Hospital-associated venous thromboembolism prophylaxis use by risk assessment at a large integrated health care network in Northern California.

BACKGROUND: Hospital-acquired venous thromboembolism (HA VTE) is a preventable complication in hospitalized patients. OBJECTIVE: We aimed to examine the use of pharmacologic prophylaxis (pPPX) and compare two risk assessment methods for HA VTE: a retrospective electronic Padua Score (ePaduaKP) and admitting clinician's choice of risk within the admission orderset (low, moderate, or high). DESIGN, SETTINGS AND PARTICIPANTS: We retrospectively analyzed prophylaxis orders for adult medical admissions (2013-2019) at Kaiser Permanente Northern California, excluding surgical and ICU patients. INTERVENTION: ePaduaKP was calculated for all admissions. For a subset of these admissions, clinician-assigned HA VTE risk was extracted. MAIN OUTCOME AND MEASURES: Descriptive pPPX utilization rates between ePaduaKP and clinician-assigned risk as well as concordance between ePaduaKP and clinician-assigned risk. RESULTS: Among 849,059 encounters, 82.2% were classified as low risk by ePaduaKP, with 42.3% receiving pPPX. In the subset with clinician-assigned risk (608,512 encounters), low and high ePaduaKP encounters were classified as moderate risk in 87.5% and 92.0% of encounters, respectively. Overall, 56.7% of encounters with moderate clinician-assigned risk received pPPX, compared to 7.2% of encounters with low clinician-assigned risk. pPPX use occurred in a large portion of low ePaduaKP risk encounters. Clinicians frequently assigned moderate risk to encounters at admission irrespective of their ePaduaKP risk when retrospectively examined. We hypothesize that the current orderset design may have negatively influenced clinician-assigned risk choice as well as pPPX utilization. Future work should explore optimizing pPPX for high-risk patients only.

Outpatient Total Hip Arthroplasty Volume up Nearly 8-Fold After Regulatory Changes With Expanding Demographics and Unchanging Outcomes: A 10-Year Analysis.

BACKGROUND: With the removal of total hip arthroplasty (THA) from the inpatient-only (IPO) lists, the orthopedic landscape across the United States has changed rapidly. Thus, this study aimed to: 1) characterize the change in THA volume for outpatient and inpatient surgeries; 2) elucidate demographical differences before and after removal from the IPO list; and 3) analyze 30-day complications, readmissions, and reoperations. METHODS: The National Surgical Quality Improvement Program database was queried for primary THAs between January 2010 and December 2021. The primary outcome was the annual volume of outpatient and inpatient THAs. Secondary outcomes involved 30-day complications, readmissions, and reoperations. The variables between cohorts were analyzed using goodness-of-fit Chi-square tests with summary statistics. RESULTS: Of the 332,423 THAs between 2010 and 2021, 88% were inpatient THAs (n = 292,974) and 12% were outpatient THAs (n = 39,449). From 2019 to 2021, the volume of inpatient THA decreased by 55% (42,779 to 19,075), while outpatient THA increased by 751% (2,518 to 21,424). Patients who had a THA after 2019 were older (P < .001), more commonly women (P < .001), white (P < .001), and more likely American Society of Anesthesiologists Class III (P < .001). The outpatient cohort had fewer 30-day complications, readmissions, and reoperations. The length of stay for both cohorts decreased until 2019, before increasing in 2020 and 2021 for inpatient THAs, while home discharge and operative time increased for both. CONCLUSIONS: The volume of outpatient THA increased almost eightfold after its removal from the IPO lists in 2020. Despite expanding eligibility with older patients and more comorbidities, 30-day complications, readmissions, and reoperations remain low. These findings support the safe transition to outpatient THA with appropriate patient selection and optimization.

Robotic Assisted Percutaneous Coronary Intervention: Initial Australian Experience.

