Robust safety monitoring and signal detection using alternatives to the standard poisson distribution.

Proper and timely characterization of the safety profile of a pharmaceutical product under development is imperative for assessing the overall benefit-risk relationship of the product and for making key development decisions. For ongoing clinical development, a comprehensive and robust safety monitoring and safety signal detection program which is based upon quantitative statistical reasoning is critical. Methods presented here can be applied to safety signal detection and periodic safety monitoring. Various statistical properties, distributions, and models, all utilizing a Bayesian framework are considered and further examined in order to identify robust methods applicable to a broad set of scenarios and situations. Methods developed for incidence counts (including those with under-dispersed distributions) with variable time-at-risk and with underlying constant or non-constant hazard rates, are proposed and compared to traditional methods designed to assess adverse event incidence rates or binomial incidence proportions (which assume an underlying constant hazard rate and subsequent Poisson distribution for modeling event counts).

Cracking under Internal Pressure: Photodynamic Behavior of Vinyl Azide Crystals through N2 Release.

When exposed to UV light, single crystals of the vinyl azides 3-azido-1-phenylpropenone (1a), 3-azido-1-(4-methoxyphenyl)propenone (1b), and 3-azido-1-(4-chlorophenyl)propenone (1c) exhibit dramatic mechanical effects by cracking or bending with the release of N2. Mechanistic studies using laser flash photolysis, supported by quantum mechanical calculations, show that each of the vinyl azides degrades through a vinylnitrene intermediate. However, despite having very similar crystal packing motifs, the three compounds exhibit distinct photomechanical responses in bulk crystals. While the crystals of 1a delaminate and release gaseous N2 indiscriminately under paraffin oil, the crystals of 1b and 1c visibly expand, bend, and fracture, mainly along specific crystallographic faces, before releasing N2. The photochemical analysis suggests that the observed expansion is due to internal pressure exerted by the gaseous product in the crystal lattices of these materials. Lattice energy calculations, supported by nanoindentation experiments, show significant differences in the respective lattice energies. The calculations identify critical features in the crystal structures of 1b and 1c where elastic energy accumulates during gas release, which correspond to the direction of the observed cracks. This study highlights the hitherto untapped potential of photochemical gas release to elicit a photomechanical response and motility of photoreactive molecular crystals.

A micro-analytic approach to understanding electronic health record navigation paths.

Clinician task performance is significantly impacted by the navigational efficiency of the system interface. Here we propose and evaluate a navigational complexity framework useful for examining differences in electronic health record (EHR) interface systems and their impact on task performance. The methodological approach includes 1) expert-based methods-specifically, representational analysis (focused on interface elements), keystroke level modeling (KLM), and cognitive walkthrough; and 2) quantitative analysis of interactive behaviors based on video-captured observations. Medication administration record (MAR) tasks completed by nurses during preoperative (PreOp) patient assessment were studied across three Mayo Clinic regional campuses and three different EHR systems. By analyzing the steps executed within the interfaces involved to complete the MAR tasks, we characterized complexities in EHR navigation. These complexities were reflected in time spent on task, click counts, and screen transitions, and were found to potentially influence nurses' performance. Two of the EHR systems, employing a single screen format, required less time to complete (mean 101.5, range 106-97 s), respectively, compared to one system employing multiple screens (176 s, 73% increase). These complexities surfaced through trade-offs in cognitive processes that could potentially influence nurses' performance. Factors such as perceptual-motor activity, visual search, and memory load impacted navigational complexity. An implication of this work is that small tractable changes in interface design can substantially improve EHR navigation, overall usability, and workflow.

A Task-Analytic Framework Comparing Preoperative Electronic Health Record-Mediated Nursing Workflow in Different Settings.

