Increased flexibility of CA3 memory representations following environmental enrichment.

Environmental enrichment (EE) improves memory, particularly the ability to discriminate similar past experiences.1,2,3,4,5,6 The hippocampus supports this ability via pattern separation, the encoding of similar events using dissimilar memory representations.7 This is carried out in the dentate gyrus (DG) and CA3 subfields.8,9,10,11,12 Upregulation of adult neurogenesis in the DG improves memory through enhanced pattern separation.1,2,3,4,5,6,11,13,14,15,16 Adult-born granule cells (abGCs) in DG are suggested to contribute to pattern separation by driving inhibition in regions such as CA3,13,14,15,16,17,18 leading to sparser, nonoverlapping representations of similar events (although a role for abGCs in driving excitation in the hippocampus has also been reported16). Place cells in the hippocampus contribute to pattern separation by remapping to spatial and contextual alterations to the environment.19,20,21,22,23,24,25,26,27 How spatial responses in CA3 are affected by EE and input from increased numbers of abGCs in DG is, however, unknown. Here, we investigate the neural mechanisms facilitating improved memory following EE using associative recognition memory tasks that model the automatic and integrative nature of episodic memory. We find that EE-dependent improvements in difficult discriminations are related to increased neurogenesis and sparser memory representations across the hippocampus. Additionally, we report for the first time that EE changes how CA3 place cells discriminate similar contexts. CA3 place cells of enriched rats show greater spatial tuning, increased firing rates, and enhanced remapping to contextual changes. These findings point to more precise and flexible CA3 memory representations in enriched rats, which provides a putative mechanism for EE-dependent improvements in fine memory discrimination.

Two-Year Outcomes of Novel Dual-Mobility Implant in Primary Total Hip Arthroplasty.

Introduction: Dual-mobility (DM) implants for total hip arthroplasty (THA) have gained popularity due to their potential to reduce hip instability and dislocation events that may lead to revision surgery. These implants consist of a femoral head articulated within a polyethylene liner, which articulates within an outer acetabular shell, creating a dual-bearing surface. Our study aimed to report our observations on the survivorship of a novel DM implant for primary total hip arthroplasty at two years. Methods: We conducted a retrospective, multicenter study to assess the clinical outcomes of patients undergoing a THA with a novel DM implant (OR3O acetabular system™, Smith & Nephew, Inc., Memphis, TN) from January 2020 to September 2021. Patient demographics, surgical information, and survivorship data were collected from medical records for patients with a minimum of two years of follow-up. Primary outcomes included overall implant survivorship at two years as well as aseptic survivorship, revision rates of the DM acetabular shell, and average time to revision. Patient-reported outcomes were collected in the form of HOOS JR. Results: A total of 250 hips in 245 patients had a minimum two-year follow-up. Primary osteoarthritis (80%) was the most common indication for index THA. The average aseptic survivorship of the DM acetabular components at two years for the cohort was 98.4% and survivorship of the acetabular implants overall was 97.6%. There were a total of four (1.6%) aseptic revisions of the DM acetabular component. Reasons for aseptic acetabular revision included one case of instability, one intraprosthetic dislocation, one periprosthetic acetabular fracture, and one malpositioned acetabular cup resulting in impingement. The mean time of follow-up was 893.9 days. Eighty-seven patients had preoperative and two-year HOOS JR available. HOOS JR improved by an average of 38.5 points. Conclusion: This novel DM acetabular implant demonstrates excellent survivorship at two years follow-up with low rates of instability and intraprosthetic dislocation and no episodes of metal-on-metal corrosion. Use of the DM implant demonstrated clinically relevant improvements in patient-reported outcomes at two years.

Practice Changes Induced by a Traveling Fellowship.

