentangle these complexities and provide a step-by-step guide for patient selection and adjusting dialysis sessional targets.

High-Target Hemodiafiltration Convective Dose Achieved in Most Patients in a 6-Month Intermediary Analysis of the CONVINCE Randomized Controlled Trial.

Introduction: High convection volumes in hemodiafiltration (HDF) result in improved survival; however, it remains unclear whether it is achievable in all patients. Methods: CONVINCE, a randomized controlled trial, randomized patients with end-stage kidney disease 1:1 to high-dose HDF versus high-flux hemodialysis (HD) continuation. We evaluated the proportion of patients achieving high-dose HDF target: convection volume per visit of ≥23 l (range ±1 l) at baseline, month 3, and month 6. We compared baseline characteristics in the following 2 ways: (i) patients on target for all 3 visits versus patients who missed target on ≥1 visits and (ii) patients on target for all 3 visits or missing it once versus patients who missed target on ≥2 visits. Results: A total of 653 patients were randomized to HDF. Their mean age was 62.2 (SD 13.5) years, 36% were female, 81% had fistula vascular access, and 33% had diabetes. Across the 3 visits, 75 patients (11%), 27 patients (4%), and 11 patients (2%) missed the convection volume target once, twice, and thrice, respectively. Apart from diabetes, there were no apparent differences in patient characteristics between patients who always achieved the high-dose target (83%) and those who missed the target either once or more (17%) or twice or more (6%). Conclusion: Achieving high-dose HDF is feasible for nearly all patients in CONVINCE and could be maintained during the 6-month follow-up period. Apart from diabetes, there were no other indications for confounding by indication on multivariable analyses that may explain the potential survival advantage for patients receiving high-dose HDF.

Social dominance in monkeys: Lack of effect on ethanol self-administration during schedule induction.

Nonhuman primate models of alcohol use disorder (AUD) frequently utilize schedule-induced polydipsia to initiate ethanol drinking. Previous research has demonstrated that specific characteristics of drinking during the final phase of induction, in which monkeys consume 1.5 g/kg of ethanol per day, can predict whether monkeys become heavy or light drinkers when they subsequently have free access to ethanol (22 hours per day; Baker, Farro, Gonzales, Helms, & Grant, 2017; Grant et al., 2008). A monkey's position in the social dominance hierarchy is another factor associated with ethanol drinking in nonhuman primates; lower social status is associated with higher ethanol intakes. In the present study, characteristics of drinking during induction were measured in 12 male cynomolgus monkeys living in three established social groups (4 monkeys per group). All monkeys were induced to consume water, then increasing doses of ethanol (0.5, 1.0, and 1.5 g/kg) for 30 sessions per dose using a 300-s fixed-time schedule of food pellet delivery. Drinking sessions occurred five days per week and monkeys were group-housed on the other two days. Contrary to our hypothesis that subordinate monkeys would show characteristics of drinking during the last phase of induction that were predictive of later heavy drinking, no significant differences were observed between dominant and subordinate monkeys in any phase of induction. When ethanol availability was subsequently increased to 22 hours per day for 5 weeks, the intakes of subordinate- and dominant-ranked monkeys diverged, with higher intakes on average in subordinates. Several factors unique to the conditions of induction may have obscured any influence of social rank, including the limited duration of sessions and limited maximal ethanol intake. The data support the conclusion that the effects of social rank on ethanol consumption require unrestricted access to ethanol.

Preloading magnesium attenuates cisplatin-associated nephrotoxicity: pilot randomized controlled trial (PRAGMATIC study).

BACKGROUND: Cisplatin is one of the most potent chemotherapeutic drugs used in head and neck cancer treatment; however, nephrotoxicity is the major side-effect limiting usage. Magnesium supplementation has been reported to reduce risk in non-controlled studies. We investigated whether preloading with magnesium prevents nephrotoxicity with a low-dose weekly cisplatin regimen. METHODS: We carried out a prospective pilot, single-blinded, randomized controlled trial to compare cisplatin-associated acute kidney injury (cis-AKI) and acute kidney disease (cis-AKD) between two groups: intravenous 0.9% NaCl 500 ml + KCL 20 mEq over 4 h pre-cisplatin 40 mg/m2 weekly for 7-8 weeks (control group) compared with additional 16 mEq magnesium added to the saline infusion (Mg group) in 30 head and neck cancer patients. Cis-AKI was defined as an increased serum creatinine (SCr) ≥ 0.3 mg/dl within 7 days and cis-AKD is an increased SCr ≥ 0.3 mg/dl between last SCr and baseline pre-chemotherapy SCr. RESULTS: The overall cisplatin tumor response rate and survival were comparable between groups. The baseline characteristics were comparable between groups, although SCr was lower in the controls (0.70 ± 0.17 versus 0.87 ± 0.17 mg/dl, P = 0.01). The incidence of cis-AKI was similar (4.6% versus 1.3%); however, the incidence of cis-AKD was higher for the control group (46.7% versus 6.7%, hazard ratio = 0.082, 95% confidence interval 0.008-0.79, P = 0.03). The time to develop cis-AKD was significantly shorter in the control group (P = 0.007). CONCLUSIONS: The magnesium-preloading regimen was safe and significantly showed a decreased incidence of cis-AKD. The encouraging results of our pilot study need to be confirmed in a large-scale randomized controlled trial.

PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer.

This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using in situ hybridization and MSI status was performed using PCR and MLH1 IHC. The PD-L1 segment was associated with increased T-cell infiltrates, while the MSI-high segment was enriched for PD-L1, CD3, and CD8. Multivariate analysis confirmed PD-L1 positivity, high CD3 and high CD8 as independent prognostic factors for both disease-free survival and overall survival (all p < 0.05). Patients with MSI-high tumours had better overall survival by both univariate and multivariate analysis. The ATM-low and HER2-high subgroups differed markedly in their immune profile; the ATM-low subgroups enriched for MSI, PD-L1 positivity and CD8 + T-cells, while the HER2 segment was enriched for MSS, with no enrichment for immune markers. Hence, we demonstrate a molecular profiling approach that can divide GC into four molecular subgroups, namely ATM-low, HER2-high, PD-L1 positive and MSI-high with differing levels of immune infiltrates and prognostic significance which may help to stratify patients for response to targeted therapies.

New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine.

During the last thirty years since the discovery of endothelin-1, the therapeutic strategy that has evolved in the clinic, mainly in the treatment of pulmonary arterial hypertension, is to block the action of the peptide either at the ET(A) subtype or both receptors using orally active small molecule antagonists. Recently, there has been a rapid expansion in research targeting ET receptors using chemical entities other than small molecules, particularly monoclonal antibody antagonists and selective peptide agonists and antagonists. While usually sacrificing oral bio-availability, these compounds have other therapeutic advantages with the potential to considerably expand drug targets in the endothelin pathway and extend treatment to other pathophysiological conditions. Where the small molecule approach has been retained, a novel strategy to combine two vasoconstrictor targets, the angiotensin AT(1) receptor as well as the ET(A) receptor in the dual antagonist sparsentan has been developed. A second emerging strategy is to combine drugs that have two different targets, the ET(A) antagonist ambrisentan with the phosphodiesterase inhibitor tadalafil, to improve the treatment of pulmonary arterial hypertension. The solving of the crystal structure of the ET(B) receptor has the potential to identify allosteric binding sites for novel ligands. A further key advance is the experimental validation of a single nucleotide polymorphism that has genome wide significance in five vascular diseases and that significantly increases the amount of big endothelin-1 precursor in the plasma. This observation provides a rationale for testing this single nucleotide polymorphism to stratify patients for allocation to treatment with endothelin agents and highlights the potential to use personalized precision medicine in the endothelin field.

In-situ, time resolved monitoring of uranium in BFS:OPC grout. Part 2: Corrosion in water.

To reflect potential conditions in a geological disposal facility, uranium was encapsulated in grout and submersed in de-ionised water for time periods between 2-47 weeks. Synchrotron X-ray Powder Diffraction and X-ray Tomography were used to identify the dominant corrosion products and measure their dimensions. Uranium dioxide was observed as the dominant corrosion product and time dependent thickness measurements were used to calculate oxidation rates. The effectiveness of physical and chemical grout properties to uranium corrosion and mobilisation is discussed and Inductively Coupled Plasma Mass Spectrometry was used to measure 238U(aq) content in the residual water of several samples.

Use of the embedded peritoneal dialysis catheter.

