Conservative Threshold Research Articles

Regression discontinuity threshold optimization.

Treatments often come with thresholds, e.g. we are given statins if our cholesterol is above a certain threshold. But which statin administration threshold maximizes our quality of life adjusted years? More generally, which threshold would optimize the average expected outcome? Regression discontinuity approaches are used to measure the local average treatment effect (LATE) and more recently also the Marginal Threshold Treatment Effect (MTTE), which shows how marginal changes in the threshold can affect the LATE. We extend this idea to define the problem of optimizing a policy threshold, i.e. selecting a threshold that optimizes the cumulative effect of the treatment on the treated. We present an estimator of the optimal threshold based on a constrained optimization framework. We show how to use machine learning (Gaussian process regression) for non-linear estimation. We also extend the estimation to a conservative threshold that is unlikely to produce harm, and we show how to include policy cost constraints. We apply these results to estimate an optimal tip-maximizing threshold for tip suggestions in taxi cabs Haggag (2014).

Editors' Note: Accuracy of CT Perfusion-Based Core Estimation of Follow-up Infarction: Effects of Time Since Last Known Well.

In a prospective multicenter study of 101 patients, Dr. Sarraj and colleagues assessed the accuracy of baseline CT perfusion (CTP) estimates of ischemic core, relative to follow-up diffusion-weighted imaging (DWI) lesion infarct volumes, in patients with ischemic stroke who achieved complete reperfusion with endovascular thrombectomy. The authors found that significant overestimation of the volume of irreversibly injured ischemic core—by 10 mL or more—was rare and was only observed in patients who presented within 90 minutes of last known well and achieved reperfusion within 120 minutes of CTP acquisition. Such overestimation also primarily occurred in the white matter. The overestimation of ischemia was eliminated by using a more conservative threshold for relative cerebral flood flow (rCBF) of <20% as opposed to the more typically used threshold of <30% in patients presenting within 90 minutes. In response, Drs. Garcia-Camba and Jacobi note that the prevalence and temporal distribution of patients with a large ischemic core (≥50 mL) was not reported; this could affect the overestimation rate in the study and potentially limit the generalizability of its findings. Replying to this, the authors note that their cohort was derived from consecutively enrolled patients at 9 high-volume thrombectomy centers and did not exclude patients from treatment based on ischemic core estimates. They note that their cohort reflects contemporary clinical practice, reporting the number of patients with different ischemic core volume thresholds, and note that overestimation rates did not vary with core size. They point to ongoing trials of thrombectomy in patients with large estimated core volumes and to the SELECT2 study, which includes CTP and noncontrast CT imaging, and will help establish if there is a ceiling to thrombectomy benefit in patients with large vessel occlusion based on noncontrast CT or CTP findings. This exchange highlights our evolving understanding of the concept and measurement of ischemic core and its changing importance in patient selection decisions for thrombectomy. In a prospective multicenter study of 101 patients, Dr. Sarraj and colleagues assessed the accuracy of baseline CT perfusion (CTP) estimates of ischemic core, relative to follow-up diffusion-weighted imaging (DWI) lesion infarct volumes, in patients with ischemic stroke who achieved complete reperfusion with endovascular thrombectomy. The authors found that significant overestimation of the volume of irreversibly injured ischemic core—by 10 mL or more—was rare and was only observed in patients who presented within 90 minutes of last known well and achieved reperfusion within 120 minutes of CTP acquisition. Such overestimation also primarily occurred in the white matter. The overestimation of ischemia was eliminated by using a more conservative threshold for relative cerebral flood flow (rCBF) of <20% as opposed to the more typically used threshold of <30% in patients presenting within 90 minutes. In response, Drs. Garcia-Camba and Jacobi note that the prevalence and temporal distribution of patients with a large ischemic core (≥50 mL) was not reported; this could affect the overestimation rate in the study and potentially limit the generalizability of its findings. Replying to this, the authors note that their cohort was derived from consecutively enrolled patients at 9 high-volume thrombectomy centers and did not exclude patients from treatment based on ischemic core estimates. They note that their cohort reflects contemporary clinical practice, reporting the number of patients with different ischemic core volume thresholds, and note that overestimation rates did not vary with core size. They point to ongoing trials of thrombectomy in patients with large estimated core volumes and to the SELECT2 study, which includes CTP and noncontrast CT imaging, and will help establish if there is a ceiling to thrombectomy benefit in patients with large vessel occlusion based on noncontrast CT or CTP findings. This exchange highlights our evolving understanding of the concept and measurement of ischemic core and its changing importance in patient selection decisions for thrombectomy.

