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Resident synovial macrophages (RSMs) are anti-inflammatory, self-renewing macrophages that provide physical immune sequestration of the joint space from the peripheral immune system. Increased permeability of this structure is associated with peripheral immune cells in the synovial fluid (SF). Direct measures of synovial barrier integrity are possible with tissue histology, but after barrier breakdown, if these cells perpetuate or initiate chronic inflammation in SF remains unknown. We sought to identify RSM in human SF as an indirect measure of synovial barrier integrity. To validate findings, we created a novel ex vivo explant model using human synovium. scRNA-seq revealed these SF RSMs upregulated pro-fibrotic and pro-osteoclastic pathways in inflammatory arthritis, but not septic arthritis. Increased frequencies of RSMs in SF was associated with increased sRANKL regardless of underlying pathology. These findings suggest the frequency of RSMs in SF may correlate with synovial barrier damage and in turn, potential damage to joint structures., Competing Interests: Declaration of competing interest The authors have declared no competing interests., (Published by Elsevier Inc.)

LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS. We report the discovery of MDI-114215 ( 85 ), a novel, potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite kinome selectivity. 85 reduces phospho-cofilin in mouse brain slices and rescues impaired hippocampal long-term potentiation in brain slices from FXS mice. We also show that LIMK inhibitors are effective in reducing phospho-cofilin levels in iPSC neurons derived from FXS patients, demonstrating 85 to be a potential therapeutic candidate for FXS that could have broad application to neurological disorders or cancers caused by LIMK1/2 overactivation and actin instability.

Background: Anatomic patellar components for total knee arthroplasty (TKA) have demonstrated favorable in vivo kinematics. A novel failure mechanism in TKA patients with an anatomic patellar component was observed prompting an investigation to identify patient- and implant-related factors associated with suboptimal performance., Methods: A retrospective evaluation was performed comparing 100 TKA patients with an anatomic patellar component to 100 gender-, age-, and body mass index-matched patients with a medialized dome component. All surgeries were performed with the same posterior-stabilized TKA system with minimum of 1-year follow-up. Several radiographic parameters were assessed. A separate computational evaluation was performed using finite-element analysis, comparing bone strain energy density through the patella bone remnant., Results: Patients with an anatomic patellar component had significantly higher rates of anterior knee pain (18 versus 2%, P < .001), chronic effusions (18 versus 2%, P < .001), and superior patellar pole fragmentation (36 versus 13%, P < .001) compared to those with a dome component. Radiographically, the anatomic group demonstrated more lateral patellar subluxation (2.3 versus 1.1 mm, P < .001) and lateral tilt (5.4 versus 4.0 mm, P = .013). Furthermore, there were more revisions in the anatomic group (7 versus 3, P = .331). On computational evaluation, all simulations demonstrated increased bone strain energy density at the superior patellar pole with the anatomic patella. Resection thickness <13 mm resulted in over 2-fold higher strain energy density, and negative resection angle of 7° resulted in 6-fold higher superior pole strain energy., Conclusions: Patients with an anatomic patellar component showed higher rates of anterior knee pain, chronic effusion, and superior pole fragmentation compared to patients with a dome patella, with higher superior patellar pole strain energy confirmed on computational evaluation. Avoiding higher resection angles and excessive patellar resection may improve the performance and survivorship of the anatomic patella., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The WWE domain is a relatively under-researched domain found in twelve human proteins and characterized by a conserved tryptophan-tryptophan-glutamate (WWE) sequence motif. Six of these WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. The general recognition of poly-ADP-ribosylated substrates by WWE domains suggests a potential avenue for development of Proteolysis-Targeting Chimeras (PROTACs). Here, we present novel crystal structures of the HUWE1, TRIP12, and DTX1 WWE domains in complex with PAR building blocks and their analogs, thus enabling a comprehensive analysis of the PAR binding site structural diversity. Furthermore, we introduce a versatile toolbox of biophysical and biochemical assays for the discovery and characterization of novel WWE domain binders, including fluorescence polarization-based PAR binding and displacement assays, 15 N-NMR-based binding affinity assays and 19 F-NMR-based competition assays. Through these assays, we have characterized the binding of monomeric iso-ADP-ribose (iso-ADPr) and its nucleotide analogs with the aforementioned WWE proteins. Finally, we have utilized the assay toolbox to screen a small molecule fragment library leading to the successful discovery of novel ligands targeting the HUWE1 WWE domain., (© 2024. The Author(s).)

Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.

Background Direct anterior total hip arthroplasty (DA-THA) has increased in popularity over recent decades. However, DA-THA has been reported to have a higher incidence of superficial wound complications, including infection and incisional dehiscence, compared to other surgical approaches to hip arthroplasty. While this indicates a need for optimal wound closure, little research exists on the preferred method of skin closure following DA-THA. This study aimed to determine if there was any difference in rates of superficial infection, wound dehiscence, or overall wound complications with skin closure using a running subcuticular 3-0 Monocryl® suture compared to surgical staples following DA-THA.  Methods Records of patients who underwent DA-THA at our institution between July 2017 to July 2022 were retrospectively reviewed. Data were abstracted on patient demographics, comorbidities, skin closure method, and wound complications from the electronic medical record. Superficial infection and wound dehiscence were classified based on explicit diagnosis in post-operative records and incision photographs taken during follow-up visits. Overall wound complications were classified in patients who experienced either superficial infection, incisional dehiscence, or both complications following surgery. Descriptive statistics and chi-squared measures were obtained from post-operative patient data, and significance was set at p [Formula: see text] 0.05. Results A total of 365 DA-THAs were completed in 349 patients. A running subcuticular 3-0 Monocryl® suture closed 207 surgeries (56.7%), while surgical staples closed 158 surgeries (43.3%). There was no significant difference in independent rates of superficial infection (p = 0.076) or wound dehiscence (p = 0.118) between suture and staple cohorts; however, suture closure (10, 2.7%) was associated with a significantly higher rate of overall wound complications compared to staple closure (1, 0.3%) (p = 0.020). Conclusion DA-THA carries the risk of overall wound complications, including superficial infection and wound dehiscence. Our findings suggest superficial skin closure with staples may be preferred over sutures due to lower rates of overall wound complications. Further studies are needed to determine the optimal method of skin closure following DA-THA., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. University of Iowa Institutional Review Board (IRB) issued approval 201904825. Approval has been electronically signed by IRB Chair, Brian Bishop, CIP, MA (09/08/22 1244). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Jacob M. Elkins declare(s) personal fees from Depuy Synthes. Dr. Elkins has previously served as consultant for Depuy Synthes. . Jacob M. Elkins declare(s) non-financial support from Journal of Arthroplasty. Dr. Elkins serves on the editorial board for The Journal of Arthroplasty. . Jacob M. Elkins declare(s) personal fees from IronMind Enterprises & Depuy Synthes. Dr. Elkins has previously received research support from IronMind Enterprises & Depuy Synthes. . Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hlas et al.)

Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases., Competing Interests: Declaration of competing interest The authors declare no financial competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Resident synovial macrophages (RSM) provide immune sequestration of the joint space and are likely involved in initiation and perpetuation of the joint-specific immune response. We sought to identify RSM in synovial fluid (SF) and demonstrate migratory ability, in additional to functional changes that may perpetuate a chronic inflammatory response within joint spaces., Methods: We recruited human patients presenting with undifferentiated arthritis in multiple clinical settings. We used flow cytometry to identify mononuclear cells in peripheral blood and SF. We used a novel transwell migration assay with human ex-vivo synovium obtained intra-operatively to validate flow cytometry findings. We used single cell RNA-sequencing (scRNA-seq) to further identify macrophage/monocyte subsets. ELISA was used to evaluate the bone-resorption potential of SF., Results: We were able to identify a rare population of CD14 dim , OPG + , ZO-1 + cells consistent with RSM in SF via flow cytometry. These cells were relatively enriched in the SF during infectious processes, but absolutely decreased compared to healthy controls. Similar putative RSM were identified using ex vivo migration assays when MCP-1 and LPS were used as migratory stimulus. scRNA-seq revealed a population consistent with RSM transcriptionally related to CD56 + cytotoxic dendritic cells and IDO + M2 macrophages., Conclusion: We identified a rare cell population consistent with RSM, indicating these cells are likely migratory and able to initiate or coordinate both acute (septic) or chronic (autoimmune or inflammatory) arthritis. RSM analysis via scRNA-seq indicated these cells are M2 skewed, capable of antigen presentation, and have consistent functions in both septic and inflammatory arthritis.

Background: While there have been significant advancements in recent years, complications following fixation for femoral neck fractures remain a concern. This retrospective cohort study aimed to investigate the influence of polytrauma and additional fractures on the occurrence of complications in patients who underwent surgical fixation for femoral neck fractures. The study focused on analyzing patient demographics, comorbidities, fracture classifications, fixation methods, and the likelihood of experiencing post-operative complications, with a specific emphasis on the impact of polytrauma and additional fractures., Methods: This retrospective cohort study analyzed data from medical records and radiographs of patients who underwent surgical fixation for femoral neck fractures at a tertiary care center between 2007 and 2020. A total of 58 patients met inclusion criteria and were assessed based on their medical history, comorbidities, fracture classification, fixation method, and the occurrence of complications such as osteonecrosis, non-union, limb length discrepancy, and conversion to Total Hip Arthroplasty (THA). Among the patients, 36 received Cancellous Screw (CS) fixation, 12 underwent Sliding Hip Screw (SHS) fixation, while the remaining 10 patients who underwent different fixation methods were excluded from the analysis due to the heterogeneity of the group., Results: Demographic characteristics and comorbidities were similar between the CS and SHS fixation groups. The overall complication rate for CS fixation was 16.7% (6/36 patients), while the rate for SHS fixation was 33.3% (4/12 patients). However, when considering the presence of polytrauma and additional fractures, a significant association with increased complication rates was observed. Cox proportional regression analysis revealed that the absence of polytrauma/additional fractures significantly reduced the complication rates by more than 90% (Hazard ratio (HRpolytrauma)=0.01, P value = 0.01). This highlights the substantial impact of polytrauma and additional fractures on complications in femoral neck fracture fixation surgeries., Conclusion: This study emphasizes the need for thorough evaluation and tailored management strategies for patients with femoral neck fractures associated with polytrauma or additional fractures to minimize the complications of femoral neck fracture surgery. Further research is warranted to explore potential preventive measures and optimized treatment approaches for this high-risk patient subset of the femoral neck fracture population. Level of Evidence: III ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2024.)

Background: 30-day readmission is an important quality metric evaluated following primary total joint arthroplasty (TJA) that has implications for hospital performance and reimbursement. Differences in how 30-day readmissions are defined between Centers for Medicare and Medicaid Services (CMS) and other quality improvement programs (i.e., National Surgical Quality Improvement Program [NSQIP]) may create discordance in published 30-day readmission rates. The purpose of this study was to evaluate 30-day readmission rates following primary TJA using two different temporal definitions., Methods: Patients undergoing primary total hip and primary total knee arthroplasty at a single academic institution from 2015-2020 were identified via common procedural terminology (CPT) codes in the electronic medical record (EMR) and institutional NSQIP data. Readmissions that occurred within 30 days of surgery (consistent with definition of 30-day readmission in NSQIP) and readmissions that occurred within 30 days of hospital discharge (consistent with definition of 30-day readmission from CMS) were identified. Rates of 30-day readmission and the prevalence of readmission during immortal time were calculated., Results: In total, 4,202 primary TJA were included. The mean hospital length of stay (LOS) was 1.79 days. 91% of patients were discharged to home. 30-day readmission rate using the CMS definition was 3.1% (130/4,202). 30-day readmission rate using the NSQIP definition was 2.7% (113/4,202). Eight readmissions captured by the CMS definition (6.1%) occurred during immortal time., Conclusion: Differences in temporal definitions of 30-day readmission following primary TJA between CMS and NSQIP results in discordant rates of 30-day readmission. Level of Evidence: III ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2024.)

Background: Bioimpedance derived whole body phase angle (ϕ), a measure of cellular integrity, has been identified as an independent marker of morbidity and mortality in many medical and surgical specialties. While similar measures of water homeostasis like extracellular edema (EE) have been associated with pre-operative risk, ϕ has not been studied in orthopaedics, despite potential to serve as a pre-operative marker. This study aims to identify relationships between ϕ, EE, and body composition metrics, laboratory values, patient reported outcomes, and comorbidities., Methods: Multi-frequency bioimpedance analysis (BIA) records, laboratory values, and patient reported outcomes of adult patients presenting to an academic arthroplasty clinic were retrospectively reviewed. Correlation coefficients between ϕ, EE, and reviewed information were conducted., Results: ϕ was significantly correlated (p<0.001) most positively with measures of lean tissue such as skeletal muscle mass (r=0.48), appendicular skeletal muscle index (r=0.39), lean body mass (r=0.43), and dry lean mass (r=0.47), while it held negative correlations (p<0.001) with age (r= -0.55), and body fat mass (r= -0.11). ϕ was not correlated with body mass index (BMI, p = 0.204). In contrast, EE demonstrated its strongest positive correlations (p<0.001) with body fat mass (r=0.32), age (r=0.50), and BMI (r=0.26), and its strongest negative correlations (p<0.001) with serum albumin (r= -0.37) and total protein (r= -0.23)., Conclusions: Based on their associations with markers of health and fitness, BIA determined ϕ and EE demonstrate relationships to markers currently implemented in orthopaedic practice. This likely indicates that ϕ has potential as a comprehensive surrogate for several commonly used markers to quantify pre-operative risk. In the future, ϕ may aid in developing risk-stratifications for intervention and prevention of complications., Competing Interests: Conflict of interest MCM and ASO do not have any conflicts of interest to disclose. JME receives research support from DePuy Synthes (Raynham, MA, US) and IronMind Enterprises (Nevada City, CA, US), and he is an editor for Journal of Arthroplasty. These disclosures are not relevant to this study., (© 2023 Michael C. Marinier et al., published by Sciendo.)

Background: The COVID-19 pandemic has had a lasting impact on patients seeking total hip and knee arthroplasty (THA, TKA) including more patients undergoing same day discharge (SDD) following total joint arthroplasty (TJA). The purpose of this study was to assess whether expansion of SDD TJA during the COVID-19 pandemic resulted in more early complications following TJA. We anticipated that as many institutions quickly launched SDD TJA programs there may be an increase in 30-day complications., Methods: We retrospectively queried the ACS-NSQIP database for all patients undergoing primary elective TJA from January 1, 2018, to December 31, 2020. Participants who underwent THA or TKA between January 1, 2018 and March 1, 2020 were grouped into pre-COVID and between March 1, 2020 and December 31, 2020 were grouped into post-COVID categories. Patients with length of stay greater than 0 were excluded. Primary outcome was any complication at 30 days. Secondary outcomes included readmission and re-operation 30 days., Results: A total of 14,438 patients underwent TKA, with 9,580 occurring pre-COVID and 4,858 post-COVID. There was no difference in rates of total complication between the pre-COVID (3.55%) and post-COVID (3.99%) groups (p=0.197). Rates of readmissions for were similar for the pre-COVID (1.75%) and post-COVID (1.98%) groups (p=0.381). There was no statistically significant difference in respiratory complications between the pre-COVID (0.41%) and post-COVID group (0.23%, p=0.03). A total of 12,265 patients underwent THA, with 7,680 occurring pre-COVID and 4,585 post-COVID. There was no difference in rates of total complication between the pre-COVID (3.25%) and post-COVID (3.49%) groups (p=0.52). Rates of readmissions for were similar for the pre-COVID (1.77%) and post-COVID (1.68%) groups (p=0.381). There was no statistically significant difference in respiratory complications between the pre-COVID (0.16%) and post-COVID group (0.07%, p=0.26). Combined data to include THA and TKA patients did not find a statistical difference in the rate of complications or readmission but did note a decrease in the rate of combined respiratory complications in the post-COVID group (0.15% vs. 0.30%, p=0.028)., Conclusion: Rapid expansion of SDD TJA during the COVID-19 pandemic did not increase overall complication, readmission, or re-operation rates. Level of Evidence: IV ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2023.)

The past few years have seen exciting discoveries in the area of tyrosine kinase structural biology including the first high resolution models of full-length receptor tyrosine kinases and new mechanistic insights into the structural mechanisms of receptor tyrosine kinase activation. Despite being a mature area of research, the application of new technologies continues to advance our understanding. In this article we highlight a selection of recent studies that illustrate the current areas of research interest, focussing in particular on the exciting progress made possible by cryo-electron-microscopy. These new discoveries may herald a wave of new design ideas for therapeutics acting through novel mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine whether deficient early callus formation can be defined objectively based on the association with an eventual nonunion and specific patient, injury, and treatment factors., Methods: Final healing outcomes were documented for 160 distal femur fractures treated with locked bridge plate fixation. Radiographic callus was measured on postoperative radiographs until union or nonunion had been declared by the treating surgeon. Deficient callus was defined at 6 and 12 weeks based on associations with eventual nonunion through receiver-operator characteristic analysis. A previously described computational model estimated fracture site motion based on the construct used. Univariable and multivariable analyses then examined the association of patient, injury, and treatment factors with deficient callus formation., Results: There were 26 nonunions. The medial callus area at 6 weeks <24.8 mm 2 was associated with nonunion (12 of 39, 30.8%) versus (12 of 109, 11.0%), P = 0.010. This association strengthened at 12 weeks with medial callus area <44.2 mm 2 more closely associated with nonunion (13 of 28, 46.4%) versus (11 of 120, 9.2%), P <0.001. Multivariable logistic regression analysis found limited initial longitudinal motion (OR 2.713 (1.12-6.60), P = 0.028)) and Charlson Comorbidity Index (1.362 (1.11-1.67), P = 0.003) were independently associated with deficient callus at 12 weeks. Open fracture, mechanism of injury, smoking, diabetes, plate material, bridge span, and shear were not significantly associated with deficient callus., Conclusion: Deficient callus at 6 and 12 weeks is associated with eventual nonunion, and such assessments may aid future research into distal femur fracture healing. Deficient callus formation was independently associated with limited initial longitudinal fracture site motion derived through computational modeling of the surgical construct but not more routinely discussed parameters such as plate material and bridge span. Given this, improved methods of in vivo assessment of fracture site motion are necessary to further our ability to optimize the mechanical environment for healing., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 structural models of the 17 canonical members of the human PARP protein family and supplemented this analysis with new experiments and an overview of recent published data. PARP proteins are typically involved in the modification of proteins and nucleic acids through mono or poly(ADP-ribosyl)ation, but this function can be modulated by the presence of various auxiliary protein domains. Our analysis provides a comprehensive view of the structured domains and long intrinsically disordered regions within human PARPs, offering a revised basis for understanding the function of these proteins. Among other functional insights, the study provides a model of PARP1 domain dynamics in the DNA-free and DNA-bound states and enhances the connection between ADP-ribosylation and RNA biology and between ADP-ribosylation and ubiquitin-like modifications by predicting putative RNA-binding domains and E2-related RWD domains in certain PARPs. In line with the bioinformatic analysis, we demonstrate for the first time PARP14's RNA-binding capability and RNA ADP-ribosylation activity in vitro. While our insights align with existing experimental data and are probably accurate, they need further validation through experiments., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Malalignment of total knee arthroplasty (TKA) components is a potential cause of clinical failure following TKA. Since the goal of a gap balancing (GB) technique is equal flexion and extension gaps secondary to soft-tissue balancing, and not necessarily component alignment, variation in component placement may exist. Our purpose was (1) to evaluate precision of component alignment in well-functioning GB TKAs performed without the aid of navigation using computed tomographic evaluation and (2) to determine any relationship between femoral version and/or tibial torsion and TKA component positioning., Methods: There were 93 well-functioning TKAs performed with an extension gap first GB technique with a minimum 2-year follow-up evaluated using computed tomography to assess component rotational alignment, as well as osseous femoral version and tibial torsion. Femoral and tibial rotational alignment was assessed by previously described methods., Results: The mean Knee Society Score was 185.7 ± 21.7. The mean range of motion was 128.5 ± 7.8°. Femoral posterocondylar axis (relative to the transepicondylar axis) values ranged from -8.3 to 4.1° with a mean of -0.78 ± 2.7° (internal rotation). Mean tibial rotation was 17.2 ± 7.9° internal rotation relative to the tibial tubercle. No correlation was found between native femoral version and femoral component rotational alignment (Pearson's correlation coefficient, r, 0.007). Weak correlation was found between native tibial torsion and tibial component alignment (r = 0.24)., Conclusion: Despite being only a secondary objective with the GB technique, most components evaluated were within the desired range of rotation. Alignment was not influenced by native osseous rotational geometry., Level of Evidence: Level III, Retrospective Cohort Study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Smoking is a known risk factor for complications following primary total joint arthroplasty (TJA). Little is known regarding the fate of patients who are asked to quit smoking before surgery. The purpose of this study was to evaluate the success of smoking cessation prior to primary TJA and the impact of smoking cessation on perioperative outcomes., Methods: This is a retrospective review of patients who presented between 2008 and 2020 to a single academic medical center with a documented smoking history and were asked to quit smoking prior to receiving a date for primary TJA. The cohort was surveyed about smoking cessation, smoking history, use of quit aids, seeking surgery elsewhere due to the cessation policy, and postoperative complications. Descriptive statistics evaluated the relationship between demographics, smoking cessation, and postoperative complications., Results: A total of 101 patients completed the survey with an overall response rate of 48%. Sixty-two percent of patients quit smoking before surgery, and 51% of these patients reported remaining smoke-free at 6 months postoperatively. The average time to quit before TJA was 45 days (range: 1-365 days), and 62% quit without quit aids. The wound complication/infection rate was significantly higher for patients who did not stop smoking prior to TJA (4 of 16; 27%) than for those who did quit prior to surgery (3 of 63; 5%; P  = .02)., Conclusions: This study demonstrates that most patients (62%) will stop smoking, if required, prior to primary TJA. Furthermore, 51% of patients reported abstinence from smoking at 6 months following TJA. TJA appears to be an effective motivator for smoking cessation., Level of Evidence: III (retrospective cohort study)., (© 2022 The Authors.)

Background: The purpose of this study was to develop projections of the prevalence of obesity in aseptic revision THA and TKA patients through the year 2029., Methods: The National Surgical Quality Improvement Project (NSQIP) was queried for years 2011-2019. Current procedural terminology (CPT) codes 27134, 27137, and 27138 were used to identify revision THA and CPT codes 27486 and 27487 were used to identify revision TKA. Revision THA/TKA for infectious, traumatic, or oncologic indications were excluded. Participant data were grouped according to body mass index (BMI) categories: underweight/normal weight, <25 kg/m2; overweight, 25-29.9 kg/m2; class I obesity, 30.034.9 kg/m2; class II obesity, 35.0-39.9 kg/m2; morbid obesity ≥ 40 kg/m2. Prevalence of each BMI category was estimated from year 2020 to year 2029 through multinomial regression analyses., Results: 38,325 cases were included (16,153 revision THA and 22,172 revision TKA). From 2011 to 2029, prevalence of class I obesity (24% to 25%), class II obesity (11% to 15%), and morbid obesity (7% to 9%) increased amongst aseptic revision THA patients. Similarly, prevalence of class I obesity (28% to 30%), class II obesity (17% to 29%), and morbid obesity (16% to 18%) increased in aseptic revision TKA patients., Conclusion: Prevalence of class II obesity and morbid obesity demonstrated the largest increases in revision TKA and THA patients. By 2029, we estimate that approximately 49% of aseptic revision THA and 77% of aseptic revision TKA will have obesity and/or morbid obesity. Resources aimed at mitigating complications in this patient population are needed. Level of Evidence: III ., (Copyright © The Iowa Orthopaedic Journal 2023.)

Background: Prosthetic joint infections (PJIs), while rare, are a devasting complication of both total joint arthroplasty (TJA). With most patients undergoing surgical treatment for PJI, options vary between one-stage or two-stage (the gold standard) procedures. Debridement, antibiotics, and implant retention (DAIR) procedures are a common, less morbid alternative to two-stage revisions, but patients undergoing DAIR procedures more often experience reinfections. This is likely in part due to non-standardized irrigation and debridement (I&D) methods within these procedures. Furthermore, DAIR procedures are often desired due to their cost effectiveness and lesser operative times, but no investigations have occurred regarding operative-time-based outcomes. This study aimed to compare reinfection incidence with procedure time in DAIR procedures. In addition, this study aimed to introduce the novel Macbeth Protocol for the I&D portion of DAIR procedures and assess its efficacy., Methods: Records of unilateral DAIR procedures for primary TJA PJI performed by arthroplasty surgeons from 2015-2022 were retrospectively reviewed for patient demographics, select medical history, body mass index (BMI), joint, microbiology, and follow-up data. In addition, a single surgeon's DAIR procedures (for primary and revision TJA) were reviewed and use of The Macbeth Protocol was noted., Results: A total of 71 patients (mean age 64.00 ± 12.81 years) who underwent unilateral DAIR were included. Patients with reinfections following their DAIR procedure had significantly (p = 0.034) lower procedure times (93.72 ± 15.01 min) compared to those without reinfections (105.87 ± 21.91 min). Twenty-two patients underwent 28 DAIR procedures by the senior author, where 11 (39.3%) DAIR procedures utilized The Macbeth Protocol. The use of this protocol did not significantly affect reinfection rate (p = 0.364)., Conclusion: This study concluded that increased operative time led to less reinfections for DAIR procedures treating unilateral primary TJA PJIs. Additionally, this study introduced The Macbeth Protocol, which demonstrated promising potential as an I&D technique despite not showing statistical significance. Arthroplasty surgeons should not sacrifice patient outcomes determined by reinfection rate for decreased operative time. Level of Evidence: III ., (Copyright © The Iowa Orthopaedic Journal 2023.)

One hundred twenty-nine protein kinases, selected to represent the diversity of the rice ( Oryza sativa ) kinome, were cloned and tested for expression in Escherichia coli . Forty of these rice kinases were purified and screened using differential scanning fluorimetry (DSF) against 627 diverse kinase inhibitors, with a range of structures and activities targeting diverse human kinases. Thirty-seven active compounds were then tested for their ability to modify primary root development in Arabidopsis. Of these, 14 compounds caused a significant reduction of primary root length compared with control plants. Two of these inhibitory compounds bind to the predicted orthologue of Arabidopsis PSKR1, one of two receptors for PSK, a small sulfated peptide that positively controls root development. The reduced root length phenotype could not be rescued by the exogenous addition of the PSK peptide, suggesting that chemical treatment may inhibit both PSKR1 and its closely related receptor PSKR2. Six of the compounds acting as root growth inhibitors in Arabidopsis conferred the same effect in rice. Compound RAF265 (CHIR-265), previously shown to bind the human kinase BRAF (B-Raf proto-oncogene, serine/threonine kinase), also binds to nine highly conserved rice kinases tested. The binding of human and rice kinases to the same compound suggests that human kinase inhibitor sets will be useful for dissecting the function of plant kinases., Competing Interests: The authors report no conflicts of interest., (© 2022 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

LIM domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics and subsequently key cellular functions such as proliferation and migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading to increased actin polymerization. As a result, LIMK inhibitors are emerging as a promising treatment strategy for certain cancers and neurological disorders. High-quality chemical probes are required if the role of these kinases in health and disease is to be understood. To that end, we report the results of a comparative assessment of 17 reported LIMK1/2 inhibitors in a variety of in vitro enzymatic and cellular assays. Our evaluation has identified three compounds (TH-257, LIJTF500025, and LIMKi3) as potent and selective inhibitors suitable for use as in vitro and in vivo pharmacological tools for the study of LIMK function in cell biology.

Background: Bioimpedance analysis (BIA) is a readily available tool to assess body composition in a clinical setting. BIA has received little attention in orthopaedics and namely joint arthroplasty. This study aims to quantify changes in body composition in the immediate peri-operative period following total joint arthroplasty., Methods: Adults scheduled for elective total joint arthroplasty were recruited to participate. Patients underwent BIA scans in the immediate peri-operative period: pre-operative on their day of surgery, post-operative day 0, and post-operative day 1., Results: 67 patients were enrolled to undergo BIA scans. Mean age was 62.64 ± 10.28 years old, and 49.2% were females. The all-supine cohort exhibited a 0.36 ± 0.61 kg increase in dry lean mass ( p < 0.001) and 1.30 ± 2.14 kg increase in lean body mass on postoperative day 0 ( p < 0.001). Patients received to 1.16 ± 0.58 kg of fluid mass, on average., Conclusion: BIA is a rapid, portable tool that allows for body composition analysis of an inpatient surgical population. This study demonstrated that BIA can detect net fluid changes and may approximate implant mass following total joint arthroplasty. This may aid surgeons in interpreting post-operative body composition changes., Competing Interests: Conflict of interest MCM and ASO do not have any conflicts of interest to disclose. JME receives research support from DePuy Synthes (Raynham, MA, U.S) and is an editor for Journal of Arthroplasty. These disclosures are not relevant to this study., (© 2022 Michael C. Marinier, Ayobami S. Ogunsola, Jacob M. Elkins, published by Sciendo.)

Background: The use of claims databases for research after total hip and knee arthroplasty (THA, TKA) has increased exponentially. These studies rely on accurate coding, and inadvertent inclusion of patients with nonroutine indications may influence results. The purpose of this study was to evaluate the complexity of THA and TKA captured by CPT code and determine if complication rates vary based on the indication., Methods: The NSQIP database was queried using CPT codes 21730 and 27447 to identify patients undergoing THA and TKA from 2018 to 2019. The surgical indication was classified based on the ICD-10 diagnosis code as routine primary, complex primary, inflammatory, fracture, oncologic, revision, infection, or indeterminant. Patient factors and 30-day complications, readmission, reoperation, and wound complications were compared., Results: A total of 86,009 THA patients had 703 ICD-10 diagnosis codes and 91.4% were routine primary indications. Complication rates were: routine primary 7.4%, complex primary 11.3%, inflammatory 12.5%, fracture 23.9%, oncologic 32.4%, revision 26.9%, infection 38.7%, and indeterminant 10.3% (P < .0001). 137,500 TKA patients had 552 ICD-10 diagnosis codes and 96.1% were routine primary cases. Complication rates were: routine primary 5.9%, complex primary 8.0%, inflammatory 7.2%, fracture 38.9%, oncologic 32.7%, revision 13.3%, infection 37.7%, and indeterminant 9.6% (P < .0001). Routine primary arthroplasty had significantly lower rates of reoperation, readmission, and wound complications., Conclusion: Using CPT code alone captures 10% of THA and 4% of TKA patients with procedures for nonroutine primary indications. It is essential to recognize identification of patients simply by CPT code has the potential to inadvertently introduce bias, and surgeons should critically assess methods used to define the study populations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Obesity is a well-established risk factor for complications following primary total knee arthroplasty (TKA). The purpose of this study is to utilize 3 national databases to develop projections of obesity within the general population and primary TKA patients in the United States through 2029., Methods: Data from the National Surgical Quality Improvement Program (NSQIP), the Behavior Risk Factor Surveillance System (BRFSS), and the National Health and Nutrition Examination Survey were queried for years 1999-2019. Current Procedural Terminology code 27447 was used to identify primary TKA patients in NSQIP. Individuals were categorized according to body mass index (kg/m 2 ) by year: normal weight (≤24.9); overweight (25.0-29.9); obese (30.0-39.9); and morbidly obese (≥40). Multinomial logistic regression was used to project categorical body mass index data for years 2020-2029., Results: A total of 8,372,221 individuals were included (7,986,414 BRFSS, 385,807 NSQIP TKA). From 2011 to 2019, the prevalence of normal weight and overweight individuals declined in the general population (BRFSS) and in primary TKA. Prevalence of obese/morbidly obese individuals increased in the general population from 31% to 36% and in primary TKA from 60% to 64%. Projection models estimate that by 2029, 46% of the general population will be obese/morbidly obese and 69% of primary TKA will be obese/morbidly obese., Conclusion: By 2029, we estimate ≥69% of primary TKA to be obese/morbidly obese. Increased resources dedicated to care pathways and research focused on improving outcomes in obese arthroplasty patients will be necessary as this population continues to grow., Level of Evidence: Level III, Retrospective Cohort Study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Body mass index (BMI) is routinely used for preoperative risk stratification; however, it does not provide a detailed assessment of body composition and intentional weight loss alone may not decrease complications. Sarcopenia-a disorder involving low muscle mass, quality, or performance-has been associated with an increased risk for postoperative complications and is treatable through nutritional supplementation or resistance training. It, counterintuitively, may occur with obesity as "sarcopenic obesity"; however, the prevalence is not widely known. The purpose of this study was to assess the prevalence of sarcopenia and sarcopenic obesity., Material and Methods: Patients underwent body composition assessment using multifrequency bioimpedance testing (InBody 770, InBody USA, California). They were classified as sarcopenic based on the appendicular skeletal muscle index and obese by percent body fat. Body composition parameters were compared between obesity or sarcopenia groups and traditional BMI-based obesity definitions., Results: A total of 219 patients underwent body composition assessment. The mean age was 62.1 years, BMI was 34.3 kg/m 2 , and 53.8% were female. Fifty-seven (26.0%) patients were not obese or sarcopenic, 130 (59.4%) were obese not sarcopenic, 18 (8.2%) were sarcopenic nonobese, and 14 (6.4%) were sarcopenic obese. There was heterogeneity in body composition between groups. Sarcopenic patients were older than those without sarcopenia. Skeletal muscle mass, body fat mass, and appendicular skeletal muscle index increased with increasing BMI., Conclusion: Sarcopenia and sarcopenic obesity were found in nearly 15% of patients. Measures of muscle quantity increased with higher BMI may influence the prevalence of sarcopenia in the morbidly obese, and these patients may require specialized criteria accounting for increased body mass., (© 2022 The Authors.)

Background: Unabated increases in the prevalence of obesity among American adults have disproportionately affected women, Black persons, and Hispanic persons. The purpose of this study was to evaluate for disparity in rates of patient eligibility for primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) based on race and ethnicity and gender by applying commonly used body mass index (BMI) eligibility criteria to two large national databases., Methods: We retrospectively reviewed data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for the years 2015-2019 for primary THA and TKA and the National Health and Nutrition Examination Survey (NHANES) from 2011-2018. Designations of race and ethnicity were standardized between cohorts. BMI cutoffs of <50 kg/m 2 , <45 kg/m 2 , <40 kg/m 2 , and <35 kg/m 2 were then applied. Rates of eligibility for surgery were examined for each respective BMI cutoff and stratified by age, race and ethnicity, and gender., Results: 143,973 NSQIP THA patients, 242,518 NSQIP TKA patients, and 13,255 NHANES participants were analyzed. Female patients were more likely to be ineligible for surgery across all cohorts for all modeled BMI cutoffs (P < .001 for all). Black patients had relatively lower rates of eligibility across all cohorts for all modeled BMI cutoffs (P < .0001 for all). Hispanic patients had disproportionately lower rates of eligibility only at a BMI cutoff of <35 kg/m 2 ., Conclusion: Using BMI cutoffs alone to determine the eligibility for primary THA and TKA may disproportionally exclude women, Black persons, and Hispanic persons. These data raise concerns regarding further disparity and restriction of arthroplasty care to vulnerable populations that are already marginalized., Level of Evidence: Retrospective Cohort Study, Level III., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: While muscle atrophy is a function of normal aging, loss of muscle in the setting of hip and knee osteoarthritis (OA) has been observed using radiographic studies. There is limited data available regarding changes in extremity composition using bioimpedance (BIA). The purpose of this study was to assess the changes in extremity composition in patients with isolated, unilateral hip or knee OA using BIA., Methods: Patients presenting to our institution's adult reconstruction clinic from February 2020 to April 2021 were retrospectively reviewed to identify those with isolated, unilateral hip and knee OA. The InBody 770 Body Composition Analyzer (InBody USA, Cerritos, California) was used to perform a complete body composition assessment, per protocol. Lean extremity mass (LEM), fat mass (FM), intracellular water (ICW), extremity body water (EBW = ICW + extracellular water (ECW)) and phase angle (PA) were determined. Differences between the affected (OA) and unaffected (no OA) extremities were compared using t-tests., Results: 38 patients had isolated hip OA. The mean age was 60.8 (±11.7) years, mean BMI was 31.7 (±6.8) kg/m2, and 39.5% were female. LEM, FM, EBW, ICW, and PA were significantly decreased in the hip OA extremity (LEM: 20.0 vs. 20.4 kg, p=0.0008, FM: 8.8 vs. 8.9 kg, p=0.0049, EBW: 15.7 vs 16.0, p=0.0011, ICW: 9.5 vs. 9.7 L, p=0.0004, PA: 4.5 vs 4.9º, p<0.0001). There were 25 patients with isolated knee OA. Mean age was 62.8 (±11.3) years, mean BMI was 33.6 (±6.9) kg/m2, and 52.0% were female. FM and PA were significantly lower in the knee OA extremity (11.3 vs 11.4 kg, p=0.0291, 4.5 vs 4.9º, p<0.0001). There were no significant differences in LEM, EBW, and ICW between the knee OA extremity and the unaffected extremity., Conclusion: Patients with isolated, unilateral hip OA had decreased LEM, FM, EBW, and ICW in the affected extremity. Both unilateral hip and knee OA was associated with decreased PA, suggestive of greater underlying dysfunction in muscle or cellular performance. Further study is needed to better define when these abnormalities develop, how they progress over time, and the impact of targeted interventions in reversing these changes. Level of Evidence: III ., (Copyright © The Iowa Orthopaedic Journal 2022.)

