Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

The complement system as a target in cancer immunotherapy.

Malignant cells are part of a complex network within the tumor microenvironment, where their interaction with host cells and soluble mediators, including complement components, is pivotal. The complement system, known for its role in immune defense and homeostasis, exhibits a dual effect on cancer progression. This dichotomy arises from its antitumoral opsonophagocytosis and cytotoxicity versus its protumoral chronic inflammation mediated by the C5a/C5aR1 axis, influencing antitumor T-cell responses. Recent studies have revealed distinct co-expression patterns of complement genes in various cancer types, correlating with prognosis. Notably, some cancers exhibit co-regulated overexpression of complement genes associated with poor prognosis, while others show favorable outcomes. However, significant intra-patient heterogeneity further complicates this classification. Moreover, the involvement of locally produced and intracellular complement proteins adds complexity to the tumor microenvironment dynamics. This review highlights the unique interplay of complement components within different cancers and patient cohorts, showing that "one size does not fit all", for complement in cancer. It summarizes the clinical trials for complement targeting in cancer, emphasizing the need for tailored therapeutic approaches. By elucidating the mechanistic basis of complement's context-dependent role, this review aims to facilitate the development of personalized cancer therapies, ultimately improving patient care and outcomes.

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

The optimal docking strength for reversibly tethered kinases.

Many kinases use reversible docking interactions to augment the specificity of their catalytic domains. Such docking interactions are often structurally independent of the catalytic domain, which allow for a flexible combination of modules in evolution and in bioengineering. The affinity of docking interactions spans several orders of magnitude. This led us to ask how the affinity of the docking interaction affects enzymatic activity and how to pick the optimal interaction module to complement a given substrate. Here, we develop equations that predict the optimal binding strength of a kinase docking interaction and validate it using numerical simulations and steady-state phosphorylation kinetics for tethered protein kinase A. We show that a kinase-substrate pair has an optimum docking strength that depends on their enzymatic constants, the tether architecture, the substrate concentration, and the kinetics of the docking interactions. We show that a reversible tether enhances phosphorylation rates most when 1) the docking strength is intermediate, 2) the substrate is nonoptimal, 3) the substrate concentration is low, 4) the docking interaction has rapid exchange kinetics, and 5) the tether optimizes the effective concentration of the intramolecular reaction. This work serves as a framework for interpreting mutations in kinase docking interactions and as a design guide for engineering enzyme scaffolds.

Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2.

Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing. We report the interaction of TLR4, MD2 and the TLR4-MD2 complex with heme and the consequences thereof by employing biochemical, spectroscopic, bioinformatic and physiologically relevant approaches. Heme binding occurs transiently through interaction with up to four HBMs in TLR4, two HBMs in MD2 and at least four HBMs in their complex. Functional studies highlight that mutations of individual HBMs in TLR4 preserve full receptor activation by heme, suggesting that heme interacts with TLR4 through different binding sites independently of MD2. Furthermore, we confirm and extend the major role of TLR4 for heme-mediated cytokine responses in human immune cells.

Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant.

BACKGROUND: Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms. METHODS: Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks-Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants' results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant). RESULTS: The median scores at baseline and at 6 months on the Bruininks-Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, -1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, -0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait. CONCLUSIONS: Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.).

Probing Glycerolipid Metabolism using a Caged Clickable Glycerol-3-Phosphate Probe.

In this study, we present the probe SATE-G3P-N3 as a novel tool for metabolic labeling of glycerolipids (GLs) to investigate lipid metabolism in yeast cells. By introducing a clickable azide handle onto the glycerol backbone, this probe enables general labeling of glycerolipids. Additionally, this probe contains a caged phosphate moiety at the glycerol sn-3 position to not only facilitate probe uptake by masking negative charge but also to bypass the phosphorylation step crucial for initiating phospholipid synthesis, thereby enhancing phospholipid labeling. The metabolic labeling activity of the probe was thoroughly assessed through cellular fluorescence microscopy, mass spectrometry (MS), and thin-layer chromatography (TLC) experiments. Fluorescence microscopy analysis demonstrated successful incorporation of the probe into yeast cells, with labeling predominantly localized at the plasma membrane. LCMS analysis confirmed metabolic labeling of various phospholipid species (PC, PS, PA, PI, and PG) and neutral lipids (MAG, DAG, and TAG), and GL labeling was corroborated by TLC. These results showcased the potential of the SATE-G3P-N3 probe in studying GL metabolism, offering a versatile and valuable approach to explore the intricate dynamics of lipids in yeast cells.

Tracing HIV-1 strains that imprint broadly neutralizing antibody responses.

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Is there an OAHI or O2 nadir that predicts the need for preoperative echocardiogram prior to adenotonsillectomy for children with severe obstructive sleep apnea?

PURPOSE: To investigate threshold values for obstructive apnea-hypopnea index (OAHI) and nadir oxygen saturation (NspO2) in children with severe obstructive sleep apnea (OSA) to identify children most appropriate for preoperative echocardiography. METHODS: A multi-institutional retrospective chart review was performed on children who underwent echocardiography and polysomnogram within a year. Children with severe OSA as defined by OAHI > 10 or NspO2 < 80% were included. Receiver operator curves and Youden's J index were used to assess the discriminatory ability and threshold values of OAHI and NspO2 for right heart strain (RHS) on echocardiography. RESULTS: A total of 173 prepubertal (< 10 years) children and 71 postpubertal (≥ 10 years) children of age were included. RHS was seen in 9 (5%) prepubertal children and 4 (6%) postpubertal children. In prepubertal children, OAHI and NspO2 were poor predictors of RHS (area under the curve [AUC] 0.53 [95%CI 0.45-0.61], p = 0.748; AUC 0.56 [95%CI 0.48-0.64], p = 0.609). In postpubertal children, threshold values of 55 events/hour and 69% were strong predictors for RHS (AUC 0.88 [95%CI 0.78-0.95], p < 0.001; AUC 0.92 [95%CI 0.83-0.97], p < 0.001). CONCLUSION: In children with severe OSA, evidence of RHS is low. Postpubertal children with OAHI > 55 and NspO2 < 69% appear most appropriate for echocardiography. Clinicians should weigh the risks and benefits of preoperative echocardiography for each child with these threshold values in mind.

High Risk of Readmission After THA Regardless of Functional Status in Patients Discharged to Skilled Nursing Facility.

BACKGROUND: The postoperative period and subsequent discharge planning are critical in our continued efforts to decrease the risk of complications after THA. Patients discharged to skilled nursing facilities (SNFs) have consistently exhibited higher readmission rates compared with those discharged to home healthcare. This elevated risk has been attributed to several factors but whether readmission is associated with patient functional status is not known. QUESTIONS/PURPOSES: After controlling for relevant confounding variables (functional status, age, gender, caregiver support available at home, diagnosis [osteoarthritis (OA) versus non-OA], Charlson comorbidity index [CCI], the Area Deprivation Index [ADI], and insurance), are the odds of 30- and 90-day hospital readmission greater among patients initially discharged to SNFs than among those treated with home healthcare after THA? METHODS: This was a retrospective, comparative study of patients undergoing THA at any of 11 hospitals in a single, large, academic healthcare system between 2017 and 2022 who were discharged to an SNF or home healthcare. During this period, 13,262 patients were included. Patients discharged to SNFs were older (73 ± 11 years versus 65 ± 11 years; p < 0.001), less independent at hospital discharge (6-click score: 16 ± 3.2 versus 22 ± 2.3; p < 0.001), more were women (71% [1279 of 1796] versus 56% [6447 of 11,466]; p < 0.001), insured by Medicare (83% [1497 of 1796] versus 52% [5974 of 11,466]; p < 0.001), living in areas with greater deprivation (30% [533 of 1796] versus 19% [2229 of 11,466]; p < 0.001), and had less assistance available from at-home caregivers (29% [527 of 1796] versus 57% [6484 of 11,466]; p < 0.001). The primary outcomes assessed in this study were 30- and 90-day hospital readmissions. Although the system automatically flags readmissions occurring within 90 days at the various facilities in the overall healthcare system, readmissions occurring outside the system would not be captured. Therefore, we were not able to account for potential differential rates of readmission to external healthcare systems between the groups. However, given the large size and broad geographic coverage of the healthcare system analyzed, we expect the readmissions data captured to be representative of the study population. The focus on a single healthcare system also ensures consistency in readmission identification and reporting across subjects. We evaluated the association between discharge disposition (home healthcare versus SNF) and readmission. Covariates evaluated included age, gender, primary payer, primary diagnosis, CCI, ADI, the availability of at-home caregivers for the patient, and the Activity Measure for Post-Acute Care (AM-PAC) 6-clicks basic mobility score in the hospital. The adjusted relative risk (ARR) of readmission within 30 and 90 days of discharge to SNF (versus home healthcare) was estimated using modified Poisson regression models. RESULTS: After adjusting for the 6-clicks mobility score, age, gender, ADI, OA versus non-OA, living environment, CCI, and insurance, patients discharged to an SNF were more likely to be readmitted within 30 and 90 days compared with home healthcare after THA (ARR 1.46 [95% CI 1.01 to 2.13]; p= 0.046 and ARR 1.57 [95% CI 1.23 to 2.01]; p < 0.001, respectively). CONCLUSION: Patients discharged to SNFs after THA had a slightly higher likelihood of hospital readmission within 30 and 90 days compared with those discharged with home healthcare. This difference persisted even after adjusting for relevant factors like functional status, home support, and social determinants of health. These results indicate that for suitable patients, direct home discharge may be a safer and more cost-effective option than SNFs. Clinicians should carefully consider these risks and benefits when making postoperative discharge plans. Policymakers could consider incentives and reforms to improve care transitions and coordination across settings. Further research using robust methods is needed to clarify the reasons for higher SNF readmission rates. Detailed analysis of patient complexity, care processes, and causes of readmission in SNFs versus home health could identify areas for quality improvement. Prospective cohorts or randomized trials would allow stronger conclusions about cause-and-effect. Importantly, no patients should be unfairly "cherry-picked" or "lemon-dropped" based only on readmission risk scores. With proper support and care coordination, even complex patients can have good outcomes. The goal should be providing excellent rehabilitation for all, while continuously improving quality, safety, and value across settings. LEVEL OF EVIDENCE: Level III, therapeutic study.

High Area Deprivation Index is Associated With Not Achieving the Patient-acceptable Symptom State After TKA.

BACKGROUND: The Area Deprivation Index (ADI) approximates a patient's relative socioeconomic deprivation. The ADI has been associated with increased healthcare use after TKA, but it is unknown whether there is an association with patient-reported outcome measures (PROMs). Given that a high proportion of patients are dissatisfied with their results after TKA, and the large number of these procedures performed, knowledge of factors associated with PROMs may indicate opportunities to provide support to patients who might benefit from it. QUESTIONS/PURPOSES: (1) Is the ADI associated with achieving the minimum clinically important difference (MCID) for the Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, Joint Replacement (JR), and Physical Function (PS) short forms after TKA? (2) Is the ADI associated with achieving the patient-acceptable symptom state (PASS) thresholds for the KOOS pain, JR, and PS short forms? METHODS: This was a retrospective study of data drawn from a longitudinally maintained database. Between January 2016 and July 2021, a total of 12,239 patients underwent unilateral TKA at a tertiary healthcare center. Of these, 92% (11,213) had available baseline PROM data and were potentially eligible. An additional 21% (2400) of patients were lost before the minimum study follow-up of 1 year or had incomplete data, leaving 79% (8813) for analysis here. The MCID is the smallest change in an outcome score that a patient is likely to perceive as a clinically important improvement, and the PASS refers to the threshold beyond which patients consider their symptoms acceptable and consistent with adequate functioning and well-being. MCIDs were calculated using a distribution-based method. Multivariable logistic regression models were created to investigate the association of ADI with 1-year PROMs while controlling for patient demographic variables. ADI was stratified into quintiles based on their distribution in our sample. Achievement of MCID and PASS thresholds was determined by the improvement between preoperative and 1-year PROMs. RESULTS: After controlling for patient demographic factors, ADI was not associated with an inability to achieve the MCID for the KOOS pain, KOOS PS, or KOOS JR. A higher ADI was independently associated with an increased risk of inability to achieve the PASS for KOOS pain (for example, the odds ratio of those in the ADI category of 83 to 100 compared with those in the 1 to 32 category was 1.34 [95% confidence interval 1.13 to 1.58]) and KOOS JR (for example, the OR of those in the ADI category of 83 to 100 compared with those in the 1 the 32 category was 1.29 [95% CI 1.10 to 1.53]), but not KOOS PS (for example, the OR of those in the ADI category of 83 to 100 compared with those in the 1 the 32 category was 1.09 [95% CI 0.92 to 1.29]). CONCLUSION: Our findings suggest that social and economic factors are associated with patients' perceptions of their overall pain and function after TKA, but such factors are not associated with patients' perceptions of their improvement in symptoms. Patients from areas with higher deprivation may be an at-risk population and could benefit from targeted interventions to improve their perception of their healthcare experience, such as through referrals to nonemergent medical transportation and supporting applications to local care coordination services before proceeding with TKA. Future research should investigate the mechanisms underlying why socioeconomic disadvantage is associated with inability to achieve the PASS, but not the MCID, after TKA. LEVEL OF EVIDENCE: Level III, therapeutic study.

The Reverse Fragility Index for Mortality End Points in Randomized Trials Comparing Uncemented and Cemented Hemiarthroplasty for Intracapsular Hip Fractures.

BACKGROUND: Interpreting clinical relevance of randomized clinical trials (RCTs) is challenging when P-values are marginally above or below the P = .05 threshold. This study examined the robustness of statistically insignificant mortality events from RCTs comparing hemiarthroplasty femoral fixation for displaced intracapsular hip fractures through the reverse fragility index (RFI). METHODS: RCTs were identified using Pubmed, OVID/Medline, and Cochrane databases. Mortality endpoints were stratified into 3 categories: (1) within 30-days, (2) within 90-days, and (3) at latest follow-up. The RFI was derived by manipulating reported mortality events utilizing a contingency table while maintaining a constant number of participants. The reverse fragility quotient (RFQ) was quantified by dividing the RFI by the study sample. RESULTS: Eight RCTs (2,494 participants) were included. The median RFI and RFQ within 30-days was 3.0 (interquartile range [IQR]: 3.0 to 6.0) and 0.016 (IQR: 0.015 to 0.021), suggesting nonsignificant findings were contingent on 1.6 mortality events/100 participants. The median RFI and RFQ within 90-days was 6.0 (IQR: 4.0 to 7.0) and 0.028 (IQR: 0.024 to 0.038), suggesting nonsignificant findings were contingent on 2.8 mortality events/100 participants. At latest follow-up, the median RFI and RFQ was 7.0 (IQR: 6.0 to 12.0) and 0.038 (IQR: 0.029 to 0.054), suggesting nonsignificant findings were contingent on only 3.8 mortality events/100 participants. Median loss to follow-up was 16.0 (IQR: 11.0 to 58.0; 228% greater than RFI), and exceeded the RFI in 6/7(85.7%) studies. CONCLUSIONS: A small number of events (median of 7) was required to convert a statistically nonsignificant finding to one that is significant for the endpoint of mortality. The median loss to follow-up exceeded the median RFI by greater than 200%, suggesting methodological limitations such as patient allocation could alter conclusions.

Despite Greater Improvement in Pain and Function Among Obese Patients Shortly After Total Knee Arthroplasty, There is No Difference in Patient-Reported Outcomes and Satisfaction Between Body Mass Index Classes at 1 Year Postoperatively.

BACKGROUND: Although obesity may be associated with an increased risk of perioperative and postoperative complications after total knee arthroplasty (TKA), body mass index (BMI) cutoffs for TKA patient selection remain a controversial topic. This study aimed to investigate patient-reported outcomes, satisfaction, and pain among BMI classes at 3 months and 1 year following TKA. METHODS: A total of 2,365 patients were categorized into Centers for Disease Control BMI classes according to preoperative values. The BMI distribution over the cohort demonstrated 7 underweight, 340 healthy weight, 731 overweight, 666 Class I, 391 Class II, and 230 Class III obesity. Preoperative and postoperative Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), satisfaction, and pain scores were compared by BMI class by Analysis of Variance with pairwise comparisons. RESULTS: Preoperative KOOS JR scores and satisfaction scores were both significantly greater for healthy weight patients compared to Class III patients (P < .0001). However, KOOS JR, satisfaction, and pain did not vary by BMI class postoperatively. Changes in scores from baseline suggest larger improvements with increasing BMI class, where Class III patients reported the greatest improvements in KOOS JR (23.24 ± 15.67, P < .0001) and pain scores (-3.56 ± 2.65, P < .0001) at 90 days. Significantly greater improvement with increasing BMI was also present at 1-year postoperatively for KOOS JR scores. A total of 85.8% of Class III patients reached the Minimal Clinically Important Difference for KOOS JR at 90 days compared to 76.8% of the healthy weight group (P = .03). Differences between BMI groups in the proportion reaching Minimal Clinically Important Difference at 1 year were not significant. CONCLUSIONS: Patients of higher BMI reported greater and earlier improvements in satisfaction, knee function, and pain following TKA. Shared decision-making remains paramount to preoperative surgical evaluation. However, rationing of this surgical intervention based on BMI alone may not be warranted.

A Nationwide Analysis of the Impact of Socioeconomic Status on Complications and Health Care Utilizations After Total Knee Arthroplasty Using the Area Deprivation Index: Consideration of the Disadvantaged Patient.

BACKGROUND: Socioeconomic status has been demonstrated to be an important prognostic risk factor among patients undergoing total joint arthroplasty. We evaluated patients living near neighborhoods with higher socioeconomic risk undergoing total knee arthroplasty (TKA) and if they were associated with differences in the following: (1) medical complications; (2) emergency department (ED) utilizations; (3) readmissions; and (4) costs of care. METHODS: A query of a national database from 2010 to 2020 was performed for primary TKAs. The Area Deprivation Index (ADI) is a weighted index comprised of 17 census-based markers of material deprivation and poverty. Higher numbers indicate a greater disadvantage. Patients undergoing TKA in zip codes associated with high ADI (90%+) were 1:1 propensity-matched to a comparison group by age, sex, and Elixhauser Comorbidity Index. This yielded 225,038 total patients, evenly matched between cohorts. Outcomes studied included complications, ED utilizations, readmission rates, and 90-day costs. Logistic regression models computed the odds ratios (OR) of ADI on the dependent variables. P values less than .003 were significant. RESULTS: High ADI led to higher rates and odds of any medical complications (11.7 versus 11.0%; OR: 1.05, P = .0006), respiratory failures (0.4 versus 0.3%; OR: 1.28, P = .001), and acute kidney injuries (1.7 versus 1.5%; OR: 1.15, P < .0001). Despite lower readmission rates (2.9 versus 3.5%), high ADI patients had greater 90-day ED visits (4.2 versus 4.0%; OR: 1.07, P = .0008). The 90-day expenditures ($15,066 versus $12,459; P < .0001) were higher in patients who have a high ADI. CONCLUSIONS: Socioeconomically disadvantaged patients have increased complications and ED utilizations. Neighborhood disadvantage may inform health care policy and improve postdischarge care. The socioeconomic status metrics, including ADI (which captures community effects), should be used to adequately risk-adjust or risk-stratify patients so that access to care for deprived regions and patients is not lost. LEVEL OF EVIDENCE: III.

