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Douglas DR Naudie,1,2 Silvio Ndoja,1 Thomas J Wood,3 Lyndsay E Somerville,1 James L Howard,1,2 Richard W McCalden,1,2 Steven J MacDonald,1,2 Brent A Lanting1,2 1Division of Orthopaedic Surgery, Department of Surgery, London Health Sciences, London, Ontario, Canada; 2Bone and Joint Institute, Western University, London, Ontario, Canada; 3Division of Orthopaedic Surgery, Department of Surgery, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, CanadaCorrespondence: Douglas DR NaudieDivision of Orthopaedic Surgery, Department of Surgery, Western University, Schulich School of Medicine, London Health Sciences Centre, University Campus, A9-028,339 Windermere Road, London, Ontario N6A 5A5, CanadaEmail Douglas.Naudie@lhsc.on.caIntroduction: Corrosion at the head–neck interface of modular components in total hip arthroplasty (THA) has been reported as a cause of failure of modern total hip replacement implants. While this method of failure has been well described, it remains poorly understood. The purpose of this study is to review the three most commonly used uncemented femoral stems at our institution over the last fifteen years and to correlate any established risk factors with rates of revision, particularly corrosion.Methods: We reviewed 2095 patients from March 2000 to September 2015 who underwent total hip arthroplasty with one of three uncemented femoral stem designs. All stems were made of a Ti6Al4V alloy with a 12/14 taper design. We included only those stems coupled with a CoCr head and a highly crosslinked polyethylene liner. We evaluated age, gender, body mass index (BMI), femoral head size, head length, neck angle and offset and correlated these to the incidence of all cause revision, as well as revision excluding infection.Results: There were no recognized corrosion-related revisions identified. There was no association between age, BMI, gender, head length, neck angle and offset to all cause revision or revision with infection excluded (p> 0.05). Femoral head size less than 32mm was associated with higher all cause revision rates (OR 4.60 (95% CI 1.8, 11.8)) and when excluding infection as a reason for revision (OR 4.94 (95% CI 1.7, 14.41)).Conclusion: Over the last fifteen years, we have not identified any cases of corrosion with the three most commonly used femoral stems used at out institution. While we acknowledge that no femoral stem is immune to corrosion, certain femoral stem designs may be uniquely resistant to this mode of failure.Level of Evidence: III.Keywords: corrosion, revision, total hip arthroplasty, femoral stems

Mohammad M Alzahrani,1 Thomas J Wood,2 Lyndsay E Somerville,3 Steven J MacDonald,3 James L Howard,3 Edward M Vasarhelyi,3 Brent A Lanting3 1Department of Orthopaedic Surgery, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 2Division of Orthopaedic Surgery, Department of Surgery, Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada; 3Division of Orthopaedic Surgery, Department of Surgery, London Health Sciences Centre University Campus, University of Western Ontario, London, Ontario N6A 5A5, CanadaCorrespondence: Mohammad M AlzahraniDepartment of Orthopaedic Surgery, College of Medicine, Imam Abdulrahman Bin Faisal University, 2835 King Faisal Road, Dammam 34212, Saudi ArabiaEmail mmalzahrani@iau.edu.saIntroduction: Outcomes and longevity of total knee arthroplasty (TKA) depend mainly on restoring knee function, through precise bony resection and appropriate soft tissue balancing. The current literature lacks evidence regarding the degree of radiographic change after intra-operative knee balancing. The purpose of our study was to assess the degree of change in coronal lower extremity alignment by comparing pre-operative to post-operative full-length radiographs (FLR) after quantifying the degree of intra-operative knee balancing and correlate patient-reported outcomes to the extent of balancing required.Patients and Methods: One hundred and fifty-four patients undergoing primary TKA for varus knee osteoarthritis were included in the study. The performed soft tissue releases and bony adjustments to obtain a balanced TKA intra-operatively were prospectively documented and were grouped into minimal, moderate and extensive release groups. Hip-knee-ankle angle (HKA), anatomical femoral-tibial angle (FTA), condylar hip angle (CH), medial proximal tibial angle (MPTA) and condylar plateau angle (CPA) were measured on full-length radiographs both pre-operatively and post-operatively. Frequencies of the soft tissue releases and bony resections in addition to descriptive statistics of the measured angles on the radiographs were recorded. In addition, patient-reported outcome scores (PROMs) were compared between the grouped patients.Results: Of those that were included in the study, 66 knees (42.9%) required minimal release to adequately balance the knee, while 70 (45.5%) required moderate release and 18 (11.7%) required extensive release. No statistically significant differences were found in change of alignment between the groups for all the measured angles. In addition, no difference in PROMs was seen between the groups both pre- and post-operatively.Conclusion: Although we found no association between post-operative coronal alignment of a TKA and the degree of soft tissue release and bony resection, this likely represents the fact that a balanced TKA is dynamic and not dependent on change of single radiographic parameters. Patient-reported outcomes were not impacted by the extent of releases.Keywords: knee arthroplasty, soft tissue, balancing, alignment, outcomes

Objective: To identify the presence and distribution of histopathological features of synovial inflammation and tissue damage, and to test their associations with ultrasound (US) imaging measures of synovitis and patient-reported measures of pain in knee osteoarthritis (OA)., Design: In the cross-sectional study of 122 patients undergoing surgery for painful late-stage (Kellgren-Lawrence Grade 3 or 4) knee OA, we compared US measures of synovitis (n = 118) and pain (Knee Injury and Osteoarthritis Outcome Score) to histopathological measures of inflammation vs. synovial tissue damage in synovial tissue biopsies. Associations of histopathological features with US measures of inflammation or pain were assessed using linear or logistic regression while controlling for covariates., Results: Histopathological features of inflammation were associated with higher odds of moderate/severe US synovitis (odds ratio [OR] = 1.34 [95%CI 1.04, 1.74), whereas features of synovial tissue damage were associated with lower odds of moderate/severe US synovitis (OR = 0.77 [95%CI 0.57, 1.03]). Worse histopathological scores for synovial tissue damage were associated with more pain (-1.47 [95%CI -2.88, -0.05]), even while adjusting for synovial inflammation (-1.61 [95%CI -3.12, -0.10])., Conclusions: Synovial tissue damage is associated with pain in late-stage knee OA, independent from inflammation and radiographic damage. These novel findings suggest that preventing synovial tissue damage may be an important goal of disease-modifying OA therapy., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: We quantified the effect of acute exposure to a high dosage of inorganic mercury on gene expression in Drosophila melanogaster using RNA-sequencing of whole adult females., Results: We found 119 genes with higher gene expression following treatment (including all 5 Drosophila metallothionine genes and a number of heat shock protein genes), and 31 with lower expression (several of which are involved in egg formation). Our results highlight biological processes and genetic pathways impacted by exposure to this toxic metal, and provide motivation for future studies to understand the genetic basis of response to mercury., (© 2024. The Author(s).)