Dynamic Reduced-Order Observer-Based Detection of False Data Injection Attacks With Application to Smart Grid Systems

This article investigates the problem of attack detection of false data injection attacks for a class of large-scale smart grid systems in the context of cyber–physical systems. First, by exploiting the graph theory to decompose the considered system into multiple interconnected subsystems, a bank of dynamic reduced-order observers are delicately constructed to generate residual signals for the attack detection task. Then, a novel decentralized attack detection scheme is proposed based on the adaptive detection thresholds with prescribed performance. Compared with the existing results, the proposed detection scheme has less conservative thresholds and enhanced robustness against process disturbance and measurement noise, such that the detectability is improved. Finally, the effectiveness and availability of the proposed scheme are verified by two simulation examples and the experimental results from IEEE 30-bus system built in the OPAL-RT real-time simulator.

Radiological malunion after ankle fractures in older adults : definitions and new thresholds derived from clinical outcome data from the AIM trial.

The rationale for exacting restoration of skeletal anatomy after unstable ankle fracture is to improve outcomes by reducing complications from malunion; however, current definitions of malunion lack confirmatory clinical evidence. Radiological (absolute radiological measurements aided by computer software) and clinical (clinical interpretation of radiographs) definitions of malunion were compared within the Ankle Injury Management (AIM) trial cohort, including people aged ≥ 60 years with an unstable ankle fracture. Linear regressions were used to explore the relationship between radiological malunion (RM) at six months and changes in function at three years. Function was assessed with the Olerud-Molander Ankle Score (OMAS), with a minimal clinically important difference set as six points, as per the AIM trial. Piecewise linear models were used to investigate new radiological thresholds which better explain symptom impact on ankle function. Previously described measures of RM and surgeon opinion of clinically significant malunion (CSM) were shown to be related but with important differences. CSM was more strongly related to outcome (-13.9 points on the OMAS; 95% confidence interval (CI) -21.9 to -5.4) than RM (-5.5 points; 95% CI -9.8 to -1.2). Existing malunion thresholds for talar tilt and tibiofibular clear space were shown to be slightly conservative; new thresholds which better explain function were identified (talar tilt > 2.4°; tibiofibular clear space > 6 mm). Based on this new definition the presence of RM had an impact on function, which was statistically significant, but the clinical significance was uncertain (-9.1 points; 95% CI -13.8 to -4.4). In subsequent analysis, RM of a posterior malleolar fracture was shown to have a statistically significant impact on OMAS change scores, but the clinical significance was uncertain (-11.6 points; 95% CI -21.9 to -0.6). These results provide clinical evidence which supports the previously accepted definitions. Further research to investigate more conservative clinical thresholds for malunion is indicated.Cite this article: Bone Jt Open2022;3(10):841-849.

Neuroscience from the comfort of your home: Repeated, self-administered wireless dry EEG measures brain function with high fidelity.

