Reducing Door-to-Puncture Times for Mechanical Thrombectomy in a Large Tertiary Hospital.

Background and Objectives: Endovascular therapy (EVT) for stroke has emerged as an important therapy for selected stroke patients, and shorter times to clot removal improve functional outcomes. EVT requires the close coordination of multiple departments and poses unique challenges to care coordination in large hospitals. We present the results of our quality improvement project that aimed to improve our door-to-groin puncture (DTP) times for patients who undergo EVT after direct presentation to our emergency department. Methods: We conducted time-motion studies to understand the full process of an EVT activation and conducted Gemba walks in multiple hospitals. We also reviewed the literature and interviewed stakeholders to create interventions that were implemented over 4 Plan-Do-Study-Act (PDSA) cycles. We retrospectively collected data starting from baseline and during every PDSA cycle. During each cycle, we studied the impact of the interventions, adjusted the interventions, and generated further interventions. A variety of interventions were introduced targeting all aspects of the EVT process. This included parallel processing to reduce waiting time, standardization of protocols and training of staff, behavioral prompts in the form of a stroke clock, and push systems to empower staff to facilitate the forward movement of the patient. A novel role-based communication app to facilitate group communications was also used. Results: Eighty-eight patients spanning across 22 months were analyzed. After the final PDSA cycle, the median DTP time was reduced by 36.5% compared with baseline (130 minutes (interquartile range [IQR] 111-140) to 82.5 minutes (IQR 74.8-100)). There were improvements in all phases of the EVT process with the largest time savings occurring in EVT decision to patient arrival at the angiosuite. Interventions that were most impactful are described. Discussion: EVT is a complex process involving multiple processes and local factors. Analysis of the process from all angles and intervening on multiple small aspects can add up to significant improvements in DTP times.

A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond.

BACKGROUND: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1). RESULTS: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01). CONCLUSIONS: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC. CLINICALTRIALS: gov Identifier: NCT03512756.

Using herbs medically without knowing their composition: are we playing Russian roulette?

Herbal medicine, a form of complementary and alternative medicine (CAM), is used throughout the world, in both developing and developed countries. The ingredients in herbal medicines are not standardized by any regulatory agency. Variability exists in the ingredients as well as in their concentrations. Plant products may become contaminated with bacteria and fungi during storage. Therefore, harm can occur to the kidney, liver, and blood components after ingestion. We encourage scientific studies to identify the active ingredients in herbs and to standardize their concentrations in all herbal preparations. Rigorous studies need to be performed in order to understand the effect of herbal ingredients on different organ systems as well as these substances' interaction with other medications.

Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo.

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.

USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases. The succinimide was identified as a key potency-driving motif, forming two strong hydrogen bonds to the allosteric pocket of USP7. Redesign of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by free energy perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.

Straight Versus Coiled Peritoneal Dialysis Catheters: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Despite a recent meta-analysis favoring straight catheters, the clinical benefits of straight versus coiled peritoneal dialysis catheters remain uncertain. We conducted a randomized controlled study to compare the complication rates associated with these 2 types of double-cuffed peritoneal dialysis catheters. STUDY DESIGN: Multicenter, open-label, randomized, controlled trial. SETTING & PARTICIPANTS: 308 adult continuous ambulatory peritoneal dialysis patients. INTERVENTION: Participants were randomly assigned to receive either straight or coiled catheters. OUTCOMES: The primary outcome was the incidence of catheter dysfunction requiring surgical intervention. Secondary outcomes included time to catheter dysfunction requiring intervention, catheter migration with dysfunction, infusion pain measured using a visual analogue scale, peritonitis, technique failure, and peritoneal catheter survival. RESULTS: 153 patients were randomly assigned to straight catheters; and 155, to coiled catheters. Among randomly assigned patients who underwent peritoneal dialysis, during a mean follow-up of 21 months, the primary outcome of catheter dysfunction or drainage failure occurred in 9 (5.8%) patients who received a coiled catheter and 1 (0.7%) patient who received a straight catheter. Straight catheters had 5.1% lower risk for catheter dysfunction (95% CI, 1.2%-9.1%; P=0.02). The HR of the primary outcome for coiled versus straight catheters was 8.69 (95% CI, 1.10-68.6; P=0.04). Patients who received a coiled catheter had similar risk for peritonitis but reported higher infusion pain scores than those who received straight catheters. LIMITATIONS: Generalizability to other peritoneal dialysis centers with lower volumes and other races and nationalities. CONCLUSIONS: Use of straight Tenckhoff catheters compared with coiled catheters reduced the rate of catheter dysfunction requiring surgical intervention. FUNDING: Funded by the Chinese University of Hong Kong. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02479295.

Randomized Controlled Trial on Adjunctive Lavage for Severe Peritonitis.