The John N. Insall Knee Society Traveling Fellowship selects four international arthroplasty or sports fellowship-trained orthopaedic surgeons to spend 1 month traveling to various Knee Society members' joint replacement and knee surgery centers in North America. The fellowship aims to foster research and education and shares ideas among fellows and Knee Society members. The role of such traveling fellowships on surgeon preferences has yet to be investigated. A 59-question survey encompassing patient selection, preoperative planning, intraoperative techniques, and postoperative protocols was completed by the four 2018 Insall Traveling Fellows before and immediately after the completion of traveling fellowship to assess anticipated practice changes (e.g., initial excitement) related to their participation in a traveling fellowship. The same survey was completed 4 years after the completion of the traveling fellowship to assess the implementation of the anticipated practice changes. Survey questions were divided into two groups based on levels of evidence in the literature. Immediately after fellowship, there was a median of 6.5 (range: 3-12) anticipated changes in consensus topics and a median of 14.5 (range: 5-17) anticipated changes in controversial topics. There was no statistical difference in the excitement to change consensus or controversial topics (p = 0.921). Four years after completing a traveling fellowship, a median of 2.5 (range: 0-3) consensus topics and 4 (range: 2-6) controversial topics were implemented. There was no statistical difference in the implementation of consensus or controversial topics (p = 0.709). There was a statistically significant decline in the implementation of changes in consensus and controversial preferences compared with the initial level of excitement (p = 0.038 and 0.031, respectively). After the John N. Insall Knee Society Traveling Fellowship, there is excitement for practice change in consensus and controversial topics related to total knee arthroplasty. However, few practice changes that had initial excitement were implemented after 4-year follow-up. Ultimately, the effects of time, practice inertia, and institutional friction overcome most of the anticipated changes induced by a traveling fellowship.

Incidence of Rapidly Progressive Osteoarthritis Following Intra-articular Hip Corticosteroid Injection: A Systematic Review and Meta-Analysis.

Background: The American Academy of Orthopedic Surgery recommends intra-articular corticosteroid injections (CSIs) for managing hip osteoarthritis (OA) based on short-term, prospective studies. Recent retrospective studies have raised concerns that CSIs may lead to rapidly progressive OA (RPOA). We sought to systematically review the literature of CSIs for hip OA to estimate the incidence of RPOA. Methods: MEDLINE, Embase, and Cochrane Library were searched to identify original research of hip OA patients receiving CSIs. Overall, 27 articles involving 5831 patients published from 1988 to 2022 were included. Study design, patient characteristics, CSI details, follow-up, and cases of RPOA were recorded. Studies were classified by their ability to detect RPOA based on follow-up. Random effects meta-analysis was used to calculate the incidence of RPOA for studies able to detect RPOA. Results: The meta-analytic estimate of RPOA incidence was 6% (95% confidence interval, 3%-9%) based on 10 articles classified as able to detect RPOA. RPOA definitions varied from progression of OA within 6 months to the presence of destructive changes. These studies were subject to bias from excluding patients with missing post-CSI radiographs. The remaining 17 articles were classified as unable to detect RPOA, including all of the studies cited in the American Academy of Orthopedic Surgery recommendation. Conclusions: The incidence of RPOA after CSIs remains unknown due to variation in definitions and follow-up. While RPOA following CSIs may be 6%, many cases are not severe, and this may reflect selection bias. Further research is needed to understand whether clinically significant RPOA is incident enough to limit CSI use.

The Use of Calcium Sulfate/Hydroxyapatite Bone Graft Substitute to Restore Acetabular Bone Loss in Revision Total Hip Arthroplasty.

Acetabular bone loss is not uncommon when performing revision total hip arthroplasty. This can create a challenge, especially on the acetabular side. In the present report, our patient presented with aseptic loosening of the acetabular component. The patient had a Paprosky IIIA acetabular defect that was reconstructed with stacked acetabular augments in addition to a highly porous acetabular cup. The remaining bone defects were addressed through the use of a calcium sulfate/hydroxyapatite bone graft substitute. We set out to describe how to reconstruct severe acetabular bone loss with a combination of acetabular augments in addition to an injectable bone graft substitute as a novel method to address a complex clinical scenario.