Background: Modular titanium fluted tapered (TFT) stems have demonstrated excellent clinical success for femoral revision total hip arthroplasty (THA) surgery. This study reports the short-term outcomes of a novel modern monoblock TFT stem used for revision and complex primary THA with a minimum of 2 years of follow-up., Methods: We identified 126 patients who received a single monoblock TFT stem: 26 patients for complex THA (failed fracture fixation) and 100 patients for revision THA. The reasons for revision THA included 40 for previous periprosthetic joint infection, 42 for aseptic loosening, 9 for trunnionosis, and 9 for periprosthetic fractures. The Paprosky grading for femoral bone loss at the time of surgery and the measured subsidence of femoral stems at 3-month follow-up were determined. We evaluated the number and indications for reoperations., Results: The mean time from surgery was 3.9 years (range, 2.0 to 6.9). A paired t-test analysis showed significant improvement from preoperative versus postoperative clinical outcome scores (P < .001) for Harris Hip Score (38.76 ± 15.24 versus 83.42 ± 15.38), Western Ontario and McMaster Universities Arthritis Index (45.6 ± 19.0 versus 69.9 ± 21.3), Veterans RAND 12 Item Health Survey Physical component (31.7 ± 8.1 versus 37.8 ± 11.3), and Veterans RAND 12 Item Health Survey Mental component (48.2 ± 12.2 versus 51.6 ± 12.5). The Paprosky grading for femoral bone loss was Grade 1 (3.9%), Grade 2 (35.7%), Grade 3A (47.6%), Grade 3B (11.1%), and Grade 4 (1.6%) cases. There were 18 reoperations (14.7%), with 13 for periprosthetic joint infection (7 treated with implant retention and 6 treated with a 2-stage revision), 4 for instability, and 1 for acetabular aseptic loosening. There were no aseptic failures of the stem., Conclusions: This novel modern monoblock TFT stem provided reliable femoral fixation and has increasingly supplanted the use of modular TFT stems for complex primary and revision surgery in our institution., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The aim of the study was to analyze the Canadian Cardiovascular Society (CCS) guidelines for routine postoperative troponin testing after elective total hip arthroplasty (THA) to reduce the mortality rate resulting from myocardial injury. The purpose of this study was to assess the prognostic relevance of implementing these guidelines to minimize cardiac events in patients undergoing elective THA., Methods: Patients who underwent THA surgery in 2020 were included in the study. The inclusion criteria were elective THA patients aged ≥45 years, while emergency, revision, and simultaneous bilateral THA surgeries were excluded. The patients were categorized into 4 groups based on the CCS guidelines., Results: The study included 669 patients who had an average age of 67 years. There were 43 patients (6.4%), who experienced a rise in troponin levels ≥30 ng/L and developed myocardial injury after noncardiac surgery. Among these patients, 8 developed cardiac complications, and one experienced a serious cardiac event that resulted in death. Notably, there was a significant increase in the length of hospital stay for patients who received the postoperative screening protocol., Conclusions: The implementation of the CCS guidelines for routine postoperative troponin testing in elective THA surgery did not significantly decrease the rate of cardiac events or mortality., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Periprosthetic joint infection (PJI) continues to be one of the leading causes of failure following total hip arthroplasty (THA). The objectives of the study were to (1) determine the minimum 2-year infection-free survivorship of 2-stage revision THA, (2) determine the causative organisms for repeat 2-stage revision THA, and (3) characterize the results of failed 2-stage revisions and evaluate patient-reported outcome measures (PROMs)., Methods: A retrospective chart review was completed for patients who underwent 2-stage revision THA for PJI. Prospective data were collected on each patient, including demographics, causative organisms, complications, and type of reoperation. The PROMs, including Harris Hip Score, 12-item Short-Form Health Survey, and Western Ontario and McMaster Universities Osteoarthritis Index scores were obtained prior to 2-stage revision THA surgery and annually as part of standard clinical and radiographic follow-up., Results: A total of 328 patients who underwent a 2-stage revision THA for a PJI were included in the study (mean age 67 years [range, 28 to 90], mean body mass index of 30.6 [range, 15 to 57]). The overall infection-free survivorship for 2-stage revision THA was 73.8% at a minimum of 2 years (range, 2 to 20). Overall, 194 (59.1%) patients who had successful infection eradication underwent a 2-revision THA only. The most common single organisms infected were Staphylococcus aureus (12.5%) and Staphylococcus epidermidis (11%). Higher reoperation rates were found in cases with methicillin-resistant Staphylococcus aureus and polymicrobial infections. All PROMs showed statistical improvement from preoperatively to the latest follow-up appointment., Conclusions: Two-stage revision THA is associated with a good success rate in the treatment of PJIs at mid-term to long-term follow-up. Polymicrobial and methicillin-resistant Staphylococcus aureus infections are poor prognostic factors, making the eradication of infection more difficult. The management of PJIs continues to be one of the most important orthopaedic challenges to treat., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Routine patellar resurfacing during primary total knee arthroplasty (TKA) remains controversial. To our knowledge, there are no studies reporting the long-term performance of a cemented biconvex all-polyethylene inlay component implanted at the time of primary TKA. The purpose of this study was to examine the 15-year survivorship and long-term clinical outcomes of this biconvex inlay patella used at our institution., Methods: We retrospectively reviewed our prospectively collected institutional database and identified 2,530 patients who underwent cemented TKA with a single prosthetic design (from 1996 to 2007) where the patella was resurfaced using this cemented biconvex inlay patella. The mean age at surgery was 68 years (range, 29 to 93). The mean body mass index was 33.0 (range, 16.4 to 76.3), with 61.9% women. At the time of analysis, the mean time from surgery was 20.4 years (range, 15 to 26). We used Kaplan-Meier analysis to calculate survivorship at 15 years. We analyzed clinical outcomes using 3 patient-reported outcome measures collected prospectively., Results: The 15-year survivorship with revision surgery for all causes as the end point was 97.1% (95% confidence interval 96.1 to 98.1%). The 15-year survivorship with revision surgery for a patella-related complication as the end point was 99.7% (95% confidence interval 99.4 to 1.0). At the final follow-up, patients showed significant improvement in scores for the Knee Society Clinical Rating System (P < .001), Western Ontario and McMaster University Osteoarthritis Index (P < .001), and Veterans Rand 12-Item Health Survey physical component (P < .001)., Conclusions: Routine patellar resurfacing using a biconvex inlay patellar component has excellent survivorship and a low rate of complications at 15 years post-TKA., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The primary aim of this study was to evaluate secondary patellar resurfacing (SPR) indications and rates in a single-surgeon series utilizing a modern TKA design and additionally, to review the functional outcomes of patients after undergoing SPR., Methods: A retrospective review of a prospectively collected institutional database was performed. All patients undergoing primary TKA by a single surgeon between 2013 and 2021 were included. During this time, the senior surgeon resurfaced the patella selectively. Patients were divided into the primary resurfaced (PR) and the primary unresurfaced (UR). All patients undergoing SPR in the UR group were identified, their radiographs reviewed, and their clinical outcomes assessed. During the study period, 1,511 TKAs were performed, with 73.1% (1,105 TKAs) being unresurfaced., Results: The all-cause revision rate was 1.2% in the PR group and 3.6% in the UR group. The rate of SPR in the UR group was 2.0% (22 of 1,105 TKAs). No patient in the PR group underwent revision surgery for a patellar complication. The mean age at primary TKA for those undergoing SPR was 65 years (range, 50 to 78). The average time for SPR from primary TKA was 3.4 years (range, 1.1 to 8.8). Postoperative radiographic progression of patellar erosion, in combination with new onset anterior knee pain, was the indication for SPR in 14 of the 22 (63.7%) SPR cases. After SPR, the Western Ontario and McMaster University Osteoarthritis Index score (P < .001) and Knee Society Score (P < .001) improved from pre-SPR., Conclusions: Secondary patellar resurfacing (SPR) was the most common (55%) reason for revision surgery after primary UR TKA in this series. An SPR improved clinical outcomes in symptomatic patients. Surgeons should consider patellar resurfacing for all patients undergoing primary TKA to reduce the burden of revision surgery post-TKA. Additionally, the paradigm that late SPR does not improve clinical outcomes needs to be revisited., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Production of metal debris from implant wear and corrosion processes is now a well understood occurrence following hip arthroplasty. Evidence has shown that metal ions can enter the bloodstream and travel to distant organs including the brain, and in extreme cases, can induce sensorial and neurological diseases. Our objective was tosimultaneously analyze brain anatomy and physiology in patients with long-term and well-functioning implants. Included were subjects who had received total hip or hip resurfacing arthroplastywith an implantation time of a minimum of 7 years (n = 28) and age- and sex-matched controls (n = 32). Blood samples were obtained to measure ion concentrations of cobalt and chromium, and the Montreal Cognitive Assessment was performed. 3T MRI brain scans were completed with an MPRAGE sequence for ROI segmentation and multiecho gradient echo sequences to generate QSM and R2* maps. Mean QSM and R2* values were recorded for five deep brain and four middle and cortical brain structures on both hemispheres: pallidum, putamen, caudate, amygdala, hippocampus, anterior cingulate, inferior temporal, and cerebellum. No differences in QSM or R2* or cognition scores were found between both groups (p > 0.6654). No correlation was found between susceptibility and blood ion levels for cobalt or chromium in any region of the brain. No correlation was found between blood ion levels and cognition scores. Clinical significance: Results suggest that metal ions released by long-term and well-functioning implants do not affect brain integrity., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Corrosion at the head-neck junction of femoral stems is a rare complication of total hip arthroplasty (THA) with manifestations ranging from subclinical wear to failure. Prior studies have identified a single femoral component design with an increased propensity for catastrophic trunnion failure. The purpose of the present study was to quantify trunnion damage of this femoral component retrieved from patients undergoing revision THA for non-trunnionosis indications., Methods: 24 femoral components from a single manufacturer were identified for study inclusion. Each prosthesis underwent stereomicroscopic inspection. Corrosion and fretting scores were assigned per the Goldberg criteria to quadrants of the trunnion. Material loss was calculated based on cone angles across trunnion quadrants. This was carried out using a coordinate measuring machine that digitised each trunnion surface. Stems were compared to a series of femoral stems with the same trunnion design., Results: 20 of the 24 (83%) trunnions demonstrated corrosion, all 24 trunnions demonstrated fretting. Corrosion scores did not statistically differ with respect to trunnion zone ( p  = 0.53), while fretting scores were higher in the inferior compared to the superior zones ( p   <  0.001). There was no significant difference in cone angles assessing material loss between stems ( p  = 0.25)., Conclusions: Evidence of trunnion damage was observed in each stem retrieved for non-trunnionosis revision. Fretting occurred more frequently about the inferior quadrants. However, digitised trunnion shapes were similar between compared stems exhibiting no material loss. Therefore, it is possible that previous reports of trunnion failures for this implant are not a systemic issue, and that further investigation is required., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Copper is one of a handful of biologically necessary heavy metals that is also a common environmental pollutant. Under normal conditions, copper ions are required for many key physiological processes. However, in excess, copper results in cell and tissue damage ranging in severity from temporary injury to permanent neurological damage. Because of its biological relevance, and because many conserved copper-responsive genes respond to nonessential heavy metal pollutants, copper resistance in Drosophila melanogaster is a useful model system with which to investigate the genetic control of the heavy metal stress response. Because heavy metal toxicity has the potential to differently impact specific tissues, we genetically characterized the control of the gene expression response to copper stress in a tissue-specific manner in this study. We assessed the copper stress response in head and gut tissue of 96 inbred strains from the Drosophila Synthetic Population Resource using a combination of differential expression analysis and expression quantitative trait locus mapping. Differential expression analysis revealed clear patterns of tissue-specific expression. Tissue and treatment specific responses to copper stress were also detected using expression quantitative trait locus mapping. Expression quantitative trait locus associated with MtnA, Mdr49, Mdr50, and Sod3 exhibited both genotype-by-tissue and genotype-by-treatment effects on gene expression under copper stress, illuminating tissue- and treatment-specific patterns of gene expression control. Together, our data build a nuanced description of the roles and interactions between allelic and expression variation in copper-responsive genes, provide valuable insight into the genomic architecture of susceptibility to metal toxicity, and highlight candidate genes for future functional characterization., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: The objective of this study was to identify the rate and risk factors for revision total knee arthroplasty (TKA) within the first 5 years postoperative. Our secondary objective was to identify the rate of additional surgical procedures and death., Methods: We conducted a retrospective cohort study among patients in Ontario, Canada who underwent an elective, primary TKA between April 1, 2007, and March 31, 2014, for osteoarthritis. We excluded patients under 40 years and who had undergone a TKA within the previous 15 years. Our final study cohort included 94,193 patients. We reported the proportion of the study cohort who experienced revision surgery within 2 and 5 years of the primary TKA; secondary surgery within 5 years. We conducted Cochran-Armitage tests for trends to assess changes in the proportion of patients who experienced each of the study outcomes, and multivariable logistic regressions to evaluate predictors of a revision TKA., Results: There were 3,112 (3.3%) patients who had a revision within 5 years, and 1,866 (2.0%) within 2 years of their primary TKA. 3,316 (3.5%) had a secondary surgery (0.6% patellar resurfacing; 1.6% manipulation; 1.3% synovectomy; 0.5% washout; 0.9% debridement). Lower age, men, lower income, higher comorbidity score, depression, previous arthroscopy, lower surgeon volume, and general anesthesia were all significant positive predictors of revision., Conclusions: In our study cohort, 2.0% of patients had a revision TKA within 2 years, and 3.3% within 5 years of their primary TKA. Preoperative identification of risk factors may reduce the future prevalence of revision TKAs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Approximately 20% of patients are dissatisfied with their total knee arthroplasty (TKA). Identifying patients likely to be dissatisfied early in the recovery process could help reduce the number of dissatisfied patients. The purpose of this study was to create an easily administered short questionnaire to identify patients likely to be dissatisfied at 1 year post surgery early in the recovery process., Methods: The study included 275 patients who underwent primary TKA for osteoarthritis. Individual 3-month postsurgery questionnaire items from the Knee Injury and Osteoarthritis Outcome Score and Knee Society Knee Scoring System were pooled together and used as candidate items to create 3 different short questionnaires. Items included in each questionnaire were selected using least absolute shrinkage and selection operator logistic regressions, a backward elimination method, and theory-based approaches. The area under the curve for each short questionnaire was calculated to evaluate predictive performances., Results: All 3 questionnaires contained a small number of items and appeared to successfully predict 1-year postsurgery dissatisfaction early in the recovery process. The least absolute shrinkage and selection operator logistic regression, backward elimination, and theory-based questionnaires were comprised of 4, 7, and 5 items and had the area under the curve scores of 0.893, 0.902, and 0.890, respectively. A question evaluating rising from sitting and activities of daily living appeared in all of the created questionnaires., Conclusion: A short questionnaire that is easy to administer and interpret can effectively predict TKA patient dissatisfaction at 1 year post surgery early in the recovery process., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To support primary care physicians (PCPs) and their patients with knee osteoarthritis (OA), we created a series of evidence-based whiteboard educational videos for patients with knee OA. In a previous study we piloted these videos with patients to understand their acceptability and impact. The purpose of this study was to explore PCPs' perspectives to understand the utility of novel patient education videos to support management., Materials and Method: We conducted a qualitative descriptive study using semi-structured interviews of newly practicing and resident PCPs after watching a series of patient education videos. A thematic analysis approach was used combining both inductive and research question driven coding, category formation, and theme identification., Results: Ten participants were included. Barriers to optimal management were identified including the challenge of patient adherence and access to non-operative treatments. PCPs indicated that the videos would support their management of patients with knee OA by (1) supporting credibility and building trust with their patient, (2) reinforcing patient understanding, and (3) enhancing their own management of patients., Conclusion: Future implementation of these resources with attention to barriers that may limit uptake is necessary and may optimize management of knee OA in primary care.IMPLICATIONS FOR REHABILITATIONThe provision of patient educational materials may support patient buy-in regarding appropriate management, enhance patient understanding, and improve physicians' future practice.Viewing these videos could potentially improve physicians' future resource use, recommendation of non-operative treatments, and the quality of their total knee replacement referrals, which has benefits to both the patient and the healthcare system.Perceived barriers to implementing evidence-based recommendations may pose a challenge for patients and clinicians and should be considered to help facilitate the uptake of educational interventions.

