Effectiveness Endpoint Research Articles

Abstract CT230: A prospective, multi-center, randomized, double-arm trial to determine the impact of the Perimeter B-Series OCT System on positive margin rates in breast conservation surgery

Abstract Background: Optical coherence tomography (OCT) is a high-resolution tissue-imaging modality that enables real-time imaging up to 2mm deep. The Perimeter B-Series OCT System combines wide field-OCT (WF-OCT) with an artificial intelligence system, ImgAssist, to assist clinicians in the detection of lesions suspicious for breast cancer. The objective of this investigational device trial is to assess adjunctive Perimeter B-Series OCT System use compared to standard care in identifying and addressing positive margins intraoperatively. Design: Prospective, multicenter, randomized, double-arm trial in females with biopsy-confirmed cancer undergoing breast conservation surgery (BCS) (NCT05113927). Following lumpectomy and standard-of-care intraoperative margin assessment participants will be randomized to a device or control arm (2:1 schema). Controls may undergo intraoperative pathology or frozen section analysis, per routine. WF-OCT will be done on all device arm specimens, with an opportunity to excise tissue from the lumpectomy cavity post-analysis. The new margin will be imaged with WF-OCT and the surgeon may take up to a maximum of 6 total shaves, including up to 2 shaves in each orientation. Eligibility: Adult females undergoing breast conservation surgery for biopsy-confirmed Stage 0-III invasive ductal and/or DCIS are eligible, including post-neoadjuvant therapy. Pregnant or lactating, those with Stage IV cancer, lobular carcinoma as primary diagnosis, previous ipsilateral breast surgery, multi-centric or bilateral disease, use of cryolocalization, or any treatment affecting margin integrity will be excluded. Specific Aim: The study hypothesis is that use of the Perimeter B-Series OCT System in BCS will reduce the proportion of subjects with at least 1 unaddressed positive margin. The primary endpoint is occurrence of aat least 1 unaddressed positive margin for a subject. The secondary endpoint is the number of unaddressed positive margins per subject. Safety includes Adverse Events; false-positive shaves per subject (device arm); and BREAST-Q Satisfaction with Breasts subscale. Other outcomes are total excised tissue volume, initial and all procedures including repeat surgeries; margin-level effectiveness (sensitivity, specificity, NPV and PPV); and operative time. Statistical Methods: The study was powered via the primary endpoint, assuming a 15% unaddressed margin rate, 90% power, 2:1 device-to-control ratio, and 10% loss of subjects due to screen or device failure. Both the primary and secondary effectiveness endpoints are based on within-subject comparison of the 2 treatments in the device arm (SOC+WF-OCT). Planned Accrual: 309 subjects (206 device, 103 control) will be enrolled at 8 centers over approximately 12 months. Citation Format: David Rempel, Andrew Berkeley, David Moos, Allison A. DiPasquale, Maryam Elmi, Richard E. Fine, Marie Lee, Bridget O’Brien, John F. Turner, Lee G. Wilke, Alastair Thompson. A prospective, multi-center, randomized, double-arm trial to determine the impact of the Perimeter B-Series OCT System on positive margin rates in breast conservation surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT230.

Outcomes from the ClotTriever Outcomes Registry show symptom duration may underestimate deep vein thrombus chronicity

ObjectiveThe all-comer ClotTriever Outcomes registry assessed indicators of thrombus chronicity in patients with acute, subacute, and chronic lower extremity deep vein thrombosis (DVT). The effectiveness of the ClotTriever System (Inari Medical, Irvine, CA) by chronicity subgroup was also assessed and reported here in this subanalysis. MethodsAll-comer patients with lower extremity DVT were enrolled, with no limitation based on the patients’ symptom duration. Chronicity was assessed three times and compared: before the procedure based on symptom duration, during the procedure based on available pre-thrombectomy imaging, and visual inspection of the extracted thrombus morphology after thrombectomy. Patients were grouped into acute, subacute, and chronic subgroups according to their post-thrombectomy thrombus chronicity based on thrombus morphology. Analyses on baseline and procedural characteristics along with thrombus removal were performed across subgroups. The effectiveness of thrombus removal was determined by Marder scores adjudicated by an independent core laboratory, with a prespecified primary effectiveness end point of complete or near-complete (≥75%) thrombus removal. ResultsOf the 260 treated limbs from 250 patients, using symptom duration alone, 70.7% were considered acute, 20.9% subacute, and 8.4% chronic. Upon visual inspection, the extracted thrombus chronicity was approximately one-third in each subgroup: 32.7% had acute thrombus, 35.4% subacute thrombus, and 31.9% chronic thrombus. Chronicity assessed using symptom duration alone mismatched the post-thrombectomy chronicity in 55.1% of limbs (P < .0001) with 49.0% being more chronic than suggested by the patients’ duration of symptoms. Chronicity assessed using pre-thrombectomy imaging mismatched the post-thrombectomy chronicity in 17.5% of limbs (P < .0001). No patients received thrombolytics and 99.6% were treated in a single session. Complete or near-complete thrombus removal was achieved in a high percentage of limbs regardless of thrombus chronicity: 90.8%, 81.9%, and 83.8% in limbs with acute, subacute, and chronic thrombus, respectively. ConclusionsThis subanalysis from the all-comer ClotTriever Outcomes registry demonstrates that extracted thrombus in DVT may be more chronic than suggested by the patients’ duration of symptoms. The addition of imaging is helpful to determine the ability of thrombus to respond to therapy. Irrespective of thrombus chronicity, the ClotTriever system can be effective at removing acute, subacute, and chronic thrombus in a single-session procedure without the need for thrombolytics.