Nutritional Laboratory Studies Prior to Total Knee Arthroplasty: Practice Versus Publication.

BACKGROUND: Recent emphasis has been placed on nutritional status assessment prior to total knee arthroplasty (TKA), including multiple American Academy of Orthopaedic Surgeons publications recommending specific laboratory studies; however, the frequency with which surgeons obtain these laboratory studies remains unclear. We sought to assess the incidence of ordering nutritional laboratory studies in the 90 days prior to TKA, utilizing data from a large administrative claims database. METHODS: With use of the PearlDiver database, we identified 557,670 patients undergoing primary TKA from 2011 to 2020 with a metabolic panel or blood cell count claim within 90 days prior to TKA. We then determined the incidence of prealbumin, transferrin, vitamin D, and zinc laboratory tests claimed 90 days prior to TKA. Associations between claims and the year of surgery, patient demographics, and clinical characteristics were assessed by comparing proportions and chi-square testing. RESULTS: Nutritional laboratory studies were infrequently claimed within 90 days prior to TKA, with studies for prealbumin being performed in 2.2% of patients; transferrin, 1.9%; vitamin D, 10.2%; and zinc, 0.2%. From 2011 to 2020, there was a moderate but steady increase in the proportion of patients with claims for prealbumin (change from 0.8% in 2011 to 3.4% in 2020; p < 0.001), transferrin (0.8% to 2.7%; p < 0.001), and vitamin D (7.6% to 9.4%; p < 0.001) laboratory tests but there was less of a change for zinc (0.1% to 0.2%; p < 0.001). There were weak-to-absent associations of age, gender, obesity, diabetes, and anemia with laboratory claims. CONCLUSIONS: Despite multiple publications and recommendations, nutritional laboratory studies are infrequently ordered prior to TKA. Although there has been a slight increase in the use of nutritional laboratory studies over the past decade, patient factors such as gender and obesity were not associated with this increase. Understanding current practice patterns may help target future areas for improvement. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

The Practice Patterns of American Association of Hip and Knee Surgeons for the Management of Chronic Periprosthetic Joint Infection After Total Knee Arthroplasty.

BACKGROUND: The management of periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) has considerable variation. In order to better capture current preferences for the management of PJI, this study sought to poll the current members of American Association of Hip and Knee Surgeons (AAHKS) first to characterize the distribution of practice patterns. METHODS: There were 32 questions in an online survey distributed to members of AAHKS. The questions were multiple choice regarding the management of PJI for TKA. There were 844 out of 2,752 members who completed the survey (response rate of 31%). RESULTS: Most of the members were in private practice (50%) compared to 28% being in an academic setting. On average, members were performing between 6 to 20 PJI cases per year. Two-stage exchange arthroplasty was performed in over 75% of the cases with either a cruciate retaining (CR) or posterior stabilized (PS) primary femoral component used in over 50% of the cases and 62% using an all-polyethylene tibial implant. Most of the members were using vancomycin and tobramycin. Typically, 2 to 3 grams of antibiotics were added per bag of cement regardless of the cement type. When indicated, amphotericin was the most often-used antifungal. Post-operative management had major variability with range of motion, brace use, and weight-bearing restrictions. CONCLUSION: There was variability in the responses from the members of AAHKS, but there was a preference toward performing a two-stage exchange arthroplasty with an articulating spacer using a metal femoral component and an all-polyethylene liner.

A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.

Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not cause abnormal lipid accumulation, and share a chemical structure that is distinct from any known cholesterol lowering drug.

Penalty for Switching Implants? Assessing the Learning Curve With a Collarless, Tapered Wedge Cementless Femoral Component.