Retrieval Analysis of Titanium Nitride Coatings for Orthopaedic Implants.

BACKGROUND: The first generation of titanium nitride (TiN) coatings for orthopaedic implants was clinically introduced in the 1990s because of their promising biocompatibility, wear resistance, and corrosion resistance. This study evaluated the in vivo performance of early TiN-coated knee and hip implants, focusing on the bearing surfaces and mechanisms of in vivo damage. METHODS: There were 13 TiN-coated implants (5 knee and 8 hip) retrieved from 8 patients as part of a multi-institutional implant retrieval program. The average implantation time was 4.25 years for knees and 17.5 years for hips. Implant revisions occurred for various reasons, including polyethylene wear, loosening, pain, infection, and instability. Components were examined using a semiquantitative scoring method, and surface roughness measurements were performed using white-light interferometry. Surface morphology, chemistry, and particle characterization were also assessed by scanning electron microscopy. RESULTS: For hips, mild corrosion was found on femoral head tapers, along with severe scratching on certain femoral heads. Knee implants exhibited low burnishing and scratching for both mechanisms. Roughness measurements (Sa) were 37.3 nm (interquartile range = 22.0 to 62.4) for hips and 85.3 nm (interquartile range = 66.3 to 110) for knees. The observed scratch depth in both hip and knee implants due to third-body particles ranged from 0.3 to 1.3 µm. The coating coverage remained intact in the majority of the implants, with 2 cases of small, localized cohesive chipping and substrate exposure. CONCLUSIONS: The results of this study confirm the potential in vivo durability of early TiN coatings and will be useful in benchmarking wear tests for modern TiN-coated orthopaedic implants.

Predictive Modeling of Medical and Orthopaedic-Related 90-Day-Readmissions Following Primary Total Knee Arthroplasty.

BACKGROUND: As the demand for total knee arthroplasty (TKA) escalates, 90-day readmissions have emerged as a pressing clinical and economic concern for the current value-based healthcare system. Consequently, healthcare providers have focused on estimating the risk levels of readmitted patients; however, it is unknown if specific factors are associated with different types of complications (i.e., medical or orthopaedic-related) that lead to readmissions. Therefore, this study aimed to: (1) Determine the overall, medical-related, and orthopaedic-related 90-day readmission rate; and (2) Develop a predictive model for risk factors affecting overall, medical-related, and orthopaedic-related 90-day readmissions following TKA. METHODS: A prospective cohort of primary unilateral TKAs performed at a large tertiary academic center in the United States from 2016 to 2020 was included (n = 10,521 patients). Unplanned readmissions were reviewed individually to determine their primary cause, either medical or orthopaedic-related. Orthopaedic-related readmissions were specific complications affecting the joint, prosthesis, or surgical wound. Medical readmissions were due to any other cause requiring medical management. Multivariable logistic regression models were used to investigate associations between pre-specified risk factors and 90-day readmissions, as well as medical/orthopaedic-related readmissions independently. RESULTS: Overall, the rate of 90-day readmissions was 6.7% (n = 704). Over 82% of these readmissions were due to medical-related causes (n = 580), with the remaining 18% being orthopaedic-related (n = 124) readmissions. The AUC for the 90-day readmission model was 0.68 (95% CI [confidence interval]: 0.67 to 0.70). Sex, smoking, length of stay (LOS), and discharge disposition (DD) were associated with orthopaedic readmission, while age, sex, race, Charlson Comorbidity Index (CCI), insurance, surgery day, opioid overdose risk (NARX) score, LOS, and DD were associated with medical-related 90-day readmissions. CONCLUSION: Medical-related readmissions after TKA are more prevalent than orthopaedic-related readmissions. Through successfully constructing and validating multiple 90-day readmission predictive models, we highlight the distinct risk profiles for medical and orthopaedic-related readmissions. This emphasizes the necessity for nuanced, patient-specific risk stratification and preventive measures.

