A live cell imaging-based assay for tracking particle uptake by clathrin-mediated endocytosis.

A popular strategy for therapeutic delivery to cells and tissues is to encapsulate therapeutics inside particles that cells internalize via endocytosis. The efficacy of particle uptake by endocytosis is often studied in bulk using flow cytometry and Western blot analysis and confirmed using confocal microscopy. However, these techniques do not reveal the detailed dynamics of particle internalization and how the inherent heterogeneity of many types of particles may impact their endocytic uptake. Toward addressing these gaps, here we present a live-cell imaging-based method that utilizes total internal reflection fluorescence microscopy to track the uptake of a large ensemble of individual particles in parallel, as they interact with the cellular endocytic machinery. To analyze the resulting data, we employ an open-source tracking algorithm in combination with custom data filters. This analysis reveals the dynamic interactions between particles and endocytic structures, which determine the probability of particle uptake. In particular, our approach can be used to examine how variations in the physical properties of particles (size, targeting, rigidity), as well as heterogeneity within the particle population, impact endocytic uptake. These data impact the design of particles toward more selective and efficient delivery of therapeutics to cells.

Liquid-like condensates that bind actin drive filament polymerization and bundling.

Liquid-like protein condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that polymerize and bundle actin. To minimize their curvature, filaments accumulated at the inner condensate surface, ultimately deforming the condensate into a rod-like shape, filled with a bundle of parallel filaments. Here we show that this behavior does not require proteins with specific polymerase activity. Specifically, we found that condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of polymerizing and bundling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds actin could bundle filaments through multivalent crosslinking. To test this idea, we added an actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that drove efficient actin polymerization and bundling. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any actin-binding protein that participates in protein condensation.

Association between switching to integrase strand transfer inhibitors and incident diabetes in people with HIV: a longitudinal cohort study.

OBJECTIVE: Integrase strand transfer inhibitors (INSTI) are associated with weight gain in people with HIV (PWH), but their impact on diabetes is unclear. We evaluated the association between switching from nonnucleoside reverse-transcriptase inhibitors (NNRTI) or protease inhibitors (PI) to INSTI and incident diabetes. DESIGN: Longitudinal cohort study. METHODS: We included PWH aged ≥18 years from the Johns Hopkins HIV Clinical Cohort (2007-2023) without history of diabetes who had used NNRTI or PI for ≥180 days. We followed participants up to 10 years from HIV primary care visits where they switched to INSTI or continued NNRTI or PI. We estimated the hazard of incident diabetes associated with switching to INSTI using weighted Cox regression with robust variance estimator. RESULTS: We included 2,075 PWH who attended 22,116 visits where they continued NNRTI or PI and 631 visits where they switched to INSTI. Switching to INSTI was associated with a weighted hazard ratio (wHR) of 1.11 (95% confidence interval [CI], 0.77-1.59) for incident diabetes. The association if no weight gain occurred during the first two years was not qualitatively different (wHR 1.22; 95% CI, 0.82-1.80). In a posthoc analysis, switching to INSTI conferred a significant wHR of 1.79 (95% CI, 1.13-2.84) for diabetes within the first two years but not after. CONCLUSIONS: Switching from NNRTI or PI to INSTI did not significantly increase overall diabetes incidence in PWH, although there may be elevated risk in the first two years. These findings can inform considerations when switching to INSTI-based regimens.

Determinants of receipt of prostate cancer screening among men living with HIV enrolled in an urban HIV Clinic in the United States over the period of 2000-2020.

BACKGROUND: Prostate cancer is projected to account for the greatest proportion of cancer-related burden among men with HIV. However, incidence is reportedly lower than in men without HIV, potentially due to differences in screening. Factors influencing receipt of screening in men with HIV are unknown. We described receipt of prostate-specific antigen (PSA) testing and assessed factors for association with receipt of PSA test. METHODS: Demographics, measures of HIV and related care, and non-HIV care were assessed for association with receipt of first PSA test in men ≥40 years old each calendar year in 2000-2020 using univariable and multivariable Poisson regression. Models were additionally stratified by calendar period to identify changes in determinants of PSA test as prostate cancer screening guidelines changed. RESULTS: Men (n = 2,063) 72% Non-Hispanic Black, median age of 47 (IQR: 41, 53), contributed median of 4.7 years (IQR: 2.3, 10.0) of follow-up. Receipt of antiretroviral therapy (aIRR = 1.33; 95% CI: 1.14, 1.55), engagement in HIV care (aIRR = 2.09; 95% CI: 1.66, 2.62), history of testosterone-replacement therapy (aIRR = 1.34; 95% CI: 1.19, 1.50), urologist evaluation (aIRR = 1.66; 95% CI: 1.35, 2.05), and receipt of PSA test in preceding two years (no elevated PSA aIRR = 2.37; 95% CI: 2.16, 2.61; elevated PSA aIRR = 4.35; 95% CI: 3.24, 5.84) were associated with PSA testing in men aged 50 or older. Associations varied across calendar time. CONCLUSION: Findings suggest men with greater interaction with healthcare are more likely to receive PSA test. Measures of control of HIV did not appear to influence the decision to screen.

Discharge Opioid Dose Indirectly Associated With Functional Outcomes 2 Weeks After Shoulder and Knee Arthroscopy in a US Military Sample.

INTRODUCTION: Postsurgical opioid utilization may be directly and indirectly associated with a range of patient-related and surgery-related factors, above and beyond pain intensity. However, most studies examine postsurgical opioid utilization without accounting for the multitude of co-occurring relationships among predictors. Therefore, this study aimed to identify factors associated with opioid utilization in the first 2 weeks after arthroscopic surgery and examine the relationship between discharge opioid prescription doses and acute postsurgical outcomes. METHODS: In this prospective longitudinal observational study, 110 participants undergoing shoulder or knee arthroscopies from August 2016 to August 2018 at Walter Reed National Military Medical Center completed self-report measures before and at 14 days postoperatively. The association between opioid utilization and both patient-level and surgery-related factors was modeled using structural equation model path analysis. RESULTS: Participants who were prescribed more opioids took more opioids, which was associated with worse physical function and sleep problems at day 14, as indicated by the significant indirect effects of discharge opioid dose on day 14 outcomes. Additional patient-level and surgery-related factors were also significantly related to opioid utilization dose and day 14 outcomes. Most participants had opioid medications leftover at day 14. CONCLUSION: Excess opioid prescribing was common, did not result in improved pain alleviation, and was associated with poorer physical function and sleep 14 days after surgery. As such, higher prescribed opioid doses could reduce subacute functioning after surgery, without benefit in reducing pain. Future patient-centered studies to tailor opioid postsurgical prescribing are needed.

Kinetic trapping organizes actin filaments within liquid-like protein droplets.

Several actin-binding proteins (ABPs) phase separate to form condensates capable of curating the actin network shapes. Here, we use computational modeling to understand the principles of actin network organization within VASP condensate droplets. Our simulations reveal that the different actin shapes, namely shells, rings, and mixture states are highly dependent on the kinetics of VASP-actin interactions, suggesting that they arise from kinetic trapping. Specifically, we show that reducing the residence time of VASP on actin filaments reduces degree of bundling, thereby promoting assembly of shells rather than rings. We validate the model predictions experimentally using a VASP-mutant with decreased bundling capability. Finally, we investigate the ring opening within deformed droplets and found that the sphere-to-ellipsoid transition is favored under a wide range of filament lengths while the ellipsoid-to-rod transition is only permitted when filaments have a specific range of lengths. Our findings highlight key mechanisms of actin organization within phase-separated ABPs.

Lipid droplets as substrates for protein phase separation.

Membrane-associated protein phase separation plays critical roles in cell biology, driving essential cellular phenomena from immune signaling to membrane traffic. Importantly, by reducing dimensionality from three to two dimensions, lipid bilayers can nucleate phase separation at far lower concentrations compared with those required for phase separation in solution. How might other intracellular lipid substrates, such as lipid droplets, contribute to nucleation of phase separation? Distinct from bilayer membranes, lipid droplets consist of a phospholipid monolayer surrounding a core of neutral lipids, and they are energy storage organelles that protect cells from lipotoxicity and oxidative stress. Here, we show that intrinsically disordered proteins can undergo phase separation on the surface of synthetic and cell-derived lipid droplets. Specifically, we find that the model disordered domains FUS LC and LAF-1 RGG separate into protein-rich and protein-depleted phases on the surfaces of lipid droplets. Owing to the hydrophobic nature of interactions between FUS LC proteins, increasing ionic strength drives an increase in its phase separation on droplet surfaces. The opposite is true for LAF-1 RGG, owing to the electrostatic nature of its interprotein interactions. In both cases, protein-rich phases on the surfaces of synthetic and cell-derived lipid droplets demonstrate molecular mobility indicative of a liquid-like state. Our results show that lipid droplets can nucleate protein condensates, suggesting that protein phase separation could be key in organizing biological processes involving lipid droplets.

Differences in internalized HIV stigma across subpopulations of people with HIV in care across the United States.

BACKGROUND: Few studies have examined which subgroups of people with HIV (PWH) carry the greatest burden of internalized HIV stigma (IHS), which may be important to care provision and interventions. METHODS: PWH in the CFAR Network of Integrated Clinical Systems (CNICS) longitudinal, US-based, multisite, clinical care cohort completed tablet-based assessments during clinic visits including a four-item, Likert scale (low 1-5 high), IHS instrument. Associations between sociodemographic characteristics and IHS scores were assessed in adjusted linear regression models. RESULTS: Twelve thousand six hundred and fifty-six PWH completed the IHS assessment at least once from February 2016 to November 2022, providing 28 559 IHS assessments. At baseline IHS assessment, the mean age was 49 years, 41% reported White, 38% Black/African American, and 16% Latine race/ethnicity, and 80% were cisgender men. The mean IHS score was 2.04, with all subgroups represented among those endorsing IHS. In regression analyses, younger PWH and those in care fewer years had higher IHS scores. In addition, cisgender women vs. cisgender men, PWH residing in the West vs. the Southeast, and those with sexual identities other than gay/lesbian had higher IHS scores. Compared with White-identifying PWH, those who identified with Black/African American or Latine race/ethnicity had lower IHS scores. Age stratification revealed patterns related to age category, including specific age-related differences by gender, geographic region and race/ethnicity. DISCUSSION: IHS is prevalent among PWH, with differential burden by subgroups of PWH. These findings highlight the benefits of routine screening for IHS and suggest the need for targeting/tailoring interventions to reduce IHS among PWH.

Liquid-like condensates mediate competition between actin branching and bundling.

Cellular remodeling of actin networks underlies cell motility during key morphological events, from embryogenesis to metastasis. In these transformations, there is an inherent competition between actin branching and bundling, because steric clashes among branches create a mechanical barrier to bundling. Recently, liquid-like condensates consisting purely of proteins involved in either branching or bundling of the cytoskeleton have been found to catalyze their respective functions. Yet in the cell, proteins that drive branching and bundling are present simultaneously. In this complex environment, which factors determine whether a condensate drives filaments to branch or become bundled? To answer this question, we added the branched actin nucleator, Arp2/3, to condensates composed of VASP, an actin bundling protein. At low actin to VASP ratios, branching activity, mediated by Arp2/3, robustly inhibited VASP-mediated bundling of filaments, in agreement with agent-based simulations. In contrast, as the actin to VASP ratio increased, addition of Arp2/3 led to formation of aster-shaped structures, in which bundled filaments emerged from a branched actin core, analogous to filopodia emerging from a branched lamellipodial network. These results demonstrate that multi-component, liquid-like condensates can modulate the inherent competition between bundled and branched actin morphologies, leading to organized, higher-order structures, similar to those found in motile cells.

Evaluating the agreement between different substance use recall periods in multiple HIV cohorts.

BACKGROUND: This study aims to evaluate the agreement in substance use on both binary and ordinal scales between 3-month and 6-month recall periods with samples from different communities, demographic backgrounds, and HIV status. METHODS: We administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to 799 participants from three different North American cohorts focused on substance use and HIV. We conducted a within-person agreement analysis by calculating the agreement levels and Kappa statistic between data collected using the 3-month recall ASSIST and 6-month custom substance use surveys as well as different terminology for each substance in multiple cohorts. RESULTS: For all drugs studied, the agreement on the binary use or ordinal frequency of use metrics showed a high agreement level between 80.4% and 97.9% and an adequate adjusted kappa value between 0.61 and 0.96, suggesting substantial agreement. According to the agreement criteria we proposed, substance use data collected using different recall periods and with variation in drug names can be harmonized across cohorts. CONCLUSIONS: This study is the first to evaluate the feasibility of data harmonization of substance use by demonstrating high level of agreement between different recall periods in different cohorts. The results can inform data harmonization efforts in consortia where data are collected from cohorts using different questions and recall periods.