Preoperative care is a critical, yet complex, time-sensitive process. Optimization of workflow is challenging for many reasons, including a lack of standard workflow analysis methods. We sought to comprehensively characterize electronic health record-mediated preoperative nursing workflow. We employed a structured methodological framework to investigate and explain variations in the workflow. Video recording software captured 10 preoperative cases at Arizona and Florida regional referral centers. We compared the distribution of work for electronic health record tasks and off-screen tasks through quantitative analysis. Suboptimal patterns and reasons for variation were explored through qualitative analysis. Although both settings used the same electronic health record system, electronic health record tasks and off-screen tasks time distribution and patterns were notably different across two sites. Arizona nurses spent a longer time completing preoperative assessment. Electronic health record tasks occupied a higher proportion of time in Arizona, while off-screen tasks occupied a higher proportion in Florida. The contextual analysis helped to identify the variation associated with the documentation workload, preparation of the patient, and regional differences. These findings should seed hypotheses for future optimization efforts and research supporting standardization and harmonization of workflow across settings, post-electronic health record conversion.

Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study.

OBJECTIVES: The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated. METHODS: Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ. RESULTS: Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6. CONCLUSIONS: OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified. TRIAL REGISTER NUMBER: NCT01242488.

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice.

Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. . IMPORTANCE: Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.

KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy.

OBJECTIVE: To compare the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy. METHODS: This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (≥16 years of age) with ≥2 unprovoked seizures in the previous 2 years and ≥1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR. FINDINGS: 1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR. CONCLUSIONS: LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures.

Glucocorticoid regulation of cancer development and progression.

Glucocorticoids are steroid hormones that regulate a host of cellular and physiological functions. However, they are arguably best known for their potent anti-inflammatory properties. Chronic inflammation is well-known to promote the development and progression of numerous types of cancer, and emerging evidence suggests that glucocorticoid regulation of inflammation affects cancer development. However, the timing, intensity, and duration of glucocorticoid signaling have important but often contradictory effects on cancer development. Moreover, glucocorticoids are widely used in parallel with radiation and chemotherapy to control pain, dyspnea, and swelling, but their use may compromise anti-tumor immunity. This review will explore the effects of glucocorticoids on cancer development and progression with particular focus on pro and anti-tumor immunity.

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice.

Background: Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter- induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and Methods: PMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. Results: HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. Conclusions: HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.

Tarantulas cling to smooth vertical surfaces by secreting silk from their feet.

Like all spiders, tarantulas (family Theraphosidae) synthesize silk in specialized glands and extrude it from spinnerets on their abdomen. In one species of large tarantula, Aphonopelma seemanni, it has been suggested that silk can also be secreted from the tarsi but this claim was later refuted. We provide evidence of silk secretion directly from spigots (nozzles) on the tarsi of three distantly related tarantula species: the Chilean rose, Grammostola rosea; the Indian ornamental, Poecilotheria regalis; and the Mexican flame knee, Brachypelma auratum, suggesting tarsal silk secretion is widespread among tarantulas. We demonstrate that multiple strands of silk are produced as a footprint when the spider begins to slip down a smooth vertical surface. The nozzle-like setae on the tarsi responsible for silk deposition have shanks reinforced by cuticular thickenings, which serve to prevent the shanks' internal collapse while still maintaining their flexibility. This is important as the spigots occur on the ventral surface of the tarsus, projecting beyond the finely divided setae of the dry attachment pads. We also reveal the structure and disposition of the silk-secreting spigots on the abdominal spinnerets of the three tarantula species and find they are very similar to those from the earliest known proto-spider spinneret from the Devonian period, giving another indication that silk secretion in tarantulas is close to the ancestral condition.

High-resolution image-guided WEB aneurysm embolization by high-frequency optical coherence tomography.