A Cost-Effectiveness Study Comparing Ready-to-Administer and Traditional Vial-and-Syringe Method for Opioids.

ObjectiveThe purpose of this study was to develop a cost-effectiveness model for manufacturer-prepared prefilled ready-to-administer (RTA) syringe products versus the traditional vial-and-syringe administration of intravenous (IV) opioids.MethodsCost parameters included cost of manufacturer-prepared prefilled RTA syringe product, traditional vial and syringe, drug preparation, drug administration, drug waste, and severity of error. Effectiveness endpoint included number of preparation and administration errors in each comparator arm. Simple decision tree was used, and incremental cost-effectiveness ratio (ICER) was calculated as the reduction in the incremental errors per observation with RTA compared with traditional vial-and-syringe method. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were conducted to test the robustness of the model. TreeAge Pro software was used to create and analyze the decision model. All the cost parameters were converted to USD 2021.ResultsBase-case analysis showed that the cost of the RTA arm was lower by $182.61 and the number of errors in the RTA arm was lower by 94%, compared with the traditional vial-and-syringe arm. The manufacturer-prepared prefilled RTA syringe product was found to be cost-effective with an incremental savings of $22,554 per additional error avoided. Sensitivity analysis showed that ICER value was most sensitive to the probability of errors; however, the results were robust in showing that RTA is the preferred cost-effective option, when both the costs and effectiveness parameters were varied substantially.ConclusionThis economic evaluation analyzed costs of using manufacturer-prepared prefilled RTA syringe product IV opioids and incremental benefits in terms of reduced errors, adverse events, and their associated costs. Manufacturer-prepared prefilled RTA syringe product was found to be cost-effective, demonstrating cost savings by reduction in the error rates. Integrating and adopting RTA syringe products within a health system could play an important role in improving care, building efficiency, increasing patient safety, and saving money.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-022-00402-z.

One-year results of the GORE EXCLUDER Conformable AAA Endoprosthesis system in the United States regulatory trial

ObjectiveTo report the 1-year clinical outcomes from the GORE EXCLUDER Conformable AAA Endoprosthesis system in the US regulatory trial. MethodsThe study is a prospective, multicenter, investigational device exemption clinical trial at 31 US sites with core laboratory assessment of imaging and independent event adjudication. The primary safety (incidence of major adverse events at 30 days) and effectiveness end points (successful aneurysm treatment at 1 year) were assessed in a cohort of patients with abdominal aortic aneurysms (AAAs). ResultsWe enrolled 80 patients between December 19, 2017, and February, 27, 2019. The mean maximum aortic diameter was 57.7 ± 7.95 mm (range, 42.5-82.7 mm) with an average patient age of 73.5 ± 8.14 years (range, 56-96 years). Overall technical success was 100% (80/80). The mean hospital length stay was 1.2 ± 0.6 days (range, 1-4 days). No primary safety end point events were observed, including no death, stroke, myocardial infarction, bowel ischemia, paraplegia, respiratory failure, renal failure, procedural blood loss of more than 1000 mL, or thromboembolic events including limb occlusion or distal emboli. There were no type I or III endoleaks detected on the 1-, 6-, or 12-month follow-up computed tomography scans. There were no stent fractures, device migrations (≥10 mm), AAA ruptures, or conversions to open surgical repair observed. Two patients had AAA sac growth of more than 5 mm at 1 year owing to type II endoleaks. There were no aneurysm-related deaths within the 12-month follow-up, and freedom from aneurysm-related mortality was 100% through 1 year. ConclusionsThe safety and effectiveness of the GORE EXCLUDER Conformable AAA Endoprosthesis system has been demonstrated with 98.5% freedom from primary effectiveness end point events at 1 year and 100% freedom from primary safety end point events assessed through 30 days.