We use ATAC-seq to examine chromatin accessibility for four different tissues in Drosophila melanogaster: adult female brain, ovaries, and both wing and eye-antennal imaginal discs from males. Each tissue is assayed in eight different inbred strain genetic backgrounds, seven associated with a reference quality genome assembly. We develop a method for the quantile normalization of ATAC-seq fragments and test for differences in coverage among genotypes, tissues, and their interaction at 44099 peaks throughout the euchromatic genome. For the strains with reference quality genome assemblies, we correct ATAC-seq profiles for read mis-mapping due to nearby polymorphic structural variants (SVs). Comparing coverage among genotypes without accounting for SVs results in a highly elevated rate (55%) of identifying false positive differences in chromatin state between genotypes. After SV correction, we identify 1050, 30383, and 4508 regions whose peak heights are polymorphic among genotypes, among tissues, or exhibit genotype-by-tissue interactions, respectively. Finally, we identify 3988 candidate causative variants that explain at least 80% of the variance in chromatin state at nearby ATAC-seq peaks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Huynh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Heavy metal pollutants can have long lasting negative impacts on ecosystem health and can shape the evolution of species. The persistent and ubiquitous nature of heavy metal pollution provides an opportunity to characterize the genetic mechanisms that contribute to metal resistance in natural populations. Methods: We examined variation in resistance to copper, a common heavy metal contaminant, using wild collections of the model organism Drosophila melanogaster . Flies were collected from multiple sites that varied in copper contamination risk. We characterized phenotypic variation in copper resistance within and among populations using bulked segregant analysis to identify regions of the genome that contribute to copper resistance. Results and Discussion: Copper resistance varied among wild populations with a clear correspondence between resistance level and historical exposure to copper. We identified 288 SNPs distributed across the genome associated with copper resistance. Many SNPs had population-specific effects, but some had consistent effects on copper resistance in all populations. Significant SNPs map to several novel candidate genes involved in refolding disrupted proteins, energy production, and mitochondrial function. We also identified one SNP with consistent effects on copper resistance in all populations near CG11825 , a gene involved in copper homeostasis and copper resistance. We compared the genetic signatures of copper resistance in the wild-derived populations to genetic control of copper resistance in the Drosophila Synthetic Population Resource (DSPR) and the Drosophila Genetic Reference Panel (DGRP), two copper-naïve laboratory populations. In addition to CG11825 , which was identified as a candidate gene in the wild-derived populations and previously in the DSPR, there was modest overlap of copper-associated SNPs between the wild-derived populations and laboratory populations. Thirty-one SNPs associated with copper resistance in wild-derived populations fell within regions of the genome that were associated with copper resistance in the DSPR in a prior study. Collectively, our results demonstrate that the genetic control of copper resistance is highly polygenic, and that several loci can be clearly linked to genes involved in heavy metal toxicity response. The mixture of parallel and population-specific SNPs points to a complex interplay between genetic background and the selection regime that modifies the effects of genetic variation on copper resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Everman, Macdonald and Kelly.)

