A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Cushioned Footwear Effect on Pain and Gait Characteristics of Individuals with Knee Osteoarthritis: A Double-Blinded 3 Month Intervention Study.

One of the recommendations for individuals with knee osteoarthritis (OA) is the use of specific footwear, such as sturdy or cushioned shoes. However, the long-term use effects of using cushioned shoes on the pain and spatiotemporal gait parameters in individuals with knee OA are yet to be reported. We therefore aimed to compare the efficacy of cushioned sport footwear versus sham shoes on motor functions, pain and gait characteristics of individuals with knee OA who used the shoes for 3 months. In a double-blinded study, we provided 26 individuals with knee OA with cushioned sport shoes and 12 individuals with knee OA with similar sport shoes without cushioning for 3 months. The gait analysis, the timed up and go (TUG) test and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) were conducted and the pain levels were measured at the baseline, 1 month, and 3 months after the baseline. We found that the cushioned shoes reduce the amount of pain (based on WOMAC) in the affected knee and increase functionality in the research group, but not in the control group. Gait velocity and cadence were increased in both groups. Gait spatiotemporal parameters and their symmetry were unaffected during the intervention. We conclude that the use of cushioned shoes should be recommended to individuals with knee OA for alleviating pain.

The impact of femoral bone quality on cementless total hip pre-operative templating.

INTRODUCTION: Accurate templating is an integral part of pre-operative planning for total hip arthroplasty (THA). Templating of cementless implant accuracy has been average. The aim of this study was to assess the impact of Dorr femoral classification on the accuracy of pre-operative digital templating. PATIENTS AND METHODS: This was a retrospective study of cementless THA pre-operative planning using one implant design. A total of 210 primary THA were reviewed. A total of 102 cementless THAs matched the exclusion and inclusion criteria, using one implant combination, were analyzed by an orthopaedic resident and a fellowship trained arthroplasty surgeon. Each x-ray was evaluated and assigned a femoral Dorr classification. Accuracy of templating was determined by comparing the templated size with the actual implant size both for the femoral and acetabular components. RESULT: Out of the 102 cases, exact templating size was achieved in 35.3% for the acetabulum, 25.5% for the femur, and only in 9.8% for both components. Reasonable templating, ± one of the actual size, was achieved in 78.4% for the acetabulum, 74.5% for the femur, and 60.8% for both components. Use of Dorr femoral type classification did not result in better templating accuracy. CONCLUSION: Pre-operative hip cementless templating using digital x-rays with double marker method do not improve accuracy compared to other methods available for templating. Accounting for bone quality using the Dorr femoral classification did not improve accuracy.

New-Onset Perioperative Atrial Fibrillation Is Associated with Increased All-Cause Mortality in Elderly Patients Undergoing Total Knee and Hip Replacements.

INTRODUCTION: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are common surgeries performed in elderly patients with osteoarthritis. Limited data address the clinical significance of perioperative atrial fibrillation (AF) in these patients. This study aimed to determine whether preexisting or new-onset AF is associated with increased 1-year all-cause mortality rates in the elderly population. METHODS: 280 patients over the age of 60 undergoing THA or TKA with perioperative AF and 280 control-matched patients were retrospectively identified, and their files reviewed. The primary end point was 1-year all-cause mortality from the date of the surgery. RESULTS: Of the 280 patients with perioperative AF, 37 had new-onset AF with a 1-year all-cause mortality rate of 10.8%. This mortality was significantly higher in patients with new-onset AF compared to patients without AF or patients with previous AF (10.8% vs. 1.1% and 2.5%, respectively; p = 0.005). On multivariate analysis, this difference remained significant after adjustment for risk factors associated with all-cause mortality. CONCLUSIONS: One-year all-cause mortality in elderly patients undergoing TKA or THA is significantly increased in the patients that develop new postoperative AF. These patients warrant increased clinical surveillance following surgery.

Total Knee Arthroplasty for Valgus Deformity via a Lateral Approach: Clinical Results, Comparison to Medial Approach, and Review of Recent Literature.

BACKGROUND: Total knee arthroplasty (TKA) for valgus deformity is a challenge. The standard medial parapatellar approach may not be universally useful for this. We have adopted the lateral approach to valgus knees. Here we describe our experience with this approach, present early results, and compare them to the medial approach. METHODS: Our institutional registry was queried for all patients with valgus deformity who underwent a TKA via a lateral approach between 2013 and 2016. The registry was also queried for patients with valgus deformity who underwent a TKA through a medial approach in previous years and this data was compared to the study group. RESULTS: Seventy-nine valgus knees in 72 patients were operated through a lateral approach. Deformity was corrected by 10.8°, from 16.2° to 5.4° (P < .001). Patellar tilt improved from -2.3° to 0.3° (P = .037). Seven implants (9%) were constrained. Mean operating time was 87 minutes (range 53-137). Twenty-five knees in 23 patients were operated via the medial approach. Deformity was corrected by 7.3°, from 13.2° to 5.9° (P < .001). Mean operating time was 137 minutes (range 90-230). Constrained implants were used in 16% of cases. The lateral approach allowed better correction of valgus deformity (10.8 vs 7.3, P = .03) and shorter operative times (87 vs 137 minutes, P < .001). CONCLUSION: A lateral approach TKA for valgus deformity improves knee alignment and patellar tilt. Compared to the medial approach, it allows better correction of the deformity, shorter operating times, and perhaps less use of constrained implants.

Ablation of the mammalian lectin galectin-8 induces bone defects in mice.

Mice overexpressing galectin-8 [gal-8 transgenic (Tg)], a secreted mammalian lectin, exhibit enhanced bone turnover and reduced bone mass, similar to cases of postmenopausal osteoporosis. Here, we show that gal-8 knockout (KO) mice have increased bone mass accrual at a young age but exhibit accelerated bone loss during adulthood. These phenotypes can be attributed to a gal-8-mediated increase in receptor activator of NF-κB ligand (RANKL) expression that promotes osteoclastogenesis, combined with direct inhibition of osteoblast differentiation, evident by reduced bone morphogenetic protein (BMP) signaling, reduced phosphorylation of receptor regulated mothers against decapentaplegic homolog (R-SMAD) and reduced expression of osteoblast differentiation markers osterix, osteocalcin, runt-related transcription factor 2 (RUNX2), dentin matrix acidic phosphoprotein-1 (DMP1), and alkaline phosphatase. At the same time, gal-8 promotes expression of estrogen receptor α (ESR1). Accordingly, the rate of bone loss is accelerated in ovariectomized, estrogen-deficient gal-8 Tg mice, whereas gal-8 KO mice, having low levels of ESR1, are refractory to ovariectomy. Finally, gal-8 mRNA positively correlates with the mRNA levels of osteoclastogenic markers RANKL, tartrate-resistant acid phosphatase, and cathepsin K in human femurs. Collectively, these findings identify gal-8 as a new physiologic player in the regulation of bone mass.-Vinik, Y., Shatz-Azoulay, H., Hiram-Bab, S., Kandel, L., Gabet, Y., Rivkin, G., Zick, Y. Ablation of the mammalian lectin galectin-8 induces bone defects in mice.

Long Term Results of Liner Polyethylene Cementation Technique in Revision for Peri-acetabular Osteolysis.

Patients with peri-acetabular osteolysis around a well fixed cementless acetabular component may be treated with liner exchange. When the locking mechanism is unreliable or unavailable, cementing the liner into the fixed acetabular component is a feasible option. The purpose of this study was to evaluate the clinical and radiographic long term results of this technique. Forty hip revisions with liner cementation in 37 patients were performed. The minimum follow up was 10 years. Modified Harris Hip Score and recent x rays were reviewed. Four hips were re-revised. Two patients were diagnosed with exacerbation of osteolysis but refused revision. Dislocation rate was relatively high (16%). Liner cementation technique in revision hip surgery is useful in patients with a well fixed metal backed acetabular component.

Comparative outcome of bomb explosion injuries versus high-powered gunshot injuries of the upper extremity in a civilian setting.

BACKGROUND: Explosion injuries to the upper extremity have specific clinical characteristics that differ from injuries due to other mechanisms. OBJECTIVES: To evaluate the upper extremity injury pattern of attacks on civilian targets, comparing bomb explosion injuries to gunshot injuries and their functional recovery using standard outcome measures. METHODS: Of 157 patients admitted to the hospital between 2000 and 2004, 72 (46%) sustained explosion injuries and 85 (54%) gunshot injuries. The trauma registry files were reviewed and the patients completed the DASH Questionnaire (Disabilities of Arm, Shoulder and Hand) and SF-12 (Short Form-12) after a minimum period of 1 year. RESULTS: Of the 157 patients, 72 (46%) had blast injuries and 85 (54%) had shooting injuries. The blast casualties had higher Injury Severity Scores (47% vs. 22% with a score of > 16, P = 0.02) and higher percent of patients treated in intensive care units (47% vs. 28%, P = 0.02). Although the Abbreviated Injury Scale score of the upper extremity injury was similar in the two groups, the blast casualties were found to have more bilateral and complex soft tissue injuries and were treated surgically more often. No difference was found in the SF-12 or DASH scores between the groups at follow up. CONCLUSIONS: The casualties with upper extremity blast injuries were more severely injured and sustained more bilateral and complex soft tissue injuries to the upper extremity. However, the rating of the local injury to the isolated limb is similar, as was the subjective functional recovery.