Recent advances have enabled the creation of wireless, “dry” electroencephalography (EEG) recording systems, and easy-to-use engaging tasks, that can be operated repeatedly by naïve users, unsupervised in the home. Here, we evaluated the validity of dry-EEG, cognitive task gamification, and unsupervised home-based recordings used in combination. Two separate cohorts of participants—older and younger adults—collected data at home over several weeks using a wireless dry EEG system interfaced with a tablet for task presentation. Older adults (n = 50; 25 females; mean age = 67.8 years) collected data over a 6-week period. Younger male adults (n = 30; mean age = 25.6 years) collected data over a 4-week period. All participants were asked to complete gamified versions of a visual Oddball task and Flanker task 5–7 days per week. Usability of the EEG system was evaluated via participant adherence, percentage of sessions successfully completed, and quantitative feedback using the System Usability Scale. In total, 1,449 EEG sessions from older adults (mean = 28.9; SD = 6.64) and 684 sessions from younger adults (mean = 22.87; SD = 1.92) were collected. Older adults successfully completed 93% of sessions requested and reported a mean usability score of 84.5. Younger adults successfully completed 96% of sessions and reported a mean usability score of 88.3. Characteristic event-related potential (ERP) components—the P300 and error-related negativity—were observed in the Oddball and Flanker tasks, respectively. Using a conservative threshold for inclusion of artifact-free data, 50% of trials were rejected per at-home session. Aggregation of ERPs across sessions (2–4, depending on task) resulted in grand average signal quality with similar Standard Measurement Error values to those of single-session wet EEG data collected by experts in a laboratory setting from a young adult sample. Our results indicate that easy-to-use task-driven EEG can enable large-scale investigations in cognitive neuroscience. In future, this approach may be useful in clinical applications such as screening and tracking of treatment response.

Deterministic and Probabilistic Dietary Exposure Assessment to Deoxynivalenol in Spain and the Catalonia Region.

Deoxynivalenol (DON) remains one of the most concerning mycotoxins produced by the Fusarium genus due to the wide occurrence in highly consumed cereal-based food and its associated toxicological effects. Previous studies conducted in Spain and other European countries suggested that some vulnerable groups such as children could be exceeding the tolerable daily intakes. Thus, the aim of this study was to conduct a comprehensive and updated dietary exposure assessment study in Spain, with a specific analysis in the region of Catalonia. Cereal-based food samples collected during 2019 were analysed using liquid chromatography coupled to tandem mass spectrometry for multi-mycotoxin detection including DON and its main metabolites and derivatives. Consumption data were gathered from the nation-wide food surveys ENALIA and ENALIA2 conducted in Spain, and a specific survey conducted in Catalonia. The data were combined using deterministic and semi-parametric probabilistic methods. The results showed that DON was widely present in cereal-based food highly consumed in Spain and the Catalonia region. Exposure to DON among the adult population was globally low; however, among infants aged 3–9 years, it resulted in the median of 192 ng/kg body weight/day and the 95th percentiles of 604 ng/kg body weight/day, that would exceed the most conservative safety threshold for infants. Bread and pasta were the main contributing foodstuffs to the global exposure to DON, even among infants; thus, those foods should be considered a priority for food control or to develop strategies to reduce the exposure. In any case, further toxicological and epidemiological studies are required in order to refine the safety thresholds accounting for the sensitivity of the infant population.

Risk characterization of microplastics in San Francisco Bay, California

Assessing microplastics risk to aquatic ecosystems has been limited by lack of holistic exposure data and poor understanding of biological response thresholds. Here we take advantage of two recent advances, a toxicological meta-analysis that produced biotic response thresholds and a method to quantitatively correct exposure data for sampling methodology biases, to assess microplastic exposure risk in San Francisco Bay, California, USA. Using compartment-specific particle size abundance data, we rescaled empirical surface water monitoring data obtained from manta trawls (> 333 μm) to a broader size (1 to 5000 μm) range, corrected for biases in fiber undercounting and spectroscopic subsampling, and assessed the introduced uncertainty using probabilistic methods. We then compared these rescaled concentrations to four risk thresholds developed to inform risk management for California for each of two effect categories/mechanisms - tissue translocation-mediated effects and food dilution - each aligned to ecologically relevant dose metrics of surface area and volume, respectively. More than three-quarters of samples exceeded the most conservative food dilution threshold, which rose to 85% when considering just the Central Bay. Within the Central Bay, 38% of the samples exceeded a higher threshold associated with management planning, which was statistically significant at the 95% confidence interval. For tissue translocation-mediated effects, no samples exceeded any threshold with statistical significance. The risk associated with food dilution is higher than that found in other systems, which likely reflects this study having been conducted for an enclosed water body. A sensitivity analysis indicated that the largest contributor to assessment variability was associated with estimation of ambient concentration exposure due to correcting for fiber undercounting. Even after compensating for biases associated with fibers and other small particles, concentrations from the trawl samples were still significantly lower than the 1-L grab samples taken at the same time, suggesting our SFB risk estimates are an underestimate. We chose to rely on the trawl data because the 1-L grab sample volume was too small to provide accurate spatial representation, but future risk characterization studies would be improved by using in-line filtration pumps that sample larger volumes while capturing a fuller range of particle size than a towed net.