The germline mobilization of transposable elements (TEs) by small RNA mediated silencing pathways is conserved across eukaryotes and critical for ensuring the integrity of gamete genomes. However, genomes are recurrently invaded by novel TEs through horizontal transfer. These invading TEs are not targeted by host small RNAs, and their unregulated activity can cause DNA damage in germline cells and ultimately lead to sterility. Here we use hybrid dysgenesis-a sterility syndrome of Drosophila caused by transposition of invading P-element DNA transposons-to uncover host genetic variants that modulate dysgenic sterility. Using a panel of highly recombinant inbred lines of Drosophila melanogaster, we identified two linked quantitative trait loci (QTL) that determine the severity of dysgenic sterility in young and old females, respectively. We show that ovaries of fertile genotypes exhibit increased expression of splicing factors that suppress the production of transposase encoding transcripts, which likely reduces the transposition rate and associated DNA damage. We also show that fertile alleles are associated with decreased sensitivity to double-stranded breaks and enhanced DNA repair, explaining their ability to withstand high germline transposition rates. Together, our work reveals a diversity of mechanisms whereby host genotype modulates the cost of an invading TE, and points to genetic variants that were likely beneficial during the P-element invasion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Lama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Drosophila melanogaster has proved an effective system with which to understand the evolutionary genetics and molecular mechanisms of insecticide resistance. Insecticide use has left signatures of selection in the fly genome, and both functional and quantitative genetic studies in the system have identified genes and variants associated with resistance. Here, we use D. melanogaster and leverage a bulk phenotyping and pooled sequencing "extreme quantitative trait loci" approach to genetically dissect variation in resistance to malathion, an organophosphate insecticide. We resolve 2 quantitative trait loci, one of which implicates allelic variation at the cytochrome P450 gene Cyp6g1, a strong candidate based on previous work. The second shows no overlap with hits from a previous genome-wide association study for malathion resistance, recapitulating other studies showing that different strategies for complex trait dissection in flies can yield apparently different architectures. Notably, we see no genetic signal at the Ace gene. Ace encodes the target of organophosphate insecticide inhibition, and genome-wide association studies have identified strong Ace-linked associations with resistance in flies. The absence of quantitative trait locus implicating Ace here is most likely because our mapping population does not segregate for several of the known functional polymorphisms impacting resistance at Ace, perhaps because our population is derived from flies collected prior to the widespread use of organophosphate insecticides. Our fundamental approach can be an efficient, powerful strategy to dissect genetic variation in resistance traits. Nonetheless, studies seeking to interrogate contemporary insecticide resistance variation may benefit from deriving mapping populations from more recently collected strains., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)

We examined the effect of developmental exposure to three heavy metals - cadmium, copper, and lead - on gene expression in adult head tissue in the model organism Drosophila melanogaster . All metals affected development time and/or gene expression level. While variation in the response to each metal was apparent, two differentially-expressed genes were upregulated in response to all three metal treatments, and 11 genes were downregulated in two of the three treatments. Our work reveals that developmental metal exposure has the potential to have long-lasting, metal-specific effects on gene expression in adults, even after the metal stress has been removed., (Copyright: © 2022 by the authors.)

Background: In March 2020, an emergency was declared in the province of Ontario owing to the COVID-19 pandemic. From March 19 to May 26, all elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures were deferred. The purpose of this study was to review the unit sales data of THA and TKA procedures in Ontario over this time period to identify any trends in surgical activity., Methods: Unit sales data for all THA and TKA procedures performed in Ontario between January 2019 and December 2020 were reviewed. All orthopedic companies contributed to the data set. Femoral stems were considered an indicator of THA procedures, while primary femurs were considered an indicator of TKA procedures. Data were analyzed to determine trends in THA and TKA procedures during the deferral period and the relative change in THA and TKA activity following resumption., Results: There was a 53% reduction in THA activity between March and May of 2020 when compared to the same interval in 2019. From June to September of 2019, THA sales activity was 87.3% that of TKA. From June to September of 2020, THA sales activity was 122.8% that of TKA., Conclusion: Provincial directives aimed at controlling the outbreak of COVID-19 contributed to a substantial reduction in THA and TKA activity in 2020. Compared to 2019, there was a disproportionate increase in THA compared to TKA activity in 2020 following resumption of surgical services. These data have implications in recovery planning for the surgical backlog of THA in Ontario., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: Bone loss remains an anticipated challenge in revision total knee arthroplasty (rTKA). Recent efforts to enhance rTKA fixation and stability have focused on metaphyseal implants, namely cones and sleeves. We sought to compare cone and sleeve implant survivorship in rTKA., Methods: One hundred eighty patients who underwent rTKA with metaphyseal implants from 2005 to 2018 were retrospectively reviewed. A total of 83 cones (22 femoral, 62 tibial) and 121 sleeves (58 femoral, 63 tibial) were identified. The mean age at the time of surgery was 72 years (range 43-97). Intraoperative Anderson Orthopaedic Research Institute bone loss classifications included the following: type 2A (25), type 2B (98), and type 3 (81). Mean follow-up was 41 months., Results: Revision-free survival for cones was 91.3% vs 92.2% for sleeves (P = .29). Twelve knees (4 cones, 8 sleeves) underwent irrigation, debridement, and polyethylene exchange with metaphyseal implant retention for acute postoperative periprosthetic joint infection (PJI). Development of chronic PJI warranted removal of 7 cones (8.4%), 6 of which were initially placed as part of a 2-stage revision TKA. Eight sleeves (6.6%) were removed for PJI, with all initially placed during a second stage reimplantation. In the absence of infection, survival was 100% and 99.1% for cones and sleeves, respectively. One sleeve was revised for periprosthetic fracture., Conclusion: Metaphyseal cones and sleeves offer equally durable survivorship in revision TKA. PJI was the most common mode of implant failure in this series. Importantly, no cases of cone or sleeve aseptic loosening were observed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To optimize non-operative management and decision making surrounding TKR we created educational whiteboard videos for patients with knee OA. The purpose of this study was to pilot our educational videos with end-users (patients) to determine patients' experiences and perspectives regarding the content and clarity of videos and to better understand their potential impact on patient's health behaviour., Materials and Methods: This was a mixed methods evaluation, using a qualitative descriptive approach, of patients attending their first consultation with an arthroplasty surgeon for TKR. We conducted in-depth semi-structured interviews with patients. Three members of the research team coded data independently, implementing a thematic analysis., Results: Thirteen participants were included. Participants indicated that the videos enhanced their confidence and clarity surrounding their decision to undergo TKR. The videos also addressed several knowledge gaps in their understanding of OA management. Barriers to uptake of the education were identified including limited access to PTs and the challenge of weight loss. Conclusions : The current educational intervention was valued by patients with knee OA. Implementation of these videos may have important implications for patients, providers, and our health care system.IMPLICATIONS FOR REHABILITATIONPatients with knee OA referred by primary care physicians to arthroplasty surgeons have knowledge gaps that may influence their self-management and decision making surrounding their condition.Educational materials can address these gaps and support patients in their understanding and management of their condition, which may have important downstream implications.Barriers to accessing non-operative care including physiotherapy must be pre-emptively addressed to ensure that enhanced knowledge is met with improved access for patients.

This study examined the association and level of agreement between criterion methods and the Apple Watch 4® and Fitbit Charge 3® for recording step count and heart rate when exercising in water on an aquatic treadmill (ATM). Sixteen healthy participants (13 females and 3 males) volunteered to take part in this study. Participants were submerged in an ATM pool to the level of their xiphoid process and completed 3-min exercise bouts at intensities that corresponded to a comfortable walk, brisk walk, jog, and running. A Polar® T31 chest strap recorded heart rate (HR) and a high-definition digital camera was utilized for recording step count (SC). Significant associations (p < 0.001) were observed between criterion methods and the Apple® (HR: R 2  = 0.99 and SC: R 2  = 0.87) and Fitbit® (HR: R 2  = 0.72 and SC: R 2  = 0.83) devices. The mean absolute error and relative error (%) for recording step count were 19.8 (7.4%) in the Apple Watch and 21.4 (8.5%) in the Fitbit and 0.90 (0.76%) in the Apple Watch and 4.2 (3.0%) in the Fitbit for recording heart rate. Both devices displayed a reasonable level of agreement for recording step count and heart rate when exercising in water. Linear regression analysis demonstrating the association between each wearable device and the Apple Watch and Fit Bit Charge for recording step count and heart rate., (© 2022. International Federation for Medical and Biological Engineering.)

Despite the value of recombinant inbred lines for the dissection of complex traits, large panels can be difficult to maintain, distribute, and phenotype. An attractive alternative to recombinant inbred lines for many traits leverages selecting phenotypically extreme individuals from a segregating population, and subjecting pools of selected and control individuals to sequencing. Under a bulked or extreme segregant analysis paradigm, genomic regions contributing to trait variation are revealed as frequency differences between pools. Here, we describe such an extreme quantitative trait locus, or extreme quantitative trait loci, mapping strategy that builds on an existing multiparental population, the Drosophila Synthetic Population Resource, and involves phenotyping and genotyping a population derived by mixing hundreds of Drosophila Synthetic Population Resource recombinant inbred lines. Simulations demonstrate that challenging, yet experimentally tractable extreme quantitative trait loci designs (≥4 replicates, ≥5,000 individuals/replicate, and selecting the 5-10% most extreme animals) yield at least the same power as traditional recombinant inbred line-based quantitative trait loci mapping and can localize variants with sub-centimorgan resolution. We empirically demonstrate the effectiveness of the approach using a 4-fold replicated extreme quantitative trait loci experiment that identifies 7 quantitative trait loci for caffeine resistance. Two mapped extreme quantitative trait loci factors replicate loci previously identified in recombinant inbred lines, 6/7 are associated with excellent candidate genes, and RNAi knock-downs support the involvement of 4 genes in the genetic control of trait variation. For many traits of interest to drosophilists, a bulked phenotyping/genotyping extreme quantitative trait loci design has considerable advantages., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Approximately 20% of total knee arthroplasty (TKA) patients are found to be dissatisfied or unsure of their satisfaction at 1-year post-surgery. This study attempted to predict 1-year post-surgery dissatisfied/unsure TKA patients with pre-surgery and surgical variables using logistic regression and machine learning methods., Methods: A retrospective analysis of patients who underwent primary TKA for osteoarthritis between 2012 and 2016 at a single institution was completed. Patients were split into satisfied and dissatisfied/unsure groups. Potential predictor variables included the following: demographic information, patella re-surfaced, posterior collateral ligament sacrificed, and subscales from the Knee Society Knee Scoring System, the Knee Society Clinical Rating System, the Western Ontario and McMaster Universities Osteoarthritis Index, and the 12-Item Short Form Health Survey version 2. Logistic regression and 6 different machine learning methods were used to create prediction models. Model performance was evaluated using discrimination (AUC [area under the receiver operating characteristic curve]) and calibration (Brier score, Cox intercept, and Cox slope) metrics., Results: There were 1432 eligible patients included in the analysis, 313 were considered to be dissatisfied/unsure. When evaluating discrimination, the logistic regression (AUC = 0.736) and extreme gradient boosted tree (AUC = 0.713) models performed best. When evaluating calibration, the logistic regression (Brier score = 0.141, Cox intercept = 0.241, and Cox slope = 1.31) and gradient boosted tree (Brier score = 0.149, Cox intercept = 0.054, and Cox slope = 1.158) models performed best., Conclusion: The models developed in this study do not perform well enough as discriminatory tools to be used in a clinical setting. Further work needs to be done to improve the performance of pre-surgery TKA dissatisfaction prediction models., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We sought to evaluate wear and kinematics in well-established implants of posterior stabilized (PS) and cruciate retaining (CR) designs. Ninety-one knees implanted for at least five years were examined. The implants were Genesis II PS (Smith & Nephew, Memphis, TN), Sigma PS (DePuy Synthes, Warsaw, IN), or Sigma CR. Radiostereometric analysis (RSA) images were acquired at multiple flexion angles and the 3D positions of the implant components were determined using model-based RSA software. The location of the center of the contact area between the femoral and polyethylene components was used to obtain contact kinematics, and the magnitude of the virtual intersection between the components indicated linear wear. All three groups had paradoxical anterior motion on both condyles, experienced similar net external rotation, and exhibited instances of internal rotation during flexion. The maximum observed wear rate was significantly greater for the Sigma PS than the Genesis II PS on the medial condyle (mean difference = 0.032 mm/year, p = 0.044), but not the lateral condyle, while there was no difference between the Sigma PS and Sigma CR for either condyle. Knees with lateral condylar separation had greater maximum wear rates on the medial condyle (mean difference = 0.033 mm/year, p = 0.001), while those with medial condylar separation had greater maximum wear rates on the lateral condyle (mean difference = 0.044 mm/year, p = 0.014). At long term follow-up in patients with well-functioning implants, there were differences in kinematics and wear resistance between implants. These results suggest that implant design affects long-term kinematics and wear in well-functioning implants and that condylar separation should be avoided to minimize wear., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The prevalence and outcomes of unexpected positive cultures (UPCs) of specimens taken during presumed aseptic revision total hip arthroplasty (THA) are unclear. The purpose of this study was to determine the prevalence of UPC and infection-free implant survival in this patient population. Secondary aims included identifying factors associated with subsequent infection-related failure in patients with UPC., Methods: We reviewed all THA revisions (n = 2,288) performed at our institution from 2006 to 2019. Presumed aseptic revision THAs with intraoperative culture(s) were eligible (n = 1,196), and those with UPC were included in a Kaplan-Meier analysis to determine the infection-free implant survival and in Cox regression analysis to identify factors associated with infection-related failure., Results: UPC(s) were documented for 9.2% (110) of 1,196 aseptic THA revisions. The 2- and 5-year infection-free implant survival in the entire UPC cohort was 93.1% (95% confidence interval [CI] = 90.5% to 95.7%) and 86.8% (95% CI = 82.9% to 90.7%), respectively. The 2- and 5-year infection-free survival with failure due to infection with the same microorganism as identified in the UPC as the end point was 95.8% (95% CI = 93.7% to 97.9%) and 94.3% (95% CI = 91.7% to 96.9%), respectively. Subsequent infection-related failures caused by the same microorganism as identified in the UPC were more likely to occur after revisions with ≥2 UPCs than after those with 1 UPC (p = 0.024). Revision due to adverse metal reaction was a risk factor for subsequent infection-related failure (hazard ratio [HR] = 14.49, 95% CI = 2.69 to 78.04). Patients with a single UPC who were not treated with antibiotics had no subsequent periprosthetic joint infections (PJIs) caused by the same microorganism as identified in the UPC., Conclusions: The prevalence of UPC was 9.2%, and the infection-free implant survival in patients with UPC is encouraging. Implant survival free of PJI caused by the same microorganism as identified in the UPC was excellent. Aseptic revision for adverse metal reaction was a risk factor for subsequent PJI in patients with UPC. No patient with a single UPC who was not treated with antibiotics developed PJI caused by the UPC-identified microorganism, suggesting that in the absence of other signs of infection a single UPC does not warrant antibiotic treatment., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The authors indicated that no external funding was received for any aspect of this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G484)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Planobispora rosea is the natural producer of the potent thiopeptide antibiotic GE2270A. Here, we present the results of a metabolomics and transcriptomics analysis of P. rosea during production of GE2270A. The data generated provides useful insights into the biology of this genetically intractable bacterium. We characterize the details of the shutdown of protein biosynthesis and the respiratory chain associated with the end of the exponential growth phase. We also provide the first description of the phosphate regulon in P. rosea . Based on the transcriptomics data, we show that both phosphate and iron are limiting P. rosea growth in our experimental conditions. Additionally, we identified and validated a new biosynthetic gene cluster associated with the production of the siderophores benarthin and dibenarthin in P. rosea . Together, the metabolomics and transcriptomics data are used to inform and refine the very first genome-scale metabolic model for P. rosea , which will be a valuable framework for the interpretation of future studies of the biology of this interesting but poorly characterized species. IMPORTANCE Planobispora rosea is a genetically intractable bacterium used for the production of GE2270A on an industrial scale. GE2270A is a potent thiopeptide antibiotic currently used as a precursor for the synthesis of two compounds under clinical studies for the treatment of Clostridium difficile infection and acne. Here, we present the very first systematic multi-omics investigation of this important bacterium, which provides a much-needed detailed picture of the dynamics of metabolism of P. rosea while producing GE2270A.

