High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility.

Genome-wide association studies (GWASs) have identified numerous lung cancer risk-associated loci. However, decoding molecular mechanisms of these associations is challenging since most of these genetic variants are non-protein-coding with unknown function. Here, we implemented massively parallel reporter assays (MPRAs) to simultaneously measure the allelic transcriptional activity of risk-associated variants. We tested 2,245 variants at 42 loci from 3 recent GWASs in East Asian and European populations in the context of two major lung cancer histological types and exposure to benzo(a)pyrene. This MPRA approach identified one or more variants (median 11 variants) with significant effects on transcriptional activity at 88% of GWAS loci. Multimodal integration of lung-specific epigenomic data demonstrated that 63% of the loci harbored multiple potentially functional variants in linkage disequilibrium. While 22% of the significant variants showed allelic effects in both A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cell lines, a subset of the functional variants displayed a significant cell-type interaction. Transcription factor analyses nominated potential regulators of the functional variants, including those with cell-type-specific expression and those predicted to bind multiple potentially functional variants across the GWAS loci. Linking functional variants to target genes based on four complementary approaches identified candidate susceptibility genes, including those affecting lung cancer cell growth. CRISPR interference of the top functional variant at 20q13.33 validated variant-to-gene connections, including RTEL1, SOX18, and ARFRP1. Our data provide a comprehensive functional analysis of lung cancer GWAS loci and help elucidate the molecular basis of heterogeneity and polygenicity underlying lung cancer susceptibility.

Zasp52 strengthens whole embryo tissue integrity through supracellular actomyosin networks.

During morphogenesis, large-scale changes of tissue primordia are coordinated across an embryo. In Drosophila, several tissue primordia and embryonic regions are bordered or encircled by supracellular actomyosin cables, junctional actomyosin enrichments networked between many neighbouring cells. We show that the single Drosophila Alp/Enigma-family protein Zasp52, which is most prominently found in Z-discs of muscles, is a component of many supracellular actomyosin structures during embryogenesis, including the ventral midline and the boundary of the salivary gland placode. We reveal that Zasp52 contains within its central coiled-coil region a type of actin-binding motif usually found in CapZbeta proteins, and this domain displays actin-binding activity. Using endogenously-tagged lines, we identify that Zasp52 interacts with junctional components, including APC2, Polychaetoid and Sidekick, and actomyosin regulators. Analysis of zasp52 mutant embryos reveals that the severity of the embryonic defects observed scales inversely with the amount of functional protein left. Large tissue deformations occur where actomyosin cables are found during embryogenesis, and in vivo and in silico analyses suggest a model whereby supracellular Zasp52-containing cables aid to insulate morphogenetic changes from one another.

Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity.

The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (eQTLs or meQTLs, respectively) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription-factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRAs along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional.

Deep Learning for Grading Endometrial Cancer.

Endometrial cancer is the fourth most common cancer in women in the United States; the lifetime risk for developing this disease is approximately 2.8%. Precise histologic evaluation and molecular classification of endometrial cancer are important for effective patient management and determining the best treatment modalities. This study introduces EndoNet, which uses convolutional neural networks for extracting histologic features and a vision transformer for aggregating these features and classifying slides based on their visual characteristics into high- and low-grade cases. The model was trained on 929 digitized hematoxylin and eosin-stained whole-slide images of endometrial cancer from hysterectomy cases at Dartmouth-Health. It classifies these slides into low-grade (endometrioid grades 1 and 2) and high-grade (endometrioid carcinoma International Federation of Gynecology and Obstetrics grade 3, uterine serous carcinoma, or carcinosarcoma) categories. EndoNet was evaluated on an internal test set of 110 patients and an external test set of 100 patients from The Cancer Genome Atlas public database. The model achieved a weighted average F1 score of 0.91 (95% CI, 0.86 to 0.95) and an area under the curve of 0.95 (95% CI, 0.89 to 0.99) on the internal test, and 0.86 (95% CI, 0.80 to 0.94) for F1 score and 0.86 (95% CI, 0.75 to 0.93) for area under the curve on the external test. Pending further validation, EndoNet has the potential to support pathologists without the need of manual annotations in classifying the grades of gynecologic pathology tumors.

