Guided Growth to Treat Anterolateral Tibial Bowing Associated with Congenital Pseudarthrosis of the Tibia.

BACKGROUND: Anterolateral tibial bowing associated with congenital tibial pseudarthrosis occurs often in patients with neurofibromatosis type 1 and results from the inability of the fractured bone to unite, leading to persistent nonunion, abnormal bone growth, and further bowing of the tibia. Current surgical and nonsurgical approaches demonstrate persistent nonunion or refracture, often resulting in amputation. METHODS: This report describes the management of 3 patients with anterolateral tibial bowing and NF1 who underwent distal tibia-guided growth. RESULTS: The patients had an average age of 1.6 years at initial operation, with a total of 3 to 4 surgeries over an average of 2.1 years. The latest follow-up on all patients is included, at a mean of 5.1 years after the initial operation. All 3 patients experienced substantial functional improvement and improved alignment of the mechanical axis of the tibia. One patient has experienced refracture. CONCLUSIONS: Our study indicates that guided growth can serve as an additional surgical option to improve ALTB and potentially reduce the risk of fracture and pseudarthrosis by restoring normal mechanical alignment. LEVEL OF EVIDENCE: Level-IV, Case Series.

Femur-First Technique for Mobile Bearing Unicompartmental Knee Arthroplasty Results in Decreased Implant Variability and Early Improvements in Function and Survivorship.

BACKGROUND: Higher failure rates of unicompartmental knee arthroplasty (UKA) are seen with lower surgical volume. Surgical techniques that introduce less variability improving implant positioning may lead to improved survivorship. A femur-first (FF) technique has been described, but survivorship data compared to traditional tibia-first (TF) technique are under-reported. We report the results of mobile-bearing UKA using the FF technique compared to the TF technique with emphasis on implant position and survivorship. METHODS: A total of 430 UKAs were performed by a single surgeon between 2007 and 2020. After 2012, there were 141 consecutive UKAs performed with the FF technique which were compared with 147 consecutive UKAs prior. Mean follow-up was 6 years (range, 2 to 13 years), average age was 63 years (range, 23 to 92 years), and there were 132 women. Postoperative radiographs were reviewed to determine implant positioning. Survivorship analyses were performed using Kaplan-Meier curves. RESULTS: The FF resulted in significantly thinner polyethylene (3.4 ± 0.7 mm versus 3.7 ± 0.9 mm) (P = .002) and 4 mm or less bearing thickness in 94% of cases. At 5 years, there was an early trend toward improved survivorship free from component revision (98% for the FF group and 94% for the TF [P = .35]). The FF cohort had higher Knee Society Functional scores at final follow-up (P < .001). CONCLUSION: Compared to traditional TF technique, the FF was more bone-preserving and improved radiographic positioning. The FF technique is an alternative method for mobile-bearing UKA and was associated with an improvement in implant survivorship and function.

Minimum 10-Year Survivorship of Mobile-Bearing Unicompartmental Arthroplasty: Single Surgeon, North American Non-Designer Consecutive Series.

BACKGROUND: Mobile-bearing unicompartmental knee arthroplasty (UKA) provides a durable option for the surgical treatment of monocompartmental knee arthritis. Despite its availability in the United States since 2004, there is only 1 published North American series reporting on the minimum 10-year results of mobile-bearing UKA. The purpose of this study is to determine the survivorship, reasons for failure, and patient-reported outcomes of the Oxford mobile-bearing UKA at minimum 10-year follow-up. METHODS: One hundred fifty-seven knees were eligible for inclusion in this study based on the date of their index surgery allowing for a minimum 10-year follow-up. The mean follow-up from implantation was 11.4 years (range 10.0-13.8). Failures were reviewed for potential etiologic factors. Survivorship free of reoperation for any reason and free of revision was determined using Kaplan-Meier curves. Functional outcomes were assessed using the Knee Society Knee and Function scores. RESULTS: There were 17 revisions (10.6%). Six were secondary to progression of lateral compartment arthritis, 5 for persistent pain, 3 for femoral component aseptic loosening, 2 polyethylene dislocations, and 1 deep infection. The mean time to revision was 4 years (range 0.1-11). The survivorship free from revision at minimum 10-year follow-up was 85%. At final follow-up, the mean Knee Society Knee Score was 93 (range 66-100) and the mean functional score was 80 (range 30-100). CONCLUSION: This single surgeon series demonstrated a survivorship of 85% at minimum 10-year follow-up. These results are comparable to published data from North America, but survivorship is lower than European series.

