Orthobiologics in Foot and Ankle Arthrodesis: A Systematic Review.

Orthobiologics are biologically-derived materials intended to promote bone formation and union. We review evidence on effectiveness and harms of orthobiologics compared to no orthobiologics for foot and ankle arthrodesis. We searched multiple databases (1995-2019) and included clinical trials and other studies with concurrent controls, English language, and reporting patient-centered outcomes, union/time to union, costs/resource utilization, or harms. Studies were organized by orthobiologic used. We describe quality and limitations of available evidence but did not formally rate risk of bias or certainty of evidence. Most of the 21 studies included were retrospective chart reviews with orthobiologics used at surgeon's discretion for patients considered at higher risk for nonunion. Ten studies compared autologous bone graft versus no graft and 2 compared remote versus local graft with few studies of other orthobiologics. All studies reported a measure of fusion and about half reported on function/quality of life. Few studies reported harms. Due to limited reporting, we were unable to assess whether effectiveness varies by risk factors for nonunion (eg, age, gender, smoking status, obesity, diabetes) or whether orthobiologics were cost-effective. Available evidence is of poor quality with small sample sizes, inadequate reporting of risk factors for nonunion, variations in orthobiologics, surgical techniques used, and outcome assessment, and potential selection bias. Research is needed to adequately inform surgeons about benefits and harms and guide patient selection for use, or type, of orthobiologics. Careful assessment of individual patient risk for nonunion is critical prior to orthobiologic use.

Delayed Bilateral Tibialis Anterior Tendon Repair in an Older Man: A Case Report.

CASE: We report a 67-year-old healthy man who sustained bilateral hyper-plantarflexion injuries falling off a ladder that resulted in bilateral tibialis anterior tendon tears one month prior to presentation. His injuries were effectively managed with bilateral delayed operative treatment. After non-weightbearing for three months, the patient was subsequently permitted to full weight bear in CAM boots for three months. At three-year follow-up he was fully functional with excellent Foot and Ankle Ability Measure (FAAM scores). CONCLUSION: The management delayed tibialis anterior tendon ruptures, whether due to traumatic or degenerative mechanisms is challenging and surgical repair can be effective when this injury occurs bilaterally.

Risk prediction models for diabetic foot ulcer development or amputation: a review of reviews.

BACKGROUND: In adults with diabetes, diabetic foot ulcer (DFU) and amputation are common and associated with significant morbidity and mortality. PURPOSE: Identify tools predicting risk of DFU or amputation that are prognostically accurate and clinically feasible. METHODS: We searched for systematic reviews (SRs) of tools predicting DFU or amputation published in multiple databases from initiation to January, 2023. We assessed risk of bias (ROB) and provided a narrative review of reviews describing performance characteristics (calibration and discrimination) of prognostically accurate tools. For such tools, we additionally reviewed original studies to ascertain clinical applicability and usability (variables included, score calculation, and risk categorization). RESULTS: We identified 3 eligible SRs predicting DFU or amputation risk. Two recent SRs (2020 and 2021) were rated as moderate and low ROB respectively. Four risk prediction models - Boyko, Martins-Mendes (simplified), Martins-Mendes (original), and PODUS 2020 had good prognostic accuracy for predicting DFU or amputation over time horizons ranging from 1- to 5-years. PODUS 2020 predicts absolute average risk (e.g., 6% risk of DFU at 2 years) and consists of 3-binary variables with a simple, summative scoring (0-4) making it feasible for clinic use. The other 3 models categorize risk subjectively (e.g., high-risk for DFU at 3 years), include 2-7 variables, and require a calculation device. No data exist to inform rescreening intervals. Furthermore, the effectiveness of targeted interventions in decreasing incidence of DFU or amputation in response to prediction scores is unknown. CONCLUSIONS: In this review of reviews, we identified 4 prognostically accurate models that predict DFU or amputation in persons with diabetes. The PODUS 2020 model, predicting absolute average DFU risk at 2 years, has the most favorable prognostic accuracy and is clinically feasible. Rescreening intervals and effectiveness of intervention based on prediction score are uncertain.

