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The standard heparin lock for dialysis catheters in US dialysis units is 1000 units/ml, though its use has significant limitations and problems. The alternative catheter lock of 4% sodium citrate is used in some patients, but a 7% solution would maintain catheter patency better than the 4% concentration. In spite of the failure of two prior catheter locks to become widely used in the US (highly concentrated citrate and Zuragen™), Ash Access worked with a compounding pharmacy to produce 7% sodium citrate with preservative in single-patient use frangible vials, at a reasonable cost to users. The product had early acceptance by a number of dialysis units and hospitals, but then follow-up orders were few. Where the project goes from here is unclear.

In course of developing an anticoagulant and antibacterial catheter lock solution, we demonstrated that the components and alcohol formed an effective skin antiseptic. Ash Access formed a sister company to focus on development and clinical trials of this skin preparation and exchanged intellectual property for part ownership. Zurex Pharma now has Food and Drug Administration (FDA) approval on the new pre-operative skin preparation, ZuraGard™, and has made successful steps toward production and marketing of the product. The steps toward FDA approval, the size of the market, and user needs are clearer for a second product in the field than for the first.

When sodium citrate is used as an anticoagulant catheter lock the best concentration is 7%, since this provides a density approximately the same as blood. Our laboratory found that the addition of methylene blue and parabens greatly augmented antibacterial properties. Ash Access sponsored a randomized clinical trial in 400 dialysis patients with tunneled CVC, and this showed a significant decrease in incidence of catheter-related bloodstream infection (CRBSI) defined by stringent criteria. The FDA decided that the study missed its primary endpoint, and that the product was mis-classified, so they did not give approval to market. The licensee decided not to appeal to the decision to the physician panel and ended support of the project. Rights to market the catheter lock eventually returned to Ash Access.

A sorbent with a high enough capacity for NH

HemoCleanse collaborated with Dr. John Sherman and Union Carbide in the 1980s to develop a cation exchanger with high selectivity for potassium and ammonium, for use in a wearable artificial kidney. Synthetic zeolites had unexpected solubility in this application but by 2000, UOP (a sister company of Union Carbide) had developed zirconium cyclosilicate (SZC). HemoCleanse performed early animal studies of SZC as an oral sorbent. These showed remarkable binding characteristics. HemoCleanse then obtained the license for SZC for medical applications, helped to form ZS Pharma, and collaborated in further animal studies and clinical trials. AstraZeneca purchased ZS Pharma in 2015, and SZC (Lokelma®) has now become an effective treatment for hyperkalemia in patients with kidney failure and cardiac conditions.

By the year 2000, there was rising interest in home hemodialysis in the United States. HemoCleanse decided to resurrect the BioLogic-HD machine, using updated components. A spin-off company Renal Solutions (RSI) created the Allient™, with sorbent regeneration of dialysate, hollow fiber dialyzer, pressure-controlled blood flow rate, controlled filtration, and single- or dual-needle access. RSI merged with Sorb Technology and the Allient™ was built, tested, and FDA-approved to market. In 2007 Fresenius Medical Corporation (FMC) bought RSI. FMC began an extensive re-design of the machine to fit the needs of both in-center and home dialysis. The redesigned machine never was marketed.

Our small RD company created a novel extracorporeal system for the treatment of hepatic coma and drug overdose, in which membrane motion in a screen-plate dialyzer served as a blood pump and also mixed dialysate containing powdered carbon. Early clinical trials of the Biologic-DT™ were successful in the treatment of patients with hepatic coma (especially from A-on-C liver failure) and FDA gave marketing approval. The BioLogic-DT™ was licensed to a venture capital-backed startup. It was marketed too widely and used in some patients without a chance for recovery or transplant. The licensing company failed, and the BioLogic-DT was not remarketed. The MARS™ device included albumin as a sorbent in dialysate, and clinical trials of this device also showed a benefit in the treatment of hepatic coma.

Background: Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. Observation: Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. Conclusions: Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.

In the course of over four decades, I have worked with an R&D team on 12 major R&D projects, all with the goal of making hemodialysis simple, safe, effective, and suitable for use in the home. Our team has worked within a University and in private companies and has collaborated with major healthcare drug and device companies. As a practicing nephrologist, my definition of success is when I see the device or drug we helped to develop in widespread clinical use. By this measure, two of the projects were highly successful, but seven failed. Most failures were due to decisions made by various corporations, governmental agencies, and venture capital groups, out of the hands or control of the R&D company. Three projects are still ongoing. There is no shortage of creativity or new ideas in nephrology and in dialysis. The major challenge is in the commercialization of the products.

Background Limited data describes the effectiveness of strategies to optimize naloxone rescue kit distribution. Mental health clinical pharmacy specialists (CPS) at VA St. Louis HCS aimed to increase distribution of naloxone rescue kits to patients with Opioid Use Disorder (OUD). An informational letter detailing the purpose of rescue kits and how to obtain one were sent to patients with OUD who had no active order for a naloxone rescue kit within the previous year. Roughly half of these patients were targeted for follow-up education via telephone. Methods A retrospective study was conducted comparing the effectiveness of these contact methods. Study groups included those contacted by letter alone and those contacted by both letter and phone call. The primary outcome was order placement for a rescue kit within 90 days of contact. Post-hoc analysis included a multivariate regression, case-control evaluation of variables potentially associated with kit distribution. Results In total, 335 patients were included. Of 185 patients targeted for phone follow-up, 81 were reached (43.8%), and 254 received the letter alone. The primary outcome was achieved by 13 (5.1%) and 52 (64.2%) participants in the letter alone and letter plus phone contact groups, respectively ( p Conclusions In patients with OUD, those contacted by phone in addition to receiving a letter were significantly more likely to receive a naloxone kit than those contacted via letter alone. In addition to contact by phone, nonwhite race, prior participation in rehabilitation and active opioid prescription were associated with a higher rate of kit obtainment.