Background:In severe peritoneal dialysis (PD)-related peritonitis, patients' response to antibiotic can be poor. We postulated that adjunctive lavage may improve the outcome in severe cases by enhancing the removal of bacteria and inflammatory cells from the peritoneum.Methods:Severe PD peritonitis was defined as poor clinical response to empirical cefazolin/ceftazidime and a PD effluent (PDE) leukocyte count > 1,090/mm3 on day 3. Enrolled patients were randomized into either the lavage group (n = 20) or control group (n = 20). In the lavage group, continuous lavage by an automated PD machine from day 3 to 5 or 6 was performed, whereas the usual PD schedule was maintained in the control group. The primary outcome was treatment success. Post hoc analysis was also performed to compare the outcome between subgroups with different severity.Results:Baseline parameters were similar in the lavage and control groups, including PDE leukocyte count on day 3 (4,871/mm3 vs 4,143/mm3, p = 0.46). Treatment success rates were high in both groups (75% vs 70%, p = 0.72). C-reactive protein (CRP) on day 3 was found to be the only predictor of treatment failure and was used to stratify all patients into tertiles of severity. Whilst a significant decline in treatment success was evident across the tertiles of increasing CRP in the control group (100% vs 85.7% vs 28.6%, p = 0.005), treatment success was relatively maintained in the lavage group (85.7% vs 71.4% vs 66.7%, p = 0.43).Conclusions:Adjunctive lavage did not improve the overall outcome, although it may be beneficial for the more severe peritonitis patients who have high CRP.

Extended Experience in the Use of Antibiotic Lock for Eradication of Biofilm Bacteria on Tenckhoff Catheter.

Whilst antibiotic lock is effective to eradicate biofilm bacteria on hemodialysis catheters, this adjunctive method has scarcely been tested in peritoneal dialysis (PD) patients. After our previous successful experience of its use to salvage two Tenckhoff catheters, we encountered another patient with problematic biofilm-associated PD peritonitis who strongly refused catheter removal. As a result, antibiotic lock was given once daily, initially, with continuation of the usual PD schedule. However, relapsing peritonitis could not be prevented until we administered antibiotic lock without dialysate in the abdomen, which led to successful eradication of biofilm bacteria. To investigate the significance of having "dry abdomen" during antibiotic lock treatment, we injected an equivalent amount of contrast into the Tenckhoff catheter under fluoroscopy. We observed that the catheter lock solution could be retained over a long period of time only with "dry abdomen," whereas rapid dissipation of the lock solution occurred in the presence of dialysate. We concluded that whilst antibiotic lock in a once-daily regimen can be highly effective against biofilm bacteria on a Tenckhoff catheter, it is essential to withhold PD exchanges during the dwell of antibiotic lock to prevent it from dissolving into the surrounding dialysate.

A Case of Adult-Onset Kawasaki Disease Shock Syndrome Complicated by Coronary Aneurysms.

We present a case of adult-onset Kawasaki disease shock syndrome complicated by coronary aneurysms, in which profound hypotension and reduced left ventricular ejection fraction were treated successfully with intravenous immunoglobulin. The diagnosis of Kawasaki disease shock syndrome should be considered in cases of rapidly developing shock, particularly in young adults with an infectious prodrome, in whom it may be under-recognized. We advocate for early identification to minimize delays in treatment with intravenous immunoglobulin, which reverses left ventricular dysfunction and decreases risk of long-term sequelae such as coronary artery aneurysms.

Nous présentons un cas de syndrome de choc dans la maladie de Kawasaki survenu à l'âge adulte et compliqué par des anévrismes des artères coronaires, chez lequel l'injection d'immunoglobulines par voie intraveineuse a permis de traiter avec succès une hypotension prononcée et une fraction d'éjection ventriculaire gauche réduite. Le diagnostic de syndrome de choc dans la maladie de Kawasaki devrait être envisagé dans les cas de choc évoluant rapidement, en particulier chez les jeunes adultes en phase prodromique d'une infection, chez lesquels cette affection peut passer inaperçue. Nous préconisons un diagnostic précoce afin de réduire au minimum les délais du traitement aux immunoglobulines par voie intraveineuse qui a pour effet d'inverser la dysfonction ventriculaire gauche et de diminuer le risque de séquelles à long terme, comme l'anévrisme des coronaires.

Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897.