Background: Surgeon learning curve associated with a tapered wedge femoral implant as measured by early femoral component subsidence and 90-day risk of reoperation was evaluated. Methods: The first 451 patients undergoing primary, cementless total hip arthroplasty by a single, fellowship-trained arthroplasty surgeon with a tapered wedge stem design were retrospectively reviewed. Early radiographic femoral component subsidence during the first 6 weeks postoperatively and 90-day reoperations was recorded. Results: When stratified by approach, there was no association between date of surgery and femoral component subsidence in the posterior approach (P-value for linear trend over time = 0.44). In the direct anterior approach, there was a significant association between date of surgery and early femoral component subsidence (P-value for linear trend over time = 0.01). For both approaches, there was an increase in implanted stem size relative to templated stem size over time (P < .01 and P = .03, respectively). There was no association between the date of surgery and risk of 90-day reoperation (P = .45). Conclusions: In a single surgeon's initial use of a tapered cementless wedge stem, early femoral component subsidence was not impacted by the surgeon's learning curve when the posterior approach was utilized. Although subsidence was associated with date of surgery in the direct anterior cohort, this was not associated with increased risk of 90-day reoperation. Should a surgeon adopt a new tapered-wedge stem, these findings suggest that the stem is forgiving both in relation to subsidence and 90-day reoperation risk when appropriate surgical technique is utilized.

CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth.

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.

Additional Distal Femoral Resection Minimally Improves Terminal Knee Extension: A Systematic Review and Meta-Regression Challenging the Dogma.

Background: Additional distal femoral resection is a common technique to address a flexion contracture during primary total knee arthroplasty (TKA) but can lead to midflexion instability and patella baja. Prior reports regarding the magnitude of knee extension obtained with additional femoral resection have varied. This study sought to systematically review research describing the effect of femoral resection on knee extension and to perform meta-regression to estimate this relationship. Methods: A systematic review was conducted using MEDLINE, PubMed, and Cochrane databases by combining the terms ("flexion contracture" OR "flexion deformity") AND ("knee arthroplasty" OR "knee replacement") to identify 481 abstracts. In total, 7 articles reporting change in knee extension after additional femoral resection or augmentation across 184 knees were included. The mean value for knee extension, its standard deviation, and the number of knees tested were recorded for each level. Meta-regression was performed using weighted mixed-effects linear regression. Results: Meta-regression estimated that each 1mm resected from the joint line produced a 2.5° gain of extension (95% confidence interval, 1.7 to 3.2). Sensitivity analyses excluding outlying observations estimated each 1mm resected from the joint line produced a 2.0° gain of extension (95% confidence interval, 1.9 to 2.2). Conclusions: Each millimeter of additional femoral resection is likely to produce only a 2° improvement in knee extension. Thus, an additional resection of 2 mm is likely to improve knee extension by less than 5°. Alternative techniques, including posterior capsular release and posterior osteophyte resection, should be considered in correcting a flexion contracture during TKA.

Hemoglobinopathy is Associated With Total Hip Arthroplasty Indication Even Beyond Sickle Cell Anemia.

Background: The extent to which hemoglobinopathies other than sickle anemia (HbSS) are associated with hip osteonecrosis is unknown. Sickle cell trait (HbS), hemoglobin SC (HbSC), and sickle/ß-thalassemia (HbSßTh) may also predispose to osteonecrosis of the femoral head (ONFH). We sought to compare the distributions of indications for a total hip arthroplasty (THA) in patients with and without specific hemoglobinopathies. Methods: PearlDiver, an administrative claims database, was used to identify 384,401 patients aged 18 years or older undergoing a THA not for fracture from 2010 to 2020, with patients grouped by diagnosis code (HbSS N = 210, HbSC N = 196, HbSßTh N = 129, HbS N = 356). ß-Thalassemia minor (N = 142) acted as a negative control, and patients without hemoglobinopathy as a comparison group (N = 383,368). The proportion of patients with ONFH was compared to patients without it by hemoglobinopathy groups using chi-squared tests before and after matching on age, sex, Elixhauser Comorbidity Index, and tobacco use. Results: The proportion of patients with ONFH as the indication for THA was higher among those with HbSS (59%, P < .001), HbSC (80%, P < .001), HbSßTh (77%, P < .001), and HbS (19%, P < .001) but not with ß-thalassemia minor (9%, P = .6) than the proportion of patients without hemoglobinopathy (8%). After matching, the proportion of patients with ONFH remained higher among those with HbSS (59% vs 21%, P < .001), HbSC (80% vs 34%, P < .001), HbSßTh (77% vs 26%, P < .001), and HbS (19% vs 12%, P < .001). Conclusions: Hemoglobinopathies beyond sickle cell anemia were strongly associated with having osteonecrosis as the indication for THA. Further research is needed to confirm whether this modifies THA outcomes.

