Review of: Daniel M. Kammen & David M. Hassenzahl, Should We Risk It: Exploring Environmental, Health, and Technological Problem Solving

A review of the book Should We Risk It: Exploring Environmental, Health, and Technological Problem Solving by Daniel M. Kammen & David M. Hassenzahl, (Princeton University Press 1999). Preface, acknowledgments, introduction, appendix, index. ISBN: 0-691-00426-9 [404 pp. $39.50. Cloth, 41 William Street, Princeton, NJ 08540]

Dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic with shear-dependent effects on platelet-collagen binding and thrombin generation

Heparin proteoglycans (HEP-PGs) carry standard heparin-mediated anticoagulant properties as well as novel antiplatelet functions, a combination that may be significant for targeting multiple pathways in a single therapy. Recent work developing semisynthetic HEP-PG mimetics has shown promising results also in vivo, however flow conditions in vitro that replicate in vivo hemodynamics have not been reported. In this work, we present several assays (platelet calcium mobilization, aggregometry, microfluidic tests at venous and arterial hemodynamics) to characterize specific mechanistic effects of dual antiplatelet and anticoagulant (APAC) constructs as mimetics of HEP-PGs. Three APACs with different conjugation levels of heparin chains (CL10, CL18, HICL) were shown to decrease platelet deposition to collagen surfaces in PPACK-treated whole blood at venous shear rate (200 s(-1)). FXIIa-inhibited whole blood (CTI: corn trypsin inhibitor, 40 mu g/mL) perfused over collagen/tissue factor showed reduced both platelet and fibrin deposition when treated with APACs. IC50 values for platelet and fibrin inhibition were calculated for each molecule at venous shear rate. Increasing the shear rate to arterial flows (1000 s(-1)) and using APAC as the sole anticoagulant, resulted in a more potent antiplatelet effect of APAC, suggesting an added effect on von Willebrand Factor (vWF) function. Additionally, APAC caused an inhibition of calcium mobilization specific to thrombin and collagen stimulation and a dose-dependent reduction in collagen-mediated platelet aggregation. Understanding the sensitivity of APAC activity to shear rate, platelet signaling and procoagulant pathways is important for applications in which APAC administration may have beneficial therapeutic effects.Peer reviewe

Prognostic factors for recovery following acute lateral ankle ligament sprain: a systematic review.

BACKGROUND: One-third of individuals who sustain an acute lateral ankle ligament sprain suffer significant disability due to pain, functional instability, mechanical instability or recurrent sprain after recovery plateaus at 1 to 5 years post injury. The identification of early prognostic factors associated with poor recovery may provide an opportunity for early-targeted intervention and improve outcome. METHODS: We performed a comprehensive search of AMED, EMBASE, Psych Info, CINAHL, SportDiscus, PubMed, CENTRAL, PEDro, OpenGrey, abstracts and conference proceedings from inception to September 2016. Prospective studies investigating the association between baseline prognostic factors and recovery over time were included. Two independent assessors performed the study selection, data extraction and quality assessment of the studies. A narrative synthesis is presented due to inability to meta-analyse results due to clinical and statistical heterogeneity. RESULTS: The search strategy yielded 3396 titles/abstracts after duplicates were removed. Thirty-six full text articles were then assessed, nine of which met the study inclusion criteria. Six were prospective cohorts, and three were secondary analyses of randomised controlled trials. Results are presented for nine studies that presented baseline prognostic factors for recovery after an acute ankle sprain. Age, female gender, swelling, restricted range of motion, limited weight bearing ability, pain (at the medial joint line and on weight-bearing dorsi-flexion at 4 weeks, and pain at rest at 3 months), higher injury severity rating, palpation/stress score, non-inversion mechanism injury, lower self-reported recovery, re-sprain within 3 months, MRI determined number of sprained ligaments, severity and bone bruise were found to be independent predictors of poor recovery. Age was one prognostic factor that demonstrated a consistent association with outcome in three studies, however cautious interpretation is advised. CONCLUSIONS: The associations between prognostic factors and poor recovery after an acute lateral ankle sprain are largely inconclusive. At present, there is insufficient evidence to recommend any factor as an independent predictor of outcome. There is a need for well-conducted prospective cohort studies with adequate sample size and long-term follow-up to provide robust evidence on prognostic factors of recovery following an acute lateral ankle sprain. TRIAL REGISTRATION: Prospero registration: CRD42014014471

Role Of Soluble Fibrin And Fibrin Degradation Products On Platelet Signaling During Trauma

Platelets and coagulation proteins work in concert to maintain proper blood flow through the vasculature. When an injury occurs, this hemostatic system must respond efficiently by sealing the wound to prevent excessive bleeding. Deviations from normal hemostasis arise in the clinic frequently; one such condition that is characterized by uncontrolled bleeding is known as trauma-induced coagulopathy (TIC). Severe platelet dysfunction is one key contributing factor to TIC, though its mechanistic causes are still yet to be fully understood. In order to investigate biological explanations for platelet dysfunction during trauma, various cell-based assays were designed and conducted in both healthy and patient populations. Specifically, intracellular calcium mobilization and other fluorescently tracked biomarkers were used as dynamic indicators of platelet activation in response to common agonists. Microtiter well plates prepared with liquid handling systems enabled high-throughput data collection and minimal manual pipetting. Significant platelet dysfunction in response to 31 unique stimulation conditions spanning several signaling pathways was observed in a cohort of trauma patients and tracked at multiple timepoints after initial hospital admission. In experiments designed to interrogate plasma effects on healthy platelet function, patient-derived plasma imparted significant inhibition which implied the presence of a unique soluble plasma species with downregulatory effects on endogenous and transfused platelets. With established knowledge of coinciding coagulant and lytic states during trauma, strategic addition of agonists to healthy platelet suspensions led to generation of soluble fibrin species and desensitization to agonist stimulation through glycoprotein VI (GPVI). Downstream platelet dysfunction was only observed when thrombin was added to the system to polymerize fibrin, whereas stimulation with other agonists or inhibition of various stages of coagulation had no effect on subsequent GPVI function. Maximal inhibition (~95%) was attained when tissue plasminogen activator (tPA) was also incorporated to lyse fibrin polymers into fibrin degradation products (FDP). Concentrations of a small FDP called D-dimer were elevated in trauma patient samples and inversely correlated with a quantitative measure of platelet function. Finally, preliminary results indicate potential binding affinity between platelet receptors and D-dimer. These results shed light on specific biological entities that may be responsible for platelet dysfunction in trauma patients