Identification of Stability Regions in Inverter-Based Microgrids

A new method for the stability assessment of inverter-based microgrids is presented in this paper. Directly determining stability boundaries by searching the multidimensional space of inverters’ droop gains is a computationally prohibitive task. Instead, we build a certified stability region by utilizing a generalized Laplacian matrix eigenvalues, which are a measure of proximity to stability boundary. We establish an upper threshold for the eigenvalues that determines the stability boundary of the entire system and demonstrate that this value depends only on the network’s R/X ratio but does not depend on the grid topology. We also provide a conservative upper threshold of the eigenvalues that are universal for any systems within a reasonable range of R/X ratios. We then construct approximate <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">certified stability regions</i> representing convex sets in the multidimensional space of droop gains that could be utilized for gains optimization. We show how the certified stability region can be maximized by properly choosing droop gains, and we provide closed-form analytic expressions for the certified stability regions. The computational complexity of our method is almost independent of the number of inverters. The proposed methodology has been tested using IEEE 123 node test system with 10 inverters.

Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma.

BackgroundWe aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma.MethodsRandomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model.ResultsSeventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73.ConclusionsPFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ≤ 0.73 has the potential to predict a significant improvement in OS.

Pharmacokinetics and Time above the MIC Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

This study determined the pharmacokinetics of cefepime in patients requiring extracorporeal membrane oxygenation (ECMO) support to guide dosage selection. Cefepime population pharmacokinetics where characterized in Pmetrics for R for six critically ill patients receiving ECMO. Simulation was employed to determine the fT>MIC and total trough concentration of varying regimens in each patient to evaluate ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity. Of the six participants, two required continuous veno-venous hemodiafiltration (CVVHDF) while four had a CrCL between 92-199 ml/min. All patients received 2 g q8h as a 3h infusion. A two-compartment model fitted the data best with median (range) parameter estimates as follows: clearance, 5.99 (4.10-10.29) L/h; volume of central compartment, 10.08 (2.45-15.14) L; and intercompartment transfer constants (k12), 3.58 (2.01-4.99) h-1 and k21, 1.70 (1.00-2.88) h-1. The 2g q8h (3h infusion) regimen resulted in >70% fT>MIC in all patients up to an MIC of 16 µg/mL, whereas 2g q12h (0.5h) resulted in 5/6 patients achieving 70% ƒT>MIC at 8 µg/mL but only 1/6 at 16 µg/mL. Aggressive dosing regimens resulted in trough concentrations exceeding conservative neurotoxicity thresholds. No patient demonstrated signs or symptoms of neurotoxicity during treatment. For ECMO patients with normal to augmented renal clearance similar to those presented here, or those receiving CVVHDF, these data support dosing regimens of 2g q8h (3h infusions) to empirically target MICs up to 16 µg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics.

Prospective Clinical Validation of Virtual Patient-Specific Quality Assurance of Volumetric Modulated Arc Therapy Radiation Therapy Plans