BACKGROUND: High-frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging technique capable of assessing device-vessel interactions at spatial resolution approaching 10 µm. We tested the hypothesis that adequately deployed Woven EndoBridge (WEB) devices as visualized by HF-OCT lead to higher aneurysm occlusion rates. METHODS: In a leporine model, elastase-induced aneurysms (n=24) were treated with the WEB device. HF-OCT and digital subtraction angiography (DSA) were performed following WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion (0-present, 1-absent) and malapposition (0-malapposed, 1-neck apposition >50%) were binary coded. A device was considered 'adequately deployed' by HF-OCT and DSA if apposed and non-protruding. Aneurysm healing on DSA was reported using the 4-point WEB occlusion score: A or B grades were considered positive outcome. Neointimal coverage was quantified on HF-OCT images at 12 weeks and compared with scanning electron microscopy (SEM). RESULTS: Adequate deployment on HF-OCT correlated with positive outcome (P=0.007), but no statistically significant relationship was found between good outcome and adequate deployment on DSA (P=0.289). Absence of protrusion on HF-OCT correlated with a positive outcome (P=0.006); however, malapposition alone had no significant relationship (P=0.19). HF-OCT showed a strong correlation with SEM for the assessment of areas of neointimal tissue (R²=0.96; P<0.001). More neointimal coverage of 78%±32% was found on 'adequate deployment' cases versus 31%±24% for the 'inadequate deployment' cases (P=0.001). CONCLUSION: HF-OCT visualizes features that can determine adequate device deployment to prognosticate early aneurysm occlusion following WEB implantation and can be used to longitudinally monitor aneurysm healing progression.

Study of EHR-mediated workflows using ethnography and process mining methods.

Rapid ethnography and data mining approaches have been used individually to study clinical workflows, but have seldom been used together to overcome the limitations inherent in either type of method. For rapid ethnography, how reliable are the findings drawn from small samples? For data mining, how accurate are the discoveries drawn from automatic analysis of big data, when compared with observable data? This paper explores the combined use of rapid ethnography and process mining, aka ethno-mining, to study and compare metrics of a typical clinical documentation task, vital signs charting. The task was performed with different electronic health records (EHRs) used in three different hospital sites. The individual methods revealed substantial discrepancies in task duration between sites. Specifically, means of 159.6(78.55), 38.2(34.9), and 431.3(283.04) seconds were captured with rapid ethnography. When process mining was used, means of 518.6(3,808), 345.5(660.6), and 119.74(210.3) seconds were found. When ethno-mining was applied instead, outliers could be identified, explained and removed. Without outliers, mean task duration was similar between sites (78.1(66.7), 72.5(78.5), and 71.7(75) seconds). Results from this work suggest that integrating rapid ethnography and data mining into a single process may provide more meaningful results than a siloed approach when studying of workflow.

We're Lost, But We are Making Good Time: Navigating Complex Pathways in a Patient-Order Management Task.

Patient order management (POM) is a mission-critical task for perioperative workflow. Interface complexity within different EHR systems result in poor usability, increasing documentation burden. POM interfaces were compared across two systems prior to (Cerner SurgiNet) and subsequent to an EHR conversion (Epic). Here we employ a navigational complexity framework useful for examining differences in EHR interface systems. The methodological approach includes 1) expert-based methods-specifically, functional analysis, keystroke level model (KLM) and cognitive walkthrough, and 2) quantitative analysis of observed interactive user behaviors. We found differences in relation to navigational complexity with the SurgiNet interface displaying a higher number of unused POM functions, with 12 in total whereas Epic displayed 7 total functions. As reflected in all measures, Epic facilitated a more streamlined task-focused user experience. The approach enabled us to scrutinize the impact of different EHR interfaces on task performance and usability barriers subsequent to system implementation.

EHR Conversion on the PreOp Care: A Pre-Post Workflow Comparison.

The impact of EHRs conversion on clinicians' daily work is crucial to evaluate the success of the intervention for Hospitals and to yield valuable insights into quality improvement. To assess the impact of different EHR systems on the preoperative nursing workflow, we used a structured framework combining quantitative time and motion study and qualitative cognitive analysis to characterize, visualize and explain the differences before and after an EHR conversion. The results showed that the EHR conversion brought a significant decrease in the patient case time and a reduced percentage of time using EHR. PreOp nurses spent a higher proportion of time caring for the patient, while the important tasks were completed in a more continuous pattern after the EHR conversion. The workflow variance was due to different nurse's cognitive process and the task time change was reduced because of some new interface features in the new EHR systems.

A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy.

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated.

Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures.