BACKGROUND & AIM: Robotic-assisted percutaneous coronary intervention (R-PCI) has been increasingly performed overseas. Initial observations have demonstrated its clinical efficacy and safety with additional potential benefits of more accurate lesion assessment and stent deployment, with reduced radiation exposure to operators and patients. However, data from randomised controlled trials or clinical experience from Australia are lacking. METHODS: This was a single-centre experience of all patients undergoing R-PCI as part of the run-in phase for an upcoming randomised clinical trial (ACTRN12623000480684). All R-PCI procedures were performed using the CorPath GRX robot (Corindus Vascular Robotics, Waltham, Massachusetts, USA). Key inclusion criteria included patients with obstructive coronary disease requiring percutaneous coronary intervention. Major exclusion criteria included ST-elevation myocardial infarction, cardiogenic shock or lesions deemed unsuitable for R-PCI by the operator. Clinical success was defined as residual stenosis <30% without in-hospital major adverse cardiovascular events (MACE). Technical success was defined as the completion of the R-PCI procedure without unplanned manual conversion. Procedural characteristics were compared between early (cases 1-3) and later (cases 4-21) cases. RESULTS: Twenty-one (21) patients with a total of 24 lesions were analysed. The mean age of patients was 66.5 years, and 66% of cases were male. Radial access was used in 18 cases (86%). Most lesions were American Heart Association/American College of Cardiology class B2/C (66%). Clinical success was achieved in 100% with manual conversion required in four cases (19%). No procedural complications or in-hospital MACE occurred. Compared to the early cases, later cases had a statistically significantly shorter fluoroscopy time (44.0mins vs 25.2mins, p<0.007), dose area product (967.3 dGy.cm2 vs 361.0dGy.cm2, p=0.01) and air kerma (2484.3mGy vs 797.4mGy, p=0.009) with no difference in contrast usage (136.7mL vs 131.4mL, p=0.88). CONCLUSIONS: We present the first clinical experience of R-PCI in Australia using the Corindus CorPath GRX robot. We achieved clinical success in all patients and technical success in the majority of cases with no procedural complications or in-hospital MACE. With increasing operator and staff experience, cases required shorter fluoroscopy time and less radiation exposure but similar contrast usage.

A Medicare Physician Fee Schedule Analysis of Reimbursement Trends in Laryngology from 2000 to 2021.

OBJECTIVE: The purpose of this study is to characterize Medicare reimbursement trends for laryngology procedures over the last two decades. METHODS: This analysis used CMS' Physician Fee Schedule (PFS) Look-Up Tool to determine the reimbursement rate of 48 common laryngology procedures, which were divided into four groups based on their practice setting and clinical use: office-based, airway, voice disorders, and dysphagia. The PFS reports the physician service reimbursement for "facilities" and global reimbursement for "non-facilities". The annual reimbursement rate for each procedure was averaged across all localities and adjusted for inflation. The compound annual growth rate (CAGR) of each procedure's reimbursement was determined, and a weighted average of the CAGR for each group of procedures was calculated using each procedure's 2020 Medicare Part B utilization. RESULTS: Reimbursement for laryngology procedure (CPT) codes has declined over the last two decades. In facilities, the weighted average CAGR for office-based procedures was -2.0%, for airway procedures was -2.2%, for voice disorders procedures was -1.4%, and for dysphagia procedures was -1.7%. In non-facilities, the weighted average CAGR for office-based procedures was -0.9%. The procedures in the other procedure groups did not have a corresponding non-facility reimbursement rate. CONCLUSION: Like other otolaryngology subspecialties, inflation-adjusted reimbursements for common laryngology procedures have decreased substantially over the past two decades. Because of the large number of physician participants and patient enrollees in the Medicare programs, increased awareness and further research into the implications of these trends on patient care is necessary to ensure quality in the delivery of laryngology care. LEVEL OF EVIDENCE: NA Laryngoscope, 134:247-256, 2024.

Are All Patients Going Home after Total Knee Arthroplasty? A Temporal Analysis of Discharge Trends and Predictors of Nonhome Discharge (2011-2020).

