Synthesis of Arylpalladium(II) Boronates: Confirming the Structure and Chemical Competence of Pre-transmetalation Intermediates in the Suzuki-Miyaura Reaction.

Palladium(II) boronates are recognized as fundamental pre-transmetalation intermediates in Suzuki-Miyaura cross-couplings. While these typically transient species have been detected and studied spectroscopically, it is conspicuous that they have never been isolated since this important reaction was discovered over forty years ago. This study reports the synthesis of a family of unprecedented arylpalladium(II) boronates that are, by design, kinetically stable at ambient temperature, both in solution and in the solid state. These properties enabled unambiguous crystallographic confirmation of their structure for the first time and their chemical competence in a Suzuki-Miyaura reaction was demonstrated.

Polyubiquitin Drives the Molecular Interactions of the NF-κB Essential Modulator (NEMO) by Allosteric Regulation.

The NF-κB essential modulator (NEMO) is the master regulator of NF-κB signaling, controlling the immune and nervous systems. NEMO affects the activity of IκB kinase-ß (IKKß), which relieves the inhibition of the NF-κB transcriptional regulation machinery. Despite major effort, there is only a very sparse, phenomenological understanding of how NEMO regulates IKKß and shows specificity in its large range of molecular interactions. We explore the key molecular interactions of NEMO using a molecular biophysics approach, incorporating rapid-mixing stopped-flow, high-pressure, and CD spectroscopies. Our study demonstrates that NEMO has a significant degree of native structural disorder and that molecular flexibility and ligand-induced conformational change are at the heart of the molecular interactions of NEMO. We found that long chain length, unanchored, linear polyubiquitin drives NEMO activity, enhancing the affinity of NEMO for IKKß and the kinase substrate IκBα and promoting membrane association. We present evidence that unanchored polyubiquitin achieves this regulation by inducing NEMO conformational change by an allosteric mechanism. We combine our quantitative findings to give a detailed molecular mechanistic model for the activity of NEMO, providing insight into the molecular mechanism of NEMO activity with broad implications for the biological role of free polyubiquitin.

ent-Labdane Diterpenoids from Dodonaea viscosa.

Seven new and two known ent-labdane diterpenoids have been isolated from a single plant specimen of Dodonaea viscosa ssp. spatulata, found in Tasmania, Australia. Prior to this study, only seven different labdane diterpenoids had been isolated from D. viscosa. The structures of the natural products were assigned via 1D and 2D NMR spectroscopy and other standard spectroscopic methods. The absolute configuration of three ent-labdane diterpenoids was determined by single-crystal X-ray crystallography of synthetic derivatives. Significantly, the results of this study suggest that the absolute configuration of some known labdane diterpenoids may have been misassigned.

Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA.

The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.

Biosynthesis of the halogenated auxin, 4-chloroindole-3-acetic acid.

Seeds of several agriculturally important legumes are rich sources of the only halogenated plant hormone, 4-chloroindole-3-acetic acid. However, the biosynthesis of this auxin is poorly understood. Here, we show that in pea (Pisum sativum) seeds, 4-chloroindole-3-acetic acid is synthesized via the novel intermediate 4-chloroindole-3-pyruvic acid, which is produced from 4-chlorotryptophan by two aminotransferases, TRYPTOPHAN AMINOTRANSFERASE RELATED1 and TRYPTOPHAN AMINOTRANSFERASE RELATED2. We characterize a tar2 mutant, obtained by Targeting Induced Local Lesions in Genomes, the seeds of which contain dramatically reduced 4-chloroindole-3-acetic acid levels as they mature. We also show that the widespread auxin, indole-3-acetic acid, is synthesized by a parallel pathway in pea.

Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion.