Role of Soluble Fibrin and Fibrin Degradation Products on Platelet Signaling During Trauma

Platelets and coagulation proteins work in concert to maintain proper blood flow through the vasculature. When an injury occurs, this hemostatic system must respond efficiently by sealing the wound to prevent excessive bleeding. Deviations from normal hemostasis arise in the clinic frequently; one such condition that is characterized by uncontrolled bleeding is known as trauma-induced coagulopathy (TIC). Severe platelet dysfunction is one key contributing factor to TIC, though its mechanistic causes are still yet to be fully understood. In order to investigate biological explanations for platelet dysfunction during trauma, various cell-based assays were designed and conducted in both healthy and patient populations. Specifically, intracellular calcium mobilization and other fluorescently tracked biomarkers were used as dynamic indicators of platelet activation in response to common agonists. Microtiter well plates prepared with liquid handling systems enabled high-throughput data collection and minimal manual pipetting. Significant platelet dysfunction in response to 31 unique stimulation conditions spanning several signaling pathways was observed in a cohort of trauma patients and tracked at multiple timepoints after initial hospital admission. In experiments designed to interrogate plasma effects on healthy platelet function, patient-derived plasma imparted significant inhibition which implied the presence of a unique soluble plasma species with downregulatory effects on endogenous and transfused platelets. With established knowledge of coinciding coagulant and lytic states during trauma, strategic addition of agonists to healthy platelet suspensions led to generation of soluble fibrin species and desensitization to agonist stimulation through glycoprotein VI (GPVI). Downstream platelet dysfunction was only observed when thrombin was added to the system to polymerize fibrin, whereas stimulation with other agonists or inhibition of various stages of coagulation had no effect on subsequent GPVI function. Maximal inhibition (~95%) was attained when tissue plasminogen activator (tPA) was also incorporated to lyse fibrin polymers into fibrin degradation products (FDP). Concentrations of a small FDP called D-dimer were elevated in trauma patient samples and inversely correlated with a quantitative measure of platelet function. Finally, preliminary results indicate potential binding affinity between platelet receptors and D-dimer. These results shed light on specific biological entities that may be responsible for platelet dysfunction in trauma patients

Role of Soluble Fibrin and Fibrin Degradation Products on Platelet Signaling During Trauma

Platelets and coagulation proteins work in concert to maintain proper blood flow through the vasculature. When an injury occurs, this hemostatic system must respond efficiently by sealing the wound to prevent excessive bleeding. Deviations from normal hemostasis arise in the clinic frequently; one such condition that is characterized by uncontrolled bleeding is known as trauma-induced coagulopathy (TIC). Severe platelet dysfunction is one key contributing factor to TIC, though its mechanistic causes are still yet to be fully understood. In order to investigate biological explanations for platelet dysfunction during trauma, various cell-based assays were designed and conducted in both healthy and patient populations. Specifically, intracellular calcium mobilization and other fluorescently tracked biomarkers were used as dynamic indicators of platelet activation in response to common agonists. Microtiter well plates prepared with liquid handling systems enabled high-throughput data collection and minimal manual pipetting. Significant platelet dysfunction in response to 31 unique stimulation conditions spanning several signaling pathways was observed in a cohort of trauma patients and tracked at multiple timepoints after initial hospital admission. In experiments designed to interrogate plasma effects on healthy platelet function, patient-derived plasma imparted significant inhibition which implied the presence of a unique soluble plasma species with downregulatory effects on endogenous and transfused platelets. With established knowledge of coinciding coagulant and lytic states during trauma, strategic addition of agonists to healthy platelet suspensions led to generation of soluble fibrin species and desensitization to agonist stimulation through glycoprotein VI (GPVI). Downstream platelet dysfunction was only observed when thrombin was added to the system to polymerize fibrin, whereas stimulation with other agonists or inhibition of various stages of coagulation had no effect on subsequent GPVI function. Maximal inhibition (~95%) was attained when tissue plasminogen activator (tPA) was also incorporated to lyse fibrin polymers into fibrin degradation products (FDP). Concentrations of a small FDP called D-dimer were elevated in trauma patient samples and inversely correlated with a quantitative measure of platelet function. Finally, preliminary results indicate potential binding affinity between platelet receptors and D-dimer. These results shed light on specific biological entities that may be responsible for platelet dysfunction in trauma patients

Durability of Response to Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, a Mitomycin-Containing Reverse Thermal Gel: OLYMPUS Trial Final Report.

PURPOSE: Our goal was to evaluate long-term safety and durability of response to UGN-101, a mitomycin-containing reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma. MATERIALS AND METHODS: In this open-label, single-arm, multicenter, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term followup; 23/41 patients (56%) remained in complete response after 12 months (95% CI 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs. CONCLUSIONS: Durability of response to UGN-101 with or without maintenance treatment is clinically meaningful, offering a kidney-sparing therapeutic alternative for patients with low-grade disease

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score \u3e40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient\u27s renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in \u3e15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma