Sall4 regulates posterior trunk mesoderm development by promoting mesodermal gene expression and repressing neural genes in the mesoderm.

The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. Analysis of gene expression and SALL4 binding suggests that Sall4 directly or indirectly regulates genes involved in presomitic mesoderm differentiation, somite formation and somite differentiation. Furthermore, ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4-dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within the mesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes.

Sall4 restricts glycolytic metabolism in limb buds through transcriptional regulation of glycolytic enzyme genes.

Recent studies illustrate the importance of regulation of cellular metabolism, especially glycolysis and pathways branching from glycolysis, during vertebrate embryo development. For example, glycolysis generates cellular energy ATP. Glucose carbons are also directed to the pentose phosphate pathway, which is needed to sustain anabolic processes in the rapidly growing embryos. However, our understanding of the exact status of glycolytic metabolism as well as genes that regulate glycolytic metabolism are still incomplete. Sall4 is a zinc finger transcription factor that is highly expressed in undifferentiated cells in developing mouse embryos, such as blastocysts and the post-implantation epiblast. TCre; Sall4 conditional knockout mouse embryos exhibit various defects in the posterior part of the body, including hindlimbs. Using transcriptomics approaches, we found that many genes encoding glycolytic enzymes are upregulated in the posterior trunk, including the hindlimb-forming region, of Sall4 conditional knockout mouse embryos. In situ hybridization and qRT-PCR also confirmed upregulation of expression of several glycolytic genes in hindlimb buds. A fraction of those genes are bound by SALL4 at the promoters, gene bodies or distantly-located regions, suggesting that Sall4 directly regulates expression of several glycolytic enzyme genes in hindlimb buds. To further gain insight into the metabolic status associated with the observed changes at the transcriptional level, we performed a comprehensive analysis of metabolite levels in limb buds in wild type and Sall4 conditional knockout embryos by high-resolution mass spectrometry. We found that the levels of metabolic intermediates of glycolysis are lower, but glycolytic end-products pyruvate and lactate did not exhibit differences in Sall4 conditional knockout hindlimb buds. The increased expression of glycolytic genes would have caused accelerated glycolytic flow, resulting in low levels of intermediates. This condition may have prevented intermediates from being re-directed to other pathways, such as the pentose phosphate pathway. Indeed, the change in glycolytic metabolite levels is associated with reduced levels of ATP and metabolites of the pentose phosphate pathway. To further test whether glycolysis regulates limb patterning downstream of Sall4, we conditionally inactivated Hk2, which encodes a rate-limiting enzyme gene in glycolysis and is regulated by Sall4. The TCre; Hk2 conditional knockout hindlimb exhibited a short femur, and a lack of tibia and anterior digits in hindlimbs, which are defects similarly found in the TCre; Sall4 conditional knockout. The similarity of skeletal defects in Sall4 mutants and Hk2 mutants suggests that regulation of glycolysis plays a role in hindlimb patterning. These data suggest that Sall4 restricts glycolysis in limb buds and contributes to patterning and regulation of glucose carbon flow during development of limb buds.

Relationship Between Oral Temperature and Bacteremia in Hospitalized Patients.

BACKGROUND: Early recognition and treatment of bacteremia can be lifesaving. Fever is a well-known marker of bacteremia, but the predictive value of temperature has not been fully explored. OBJECTIVE: To describe temperature as a predictor of bacteremia and other infections. DESIGN: Retrospective review of electronic health record data. SETTING: A single healthcare system comprising 13 hospitals in the United States. PATIENTS: Adult medical patients admitted in 2017 or 2018 without malignancy or immunosuppression. MAIN MEASURES: Maximum temperature, bacteremia, influenza and skin and soft tissue (SSTI) infections based on blood cultures and ICD-10 coding. KEY RESULTS: Of 97,174 patients, 1,518 (1.6%) had bacteremia, 1,392 (1.4%) had influenza, and 3,280 (3.3%) had an SSTI. There was no identifiable temperature threshold that provided adequate sensitivity and specificity for bacteremia. Only 45% of patients with bacteremia had a maximum temperature ≥ 100.4˚F (38˚C). Temperature showed a U-shaped relationship with bacteremia with highest risk above 103˚F (39.4˚C). Positive likelihood ratios for influenza and SSTI also increased with temperature but showed a threshold effect at ≥ 101.0 ˚F (38.3˚C). The effect of temperature was similar but blunted for patients aged ≥ 65 years, who frequently lacked fever despite bacteremia. CONCLUSIONS: The majority of bacteremic patients had maximum temperatures below 100.4 ˚F (38.0˚C) and positive likelihood ratios for bacteremia increased with high temperatures above the traditional definition of fever. Efforts to predict bacteremia should incorporate temperature as a continuous variable.