Intralipid is a fat emulsion that is regularly infused into humans and animals. Despite its routine use, Intralipid infusion can cause serious adverse reactions, including immunosuppression. Intralipid is a complex mix of proteins, lipids, and other small molecules, and the effect of its infusion on the human plasma metabolome is unknown. We hypothesized that untargeted metabolomics of human plasma after an Intralipid infusion would reveal novel insights into its effects. We infused Intralipid and saline into 10 healthy men in a double-blind, placebo-controlled experiment and used GC/MS, LC/MS, and NMR to profile the small-molecule composition of their plasma before and after infusion. Multivariate statistical analysis of the 40 resulting plasma samples revealed that after Intralipid infusion, a less-well-characterized pathway of linoleic acid metabolism had resulted in the appearance of (9Z)-12,13-dihydroxyoctadec-9-enoic acid (12,13-DHOME, P < 10(-3)), a leukotoxin that has powerful physiological effects and is known to inhibit the neutrophil respiratory burst. Intralipid infusion caused increased plasma 12,13-DHOME. Given that 12,13-DHOME is known to directly affect neutrophil function, we conclude that untargeted metabolomics may have revealed a hitherto-unknown mechanism of intralipid-induced immunosuppression.

Metal-on-metal total hip arthroplasty: do symptoms correlate with MR imaging findings?

PURPOSE: To determine the prevalence of magnetic resonance (MR) imaging abnormalities after metal-on-metal total hip arthroplasty and to determine whether presence of symptoms correlates with findings at MR imaging. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board, and informed consent was waived. MR imaging was performed with conventional sequences and a 1.5-T clinical imager in 192 hips (174 patients) evaluated during a 15-month period. Two observers retrospectively reviewed the images for the presence and size of pseudotumor, communication with the pseudocapsule, wall thickness, synovial hypertrophy, compartmentalization, solid components, foci of wall susceptibility, osteolysis, bone marrow edema, abductor muscle or tendon abnormality, and Anderson MR grade (normal, infection, or varying severity of metal-on-metal disease). These findings were compared between asymptomatic and symptomatic patients by using the Fisher exact test or the Wilcoxon-Mann-Whitney test, as appropriate. RESULTS: Prevalence of pseudotumors per patient and per hip was 69% (120 of 174 patients, 132 of 192 hips). Bone marrow edema (present in six asymptomatic patients and 19 patients with pain, P < .01) and tendon tearing (present in five asymptomatic patients and 13 patients with pain, P < .05) were predictors of pain. Presence of symptoms was not correlated with presence (P = .4151) or size of pseudotumors. Anderson MR grade binarized into normal versus abnormal showed moderate agreement between readers (κ = 0.439) but was also not correlated with symptoms (P = .6648). CONCLUSION: The presence of bone marrow edema and abductor tendon tears but not the presence or size of pseudotumor was associated with patient pain.

Transgenic production of arachidonic acid in oilseeds.

We describe a transgenic microalgal Δ9-elongase pathway transformed in both Brassica napus and Arabidopsis thaliana seed resulting in the production of arachidonic acid (ARA). This pathway is noteworthy for both the production of ARA in seed tissue and the low levels of intermediate C20 fatty acids that accumulate. We also demonstrate that the arachidonic acid is naturally enriched at the sn2 position in triacylglycerol. This is the first report of ARA production by the Δ9-elongase pathway in an oilseed.

One night's CPAP withdrawal in otherwise compliant OSA patients: marked driving impairment but good awareness of increased sleepiness.

PURPOSE: Obstructive sleep apnoea (OSA) patients effectively treated by and compliant with continuous positive air pressure (CPAP) occasionally miss a night's treatment. The purpose of this study was to use a real car interactive driving simulator to assess the effects of such an occurrence on the next day's driving, including the extent to which these drivers are aware of increased sleepiness. METHODS: Eleven long-term compliant CPAP-treated 50-75-year-old male OSA participants completed a 2-h afternoon, simulated, realistic monotonous drive in an instrumented car, twice, following one night: (1) normal sleep with CPAP and (2) nil CPAP. Drifting out of road lane ('incidents'), subjective sleepiness every 200 s and continuous electroencephalogram (EEG) activities indicative of sleepiness and compensatory effort were monitored. RESULTS: Withdrawal of CPAP markedly increased sleep disturbance and led to significantly more incidents, a shorter 'safe' driving duration, increased alpha and theta EEG power and greater subjective sleepiness. However, increased EEG beta activity indicated that more compensatory effort was being applied. Importantly, under both conditions, there was a highly significant correlation between subjective and EEG measures of sleepiness, to the extent that participants were well aware of the effects of nil CPAP. CONCLUSIONS: Patients should be aware that compliance with treatment every night is crucial for safe driving.

Migration of Hospital Total Hip and Knee Arthroplasty Procedures to an Ambulatory Surgery Center Setting and Postsurgical Opioid Use: A Private Practice Experience.

Background: An enhanced recovery pathway using individualized multimodal pain management with scheduled nonopioid and opioid regimens previously enabled reproducible same-day discharge of Medicare beneficiaries and commercially insured patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) procedures in the hospital or in ambulatory surgery center settings. Objective: To analyze the migration trends for TKA and THA procedures from a hospital to an ambulatory surgery center facility and to assess perioperative outcomes before and after incorporating liposomal bupivacaine into a multimodal pain management regimen for these procedures. Methods: This retrospective medical chart review study included patients undergoing THA or TKA with an enhanced recovery pathway in a hospital or an ambulatory surgery center between 2013 and 2019. The outcome measures included length of stay at the hospital or the ambulatory center, and opioid consumption. We compared the outcomes before and after the addition of liposomal bupivacaine to surgeon-applied periarticular intraoperative local anesthetic field blocks between in-hospital patients who received and patients who did not receive liposomal bupivacaine in 2013 and 2014, and the impact of liposomal bupivacaine use in the hospital versus the ambulatory center from 2015 to 2019. Results: In 2013 and 2014, the addition of liposomal bupivacaine increased the same-day hospital discharge rate to 32% versus 4% without liposomal bupivacaine (odds ratio, 14.3; 95% confidence interval, 5.9-33.3; P <.0001); the same-day hospital discharge rates increased to 73% in 2015. From 2015 through 2019, 89% of all patients were discharged on the same day from the hospital. In-hospital opioid use was 22% lower in the liposomal bupivacaine cohort than in the patients who did not receive this medication (P = .0035). In 2018 and 2019, same-day discharge from the hospital or the ambulatory surgery center rates were 96% and 100%, respectively, and 84% of the patients used postsurgical opioid prescriptions of 30 or fewer tablets. The complication rates and healthcare resource utilization did not increase with the incorporation of liposomal bupivacaine into the enhanced recovery pathway and increased same-day discharge rates. Conclusion: An enhanced recovery pathway using individualized, scheduled multimodal pain management protocol in patients undergoing THA or TKA facilitated reproducible, high same-day discharge rates and low postoperative opioid consumption. These results suggest that the use of liposomal bupivacaine for intraoperative field blocks supports predictable same-day discharge rates after THA or TKA. This protocol could facilitate same-day hospital discharge and the migration of THA and TKA procedures from the hospital to lower-cost ambulatory surgery centers.

Cardiac Comorbidity Risk Score: Zero-Burden Machine Learning to Improve Prediction of Postoperative Major Adverse Cardiac Events in Hip and Knee Arthroplasty.

Background In this retrospective, observational study we introduce the Cardiac Comorbidity Risk Score, predicting perioperative major adverse cardiac events (MACE) after elective hip and knee arthroplasty. MACE is a rare but important driver of mortality, and existing tools, eg, the Revised Cardiac Risk Index demonstrate only modest accuracy. We demonstrate an artificial intelligence-based approach to identify patients at high risk of MACE within 4 weeks (primary outcome) of arthroplasty, that imposes zero additional burden of cost/resources. Methods and Results Cardiac Comorbidity Risk Score calculation uses novel machine learning to estimate MACE risk from patient electronic health records, without requiring blood work or access to any demographic data beyond that of sex and age, and accounts for variable/missing/incomplete information across patient records. Validated on a deidentified cohort (age >45 years, n=445 391), performance was evaluated using the area under the receiver operator characteristics curve (AUROC), sensitivity/specificity, positive predictive value, and positive/negative likelihood ratios. In our cohort (age 63.5±10.5 years, 58.2% women, 34.2%/65.8% hip/knee procedures), 0.19% (882) experienced the primary outcome. Cardiac Comorbidity Risk Score achieved area under the receiver operator characteristics curve=80.0±0.4% (95% CI) for women and 80.1±0.5% (95% CI) for males, with 36.4% and 35.1% sensitivities, respectively, at 95% specificity, significantly outperforming Revised Cardiac Risk Index across all studied age-, sex-, risk-, and comorbidity-based subgroups. Conclusions Cardiac Comorbidity Risk Score, a novel artificial intelligence-based screening tool using known and unknown comorbidity patterns, outperforms state-of-the-art in predicting MACE within 4 weeks postarthroplasty, and can identify patients at high risk that do not demonstrate traditional risk factors.