Introduction The use of embedded peritoneal dialysis (PD) catheters is purported to offer numerous benefits over standard placement. However, the optimum period of embedment and the effect of prolonged embedment on subsequent catheter function remain unclear. Methods This retrospective observational study looked at adult patients undergoing embedded PD catheter insertion in a large tertiary referral centre in the UK. Possible predictors for catheter non-function at externalisation were investigated. These included patient factors (age, sex, diabetic status, body mass index, ethnicity, smoking status, previous surgery, estimated glomerular filtration rate), procedural factors (modality of surgery, concurrent surgical procedure), duration of catheter embedment and catheter damage at externalisation. Outcomes examined were proportion of catheters functioning after externalisation, futile placement rate, surgical reintervention rate, infectious complication rate and proportion of externalised catheters lost owing to malfunction. Results Sixty-six catheters were embedded and two-thirds (n=47, 63.6%) were externalised after a median embedment period of 39.4 weeks. Of these, 25 (53.2%) functioned on externalisation. Fourteen (63.6%) of the 22 non-functioning catheters were salvaged. The overall utilisation of PD was 34/47 (72.3%) and the futile placement rate was 12.1%. Over half of the externalised catheters (n=27, 57.4%) were lost directly as a result of catheter related complications, with a median survival time of 39.4 weeks. In adjusted analysis, increasing embedment duration was significantly predictive of catheter non-function at externalisation (adjusted odds ratio: 0.957, 95% confidence interval [CI]: 0.929-0.985, p=0.003) while subsequent catheter loss was highly dependent on catheter function at externalisation (hazard ratio: 0.258, 95% CI: 0.112-0.594, p=0.001). Conclusions Prolonged embedment of PD catheters is associated with a significantly higher likelihood of catheter dysfunction following externalisation, which is in turn associated with subsequent catheter loss. We have discontinued the use of this technique in our unit.

Differences in the prevalence of sarcopenia in haemodialysis patients: the effects of gender and ethnicity.

BACKGROUND: There is no universal consensus definition of sarcopenia, although there is agreement that sarcopenia is a risk factor for mortality in haemodialysis (HD) patients. We aimed to determine the effect of using different operational definitions in a multiracial group of HD patients. METHODS: We measured hand grip strength (HGS) and appendicular lean mass (ALM) by segmental bioimpedance using the Foundation for the National Institutes of Health Sarcopenia Project (FNIH), European Working Group on Sarcopenia (EWGS) and Asian Working Group on Sarcopenia definitions for HGS weakness and loss of appendicular lean mass. RESULTS: In total, there were 600 HD patients: 373 men (62.2%), mean (SD) age 66.3 (14.7) years, 45.6% diabetic, ethnicity: 281 (48.5%) White, 167 (27.8%) Asian and 149 (24.8%) Black. On HGS criteria, 90.5% of Asian women and 88.5% of Asian men were weak according to EWGS compared to 62.3% of Black women and 52.5% of Black men and 64.5% of White women and 69.1% of White men by FNIH criteria (P < 0.001). On adding appendicular lean mass, the prevalence of sarcopenia was 68.3% for Asian, 27.1% for Black and 36.6% for White women by FNIH and 59.6% Asian, 21.3% Black and 39.9% White men by EWGS criteria. CONCLUSIONS: Current definitions of sarcopenia report a greater prevalence of muscle weakness compared to appendicular muscle loss in female compared to male HD patients and this is greater for Asian compared to Black and White patients. Because HGS weakness is a greater risk for death, definitions of sarcopenia may underestimate risk in HD patients.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

In-situ, time resolved monitoring of uranium in BFS:OPC grout. Part 1: Corrosion in water vapour.

Uranium encapsulated in grout was exposed to water vapour for extended periods of time. Through synchrotron x-ray powder diffraction and tomography measurements, uranium dioxide was determined the dominant corrosion product over a 50-week time period. The oxide growth rate initiated rapidly, with rates comparable to the U + H2O reaction. Over time, the reaction rate decreased and eventually plateaued to a rate similar to the U + H2O + O2 reaction. This behaviour was not attributed to oxygen ingress, but instead the decreasing permeability of the grout, limiting oxidising species access to the metal surface.

Changes in serum osmotic pressure following haemodialysis treatments lead to changes in bioimpedance spectroscopy estimates of lean and adipose tissue.

Haemodialysis (HD) patients are at risk of sarcopenia. Newer bioimpedance devices (BIS) using a three-compartmental body composition model, separate extracellular water overhydration from normo-hydrated lean tissue mass (LTM) and adipose tissue mass (ATM). During HD hydration status changes, along with changes in electrolytes and solutes, and may alter body composition measurements. As such, we measured BIS and serum osmotic pressure (sOP) pre- and post dialysis in 43 patients. There were no significant changes in LTM (39.5±15.1 vs 39.3±15.2 kg) or sOP (33.2±8.3 vs 35.9±9.7 mm Hg). Higher post-dialysis sOP was associated with a greater percentage fall in LTM (r=0.43, P=0.08) and increase in ATM (r=-0.43, P=0.017). Increased sOP post dialysis was associated with a reduction in LTM (r=0.36, P=0.033) and increased ATM (r=-0.44, P=0.013). Changes in sOP with HD are associated with changes in BIS body composition measurements. BIS measurements should preferably be made when patients are least overhydrated.