Prescribing of anticoagulation for atrial fibrillation in primary care.

Atrial fibrillation (AF) is common in primary care patients. Many patients who could benefit from anticoagulation do not receive it. The objective of this study was to describe anticoagulation prescribing by primary care physicians. We conducted an observational study in the Cleveland Clinic Health System among patients with AF and ≥ 1 primary care appointment between 2015 and 2018 and their physicians. We estimated differences in the odds of an eligible patient receiving anticoagulation versus not and a DOAC versus warfarin using two mixed effects logistic regression models, adjusted for patient sociodemographic factors, history of falls or dementia, and CHA2DS2-VASc and HAS-BLED scores. We categorized physicians into prescribing tertiles, based on their adjusted prescribing rate, which we included as predictors in the models. Among 5253 patients, 47% received anticoagulation. Of those, 56% received a DOAC. CHA2DS2-VASc and HAS-BLED scores were not associated with anticoagulation prescription. Black race was negatively associated with receiving anticoagulation overall (aOR:0.71; 95%CI:0.56-0.89) and with prescription for a DOAC (aOR:0.65; 95%CI:0.45-0.93). Among 195 physicians, the anticoagulation prescribing rate ranged from 27% to 57% and DOAC rates ranged from 34% to 69%. Physician prescribing tertile was associated with odds of a patient receiving anticoagulation overall (aOR:1.51; 95%CI: 1.13-2.01 for the highest versus lowest tertile), but not DOAC prescriptions. When prescribing anticoagulation, physicians appear not to consider risk of stroke or bleeding but patient race is an important determinant. Seeing a physician with a high anticoagulation prescribing rate was strongly associated with a patient receiving it, suggesting a lack of individualization.

Volume and Outcomes of Joint Arthroplasty.

BACKGROUND: Joint arthroplasties are among the most commonly performed elective surgeries in the United States. Surgical outcomes are known to improve with volume but it is unclear whether this has led to consolidation among elective surgeries. We examined trends in volumes per surgeon and hospital to assess whether the known volume-outcome relationship has led to consolidation in elective joint arthroplasty and to determine if there exist volume thresholds above which outcomes do not change. METHODS: Among Medicare beneficiaries who underwent either total knee or total hip arthroplasty from 2009 through 2015, we described volume trends and used mixed-effect models to relate annual surgeon and hospital volumes with 30-day complications or mortality. We tested for optimal volume cut points at both the hospital and surgeon level. RESULTS: Adjusted annual complication rates were inversely associated with volume for both procedures at both the surgeon level and hospital level, but there was minimal consolidation between 2009 and 2015. Complications no longer declined after volumes of each case exceeded 260 per year. The vast majority of cases (around 93% of hip and 88% of knee arthroplasties) were performed by surgeons operating at suboptimal volumes. CONCLUSION: More than 2 decades after the volume-outcome relationship was established for joint arthroplasty, many cases continue to be performed by low-volume surgeons, with far more cases performed by surgeons operating at suboptimal volumes. Further improvement could be expected through consolidation at both the hospital and surgeon level, with a target of at least 260 cases per surgeon annually for each operation. Payers seem best-equipped to drive consolidation.

Delineation of blacktip shark (Carcharhinus limbatus) nursery habitats in the north-western Gulf of Mexico.