Background: Residency is known to consist of rigorous training that has contributed to increased rates of resident burn out, depression, and suicide. There have been recent efforts to attempt to combat and solve the rising levels of mental health concerns amongst physicians and physicians in training. While studies have examined the adverse effects of medical training on mental health, few have examined the associated changes in physical health. This study aimed to identify and compare baseline body composition and hand grip strength of orthopaedic surgery residents. The second aim was to identify and compare changes that may occur over the course of the training program., Methods: First year orthopaedic surgery residents ("interns") were recruited to undergo body composition measurements via bioimpedance analysis (BIA) during their first, third, and twelfth month of post-graduate training. At each interval, three hand-grip-strength measurements per hand were captured. Additionally, orthopaedic surgery residents who had already completed their first year ("non-interns") were recruited to undergo baseline and 12-month BIA for comparison., Results: Six interns and six non-interns were recruited. The interns lost 2.88 ± 4.26 kg (-3.31% ± 4.75%) of their initial body mass with most of the loss being body fat mass (1.97 ± 2.62 kg) by three months. Interns recovered a fair amount of mass loss by 12 months with a net change of -0.78 ± 3.14 kg (-1.09% ± 3.90%). Non-interns experienced an overall net weight gain (1.20 ± 3.64 kg; 1.68% ± 5.55%) over the same period. Intern HGS changed by -1.92 ± 2.49 kg and 3.39 ± 2.34 kg at 3- (n=6) and 12-months (n=3), respectively., Conclusion: This study demonstrates that there is an appreciable decrease in overall body mass, lean tissue mass, and body fat throughout the orthopaedic resident's intern year. The results demonstrate an initial fall in each body metric and strength by 3-months followed by partial recovery by 12-months. This pattern contrasts the average gain of body mass in each measured metric by non-interns. This study is limited by population sizes and by incompleteness of HGS data. Level of Evidence: II ., (Copyright © The Iowa Orthopaedic Journal 2022.)

Background: Obesity is associated with higher rates of adverse outcomes following primary total hip arthroplasty (THA). The purpose of this study is to utilize 3 national databases to develop projections of obesity within the general population and primary THA patients in the United States through 2029., Methods: Data from the National Surgical Quality Improvement Program (NSQIP), the Behavior Risk Factor Surveillance System (BRFSS), and the National Health and Nutrition Examination Survey were queried for years 1999-2019. Current Procedural Terminology code 27130 was used to identify primary THA patients in NSQIP. Individuals were categorized according to body mass index (kg/m 2 ) by year: normal weight (≤24.9); overweight (25.0-29.9); obese (30.0-39.9); and morbidly obese (≥40). Multinomial logistic regression was used to project categorical body mass index data for years 2020-2029., Results: A total of 8,222,013 individuals were included (7,986,414 BRFSS, 235,599 NSQIP THA). From 2011 to 2019, the prevalence of normal weight and overweight individuals declined in the general population (BRFSS) and in primary THA. Prevalence of obese/morbidly obese individuals increased in the general population from 31% to 36% and in primary THA from 42% to 49%. Projection models estimate that by 2029, 46% of the general population will be obese/morbidly obese and 55% of primary THA will be obese/morbidly obese., Conclusion: By 2029, we estimate ≥55% of primary THA to be obese/morbidly obese. Increased resources dedicated to care pathways and research focused on improving outcomes in obese arthroplasty patients will be necessary as this population continues to grow., Level of Evidence: Level III, Retrospective Cohort Study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Demographic characteristics, risk factors, and clinical variables associated with gonorrhea and chlamydial infection in women being treated in emergency departments (EDs) in the United States are incompletely characterized. We used univariable and multivariable regression analyses on 17,411 encounters from women 18 years and older who presented to EDs in northeast Ohio and were tested for gonorrhea or chlamydial infection. There were 1,360 women (7.8%) who had Chlamydia trachomatis infection and 510 (2.9%) who had Neisseria gonorrhoeae infection. Those infected with C. trachomatis or N. gonorrhoeae were younger (23.8 vs. 29.2 years), unmarried (97.7% vs. 90.1%), Black (93.3% vs. 88.0%), infected with Trichomonas vaginalis (39.9% vs. 27.2%), diagnosed with urinary tract infection (15.7% vs. 10.6%), and treated for gonorrhea and chlamydial infection during the ED visit (31.6% vs. 17.4%) (all ps < .001). Women infected with C. trachomatis or N. gonorrhoeae had more urine white blood cells (WBCs) (23.9 vs. 16.4 cells per high-power field [HPF]) and leukocyte esterase (1.2+ vs. 0.8+) on urinalysis. They had more WBCs (18.5 vs. 12.4 cells/HPF) and odds of having T. vaginalis infection (12.8% vs. 8.2%) on vaginal wet preparation (all ps < .001). Women infected with C. trachomatis were more likely to be younger and not Black; they were less likely to be treated for gonorrhea and chlamydial infection in the ED and to have lower levels of urine WBCs, leukocyte esterase, and blood than those infected with N gonorrhoeae (all ps ≤ .05)., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The Protein Kinase N proteins (PKN1, PKN2 and PKN3) are Rho GTPase effectors. They are involved in several biological processes such as cytoskeleton organization, cell mobility, adhesion, and cell cycle. Recently PKNs have been reported as essential for survival in several tumor cell lines, including prostate and breast cancer. Here, we report the development of dihydropyrrolopyridinone-based inhibitors for PKN2 and its closest homologue, PKN1, and their associated structure-activity relationship (SAR). Our studies identified a range of molecules with high potency exemplified by compound 8 with K i  = 8 nM for PKN2 and 14x selectivity over PKN1. Membrane permeability and target engagement for PKN2 were assessed by a NanoBRET cellular assay. Importantly, good selectivity across the wider human kinome and other kinase family members was achieved. These compounds provide strong starting points for lead optimization to PKN1/2 development compounds., (Copyright © 2022. Published by Elsevier Ltd.)

Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.