Selective Binding of Small Molecules to Vibrio cholerae DsbA Offers a Starting Point for the Design of Novel Antibacterials.

DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram-negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli. Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal that DsbA enzymes share a similar fold, however, the hydrophobic groove adjacent to the active site, which is implicated in substrate binding, is shorter and flatter in the structure of V. cholerae DsbA (VcDsbA) compared to E. coli DsbA (EcDsbA). The flat and largely featureless nature of this hydrophobic groove is challenging for the development of small molecule inhibitors. Using fragment-based screening approaches, we have identified a novel small molecule, based on the benzimidazole scaffold, that binds to the hydrophobic groove of oxidized VcDsbA with a KD of 446±10 µM. The same benzimidazole compound has ∼8-fold selectivity for VcDsbA over EcDsbA and binds to oxidized EcDsbA, with KD >3.5 mM. We generated a model of the benzimidazole complex with VcDsbA using NMR data but were unable to determine the structure of the benzimidazole bound EcDsbA using either NMR or X-ray crystallography. Therefore, a structural basis for the observed selectivity is unclear. To better understand ligand binding to these two enzymes we crystallized each of them in complex with a known ligand, the bile salt sodium taurocholate. The crystal structures show that taurocholate adopts different binding poses in complex with VcDsbA and EcDsbA, and reveal the protein-ligand interactions that stabilize the different modes of binding. This work highlights the capacity of fragment-based drug discovery to identify inhibitors of challenging protein targets. In addition, it provides a starting point for development of more potent and specific VcDsbA inhibitors that act through a novel anti-virulence mechanism.

Reduced false positives in autism screening via digital biomarkers inferred from deep comorbidity patterns.

Here, we develop digital biomarkers for autism spectrum disorder (ASD), computed from patterns of past medical encounters, identifying children at high risk with an area under the receiver operating characteristic exceeding 80% from shortly after 2 years of age for either sex, and across two independent patient databases. We leverage uncharted ASD comorbidities, with no requirement of additional blood work, or procedures, to estimate the autism comorbid risk score (ACoR), during the earliest years when interventions are the most effective. ACoR has superior predictive performance to common questionnaire-based screenings and can reduce their current socioeconomic, ethnic, and demographic biases. In addition, we can condition on current screening scores to either halve the state-of-the-art false-positive rate or boost sensitivity to over 60%, while maintaining specificity above 95%. Thus, ACoR can significantly reduce the median diagnostic age, reducing diagnostic delays and accelerating access to evidence-based interventions.

I think I'm sleepy, therefore I am - Awareness of sleepiness while driving: A systematic review.

Driver drowsiness contributes to 10-20% of motor vehicle crashes. To reduce crash risk, ideally drivers would be aware of the drowsy state and cease driving. The extent to which drivers can accurately identify sleepiness remains under much debate. We systematically examined whether individuals are aware of sleepiness while driving, and whether this accurately reflects driving impairment, using meta-analyses and narrative review. Within this scope, there is high variability in measures of subjective sleepiness, driving performance and physiologically-derived drowsiness, and statistical analyses. Thirty-four simulated/naturalistic driving studies were reviewed. To summarise, drivers were aware of sleepiness, and this was associated to physiological drowsiness and driving impairment, such that high levels of sleepiness significantly predicted crash events and lane deviations. Subjective sleepiness was more strongly correlated (i) with physiological drowsiness compared to driving outcomes; (ii) under simulated driving conditions compared to naturalistic drives; and (iii) when examined using the Karolinska sleepiness scale (KSS) compared to other measures. Gaps remain in relation to how age, sex, and varying degrees of sleep loss may influence this association. This review provides evidence that drivers are aware of drowsiness while driving, and stopping driving when feeling 'sleepy' may significantly reduce crash risk.