Performing measurement-based patient-specific quality assurance (PSQA) is recognized as a resource-intensive and time inefficient task in the radiation therapy treatment workflow. Paired with technological refinements in modern radiation therapy, research toward measurement-free PSQA has seen increased interest during the past 5 years. However, these efforts have not been clinically implemented or prospectively validated in the United States. We propose a virtual QA (VQA) system and workflow to assess the safety and workload reduction of measurement-free PSQA. An XGBoost machine learning model was designed to predict PSQA outcomes of volumetric modulated arc therapy plans, represented as percent differences between the measured ion chamber point dose in a phantom and the corresponding planned dose. The final model was deployed within a web application to predict PSQA outcomes of clinical plans within an existing clinical workflow. The application also displays relevant feature importance and plan-specific distribution analyses relative to database plans for documentation and to aid physicist interpretation and evaluation. VQA predictions were prospectively validated over 3 months of measurements at our clinic to assess safety and efficiency gains. Over 3 months, VQA predictions for 445 volumetric modulated arc therapy plans were prospectively validated at our institution. VQA predictions for these plans had a mean absolute error of 1.08% ± 0.77%, with a maximum absolute error of 2.98%. Using a 1% prediction threshold (ie, plans predicted to have an absolute error <1% would not require a measurement) would yield a 69.2% reduction in QA workload, saving 32.5 hours per month on average, with 81.5% sensitivity, 72.4% specificity, and an area under the curve of 0.81 at a 3% clinical threshold and 100% sensitivity, 70% specificity, and an area under the curve of 0.93 at a 4% clinical threshold. This is the first prospective clinical implementation and validation of VQA in the United States, which we observed to be efficient. Using a conservative threshold, VQA can substantially reduce the number of required measurements for PSQA, leading to more effective allocation of clinical resources.

Economic Evaluation of Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate for the Treatment of Moderate to Very Severe Chronic Obstructive Pulmonary Disease in China Using a Semi-Markov Model.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic respiratory disease with considerable clinical and socioeconomic impact. Budesonide/glycopyrrolate/formoterol fumarate (BGF) is a newly approved pharmacotherapy for COPD in China that has been shown to improve lung function and reduce the risk of exacerbations, but the cost-effectiveness of BGF remains unknown. The objective of this study was to evaluate the cost-effectiveness of BGF in patients with moderate to very severe COPD from a Chinese healthcare system perspective. A semi-Markov model was developed to compare the costs and benefit of treatment with BGF versus a composite comparator of long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) therapies. Clinical inputs for BGF and the composite comparator were based on the KRONOS study (NCT02497001) and a network meta-analysis. Cost inputs were derived from published literature and Chinese government documents, supplemented by expert opinion where necessary. Health-related quality-of-life inputs were also obtained based on the KRONOS study. Lifetime costs, number of exacerbations, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. Costs were measured in 2020 Chinese Yuan (CN¥) and converted into US dollars (US$). Scenario analyses and sensitivity analyses were conducted. Over the lifetime horizon, BGF treatment led to fewer moderate and severe exacerbations (4.01 and 0.87, respectively) versus the composite comparator (8.42 and 2.04, respectively), with a base-case ICER of CN¥13,685.94 (US$1983.47) per QALY gained. Scenario analyses considering different population and utilities resulted in ICERs ranging from dominant to CN¥13,673.91 (US$1981.73). Extensive sensitivity analyses indicated robust base-case results since all analyses yielded ICERs below the conservative cost-effectiveness threshold of one times the Chinese per capita gross domestic product (CN¥72,447.00 [US$10,499.57], 2020). Triple therapy with BGF was predicted to improve outcomes and be a cost-effective treatment option compared with LAMA/LABA therapies for patients with moderate to very severe COPD in China.

Accuracy of CT Perfusion-Based Core Estimation of Follow-up Infarction: Effects of Time Since Last Known Well.