Objective: History and physical examination findings can be unreliable for prediction of genitourinary tract infections and differentiation of urinary tract infections from sexually transmitted infections (STIs). The study objective was to develop a prediction tool to more accurately identify patients with STIs., Methods: A retrospective review of 64,490 emergency department (ED) encounters between April 18, 2014, and March 7, 2017, where patients age 18 years or older had urinalysis and urine culture or testing for gonorrhea, chlamydia, or trichomonas, was used to develop a prediction model for men and women with Neisseria gonorrhoeae or Chlamydia trachomatis, or both, and for women with Trichomonas vaginalis. The data set was randomly divided into two-thirds discovery and one-third validation. Groups were assigned through a random number generator. Backward step regression modeling was used to identify the best model for each outcome., Results: With use of age, race, marital status, and findings from vaginal wet preparation (white blood cells [WBCs], clue cells, and yeast) and urinalysis (squamous epithelial cells, protein, leukocyte esterase, and WBCs), the models had areas under the receiver operating characteristic curve of 0.80 for men with N gonorrhoeae or C trachomatis, or both; 0.75 for women with N gonorrhoeae or C trachomatis, or both; and 0.73 for women with T vaginalis., Conclusions: The model estimated likelihood of ED patients having STIs was reasonably accurate with a limited number of demographic and laboratory variables. In the absence of point-of-care STI testing, use of a prediction tool for STIs may improve antimicrobial stewardship., Competing Interests: Declaration of Competing Interest All authors report no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients often turn to the online resources to learn about orthopedic procedures. As the rate of joint arthroplasty is projected to increase, the corresponding interest in relevant online education material will increase as well. The American Medical Association (AMA) and National Institutes of Health (NIH) recommend that publicly available online health information be written at the 6th grade or lower reading level to be fully understood by the average adult in the United States. Additionally, educational resources should be written such that readers can process key information (understandability) or identify available actions to take (actionability). The purpose of this study was to quantify the readability, understandability, and actionability of online patient educational materials regarding total knee arthroplasty (TKA)., Methods: The most common Google™ search term utilized by the American public was determined to be "knee replacement". Subsequently two independent online searches (Google.com) were performed. From the top 50 search results, websites were included if directed at educating patients regarding TKA. Non-text websites (audiovisual), articles (news/research/industry), and unrelated resources were excluded. Readability was quantified using the following valid objective algorithms: Flesch-Kincaid Grade-Level (FKGL), Simple Measure of Gobbledygook (SMOG) grade, Coleman-Liau Index (CLI), and Gunning-Fog Index (GFI). PEMAT was utilized to assess understandability and actionability (0-100%; score ≥70% indicates acceptable scoring). The relationship between search rank with FKGL and PEMAT scores was quantified., Results: A total of 34 (68%) unique websites met inclusion criteria. The mean FKGL, SMOG, CLI, and GFI was 11.8±1.6, 11.1±1.2, 11.9±1.4, and 14.7±1.6, respectively. None of the websites scored within the acceptable NIH/AMA recommended reading levels. Mean understandability and actionability scores were 54.9±12.1 and 30.3±22.0. Only 5.9% (n=2) and 9.2% (n=1) of websites met the ≥70% threshold for understandability and actionability. Only 29.4% (n=10) sources used common language and only 26.9% (n=9) properly defined complicated medical terms. Based on website type, the mean understandability scores for academic institution, private practice, and health information publisher websites were 57.2±8.8%, 52.6±11.1%, and 54.3±15.3% (p=0.67). Readability (rho: -0.07; p=0.69), understandability (rho: -0.02; p=0.93), and actionability (rho: -0.22; p=0.23) scores were not associated with Google™ search rank., Conclusion: TKA materials scored poorly with respect to readability, understandability, and actionability. None of the resources scored within the recommended AMA/NIH reading levels. Only 5.9% scored adequately on understandability measures. Substantial efforts are needed to improve online resources to optimize patient comprehension and facilitate informed decision-making. Level of Evidence: III ., (Copyright © The Iowa Orthopaedic Journal 2022.)

Background: The use of vaginal white blood cell (WBC) counts to predict sexually transmitted infections (STIs) in the emergency department (ED) is incompletely characterized., Objectives: Our objective was to assess the relationship between vaginal wet preparation WBC counts and STIs and to determine whether WBC counts of at least 11 WBCs per high-power field (HPF) could be useful for identifying STIs in women in the ED., Methods: Female ED patients 18 years or older who were evaluated in a single health system between April 18, 2014, and March 7, 2017, and had a genital wet preparation WBC result were retrospectively examined using univariable and multivariable analysis., Results: Vaginal wet preparation WBC counts were examined for 17,180 patient encounters. Vaginal WBC counts of at least 11 WBCs/HPF were associated with increased odds of having gonorrhea, chlamydia, or trichomoniasis. When this threshold was used for the diagnosis of each STI, sensitivity ranged from 48.2% to 53.9%, and specificity ranged from 67.2% to 68.8%., Conclusion: Women with STIs are more likely to have higher vaginal WBC counts. However, higher vaginal wet preparation WBC counts in isolation have limited diagnostic utility for gonorrhea, chlamydia, and trichomoniasis. Incorporation of age, urine leukocyte esterase results, and vaginal WBC counts provided a better predictor of an STI than vaginal WBC counts alone., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported.

Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5- b ]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5- b ]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.

Introduction Epididymitis and orchitis are illnesses characterized by pain and inflammation of the epididymis and testicle. They represent the most common causes of acute scrotal pain in the outpatient setting. Epididymitis and orchitis have both infectious and noninfectious causes, with most cases being secondary to the invasive pathogens chlamydia, gonorrhea, and  Escherichia coli  ( E.coli) . The study's objective was to examine the epidemiology and clinical characteristics of men diagnosed with epididymitis or orchitis in a United States emergency department. Methods We examined a dataset of 75,000 emergency department (ED) patient encounters from a single health system in Northeast Ohio who underwent nucleic acid amplification testing (NAAT) for chlamydia, gonorrhea, or trichomonas, or who received a urinalysis and urine culture. All patients were ≥18 years of age, and all encounters took place between April 18, 2014, and March 7, 2017. The analysis only included men receiving an ED diagnosis of epididymitis, orchitis, or both. We evaluated laboratory and demographic data using univariable and multivariable analyses. Results There were 1.3% (256/19,308) of men in the dataset diagnosed with epididymitis, orchitis, or both. Only 50.1% (130/256) of men diagnosed with epididymitis, orchitis, or both were tested for gonorrhea and chlamydia during their clinical encounter, and among those 13.8% (18/130) were positive. Chlamydia (12.3% [16/130]) was more common than both gonorrhea (3.1% [4/129]) and trichomonas (8.8% [3/34]) among men <35 years of age diagnosed with epididymitis, orchitis, or both. Only 62.1% of men diagnosed with epididymitis, orchitis, or both received a urine culture, of which 20.1% grew bacteria at ≥10,000 CFU/ml.  E. coli  (N= 20) was the most common bacteria growing in urine culture followed by Streptococcus (N= 3), Klebsiella (N= 2), Pseudomonas (N= 2), and Serratia (N= 2). Men diagnosed with epididymitis, orchitis, or both who had a positive urine culture were more likely to be ≥35 years of age, married, had higher urine white blood cells (WBCs), more urine bacteria, higher urine leukocyte esterase, more likely to have urine nitrite, and were less likely to be empirically treated for gonorrhea and chlamydia ( P ≤.03 for all).   Conclusions In the ED, epididymitis, orchitis, or both are uncommonly diagnosed among patients undergoing genitourinary tract laboratory testing. Sexually transmitted infections (STIs) are common in men <35 years of age diagnosed with epididymitis, orchitis, or both, with chlamydia being most common. E. coli was the most common bacteria growing in urine culture., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bonner et al.)