Coevolution with predators leads to the use of low-risk habitats by many prey species, which promotes survival during early developmental phases. These nurseries are valued by conservation and management agencies because of their contributions to adult populations. However, the physical and geographic characteristics, like shallow depths and isolation from other marine habitats, that restrict access to predators and thereby reduce risk to juvenile animals can also limit scientific research. Consequently, many nursery habitats are still unidentified and understudied. Here we used gillnet monitoring from 1982 to 2018 to delineate blacktip shark (Carcharhinus limbatus) nurseries in the north-western Gulf of Mexico and elucidated their physical, environmental and biological characteristics. Nursery habitats within estuaries (<2% of spatial area) were proximate to the Gulf of Mexico and exhibited significantly lower variability in salinity than non-nurseries. However, relative abundances of predators and prey were not significant delineators of nursery habitats. As such, food and risk may not influence juvenile blacktip habitat use as expected. Alternatively, reduced osmoregulatory stress attributed to predictable environments likely provides advantageous conditions for blacktips to develop foraging and antipredator tactics, which is vital prior to the winter migration of juvenile sharks into the Gulf of Mexico.

Dual TGFß and Wnt inhibition promotes Mesp1-mediated mouse pluripotent stem cell differentiation into functional cardiomyocytes.

Efficient derivation of cardiomyocytes from mouse pluripotent stem cells has proven challenging, and existing approaches rely on expensive supplementation or extensive manipulation. Mesp1 is a transcription factor that regulates cardiovascular specification during embryo development, and its overexpression has been shown to promote cardiogenesis. Here, we utilize a doxycycline-inducible Mesp1-expressing mouse embryonic stem cell system to develop an efficient differentiation protocol to generate functional cardiomyocytes. Our cardiac differentiation method involves transient Mesp1 induction following by subsequent dual inhibition of TGFß and Wnt signaling pathways using small molecules. We discovered that whereas TGFß inhibition promoted Mesp1-induced cardiac differentiation, Wnt inhibition was ineffective. Nevertheless, a combined inhibition of both pathways was superior to either inhibition alone in generating cardiomyocytes. These observations suggested a potential interaction between TGFß and Wnt signaling pathways in the context of Mesp1-induced cardiac differentiation. Using a step-by-step approach, we have further optimized the windows of Mesp1 induction, TGFß inhibition and Wnt inhibition to yield a maximal cardiomyocyte output - Mesp1 was induced first, followed by dual inhibition of TGFß and Wnt signaling. Our protocol is capable of producing approximately 50% of cardiomyocytes in 12 days, which is comparable to existing methods, and have the advantages of being technically simple and inexpensive. Moreover, cardiomyocytes thus derived are functional, displaying intrinsic contractile capacity and contraction in response to electric stimulus. Derivation of mouse cardiomyocytes without the use of growth factors or other costly supplementation provides an accessible cell source for future applications.

Net clinical benefit of anticoagulation for atrial fibrillation following intracerebral hemorrhage.

Following an anticoagulation-associated intracerebral hemorrhage (ICH), whether and when to resume anticoagulation is controversial. Patient-level recurrence risk is difficult to predict with accuracy, but time-based recurrence risk may be more predictable. To better inform clinical decisions, we set out to estimate the net clinical benefit of anticoagulation over time among patients with atrial fibrillation. Using a large administrative dataset with 5339 index ICH hospitalizations and 132 readmissions for ICH, we created a two-stage prediction model, first predicting patient-level risk of recurrence and then predicting timing, conditional on recurrence. A log-normal survival function best explained the declining risk of recurrent ICH over time. We then compared risk of recurrent ICH over time against ischemic stroke risk, weighting the two outcomes to compute the net clinical benefit on each day following an index discharge. Using a bootstrapping approach, we identified the first day following discharge on which anticoagulation would lead to net benefit rather than net harm. Anticoagulation remains harmful for at least 11 days following index discharge and, depending on desired confidence level and assumptions, may remain harmful for as long as 62 days after discharge. Results were sensitive to the overall ICH recurrence risk. Although patient-level risk of recurrent ICH is difficult to predict accurately, recurrence risk declines rapidly over time. The survival function presented herein can inform decision-analytic models regarding when patients should resume anticoagulation following ICH.

How Are We Measuring Cost-Effectiveness in Total Joint Arthroplasty Studies? Systematic Review of the Literature.