Coordination of Di-Acetylated Histone Ligands by the ATAD2 Bromodomain.

The ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD) has a canonical bromodomain structure consisting of four α-helices. ATAD2 functions as a co-activator of the androgen and estrogen receptors as well as the MYC and E2F transcription factors. ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition, ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric, endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data, and isothermal titration calorimetry further confirm the monomeric state of the functionally active ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the conserved asparagine (N1064), the "RVF" shelf residues, and the flexible ZA loop. Coordination of a second acetyllysine group also occurs within the same binding pocket but is essentially governed by unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination more specific than previously presumed.

Purification of sarcoplasmic reticulum vesicles from horse gluteal muscle.

We have analyzed protein expression and enzyme activity of the sarcoplasmic reticulum Ca2+-transporting ATPase (SERCA) in horse gluteal muscle. Horses exhibit a high incidence of recurrent exertional rhabdomyolysis, with myosolic Ca2+ proposed, but yet to be established, as the underlying cause. To better assess Ca2+ regulatory mechanisms, we developed an improved protocol for isolating sarcoplasmic reticulum (SR) vesicles from horse skeletal muscle, based on mechanical homogenization and optimized parameters for differential centrifugation. Immunoblotting identified the peak subcellular fraction containing the SERCA1 protein (fast-twitch isoform). Gel analysis using the Stains-all dye demonstrated that calsequestrin (CASQ) and phospholipids are highly enriched in the SERCA-containing subcellular fraction isolated from horse gluteus. Immunoblotting also demonstrated that these horse SR vesicles show low content of glycogen phosphorylase (GP), which is likely an abundant contaminating protein of traditional horse SR preps. The maximal Ca2+-activated ATPase activity (Vmax) of SERCA in horse SR vesicles isolated using this protocol is 5‒25-fold greater than previously-reported SERCA activity in SR preps from horse skeletal muscle. We propose that this new protocol for isolating SR vesicles will be useful for determining enzymatic parameters of horse SERCA with high fidelity, plus assessing regulatory effect of SERCA peptide subunit(s) expressed in horse muscle.

Total Hip Arthroplasty in Patients With Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) comprises a spectrum of disorders that result in bone fragility. This presents unique challenges when performing total joint arthroplasty in patients with OI. The purpose of this study is to determine the survivorship and clinical outcomes of total hip arthroplasty (THA) in patients with OI. METHODS: We retrospectively reviewed our institution's total joint registry from 1969 to 2018 for all primary THAs in patients with a history of OI. There were 11 patients (13 hips) with a mean follow-up of 13 years (range 6-20). Survivorship free of component revision was determined using Kaplan-Meier analysis. Patient-reported clinical outcomes were assessed using Harris Hip Scores. RESULTS: At final follow-up, the status of the implant was known in all 13 hips. One patient (1 hip) was deceased. Four hips (31%) underwent revision surgery at a mean of 9 years (range 5-17). Survivorship free of component revision was 52% at 20 years. Mean Harris Hip Scores at final follow-up were fair (75, 47-97), but significantly improved compared to available preoperative scores (P = .0015). No intraoperative complications occurred during the 13 primary THAs. CONCLUSION: THA in patients with OI is associated with high revision rates and low survivorship at long-term follow-up. Although this is a very challenging patient population, THA provided these patients with improved functional outcomes. To the authors' knowledge, this is the largest series of primary THA in patients with OI reported in the literature and therefore provides surgeons with important data regarding the expected outcomes following THA in this unique patient population. LEVEL OF EVIDENCE: Level IV.

Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain.