PVT lapses differ according to eyes open, closed, or looking away.

STUDY OBJECTIVES: A lapse during the psychomotor vigilance task (PVT) is usually defined as a response longer than 500 ms; however, it is currently unknown what psychobiological phenomena occur during a lapse. An assessment of what a participant is doing during a lapse may depict varying levels of "disengagement" during these events and provide more insight into the measurement of both a lapse and sleepiness. DESIGN: Repeated measures. SETTING: Participants underwent extended 30-min PVT sessions twice, at 22:00 and 04:00, under: (i) typical non-distractive laboratory conditions, and (ii) an additional distractive condition. PARTICIPANTS: Twenty-four healthy young adults (mean age: 23.2 y +/- 2 y; range 21-25 y [12 m; 12 f]) without any sleep or medical problems and without any prior indication of daytime sleepiness. INTERVENTIONS: One night of sleep loss. Distraction comprised a TV located at 90 degrees in the visual periphery showing a popular TV program. For the non-distraction condition, the TV was turned off. MEASUREMENTS & RESULTS: Video data (bird's-eye and frontal view) were used to classify each lapse (> or = 500 ms) as occurring with eyes open (EO), eyes closed (EC), or due to a head turn (HT). EO lapses were more prevalent, with all lapses (EO, EC, and HT) increasing with sleepiness. There was a significant effect of distraction for HT lapses which was exacerbated when sleepy. For lapse duration there was little effect of sleepiness for EO lapses but a significant effect for EC and HT. The 95% confidence intervals for lapse duration and associated behavior showed those lapses greater than 2669 ms were 95% likely to be EC, whereas those 500-549 ms were 95% likely to be EO. Response times of 1217 ms had a 50:50 probability of being EO:EC. CONCLUSIONS: Discriminating the varying causes of lapses whether due to visual inattention (eyes open), microsleep (eyes closed), or distraction (head turn) may provide further insight into levels of disengagement from the PVT and further insight into developing sleepiness.

Presurgical optimization and opioid-minimizing enhanced recovery pathway for ambulatory knee and hip arthroplasty: postsurgical opioid use and clinical outcomes.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways offer approaches to achieve successful ambulatory primary total knee and total hip arthroplasty (TKA/THA) while meeting the "Triple Aim" of healthcare: patient satisfaction, population health, and value. We evaluated outcomes from an ERAS pathway designed to maximize patients' eligibility for ambulatory TKA/THA while reducing costs, complications, and postsurgical opioid use. METHODS: This retrospective study included 220 consecutive unique commercially insured patients who underwent TKA (n = 113) or THA (n = 138) in an ambulatory surgery center between June 1, 2015 and November 16, 2017. The ERAS pathway encompassed early presurgical through home recovery periods. Key elements included presurgical patient engagement; creation of realistic expectations; optimization of modifiable medical, physical, and social factors; and creation of individualized multimodal opioid-sparing pain management. No home services were used. Adverse events and unplanned admissions within 30 and 60 days, satisfaction, and opioid use were analyzed descriptively. RESULTS: All patients (mean [range] age, 58 [22-84] years; 49% women) had same-day discharge. Within 30 days, 7 (2.8%) patients experienced an adverse event, 3 (1.2%) had an emergency department or urgent care visit without admission, and 8 (3.2%) had an unplanned admission. Within 60 days, 3 additional patients had an emergency department/urgent care visit. Most patients (206 [82.1%]) did not require a second opioid prescription. Patient satisfaction was high. CONCLUSIONS: This ERAS pathway may help meet the Triple Aim for outpatient joint replacement, expand the eligible patient population, and reduce postsurgical opioid use. Further research is warranted.

Characterization of lipophilic drug binding to rat intestinal fatty acid binding protein.