BACKGROUND: As volumes of total hip arthroplasty (THA) and total knee arthroplasty (TKA) continue to rise, it is important to understand their economic impact. No systematic review on cost-effectiveness of THA/TKA has been performed since 2016 despite recent changes in the healthcare environment. The purpose of the study is to provide a contemporary analysis of the cost-effectiveness of total joint arthroplasty and the use of quality-adjusted life years (QALYs). METHODS: A systematic review was performed from 2005 to 2020. Online databases (OVID Medline, PubMed, Cost-Effectiveness Analysis Registry, Google Scholar, Elton B. Stephens Co) were queried to identify economic analyses that evaluated the cost-effectiveness of THA/TKA. RESULTS: In total, 38 studies met the screening criteria. Study designs were primarily Markov models (68%), cohort studies (16%), and randomized trials (8%). Most studies adopted either a societal perspective (45%) or a health system perspective (39%). Analysis revealed that THA/TKA was strongly cost-effective compared to nonsurgical treatment. THA/TKA procedures that were not delayed were more cost-effective than delayed intervention. The majority of studies used QALYs as the primary quality metric (82%); in all these studies there was a significant improvement in QALYs gained. CONCLUSION: Given the high economic impact of arthroplasty, ongoing assessment of cost-effectiveness is needed. Twenty-four percent of studies included in this systematic review were published in the last 4 years of this 15-year study period, highlighting the need for continuous assessment of aggregate data. Future studies should incorporate the cost-effectiveness of THA and TKA with respect to the work-value provided by surgeon providers to support health policy and reimbursement.

Single-cell RNA-seq analysis of Mesp1-induced skeletal myogenic development.

The Mesp1 lineage contributes to cardiac, hematopoietic and skeletal myogenic development. Interestingly, muscle stem cells residing in craniofacial skeletal muscles primarily arise from Mesp1+ progenitors, but those in trunk and limb skeletal muscles do not. To gain insights into the difference between the head and trunk/limb muscle developmental processes, we studied Mesp1+ skeletal myogenic derivatives via single-cell RNA-seq and other strategies. Using a doxycycline-inducible Mesp1-expressing mouse embryonic stem cell line, we found that the development of Mesp1-induced skeletal myogenic progenitors can be characterized by dynamic expression of PDGFRα and VCAM1. Single-cell RNA-seq analysis further revealed the heterogeneous nature of these Mesp1+ derivatives, spanning pluripotent and mesodermal to mesenchymal and skeletal myogenic. We subsequently reconstructed the single-cell trajectories of these subpopulations. Our data thereby provide a cell fate projection of Mesp1-induced skeletal myogenesis.

Cost-Effectiveness of Bridging Anticoagulation Among Patients with Nonvalvular Atrial Fibrillation.

BACKGROUND: Bridging anticoagulation is commonly prescribed to patients with atrial fibrillation during initiation and interruption of warfarin. Guidelines recommend bridging patients at high risk of stroke, while a recent randomized trial demonstrated overall harm in a population at comparatively low risk of ischemic stroke. Theory suggests that patients at high risk of stroke and low risk of hemorrhage may benefit from bridging, but data informing patient selection are scant. OBJECTIVE: To estimate the utility and cost-effectiveness of bridging anticoagulation among patients with nonvalvular atrial fibrillation, stratified by thromboembolic and hemorrhagic risk DESIGN: Cost-effectiveness analysis with lifelong time horizon, from the perspective of a third-party payer MAIN MEASURES: Quality-adjusted life years (QALYs) per bridged patient; US dollars per QALY gained KEY RESULTS: Unselected patients with nonvalvular atrial fibrillation may be harmed by bridging anticoagulation. Hospital admission for bridging is almost never cost-effective, and generally harmful. Among patients carefully selected by both thromboembolic and hemorrhagic risks, outpatient bridging can be beneficial and cost-effective. Results were sensitive to how effectively heparin products reduce stroke risk. CONCLUSIONS: Outpatient bridging anticoagulation can be beneficial and cost-effective for a subset of patients with nonvalvular atrial fibrillation during interruption or initiation of warfarin. Admission for bridging should be avoided.

Anticipated Rates and Costs of Guideline-Concordant Preoperative Stress Testing.