Assessing the neurotoxicity of airborne nano-scale particulate matter in human iPSC-derived neurons using a transcriptomics benchmark dose model

Airborne nano-scale particulate matter (nPM) exposure is a risk factor for neurological diseases. However, to date, there has been no comprehensive evaluation of ambient nPM's neurotoxicity. We examined the toxic effects of nPM on human neurons derived from induced pluripotent stem cells (iPSCs) at doses ranging from 0 to 200 μg/mL, and employed whole-genome RNA-sequencing in different dose groups to gain further insight into the neurotoxicity of ambient nPM. Our findings showed that nPM was absorbed by neurons, and induced a variety of toxic effects. The apical benchmark dose lower confidence bound (aBMDL) values of each effect endpoint were ranked as follows, in ascending order: mitochondrial membrane potential, neurite length, early apoptosis, cell viability. BMD analysis based on transcriptomic data revealed that the point of departure (PoD) of the 20 pathways with the lowest p-values (0.75 μg/mL), the top 20 upstream regulators (0.79 μg/mL) and the neurological diseases (0.77 μg/mL) could be appropriate for nPM neurotoxicity evaluation. The transcriptomic PoDs (tPoDs) were similar to apical PoDs (aPoDs) since their absolute fold differences were within 10-fold. Further analysis of the transcriptomic data revealed that nPM exposure could disturb the pathways related to ferroptosis, neurotransmitters, xenobiotic metabolism, etc., which might be critical in regulating nPM neurotoxicity. We also found that low-dose nPM induced cytokine signaling pathways, while high doses of nPM activated cell-cycle regulation and DNA repair pathways. Our results indicate that BMD modeling based on transcriptomic data could be useful in illustrating the neurotoxic mechanism, and also could be a promising method for evaluating the potential health risks of nPM.

100-LB: Glycemic Control Using Recommended Settings in Youth and Adults with Type 1 Diabetes (T1D) —Minimed 780G System with the Calibration-Free Guardian 4 Sensor Results

Background: Safety and effectiveness outcomes of individuals using the MiniMed™ 780G system with the no-calibration Guardian™ 4 sensor during the first three months of use were analyzed. Methods: Participants (N=176, aged 7-75 years) with T1D used the Conformitè Europëenne-marked MiniMed™ 780G system. Safety and effectiveness endpoints (mean A1C, sensor glucose [SG], percentage of time spent at SG ranges and glucose variability) were collected over three months and summarized. Endpoints were also assessed when recommended settings (target of 100mg/dL and active insulin time of 2-3 hours) were used. Results: There was no DKA or severe hypoglycemia. At 3 months, A1C was 7.1% (N=164) , 7.2% (N=101) and 6.8% (N=63) for overall, pediatric and adult participants, respectively. Additional glycemic metrics are shown (Table) . With recommended settings, time spent in target range (TIR, 70-180 mg/dL) was 74.7% (N=119) , 72.7% (N=65) and 77.0% (N=54) , respectively, and time spent below range (TBR&amp;lt;70mg/dL) was 2.1%, 2.4% and 1.7%, respectively. Conclusion: This analysis demonstrates that individuals safely exceeded international consensus-recommended TIR and TBR goals when using the MiniMed™ 780G system with the Guardian™ 4 sensor. These results mirror those of the pivotal trial during use of the calibration-requiring Guardian™ sensor 3. Disclosure R. A. Vigersky: Employee; Medtronic. C. Pihoker: None. R. Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. J. Reed: None. J. Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Speaker’s Bureau; Lilly Diabetes. D. I. Shulman: Advisory Panel; Medtronic. R. H. Slover: None. J. Thrasher: Advisory Panel; Eli Lilly and Company, Medtronic, Board Member; Medtronic, Consultant; Eli Lilly and Company, Medtronic, Research Support; Eli Lilly and Company, Medtronic, Novo Nordisk, Speaker’s Bureau; Bayer AG, Eli Lilly and Company, Medtronic, Sanofi. X. Chen: Employee; Medtronic, Medtronic. M. Liu: None. T. L. Cordero: Employee; Medtronic, Medtronic. B. W. Bode: Advisory Panel; CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Consultant; Bigfoot Biomedical, Inc., Research Support; Abbott, Beta Bionics, Inc., Dexcom, Inc., Diasome, Dompé, Eli Lilly and Company, Insulet Corporation, IQVIA Inc., Jaeb Center for Health Research, Medtronic, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanvita Medical, Senseonics, ViaCyte, Inc., Speaker’s Bureau; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; AgaMatrix, Glytec, LLC. M. Vella: Employee; Medtronic. A. S. Rhinehart: Employee; Medtronic, Stock/Shareholder; Medtronic. J. Shin: Employee; Medtronic. R. L. Brazg: Research Support; Abbott Diabetes, Lilly Diabetes, Medtronic, Novo Nordisk, Roche Diagnostics, Senseonics. B. A. Buckingham: Advisory Panel; Arecor, Lilly Diabetes, Medtronic, Other Relationship; Insulet Corporation, Research Support; Insulet Corporation, Lilly Diabetes, Medtronic. A. L. Carlson: Advisory Panel; MannKind Corporation, Employee; Bright Health Group, Other Relationship; Medtronic, Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi, UnitedHealth Group. K. B. Kaiserman: Advisory Panel; Medtronic, Consultant; Medtronic, Employee; MannKind Corporation, Research Support; Medtronic, Speaker’s Bureau; Medtronic, Stock/Shareholder; MannKind Corporation. M. Kipnes: None. D. R. Liljenquist: None. A. Philis-tsimikas: Advisory Panel; Bayer AG, Novo Nordisk, Research Support; Lilly Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Viking Therapeutics.