Introduction: Bartholin gland cysts or abscesses account for many gynecologic visits in the emergency department (ED). Previous smaller studies have suggested a link between Bartholin cysts/abscesses and sexually transmitted infections (STIs), but few studies have involved the ED., Methods: We retrospectively identified patients aged 18 years or older seen in 1 ED between January 2012 and March 2017 who had urinalysis and urine culture and/or were tested for gonorrhea, chlamydia, or trichomonas by nucleic acid amplification testing. Univariate and multivariate analyses were used to evaluate associations between Bartholin cysts/abscess and demographics, laboratory findings, and ED diagnoses., Results: Data were collected for 75,000 ED patients; 64 patients had a diagnosis of Bartholin cyst or abscess, 40 of whom were also tested for Neisseria gonorrhoeae or Chlamydia trachomatis. Ten percent of patients with a Bartholin cyst/abscess were infected with N gonorrhoeae, compared with 3% of those without a Bartholin cyst/abscess (P = .008). The rates of C trachomatis and Trichomonas vaginalis infections were 13% and 26%, respectively, among patients with a Bartholin cyst/abscess, compared with 8% and 30%, respectively, among those without a Bartholin cyst/abscess (P > .05 for both). On regression analysis, only increased urobilinogen level (β, 0.31; odds ratio, 1.36; 95% CI, 1.11-1.66; P = .003) and infection with N gonorrhoeae (β, 1.69; odds ratio, 5.40; 95% CI, 1.43-20.35; P = .01) were associated with a Bartholin cyst/abscess., Conclusions: Clinicians in the ED should consider testing patients with a Bartholin cyst/abscess for gonorrhea., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Prostatitis is one of the most common urologic diseases in ambulatory patients. However, prostatitis data are limited from the emergency department (ED) setting., Methods: A data set was examined of patients age 18 years or older who received urinalysis and urine culture or were tested for gonorrhea, chlamydia, or trichomonas in the ED from a health care system in northeast Ohio., Results: Of 19,308 ED encounters of male patients, 77 encounters (0.4%) involved the diagnosis of prostatitis. Men with prostatitis were younger (52.4 vs 66.3 years), were less likely to be hospitalized (27.3% vs 43.1%), had shorter clinical encounters (1336.5 vs 3019.3 min), and were less likely to arrive by emergency medical services or police (6.5% vs 45.5%) than men diagnosed with urinary tract infection (UTI) without prostatitis (n = 2527) (P ≤ .007 for all). Of the men with urinalysis, those with prostatitis had less bacteria (0.9+ vs 1.8+), blood (0.9+ vs 1.5+), glucose (4.0% vs 13.0%), leukocyte esterase (0.9+ vs 2.3+), nitrite positive (8.0% vs 21.4%), protein (0.5+ vs 1.2+), squamous epithelial cells (0.6 vs 1.7 per high-power field [HPF]), red blood cells (18.3/HPF vs 29.5/HPF), and white blood cells (31.6/HPF vs 57.6/HPF) than men diagnosed with UTI and no prostatitis (P ≤ .005 for all). Escherichia coli was the most common bacterium growing in the urine (58.8%; n = 10) and the blood (100.0%; n = 2) of men with prostatitis; however 73.0% (n = 17) of urine cultures and 90.9% (n = 22) of blood cultures had no bacterial growth. Of 77 patient encounters with prostatitis, 16 (20.8%) underwent testing for Neisseria gonorrhoeae and Chlamydia trachomatis and 3 (3.9%) for Trichomonas vaginalis. Of those tested, only 1 person was infected, with C trachomatis., Conclusion: Prostatitis was uncommonly diagnosed in men undergoing urinalysis and urine culture or testing for sexually transmitted infections in the ED., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2., Competing Interests: Declaration of interests M.F., J.B., and T.H. are employees of Merck KGaA, Darmstadt, Germany. M.A. was an employee of Merck KGaA, Darmstadt, Germany at the time of experimental procedures and is now an employee of Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. Other authors have no conflict of interest to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Spinopelvic pathology has been identified as a potential risk factor for instability after total hip arthroplasty. Spinopelvic radiographic parameters used to diagnose spinopelvic disease may also impact optimal cup placement. The purpose of this study was to assess the arthroplasty surgeon accuracy in making spinopelvic measurements., Methods: Five fellowship-trained or in-training arthroplasty surgeons reviewed 44 lateral lumbar radiographs in two sessions. All evaluators were instructed how to perform measurements but had little experience in doing so. Traditional measurements included the pelvic tilt (PT), pelvic incidence (PI), and sacral slope (SS), and novel measurements included the acetabular ante-inclination (AI) and pelvic femoral angle. Surgeon measurements were compared with those made by experienced engineers. intraclass coefficients (ICCs) were calculated and interpreted., Results: The interobserver reliability for 4 of 5 of the spinopelvic parameters was good to excellent (ICC >0.75) with the highest reliability seen for PI measurement (ICC = 0.939). Only moderate interobserver reliability was observed for AI measurement (ICC = 0.559). Intraobserver reliability was the highest for the PI and SS, ranging from moderate to good (ICC, 0.718 to 0.896). The lowest intraobserver reliability was seen for the AI (ICC range, 0.026 to 0.545) and pelvic femoral angle (ICC range, 0.035 to 0.828). Surgeon measurements of PT and SS were compared with engineer measurements with extremely poor correlation observed (ICC <0 for all)., Conclusion: Surgeon intraobserver and interobserver reliability in making novel radiographic measurements was low compared with traditional radiographic measurements. Surgeon reliability in making traditional measurements of the PT and SS was very poor compared with experienced assessors using software-based measurements., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction Vaginal infections are common in the emergency department (ED) but the frequency of vaginal coinfections identified on wet preparation is unknown. Methods The study examined a data set of 75,000 ED patient encounters between April 18, 2014, and March 7, 2017, who had received testing for gonorrhea, chlamydia, or trichomonas or had received a urinalysis and urine culture during the ED encounter. From this data set we reviewed 16,484 patient encounters where a vaginal wet preparation was performed on women age 18 years and older. Findings from the vaginal wet preparation and ED discharge diagnoses were examined to evaluate the frequency of vaginal coinfections with vulvovaginal candidiasis, trichomoniasis, and bacterial vaginosis. Results Among the women who had wet preparations, 4,124 patient encounters (25.0%) had a diagnosis of bacterial vaginosis, 625 (3.8%) had a diagnosis of vulvovaginal candidiasis, and 1,802 (10.9%) were infected with Trichomonas vaginalis . Twenty encounters (0.1%) had a diagnosis of vulvovaginal candidiasis and trichomoniasis; 150 (0.9%), bacterial vaginosis and trichomoniasis; 136 (0.8%), vulvovaginal candidiasis and bacterial vaginosis; and 10 (0.1%), trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis. On vaginal wet preparation, the mean white blood cell count was 13.0 per high-power field. Clue cells were found in 6,988 wet preparations (42.4%); 1,065 wet preparations (6.5%) had yeast and 1,377 (8.4%) had T. vaginalis . T. vaginalis was identified in 2.5% (266/10,542) of urinalyses and 8.4% (406/4,821) of nucleic acid amplification tests. Conclusions Vaginal coinfections were uncommon among women receiving a vaginal wet preparation in the emergency department. The most common vaginal coinfection was bacterial vaginosis and trichomonas., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Elkins et al.)

Introduction Sexually transmitted infections are commonly tested for in the emergency department (ED), but diagnostic test results are often unavailable during the clinical encounter. Methods We retrospectively reviewed health records of 3,132 men ≥18 years that had an emergency department visit in northeast Ohio between April 18, 2014 and March 7, 2017. All subjects underwent testing for Neisseria gonorrhoeae and Chlamydia trachomatis. Independent t-tests and chi-square analyses were performed as well as multivariable regression analysis. Results On univariable analysis, men with N gonorrhoeae and/or C trachomatis, compared with uninfected men, were younger (25.9 vs 32.4 years), more likely to be of Black race (91.7% vs 85.6%), less likely to be married (3.7% vs 10.2%), less likely to arrive to the ED by ambulance or police (1.7% vs 4.1%), and more likely to be diagnosed with a urinary tract infection (8.3% vs 3.7%), to be treated for gonorrhea and chlamydia in the ED (84.6% vs 54.9%), and to have higher emergency severity index (ESI) scores (3.8 vs 3.6) (P ≤ .03 for all). On urinalysis, men infected with N gonorrhoeae and/or C trachomatis had significantly more white blood cells (55.1 vs 20.9); more mucus (1.3 vs 1.2); higher leukocyte esterase (1.5 vs .4); fewer squamous epithelial cells (.6 vs 1.4); higher urobilinogen (1.1 vs .8); higher bilirubin (.09 vs .05); and more protein (.4 vs .3) (P ≤ .04). Conclusions Demographic and urinalysis findings can be associated with an increased odds of men being infected with N gonorrhoeae and/or C trachomatis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Elkins et al.)