Rare germline deleterious variants increase susceptibility for lung cancer.

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls. In single-variant analyses, we identified a new RDV, rs77187983 [EHBP1, odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.34-7.30, P = 0.008] and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25-3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04-13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair [carrier frequency (CF) = 22.9% versus 19.5%, P = 0.017] and Fanconi anemia (CF = 12.5% versus 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing corrections but were enriched in cases versus controls from large scale public biobank resources, including The Cancer Genome Atlas, FinnGen and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair-related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.

Estimating the interfacial permeability for flow into a poroelastic medium.

Boundary conditions between a porous solid and a fluid has been a long-standing problem in modeling porous media. For deformable poroelastic materials such as hydrogels, the question is further complicated by the elastic stress from the solid network. Recently, an interfacial permeability condition has been developed from the principle of positive energy dissipation on the hydrogel-fluid interface. Although this boundary condition has been used in flow computations and yielded reasonable predictions, it contains an interfacial permeability η as a phenomenological parameter. In this work, we use pore-scale models of flow into a periodic array of solid cylinders or parallel holes to determine η as a function of the pore size and porosity. This provides a means to evaluate the interfacial permeability for a wide range of poroelastic materials, including hydrogels, foams and biological tissues, to enable realistic flow simulations.

A theory of hydrogel mechanics that couples swelling and external flow.

Two aspects of hydrogel mechanics have been studied separately in the past. The first is the swelling and deswelling of gels in a quiescent solvent bath triggered by an environmental stimulus such as a change in temperature or pH, and the second is the solvent flow around and into a gel domain, driven by an external pressure gradient or moving boundary. The former neglects convection due to external flow, whereas the latter neglects solvent diffusion driven by a gradient in chemical potential. Motivated by engineering and biomedical applications where both aspects coexist and potentially interact with each other, this work presents a poroelasticity model that integrates these two aspects into a single framework, and demonstrates how the coupling between the two gives rise to novel physics in relatively simple one-dimensional and two-dimensional flows.

Treating Hepatitis C Before Total Knee Arthroplasty is Cost-Effective: A Markov Analysis.

BACKGROUND: Patients who have the hepatitis C virus (HCV) have increased mortality and complication rates following total knee arthroplasty (TKA). Recent advances in HCV therapy have enabled clinicians to eradicate the disease using direct-acting antivirals (DAAs); however, its cost-effectiveness before TKA remains to be demonstrated. The aim of this study was to perform a cost-effectiveness analysis comparing no therapy to DAAs before TKA. METHODS: A Markov model using input values from the published literature was performed to evaluate the cost-effectiveness of DAA treatment before TKA. Input values included event probabilities, mortality, cost, and health state quality-adjusted life-year (QALY) values for patients who have and do not have HCV. Patients who have HCV were modeled to have an increased rate of periprosthetic joint infection (PJI) infection (9.9 to 0.7%). The incremental cost-effectiveness ratio (ICER) of no therapy versus DAA was compared to a willingness-to-pay threshold of $100,000/QALY. Sensitivity analyses were performed to investigate the effects of uncertainty associated with input variables. RESULTS: Total knee arthroplasty in the setting of no therapy and DAA added 8.1 and 13.5 QALYs at a cost of $25,000 and $114,900. The ICER associated with DAA in comparison to no therapy was $16,800/QALY, below the willingness-to-pay threshold of $100,000/QALY. Sensitivity analyses demonstrated that the ICER was affected by patient age, inflation rate, DAA cost and effectiveness, HCV-associated mortality, and DAA-induced reduction in PJI rate. CONCLUSION: Direct-acting antiviral treatment before TKA reduces risk of PJI and is cost-effective. Strong consideration should be given to treating patients who have HCV before elective TKA. LEVEL OF EVIDENCE: Cost-effectiveness Analysis; Level III.

Opioid Consumption and Mobilization in Staged Bilateral Total Joint Arthroplasty: Did We Learn Our Lesson the First Time?