Multicenter, Double-Blinded, Randomized, Active-Sham Controlled Clinical Study Design to Assess the Safety and Effectiveness of a Novel High Frequency Electric Nerve Block System in the Treatment of Post-Amputation Pain (The QUEST Study).

BackgroundChronic pain that follows amputation of a limb is reported as “one of the most severe pains in the human experience,” due to the magnitude of tissue injury and the multiple potential of pain generators at the local peripheral, spinal, and cortical levels. The Altius® System was developed to deliver high-frequency nerve block (HFNB) therapy via a cuff electrode applied to the peripheral nerve(s) and an implantable pulse generator. We report a novel clinical trial design for the first study of an active-implantable medical device in subjects with lower-limb post-amputation pain utilizing a multicenter, double-blinded, randomized, active-sham controlled clinical study protocol called QUEST, which is an ongoing investigational device exemption study to support United States Food and Drug Administration approval.MethodsThe study enrollment of 180 subjects was completed in September 2021. Subjects were randomized 1:1 to the treatment group or the active-sham control group for the 3-month primary effectiveness and safety endpoints. After month 3, the active-sham control program group crossed over to the treatment program group and all subjects continued to the 12-month study endpoint. Study effectiveness success is determined by a superiority test between responder rates in the treatment and control groups at 3 months. A responder is defined as someone who experiences a 50% or greater reduction in pain scores – after a 30-minute treatment session – for more than 50% of all pain episodes in which the treatment was used.DiscussionThe QUEST study design employs an active-sham control group to objectively assess the effectiveness of HFNB therapy. Additionally, the electronic diary repeated measures data collection in QUEST is expected to reduce the intra-subject variation typically observed in pain treatment studies. Finally, the longitudinal measurement of health-related quality of life and use of pain medication may, for example, show effectiveness in reducing opioid use over time.

Polymer-Based Versus Polymer-Free Stents in High Bleeding Risk Patients: Final 2-Year Results From Onyx ONE.

Resolute Onyx polymer-based zotarolimus-eluting stents (ZES) were noninferior in safety and effectiveness to BioFreedom polymer-free biolimus A9-coated stents (DCS) in high-bleeding-risk (HBR) patients treated with 1-month dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) at 1 year. This study reports the final 2-year results of the randomized Onyx ONE trial. The Onyx ONE (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy (DAPT) for High-Bleeding Risk Patients) trial randomly assigned HBR patients to treatment with ZES or DCS. Following 1-month DAPT, event-free patients received SAPT (either aspirin or a P2Y12 inhibitor at physician discretion). The primary safety endpoint, a composite of cardiac death, myocardial infarction, or stent thrombosis at 1 year, was determined at 1 year. Rates of primary and secondary endpoints were calculated after final follow-up at 2 years. A total of 1,003 patients were randomly allocated to ZES and 993 patients to DCS. Follow-up was complete in 980 (97.7%) ZES patients and 962 (96.9%) DCS patients at 2 years. The primary safety endpoint occurred in 208 (21.2%) patients in the ZES group and 199 (20.7%) patients in the DCS group (risk difference: 0.5%; 95%CI: -3.1% to 4.2%; P=0.78) at 2 years without significant differences in individual components of the composite endpoint. The secondary effectiveness endpoint occurred in 217 (22.1%) patients in the ZES group and 202 (21.0%) patients in the DCS group (risk difference: 1.1%; 95%CI: -2.5% to 4.8%; P=0.54). Among patients at HBR treated with 1-month DAPT followed by SAPT, the Resolute Onyx polymer-based ZES had similar 2-year outcomes for the primary safety and secondary effectiveness endpoint compared with the BioFreedom polymer-free DCS. (A Randomized Controlled Trial With Resolute Onyx in One Month Dual Antiplatelet Therapy [DAPT] for High-Bleeding Risk Patients [Onyx ONE]; NCT03344653).