Screening for muscle loss in patients established on peritoneal dialysis using bioimpedance.

Background/objectivesKidney dialysis patients with sarcopenia have increased mortality. Screening for low muscle mass may allow interventions at an earlier stage to help improve outcomes. We wished to determine the prevalence of low muscle mass in a cohort of peritoneal dialysis (PD) patients.Subjects/methodsWe measured lean body mass index (LBMI) in 490 PD patients by bioimpedance, grading patients using two different classifications of sarcopenia. RESULTS: LBMI was 9.7±1.9 kg/m2, mean age was 55.3±16.4 years, 53.1% were male, 33.7% were diabetic and 51% were Caucasoid. 98.5% of patients were classified as having sarcopenia based on LBMI cutoffs from NHANES data, whereas 28.8% had moderate and 6.3% severe sarcopenia using a grading correlated with functional disability. Lower muscle mass was associated with increasing co-morbidity (ß=0.34, P=0.02) and age (ß=0.01, P=0.006), and negatively with body mass index (ß=-0.23, P<0.001), log serum creatinine (ß=-0.231, P<0.001), normalised protein nitrogen appearance (ß=-1.33, P<0.001) and log urine volume (ß=-0.28, P=0.002). There was no association with duration of PD, dialysis prescription, residual renal function or solute clearances. CONCLUSIONS: There is currently no agreed universal definition for sarcopenia, and prevalence varied markedly depending on the scoring system. Prevalence was not associated with small solute clearances, but was associated with sex, age co-morbidity, BMI and ethnicity. There was an association with dietary protein intake and urine volume, which may allow for dietary interventions and strategies to preserve urine output to reduce muscle loss in PD patients.

Changes in body composition following haemodialysis as assessed by bioimpedance spectroscopy.

BACKGROUND/OBJECTIVES: Patients with chronic kidney disease treated by haemodialysis (HD) are at increased risk of sarcopenia. Bioelectrical impedance spectroscopy (BIS) can be used to determine body composition, and is one of the several potential screening tools for sarcopenia. The newer generation of portable hand-held devices can be readily used in dialysis centres. The results from BIS devices using a two-compartmental model of body composition can be affected by hydration status and so ideally measurements should be made when patients are not overhydrated. More recently BIS devices using a three-compartmental body model, which separate normally hydrated lean tissues from extracellular water (ECW) excess. We wished to determine whether body composition measured using such a BIS device was affected by hydration status. SUBJECTS/METHODS: We performed BISs pre and post HD using a three-body compartmental model. RESULTS: BISs were recorded in 48 patients; 68.8% male; mean age 67.70±14.21 years, weight pre dialysis 70.54±18.07, which fell post to 68.58±17.78 kg, ECW fell 16.92±4.76 vs 15.66±4.43 l, P<0.001, whereas there was no change for intracellular water 14.84±4.27 vs 14.90±4.68 l. Fat-free mass index (FFMI) fell 17.87±3.98 vs 16.78±3.97 kg/m2, P<0.001, whereas fat mass index (FMI) increased from 7.87±3.98 vs 8.12±3.81 kg/m2, P=0.002. A fall in FFMI was associated with an increase in FMI (r=0.804, P<0.001). CONCLUSION: FMI and FFMI measured by bioelectrical impedance assessment are both confounded by hydration status. Although pre-dialysis measurements are more convenient, we suggest BIS should preferably be performed post-dialysis when patients are less overhydrated and have less electrolyte imbalances.

Interobserver variability amongst gastrointestinal pathologists in assessing prognostic parameters of malignant colorectal polyps: a cause for concern.

BACKGROUND: Malignant colorectal polyps (MCRP) have become a major challenge in the field of coloproctology from diagnosis to full treatment. One important facet of the challenge is the histopathological staging of the lesion and identifying various prognostic parameters. The primary aim of this study was to find the interobserver variation amongst 4 experienced gastrointestinal pathologists when assessing important parameters and staging systems (Haggitt, Kikuchi and Ueno) in MCRPs. METHODS: Four experienced gastrointestinal pathologists independently assessed 56 cases of MCRP, and each pathologist completed a pro forma for each case. The results were collated and statistically analysed. RESULTS: There was a significant variation in the assessments using the various published staging systems agreed upon on important prognostic parameters. CONCLUSIONS: None of the staging systems used is suitable for all polyp types or has good reproducibility. There is an urgent need to make pathologists' assessment of MCRPs easier and more reproducible.