Association of Osteoarthritis and Functional Limitations With Cognitive Impairment Among Older Adults in the United States.

Objective: Given overlapping pathophysiology, this study sought to assess the association between osteoarthritis (OA), functional impairment, and cognitive impairment in the aging population. Methods: The National Health and Nutrition Examination Survey was used to identify participants >60 years of age. We analyzed multivariable associations of grouped participants that underwent cognitive function testing using linear and logistic regression, adjusting for sex, age, race, and ethnicity. Results: Of 2776 identified participants representing a population of 50,242,917, 40% did not report OA or functional limitations; 21% had OA but not functional limitations; 15% did not have OA but had functional limitations; 17% had OA and related functional limitations; and 7% had OA and non-arthritic functional limitations. OA was not independently associated with cognitive impairment. Contrarily, functional limitations were associated with cognitive impairment regardless of OA diagnosis. Discussion: Cognitive impairment is not associated with OA, but rather functional limitations, potentially guiding future intervention.

Leptin-based hexamers facilitate memory and prevent amyloid-driven AMPA receptor internalisation and neuronal degeneration.

Key pathological features of Alzheimer's disease (AD) include build-up of amyloid ß (Aß), which promotes synaptic abnormalities and ultimately leads to neuronal cell death. Metabolic dysfunction is known to influence the risk of developing AD. Impairments in the leptin system have been detected in AD patients, which has fuelled interest in targeting this system to treat AD. Increasing evidence supports pro-cognitive and neuroprotective actions of leptin and these beneficial effects of leptin are mirrored by a bioactive leptin fragment (leptin116-130 ). Here we extend these studies to examine the potential cognitive enhancing and neuroprotective actions of 8 six-amino acid peptides (hexamers) derived from leptin116-130 . In this study, we show that four of the hexamers (leptin116-121, 117-122, 118-123 and 120-125 ) replicate the ability of leptin to promote α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and facilitate hippocampal synaptic plasticity. Moreover, the pro-cognitive effects of the hexamers were verified in behavioural studies, with the administration of leptin117-122 enhancing performance in episodic memory tasks. The bioactive hexamers replicated the neuroprotective actions of leptin by preventing the acute hippocampal synapto-toxic effects of Aß, and the chronic effects of Aß on neuronal cell viability, Aß seeding and tau phosphorylation. These findings provide further evidence to support leptin and leptin-derived peptides as potential therapeutics for AD.

GATA6 is a crucial factor for Myocd expression in the visceral smooth muscle cell differentiation program of the murine ureter.

Smooth muscle cells (SMCs) are a crucial component of the mesenchymal wall of the ureter, as they account for the efficient removal of the urine from the renal pelvis to the bladder by means of their contractile activity. Here, we show that the zinc-finger transcription factor gene Gata6 is expressed in mesenchymal precursors of ureteric SMCs under the control of BMP4 signaling. Mice with a conditional loss of Gata6 in these precursors exhibit a delayed onset and reduced level of SMC differentiation and peristaltic activity, as well as dilatation of the ureter and renal pelvis (hydroureternephrosis) at birth and at postnatal stages. Molecular profiling revealed a delayed and reduced expression of the myogenic driver gene Myocd, but the activation of signaling pathways and transcription factors previously implicated in activation of the visceral SMC program in the ureter was unchanged. Additional gain-of-function experiments suggest that GATA6 cooperates with FOXF1 in Myocd activation and SMC differentiation, possibly as pioneer and lineage-determining factors, respectively.