Hepatitis C Treatment in People With HIV: Potential to Eliminate Disease and Disparity.

Access to direct acting antivirals (DAAs) may be associated with reductions in hepatitis C virus (HCV) viremia prevalence among people with human immunodeficiency virus (PWH). Among 3755 PWH, estimated HCV viremia prevalence decreased by 94.0% from 36% (95% confidence interval [CI], 27%-46%) in 2009 (pre-DAA era) to 2% (95% CI, 0%-4%) in 2021 (DAA era). Male sex, black race, and older age were associated with HCV viremia in 2009 but not in 2021. Injection drug use remained associated with HCV viremia in 2009 and 2021. Targeted interventions are needed to meet the HCV care needs of PWH who use drugs.

Transmembrane coupling of liquid-like protein condensates.

Liquid-liquid phase separation of proteins occurs on both surfaces of cellular membranes during diverse physiological processes. In vitro reconstitution could provide insight into the mechanisms underlying these events. However, most existing reconstitution techniques provide access to only one membrane surface, making it difficult to probe transmembrane phenomena. To study protein phase separation simultaneously on both membrane surfaces, we developed an array of freestanding planar lipid membranes. Interestingly, we observed that liquid-like protein condensates on one side of the membrane colocalized with those on the other side, resulting in transmembrane coupling. Our results, based on lipid probe partitioning and mobility of lipids, suggest that protein condensates locally reorganize membrane lipids, a process which could be explained by multiple effects. These findings suggest a mechanism by which signals originating on one side of a biological membrane, triggered by protein phase separation, can be transferred to the opposite side.

Risk Factors for Hospitalization and Effect of Immunosuppression on Clinical Outcomes Among an Urban Cohort of Patients With Mpox.

Background: During the 2022 mpox outbreak most patients were managed as outpatients, but some required hospitalization. Uncontrolled human immunodeficiency virus (HIV) has been identified as a risk factor for severe mpox. Methods: Patients with mpox diagnosed or treated within the Johns Hopkins Health System between 1 June and 15 December 2022 were included. The primary outcome of interest was risk of hospitalization. Demographic features, comorbid conditions, treatment, and clinical outcomes were determined. Results: A total of 353 patients were tested or treated for mpox; 100 had mpox diagnosed or treated (median age, 35.3 years; 97.0% male; 57.0% black and 10.0% Hispanic; 46.0% people with HIV [PWH]). Seventeen patients (17.0%) required hospitalization, 10 of whom were PWH. Age >40 years, race, ethnicity, HIV status, insurance status, and body mass index >30 (calculated as weight in kilograms divided by height in meters squared) were not associated with hospitalization. Eight of 9 patients (88.9%) with immunosuppression were hospitalized. Immunosuppression was associated with hospitalization in univariate (odds ratio, 69.3 [95% confidence interval, 7.8-619.7]) and adjusted analysis (adjusted odds ratio, 94.8 [8.5-1060.1]). Two patients (11.8%) who were hospitalized required intensive care unit admission and died; both had uncontrolled HIV infection and CD4 T-cell counts <50/µL. Median cycle threshold values for the first positive mpox virus sample did not differ between those who were hospitalized and those who were not. Conclusions: Immunosuppression was a significant risk factor for hospitalization with mpox. PWH with CD4 T-cell counts <50/µL are at high risk of death due to mpox infection. Patients who are immunosuppressed should be considered for early and aggressive treatment of mpox, given the increased risk of hospitalization.

Selective Endocytic Uptake of Targeted Liposomes Occurs within a Narrow Range of Liposome Diameters.