The Perioperative Pain Self-Management (PePS) randomized controlled trial protocol: Preventing chronic post-surgical pain and prolonged opioid use.

BACKGROUND: Total joint arthroplasties are common orthopedic surgeries that carry risk for developing chronic post-surgical pain. In addition to pre- and post-operative pain severity, psychological distress (e.g., anxiety, pain catastrophizing) is a risk factor for chronic postsurgical pain. Cognitive behavioral therapy (CBT) for chronic pain is an empirically supported approach to managing chronic pain, functional impairment, and related distress. While CBT has been used extensively in patients with established chronic pain, using it as a preventive intervention targeting the transition from acute to chronic postsurgical pain is a novel application. OBJECTIVES: The Perioperative Pain Self-Management (PePS) program is a pain self-management intervention based on the principles of CBT. This innovative intervention is brief, flexible, and is delivered remotely. The current study aims to determine the efficacy of PePS compared to standard care on reducing the incidence of significant surgical site pain at 6-months post-surgery. The current study also aims to evaluate the context for subsequent implementation. METHODS: This study is a hybrid type I efficacy-preparing for implementation trial. It is a two-site, single-blind, two-arm, parallel, randomized control trial. Surgical patients will be randomized to either receive: 1) PePS plus standard care, or 2) Standard care. The primary end point will be surgical site pain severity at 6-months post-surgery. CONCLUSION: Results from this study are expected to result in support for a brief scalable intervention (PePS) that can prevent the development of chronic pain and prolonged post-surgical opioid use, as well as key details to inform subsequent implementation. CLINICALTRIALS: govIdentifier:NCT04979429.

Role of the p38 mitogen-activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes.

The p38 mitogen-activated protein kinase (MAPK) pathway is activated by IFNs and other cytokines to mediate signals for important cellular functions, including transcriptional regulation and apoptosis. We examined the role of the p38 pathway in the generation of the effects of myelosuppressive cytokines on human hematopoiesis. Pharmacologic inhibition of p38 using BIX-01208 resulted in reversal of IFN-, tumor necrosis factor-alpha (TNF-alpha)-, and transforming growth factor-beta (TGF-beta)-mediated suppression of human erythroid (blast-forming unit-erythroid) and myeloid (granulocyte-macrophage colony-forming unit) colony formation, consistent with a key role for p38 in the generation of myelosuppressive signals by different cytokines. Similarly, the myelosuppressive effects of TNF-alpha and TGF-beta were reversed by small interfering RNAs targeting p38alpha expression, further establishing the requirement of this kinase in the induction of myelosuppressive responses. As TNF overproduction has been implicated in the pathophysiology of bone marrow failure states, we determined whether pharmacologic inhibition of p38 reverses the hematopoietic defects seen in bone marrows from patients with myelodysplastic syndromes (MDS) and the anemia of chronic disease. Addition of pharmacologic inhibitors of p38 on such bone marrows resulted in increased numbers of erythroid and myeloid progenitors. Similarly, inhibition of the activity of the downstream effectors of p38, MAPK activated protein kinase-2, and mitogen and stress activated kinase 1 partially restored the hematopoietic defect seen in these bone marrows. Taken altogether, our data implicate the p38 MAPK in the pathophysiology of myelodysplasias and suggest that p38 pharmacologic inhibitors may have therapeutic applications in the treatment of MDS.

Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells.

Arsenic trioxide (As(2)O(3)) exhibits important antitumor activities in vitro and in vivo, but the precise mechanisms by which it induces its effects are not known. We provide evidence that during treatment of BCR-ABL-expressing cells with As(2)O(3), there is activation of a cellular pathway involving the p70 S6 kinase (p70S6K). Our data show that p70S6K is rapidly phosphorylated on Thr(421) and Ser(424) and is activated in an As(2)O(3)-inducible manner. The mammalian target of rapamycin (mTOR) is also phosphorylated/activated in an As(2)O(3)-inducible manner, and its activity is required for downstream engagement of p70S6K. p70S6K subsequently phosphorylates the S6 ribosomal protein on Ser(235)/Ser(236) and Ser(240)/Ser(244) to promote initiation of mRNA translation. Treatment of chronic myelogenous leukemia-derived cell lines with As(2)O(3) also results in phosphorylation of the 4E-BP1 repressor of mRNA translation on Thr(37)/Thr(46) and Thr(70), sites required for its deactivation and its dissociation from the eukaryotic initiation factor 4E complex to allow cap-dependent mRNA translation. In studies to determine the functional relevance of this pathway, we found that inhibition of mTOR and downstream cascades enhances induction of apoptosis by As(2)O(3). Consistent with this, the mTOR inhibitor rapamycin strongly potentiated As(2)O(3)-mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, our data show that the mTOR/p70S6K pathway is activated in a negative feedback regulatory manner in response to As(2)O(3) in BCR-ABL-transformed cells and plays a key regulatory role in the induction of anti-leukemic responses.