Analysis of bowel function, urogenital function, and long-term follow-up outcomes associated with robotic and laparoscopic sphincter-preserving surgical approaches to total mesorectal excision in low rectal cancer: a retrospective cohort study

ObjectiveThe present study comparatively analyzed short-term clinical effectiveness and long-term follow-up endpoints associated with robotic-assisted sphincter-preserving surgery (RAS) and laparoscopic-assisted sphincter-preserving surgery (LAS) when used to treat low rectal cancer.MethodWithin such a single-center retrospective cohort analysis, low rectal cancer patients that underwent RAS (n=200) or LAS (n=486) between January 2015 and beginning of July 2018 were enrolled.ResultsThe mean operative durations in the RAS and LAS cohorts were 249±64 min and 203±47 min, respectively (P<0.001). Temporary ileostomy rates in the RAS and LAS cohorts were 64.5% and 51.6% (P = 0.002). In addition, major variations across such cohorts regarding catheter removal timing, time to liquid intake, time to first leaving bed, and length of hospitalization (all P<0.001). This distal resection margin distance within the RAS cohort was diminished in comparison to LAS cohort (P=0.004). For patients within the LAS cohort, the time required to recover from reduced urinary/female sexual function was > 6 months post-surgery (P<0.0001), whereas within the RAS cohort this interval was 3 months (P<0.0001). At 6 months post-surgery, male sexual function within RAS cohort was improved in comparison to LAS cohort (P<0.001). At 6 months post-surgery, Wexner scores revealed similar results (P<0.001). No major variations within overall or disease-free survival were identified across these cohorts at 3 or 5 years post-surgery.ConclusionRobotic sphincter-preserving surgery is a safe and effective surgical technique in low rectal patients in terms of postoperative oncological safety and long-term endpoints. And the RAS strategy provides certain additional benefits with respect to short-term urogenital/anorectal functional recovery in treated patients compared to LAS.

Plastics in scene: A review of the effect of plastics in aquatic crustaceans

Plastic pollution in aquatic environments is present in all compartments from surface water to benthic sediment, becoming a topic of emerging concern due to the internalization, retention time, and its effects on aquatic biota. Crustacea with nearly 70,000 species, broad distribution and different roles in the trophic webs is a significant target of the increasing plastic pollution. At least 98 publications in the last 10 years report the impact of plastics in crustaceans, all suggesting that this taxon is at high risk for ecosystem disadvantage by plastic contamination loads. This review compiles the current knowledge on physiological effects (endpoints) by plastic contamination analyzed in crustaceans in the last 10 years, highlighting their use as model species for ecotoxicological tests, sentinels species and bioindicators. Plastic contamination analyzed in this review includes macroplastic, microplastic, and nanoplastic, in a wide variety of types. The studies were focused on 38 marine species with an economic interest in fisheries and aquaculture; 14 freshwater with a higher frequency in standard test species and 4 estuarial and 3 mangrove species with ecological interest. The publications reviewed were divided into studies describing plastic presence in crustaceans without reporting toxic effects and those with analysis of plastic toxicity. Publications describing the plastic presence in the organisms show that the ingestion in individual effects and food-web transfer in ecological effects were the most frequent endpoints. The publications that analyzed plastic toxicity through survival, nutrition-metabolism-assimilation, and reproduction in individual effects, and bioaccumulation in ecological effects were the most frequent endpoints. This review gathers the available information on the use of crustaceans as model species in environmental impact for toxicity screening and hazard assessment. Besides, identifying knowledge gaps will let us propose some future directions in research and the effects on target fisheries species which involves a possible effect on human health.

Moving beyond Risk Quotients: Advancing Ecological Risk Assessment to Reflect Better, More Robust and Relevant Methods.

Under standard guidance for conducting Ecological Risk Assessments (ERAs), the risks of chemical exposure to diverse organisms are most often based on deterministic point estimates evaluated against safety-factor-based levels of concern (LOCs). While the science and guidance for mechanistic effect models (e.g., demographic, population, and agent-based) have long been demonstrated to provide more ecologically relevant effect endpoints upon which risk can be evaluated, their application in ERAs has been limited, particularly in the US. This special issue highlights the state of the science in effect modeling for ERAs through demonstrated application of the recently published Population modeling Guidance, Use, Interpretation, and Development for ERA (Pop-GUIDE). We introduce this issue with a perspective on why it is critical to move past the current application of deterministic endpoints and LOCs. We demonstrate how the current, widely used approaches contain extensive uncertainty that could be reduced considerably by applying models that account for species life histories and other important endogenous and exogenous factors critical to species sustainability. We emphasize that it is long past time to incorporate better, more robust, and ecologically relevant effect models into ERAs, particularly for chronic risk determination. The papers in this special issue demonstrate how mechanistic models that follow Pop-GUIDE better inform ERAs compared to the current standard practice.

A PETAR method for risk assessment of human health and environment on the regional scale.