BACKGROUND: In patients who require bilateral total hip arthroplasty (THA) or total knee arthroplasty (TKA), staged procedures are a reasonable option for treatment of bilateral osteoarthritis. We sought to determine whether perioperative outcomes differed between first and second total joint arthroplasty (TJA). METHODS: This was a retrospective review of all patients who underwent staged, bilateral THA or TKA between January 30, 2017, and April 8, 2021. All patients who were included underwent their second procedure within 1 year of the first. Patients were separated based on whether both their procedures took place before or subsequently after an institution-wide opioid-sparing protocol that was implemented on October 1, 2018. A total of 961 patients who underwent 1,922 procedures met the inclusion criteria for this study. For THA, 388 unique patients comprised 776 procedures, while 573 unique patients comprised 1,146 TKAs. Opioid prescriptions were prospectively documented on nursing opioid administration flowsheets and converted to morphine milligram equivalents (MME) for comparison. Activity measure scores for postacute care (AM-PAC) were used as a measurement of physical therapy progression. RESULTS: Hospital stays, home discharges, perioperative opioid usages, pain scores, and AM-PAC scores were not significantly different for the second THA or TKA compared to first procedure, regardless of timing in relation to the opioid-sparing protocol. CONCLUSION: Patients experienced similar outcomes following their first versus their second TJA. Limited opioid prescriptions following TJA do not negatively impact pain and functional outcomes. These protocols can safely be instituted to help mitigate the opioid epidemic. LEVEL III EVIDENCE: Retrospective Cohort Study.

Treating Hepatitis C Prior to Total Hip Arthroplasty is Cost-effective: A Markov Analysis.

BACKGROUND: Patients infected with the hepatitis C virus (HCV) have high complication rates following total hip arthroplasty (THA). Advances in HCV therapy now enable clinicians to eradicate the disease; however, its cost-effectiveness from an orthopaedic perspective remains to be demonstrated. We sought to conduct a cost-effectiveness analysis comparing no therapy to direct-acting antiviral (DAA) therapy prior to THA among HCV-positive patients. METHODS: A Markov model was utilized to evaluate the cost-effectiveness of treating HCV with DAA prior to THA. The model was powered with event probabilities, mortality, cost, and quality-adjusted life year (QALY) values for patients with and without HCV that were obtained from the published literature. This included treatment costs, successes of HCV eradication, incidences of superficial or periprosthetic joint infection (PJI), probabilities of utilizing various PJI treatment modalities, PJI treatment success/failures, and mortality rates. The incremental cost-effectiveness ratio was compared to a willingness-to-pay threshold of $50,000/QALY. RESULTS: Our Markov model indicates that in comparison to no therapy, DAA prior to THA is cost-effective for HCV-positive patients. THA in the setting of no therapy and DAA added 8.06 and 14.39 QALYs at a mean cost of $28,800 and $115,800. The incremental cost-effectiveness ratio associated with HCV DAA in comparison to no therapy was $13,800/QALY, below the willingness-to-pay threshold of $50,000/QALY. CONCLUSION: Hepatitis C treatment with DAA prior to THA is cost-effective at all current drug list prices. Given these findings, strong consideration should be given to treating patients for HCV prior to elective THA. LEVEL OF EVIDENCE: Cost-effectiveness Analysis; Level III.

Total knee arthroplasty is associated with greater immediate post-surgical pain and opioid use than total hip arthroplasty.

BACKGROUND: As greater emphasis is being placed on opioid reduction strategies and implementation of multimodal analgesia, we sought to determine whether immediate post-surgical opioid consumption was different between THA and TKA. METHODS: A single-institution total joint arthroplasty database was used to identify patients who underwent elective THA and TKA from 2016 to July 2019. Baseline demographic data, operative time (defined by incision time), and American Society of Anesthesiologist (ASA) class were collected. Morphine milligram equivalents (MME) were calculated and derived from prospectively documented nursing opioid administration events, while visual analog scale (VAS) scores represented pain levels, both of which were collected as part of our institution's standard protocols. Activity Measure for Post-Acute Care (AMPAC) was used to determine physical therapy progress. RESULTS: A total of 11,693 cases were identified: 5,909 THA (50.53%) and 5784 (49.47%) TKA. THA patients tended to be slightly younger (63.38 years, SD 11.61 years, vs 65.72 years, SD 9.56 years; p < 0.01) and have lower BMIs (28.92 kg/m2 vs 32.52 kg/m2; p < 0.01). THA patients had lower ASA scores in comparison to TKA patients (p < 0.01). Aggregate opioid consumption (93.76 MME vs 147.55 MME; p < 0.01) along with first 24-h and 48-h usage was significantly less for THA as compared to TKA. Similarly, mean pain scores (4.15 vs 5.08; p < 0.01) were lower for THA, while AMPAC mobilization scores were higher (20.88 vs 19.29; p < 0.01) when compared to TKA. CONCLUSION: THA patients reported lower pain scores and were found to require less opioid medication in the immediate post-surgical period than TKA patients.

A three-dimensional vertex model forDrosophilasalivary gland invagination.

During epithelial morphogenesis, force generation at the cellular level not only causes cell deformation, but may also produce coordinated cell movement and rearrangement on the tissue level. In this paper, we use a novel three-dimensional vertex model to explore the roles of cellular forces during the formation of the salivary gland in theDrosophilaembryo. Representing the placode as an epithelial sheet of initially columnar cells, we focus on the spatial and temporal patterning of contractile forces due to three actomyosin pools: the apicomedial actomyosin in the pit of the placode, junctional actomyosin arcs outside the pit, and a supracellular actomyosin cable along the circumference of the placode. In anin silico'wild type' model, these pools are activated at different times according to experimental data. To identify the role of each myosin pool, we have also simulated variousin silico'mutants' in which only one or two of the myosin pools are activated. We find that the apicomedial myosin initiates a small dimple in the pit, but this is not essential for the overall invagination of the placode. The myosin arcs are the main driver of invagination and are responsible for the internalization of the apical surface. The circumferential actomyosin cable acts to constrict the opening of the developing tube, and is responsible for forming a properly shaped lumen. Cell intercalation tends to facilitate the invagination, but the geometric constraints of our model only allow a small number of intercalations, and their effect is minor. The placode invagination predicted by the model is in general agreement with experimental observations. It confirms some features of the current 'belt-and-braces' model for the process, and provides new insights on the separate roles of the various myosin pools and their spatio-temporal coordination.

A mechanical test of the tenertaxis hypothesis for leukocyte diapedesis.

As part of the immune response, leukocytes can directly transmigrate through the body of endothelial cells or through the gap between adjacent endothelial cells. These are known, respectively, as the transcellular and paracellular route of diapedesis. What determines the usage of one route over the other is unclear. A recently proposed tenertaxis hypothesis claims that leukocytes choose the path with less mechanical resistance against leukocyte protrusions. We examined this hypothesis using numerical simulation of the mechanical resistance during paracellular and transcellular protrusions. By using parameters based on human lung endothelium, our results show that the required force to breach the endothelium through the transcellular route is greater than paracellular route, in agreement with experiments. Moreover, experiments have demonstrated that manipulation of the relative strength between the two routes can make the transcellular route preferable. Our simulations have demonstrated this reversal and thus tentatively confirmed the hypothesis of tenertaxis.

Discontinuation of Intraoperative Liposomal Bupivacaine in Primary THA Does Not Clinically Change Postoperative Subjective Pain, Opioid Consumption, or Objective Functional Status.