Background: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children. To date, no vaccine is approved for the broad population of healthy infants. MEDI8897, a potent anti-RSV fusion antibody with extended serum half-life, is currently under clinical investigation as a potential passive RSV vaccine for all infants. As a ribonucleic acid virus, RSV is prone to mutation, and the possibility of viral escape from MEDI8897 neutralization is a potential concern. Methods: We generated RSV monoclonal antibody (mAb)-resistant mutants (MARMs) in vitro and studied the effect of the amino acid substitutions identified on binding and viral neutralization susceptibility to MEDI8897. The impact of resistance-associated mutations on in vitro growth kinetics and the prevalence of these mutations in currently circulating strains of RSV in the United States was assessed. Results: Critical residues identified in MARMs for MEDI8897 neutralization were located in the MEDI8897 binding site defined by crystallographic analysis. Substitutions in these residues affected the binding of mAb to virus, without significant impact on viral replication in vitro. The frequency of natural resistance-associated polymorphisms was low. Conclusions: Results from this study provide insights into the mechanism of MEDI8897 escape and the complexity of monitoring for emergence of resistance.

Clinical study on low-molecular weight heparin infusion as anticoagulation for nocturnal home haemodialysis.

AIM: This study was conducted to evaluate low-molecular weight heparin (LMWH) as anticoagulation for nocturnal home haemodialysis (NHHD). While its longer half-life may cause drug accumulation in frequent dialysis, the essential need of a supplementary intra-dialytic bolus for the sleeping patients also renders LMWH's use impractical. METHODS: The recruited patients, who were on alternate-day 8 h haemodialysis, were randomized to receive either nadroparin or unfractionated heparin (UFH) for a week. They underwent crossover to receive the alternate anticoagulant in the next week. A nadroparin infusion regimen was adopted to enhance its practicability, which consisted of a loading dose of 35 IU/kg and a continuous infusion of 10 IU/kg per hour for 6 h. RESULTS: A total of 12 NHHD patients were recruited. With nadroparin infusion, the mean anti-Xa levels at the 2nd , 4th , 6th and 8th hours of dialysis were 0.46 ± 0.11, 0.55 ± 0.14, 0.61 ± 0.15 and 0.45 ± 0.15 IU/mL respectively. Comparing to UFH, which offered satisfactory anticoagulation according to the activated partial thromboplastin time, nadroparin-treated dialysis achieved similar thrombus scores and dialyser urea/creatinine clearances at the end of haemodialysis. During the post-dialysis period, one patient demonstrated residual LMWH effect (anti-Xa level 0.09 IU/mL) on the next day, whereas none had detectable anti-Xa activities 2 days afterwards upon next dialysis. CONCLUSIONS: Low-molecular weight heparin infusion is practical and effective as anticoagulation for NHHD. It can be safely used in an alternate-day haemodialysis schedule. A close monitoring for LMWH accumulation is recommended if long dialysis is performed daily.

Venous air embolism related to the use of central catheters revisited: with emphasis on dialysis catheters.

Venous air embolism is a dreaded condition particularly relevant to the field of nephrology. In the face of a favourable, air-to-blood pressure gradient and an abnormal communication between the atmosphere and the veins, air entrance into the circulation is common and can bring about venous air embolism. These air emboli can migrate to different areas through three major routes: pulmonary circulation, paradoxical embolism and retrograde ascension to the cerebral venous system. The frequent undesirable outcome of this disease entity, despite timely and aggressive treatment, signifies the importance of understanding the underlying pathophysiological mechanism and of the implementation of various preventive measures. The not-that-uncommon occurrence of venous air embolism, often precipitated by improper patient positioning during cervical catheter procedures, suggests that awareness of this procedure-related complication among health care workers is not universal. This review aims to update the pathophysiology of venous air embolism and to emphasize the importance of observing the necessary precautionary measures during central catheter use in hopes of eliminating this unfortunate but easily avoidable mishap in nephrology practice.

Correlation between activated partial thromboplastin time and anti-Xa activity in patients who received low-molecular weight heparin as anticoagulation for haemodialysis.

Plasma anti-Xa activity, the recommended test to monitor low-molecular weight heparin (LMWH) therapy, is not readily available in many laboratories. In our clinical trials on the use of LMWH as anticoagulation for haemodialysis, a consistent prolongation of APTT in addition to the elevated anti-Xa activity was observed in the patients after LMWH administration. Hence, the paired anti-Xa activity and APTT data were re-analyzed. The APTT ratio, which was the proportional change in APTT from the baseline value after LMWH administration, was found to have a strong correlation with anti-Xa activity (coefficient of determination, R 2 = 0.72, P < 0.001). In the receiver operating characteristic analysis, the APTT ratio was also found to be an excellent predictor of therapeutic anti-Xa activity ≧0.5 IU/mL (area under curve = 0.93, P < 0.001). The sensitivity was 88% and the specificity was 83.3% when an APTT ratio ≧1.4 was used as the cut point to predict the achievement of therapeutic anti-Xa activity. Our results illustrated that APTT is a potentially useful screening test to assess the degree of anticoagulation achieved by LMWH during haemodialysis, if the testing for plasma anti-Xa activity is not available.

Antibiotic Lock in Tenckhoff Catheter for Biofilm-Associated Peritonitis.