Natural history of changes in knee skin temperature following total knee arthroplasty: a systematic review and meta-analysis.

Patients undergoing total-knee arthroplasty (TKA) have transient increases in anterior knee skin temperature (ST) that subside as recovery progresses-except in cases of systemic or local prosthetic joint infections (PJI). This meta-analysis was designed to quantify the changes in knee ST following TKA in patients with uncomplicated recovery as a prerequisite for assessing the usefulness of thermal imaging for diagnosis of PJI. This meta-analysis (PROSPERO-CRD42021269864) was performed according to PRISMA guidelines. PUBMED and EMBASE were searched for studies reporting knee ST of patients that underwent unilateral TKA with uncomplicated recovery. The primary outcome was the weighted means of the differences in ST between the operated and the non-operated knees (ΔST) for each time point (before TKA, and 1 day; 1,2, and 6 weeks; and 3,6, and 12-months post-TKA). For this analysis, 318 patients were included from 10 studies. The elevation in ST was greatest during the first 2-weeks (ΔST = 2.8 °C) and remained higher than pre-surgery levels at 4-6 weeks. At 3-months, ΔST was 1.4 °C. It decreased to 0.9 °C and 0.6 °C at 6 and 12-months respectively. Establishing the baseline profile of knee ST following TKA provides the necessary first step for evaluating the usefulness of thermography for the diagnosis of post-procedural PJI.

Total knee arthroplasty using a computerized assisted stereotaxic navigation system with bluetooth communication in obese patients - A randomized controlled study.

Correct mechanical alignment (180° hip-knee-angle (HKA)) may be difficult to obtain on a consistent basis in obese patients. This is a randomized controlled study comparing the post-operative coronal alignment in obese patients between two surgical total knee arthroplasty (TKA) techniques - conventional and computer assisted navigation. The primary outcome was the post-operative HKA. A total of 60 patients were assigned to undergo conventional total knee arthroplasty (30 patients) or computerized assisted stereotaxic navigation system with Bluetooth communication surgery (30 patients). One patient from the study group was excluded due to malfunction of the navigation system. Good quality x-rays were available in 57 patients. There was no difference between the groups. Post-operative HKA was 2.8° and 2.9° in the study and control groups, respectively (p = 0.87). In obese patients undergoing TKA, computerized navigation had no impact on post-op HKA. Clincal Trial Registration Number: HMO 0092-13.

How resources affect management of periprosthetic fractures of the distal femur: perspectives from Israel, South Sudan, and South Africa.

Periprosthetic fractures of the distal femur have significant morbidity in both total hip and total knee arthroplasty (THA and TKA, respectively). The incidence of these fractures is growing, with the predominant mechanism of injury being a fall from a standing height and therefore considered fragility fractures. In many countries, improved public funding and a flourishing private health care sector, when coupled with increased life expectancy, translates to more older patients receiving both TKA and THA and therefore an increased prevalence of periprosthetic fractures and their associated complications. These fractures may occur below a long stem THA, above a TKA, or between the two (so-called "interprosthetic fracture"). We will outline fracture classification, risk factors, diagnosis, and treatment options, highlighting perspectives on treating these fractures in Israel, South Africa, and South Sudan. These countries represent differing access to resources, varied comorbidity factors, and differing health care systems. The points of difference and the points of similarity will be considered.

The outcome of surgically treated femur fractures associated with long-term bisphosphonate use.