Cell surface receptors facilitate signaling and nutrient uptake. These processes are dynamic, requiring receptors to be actively recycled by endocytosis. Due to their differential expression in disease states, receptors are often the target of drug-carrier particles, which are adorned with ligands that bind specifically to receptors. These targeted particles are taken into the cell by multiple routes of internalization, where the best-characterized pathway is clathrin-mediated endocytosis. Most studies of particle uptake have utilized bulk assays rather than observing individual endocytic events. As a result, the detailed mechanisms of particle uptake remain obscure. To address this gap, we employed a live-cell imaging approach to study the uptake of individual liposomes as they interact with clathrin-coated structures. By tracking individual internalization events, we find that the size of liposomes rather than the density of the ligands on their surfaces primarily determines their probability of uptake. Interestingly, targeting has the greatest impact on endocytosis of liposomes of intermediate diameters, with the smallest and largest liposomes being internalized or excluded, respectively, regardless of whether they are targeted. These findings, which highlight a previously unexplored limitation of targeted delivery, can be used to design more effective drug carriers.

Psychotherapy process research: Identifying productive in-session processes to enhance treatment outcomes and therapist responsiveness.

This paper provides an overview of my research programme for the past 37 years. The focus of my work has been on identifying productive in-session processes to enhance treatment outcomes and therapist responsiveness. Two foci will be reviewed, first, my research on client and therapist interpersonal process and second, productive processing in psychotherapy in three different therapeutic approaches including EFT, CBT and CCT. Given that many competing theoretical perspectives are effective, I was curious about change processes that are common and unique to each. In my work, I employed a variety of research methodologies drawing on frameworks with alternative epistemological and ontological assumptions to capture specific in-session change processes in an attempt to reveal the richness and complexity of the phenomena being studied and illuminate the process of change.

Measuring time in buprenorphine treatment stages among people with HIV and opioid use disorder by retention definition and its association with cocaine and hazardous alcohol use.

BACKGROUND: We use a novel, longitudinal approach to describe average time spent in opioid use disorder (OUD) cascade of care stages for people with HIV (PWH) and with OUD, incorporating four definitions of treatment retention. Using this approach, we describe the impact of cocaine or hazardous alcohol use on time spent retained on buprenorphine. METHODS: We followed PWH with OUD enrolled in the Johns Hopkins HIV Clinical Cohort from their first buprenorphine treatment episode between 2013 and 2020. We estimated 4-year restricted mean time spent on buprenorphine below buprenorphine retention threshold, on buprenorphine above retention threshold, off buprenorphine and in HIV care, loss to follow-up, and death. Retention definitions were based on retention threshold (180 vs 90 days) and allowable treatment gap (7 vs 30 days). Differences in 2-year restricted mean time spent retained on buprenorphine were estimated for patients with and without cocaine or hazardous alcohol use. RESULTS: The study sample (N = 179) was 63% male, 82% non-Hispanic Black, and mean age was 53 (SD 8) years. Patients spent on average 13.9 months (95% CI 11.4, 16.4) on buprenorphine over 4 years. There were differences in time spent retained on buprenorphine based on the retention definition, ranging from 6.5 months (95% CI 4.6, 8.5) to 9.6 months (95% CI 7.4, 11.8). Patients with cocaine use spent fewer months retained on buprenorphine. There were no differences for patients with hazardous alcohol use. CONCLUSIONS: PWH with OUD spend relatively little time receiving buprenorphine in their HIV primary care clinic. Concurrent cocaine use at buprenorphine initiation negatively impact time on buprenorphine.

Ubiquitin-driven protein condensation promotes clathrin-mediated endocytosis.

Clathrin-mediated endocytosis is an essential cellular pathway that enables signaling and recycling of transmembrane proteins and lipids. During endocytosis, dozens of cytosolic proteins come together at the plasma membrane, assembling into a highly interconnected network that drives endocytic vesicle biogenesis. Recently, multiple labs have reported that early endocytic proteins form liquid-like condensates, which provide a flexible platform for the efficient assembly of endocytic vesicles. Given the importance of this network in the dynamics of endocytosis, how might cells regulate its stability? Many receptors and endocytic proteins are ubiquitylated, while early endocytic proteins such as Eps15 contain ubiquitin-interacting motifs. Therefore, we examined the influence of ubiquitin on the stability of the early endocytic protein network. In vitro, we found that recruitment of small amounts of polyubiquitin dramatically increased the stability of Eps15 condensates, suggesting that ubiquitylation could nucleate endocytic sites. In live cell imaging experiments, a version of Eps15 that lacked the ubiquitin-interacting motif failed to rescue defects in endocytic initiation created by Eps15 knockout. Furthermore, fusion of Eps15 to a deubiquitinase enzyme destabilized nascent endocytic sites within minutes. These results suggest that ubiquitylation drives assembly of the flexible protein network responsible for catalyzing endocytic events. More broadly, this work illustrates a biophysical mechanism by which ubiquitylated transmembrane proteins at the plasma membrane could regulate the efficiency of endocytic recycling.