Complexities of sorbent regeneration of dialysate led me to look at other ways to use sorbents to remove uremic toxins. An oral sorbent containing cation and anion exchangers showed effective binding of potassium, phosphate, sodium, hydrogen, and ammonium (from urea) in vitro. Animal studies are ongoing. Carbon block columns can effectively bind organic and middle molecules toxins from the dialysate. Together, these two technologies have the potential to greatly simplify dialysis for end-stage renal disease patients.

This biography of serial inventor and medical doctor Willem J. ("Pim") Kolff is written by scientific/historical journalist Herman Broers. The book provides an objective and multi-perspective account of the life and work of Dr. Kolff, who put an undisputed mark on the history of organ-replacement devices by secretly inventing the first clinically functioning hemodialysis machine (in a Nazi-occupied Holland) and later in the United States leading the team that realized the first implantable fully artificial heart. Besides offering a solid historical account, the book also describes the present revival of innovation in the artificial kidney field and contains valuable lessons for a broad variety of readers. Suitable for an audience ranging from medical professionals interested in technology & technologists interested in medicine, to patients & their families, as well as policy makers & research funding parties. The review of this scientific/historic book was composed using the recommendations of Gupta for book reviews of scientific and technical books. Additionally, the reviewer team, composed of a biomedical engineer, a dialysis patient, and a nephrologist, tried to distil some lessons that may be learned from the book.

Our laboratory's in vitro studies showed that sodium citrate at concentrations from 23% to 47% is antibacterial, and a non-randomized clinical trial showed that its use as a lock solution in dialysis catheters greatly decreased the incidence of CRBSI. The licensee placed 30 ml bottles of 47% sodium citrate in kits containing the Ash Split Cath, with clear instructions to dilute the solution and inject only the catheter volume as a catheter lock. Gross misuse of the solution by one physician led to a serious adverse outcome. FDA instructed the company to remove the product from the market and issued a warning not to use concentrated citrate off-label. Sodium citrate at 23%-30% is widely used in Europe, without major complications or side effects. However, our EPO patent was contested by a Dutch company and they eventually prevailed.

The evolution of the diamond (111) surface as it undergoes reconstruction and subsequent graphene formation is investigated with angle-resolved photoemission spectroscopy, low energy electron diffraction, and complementary density functional theory calculations. The process is examined starting at the C(111)-(2x1) surface reconstruction that occurs following detachment of the surface adatoms at 920 {\deg}C, and continues through to the liberation of the reconstructed surface atoms into a free-standing monolayer of epitaxial graphene at temperatures above 1000 {\deg}C. Our results show that the C(111)-(2x1) surface is metallic as it has electronic states that intersect the Fermi-level. This is in strong agreement with a symmetrically {\pi}-bonded chain model and should contribute to resolving the controversies that exist in the literature surrounding the electronic nature of this surface. The graphene formed at higher temperatures exists above a newly formed C(111)-(2\times1) surface and appears to have little substrate interaction as the Dirac-point is observed at the Fermi-level. Finally, we demonstrate that it is possible to hydrogen terminate the underlying diamond surface by means of plasma processing without removing the graphene layer, forming a graphene-semiconductor interface. This could have particular relevance for doping the graphene formed on the diamond (111)surface via tuneable substrate interactions as a result of changing the terminating species at the diamond-graphene interface by plasma processing., Comment: 10 pages, 4 figures

The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction.

BackgroundSodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)].MethodsIn all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia.ResultsSignificant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P ConclusionsSZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate

To fully enable the development of diagnostic tools and progressive pharmaceutical drugs, it is imperative to understand the molecular changes occurring before and during disease onset and progression. Systems biology assessments utilizing multi-omic analyses (e.g. the combination of proteomics, lipidomics, genomics, etc.) have shown enormous value in determining molecules prevalent in diseases and their associated mechanisms. Herein, we utilized multi-omic evaluations, multi-dimensional analysis methods, and new cheminformatics-based visualization tools to provide an in depth understanding of the molecular changes taking place in preeclampsia (PRE) and gestational diabetes mellitus (GDM) patients. Since PRE and GDM are two prevalent pregnancy complications that result in adverse health effects for both the mother and fetus during pregnancy and later in life, a better understanding of each is essential. The multi-omic evaluations performed here provide new insight into the end-stage molecular profiles of each disease, thereby supplying information potentially crucial for earlier diagnosis and treatments.

In the 1980s, I led a team to build a hemodialysis machine with sorbent regeneration of dialysate, ultrafiltration control, and single-needle access. The BioLogic-HD™ was perfectly suited for home hemodialysis, but not for in-center or acute dialysis. The home dialysis market in the United States was decimated by HCFA's decision in 1987 to stop paying for home helpers. As a result, our Venture Capital partners stopped supporting our small company, and the BioLogic-HD was never marketed. There is criticism of nephrologists for the lack of innovation in dialysis, but the major problem has been the commercialization of new dialysis technology.

We present design and characteristics of a population inversion X-ray laser oscillator (XLO) at LCLS. We report on first experiments and future plans towards XLO demonstration. We also discuss necessary upgrades to LCLS for optimized XLO performance.