Value-based orthopaedic surgery and reimbursement changes for total knee arthroplasty (TKA) are potential factors shaping arthroplasty practice nationwide. This study aimed to evaluate (1) trends in discharge disposition (home vs nonhome discharge), (2) episode-of-care outcomes for home and nonhome discharge cohorts, and (3) predictors of nonhome discharge among patients undergoing TKA from 2011 to 2020. The National Surgical Quality Improvement Program database was reviewed for all primary TKAs from 2011 to 2020. A total of 462,858 patients were identified and grouped into home discharge (n = 378,771) and nonhome discharge (n = 84,087) cohorts. The primary outcome was the annual rate of home/nonhome discharges. Secondary outcomes included trends in health care utilization parameters, readmissions, and complications. Multivariable logistic regression analyses were performed to evaluate factors associated with nonhome discharge. Overall, 82% were discharged home, and 18% were discharged to a nonhome facility. Home discharge rates increased from 65.5% in 2011 to 94% in 2020. Nonhome discharge rates decreased from 34.5% in 2011 to 6% in 2020. Thirty-day readmissions decreased from 3.2 to 2.4% for the home discharge cohort but increased from 5.6 to 6.1% for the nonhome discharge cohort. Female sex, Asian or Black race, Hispanic ethnicity, American Society of Anesthesiology (ASA) class > II, Charlson comorbidity index scores > 0, smoking, dependent functional status, and age > 60 years were associated with higher odds of nonhome discharge. Over the last decade, there has been a major shift to home discharge after TKA. Future work is needed to further assess if perioperative interventions may have a positive effect in decreasing adverse outcomes in nonhome discharge patients.

Measuring food insecurity among a national sample of children with recurrent acute otitis media.

INTRODUCTION: Acute otitis media is one of the most common reasons for pediatric medical visits in the United States. Additionally, past studies have linked food insecurity and malnutrition with increased infections and worse health outcomes. However, there is a lack of information on the risk factors for food insecurity in specific patient populations, including the pediatric recurrent acute otitis media (RAOM) population. METHODS: The 2011 to 2018 National Health Interview Survey (NHIS) datasets were used to obtain a national estimate of the presentation of food insecurity within pediatric patients with RAOM. Relevant sociodemographic information and prevalence were identified. A multivariable logistic regression model was used to determine sociodemographic risk factors. Calculations were conducted using R with the "survey" package to account for the clustering and sampling of the NHIS. RESULTS: Of 3844 children with RAOM who responded to the food insecurity module, 20.8 % (19.0-22.6 %) were food insecure. Age, race/ethnicity, percentage of federal poverty level status, insurance status, and self-reported health status were significant and were not independent of food insecurity status. Using multivariable regression, this study found the following sociodemographic risk factors: age 6-10 and age > 10 (reference: age 0-2); Black (reference: Non-Hispanic White); 100 % to 200 % and <100 % federal poverty level (reference: >200 % federal poverty level); public insurance or uninsured status (reference: private insurance); and poor to fair self-reported health status (reference: good to excellent). DISCUSSION: Children with RAOM who were older, Black, less insured, living in lower-income households, and of poorer health had a greater association with being food insecure. Due to the frequency of RAOM pediatric visits, identifying at-risk groups as well as incorporating food insecurity screening and food referral programs within clinical practice can enable otolaryngologists to reduce disparities and improve outcomes in a targeted approach.

Stomatin-like protein 3 modulates the responses of Aδ, but not C fiber bone afferent neurons to noxious mechanical stimulation in an animal model of acute experimental bone pain.

STOML3 is a membrane bound scaffolding protein that has been shown to facilitate the opening of mechanically sensitive ion channels and contribute to noxious mechanical sensation, allodynia and hyperalgesia. In this study, we aimed to determine the role of STOML3 in noxious mechanical sensitivity of bone afferent neurons and carrageenan-induced acute inflammation in the bone. An in vivo, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons that innervate the tibial marrow cavity in anaesthetised rats, in response to noxious mechanical stimuli delivered to the marrow cavity, before and after injection of either the STOML3 oligomerisation inhibitor OB-1 or vehicle, in either naïve animals or animals with carrageenan-induced inflammation of the marrow cavity. A dynamic weight-bearing apparatus was used to measure weight bearing in response to inflammatory pain before and after injection of OB-1 or saline into the tibial marrow cavity in the presence of carrageenan-induced inflammation. Electrophysiological recordings revealed that Aδ, but not C bone afferent neurons have a reduced discharge frequency in response to mechanical stimulation, and that carrageenan-induced sensitisation of Aδ, but not C bone afferent neurons was attenuated by inhibition of STOML3 oligomerisation with OB-1. Animals treated with OB-1 spent a significantly greater amount of time on the limb injected with carrageenan than animals treated with saline. Our findings demonstrate that inhibition of STOML3 oligomerisation reduces inflammatory bone pain by reducing the sensitivity of Aδ bone afferent neurons to mechanical stimulation. Targeting STOML3 may be an effective approach to reduce pain from noxious pressure and/or painful inflammatory pathology in bone.

