MHC heterozygosity limits T cell receptor variability in CD4 T cells.

αß T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes.

Tips and Tricks to Save You During Revision Total Knee Arthroplasty.

The number of revision total knee arthroplasties (TKAs) performed annually continues to rise. This article is a summary of a symposium on revision TKAs presented at the 2023 American Association of Hip and Knee Surgeons annual meeting. It will provide an overview of the surgical tips and tricks for exposure and component removal, use of metaphyseal fixation and stems to manage bone loss and optimize fixation, constraint in TKA, as well as how to manage extensor mechanism disruptions with a synthetic mesh reconstruction. LEVEL OF EVIDENCE: V.

Financial Conflicts of Interest and Industry Funding are Associated With Conclusions Favorable to New Technologies: A Review of Published Economic Analyses in Hip and Knee Arthroplasty.

BACKGROUND: New technologies in hip and knee arthroplasty are commonly evaluated using cost-effectiveness analyses and similar economic assessments. There is a wide variation in the methodology of these studies, introducing the potential for bias. The purpose of this study was to evaluate associations between potential financial conflicts of interest (COI) and the outcomes of economic analyses. We hypothesized that authors' COI and industry funding would be associated with conclusions favorable to a new technology. METHODS: Economic analyses making cost-effectiveness or economic implementation claims on patient-specific instrumentation, robotics, and implants used in hip and knee arthroplasty published from 2010 to 2022 were identified. Papers were evaluated to determine if conclusions were favorable to the new technology being studied. Fisher's exact test was utilized to determine the relationship between the presence of COI and an article's conclusions. RESULTS: Of 43 eligible articles, 76.7% were cost-effectiveness analyses, 23.2% were cost analyses, and 67.4% of articles had conclusions favorable to a technology. Of the 29 articles with favorable conclusions, 26 had an author with a financial COI (89.7%), and 14 had industry funding (48.3%). Of the 33 articles with a financial COI, 26 (78.8%) had favorable conclusions, and of the 16 articles with industry funding, 14 (87.5%) had favorable conclusions. Fisher's exact test revealed a statistically significant association between an article having favorable conclusions and the presence of an author's COI or industry funding (odds ratio, 13.5; 95% CI [confidence interval], 2.3 to 79.9; P = .003). CONCLUSIONS: Financial COIs were present in 79.1% of lower extremity arthroplasty economic analyses on technologies and were associated with an article having conclusions favorable to the new technology. Surgeons and decision-makers should be aware of the variability and assumptions in these studies and the potential bias of the conclusions.

TGF-ß broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner.

Transforming growth factor ß (TGF-ß) directly acts on naive, effector, and memory T cells to control cell fate decisions, which was shown using genetic abrogation of TGF-ß signaling. TGF-ß availability is altered by infections and cancer; however, the dose-dependent effects of TGF-ß on memory CD8 T cell (Tmem) reactivation are still poorly defined. We examined how activation and TGF-ß signals interact to shape the functional outcome of Tmem reactivation. We found that TGF-ß could suppress cytotoxicity in a manner that was inversely proportional to the strength of the activating TCR or proinflammatory signals. In contrast, even high doses of TGF-ß had a comparatively modest effect on IFN-γ expression in the context of weak and strong reactivation signals. Since CD8 Tmem may not always receive TGF-ß signals concurrently with reactivation, we also explored whether the temporal order of reactivation versus TGF-ß signals is of importance. We found that exposure to TGF-ß before or after an activation event were both sufficient to reduce cytotoxic effector function. Concurrent ATAC-seq and RNA-seq analysis revealed that TGF-ß altered ~10% of the regulatory elements induced by reactivation and also elicited transcriptional changes indicative of broadly modulated functional properties. We confirmed some changes on the protein level and found that TGF-ß-induced expression of CCR8 was inversely proportional to the strength of the reactivating TCR signal. Together, our data suggest that TGF-ß is not simply suppressing CD8 Tmem but modifies functional and chemotactic properties in context of their reactivation signals and in a dose-dependent manner.

Static Non-articulating Knee Spacers Are Associated with a High Degree of Morbidity in Challenging Clinical Scenarios.

The morbidity associated with the use of static non-articulating knee spacers for the treatment of periprosthetic joint infection (PJI) in challenging clinical scenarios has not been well described. From 2011-2019, 63 molded block static spacers were utilized at two academic institutions for the treatment of PJI with associated severe soft tissue compromise (59%), collateral ligament deficiency (49%), extensor mechanism compromise (48%), or type 3 bone defects (44%). Complications and outcomes were assessed. Complications with the use of static spacers were common and included further bone loss (46%), spacer migration (16%), extensor mechanism compromise (16%), cast or related soft tissue injuries (16%), fracture (13%), and spacer breakage (3%). Ultimately, 22% of patients underwent amputation. Patient variables such as age and body mass index were not associated with outcomes. Static knee spacers are associated with substantial morbidity in challenging clinical scenarios and alternatives may need to be considered. (Journal of Surgical Orthopaedic Advances 32(2):122-126, 2023).