Reduced-Order Neural Network Synthesis With Robustness Guarantees.

In the wake of the explosive growth in smartphones and cyber-physical systems, there has been an accelerating shift in how data are generated away from centralized data toward on-device-generated data. In response, machine learning algorithms are being adapted to run locally on board, potentially hardware-limited, devices to improve user privacy, reduce latency, and be more energy efficient. However, our understanding of how these device-orientated algorithms behave and should be trained is still fairly limited. To address this issue, a method to automatically synthesize reduced-order neural networks (having fewer neurons) approximating the input-output mapping of a larger one is introduced. The reduced-order neural network's weights and biases are generated from a convex semidefinite program that minimizes the worst case approximation error with respect to the larger network. Worst case bounds for this approximation error are obtained and the approach can be applied to a wide variety of neural networks architectures. What differentiates the proposed approach to existing methods for generating small neural networks, e.g., pruning, is the inclusion of the worst case approximation error directly within the training cost function, which should add robustness to out-of-sample data points. Numerical examples highlight the potential of the proposed approach. The overriding goal of this article is to generalize recent results in the robustness analysis of neural networks to a robust synthesis problem for their weights and biases.

Self-Reported Health of Severely Obese US Adults With Osteoarthritis.

BACKGROUND: Severe obesity is associated with complications following arthroplasty, leading surgeons to increasingly counsel patients regarding weight loss. For patients seeking arthroplasty, learning that severe obesity may be a relative contraindication to surgery can create a challenging clinical interaction. We sought to describe the self-reported health of United States (US) adults who had severe obesity and osteoarthritis (OA) to better understand patient perspectives. METHODS: The National Health and Nutrition Examination Survey, a nationally representative sample of the US population, was used to identify adult participants who had a body mass index (BMI) over 35 and an OA diagnosis. In total, 889 participants representing a US population of 9,604,722 were included. Self-reported health was dichotomized as poor to fair versus good to excellent. Analyses were weighted to produce national estimates. Associations between obesity severity and patient characteristics with self-reported health were assessed. RESULTS: Of US adults with a BMI over 35 and OA diagnosis, 64% rated their health as good or better. For adults who had a BMI over 45, 55% still reported their health as good or better. The strongest predictors of self-reported health were measures of physical functioning. Only 37% of participants who had much difficulty walking a quarter mile rated their health as good or better compared to 86% without difficulty (P < .001). CONCLUSION: Approximately two-thirds of patients who have severe obesity and OA do not perceive their health as compromised and consider decreased physical function as the primary driver of decreased health. This suggests that counseling about the association between obesity and overall health may improve shared decision making and that patient satisfaction metrics may be difficult to interpret in these clinical situations.

Chromatin remodeling is restricted by transient GATA6 binding during iPSC differentiation to definitive endoderm.

In addition to cooperatively driving transcriptional programs, emerging evidence supports transcription factors interacting with one another to modulate the outcome of binding events. As such, transcription factor interactions fine-tune the unique gene expression profiles required for developmental progression. Using human-induced pluripotent stem cells as a model of human endoderm lineage commitment, we reveal that GATA6 transiently co-localizes with EOMES at regions associated with non-endodermal lineages and is required for the repression of chromatin opening at these loci. Our results indicate that GATA6-dependent repression of chromatin remodeling, which is potentially mediated via the recruitment of NCOR1 to the EOMES interactome, contributes to definitive endoderm commitment. We anticipate that similar mechanisms are common during human development, furthering our understanding of the complex mechanisms that define cell fate decisions.