BACKGROUND: There is debate regarding the benefit of liposomal bupivacaine (LB) as part of a periarticular injection (PAI) in total hip arthroplasty (THA). Here, we evaluate the effect of discontinuing intraoperative LB PAI on immediate postoperative subjective pain, opioid consumption, and objective functional outcomes. METHODS: On July 1, 2019, an institutional policy discontinued the use of intraoperative LB PAI. A consecutive cohort that received LB PAI and a subsequent cohort that did not were compared. All patients received the same opioid-sparing protocol. Nursing documented verbal rating scale pain scores were averaged per patient per 12-hour interval. Opiate administration events were converted into morphine milligram equivalences per patient per 24-hour interval. The validated Activity Measure for Postacute Care (AM-PAC) tool was used to evaluate functional outcomes. RESULTS: Six hundred thirty eight primary THAs received LB followed by 939 that did not. In the non-LB THAs, BMI was higher (30.06 vs 29.43; P < .05). Besides marital status, the remaining baseline demographics were similar between the two cohorts (P > .05). The non-LB THA cohort demonstrated a marginal increase in verbal rating scale pain scores between 12 to 24 hours (4.42 ± 1.70 vs 4.20 ± 1.87; P < .05) and 36 to 48 hours (4.49 ± 1.72 vs 4.21 ± 1.83; P < .05). There was no difference in inpatient opioid administration up to 96 hours postoperatively (P > .05) or AM-PAC functional scores within the first 24 hours (P > .05). CONCLUSION: A small statistical, but not clinically meaningful, difference was observed in subjective pain scores with LB PAI discontinuation. Opioid consumption and postoperative AM-PAC functional scores were unchanged after LB PAI discontinuation.

Adductor Canal Blocks Reduce Inpatient Opioid Consumption While Maintaining Noninferior Pain Control and Functional Outcomes After Total Knee Arthroplasty.

BACKGROUND: The use of perioperative adductor canal blocks (PABs) continues to be a highly debated topic for total knee arthroplasty (TKA). Here, we evaluate the effect of PABs on immediate postoperative subjective pain scores, opioid consumption, and objective functional outcomes. METHODS: On December 1, 2019, an institution-wide policy change was begun to use PABs in primary elective TKAs. Patient demographics, immediate postoperative nursing documented pain scores, opioid administration events, and validated physical therapy functional scores were prospectively collected as part of the standard of care and retrospectively queried through our electronic data warehouse. A historical comparison cohort was derived from consecutive patients undergoing TKA between July 1, 2019 and November 30, 2019. RESULTS: 405 primary TKAs received PABs, while 789 patients were in the control cohort. Compared with controls, average verbal rating scale pain scores were lower among PAB recipients from 0-12 hours (2.42 ± 1.60 vs 2.05 ± 1.60; <.001) and 24-36 hours (4.92 ± 2.00 vs 4.47 ± 2.27; <.01). PAB recipients demonstrated significantly lower opioid consumption within the first 24 hours (44.34 ± 40.98 vs 36.83 ± 48.13; P < .01) and during their total inpatient stay (92.27 ± 109.81 vs 77.52 ± 123.11; <.05). AM-PAC scores within the first 24 hours were also higher for PABs (total scores: 20.28 ± 3.06 vs 20.71 ± 3.12; <.05). CONCLUSION: While the minimal clinically important differences in pain scores and functional status were comparable between both cohorts, patients demonstrated a significant reduction in overall inpatient opiate consumption after the introduction of PABs. Surgeons should consider these findings when evaluating for perioperative pain management, opioid-sparing, and rapid discharge protocols.

How are peri-implant fractures below short versus long cephalomedullary nails different?

BACKGROUND: Cephalomedullary nails are a commonly used implant for the treatment of many pertrochanteric femur fractures and are available in short and long configurations. There is no consensus on ideal nail length. Relative advantages can be ascribed to short and long intramedullary nails, yet both implant styles share the potentially devastating complication of peri-implant fracture. Determining the clinical sequelae after fractures below nails of different lengths would provide valuable information for surgeons choosing between short or long nails. Thus, the purpose of the study was to compare injury patterns and treatment outcomes following peri-implant fractures below short or long cephalomedullary nails. METHODS: This was a multicenter retrospective cohort study that identified 33 patients referred for treatment of peri-implant fractures below short and long cephalomedullary nails (n = 19 short, n = 14 long). We compared fracture pattern, treatment strategy, complications, and outcomes between these two groups. RESULTS: Short nails were associated with more diaphyseal fractures (odds ratio [OR] 13.75, CI 2.2-57.9, p 0.002), which were treated more commonly with revision intramedullary nailing (OR, infinity; p 0.01), while long nails were associated with distal metaphyseal fractures (OR 13.75, CI 2.2-57.9, p 0.002), which were treated with plate and screw fixation (p 0.002). After peri-implant fracture, there were no differences in blood loss, operative time, weight bearing status, or complication rates based on the length of the initial nail. In patients treated with revision nailing, there was greater estimated blood loss (EBL, median 300 cc, interquartile range [IQR] 250-1200 vs median 200 cc, IQR 100-300, p 0.03), blood product utilization and complication rates (OR 11.1, CI 1.1-135.7, p 0.03), but a trend toward unrestricted post-operative weight-bearing compared to patients treated with plate and screw constructs. CONCLUSION: Understanding fracture patterns and patient outcomes after fractures below nails of different lengths will help surgeons make more informed implant choices when treating intertrochanteric hip fractures. Revision to a long nail for the treatment of fractures at the tip of a short nail may be associated with increased patient morbidity.