To assess the accuracy of baseline CT perfusion (CTP) ischemic core estimates. From SELECT (Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke), a prospective multicenter cohort study of imaging selection, patients undergoing endovascular thrombectomy who achieved complete reperfusion (modified Thrombolysis In Cerebral Ischemia score 3) and had follow-up diffusion-weighted imaging (DWI) available were evaluated. Follow-up DWI lesions were coregistered to baseline CTP. The difference between baseline CTP core (relative cerebral blood flow [rCBF] <30%) volume and follow-up infarct volume was classified as overestimation (core ≥10 mL larger than infarct), adequate, or underestimation (core ≥25 mL smaller than infarct) and spatial overlap was evaluated. Of 101 included patients, median time from last known well (LKW) to imaging acquisition was 138 (82-244) minutes. The median baseline ischemic core estimate was 9 (0-31.9) mL and median follow-up infarct volume was 18.4 (5.3-68.7) mL. All 6/101 (6%) patients with overestimation of the subsequent infarct volume were imaged within 90 minutes of LKW and achieved rapid reperfusion (within 120 minutes of CTP). Using rCBF <20% threshold to estimate ischemic core in patients presenting within 90 minutes eliminated overestimation. Volumetric correlation between the ischemic core estimate and follow-up imaging improved as LKW time to imaging acquisition increased: Spearman ρ <90 minutes 0.33 (p = 0.049), 90-270 minutes 0.63 (p < 0.0001), >270 minutes 0.86 (p < 0.0001). Assessment of the spatial overlap between baseline CTP ischemic core lesion and follow-up infarct demonstrated that a median of 3.2 (0.0-9.0) mL of estimated core fell outside the subsequent infarct. These regions were predominantly in white matter. Significant overestimation of irreversibly injured ischemic core volume was rare, was only observed in patients who presented within 90 minutes of LKW and achieved reperfusion within 120 minutes of CTP acquisition, and occurred primarily in white matter. Use of a more conservative (rCBF <20%) threshold for estimating ischemic core in patients presenting within 90 minutes eliminated all significant overestimation cases. ClinicalTrials.gov: NCT03876457.

Concept End Points Informing Design Considerations for Confirmatory Clinical Trials in Osteoarthritis.

There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective was to propose concept clinical end points that directly capture clinical benefit in this setting and evaluate the feasibility of their use. This analysis used the multicenter, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to 9 years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes. We examined this data set to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate end points by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. We identified candidate end points based on total knee replacement (TKR) and composite end points defined by TKR and conservative thresholds of patient-reported outcomes of pain and function. Using time to TKR as an end point, a study with an average follow-up time of 3 years requires approximately 3,000 to 18,000 subjects, depending on effect size. Alternatively, for a composite end point, such as "time to TKR or severe pain or severely impaired functioning," the required sample sizes ranged from approximately 2,000 to 11,000 for a 3-year study. The proposed concept end points can reliably and feasibly evaluate the effectiveness of therapies for this unmet need. In particular, the composite end point approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.

Should Age-Based Eligibility Thresholds Differ for Repeat Heart Transplantation? Analysis of the United Network of Organ Sharing Database

<h3>Purpose</h3> Risk-adjusted survival after cardiac re-transplantation may be comparable to primary transplant, but the efficacy of re-transplantation in older candidates is not established. We evaluated outcomes after re-transplantation in recipients > 60 years. <h3>Methods</h3> The United Network for Organ Sharing Database identified 1295 adult patients undergoing heart re-transplants between 2003 and 2020 (excluding heart-lung transplants). Unadjusted 5-year survival of older recipients (> 60 years, n=212) was compared to younger recipients (<= 60 years, n=1083). Adjusted Cox model using restricted cubic splines explored the non-linear relationship between recipient age and mortality risk after re-transplantation. A separate multivariate Cox model analyzed recipients>60 years undergoing either primary transplant (n=12826) or re-transplantation (n=181, excluding re-transplants for acute/hyperacute rejection or primary graft dysfunction) to evaluate the impact of re-transplantation on mortality. <h3>Results</h3> In patients undergoing re-transplantation, older recipients had more pre-transplant ECMO use (9.9% vs. 5.8%, p=0.027) and received grafts from older donors (34, IQR 24-46 vs. 28, IQR 21-38 years, p<0.0001). Recipient age >60 was associated with inferior unadjusted survival (Figure 1A). Restricted cubic spline (Figure 1B) showed a significant increase in mortality risk when recipient age becomes older than 61.8 years (corresponding HR 1.35, 95% CI 1.01-1.79). In recipients >60 years undergoing either primary transplant or re-transplantation, re-transplantation was independently associated with increased risk of mortality (HR 1.33, 95% CI 1.07-1.65, p=0.01) compared to primary transplant. <h3>Conclusion</h3> Re-transplanting patients greater than 60 years old is independently associated with increased risk of mortality. More conservative age-based thresholds for re-transplantation may be appropriate.