Background: Approximately 20% of patients are dissatisfied with their total knee arthroplasty (TKA) at 1-year post-surgery. Met expectations have been found by some to significantly predict satisfaction. The role of met expectations in determining patient satisfaction has not been exhaustively explored. The primary aim of this study is to evaluate if met expectations moderate the relationship between pain and function variables and satisfaction., Methods: Patients who underwent primary TKA for osteoarthritis were included in the study (n = 304). Patient-reported outcomes at pre-surgery and 1-year post-surgery were collected. The Knee Society Score (KSS) satisfaction subscale was used as the dependent variable. Candidate independent variables included the following: demographics, KSS, Knee injury and Osteoarthritis Outcome Score (KOOS), 12-Item Short Form Health Survey (SF-12), Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, Self-Administered Comorbidity Questionnaire, and University of California Los Angeles activity score. Separate linear regression models were created to test interactions for KSS met expectations with pain and KSS met expectations with function., Results: Significant predictors of satisfaction were KSS symptoms (pain), KOOS activities of daily living (function), KSS met expectations, KOOS pre-surgery activities of daily living, body mass index, and SF-12 general health. A significant interaction between met expectations and pain was found (P = .043) and the met expectations and function interaction approached significance (P = .086). For both interactions, as met expectations increased, pain and function predicted satisfaction less strongly., Conclusion: Met expectations were found to moderate the relationship between pain and satisfaction. There may be more value in improving pain for patients with low met expectations., Level of Evidence: Level IV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The American Association of Hip and Knee Surgeons (AAHKS) Annual Scientific Meeting is a leading forum for the presentation and dissemination of research regarding the management of hip and knee pathology making research presented at these meetings a representation of the current literature in the field. The purpose of this study was to quantify the level of evidence of podium presentations presented at the AAHKS annual meeting from 2015 to 2019., Methods: Two reviewers evaluated the abstracts for the available presentations. Basic science and biomechanical studies were excluded from the review. Economic studies that were not able to be evaluated based on the American Academy of Orthopedic Surgeon guidelines were also excluded. The two reviewers then independently evaluated each abstract and assigned a level of evidence (level I-V) based on the American Academy of Orthopedic Surgeon classification scheme., Results: A total of 258 podium presentations were included. In total, 17 (7%) abstracts were graded level I evidence, 57 (22%) were graded level II, 85 (33%) were graded level III, and 98 (38%) were graded level IV (Table 1). There was a significant change in the distribution of the level of evidence of podium presentations over time (χ 2  = 24.6, P = .02). The proportion of level I studies has increased between 2015 and 2019 (from 3.9% to 11.8%) with a concomitant decrease in level IV studies (from 42.3% to 21.6%) over that time period., Conclusions: There has been a significant improvement in the levels of evidence of podium presentations at the AAHKS Annual Meeting from 2015 to 2019., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The escalating socioeconomic burden of knee osteoarthritis (OA) underscores the need for innovative strategies to reduce wait times for total knee arthroplasty (TKA). The purpose of this study was to evaluate resource use, costs and health-related quality of life (HRQoL) across the continuum of care for patients with knee OA., Methods: This was a prospective study of 383 patients recruited from a high-volume teaching hospital at different stages of care (referral, consultation and presurgery). Outcomes included health care resource use; costs captured from the health care payer, private sector and societal perspectives; HRQoL measured using the Western Ontario and McMaster Universities Osteoarthritis Index, the 12-Item Short Form Health Survey, and EuroQoL 5-Dimension 5-Level tool; wait times; and the proportion of referrals deemed suitable candidates for surgery., Results: The most commonly used conservative treatments were pharmacotherapy, exercise and lifestyle modification. Forty percent of patients referred for TKA were deemed not to be suitable candidates for surgery. The greatest proportion of costs was borne by the patient or private insurer; a small proportion was borne by the public payer. Across all stages of care, more than 60% of the total costs was attributed to productivity losses. HRQoL remained relatively stable throughout the waiting period (mean wait time from referral to TKA 13.2 mo) but improved postoperatively., Conclusion: The suboptimal primary care management of knee OA calls for the development of innovative models of care. This study may provide valuable guidance on the design and implementation of a new online educational platform to improve referral efficiency and expedite wait times for TKA., Competing Interests: S. MacDonald reports receiving personal fees from DePuy Synthes and holding stock or stock options from Hip Innovations Technology, JointVue, CurvaFix, Parvizi Surgical Innovation, Smith & Nephew and Stryker, outside the submitted work. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

A range of heavy metals are required for normal cell function and homeostasis. However, the anthropogenic release of metal compounds into soil and water sources presents a pervasive health threat. Copper is one of many heavy metals that negatively impacts diverse organisms at a global scale. Using a combination of quantitative trait locus (QTL) mapping and RNA sequencing in the Drosophila Synthetic Population Resource, we demonstrate that resistance to the toxic effects of ingested copper in D. melanogaster is genetically complex and influenced by allelic and expression variation at multiple loci. QTL mapping identified several QTL that account for a substantial fraction of heritability. Additionally, we find that copper resistance is impacted by variation in behavioral avoidance of copper and may be subject to life-stage specific regulation. Gene expression analysis further demonstrated that resistant and sensitive strains are characterized by unique expression patterns. Several of the candidate genes identified via QTL mapping and RNAseq have known copper-specific functions (e.g., Ccs, Sod3, CG11825), and others are involved in the regulation of other heavy metals (e.g., Catsup, whd). We validated several of these candidate genes with RNAi suggesting they contribute to variation in adult copper resistance. Our study illuminates the interconnected roles that allelic and expression variation, organism life stage, and behavior play in copper resistance, allowing a deeper understanding of the diverse mechanisms through which metal pollution can negatively impact organisms., (© The Author(s) 2020. Published by Oxford University Press on behalf of Genetics Society of America.)

Evolution by natural selection occurs when the frequencies of genetic variants change because individuals differ in Darwinian fitness components such as survival or reproductive success. Differential fitness has been demonstrated in field studies of many organisms, but it remains unclear how well we can quantitatively predict allele frequency changes from fitness measurements. Here, we characterize natural selection on millions of Single Nucleotide Polymorphisms (SNPs) across the genome of the annual plant Mimulus guttatus. We use fitness estimates to calibrate population genetic models that effectively predict allele frequency changes into the next generation. Hundreds of SNPs experienced "male selection" in 2013 with one allele at each SNP elevated in frequency among successful male gametes relative to the entire population of adults. In the following generation, allele frequencies at these SNPs consistently shifted in the predicted direction. A second year of study revealed that SNPs had effects on both viability and reproductive success with pervasive trade-offs between fitness components. SNPs favored by male selection were, on average, detrimental to survival. These trade-offs (antagonistic pleiotropy and temporal fluctuations in fitness) may be essential to the long-term maintenance of alleles. Despite the challenges of measuring selection in the wild, the strong correlation between predicted and observed allele frequency changes suggests that population genetic models have a much greater role to play in forward-time prediction of evolutionary change., Competing Interests: The authors have declared that no competing interests exist.