A Rho-GTPase based model explains group advantage in collective chemotaxis of neural crest cells.

A cluster of neural crest cells (NCCs) may chemotax up a shallow external gradient to which a single cell is unresponsive. To explain this intriguing 'group advantage', we propose a chemo-mechanical model based on the signaling proteins Rac1 and RhoA. We represent each cell as a polygon with nodes connected by elastic membranes. Via reaction-diffusion on the membrane and exchange with their cytosolic pools, Rac1 and RhoA interact to produce cell polarization and repolarization subject to random noise. Mechanically, we represent cell motility via overdamped nodal motion subject to passive elastic membrane forces and active protrusive or contractile forces where Rac1 or RhoA dominates. The model reproduces the random walk of a single cell in a weak gradient and two modes of cell-cell interaction: contact inhibition of locomotion and co-attraction. The simultaneous action of contact inhibition and co-attraction suppresses random Rac1 bursts on the membrane and serves to preserve existing protrusions. This amounts to an emergent persistence of polarity that markedly enhances the ability of a cluster of NCCs to chemotax in a weak gradient against random noise, thereby giving rise to the group advantage.

A biomechanical model for the transendothelial migration of cancer cells.

We propose a biomechanical model for the extravasation of a tumor cell (TC) through the endothelium of a blood vessel. Based on prior in vitro observations, we assume that the TC extends a protrusion between adjacent endothelial cells (ECs) that adheres to the basement membrane via focal adhesions (FAs). As the protrusion grows in size and branches out, the actomyosin contraction along the stress fibers (SFs) inside the protrusion pulls the relatively rigid nucleus through the endothelial opening. We model the chemo-mechanics of the SFs and the FAs by following the kinetics of the active myosin motors and high-affinity integrins, subject to mechanical feedback. This is incorporated into a finite-element simulation of the extravasation process, with the contractile force pulling the nucleus of the TC against elastic resistance of the ECs. To account for the interaction between the TC nucleus and the endothelium, we consider two scenarios: solid-solid contact and lubrication by cytosol. The former gives a lower bound for the required contractile force to realize transmigration, while the latter provides a more realistic representation of the process. Using physiologically reasonable parameters, our model shows that the SF and FA ensemble can produce a contractile force on the order of 70 nN, which is sufficient to deform the ECs and enable transmigration. Furthermore, we use an atomic force microscope to measure the resistant force on a human bladder cancer cell that is pushed through an endothelium cultured in vitro. The magnitude of the required force turns out to be in the range of 70-100 nN, comparable to the model predictions.

Barriers to Revision Total Hip Service Lines: A Surgeon's Perspective Through a Deterministic Financial Model.