Cost effectiveness analysis of total laparoscopic hysterectomy versus total abdominal hysterectomy for uterine fibroids in Western China: a societal perspective

BackgroundAs a common female pelvic tumor, uterine fibroids remain the leading cause for hysterectomy in China. Hysterectomy provides a good surgical treatment of uterine fibroids, and it guarantees the removal of all uterine fibroids without lower risk of recurrence. This study compares the cost effectiveness of total laparoscopic hysterectomy (TLH) versus total abdominal hysterectomy (TAH) for women with uterine fibroids from a societal perspective.MethodsAn economic analysis was conducted in 392 patients (TLH n = 75; TAH n = 317), including all relevant costs over a 12-month time horizon. Primary outcome was major surgical complications; secondary outcomes were postoperative discomfort symptoms and time of return to normal activities. Clinical, outcomes and costs data were collected from medical records, telephone survey and financial information system. Generalized linear models were used to assess costs and outcomes differences between the two groups. Incremental cost effectiveness ratio (ICER) was used to estimate the cost effectiveness.ResultsMean direct costs were $2,925.71 for TLH, $2,436.24 for TAH, respectively. Mean indirect costs were $1,133.22 for TLH, $1,394.85 for TAH, respectively. Incremental societal costs were $256.86 (95%CI: 249.03–264.69). Mean differences in outcome were: 4.53% (95%CI: 4.35–4.71) for major surgical complications; 6.75% (95%CI: 6.45–7.05) for postoperative discomfort symptoms; 1.27 (95%CI: 1.23–1.30) weeks for time to return to normal activities. ICER of TLH was $5,669.16 (95%CI: 5,384.76–5,955.56) per complication averted, $3,801.54 (95%CI: 3,634.81–3,968.28) per postoperative discomfort symptoms averted and $202.96 (95%CI: 194.97–210.95) per week saved to return to normal activities.ConclusionsTLH is cost effective compared with TAH in preventing additional complications based on our estimated conservative threshold in China. The findings provide useful information for researchers to conduct further cost effectiveness analysis based on prospective study which can provide stronger and more evidence, in China. In addition, the data may be useful for Chinese health care policy-makers and medical insurance payers to make related health care decisions.

Black hole spectroscopy horizons for current and future gravitational wave detectors

Black hole spectroscopy is the proposal to observe multiple quasinormal modes in the ringdown of a binary black hole merger. In addition to the fundamental quadrupolar mode, overtones and higher harmonics may be present and detectable in the gravitational wave signal, allowing for tests of the no-hair theorem. We analyze in detail the strengths and weaknesses of the standard Rayleigh criterion supplied with a Fisher matrix error estimation, and we find that the criterion is useful, but too restrictive. Therefore we motivate the use of a conservative high Bayes factor threshold to obtain the black hole spectroscopy horizons of current and future detectors, i.e., the distance (averaged in sky location and binary inclination) up to which one or more additional modes can be detected and confidently distinguished from each other. We set up all of our searches for additional modes starting at $t = 10(M_1+M_2)$ after the peak amplitude in simulated signals of circular nonspinning binaries. An agnostic multimode analysis allows us to rank the subdominant modes: for nearly equal mass binaries we find $(\ell, m, n) = (2,2,1)$ and $(3,3,0)$ and, for very asymmetric binaries, $(3,3,0)$ and $(4,4,0)$, for the secondary and tertiary modes, respectively. At the current estimated rates for heavy stellar mass binary black hole mergers, with primary masses between 45 and 100 solar masses, we expect an event rate of mergers within our conservative estimate for the $(2,2,1)$ spectroscopy horizon of $0.03 - 0.10\ {\rm yr}^{-1}$ for LIGO at design sensitivity and $(0.6 - 2.4) \times 10^3\ {\rm yr}^{-1}$ for the future third generation ground-based detector Cosmic Explorer.

An Asynchronized Observer Based Fault Detection Approach for Uncertain Switching Systems With Mode Estimation

This brief addresses the design issues of real-time asynchronized observer based fault detection in uncertain switched systems combining with a mode estimation unit. To this end, the so-called <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mathcal {L}_{\infty }/\mathcal {L}_{2}$ </tex-math></inline-formula> type of residual generators is investigated in the asynchronized switching manner with the aid of average dwell time approach for the first time. A mode estimation unit is developed based on the measurements collected from the residual generators and the process, and further embedded in a multi-level detection logic. As a result, the conservative threshold setting caused by the model mismatch in the asynchronized residual generation, and the fault detectability can be improved.

