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.

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.

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.

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.

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.

Do bicarbonate-based solutions for continuous renal replacement therapy offer better control of metabolic acidosis than lactate-containing fluids?

INTRODUCTION: Evidence that bicarbonate haemofiltration and dialysate fluids are superior to lactate in patients with acute kidney injury treated by continuous renal replacement therapy (CRRT) remains controversial. METHODS: We prospectively audited acid-base during the first 48 h of CRRT in 62 patients, using bicarbonate and lactate fluids. RESULTS: Baseline lactate was greater in the bicarbonate group (4.76 ± 0.77 vs. 2.92 ± 0.5 mmol/l, p < 0.01), but pH, bicarbonate, chloride and base excess were similar. Lactate fell significantly in the bicarbonate group to 2.88 ± 0.3 mmol/l at 24 h and 2.39 ± 0.2 mmol/l at 48 h, but not in the lactate group. Base excess improved more with bicarbonate, median increase in the first 24 h was 51.6% (29.1-96.9) versus 18.5% (-5 to 55) with lactate and 74.2% (38.5-123) versus 36.1% (-3.6 to 68), p < 0.05 at 48 h. However, there were no significant differences in bicarbonate, chloride, pH, blood pressure and vasopressor requirements. 13.3% of patients were switched from lactate to bicarbonate fluids due to failure to correct acidosis. Subgroup analysis of 19 patients with liver failure showed similar results. CONCLUSION: Bicarbonate fluids led to a more rapid fall in lactate and greater improvement in base excess during CRRT, but not overall control of acidosis.

Reversible acute kidney injury (AKI) by active removal of serum light chains in an HIV positive patient with myeloma kidney.

BACKGROUND: The association of HIV and myeloma has rarely been reported in the literature. This following case discusses the presentation of acute kidney injury (AKI) in a 53-year-old lady with HIV, subsequently diagnosed with myeloma. Furthermore, we describe recovery of renal function and dialysis independence using a combination of light chain removal by dialysis with a high cut-off dialyzer and chemotherapy. INVESTIGATIONS: Physical examination, urine, blood tests, renal biopsy, bone marrow aspirate and trephine, US scan. DIAGNOSIS: Myeloma. MANAGEMENT: Dialysis and chemotherapy.

ADQI 7: the clinical management of the Cardio-Renal syndromes: work group statements from the 7th ADQI consensus conference.

Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are prone to cardiac failure. This has led to the concept of cardio-renal syndromes, which can be an acute or chronic cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic Reno-Cardiac syndrome, when renal dysfunction leads to cardiac failure. Patients who develop these syndromes have increased risk of hospital admission and mortality. Although there are clinical guidelines for managing both heart failure and chronic kidney disease, there are no agreed guidelines for managing patients with cardio-renal and/or Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore reviewed the currently available published literature to outline a consensus of current best clinical practice for these patients.

Acute neurological presentation due to copper deficiency in a hemodialysis patient following gastric bypass surgery.

Acquired copper deficiency has been recently recognized as a cause of myelopathy, and has been reported to occur many years after gastric bypass surgery performed to aid weight reduction in morbidly obese patients. We report a case of a young woman treated by hemodialysis who presented with acute neurological symptoms 5 months after gastric bypass surgery for severe obesity. She had symptoms and signs of cerebellar, spinal cord and peripheral nerve disease, which improved following parenteral copper supplementation. Now that gastric bypass surgery is being offered to morbidly obese hemodialysis patients, this case highlights the importance of monitoring copper levels in hemodialysis patients following gastric bypass surgery.

Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1.

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

Membrane designs and composition for hemodialysis, hemofiltration and hemodialfiltration: past, present and future.

Today hemodialysis is a routine outpatient treatment, not only carried out in hospitals, but more commonly in free standing units without on site medical supervision. One of the key advances that have underpinned this expansion of hemodialysis provision has been the technological advances in dialyzer membrane technology. Dialyzer membranes have undergone a sea change from collodion tubes to cellulose sheets to the modern day capillary fiber dialyzer. Improvements have not only been limited to reliability of manufacture, but also reduction in bio-incompatibility, and improved small solute clearances. However, the holy Grail remains the development of a dialyzer capable of removing middle sized azotemic retention solutes, and protein bound or lipophilic solutes.