Biofilm bacteria in the Tenckhoff catheter are notoriously difficult to eradicate. They are the potential sources of relapsing or repeat peritonitis among peritoneal dialysis (PD) patients. Inadequate penetration into biofilms by standard intraperitoneal antibiotics, as well as a lack of effective adjunctive treatment, leads to a high rate of Tenckhoff catheter loss as a result of biofilm bacteria. In hemodialysis, on the other hand, catheter-related bloodstream infection caused by biofilm bacteria does not necessarily lead to a loss of catheter. Here, the use of antibiotic lock in conjunction with systemic antibiotics has been shown to be an effective treatment. In this case report, we present 2 cases of biofilm-associated PD peritonitis. The success in salvaging the Tenckhoff catheters by antibiotic lock suggested a potentially similar efficacy in PD patients using this adjunctive treatment, which has not been thoroughly investigated in the literature. Relevant clinical trials are necessary to evaluate whether antibiotic lock is also effective in eradicating biofilm bacteria in the Tenckhoff catheter.

Low-molecular weight heparin infusion as anticoagulation for haemodialysis.

BACKGROUND: Low-molecular weight heparin (LMWH) is commonly used as an anticoagulant for haemodialysis by a single-bolus injection. However, its application in extended haemodialysis has been infrequently studied. In particular, for nocturnal home haemodialysis patients sleeping throughout treatment, the need for additional intradialytic bolus might render the use of LMWH impractical. To overcome this limitation, we changed traditional bolus injections to continuous infusion. We first tested our method among in-centre 4-h haemodialysis patients to establish a feasible and safe infusion regimen before utilizing it in extended dialyses at home. METHODS: Recruited patients were given nadroparin (standardized at 65 IU/kg) as an anticoagulant for haemodialysis. They were first randomized to receive nadroparin either by bolus injection or infusion. Afterwards, the patients underwent crossover to receive the alternate method of LMWH anticoagulation. The degrees of anticoagulation and bleeding complications were compared. RESULTS: Sixteen haemodialysis patients were recruited. After nadroparin administration, anti-Xa levels at the first hour were significantly higher by the bolus than the infusion methods (0.68 ± 0.10 versus 0.49 ± 0.10 IU/mL, P < 0.001) and were similar by the second hour (0.56 ± 0.10 versus 0.55 ± 0.11 IU/mL, P = 0.64). At the sixth hour, anti-Xa levels by the infusion method were significantly higher (0.35 ± 0.13 versus 0.25 ± 0.10 IU/mL, P < 0.001), suggesting the infusion approach required a dosage reduction. There were no bleeding events reported in either method. CONCLUSIONS: LMWH infusion is feasible and safe. The method avoids early excessive anticoagulation caused by bolus injection and reduces the LMWH dose. Future studies should be conducted to evaluate LMWH infusion in extended haemodialysis treatment.

Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083).

The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin-proteasome system (UPS) mediated protein degradation, endoplasmic reticulum-associated degradation (ERAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell death. In tumor bearing mice, oral administration of 71 causes rapid accumulation of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to sustained antitumor activity in in vivo xenograft models of both solid and hematological tumors. 71 has been taken into phase 1 clinical trials in patients with multiple myeloma and solid tumors.

Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis.

p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.

The B-type channel is a major route for iron entry into the ferroxidase center and central cavity of bacterioferritin.

Bacterioferritin is a bacterial iron storage and detoxification protein that is capable of forming a ferric oxyhydroxide mineral core within its central cavity. To do this, iron must traverse the bacterioferritin protein shell, which is expected to occur through one or more of the channels through the shell identified by structural studies. The size and negative electrostatic potential of the 24 B-type channels suggest that they could provide a route for iron into bacterioferritin. Residues at the B-type channel (Asn-34, Glu-66, Asp-132, and Asp-139) of E. coli bacterioferritin were substituted to determine if they are important for iron core formation. A significant decrease in the rates of initial oxidation of Fe(II) at the ferroxidase center and subsequent iron mineralization was observed for the D132F variant. The crystal structure of this variant shows that substitution of residue 132 with phenylalanine caused a steric blockage of the B-type channel and no other material structural perturbation. We conclude that the B-type channel is a major route for iron entry into both the ferroxidase center and the iron storage cavity of bacterioferritin.

Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity.

Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. Surprisingly, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. Bacterial A2Ms are located in the periplasm where they are believed to provide protection to the cell by trapping external proteases through a covalent interaction with an activated thioester. Here we report the crystal structures and characterization of Salmonella enterica ser. Typhimurium A2M in different states of thioester activation. The structures reveal thirteen domains whose arrangement displays high similarity to proteins involved in eukaryotic immune defence. A structural lock mechanism maintains the stability of the buried thioester, a requirement for its protease-trapping activity. These findings indicate that bacteria have developed a rudimentary innate immune system whose mechanism mimics that of eukaryotes.