BACKGROUND: Current guidelines recommend that patients have preoperative assessment of cardiac risk and functional status, and that patients at "elevated" cardiac risk with poor or unknown functional status be referred for preoperative stress testing. Little is known about current rates of testing or resultant medical costs. We set out to estimate the expected rates of preoperative stress testing and resultant costs if physicians in the United States were to follow current guidelines and to investigate differences that would arise from 2 risk prediction methods included in current guidelines. METHODS: We applied 2 risk prediction tools (Revised Cardiac Risk Index and Myocardial Infarction or Cardiac Arrest) included in current American College of Cardiology/American Heart Association guidelines to a multicenter prospective registry of patients undergoing surgery in the United States in 2009. We then calculated expected rates of preoperative cardiac stress testing if physicians were to follow American College of Cardiology/American Heart Association guidelines, expected nationwide direct medical expenditures that would result (in 2017 US dollars), and agreement beyond chance between the 2 risk prediction tools. RESULTS: Current guidelines recommend considerable spending on preoperative stress testing. Guideline-recommended spending would differ substantially depending on the risk prediction tool used and the reliability of the functional status assessment. Rates of testing and resultant spending are likely much greater among patients at "elevated" risk, compared with patients at "low" risk. Two guideline-recommended risk assessment tools, Revised Cardiac Risk Index and Myocardial Infarction or Cardiac Arrest, have poor agreement beyond chance across the currently recommended risk threshold. CONCLUSIONS: Preoperative stress testing is likely a considerable source of medical spending, despite unproven benefit. Which perioperative risk assessment tool clinicians should use, what risk thresholds are appropriate for patient selection, and the reliability of the functional status assessment all warrant further attention.

Personalizing Bridging Anticoagulation in Patients with Nonvalvular Atrial Fibrillation-a Microsimulation Analysis.

BACKGROUND: Bridging anticoagulation is commonly prescribed to patients with atrial fibrillation who are initiating warfarin or require interruption of anticoagulation. Current guidelines recommend bridging for patients at high risk of stroke. Among patients with atrial fibrillation and one or more risk factors for ischemic stroke, the recently published BRIDGE trial found forgoing bridging during interruption to be, on average, noninferior to bridging with respect to ischemic complications, with significantly fewer hemorrhagic complications. OBJECTIVE: We sought to examine the benefits and harms of bridging anticoagulation across the spectrum of ischemic and hemorrhagic stroke risk and thereby enable more nuanced, risk-stratified decision-making when bridging is considered during initiation or interruption of vitamin K antagonists. DESIGN: A Monte Carlo simulation, using a combination of literature-derived estimates, registry data, and trial data. MAIN MEASURES: Net clinical benefit, weighting for ischemic strokes, intracranial hemorrhages, and extracranial major hemorrhages. KEY RESULTS: The benefits and harms of bridging anticoagulation vary according to underlying patient risk profiles for both thromboembolic stroke and major intracranial bleeding. Patients at high risk of ischemic stroke and low risk of hemorrhage derive benefit from bridging during initiation or interruption of warfarin therapy. Patients at similarly high or low risk of both outcomes may receive benefit from bridging during initiation and bridging during interruption, but this was sensitive to underlying assumptions. The need for stratification along both axes of risk was robust to a wide range of parameters. CONCLUSIONS: Bridging anticoagulation may provide benefit to patients at high risk of ischemic stroke and low risk of intracranial hemorrhage who are initiating or interrupting warfarin therapy, while patients at high or low risk of both complications may be harmed. The use of bridging anticoagulation in patients with non-valvular atrial fibrillation should be considered only after stratification by risk of ischemic and hemorrhagic complications.

Impact of Embedding a Venous Thromboembolism Risk Assessment Model in the Electronic Health Record Versus Usual Care: A Cluster-Randomized Trial.