Oxidation and Damage Mechanisms of Second-Generation Highly Cross-Linked Polyethylene Tibial Inserts.

BACKGROUND: After clinical introduction in 2005, sequentially annealed, highly cross-linked polyethylene (SA HXLPE) was studied for retrievals with short implantation times; however, long-term follow-ups are lacking. The objective of this study was to examine and compare the revision reasons, damage mechanisms, and oxidation indices of SA HXLPE and conventional gamma inert-sterilized (Gamma Inert) ultra-high-molecular-weight polyethylene tibial inserts implanted for >5 years. METHODS: There were 74 total knee arthroplasty tibial inserts (46 SA HXLPEs, 28 Gamma Inerts) implanted for >5 years (mean 7 ± 2 years) retrieved as part of a multicenter retrieval program. Cruciate-retaining implants comprised 44% of the SA HXLPEs and 14% of the Gamma Inerts. Patient factors and revision reasons were collected from revision operating notes. A semiquantitative scoring method was used to assess surface damage mechanisms. Oxidation was measured using Fourier transform infrared microscopy according to American Society for Testing and Materials 2102. Differences between cohorts were assessed with Mann-Whitney U-tests. RESULTS: Loosening (Gamma Inert: 17 of 28, SA HXLPE: 15 of 46) and instability (Gamma Inert: 6 of 28, SA HXLPE: 15 of 46) were the most common revision reasons for both cohorts. The most prevalent surface damage mechanisms were burnishing, pitting, and scratching, with burnishing of the condyles being higher in Gamma Inert components (P = .022). Mean oxidation was higher in the SA HXLPE inserts at the articulating surface (P = .002) and anterior-posterior faces (P = .023). No difference was observed at the backside surface (P = .060). CONCLUSIONS: Revision reasons and surface damage mechanisms were comparable in the Gamma Inert and SA cohorts. Further studies are needed to continue to assess the in vivo damage and clinical relevance, if any, of oxidation in SA HXLPE over longer implantation times, particularly for implants implanted for more than 10 years.

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

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

Do Patients With Hypoallergenic Total Knee Arthroplasty Implants for Metal Allergy Do Worse? An Analysis of Health Care Utilizations and Patient-Reported Outcome Measures.

BACKGROUND: Metal allergy is a rare and controversial cause of implant failure and poor outcomes following total knee arthroplasty (TKA). Few studies have investigated clinical and patient-reported outcome measures (PROMs) in patients treated with hypoallergenic implants. This investigation aimed to compare: (1) health care utilizations (eg, hospital length of stay, 90-day readmission rate, and incidence of nonhome discharge) and (2) 1-year PROMs between patients who received hypoallergenic and standard TKA implants. METHODS: This was a retrospective review of prospectively collected data from patients who underwent primary TKA between 2018 and 2019. Propensity score matching (3:1) was used to compare standard TKA patients with those who received hypoallergenic TKA implants, respectively. Knee injury and Osteoarthritis Outcome Score (KOOS) pain, KOOS Physical function Shortform (PS), and Veterans RAND 12-Item Health Survey Mental Component Score were collected preoperatively and at 1-year. After matching, 190 hypoallergenic and 570 standard TKAs were analyzed. RESULTS: No differences were observed in length of stay (P = .98), 90-day readmission (P = .89), and nonhome discharge (P = .82). Additionally, there was no significant difference in change from preoperative to 1-year PROMs (KOOS pain, P = .97; KOOS PS, P = .88; Veterans RAND 12-Item Health Survey Mental Component Score, P = .28). Patient-reported satisfaction was similar at 1-year (P = .23). Patients achieved similar rates of Patient Acceptable Symptom State (PASS) and minimal clinically important difference (MCID) for KOOS pain (PASS, P = .77; MCID, P = .33) and KOOS PS (PASS, P = .44; MCID, P = .65). CONCLUSION: Patients treated with hypoallergenic TKA implants for suspected metal allergy had similar outcomes compared to patients who had standard implants and no metal allergy.