TGF-ß broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner.

Transforming growth factor ß (TGF-ß) directly acts on naïve, effector and memory T cells to control cell fate decisions, which was shown using genetic abrogation of TGF-ß signaling. TGF-ß availability is altered by infections and cancer, however the dose-dependent effects of TGF-ß on memory CD8 T cell (Tmem) reactivation are still poorly defined. We examined how activation and TGF-ß signals interact to shape the functional outcome of Tmem reactivation. We found that TGF-ß could suppress cytotoxicity in a manner that was inversely proportional to the strength of the activating TCR or pro-inflammatory signals. In contrast, even high doses of TGF-ß had a comparatively modest effect on IFN-γ expression in the context of weak and strong reactivation signals. Since CD8 Tmem may not always receive TGF-ß signals concurrently with reactivation, we also explored whether the temporal order of reactivation versus TGF-ß signals is of importance. We found that exposure to TGF-ß prior to as well as after an activation event were both sufficient to reduce cytotoxic effector function. Concurrent ATAC-seq and RNA-seq analysis revealed that TGF-ß altered ~10% of the regulatory elements induced by reactivation and also elicited transcriptional changes indicative of broadly modulated functional properties. We confirmed some changes on the protein level and found that TGF-ß-induced expression of CCR8 was inversely proportional to the strength of the reactivating TCR signal. Together, our data suggest that TGF-ß is not simply suppressing CD8 Tmem, but modifies functional and chemotactic properties in context of their reactivation signals and in a dose-dependent manner.

Go Big or Go Home: Obesity and Total Joint Arthroplasty.

Obesity is highly prevalent, and it is expected to grow considerably in the United States. The association between obesity and an increased risk of complications following total joint arthroplasty (TJA) is widely accepted. Many believe that patients with body mass index (BMI) >40 have complications rates that may outweigh the benefits of surgery and should consider delaying it. However, the current literature on obesity and outcomes following TJA is observational, very heterogeneous, and full of confounding variables. BMI in isolation has several flaws and recent literature suggests shifting from an exclusively BMI <40 cutoff to considering 5 to 10% preoperative weight loss. BMI cutoffs to TJA may also restrict access to care to our most vulnerable, marginalized populations. Moreover, only roughly 20% of patients instructed to lose weight for surgery are successful and the practice of demanding mandatory weight loss needs to be reconsidered until convincing evidence exists that supports risk reduction as a result of preoperative weight loss. Obese patients can benefit greatly from this life-changing procedure. When addressing the potential difficulties and by optimizing preoperative assessment and intraoperative management, the surgery can be conducted safely. A multidisciplinary patient-centered approach with patient engagement, shared decision-making, and informed consent is recommended.

Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.

The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three Tet genes in the mouse genome. Tet1/2/3-inducible TKO (iTKO) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of Tet iTKO bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the stefin/cystatin gene cluster on mouse chromosome 16. In patients with AML, high stefin/cystatin gene expression correlates with poor clinical outcomes. Increased expression of the clustered stefin/cystatin genes was associated with a heterochromatin-to-euchromatin compartment switch with readthrough transcription downstream of the clustered stefin/cystatin genes as well as other highly expressed genes, but only minor changes in DNA methylation. Our data highlight roles for TET enzymes that are distinct from their established function in DNA demethylation and instead involve increased transcriptional readthrough and changes in three-dimensional genome organization.

Catastrophic Early Failure and Fragmentation of a Modern Moderately Cross-linked Polyethylene Acetabular Liner.

A 60-year-old man who underwent uncomplicated staged bilateral total hip arthroplasty for femoral head osteonecrosis presented with mechanical catching of his left total hip arthroplasty 3 years after index surgery. Radiographs revealed eccentricity of the left femoral head, concerning the failure of a modern moderately cross-linked polyethylene liner. Catastrophic polyethylene liner failure with significant wear, fragmentation, and femoral head abrasion was noted during revision surgery. The original liner and head were replaced, and the patient has exhibited no complications, pain, or difficulty ambulating 6 months postoperatively. This report highlights one potential novel mechanism for the failure of the Exactech Connexion GXL liner (Exactech Inc., Gainesville, FL), an implant recently reported to have a higher-than-expected failure rate, potentially due to insufficient packaging and increased oxidative processes.

Commitments for Ethically Responsible Sourcing, Use, and Reuse of Patient Data in the Digital Age: Cocreation Process.