Background: Total knee arthroplasty (TKA) is a common treatment for end-stage knee osteoarthritis but is associated with increased complication rates compared with unicompartmental knee arthroplasty (UKA). UKA offers better functional outcomes but is associated with a higher risk of revision. The purpose of this study was to apply good-practice, stated-preference methods to quantify patient preferences for benefit-risk tradeoffs associated with arthroplasty treatments for end-stage knee osteoarthritis., Methods: A discrete-choice experiment was developed with the following attributes: chance of complications, functional ability, awareness of the knee implant, and chance of needing another operation within 10 years. Patients included those aged 40 to 80 years with knee osteoarthritis. A pivot design filtered respondents into 1 of 2 surveys on the basis of self-reported functional ability (good compared with fair or poor) as measured by the Oxford Knee Score. Treatment-preference data were collected, and relative attribute-importance weights were estimated., Results: Two hundred and fifty-eight completed survey instruments from 92 males and 164 females were analyzed, with 72 respondents in the good-function cohort and 186 in the fair/poor-function cohort. Patients placed the greatest value or relative importance on serious complications and rates of revision in both cohorts. Preference weights did not vary between cohorts for any attribute. In the good-function cohort, 42% of respondents chose TKA and 58% chose UKA. In the fair/poor-function cohort, 54% chose TKA and 46% chose UKA., Conclusions: Patient preferences for various treatment attributes varied among patients in a knee osteoarthritis population. Complication and revision rates were the most important factors to patients, suggesting that physicians should focus on these areas when discussing treatments. The proportion of patients who chose UKA suggests that the current trend of increased UKA utilization is aligned with patient preferences., Clinical Relevance: Systematic elicitation of patient preferences for knee arthroplasty procedures, which lays out evidence-based risks and benefits of different treatments, indicates a larger subset of the knee osteoarthritis population may prefer UKA than would be suggested by the current rates of utilization of the procedure. Arthroplasty treatment should align with patient preferences and eligibility criteria to better deliver patient-centered care.

Imaginal disc morphogenesis during metamorphosis in Drosophila melanogaster provides an excellent model to uncover molecular mechanisms by which hormonal signals effect physical changes during development. The broad ( br ) Z2 isoform encodes a transcription factor required for disc morphogenesis in response to 20-hydroxyecdysone, yet how it accomplishes this remains largely unknown. Here, we use functional studies of amorphic br 5 mutants and a transcriptional target approach to identify processes driven by br and its regulatory targets in leg imaginal discs. br 5 mutants fail to properly remodel their basal extracellular matrix (ECM) between 4 and 7 hr after puparium formation. Additionally, br 5 mutant discs do not undergo the cell shape changes necessary for leg elongation and fail to elongate normally when exposed to the protease trypsin. RNA-sequencing of wild-type and br 5 mutant leg discs identified 717 genes differentially regulated by br , including a large number of genes involved in glycolysis, and genes that encode proteins that interact with the ECM. RNA interference-based functional studies reveal that several of these genes are required for adult leg formation, particularly those involved in remodeling the ECM. Additionally, br Z2 expression is abruptly shut down at the onset of metamorphosis, and expressing it beyond this time results in failure of leg development during the late prepupal and pupal stages. Taken together, our results suggest that br Z2 is required to drive ECM remodeling, change cell shape, and maintain metabolic activity through the midprepupal stage, but must be switched off to allow expression of pupation genes., (Copyright © 2020 by the Genetics Society of America.)

Provision of supplementary food for garden birds is practiced on a large scale in multiple countries. While this resource has benefits for wild bird populations, concern has been expressed regarding the potential for contamination of foodstuffs by mycotoxins, and the implications this might have for wildlife health. We investigated whether aflatoxin (AF) and ochratoxin A (OA) residues are present in foodstuffs sold for wild bird consumption at point of sale in Great Britain using high pressure liquid chromatography analyses. The hypothesis that production of these mycotoxins occurs in British climatic conditions, or under storage conditions after the point of sale, was tested under experimental conditions but was not proved by our study. While the majority of peanut samples were negative for AF residues, 10% (10/98) of samples at point of sale and 11% (13/119) of those across the storage and climate exposure treatment replicates contained AFB 1 that exceeded the maximum permitted limit of 20 μg/kg. No significant difference was found in the detection of either mycotoxin between branded and non-branded products. The clinical significance, if any, of exposure of wild birds to mycotoxins requires further investigation. Nevertheless, the precautionary principle should be adopted and best practice steps to reduce the likelihood of wild bird exposure to mycotoxins are recommended., 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 © 2020 Elsevier B.V. All rights reserved.)

Background: Lateral approaches to total knee arthroplasty (TKA) provide good surgical exposure and may provide greater ease of soft tissue balancing in patients with a valgus deformity; however, little is known about the versatility in non-valgus knees. The present study evaluated if a lateral subvastus approach can achieve adequate surgical exposure while maintaining less soft tissue damage compared with the medial parapatellar approach in knees without any significant deformity., Methods: Using paired fresh-frozen cadaveric knees, the present study provides the first specimen-matched, side-by-side comparison of the lateral subvastus approach to the standard medial parapatellar approach to TKA. Ten knees were selected to undergo a lateral subvastus approach; the contralateral knee had a medial parapatellar approach as control. Incision length, surgical exposure and iatrogenic soft tissue damage were compared between the two approaches., Results: The lateral subvastus approach was successfully performed using an incision length that was not different from that used in the medial parapatellar approach (p > 0.05). The resultant surgical exposure was comparable between approaches (p > 0.05). The risk of the approach included tearing of the vastus lateralis fibers, and/or abrasion of the iliotibial tract/patellar ligament., Conclusions: The lateral subvastus approach to TKA provided a comparable method to the standard medial parapatellar approach. Despite adequate exposure, the approach did risk soft tissue injury. Caution needs to be exercised to reduce the risk of iatrogenic injury to the vastus lateralis and surrounding ligaments. The successful implementation in this cadaveric study substantiates the need for further consideration of this approach in clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The rise in total hip arthroplasty (THA) has led to a concomitant increase in revision THAs. Tracking implant performance therefore remains a significant element of scientific inquiry to garner and maintain public trust in this procedure. There are few available reports of outcomes of a single manufacturer's total hip system outside registry data., Methods: We performed a retrospective review of a prospectively generated database to evaluate outcomes of a single manufacturer's femoral stem and acetabular shell for THA. We report the functional outcomes, revision data, and survivorship for this total hip system., Results: A total of 1942 primary THAs were implanted into 1672 patients. There were of 57 revisions. There were no cases of acetabular failure at 10-year follow-up. All functional outcome scores demonstrated significant improvements following THA. Kaplan-Meier survival analysis for all-cause revisions demonstrated 2-year implant survival of 97.6% (95% confidence interval [CI], 96.9-98.3), 5-year implant survival of 97.3% (95% CI, 96.5-98.1), and 10-year implant survival of 97.0% (95% CI, 96.0-98.0). When infection was excluded, implant survivorship improved to 99.2% (95% CI, 98.8-99.6) at 2 years, 98.9% (95% CI, 98.5-99.4) at 5 years, and 98.7% (95% CI, 98.1-99.4) at 10 years., Conclusion: This THA implant system comprising an uncemented press-fit acetabulum used alongside a triple-tapered femoral stem is an excellent option for THA. Implant survivorship at 2, 5, and 10 years is among the best reported for any total hip system in the world., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Rotating hinge knee prostheses (with or without distal femoral replacement) are indicated in cases of unreconstructible bony or soft tissue compromise. Despite their versatility, these implants have demonstrated high rates of mechanical failure. We aimed to review clinical outcomes of a novel hinged knee arthroplasty system., Methods: We reviewed all cases in a prospective database of hinged total knee arthroplasty (with and without distal femoral arthroplasty) involving a single manufacturer's implant system at a large tertiary-level academic health sciences center. We collected reasons for surgery, implant survivorship, reasons for revision, and clinical outcomes (Short Form 12, Western Ontario and McMaster Universities Osteoarthritis Index, and Knee Society Scores)., Results: Seventy-six cases of hinged knee implants using the knee system under investigation were performed (39 hinged total knee and 37 distal femoral replacements) between 2011 and 2018, inclusive. Indications for surgery varied, with second-stage reimplantation most common for rotating hinge and fracture most common for distal femoral arthroplasty. There were 6 revisions in the rotating hinge group (none for aseptic loosening) and 5 in the distal femoral arthroplasty group (1 for aseptic loosening). Average follow-up was 2.89 ± 2.09 years. Postoperative Short Form 12 (Physical Component), Western Ontario and McMaster Universities Osteoarthritis Index, and Knee Society Scores were 30.12 ± 10.17, 55.90 ± 21.51, and 115.62 ± 45.20, respectively., Conclusion: This novel hinged knee system is a highly durable option for complex and revision knee arthroplasty. Early failures tend to be secondary to infection. We observed only a single case of aseptic loosening. Although these early results are encouraging, ongoing follow-up is required to determine long-term prognosis in patients receiving this implant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Evidence of fungal contamination of cannabis plants during drying has raised concerns of potential mycotoxin contamination of leaves and flowers and subsequent contamination of derived edible cannabis products. Methods are, therefore, needed for routine monitoring of cannabis to ensure consumer safety consistent with long-standing controls for mycotoxins such as aflatoxins and ochratoxin A (OTA) in foodstuffs., Objective: To generate preliminary validation data to demonstrate fitness-for-purpose of methods for aflatoxins and OTA in cannabis and cannabis products., Methods: Extraction of solid matrices with acetonitrile-water (75 + 25) and direct analysis of energy drinks after dilution. Extracts were either passed manually though an immunoaffinity column (IAC) containing antibodies to both aflatoxins and OTA or were analyzed sequentially using an automated system with in-line reusable immunoaffinity cartridges for aflatoxins or OTA. In both cases, analysis was by LC with fluorescence detection., Results: Recoveries were in the range of 76-120% with relative SDs from 0.8 to 6.6% for aflatoxins and OTA spiked into cannabis dried leaves and flowers, hemp tea, oils, capsules, cookies, chocolate brownies, and an energy drink., Conclusions: The methods described in this paper are suitable for the cleanup of sample extracts of cannabis and cannabis products., Highlights: Manual and automated methods with IAC cleanup have been shown to be suitable for routine control of aflatoxins and OTA in cannabis and cannabis products., (Copyright ©2020 by AOAC International, Inc. All rights reserved.)