Complications of total hip arthroplasty.

Complications following hip arthroplasty have a wide variation and range in incidence from 1.1% for pulmonary embolism to over 70% for infrapopliteal deep vein thrombosis. Recognition of the risk factors and all of the possible types of complications places the surgeon in a better position to detect such complications and formulate a plan to treat them. This article documents some ofthe complications that can occur during or after surgery following hip surgery. These complications are stratified as systemic and procedure specific.

Gait analysis comparison of cruciate retaining and substituting TKA following PCL sacrifice.

The role of the posterior cruciate ligament (PCL) remains controversial in total knee arthroplasty (TKA), with some surgeons who believe in PCL sacrifice and substitution and others who believe in PCL preservation for stability. Manufacturers have developed both cruciate-substituting/posterior stabilized (PS) implants typically used when the ligament is sacrificed and cruciate retaining (CR) implants designed for ligament preservation. However, studies demonstrate excellent clinical results with CR implants despite PCL sacrifice. This study sought to determine functional stability differences between PS and CR TKAs following PCL sacrifice. Eighteen (9 matched pairs) subjects with either a PS or CR TKA and sacrificed PCL and a normal contralateral knee were subjected to physical exam and gait analysis (walking, stair ascent and descent) using a staircase model, passive reflective arrays and an optoelectric system. No differences were detected between the two groups among any of the measured parameters (knee flexion angle, knee flexion moment, knee power absorption, pelvic tilt). PCL sacrifice in a well-balanced cruciate retaining TKA did not result in instability during stair descent based on gait parameters. The decision to use a posterior stabilized design when faced with an incompetent PCL intraoperatively should be based on factors other than anticipated instability.

Limb salvage in an unstable ankle fracture of a diabetic patient with Charcot arthropathy.

The treatment of ankle fractures in the presence of diabetes mellitus can be difficult because of a higher complication rate with this subset of the population. When peripheral neuropathy is present at the time of trauma, there is an increased risk of developing Charcot arthropathy, a limb-threatening complication that often creates breakdown, instability, and chronic ulceration of the limb. The authors present a case report of a diabetic patient who sustained an unstable ankle fracture with subsequent neuroarthropathic event that required multiple surgical procedures for salvage of the limb.

Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells.

The interferons (IFNs) are cytokines that play key roles in host defense against viral infections and immune surveillance against cancer. We report that BCR-ABL transformation of hematopoietic cells results in suppression of IFN-dependent responses, including transcription of IFN-inducible genes and generation of IFN-mediated antiviral effects. BCR-ABL transformation suppresses expression of several IFN-regulated genes containing IFN-sensitive response element (ISRE) or GAS elements in their promoters, including Isg15, Irf1, Irf9, and Ifit2 (interferon-induced protein with tetratricopeptide repeats 2). Suppression of transcription of ISRE-containing genes is also seen in cells expressing various BCR-ABL kinase domain mutants, including T315I, H396P, Y253F, and E255K, but not kinase-defective BCR-ABL. Such effects are associated with impaired IFN-dependent phosphorylation of Stat1 on Tyr(701) and Stat3 on Tyr(705) and defective binding of Stat complexes to ISRE or GAS elements. Beyond suppression of Stat activities, BCR-ABL inhibits IFN-inducible phosphorylation/activation of the p38 MAPK, suggesting a dual mechanism by which this abnormal fusion protein blocks IFN transcriptional responses. The inhibitory activities of BCR-ABL ultimately result in impaired IFNalpha-mediated protection against encephalomyocarditis virus infection and reversal of IFN-dependent growth suppression. Altogether, our data provide evidence for a novel mechanism by which BCR-ABL impairs host defenses and promotes malignant transformation, involving dual suppression of IFN-activated signaling pathways.

Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses.

Arsenic trioxide (As(2)O(3)) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the mechanisms that mediate such effects are not well understood. We provide evidence that the Akt kinase is phosphorylated/activated during treatment of leukemia cells with As(2)O(3), to regulate downstream engagement of mammalian target of rapamycin (mTOR) and its effectors. Using cells with targeted disruption of both the Akt1 and Akt2 genes, we found that induction of arsenic trioxide-dependent apoptosis is strongly enhanced in the absence of these kinases, suggesting that Akt1/Akt2 are activated in a negative feedback regulatory manner, to control generation of As(2)O(3) responses. Consistent with this, As(2)O(3)-dependent pro-apoptotic effects are enhanced in double knock-out cells for both isoforms of the p70 S6 kinase (S6k1/S6k2), a downstream effector of Akt and mTOR. On the other hand, As(2)O(3)-dependent induction of apoptosis is diminished in cells with targeted disruption of TSC2, a negative upstream effector of mTOR. In studies using primary hematopoietic progenitors from patients with acute myeloid leukemia, we found that pharmacological inhibition of mTOR enhances the suppressive effects of arsenic trioxide on leukemic progenitor colony formation. Moreover, short interfering RNA-mediated inhibition of expression of the negative downstream effector, translational repressor 4E-BP1, partially reverses the effects of As(2)O(3). Altogether, these data provide evidence for a key regulatory role of the Akt/mTOR pathway in the generation of the effects of As(2)O(3), and suggest that targeting this signaling cascade may provide a novel therapeutic approach to enhance the anti-leukemic properties of As(2)O(3).

Component removal in revision total hip arthroplasty.

Component removal is a time-consuming yet necessary step during revision hip surgeries. Because of the diversity of the components and the methods used to secure them, an equal diversity of approaches and tools are necessary for component removal. Careful and detailed preoperative planning is mandatory, the mode of failure must be understood, and detailed imaging should be available to the surgeon. Understanding the basic principles and indications for each of the techniques would optimize outcome. We review the approaches, tools, and techniques for component removal in revision hip procedures in stepwise sequence.

Total knee arthroplasty in patients on workers' compensation: a matched cohort study with an average follow-up of 4.5 years.

Little information in the literature exists regarding the outcome of total knee arthroplasty (TKA) in patients who are on workers' compensation (WC). Twenty-one WC patients who underwent 23 TKA procedures (cases) were compared with 16 randomly selected, age-matched control patients (controls) undergoing 21 TKA procedures. The mean follow-up was 56 months (34-112 months) for both groups. The results were evaluated using the scoring system of the Knee Society (KSS). Significant improvements in KSS were noted in both groups, and all subjects indicated that they would undergo the procedure again. The KSS were statistically better in the control group relative to the WC group. There was no difference in range of motion, stability, or radiographic alignment. Despite high satisfaction with the results of surgery in both groups, only 5 of 21 patients in the WC group returned to their previous occupation. TKA improves pain and function scores in WC patients with end-stage knee disease. Understanding how WC issues affect the results of TKA is critical to the selection of appropriate surgical candidates.

The cementless femoral stem revisited.

Despite the success of Sir John Charnley's cemented total hip arthroplasty (THA), large numbers of patients demonstrated mechanical failure due to loosening. The two main initial concerns were infection and wear. With the recent advances in antibiotics and aseptic techniques and with improvement in surgical technique, the incidence of infection has decreased tremendously. Subsequently, the issues of wear and osteolysis have become the main concern. Initially attributing these problems to so-called "cement disease," clinicians sought out alternative methods of fixation; hence arose cementless femoral stem fixation. This article provides an overview of our modern understanding of cementless femoral stem fixation, focusing on design issues and outcomes. Particular attention is paid to three areas of continuing controversy with regard to the uncemented femoral stem: geometric design, material composition, and type and extent of porous coating.