BACKGROUND: Personal information, including health-related data, may be used in ways we did not intend when it was originally shared. However, the organizations that collect these data do not always have the necessary social license to use and share it. Although some technology companies have published principles on the ethical use of artificial intelligence, the foundational issue of what is and is not acceptable to do with data, not just the analytical tools to manage it, has not been fully considered. Furthermore, it is unclear whether input from the public or patients has been included. In 2017, the leadership at a web-based patient research network began to envision a new kind of community compact that laid out what the company believed, how the company should behave, and what it promised both to the individuals who engaged with them and to the community at large. While having already earned a social license from patient members as a trusted data steward with strong privacy, transparency, and openness policies, the company sought to protect and strengthen that social license by creating a socially and ethically responsible data contract. Going beyond regulatory and legislative requirements, this contract considered the ethical use of multiomics and phenotypic data in addition to patient-reported and generated data. OBJECTIVE: A multistakeholder working group sought to develop easy-to-understand commitments that established expectations for data stewardship, governance, and accountability from those who seek to collect, use, and share personal data. The working group cocreated a framework that was radically patient-first in its thinking and collaborative in the process of its codevelopment; it reflected the values, ideas, opinions, and perspectives of the cocreators, inclusive of patients and the public. METHODS: Leveraging the conceptual frameworks of cocreation and participatory action research, a mixed methods approach was used that included a landscape analysis, listening sessions, and a 12-question survey. The methodological approaches used by the working group were guided by the combined principles of biomedical ethics and social license and shaped through a collaborative and reflective process with similarities to reflective equilibrium, a method well known in ethics. RESULTS: Commitments for the Digital Age are the output of this work. The six commitments in order of priority are (1) continuous and shared learning; (2) respect and empower individual choice; (3) informed and understood consent; (4) people-first governance; (5) open communication and accountable conduct; and (6) inclusivity, diversity, and equity. CONCLUSIONS: These 6 commitments-and the development process itself-have broad applicability as models for (1) other organizations that rely on digitized data sources from individuals and (2) patients who seek to strengthen operational policies for the ethical and responsible collection, use, and reuse of that data.

A bifurcated role for c-Maf in Th2 and Tfh2 cells during helminth infection.

Differences in transcriptomes, transcription factor usage, and function have identified T follicular helper 2 (Tfh2) cells and T helper 2 (Th2) cells as distinct clusters of differentiation 4+",(CD4) T-cell subsets in settings of type-2 inflammation. Although the transcriptional programs driving Th2 cell differentiation and cytokine production are well defined, dependence on these classical Th2 programs by Tfh2 cells is less clear. Using cytokine reporter mice in combination with transcription factor inference analysis, the b-Zip transcription factor c-Maf and its targets were identified as an important regulon in both Th2 and Tfh2 cells. Conditional deletion of c-Maf in T cells confirmed its importance in type-2 cytokine expression by Th2 and Tfh2 cells. However, while c-Maf was not required for Th2-driven helminth clearance or lung eosinophilia, it was required for Tfh2-driven Immunoglobulin E production and germinal center formation. This differential regulation of cell-mediated and humoral immunity by c-Maf was a result of redundant pathways in Th2 cells that were absent in Tfh2 cells, and c-Maf-specific mechanisms in Tfh2 cells that were absent in Th2 cells. Thus, despite shared expression by Tfh2 and Th2 cells, c-Maf serves as a unique regulator of Tfh2-driven humoral hallmarks during type-2 immunity.

Can the American Joint Replacement Registry Utilize Administrative Claims Data to Accurately Classify Revision Total Hip Arthroplasty (THA) Surgical Diagnoses?

BACKGROUND: The American Joint Replacement Registry (AJRR) is a valuable tool for studying revision total hip arthroplasty (rTHA). Currently, International Classification of Diseases-10 (ICD-10) codes are utilized by the AJRR for classifying surgical diagnoses. However, the validity of this methodology is unknown. The purpose of this study was to determine the accuracy of these codes, as used by AJRR, in classifying rTHA diagnoses. METHODS: We identified 908 rTHAs performed at our institution from 2015 to 2021 using our total joint registry (TJR). Revision diagnoses were obtained from the TJR, which contains prospectively recorded surgical diagnoses collected by trained abstractors, independent from ICD-10 data. The ICD-10 diagnosis codes, as submitted to AJRR, were retrieved for the same procedures. The accuracy of ICD-10 codes for classifying rTHA diagnoses as septic versus aseptic, instability, aseptic loosening, and periprosthetic fracture was assessed using Cohen's Kappa statistic, sensitivity, and specificity. RESULTS: Concordance between AJRR-submitted data and TJR for classifying rTHA as septic or aseptic was excellent (96.9%; k = 0.87). Agreement for aseptic diagnoses varied from very good for instability (k = 0.76) and loosening (k = 0.67) to moderate for periprosthetic fracture (k = 0.54). Specificity was high (>96%) for all 3 aseptic diagnoses, but sensitivity was lower at 74%, 68%, and 44% for instability, loosening, and periprosthetic fracture, respectively. CONCLUSION: The AJRR submitted ICD-10 data correctly classifies the infection status of rTHA procedures with outstanding accuracy, but the accuracy for more granular diagnoses was variable. These data demonstrate the potential for diagnosis specific limitations when utilizing ICD-10 administrative claims for registry reporting.