Online Patient Education Materials on Iron Deficiency Anemia Are Too Difficult to Read and Low Quality: A Readability and Quality Analysis.

Introduction Patients increasingly rely on online health information to understand and manage their diseases. Concerns about the quality and readability of these materials have been reported in the literature. Poor quality and difficult-to-read information lead to delayed diagnoses and adverse outcomes. We assessed the quality and readability of online health information about iron deficiency anemia (IDA) on Google. Method We searched for online web pages using the term "iron deficiency anemia"on Google. One hundred and twelve out of 200 web pages were included. We assessed web page typology, readability, the Journal of the American Medical Association (JAMA) score, the DISCERN score, and the Health on the Net Foundation certification (HONcode). Statistical analysis was performed with R version 4.2.2. Result Non-profit and scientific journal web pages were the most common. Scientific journal web pages were of the highest quality. News web pages were the most readable. The first Google Page web pages did not have greater JAMA scores or lower Flesch-Kinkaid Reading Grade Level (FKGL) and Simple Measure of Gobbledygook (SMOG) scores. Forty-six percent of all web pages were high-quality. Web pages on the first Google page were more likely to have HONCode certification. Conclusion We highlight gaps in the readability and quality of online information about IDA. Online web pages exceeded the recommended reading level for patients. Most web pages were low quality; only a quarter were HONcode-certified; and the first Google page web pages were not higher in quality than the later web pages on search.

Early Effects of Ticagrelor Versus Clopidogrel on Peripheral Endothelial Function After Non-ST-Elevation Acute Coronary Syndrome and Assessment of Its Relationship With Coronary Microvascular Function.

Peripheral endothelial dysfunction is an independent predictor of adverse long-term prognosis after acute coronary syndrome. Data are lacking on the effects of oral P2Y12-inhibitors on peripheral endothelial function in non-ST-elevation acute coronary syndrome (NSTEACS). Furthermore, the relation between peripheral endothelial function and invasive indexes of coronary microvascular function in NSTEACS is unclear. Between March 2018 and July 2020, hospitalized patients with NSTEACS were randomized (1:1) to ticagrelor or clopidogrel. Peripheral endothelial function was assessed with brachial artery flow-mediated vasodilation (FMD). Invasive indexes of coronary microvascular function were obtained using an intracoronary pressure-temperature sensor-tipped wire. In 70 patients included, mean age was 58.6 years, 78.6% (n = 55) were male and 20% (n = 14) had diabetes mellitus. Compared with clopidogrel, ticagrelor significantly improved FMD (14.2 ± 5.4% vs 8.9 ± 5.3%, p <0.001) after a median treatment time of 41.2 hours. The FMD was significantly correlated with the index of microcirculatory resistance (IMR) measured in the infarct-related artery (r = -0.38, p = 0.001), with a stronger correlation found in those who did not have percutaneous coronary intervention (r = -0.52, p = 0.03). Using receiver operating characteristic curve analysis, an FMD of 8.2% identified an IMR of >34 as the threshold, with 77.6% sensitivity and 52.4% specificity. In patients who did not have a percutaneous coronary intervention, an FMD of 11.49% identified an IMR of >34 with 84.6% sensitivity and 80% specificity. In conclusion, ticagrelor significantly improved peripheral endothelial function compared with clopidogrel in patients with NSTEACS. There was a significant correlation between brachial artery FMD and IMR of the infarct-related artery.

Major National Shifts to Outpatient Total Knee Arthroplasties in the United States: A 10-Year Trends Analysis of Procedure Volumes, Complications, and Healthcare Utilizations (2010 to 2020).