BACKGROUND: Revision THA represents approximately 5% to 10% of all THAs. Despite the complexity of these procedures, revision arthroplasty service lines are generally absent even at high-volume orthopaedic centers. We wanted to evaluate whether financial compensation is a barrier for the development of revision THA service lines as assessed by RVUs. QUESTIONS/PURPOSES: Therefore, we asked: (1) Are physicians fairly compensated for revision THA on a per-minute basis compared with primary THA? (2) Are physicians fairly compensated for revision THA on a per-day basis compared with primary THA? METHODS: Our deterministic financial model was derived from retrospective data of all patients undergoing primary or revision THA between January 2016 and June 2018 at an academic healthcare organization. Patients were divided into five cohorts based on their surgical procedure: primary THA, head and liner exchange, acetabular component revision THA, femoral component revision THA, and combined femoral and acetabular component revision THA. Mean surgical times were calculated for each cohort, and each cohort was assigned a relative value unit (RVU) derived from the 2018 Center for Medicaid and Medicare assigned RVU fee schedule. Using a combination of mean surgical time and RVUs rewarded for each procedure, three models were developed to assess the financial incentive to perform THA services for each cohort. These models included: (1) RVUs earned per the mean surgical time, (2) RVUs earned for a single operating room for a full day of THAs, and (3) RVUs earned for two operating rooms for a full day of primary THAs versus a single rooms for a full day of revision THAs. A sixth cohort was added in the latter two models to more accurately reflect the variety in a typical surgical day. This consisted of a blend of revision THAs: one acetabular, one femoral, and one full revision. The RVUs generated in each model were compared across the cohorts. RESULTS: Compared with primary THA by RVU per minute, in revision THA, head and liner exchange demonstrated a 4% per minute deficit, acetabular component revision demonstrated a 29% deficit, femoral component revision demonstrated a 32% deficit, and full revision demonstrated a 27% deficit. Compared with primary service lines with one room, revision surgeons with a variety of revision THA surgeries lost 26% potential relative value units per day. Compared with a two-room primary THA service, revision surgeons lost 55% potential relative value units per day. CONCLUSIONS: In a comparison of relative value units of a typical two-room primary THA service line versus those of a dedicated revision THA service line, we found that revision specialists may lose between 28% and 55% of their RVU earnings. The current Centers for Medicare and Medicaid Services reimbursement model is not viable for the arthroplasty surgeon and limits patient access to revision THA specialists. LEVEL OF EVIDENCE: Level III, economic and decision analysis.

The Impact of Arthroplasty Fellowship Training on Total Joint Arthroplasty: Comparison of Peri-Operative Metrics between Fellowship-Trained Surgeons and Non-Fellowship-Trained Surgeons.

BACKGROUND: We sought to identify differences between total joint arthroplasties (TJAs) performed by adult reconstruction fellowship-trained surgeons (FT) than non-fellowship-trained surgeons (NFT). METHODS: A single-institution database was utilized to identify patients who underwent elective TJA between 2016 and 2019. RESULTS: In total, 16,882 TJAs were identified: 9111 total hip arthroplasties (THAs) and 7771 total knee arthroplasties (TKAs). Patients undergoing THA by FT surgeons were older (63.11 vs 61.84 years, P < .001), more likely to be white, insured by Medicare, and less likely to be active smokers (P < .0001). Both surgical time (90.03 vs 113.1 minutes, P < .0001) and mean length of stay (LOS) (1.85 vs 2.72 days, P < .0001) were significantly shorter for THAs performed by FT surgeons than NFT surgeons. A significantly greater percentage of patients were discharged home after THA by FT surgeons than NFT surgeons (88.7% vs 85.2%, P = .002). FT patients were quicker to mobilize with therapy and required 25% less opioids. TKAs performed by FT surgeons were associated with shorter surgical times (87.4 vs 94.92 minutes, P < .0001), LOS (2.62 vs 2.84 days, P < .0001), and nearly 19% less opioid requirement in the peri-operative period. In addition to higher Activity Measure for Post-Acute Care scores associated with FT surgeons after TKA, a significantly greater percentage of patients were discharged home after TKA by FT surgeons than NFT surgeons (83.97% vs 80.16%, P < .001). CONCLUSION: For both THA and TKA, patients had significantly shorter surgical times, LOS, and required less opioids when their procedure was performed by FT surgeons compared to NTF surgeons. Patients who had their TJA performed by a FT surgeon achieved higher Activity Measure for Post-Acute Care scores and were discharged home more often than NFT surgeons. In an era of value-based care, more attention should be paid to the patient outcomes and financial implications associated with arthroplasty fellowship training. LEVEL III EVIDENCE: Retrospective Cohort Study.