Objective: Segregating genetic variants contribute to the response to toxic, xenobiotic compounds, and identifying these causative sites can help describe the mechanisms underlying metabolism of toxic compounds. In previous work we implicated the detoxification gene Ugt86Dd in the genetic control of larval nicotine resistance in Drosophila melanogaster. Furthermore, we suggested that a naturally-occurring 22-bp deletion that leads to a stop codon in exon 2 of the gene markedly reduces resistance. Here we use homology directed CRISPR/Cas9 gene editing to specifically test this hypothesis., Results: We edited chromosome three from an inbred strain named A4 which carries the insertion allele at Ugt86Dd, successfully generated four alleles carrying the 22-bp Ugt86Dd deletion, and substituted edited chromosomes back into the A4 background. The original A4 strain, and an un-edited control strain in the same A4 background, show no significant difference in egg-to-adult or larva-to-adult viability on either control media or nicotine-supplemented media, and only slightly delayed development in nicotine media. However, strains carrying the 22-bp deletion showed reduced viability in nicotine conditions, and significantly longer development. Our data strongly suggest that the naturally-occurring 22-bp insertion/deletion event in Ugt86Dd directly impacts variation in nicotine resistance in D. melanogaster.

There is considerable variation in sleep duration, timing and quality in human populations, and sleep dysregulation has been implicated as a risk factor for a range of health problems. Human sleep traits are known to be regulated by genetic factors, but also by an array of environmental and social factors. These uncontrolled, non-genetic effects complicate powerful identification of the loci contributing to sleep directly in humans. The model system, Drosophila melanogaster , exhibits a behavior that shows the hallmarks of mammalian sleep, and here we use a multitiered approach, encompassing high-resolution QTL mapping, expression QTL data, and functional validation with RNAi to investigate the genetic basis of sleep under highly controlled environmental conditions. We measured a battery of sleep phenotypes in >750 genotypes derived from a multiparental mapping panel and identified several, modest-effect QTL contributing to natural variation for sleep. Merging sleep QTL data with a large head transcriptome eQTL mapping dataset from the same population allowed us to refine the list of plausible candidate causative sleep loci. This set includes genes with previously characterized effects on sleep and circadian rhythms, in addition to novel candidates. Finally, we employed adult, nervous system-specific RNAi on the Dopa decarboxylase , dyschronic , and timeless genes, finding significant effects on sleep phenotypes for all three. The genes we resolve are strong candidates to harbor causative, regulatory variation contributing to sleep.

Background: There is controversy regarding the superiority of posterior-stabilizing (PS) total knee arthroplasty (TKA) and cruciate-retaining (CR) TKA. Substantial work has made comparisons between PS and CR TKA at follow-ups of less than 5 years. It was the goal of the present study to compare the kinematics at greater than 5 years postoperatively between CR and PS TKA, with a secondary goal of comparing patient function., Methods: A total of 42 knees were investigated, with equal representation in the PS and CR TKA groups. Patients underwent radiostereometric analysis imaging at 0°, 20°, 40°, 60° 80°, and 100° of flexion. Contact position, magnitude of excursion, and condylar separation on each condyle were measured. A Timed-Up-and-Go functional test was also performed by patients, with the total test time being measured. Preoperative and postoperative clinical outcome scores were also collected., Results: There were differences in contact position on both the medial and lateral condyles at multiple angles of flexion (P < .05). There was no difference (P = .89) in medial excursion; however, PS TKA had greater lateral excursion than CR TKA (P < .01). No difference (P > .99) was found in frequency of condylar separation. PS TKA was associated with faster (P = .03) total Timed-Up-and-Go test times. There were no differences in clinical outcome scores between the groups preoperatively or postoperatively., Conclusion: We found kinematic and functional differences that favor PS TKA. Our results suggest posterior cruciate ligament insufficiency in CR TKA, indicating that perhaps the cam/post systems in PS TKA better maintain knee kinematics and function long term., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The aim of the present study is to assess the long-term clinical and radiological outcomes of a proximal porous-coated, dual-offset, tapered titanium alloy uncemented stem at a minimum of 15 years of follow-up., Methods: We reviewed 210 total hip arthroplasties (in 193 patients) performed between 1996 and 1999 and followed prospectively in our database who received the Synergy stem. We report a Kaplan-Meier survival analysis as well as the Harris Hip Score, the Western Ontario and McMaster University Arthritis Index, and the Short Form Health Survey-12 scores. Radiographs were evaluated for evidence of subsidence, osteolysis, osteointegration, or loosening., Results: The average follow-up was 16 years (range, 15-17.7 years). Kaplan-Meier survival analysis with revision of stem for aseptic mechanical loosening (1 stem) as the end point revealed a cumulative survival rate of 99.5% at 16 years. The Harris Hip Score, the Western Ontario and McMaster University Arthritis Index, and the Short Form Health Survey-12 physical scores were all significantly improved (P < .001) from the preoperative period to latest follow-up. Minor osteolysis was observed proximally in 14 hips (6.6%) with no osteolysis distal to the porous coating., Conclusion: To our knowledge, this study represents the largest series reporting the longest clinical follow-up of this third-generation, dual-offset, proximal ingrowth, tapered cementless stem. The Synergy stem design has achieved excellent clinical outcomes, predictable osteointegration, and outstanding survivorship of 99.5% at a minimum of 15 years follow-up, representing the standard for femoral stems at our institution., (Copyright © 2019 Elsevier Inc. All rights reserved.)