Comparison of resting and total energy expenditure in peritoneal dialysis patients and body composition measured by dual-energy X-ray absorptiometry.

Under basal resting conditions muscle metabolism is reduced, whereas metabolism increases with physical activity. We wished to determine whether there was an association between resting energy expenditure (REE) and total energy expenditure (TEE) in peritoneal dialysis (PD) patients and lean body mass (LBM). We determined REE and TEE by recently validated equations, using doubly labelled isotopic water, and LBM by dual-energy X-ray absorptiometry (DXA) scanning. We studied 87 patients, 50 male (57.4%), 25 diabetic (28.7%), mean age 60.3±17.6 years, with a median PD treatment of 11.4 (4.7-29.5) months. The mean weight was 70.1±17.7 kg with a REE of 1509±245 kcal/day and TEE 1947±378 kcal/day. REE was associated with body size (weight r=0.78 and body mass index (BMI) r=0.72) and body composition (LBM r=0.77, lean body mass index (LBMI) r=0.76, r=0.62), all P<0.001). For TEE, there was an association with weight r=0.58, BMI r=0.49 and body composition (LBM r=0.64, LBMI (r=0.54), all P<0.001). We compared LBMI measured by DXA and that estimated by the Boer equation using anthropomorphic measurements, which overestimated and underestimated LBM for smaller patients and heavier patients, respectively. Muscle metabolism is reduced at rest and increases with physical activity. Whereas previous reports based on REE did not show any association with LBM, we found an association between both REE and TEE, using a recently validated equation derived from dialysis patients, and LBM measured by DXA scanning. Estimation of muscle mass from anthropomorphic measurements systematically overestimated LBM for small patients and conversely underestimated for heavier patients.

Role of substrate induced electron-phonon interactions in biased graphitic bilayers.

Bilayers of graphitic materials have potential applications in field effect transistors (FETs). A potential difference applied between certain ionic bilayers made from insulating graphitic materials such as BN, ZnO and AlN could reduce gap sizes, turning them into useful semiconductors. On the other hand, opening of a small semiconducting gap occurs in graphene bilayers under applied field. The aim here is to investigate to what extent substrate induced electron-phonon interactions (EPIs) modify this gap change. We examine EPIs in several lattice configurations of graphitic bilayers, using a perturbative approach. The typical effect of EPIs on the ionic bilayers is an undesirable gap widening. The size of this gap change varies considerably with lattice structure and the magnitude of the bias. When bias is larger than the non-interacting gap size, EPIs have the smallest effect on the bandgap, especially in configurations with [Formula: see text] and AB structures. Thus careful selection of substrate, lattice configuration and bias strength to minimise the effects of EPIs could be important for optimising the properties of electronic devices. We use parameters related to BN in this article. In practice, the results presented here are broadly applicable to other graphitic bilayers, and are likely to be qualitatively similar in metal dichalcogenide bilayers such as MoS2, which are already of high interest for their use in FETs.

PO-51 - Expression of proteins of the tissue factor thrombin pathway is upregulated in the stroma and epithelium of colorectal cancer.