PURPOSE: To evaluate the efficacy and tolerability of adjunctive levetiracetam in very young children (aged 1 month to <4 years) with partial-onset seizures inadequately controlled with one or two antiepileptic drugs. METHODS: This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1-day up-titration; 48-h evaluation video-EEG in the last 2 days). Children who experienced at least two partial-onset seizures during the 48-h baseline video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/kg/day (age >or=6 months to <4 years] or placebo. RESULTS: Of 175 patients screened, 116 patients were randomized [60 levetiracetam; 56 placebo; intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average daily partial-onset seizures frequency (48-h video-EEG monitoring; primary efficacy variable) was 43.1% for levetiracetam [modified ITT (mITT) = 58] versus 19.6% for placebo (mITT = 51; p=0.013), with odds ratio for response 3.11 [95% confidence interval (CI), 1.22-8.26]. The median percent reduction from baseline in average daily partial-onset seizure frequency was 43.6% for levetiracetam and 7.1% for placebo with a median difference between treatment groups of 39.2% (95% CI, 17.5-62.2; p < 0.001). In general, levetiracetam was well tolerated. Treatment-emergent adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse events were somnolence (13.3% levetiracetam, 1.8% placebo) and irritability (11.7% levetiracetam, 0% placebo). DISCUSSION: Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partial-onset seizures in infants and young children.

Process Mining and Ethnography Study of Medication Reconciliation Tasks.

We studied the medication reconciliation (MedRec) task through analysis of computer logs and ethnographic data. Time spent by healthcare providers performing MedRec was compared between two different EHR systems used at four different regional perioperative settings. Only one of the EHRs used at two settings generated computer logs that supported automatic discovery of the MedRec task. At those two settings, 53 providers generated 383 MedRec instances. Findings from the computer logs were validated with ethnographic data, leading to the identification and removal of 47 outliers. Without outliers, one of the settings had slightly smaller mean (SD) time in seconds 67.3 (40.2) compared with the other, 92.1 (25). The difference in time metrics was statistically significant (p<.001). Reusability of an existing task-based analytic method allowed for rapid study of EHR-based workflow and task.

Multi-Method Study of Electronic Health Records Workflows.

EHRs transform work practices in ways that enhance or impede the quality of care. There is a need for in-depth analysis of EHR workflows, particularly in complex clinical environments. We investigated EHR-basedpre-operative workflows by combining findings from 18 interviews, 7 days of observations, and process mining of EHR interactions from 31 personnel caring for 375 patients at one tertiary referral center. We provided high-definition descriptions of workflows and personnel roles. One third (32.2%) of the time with each patient was spent interacting with the EHR and 4.2% using paper-based artifacts. We also mined personnel social networks validating observed personnel's EHR-interactions. When comparing workflows between two similar pre-operative settings at different hospitals, we found significant differences in physical organization, patient workflow, roles, use of EHR, social networks and time efficiency. This study informs Mayo Clinic's enterprise-wide conversion to a single EHR and will guide before and after workflow comparisons.

In Search of Vital Signs: A Comparative Study of EHR Documentation.

Vital sign documentation is an essential part of perioperative workflow. Health information technology can introduce complexity into all facets of documentation and burden clinicians with high cognitive load3-4. The Mayo Clinic enterprise is in the process of documenting current EHR-mediated workflow prior to a system-wide EHR conversion. We compared and evaluated three different vital sign documentation interfaces in pre-operative nursing assessments at three different Mayo Clinic sites. The interfaces differed in their modes of interaction, organization of patient information and cognitive support. Analyses revealed that accessing displays and the organization of interface elements are often unintuitive and inefficient, creating unnecessary complexities when interacting with the system. These differences surface through interface workflow models and interactive behavior measures for accessing, logging and reviewing patient information. Different designs differentially mediate task performance, which can ultimately mitigate errors for complex cognitive tasks, risking patient safety. Identifying barriers to interface usability and bottlenecks in EHR-mediated workflow can lead to system redesigns that minimize cognitive load while improving patient safety and efficiency.