BACKGROUND: There are multiple risk assessment models (RAMs) for venous thromboembolism prophylaxis, but it is unknown whether they increase appropriate prophylaxis. METHODS: To determine the impact of a RAM embedded in the electronic health record, we conducted a stepped-wedge hospital-level cluster-randomized trial conducted from October 1, 2017 to February 28, 2019 at 10 Cleveland Clinic hospitals. We included consecutive general medical patients aged 18 years or older. Patients were excluded if they had a contraindication to prophylaxis, including anticoagulation for another condition, acute bleeding, or comfort-only care. A RAM was embedded in the general admission order set and physicians were encouraged to use it. The decisions to use the RAM and act on the results were reserved to the treating physician. The primary outcome was the percentage of patients receiving appropriate prophylaxis (high-risk patients with pharmacological thromboprophylaxis plus low-risk patients without prophylaxis) within 48 hours of hospitalization. Secondary outcomes included total patients receiving prophylaxis, venous thromboembolism among high-risk patients at 14 and 45 days, major bleeding, heparin-induced thrombocytopenia, and length of stay. Mixed-effects models were used to analyze the study outcomes. RESULTS: A total of 26 506 patients (mean age, 61; 52% female; 73% White) were analyzed, including 11 134 before and 15 406 after implementation of the RAM. After implementation, the RAM was used for 24% of patients, and the percentage of patients receiving appropriate prophylaxis increased from 43.1% to 48.8% (adjusted odds ratio, 1.11 [1.00-1.23]), while overall prophylaxis use decreased from 73.5% to 65.2% (adjusted odds ratio, 0.87 [0.78-0.97]). Rates of venous thromboembolism among high-risk patients (adjusted odds ratio, 0.72 [0.38-1.36]), rates of bleeding and heparin-induced thrombocytopenia (adjusted odds ratio, 0.19 [0.02-1.47]), and length of stay were unchanged. CONCLUSIONS: Implementation of a RAM for venous thromboembolism increased appropriate prophylaxis use, but the RAM was used for a minority of patients. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03243708?term=nct03243708&rank=1; Unique identifier: NCT03243708.

Clinicians' interpretation of thresholds in hospital antibiograms for gram-negative rod infections: A survey and contingent valuation study of hospitalists.

Clinical guidelines suggest that hospital antibiograms are a key component when deciding empiric therapy, but little is known about how often clinicians use antibiograms and how they influence clinicians' empiric therapy decisions. We surveyed hospitalists at seven healthcare systems in the United States on their reported practices related to antibiograms and their hypothetical prescribing for four clinical scenarios associated with gram-negative rod pathogens. Each was given a randomly assigned antibiogram susceptibility percentage, and we used contingent valuation analysis to assess whether the antibiogram susceptibility percentage was associated with prescribing practices. Of the 193 survey responders, only 52 (26.9%) respondents reported using antibiograms more than monthly. Across all four clinical scenarios, there was no evidence that antibiogram susceptibility levels influenced antibiotic prescribing practices. With limited utilization and no evidence that they influenced practice, antibiograms may have a limited role in hospitalist care delivery for common gram-negative rod infections.

Diagnostic and prognostic value of cardiac stress testing before major noncardiac surgery-A cohort study.

OBJECTIVE: To assess the incremental contribution of preoperative stress test results toward a diagnosis of obstructive coronary artery disease (CAD), prediction of mortality, or prediction of perioperative myocardial infarction in patients considering noncardiac, nonophthalmologic surgery. DESIGN, SETTING, PARTICIPANTS: A retrospective cohort study of visits to a preoperative risk assessment and optimization clinic in a large health system between 2008 and 2018. MEASUREMENTS: To assess diagnostic information of preoperative stress testing, we used the Begg and Greenes method to calculate test characteristics adjusted for referral bias, with a gold standard of angiography. To assess prognostic information, we first created multiply-imputed logistic regression models to predict 90-day mortality and perioperative myocardial infarction (MI), starting with two tools commonly used to assess perioperative cardiac risk, Revised Cardiac Risk Index (RCRI) and Myocardial Infarction or Cardiac Arrest (MICA). We then added stress test results and compared the discrimination for models with and without stress test results. MAIN RESULTS: Among 136,935 visits by patients without an existing diagnosis of CAD, the decision to obtain preoperative stress testing identified around 4.0% of likely new diagnoses. Stress testing increased the likelihood of CAD (likelihood ratio: 1.31), but for over 99% of patients, stress testing should not change a decision on whether to proceed to angiography. In 117,445 visits with subsequent noncardiac surgery, stress test results failed to improve predictions of either perioperative MI or 90-day mortality. Reweighting the models and adding hemoglobin improved the prediction of both outcomes. CONCLUSIONS: Cardiac stress testing before noncardiac, nonophthalmologic surgery does not improve predictions of either perioperative mortality or myocardial infarction. Very few patients considering noncardiac, nonophthalmologic surgery have a pretest probability of CAD in a range where stress testing could usefully select patients for angiography. Better use of existing patient data could improve predictions of perioperative adverse events without additional patient testing.