INTRODUCTION: Colorectal cancer expression of Tissue Factor (TF), PAR1 and PAR2 is associated with a poor prognosis. Their stromal, rather than epithelial, expression has prognostic significance in other cancers, this has not been explored in colorectal cancer. AIM: We aimed to determine the expression patterns of Tissue Factor (TF), PAR1 and PAR2 and thrombin in colorectal cancer and normal tissue. MATERIALS AND METHODS: Cancer and distant normal tissue were sampled from 37 patients. Expression of TF, Thrombin, PAR1 and PAR2 were determined by immunohistochemistry. Two observers scored expression level (0-3) in individual cells. Percentage of cells having each level of expression was determined and an H-score calculated which are given with 95% CI. RESULTS: Normal epithelium did not express TF, but it was expressed by cancer epithelium (36.5 (95% CI 17.6 - 55.4) p<0.001). Thrombin expression was increased in cancer vs normal epithelium (126.2 (95% CI 110.6 - 141.7) vs 101.6 (95% CI 92.5-110.8) p=0.01) as was PAR2 (172.4 (95% CI 152.9-191.8) vs 123.4 (95% CI 107.8-139.0) p<0.001). The increase in cancer epithelium PAR1 expression compared to normal (105.4 (95%CI 84.3-126.5) vs 89.0 (95% CI 80.4-97.6)) was not significant. Normal stroma did not express TF or thrombin however both were expressed by cancer stroma (TF 46.3 (95% CI 24.6-68.0) p<0.001, thrombin 11.4 (95% CI 6.2-16.7) p<0.001). PAR1 and PAR2 were both expressed in normal stroma but demonstrated increased expression in cancer stroma (cancer vs normal; PAR 1: 130.7 (95% CI 112.2-149.2) vs 19.5 (95% CI 11.24-27.7) p<0.001; PAR2: 21.5 (95% CI 12.9-30.1) vs 2.21 (95% CI 0.49-3.92) p<0.001). CONCLUSIONS: Upregulated expression of tissue thrombin pathway proteins is seen in colorectal cancer in both epithelial and stromal cells. Procoagulant tumour cells and tumour microenvironment may provide a novel therapeutic target for treatment in colorecal cancer.

Pinch grip strength as an alternative assessment to hand grip strength for assessing muscle strength in patients with chronic kidney disease treated by haemodialysis: a prospective audit.

BACKGROUND: Muscle weakness and wasting are prevalent in haemodialysis (HD) patients, and substantially increase mortality. Convenient, readily applicable screening tests for routine clinical practice are required. Hand grip strength (HGS) has been validated in HD patients but cannot be readily measured during a HD session. On the other hand, pinch strength (PS) can be measured during a HD session, and we aimed to compare the two methods of assessing muscle strength. METHODS: We measured pinch strength (PS) and hand grip strength (HGS) in 209 adult HD patients. The mean of three measurements was taken. RESULTS: The mean (SD) HGS was 15.3 (7.1) kg, compared to a PS of 2.9 (1.5) kg (P < 0.0001). HGS was weaker in the arteriovenous fistula (AVF) arm than the non-AVF arm [14.01 (6.9) versus 16.4 (7.1) kg (P < 0.001)], as was PS [AVF arm 2.63 (1.30) versus 3.08 (1.65) kg (P < 0.001)]. We found a strong correlation between HGS and PS (r = 0.82, P < 0.001. Comparing HGS and PS, we found a mean difference of 12.08 kg (Bland-Altman analysis), although the absolute difference was smaller with lower HGS. CONCLUSIONS: We found PS to be highly correlated with HGS, and was more convenient for patients because PS could be readily performed during the HD session. PS may provide an easier screening tool for muscle strength than HGS for dialysis patients, although further validation studies are required.

Changes in muscle and fat mass with haemodialysis detected by multi-frequency bioelectrical impedance analysis.

BACKGROUND/OBJECTIVES: Multi-frequency bioelectrical impedance analysis (MFBIA) is becoming more widely used to assess hydration status and body composition in haemodialysis patients. Most centres only measure MFBIA pre dialysis when patients are overhydrated. We wished to determine whether body composition assessments change post dialysis following fluid removal. SUBJECTS/METHODS: Lean body and fat mass were measured by MFBIA pre and post haemodialysis in 676 stable outpatients. RESULTS: Weight fell post dialysis from 72.9 ± 17.8 to 70.9 ± 19.9 kg, P<0.001, soft lean mass from 48.2 ± 12.1 to 45.4 ± 11.0 kg and fat-free mass from 51.8 ± 19.2 to 48.1 ± 11.8 kg, P<0.001, whereas percentage body fat (PBF) increased from 28.8 ± 11.9 to 30.8 ± 12.1% post dialysis, P<0.001, with a mean increase post dialysis of 2.0% (95% confidence limits 1.55 to 2.45). There were correlations between the fall in total body water and extracellular water and skeletal muscle mass (r=0.826, P<0.001 and r=0.711, P<0.001, respectively), and negative correlation between the fall in total body water and ICW and the increase in PBF (r=-0.72, P<0.001, and -0.72, P<0.001, respectively). The relative changes were greater for the arms compared with the legs. CONCLUSIONS: Although more convenient for both patients and staff to undertake bioimpedance measurements pre dialysis, overhydration over estimates muscle mass and under estimates fat. For more reliable and reproducible assessments of nutritional status, we suggest that bioimpedance measurements of body composition should be made when patients are closer to their target weight than when overhydrated.