What can we learn from COVID-19 to improve opioid treatment? Expert providers respond.

BACKGROUND: The COVID-19 pandemic has had devasting effects on drug abuse treatment systems already stressed by the opioid crisis. Providers within opioid use disorder (OUD) outpatient treatment programs have had to adjust to rapid change and respond to new service delivery provisions such as telehealth and take-home medication. Using the COVID-19 pandemic and subsequent organizational challenges as a backdrop, this study explores providers' perspectives about strategies and policies that, if made permanent, can potentially improve access to and quality of OUD treatment. METHODS: This qualitative study was conducted in Los Angeles County, which has one of the largest substance use disorder (SUD) treatment systems in the United States serving a diverse population, including communities impacted by the opioid crisis. We collected qualitative interview data from 30 high-performing programs (one manager/supervisor per program) where we based high performance on empirical measures of access, retention, and program completion outcomes. The study team completed data collection and analysis using constructivist grounded theory (CGT) to describe the social processes in which the participating managers engaged when faced with the pandemic and subsequent organizational changes. We developed 14 major codes and six minor codes with definitions. The interrater reliability tests showed pooled Cohen's kappa statistic of 93 %. RESULTS: Our results document the impacts of COVID-19 on SUD treatment systems, their programmatic responses, and the strategic innovations they developed to improve service delivery and quality and which managers plan to sustain within their organizations. CONCLUSION: Providers identified three primary areas for strategic innovation designed to improve access and quality: (1) designing better medication utilization, (2) increasing telemedicine capacity, and (3) improving reimbursement policies. These strategies for system transformation enable us to use lessons from the COVID-19 pandemic to direct policy and programmatic reform, such as expanding eligibility for take-home medication and enhancing access to telehealth services.

Longitudinal Predictors of PROMIS Satisfaction With Social Roles and Activities After Shoulder and Knee Sports Orthopaedic Surgery in United States Military Servicemembers: An Observational Study.

Background: Satisfaction with social roles and activities is an important outcome for postsurgical rehabilitation and quality of life but not commonly assessed. Purpose: To evaluate longitudinal patterns of the Patient-Reported Outcomes Measurement Information System (PROMIS) Satisfaction with Social Roles and Activities measure, including how it relates to other biopsychosocial factors, before and up to 6 months after sports-related orthopaedic surgery. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Participants (N = 223) who underwent knee and shoulder sports orthopaedic surgeries between August 2016 and October 2020 completed PROMIS computer-adaptive testing item banks and pain-related measures before surgery and at 6-week, 3-month, and 6-month follow-ups. In a generalized additive mixed model, covariates included time point; peripheral nerve block; the PROMIS Anxiety, Sleep Disturbance, and Pain Behavior measures; and previous 24-hour pain intensity. Patient-reported outcomes were modeled as nonlinear (smoothed) effects. Results: The linear (estimate, 2.06; 95% CI, 0.77-3.35; P = .002) and quadratic (estimate, 2.93; 95% CI, 1.78-4.08; P < .001) effects of time, as well the nonlinear effects of PROMIS Anxiety (P < .001), PROMIS Sleep Disturbance (P < .001), PROMIS Pain Behavior (P < .001), and pain intensity (P = .02), were significantly associated with PROMIS Satisfaction with Social Roles and Activities. The cubic effect of time (P = .06) and peripheral nerve block (P = .28) were not. The proportion of patients with a 0.5-SD improvement in the primary outcome increased from 23% at 6 weeks to 52% by 6 months postsurgery, whereas those reporting worsening PROMIS Satisfaction with Social Roles and Activities decreased from 30% at 6 weeks to 13% at 6 months. Conclusion: The PROMIS Satisfaction with Social Roles and Activities measure was found to be related to additional domains of function (eg, mental health, behavioral, pain) associated with postsurgical rehabilitation.