INTRODUCTION: Bisphosphonates (BPs) evolved as the mainstay for the treatment of osteoporosis, reducing the incidence of fractures. Recently several publications described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term BP use. The aim of this study was to describe the outcome of surgically treated femur fractures associated with prolonged BP use. PATIENTS: Fifteen patients suffering from 17 atypical femoral fragility fractures associated with long-term (>3 years) BP use were located. Data included fracture type, time of BP use, last bone mineral density DEXA scores for the femoral neck and spine, type of surgery, and the need for revision. RESULTS: Fourteen female patients and one male patient were identified. The median age was 73 years (range, 51-80 years). The mean BP use was 7.8 years (range, 4-13 years). Fourteen patients had low-energy traumatic femoral shaft (proximal and distal) or low subtrochanteric fractures. The mean lumbar spine (for 13 patients) bone mineral density T-score was -3.0, whereas mean femoral neck T-score was -1.8 with only three patients in the osteoporotic range.Fracture healing after the first procedure for patients treated with nails was 54%, with 46% of patients requiring revision surgery. These included nail dynamization, exchange nailing, and one revision to a blade plate. All of these eventually healed. CONCLUSIONS: BP-related fractures are a recently described phenomenon. Despite initial osteoporosis, the DEXA scan may appear outside the osteoporotic range for the femoral neck in these patients. In addition, a much higher failure rate with intramedullary nailing requiring revision surgery may occur with these patients.

Current topics in robotic-assisted total hip arthroplasty: a review.

Total hip arthroplasty (THA) is among the most successful procedures of modern medicine, yet failures and complications continue to occur, leaving room for improvement. Robotics is a cutting-edge technology that tries to improve joint arthroplasty surgery. There is some evidence that shows that robotic-assisted THA improves implant positioning, but less is known about its effect on clinical outcomes or the rate of complications. This article reviews the literature on robotic-assisted THA to elucidate the history, advantages, disadvantages, and current clinical understanding of this procedure.

A novel approach for knee osteoarthritis using high molecular weight hyaluronic acid conjugated to plasma fibrinogen - interim findings of a double-blind clinical study.

OBJECTIVE: Osteoarthritis (OA) is a widespread degenerative joint disease leading to progressive loss of function and pain. Available treatments do not provide long-term relief or improvement. This study aimed to assess the safety and efficacy of a novel intra articular supplement, made of high molecular-weight hyaluronic acid (HA) uniquely conjugated to either purified (RegenoGel) or autologous plasma-derived fibrinogen (RegenoGel-OSP), as a long-term treatment for knee OA. METHODS: Sixty-seven consecutive participants (mean age 67.26 ± 7 years) with symptomatic OA were randomly assigned to receive intraarticular injections of either RegenoGel, RegenoGel-OSP or saline solution (placebo). The active treatment groups received a second, repeat injection of the corresponding treatment at the 3-month evaluation, at which time, the placebo group was divided into two subgroups, one receiving RegenoGel and the other receiving RegenoGel-OSP. The OA symptoms were assessed by VAS, WOMAC, and IKDC questionnaires at baseline and at 1, 3, 4, and 6 months following the first injection. OA-related quality of life was evaluated by the SF-12 survey. RESULTS: Our preliminary data suggests that both fibrin-HA formulations have positive effects on OA symptoms for all assessed parameters with the most prominent trend for reduction in OA-associated pain. Pooled data analysis of RegenoGel and RegenoGel-OSP shows significantly improved VAS scores compared to placebo at three months after the first injection, and sustained for another three months after the second injection. Both RegenoGel, RegenoGel-OSP had an excellent safety profile. CONCLUSIONS: Interim analysis results indicate that RegenoGel and RegenoGel-OSP are safe and are potentially effective for at least six months in alleviating pain and symptoms of knee OA.

Effect of severe aortic stenosis on the outcome in elderly patients undergoing repair of hip fracture.

BACKGROUND: The perioperative assessment and management of elderly patients with hip fracture and significant aortic stenosis (AS) is an increasingly common clinical problem with little data available to guide perioperative management. OBJECTIVES: It was the aim of this study to examine the incidence of perioperative events in an elderly population of patients with severe AS undergoing repair of hip fracture as compared with controls without severe AS. METHODS: Patients over the age of 70 with an echocardiographic diagnosis of severe AS defined as an aortic valve area

Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture.