Consequences of preoperative cardiac stress testing-A cohort study.

OBJECTIVE: To understand the consequences of functional cardiac stress testing among patients considering noncardiac nonophthalmologic surgery. DESIGN: A retrospective cohort study of 118,552 patients who made 159,795 visits to a dedicated preoperative risk assessment and optimization clinic between 2008 and 2018. SETTING: A large integrated health system. PATIENTS: Patients who visited a dedicated preoperative risk assessment and optimization clinic before noncardiac nonophthalmologic surgery. MEASUREMENTS: To assess changes to care delivered, we measured the probability of completing additional cardiac testing, cardiac surgery, or noncardiac surgery. To assess outcomes, we measured time-to-mortality and total one-year mortality. MAIN RESULTS: In causal inference models, preoperative stress testing was associated with increased likelihood of coronary angiography (relative risk: 8.6, 95% CI 6.1-12.1), increased likelihood of percutaneous coronary intervention (RR: 4.1, 95% CI: 1.8-9.2), increased likelihood of cardiac surgery (RR: 6.8, 95% CI 4.9-9.4), decreased likelihood of noncardiac surgery (RR: 0.77, 95% CI 0.75-0.79), and delayed noncardiac surgery for patients completing noncardiac surgery (mean 28.3 days, 95% CI: 23.1-33.6). The base rate of downstream cardiac testing was low, and absolute risk increases were small. Stress testing was associated with higher mortality in unadjusted analysis but was not associated with mortality in causal inference analyses. CONCLUSIONS: Preoperative cardiac stress testing likely induces coronary angiography and cardiac interventions while decreasing use of noncardiac surgery and delaying surgery for patients who ultimately proceed to noncardiac surgery. Despite changes to processes of care, our results do not support a causal relationship between stress testing and postoperative mortality. Analyses of care cascades should consider care that is avoided or substituted in addition to care that is induced.

A Novel Risk Assessment Model Predicts Major Bleeding Risk at Admission in Medical Inpatients.

Background: Venous thromboembolism (VTE) is the leading cause of preventable hospital death in the US. Guidelines from the American College of Chest Physicians and American Society for Hematology recommend providing pharmacological VTE prophylaxis to acutely or critically ill medical patients at acceptable bleeding risk, but there is currently only one validated risk assessment model (RAM) for estimating bleeding risk. We developed a RAM using risk factors at admission and compared it with the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model. Methods: A total of 46,314 medical patients admitted to a Cleveland Clinic Health System hospital from 2017-2020 were included. Data were split into training (70%) and validation (30%) sets with equivalent bleeding event rates in each set. Potential risk factors for major bleeding were identified from the IMPROVE model and literature review. Penalized logistic regression using LASSO was performed on the training set to select and regularize important risk factors for the final model. The validation set was used to assess model calibration and discrimination and compare performance with IMPROVE. Bleeding events and risk factors were confirmed through chart review. Results: The incidence of major in-hospital bleeding was 0.58%. Active peptic ulcer (OR = 5.90), prior bleeding (OR = 4.24), and history of sepsis (OR = 3.29) were the strongest independent risk factors. Other risk factors included age, male sex, decreased platelet count, increased INR, increased PTT, decreased GFR, ICU admission, CVC or PICC placement, active cancer, coagulopathy, and in-hospital antiplatelet drug, steroid, or SSRI use. In the validation set, the Cleveland Clinic Bleeding Model (CCBM) had better discrimination than IMPROVE (0.86 vs. 0.72, p < .001) and, at equivalent sensitivity (54%), categorized fewer patients as high-risk (6.8% vs. 12.1%, p < .001). Conclusions: From a large population of medical inpatients, we developed and validated a RAM to accurately predict bleeding risk at admission. The CCBM may be used in conjunction with VTE risk calculators to decide between mechanical and pharmacological prophylaxis for at-risk patients.