BACKGROUND: The removal of total knee arthroplasty (TKA) from inpatient-only lists accelerated changes in orthopaedic surgical practices across the United States. This study aimed to (1) quantify the annual volume of inpatient/outpatient primary TKAs; (2) compare patient characteristics before/after the year 2018; and (3) compare annual trends in 30-day readmissions, 30-day complications, and healthcare utilization parameters for inpatient/outpatient TKAs. METHODS: The National Surgical Quality Improvement Program was reviewed (January 2010 to December 2020) for patients who underwent primary TKA (n = 470,456). The primary outcome was annual volumes of inpatient/outpatient TKA. Secondary outcomes included 30-day readmissions, 30-day reoperations, and 30-day major/minor complications. Demographic characteristics and healthcare utilization parameters (hospital lengths of stay and discharge dispositions) were compared between cohorts via Chi-square goodness-of-fit tests. RESULTS: Overall, 89% had inpatient TKA (n = 416,972) and 11% had outpatient TKA (n = 53,854). Between 2017 and 2020, annual volumes of outpatient TKA increased by 1,925 (1,019 to 20,633), while inpatient TKA decreased by 53% (61,874 to 29,280). Patients who had outpatient TKA after 2018 were older (P < .001), predominantly males (P < .001), more commonly White (P < .001), and had a greater proportion of American Society of Anesthesiologists class III (P < .001). The inpatient cohort had higher rates of 30-day readmissions, reoperations, and complications. Average length of stay and nonhome discharges decreased for both cohorts. CONCLUSION: Outpatient TKA increased 20-fold at NSQIP hospitals. The changes in comorbidity profiles and the increase in volumes of outpatient TKA were not associated with a rise in cumulative 30-day readmissions and complications. Further research and policy endeavors should focus on identifying patients who still require or benefit from inpatient TKA.

Geographic disparities in access to immunotherapy clinical trials for metastatic melanoma.

Survival outcomes for metastatic melanoma have drastically improved with the advent of immunotherapy. Access to ongoing immunotherapy clinical trials has become increasingly important to patients with advanced disease. We sought to quantify geographic disparities in access to these trials by U.S. division, region, urban/rural status, and median income. We searched ClinicalTrials.gov for interventional immunotherapy trials for metastatic melanoma from 2015 to 2021 and identified U.S. zip codes for each participating trial site. ArcGIS was used to calculate the one-way driving time from each zip code to the nearest treatment center. Melanoma burden in each zip code outside a 60 min driving radius was calculated by multiplying population by the corresponding state's cancer-specific mortality rate. χ2 tests were used to test for significance between census regions, divisions, and urban vs. rural zip codes, while logistic regression was used to quantify risk of poor access with median income. Across 148 trials, 4844 treatment centers were located in 1102 unique zip codes. 9010 zip codes were located greater than one-hour driving time from the nearest clinical trial. Southern regions were most likely to have poor access of all regions (p < 0.001), and rural status also significantly correlated with poor access (p < 0.001). For every $10,000 increase in median income, the likelihood of a zip code being within 60 min from a trial increased by 1.315. While immunotherapy continue to improve survival outcomes for metastatic melanoma, geographic access to clinical trials investigating these therapies remains a challenge for a significant proportion of the U.S. population.

Normative values of renin and aldosterone in clinically stable preterm neonates.

BACKGROUND: There is a paucity of literature on the normative levels of plasma renin concentration (PRC) and serum aldosterone (SA) in premature neonates. This study aims to provide normative data on PRC and SA levels in preterm neonates in the first 2 weeks after birth and explore associations with maternal, perinatal, or postnatal factors. METHODS: Neonates born at 26- to 34-week gestation were recruited from two neonatal intensive care units in Canada and Australia. The direct renin assay PRC and SA were analyzed on day 1 and days 14-21 after birth to compare across categorical variables and to produce normative values. RESULTS: A total of 262 subjects were enrolled from the Canadian (29%) and Australian (71%) sites. The mean gestational age was 30 weeks, with a mean birth weight of 1457 g. The normative values of PRC and SA for neonates born between 26 + 0 and 29 + 6 weeks and 30 + 0 and 34 + 0 weeks of gestation were produced for day 1 and day 14-21 after birth. Both PRC and SA increased from day 1 to day 14-21. The more premature neonates reached a higher PRC on days 14-21 after birth but exhibited lower SA levels on day 1 after birth. When comparing gender, birth weight, and maternal risk factor categories, no statistical differences in PRC or SA were found. A small but significant decrease in PRC, but not SA, was noted for neonates with placental pathology. CONCLUSIONS: This study produced normative values of PRA and SA in clinically stable preterm neonates that can be referenced for use in clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.