BACKGROUND: Hip fracture repair is commonly performed in elderly adults and is associated with high mortality. Limited data address the significance of perioperative atrial fibrillation (AF) and its subsequent treatment in emergent orthopedic surgery in the elderly. This study aimed to determine whether newly diagnosed AF among patients initially in sinus rhythm undergoing hip fracture repair is predictive of one-year mortality and whether medical therapy of AF attenuated this finding. METHODS: All patients over the age of 65 who underwent repair of hip fracture in our institution were retrospectively identified. Potential subjects with chronic atrial fibrillation were excluded. 410 subjects were identified and were eligible. The primary endpoint was one year mortality from the date of surgery. RESULTS: Of the 410 subjects 15 (3.7%) developed AF during hospitalization and 395 (96.3%) did not. Only a previous history of AF and current use of beta blockers were predictive of the development of AF following hip surgery. Mortality among patients with new onset AF was significantly higher than in patients without AF (60% vs 19.5%; p 0.001). Chronic treatment with anti-arrhythmic therapy as well as treatment with anticoagulation were also associated with one-year mortality. On multivariable analysis, AF during hospitalization was the variable most significantly associated with mortality (hazard ratio 6.7 95% CI 2.1-21.4). CONCLUSIONS: One-year mortality in elderly patients undergoing hip fracture repair is significantly increased in patients with postoperative AF. This association did not appear to be attenuated by medical treatment of the AF with anti-arrhythmic therapy.

Limb alignment, subluxation, and bone density relationship in the osteoarthritic varus knee.

Lower limb alignment, tibiofemoral (TF) subluxation, and bone density changes around the knee are significant factors related to the development of knee osteoarthritis (OA) and have great impact on its severity. The relation of each factor to knee OA was evaluated separately in previous studies; however, few studies have attempted to integrate their respective effects. The purpose of this study was to determine if an identifiable interaction exists between coronal limb alignment, TF subluxation, and bone density in the development of knee OA. A total of 120 patients with symptomatic, varus knee OA, with preoperative standing anteroposterior (AP) hip-to-ankle radiographs and a computed tomographic scan of the knee, were included in this study. Overall mechanical lower extremity alignment, and TF subluxation were measured on the AP radiographs, while trabecular bone density (TBD) was measured in four regions of interest for both the tibial plateau and distal femur in all patients. The patients were stratified into the following four cohorts: (A) high subluxation, high angulation; (B) high subluxation, low angulation; (C) low subluxation, high angulation; and (D) low subluxation, low angulation. The mean TBD in group B was significantly higher than in groups C and D (p = 0.003 and 0.03, respectively). In addition, the mean TBD in group A was significantly higher than in group C. This study highlights the relationship between limb alignment, knee subluxation, and bone density in the osteoarthritic knee. These preliminary results present a proof-of-principle, that bone mineral density affects the degree of coronal alignment and TF subluxation in OA.

Challenges of technology integration and computer-assisted surgery.

The rapid progress of modern computerized capabilities has not been paralleled by a similar progress in the operating room setting and in operating techniques. The major advance in orthopaedic surgery during the past fifty years has been the introduction of intraoperative fluoroscopic imaging, while surgical techniques have remained mostly unchanged. Orthopaedic procedures dealing with bones--a nondeformable tissue--are suitable for computerized guidance based on preoperatively and intraoperatively obtained images. Computer-assisted surgery progressed from the first-generation systems of the 1990 s to the present third-generation systems, enabling surgeons to implant a knee or hip prosthesis with high precision. However, most orthopaedic surgeons avoid using computer-navigation surgical techniques. Why has the implementation of computer-assisted surgery procedures met so many hurdles and obstacles? The factors that make up the answer to this question can be grouped into three categories: human, technological, and financial. Computer-assisted surgery has the potential to revolutionize orthopaedic surgery just as fluoroscopy did a few decades ago; however, its widespread use has been hampered by a lack of sufficient clinical data on the one hand and by a reluctance to use the technique and thereby collect and share data on the other. The challenge is to overcome the human, technological, and financial hurdles. Once these obstacles are addressed, we believe that computer-assisted surgery will set a new standard of care. Until that time, some will be willing to lead the revolution and pay the price of progress, and others will be reluctant to take part in this endeavor.

Polyethylene liner cementation technique in asymptomatic versus symptomatic osteolysis.

Osteolysis around a cementless acetabular component can lead to severe bone loss. This study examined whether osteolysis should be treated while still asymptomatic. Thirty-seven liner cementation revisions were performed in 34 patients. Mean patient age was 61 years, and mean time elapsed after index surgery was 85 months (range, 36-168 months). Patients were evaluated by Harris Hip Score (HHS), and mean follow-up was 5 years (range, 43-82 months). Average HHS was 87 with a pain component of 39. In asymptomatic patients, both the HHS and the pain score were significantly higher: 95 and 43, respectively (P<.01). One patient with extensive bone loss had a fracture of the acetabulum and underwent revision at another institution. Revision of the polyethylene liner and cementation of a new one is a useful technique in patients with a stable acetabular shell. This is especially true for asymptomatic patients with osteolysis and thus should be performed early; however, high dislocation rate is still a concern.