P138 Psychometric validation and interpretation of a patient-reported outcomes instrument to assess bowel urgency among adults with moderate to severe Ulcerative Colitis

Abstract Background Urgency, the sudden or immediate need for a bowel movement, is one of the most bothersome symptoms experienced by Ulcerative Colitis (UC) patients. We aimed to evaluate the psychometric properties of the Urgency Numeric Rating Scale (UNRS), inform the clinically meaningful within-patient change (MWPC) threshold and determine the UNRS threshold associated with clinical, endoscopic and histologic remission. Methods In this study, the UNRS was collected daily through an electronic diary that measures the severity of the urgency to have a bowel movement in the past 24 hours using an 11-point NRS ranging from 0 (no urgency) to 10 (worst possible urgency). A weekly score was calculated for a 7-day period by averaging the observed entries if 4 or more observations are available. Item performance, reliability, validity, responsiveness, and score interpretation were assessed at baseline (BL) and week 12 in moderate-severe patients with UC enrolled in a multicenter, randomized, placebo-controlled Phase 3 study. Results The full distribution of responses was provided by patients at BL and Week 12, with no floor or ceiling effects. Test-retest reliability was strong, with intra-class correlation coefficients ranging 0.76–0.89. As expected, moderate to high correlations were seen between the UNRS and health-related quality of life measures, patient ratings of UC severity, disease change, stool frequency and rectal bleeding (establishing convergent validity), while low correlations were seen with endoscopy and histology measures (establishing discriminant validity) (Table 1). As predicted, statistically higher UNRS scores were found in patients with more severe UC compared to those with less severe UC, providing evidence of known groups validity. Findings also indicated the UNRS is responsive to changes over time. Anchor-based analyses suggested that a 3-point score reduction from BL to week 12 constitutes a MWPC (Figure 1). A UNRS score of 0, 1, or 2 best reflected urgency severity level when patients were in clinical (YI=0.36), histologic (YI=0.27), or endoscopic remission (YI=0.27) (Table 2). A UNRS score of 0 or 1 may be a more conservative endpoint to define patients with no to minimal urgency. Conclusion The UNRS is a valid and reliable patient-reported measure of urgency in adults with UC. A 3-point improvement is a MWPC threshold. A UNRS score of 0 or 1 is a conservative threshold that reflects clinical, endoscopic and histologic remission. These findings provide strong evidence supporting that the UNRS is appropriate for inclusion as an endpoint in clinical trials to evaluate UC treatments efficacy.

Timing and magnitude of climate-driven range shifts in transboundary fish stocks challenge their management.

Climate change is shifting the distribution of shared fish stocks between neighboring countries’ Exclusive Economic Zones (EEZs) and the high seas. The timescale of these transboundary shifts determines how climate change will affect international fisheries governance. Here, we explore this timescale by coupling a large ensemble simulation of an Earth system model under a high emission climate change scenario to a dynamic population model. We show that by 2030, 23% of transboundary stocks will have shifted and 78% of the world's EEZs will have experienced at least one shifting stock. By the end of this century, projections show a total of 45% of stocks shifting globally and 81% of EEZs waters with at least one shifting stock. The magnitude of such shifts is reflected in changes in catch proportion between EEZs sharing a transboundary stock. By 2030, global EEZs are projected to experience an average change of 59% in catch proportion of transboundary stocks. Many countries that are highly dependent on fisheries for livelihood and food security emerge as hotspots for transboundary shifts. These hotspots are characterized by early shifts in the distribution of an important number of transboundary stocks. Existing international fisheries agreements need to be assessed for their capacity to address the social–ecological implications of climate‐change‐driven transboundary shifts. Some of these agreements will need to be adjusted to limit potential conflict between the parties of interest. Meanwhile, new agreements will need to be anticipatory and consider these concerns and their associated uncertainties to be resilient to global change.