Intestinal fatty acid binding protein (I-FABP) is present at high levels in the absorptive cells of the intestine (enterocytes) where it plays a role in the intracellular solubilization of fatty acids (FA). However, I-FABP has also been shown to bind to a range of non-FA ligands, including some lipophilic drug molecules, albeit with generally lower affinity than FA. The significance of these lower affinity interactions with exogenous compounds is not known. In this manuscript, we describe further characterization of drug-rat I-FABP binding interactions using a thermal-shift assay. A structural explanation of the observed affinity of rat I-FABP for different drugs based on spectroscopic data and modeling experiments is presented. In addition, immunocytochemistry has been used to probe the expression of I-FABP in a cell culture model reflective of the absorptive cells of the small intestine. Taken together, these data suggest a possible role for I-FABP in the disposition of some lipophilic drugs within the enterocyte.

Self-reported 'sleep deficit' is unrelated to daytime sleepiness.

Seemingly, many healthy adults have accrued a sleep debt, as determined by findings based on the multiple sleep latency test (MSLT). However, our recent, extensive survey found self-reported sleep deficit was not linked to daytime sleepiness determined by the Epworth sleepiness scale (ESS). Here, we report on the link between self-reported sleep deficit and gold standard measures of sleepiness: MSLT, Psychomotor vigilance test (PVT) and Karolinska Sleepiness Scale (KSS). Habitual sleep time in forty-three participants, from using a week long sleep diary and actiwatch data, compared with self-ratings of how much sleep they needed, provided estimates of apparent sleep deficit or otherwise. They were split into categories: 'sleep deficit' (Av. -47 min), 'sleep plus' (Av. 47 min) or 'neutral' (Av. 0+/-15 min), depicting perceived shortfall (or excess) sleep. Although the deficit group desired to sleep longer than the other groups, they actually obtained similar habitual nightly sleep as the neutral group, but less than the sleep plus group. 'Survival curves' based on those falling asleep during the MSLT showed no difference between the groups. Neither was there any difference between the groups for the PVT, KSS, or ESS. Here, factors other than sleepiness seem to influence self-perceived sleep deficits.

Expert image analysts show enhanced visual processing in change detection.

Expertise facilitates change detection performance, but the neural underpinnings of these benefits are unknown. Expert image analysts showed larger change-related ERP effects between about 100-200 msec after stimulus onset than did novices, which correlated with both accuracy and years of analysis experience. These results demonstrate that years of visual experience can induce fundamental changes in early visual processing which are related to change detection abilities.

Patient-optimizing enhanced recovery pathways for total knee and hip arthroplasty in Medicare patients: implication for transition to ambulatory surgery centers.

BACKGROUND: Medicare-insured patients may be candidates for outpatient total knee and hip arthroplasty (TKA/THA) because postsurgical complications are often age unrelated. We evaluated an opioid-minimizing enhanced recovery after surgery (ERAS) pathway in an inpatient setting designed to presurgically optimize and prepare patients to reduce risk of avoidable postsurgical complications and maximize feasibility of same-day discharge. METHODS: This single-center retrospective chart review included 601 unique consecutive Medicare-insured patients who underwent TKA (n = 337) or THA (n = 308) between June 1, 2015 and November 16, 2017. The ERAS pathway included presurgical nonarthroplasty treatment of osteoarthritis; physical, medical, and social optimization; and medication trials to individualize perioperative analgesia. All patients were discharged directly home without home services. Adverse events, satisfaction, and opioid use were analyzed descriptively. RESULTS: Mean (range) age was 72 (32-92) years; 56.7% of patients were women; 84.0% were discharged the same day, 13.8% in 1 day, and 2.2% in >1 day. Rates of minor and severe adverse events within 30 days were 0.5% and 1.1%, respectively. There were no intubations, sepsis, or deaths. Twelve patients (1.9%) had unplanned readmissions within 30 days. Patient-reported satisfaction with facility, analgesia, and communication were high. Most patients (84.2%) did not require >1 seven-day opioid prescription from the surgeon within 8 weeks postsurgery. CONCLUSIONS: Using a patient-optimizing, opioid-minimizing ERAS pathway without home services, Medicare-insured patients undergoing TKA/THA experienced low complication rates and high satisfaction. Exploratory analysis suggests limited postsurgical opioid use. This presurgical patient-engagement approach may aid transition to freestanding ambulatory surgery centers.