Risk assessments are necessary to effectively reveal the state of the degradation of living environments on a regional scale. However, risk assessments are often limited by time, cost, and technology, which make conducting effective evaluations difficult. Thus, in this study, the procedure for ecological tiered assessment of risk (PETAR) method was used to analyze the human health and environmental risks in Daye, China. This method first used the United States Environmental Protection Agency's risk assessment approach to qualitatively determine the risk sources, pressures, receptors, and effect endpoints and constructed a conceptual model of threats to the human living environment. Each risk-prone subregion was then evaluated using the fuzzy logic method. Next, a quantitative assessment was conducted for the subregions with the most serious environmental degradation. Finally, quantitative analyses were performed to verify the original hypotheses. The results showed that the high-risk areas were distributed in the industrial regions of Daye, wherein mining and processing clusters and mining settlements are widespread and confirmed the locations of the particular subregions with the most serious human health and environmental risks. This study also validated the practicality of the PETAR method for human health risk assessments in mining areas with large-scale, multifactor, and multihazard paths. Integr Environ Assess Manag 2023;19:239-253. © 2022 SETAC.

Acute results of a novel flexible tip radiofrequency catheter incorporating contact force sensing

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Abbott Background Catheter ablation is an established therapy for paroxysmal atrial fibrillation (PAF). The TactiFlex Ablation Catheter, Sensor-Enabled (TactiFlex SE) is a next-generation radiofrequency ablation catheter incorporating highly accurate fiber optics-based contact force sensing technology with a flexible, laser-cut tip. This is the first report of results from the TactiFlex IDE clinical study. Purpose To demonstrate that ablation with TactiFlex SE is safe and effective for the treatment of drug refractory, symptomatic PAF. Methods The TactiFlex IDE (NCT04356040) is a prospective, non-randomized, multi-center clinical study which enrolled 305 subjects worldwide in the main study. Enrollment in the main study began on June 26, 2020 and completed on June 8, 2021. Subjects underwent de novo Pulmonary Vein Isolation (PVI) and, if indicated, a Cavotricuspid Isthmus ablation (CTI line) for CTI-dependent atrial flutter. Results Acute procedural success was achieved in 98.6% (274/278) of the main study cohort who underwent an ablation procedure using the TactiFlex SE. First pass success, defined as isolation of all pulmonary veins (PVs) confirmed after a minimum 20 min waiting period was achieved in 89.6% (249/278) of subjects. This was a significant improvement versus the TactiSense IDE trial (TactiCath Ablation Catheter, Sensor-Enabled). Significant decreases were also seen in total procedure time (123 min [101.0, 163.5]), total PV ablation time (55.5 min [35.0, 81.0]), total fluoroscopy time (6.0 min [0.0, 13.0]) and irrigation fluid volume (450.0 mL [346.0, 636.0]) (values given as Median [Q1, Q3]), see FIGURE. All subjects have completed at least 90 days of follow-up. Only 2.6% (7/271) of subjects required a repeat procedure during the 90-day blanking period. The primary safety and effectiveness endpoints will be evaluated at 12-months. At 90 days, 4.3% (12/281) subjects had experienced a primary safety endpoint event. Conclusions The acute data from the TactiFlex IDE clinical study demonstrate safety and effectiveness of the TactiFlex SE catheter in the treatment of PAF. Ablation procedures performed using the next-generation TactiFlex SE catheter were shorter and had improved acute clinical effectiveness outcomes versus the TactiSense IDE. It is anticipated these results will also be reflected in the 12-month safety and effectiveness endpoints.

Safety and feasibility of a novel multilectrode array catheter in mapping atrial and ventricular arrhythmias with high density: results from the multi-center OPTIMUM study