A Case of Complex Percutaneous Coronary Intervention for ST Elevation Myocardial Infarction Caused by Extension of Type A Aortic Dissection into the Left Main Coronary Artery.

Aortic dissection extending into the left main coronary artery is rare and carries high mortality, especially when resulting in extensive myocardial infarction. Here we report a case of retrograde extension of type A aortic dissection into the left main coronary artery causing ST-segment elevation myocardial infarction managed by complex percutaneous coronary intervention, which resulted in temporary stabilization of the patient. We briefly review current literature on this approach.

Trends and Risk Factors for Venous Thromboembolism Among Hospitalized Medical Patients.

Importance: While hospital-associated venous thromboembolism (HA-VTE) is a known complication of hospitalization, contemporary incidence and outcomes data are scarce and methodologically contested. Objective: To define and validate an automated electronic health record (EHR)-based algorithm for retrospective detection of HA-VTE and examine contemporary HA-VTE incidence, previously reported risk factors, and outcomes. Design, Setting, and Participants: This cohort study was conducted using hospital admissions between January 1, 2013, and June 30, 2021, with follow-up until December 31, 2021. All medical (non-intensive care unit) admissions at an integrated health care delivery system with 21 hospitals in Northern California during the study period were included. Data were analyzed from January to June 2022. Exposures: Previously reported risk factors associated with HA-VTE and administration of pharmacological prophylaxis were evaluated as factors associated with HA-VTE. Main Outcomes and Measures: Yearly incidence rates and timing of HA-VTE events overall and by subtype (deep vein thrombosis, pulmonary embolism, both, or unknown), as well as readmissions and mortality rates. Results: Among 1 112 014 hospitalizations involving 529 492 patients (268 797 [50.8%] women; 75 238 Asian [14.2%], 52 697 Black [10.0%], 79 398 Hispanic [15.0%], and 307 439 non-Hispanic White [58.1%]; median [IQR] age, 67.0 [54.0-79.0] years), there were 13 843 HA-VTE events (1.2% of admissions) occurring in 10 410 patients (2.0%). HA-VTE events increased from 307 of 29 095 hospitalizations (1.1%) in the first quarter of 2013 to 551 of 33 729 hospitalizations (1.6%) in the first quarter of 2021. Among all HA-VTE events, 10 746 events (77.6%) were first noted after discharge. In multivariable analyses, several factors were associated with increased odds of HA-VTE, including active cancer (adjusted odds ratio [aOR], 1.96; 95% CI, 1.85-2.08), prior VTE (aOR, 1.71; 95% CI, 1.63-1.79), and reduced mobility (aOR, 1.63; 95% CI, 1.50-1.77). Factors associated with decreased likelihood of HA-VTE included Asian race (vs non-Hispanic White: aOR, 0.65; 95% CI, 0.61-0.69), current admission for suspected stroke (aOR, 0.73; 95% CI, 0.65-0.81), and Hispanic ethnicity (vs non-Hispanic White: aOR, 0.81; 95% CI, 0.77-0.86). HA-VTE events were associated with increased risk of readmission (hazard ratio [HR], 3.33; 95% CI, 3.25-3.41) and mortality (HR, 1.63; 95% CI, 1.57-1.70). Conclusions and Relevance: This study found that HA-VTE events occurred in 1.2% of medical admissions, increased over time, and were associated with increased adverse outcomes. These findings suggest that approaches designed to mitigate occurrence and outcomes associated with HA-VTE may remain needed.

Decoding kinase-adverse event associations for small molecule kinase inhibitors.

Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. In this study, we construct a multi-domain dataset from a total of 4638 patients in the registrational trials of 16 FDA-approved SMKIs and employ a machine-learning model to examine the relationships between kinase targets and adverse events (AEs). Internal and external (datasets from two independent SMKIs) validations have been conducted to verify the usefulness of the established model. We systematically evaluate the potential associations between 442 kinases with 2145 AEs and made publicly accessible an interactive web application "Identification of Kinase-Specific Signal" ( https://gongj.shinyapps.io/ml4ki ). The developed model (1) provides a platform for experimentalists to identify and verify undiscovered KI-AE pairs, (2) serves as a precision-medicine tool to mitigate individual patient safety risks by forecasting clinical safety signals and (3) can function as a modern drug development tool to screen and compare SMKI target therapies from the safety perspective.