Surface charge--induced ordering of the au(111) surface.

Synchrotron surface x-ray scattering (SXS) studies have been carried out at the Au(lll)/electrolyte interface to determine the influence of surface charge on the microscopic arrangement of gold surface atoms. At the electrochemical interface, the surface charge density can be continuously varied by controlling the applied potential. The top layer of gold atoms undergoes a reversible phase transition between the (1 x 1) bulk termination and a (23 x radical3) reconstructed phase on changing the electrode potential. In order to differentiate the respective roles of surface charge and adsorbates, studies were carried out in 0.1 M NaF, NaCl, and NaBr solutions. The phase transition occurs at an induced surface charge density of 0.07 +/- 0.02 electron per atom in all three solutions.

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.

Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension.

Cardiovascular disease remains the most common cause of mortality in patients with end-stage kidney disease treated by regular hemodialysis. To improve blood pressure control and reduce cardiovascular risk, the United Kingdom Renal Association standards committee introduced pre- and post-dialysis target blood pressures of less than 140/90 and 130/80 mm Hg, respectively. We audited blood pressure control and symptomatic intradialytic hypotension requiring fluid resuscitation in the Greater London area renal centers that serve 2630 patients. The study captured 7890 hemodialysis sessions during a 1-week period where only 36% of the patients achieved the pre-dialysis target and 42% the post-dialysis target, with a wide variation between centers. Different antihypertensive medication prescriptions did not affect achievement of these targets. Fifteen percent of the patients suffered symptomatic hypotension requiring fluid resuscitation associated with significantly greater interdialytic weight gains. Our study found that intradialytic hypotension was significantly greater in centers that achieved better post-dialysis blood pressure targeting.

Hemodialysis of chronic kidney failure patients requiring ablative radioiodine therapy.

Ablative radioiodine therapy is the standard treatment for thyroid carcinoma, but as (131)I is predominantly cleared by renal excretion, its clearance will be reduced in patients with chronic kidney disease, particularly in anuric patients on dialysis. The high dose of radioactivity used in the procedure results in an increased risk of radioactive exposure to the patient, the dialysis staff, and the machinery. Here, we describe how to successfully hemodialyze patients with chronic kidney failure requiring ablative (131)I therapy for thyroid cancer while minimizing risks to the patient and dialysis staff. With appropriate training, hemodialysis treatments can be safely delivered to patients receiving radiotherapy.

A wearable hemofilter for continuous ambulatory ultrafiltration.

Ultrafiltration is effective for treating fluid overload, but there are no suitable machines for ambulatory treatment. This study summarizes the use of a light-weight wearable continuous ambulatory ultrafiltration device consisting of a hollow fiber hemofilter, a battery operated pulsatile pump, and two micropumps to control heparin administration and ultrafiltration. Six volume-overloaded patients underwent ultrafiltration for 6 h with treatment discontinued in one patient due to a clotted catheter. Blood flow averaged 116 ml min(-1), the ultrafiltration rate ranged from 120-288 ml h(-1) with about 150 mmol of sodium removed. Blood pressure, pulse, and biochemical parameters remained stable with no significant hemolysis or complications. Our data show that the wearable hemofilter appears to be safe, effective, and practical for patients. This device could have a major impact on the quality of life of fluid-overloaded patients with heart failure. Additional studies will be needed to confirm these initial promising results.

A follow-up of four cases of nephrogenic systemic fibrosis: is gadolinium the specific trigger?

We originally reported four patients with nephrogenic systemic fibrosis (NSF) in the British Journal of Dermatology in 2003, and now present an update of their outcome. All four patients (three females and one male) presented within a six month period at our institution, and had received gadolinium contrast agents prior to disease onset. Two patients with functioning renal transplants had limited cutaneous disease, two patients maintained on haemodialysis had more severe disease and died one year after disease onset. Gadolinium deposition was demonstrated in lesional skin of one patient using electron microscopy and energy dispersive spectroscopy.