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): This study was funded by Biosense Webster, Inc. Background/Introduction The novel multielectrode array mapping catheter includes 48 electrodes symmetrically distributed across and along 6 splines (Picture), with an additional unipolar reference electrode to reduce far-field signals built in at the tip of the irrigation lumen. Preclinical studies demonstrated its ability to provide high density and high resolution mapping in complex substrates, but its usability and safety in patients with atrial or ventricular arrhythmias have not been investigated. Purpose To assess the safety and mapping performance of the catheter with the electroanatomical navigation system for mapping in the atria and ventricle in patients with a variety of complex arrhythmias. Methods The OPTIMUM study was a prospective, single arm study conducted at 3 European sites. Patients with scar-related atrial tachycardia (AT), PAF and persistent AF (PsAF), ventricular tachycardia (VT), or premature ventricular complexes (PVC) underwent pre-ablation mapping with the study catheter, and subsequent ablation according to institutional standard of care practice; the follow up period was 7 days. The primary safety endpoint was the incidence of device-related serious adverse events (SAE) within 7 days following the procedure. The primary effectiveness endpoint was the completion of protocol-required fast activation and electro anatomical pre-ablation mapping without resort to non-study mapping catheter(s), including fast anatomical mapping, mapping of substrate or any area of interest, and identification of conduction channel(s), gap(s) and critical isthmuses. General procedural characteristics as well as physician feedback (7-point Likert scale: 1 = poor and 7 = excellent) on various aspects of deployment, signal quality, and learning curve were also evaluated. Results Thirty-one patients (mean age: 59.8±14 years, 71.0% male) were enrolled and treated (9 scar-related AT, 12 PAF, and 1 PsAF, 6 VT, and 3 PVC). There was no (0/31) SAE reported, and the primary effectiveness endpoint was achieved in all subjects (31/31). Almost all operators rated highly (≥ 5) on noise reduction in bipolar maps (30/31) and short learning curve (27/31). Bipolar signals and catheter maneuverability were rated highly favorable (≥5) in the left and right atria and met-expectation-and-above (≥4) in the left and right ventricles. Conclusion(s) The first-in-human clinical data demonstrate the safety and effectiveness of the novel microelectrode array mapping catheter to efficiently map various atrial and ventricular complex arrhythmias with good signal quality. Physicians indicated high satisfaction with the learning curve, catheter maneuverability, tissue characterization in all cardiac chambers.

Treatment of large and giant posterior communicating artery aneurysms with the Surpass streamline flow diverter: results from the SCENT trial

BackgroundThe Surpass flow diverter was developed to treat intracranial aneurysms not amenable to standard treatment. Indications for use allow placement in the internal carotid artery to the terminus, including the...

Effectiveness of three delivery models for promoting access to pre-exposure prophylaxis in HIV-1 serodiscordant couples in Nigeria.

To evaluate the effectiveness of three models for pre-exposure prophylaxis (PrEP) service delivery to HIV-1 serodiscordant couples in Nigeria. 297 heterosexual HIV-1 serodiscordant couples were recruited into three PrEP delivery models and followed up for 18 months. The models were i) Outpatient clinic model providing PreP in routine outpatient care; ii) Antiretroviral therapy (ART) clinic model providing PrEP in ART clinics; and iii) Decentralized care model providing PrEP through primary and secondary care centres linked to a tertiary care centre. The primary effectiveness endpoint was incident HIV-1 infection. The HIV incidence before and after the study was compared and the incidence rate ratio computed for each model. Survival analysis was conducted, Cox regression analysis was used to compare the factors that influenced couple retention in each of the models. Kaplan-Meier survival analysis was used to estimate the median retention time (in months) of the study participants in each of the study models, and log-rank test for equality of survival functions was conducted to test for significant differences among the three models. There was no significant difference (p>0.05) in the couple retention rates among the three models. At months 3, 6 and 9, adherence of the HIV-1-infected partners to ART was highest in the decentralized model, whereas at months 9 and 12, the outpatient model had the highest proportion of HIV-1- uninfected partners adhering to PrEP (p<0.001). The HIV incidence per 100 person-years was zero in the general outpatient clinic and ART clinic models and 1.6 (95% CI: 0.04-9.1) in the decentralized clinic model. The difference in the observed and expected incidence rate was 4.3 (95% CI: 0.44-39.57) for the decentralized clinic model. Although incidence of HIV seroconversion was highest in the decentralized clinic model, this difference may be due to the higher sexual risk behavior among study participants in the decentralized model rather than the type of service delivery. The study findings imply that any of the models can effectively deliver PrEP services.

MO316: Eculizumab for Adult Patients With Atypical Haemolytic-Uremic Syndrome: Full Dataset Analysis of Post-Marketing Surveillance in Japan

Abstract BACKGROUND AND AIMS Atypical haemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) associated with dysregulation of the alternative complement pathway [1]. It is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the USA, two adults per million develop aHUS each year, whereas 1 to 2 patients per million are estimated in Japan [2, 3]. Eculizumab has been approved for aHUS in Japan since 2013. A regulatory-mandated post-marketing surveillance (PMS) was conducted in a real-world setting from September 2013 to July 2018, for which an interim analysis has been published [3]. Here, we report the findings from the full data set analysis of the data from the PMS. METHOD The PMS enrolled adult patients diagnosed with aHUS and treated with at least one dose of eculizumab. The patients without underlying diseases, i.e. autoimmune diseases, drugs, infection, malignant tumours, metabolic disorders or transplantation, were evaluated for serious adverse events (SAE) and clinical effectiveness endpoints, i.e. haematologic normalization, platelet count (PLT) normalization, lactic dehydrogenase (LDH) normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, TMA event-free status and a complete TMA response (haematologic normalization and a ≥ 25% decrease in sCr that persisted for ≥ 4 weeks during eculizumab treatment). In addition, the difference of baseline (i.e. at treatment initiation of eculizumab) patient characteristics between patients who met and did not meet effectiveness endpoints was evaluated. RESULTS In this analysis, 79 adult patients were included; the median age was 54.0 years. Median eculizumab treatment duration was 30 weeks. The total exposure time of eculizumab was 75.51 person-years and 94 SAEs (1.24 per person-years) were reported in 39 patients. No unexpected safety signals were identified in this population by the end of observation. No meningococcal infection was reported throughout the observation period. Mean PLT (P &amp;lt; .001), LDH (P &amp;lt; .05) and estimated glomerular filtration rate (P &amp;lt; .01) were significantly improved after 7 days. Complete TMA response, haematologic normalization, PLT normalization, LDH normalization, improvement of sCr levels, and TMA event-free status were met by 35.3%, 40.4%, 49.2%, 50.0%, 51.3% and 50.0% of patients, respectively. Median treatment duration was shorter in patients who did not meet complete TMA response than in patients who met (6 weeks versus 114 weeks; P &amp;lt; .001). Multivariate analysis suggested that the time from most recent TMA to eculizumab treatment (OR 0.899; P = .007) and the days of plasma therapy (OR 0.807; P = .008) were negatively associated with improvement of sCr levels. CONCLUSION The percentages of patients who met effectiveness endpoints were similar to the interim analysis [3], yet the percentages of patients who met complete TMA responses were lower than in clinical trials [4]; the disparity in these outcomes could be attributed to the differences between clinical and real-world studies. This PMS analysis further demonstrated the safety and effectiveness of eculizumab in Japanese patients with aHUS in a real-world setting.

Submental fat reduction using sequential treatment approach with cryolipolysis and ATX-101.

BackgroundSubmental fat (SMF) detracts from facial aesthetics and negatively impacts self‐image.AimsTo evaluate safety, effectiveness, and satisfaction of cryolipolysis and ATX‐101 used sequentially to reduce SMF.MethodsA prospective, open‐label, interventional, single‐site study enrolling 22‐ to 65‐year‐old participants rated as Grade 4 (extreme) on the Clinician‐Rated SMF Rating Scale (CR‐SMFRS). Co‐primary effectiveness endpoints were proportions of participants with ≥1‐grade and ≥2‐grade improvement on CR‐SMFRS at 12 weeks post final treatment. Additional assessments included ultrasound measurement of fat thickness and Subject Self‐Rating Scale (SSRS) scores at 12 weeks post final treatment. Safety was assessed throughout the study.ResultsOf 16 enrolled participants, 62.5% were female, mean age of 43, and mean body mass index of 31.8 kg/m2. 100% of participants achieved ≥1‐grade improvement, and 71.4% achieved ≥2‐grade CR‐SMFRS improvement. Mean (SD) reduction in SMF thickness was 0.2 mm (1.3), and SSRS scores ≥4 (slightly to extremely satisfied) were reported by 71.4% of participants. Adverse events (AEs) were mild and resolved by study end. No unanticipated adverse device effects or serious or unexpected AEs occurred.ConclusionSequential treatment with cryolipolysis and ATX‐101 was found safe and effective for reducing extreme SMF, resulting in approximately a 2‐grade improvement.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Evaluation of the effect of targeted Mass Drug Administration and Reactive Case Detection on malaria transmission and elimination in Eastern Hararghe zone, Oromia, Ethiopia: a cluster randomized control trial

BackgroundReactive and proactive case detection measures are widely implemented by national malaria elimination programs globally. Ethiopia decided to include Reactive Case Detection (RCD) and targeted Mass Drug Administration (tMDA) approaches as part of their elimination strategy along with rigorous evaluation. The purpose of this study is to compare the impact of RCD and tMDA on malaria elimination over the 2-year study period, by looking at the annual parasite incidence before and after the intervention.MethodsThe study will be conducted in the East Hararghe zone of Ethiopia. Malaria transmission in the area is low to moderate. This study will deploy a community-based, three-arm, cluster-randomized control trial implemented over 2 years. Forty-eight clusters (16 clusters per arm) will be selected based on the annual number of confirmed malaria cases seen in the cluster. All clusters will receive the current standard of care in terms of malaria elimination interventions provided by the national malaria control program. In addition, following the identification of malaria parasite infection, individuals who reside within a 100-m radius of the index case will receive a diagnosis for malaria and treatment if positive in the RCD arm or presumptive treatment in the tMDA arm. The primary effectiveness endpoint will be measured at baseline and endline for each intervention arm and compared to the control arm using a difference in difference approach.DiscussionThis randomized controlled trial will provide evidence of the impact of the proposed intervention approaches for malaria elimination.Trial registrationClinicalTrials.gov NCT04241705. Registration date: January 27, 2020.