The ATPase family, AAA domain-containing protein 2 (ATAD2) has a C-terminal bromodomain, which functions as a chromatin reader domain recognizing acetylated lysine on the histone tails within the nucleosome. ATAD2 is overexpressed in many cancers and its expression is correlated with poor patient outcomes, making it an attractive therapeutic target and potential biomarker. We solved the crystal structure of the ATAD2 bromodomain and found that it contains a disulfide bridge near the base of the acetyllysine binding pocket (Cys1057-Cys1079). Site-directed mutagenesis revealed that removal of a free C-terminal cysteine (C1101) residue greatly improved the solubility of the ATAD2 bromodomain in vitro. Isothermal titration calorimetry experiments in combination with the Ellman's assay demonstrated that formation of an intramolecular disulfide bridge negatively impacts the ligand binding affinities and alters the thermodynamic parameters of the ATAD2 bromodomain interaction with a histone H4K5ac peptide as well as a small molecule bromodomain ligand. Molecular dynamics simulations indicate that the formation of the disulfide bridge in the ATAD2 bromodomain does not alter the structure of the folded state or flexibility of the acetyllysine binding pocket. However, consideration of this unique structural feature should be taken into account when examining ligand-binding affinity, or in the design of new bromodomain inhibitor compounds that interact with this acetyllysine reader module.

Single-Dose Perioperative Antibiotics Do Not Increase the Risk of Surgical Site Infection in Unicompartmental Knee Arthroplasty.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) is commonly performed as an outpatient procedure. To facilitate this process, a single-dose intravenous (IV) perioperative antibiotic administration is required compared to 24-hour IV antibiotic dosing schedules that are typical of most inpatient arthroplasty procedures. There is a paucity of literature to guide surgeons on the safety of single-dose perioperative antibiotic administration for arthroplasty procedures, particularly those that will be performed in the outpatient setting. The purpose of this study is to evaluate a large series of UKA performed with single-dose vs 24-hour IV antibiotic coverage to determine the impact on risk for surgical site infection (SSI). METHODS: All UKA cases were evaluated from 2007 to 2017 performed by a single surgeon at an academic institution. There were 296 UKAs in the cohort: 40 were outpatient procedures receiving single-dose antibiotics and 256 were inpatient procedures receiving 24-hour antibiotics. No patients were prescribed adjuvant oral antibiotics. Mean age was 64 years, 50% were female, mean body mass index was 32 kg/m2, and mean follow-up was 4.1 years (range 1.0-10.4). Perioperative antibiotic regimen was evaluated and SSI, defined as occurring within 1 year of surgery, was abstracted through a prospective total joint registry and manual chart review. RESULTS: SSI occurred in 2 of 296 cases (0.7%) in the entire cohort, 2 of 256 inpatient UKAs (0.8%), and 0 of 40 outpatient UKAs (0%) (P = 1.00). One SSI was a deep infection occurring 6 weeks postoperatively that required 2-stage exchange and conversion to total knee arthroplasty. The other was a superficial infection treated with 2 weeks of oral antibiotics. CONCLUSION: This study demonstrates a low SSI risk (0.8% or less) following UKA with both single-dose and 24-hour IV antibiotics. Administering single-dose perioperative antibiotics is safe for UKA, which should alleviate that potential concern for outpatient surgery. LEVEL OF EVIDENCE: Level III, Therapeutic.

Mechanism of Histone H3K4me3 Recognition by the Plant Homeodomain of Inhibitor of Growth 3.

Aberrant access to genetic information disrupts cellular homeostasis and can lead to cancer development. One molecular mechanism that regulates access to genetic information includes recognition of histone modifications, which is carried out by protein modules that interact with chromatin and serve as landing pads for enzymatic activities that regulate gene expression. The ING3 tumor suppressor protein contains a plant homeodomain (PHD) that reads the epigenetic code via recognition of histone H3 tri-methylated at lysine 4 (H3K4me3), and this domain is lost or mutated in various human cancers. However, the molecular mechanisms targeting ING3 to histones and the role of this interaction in the cell remain elusive. Thus, we employed biochemical and structural biology approaches to investigate the interaction of the ING3 PHD finger (ING3PHD) with the active transcription mark H3K4me3. Our results demonstrate that association of the ING3PHD with H3K4me3 is in the sub-micromolar range (KD ranging between 0.63 and 0.93 µm) and is about 200-fold stronger than with the unmodified histone H3. NMR and computational studies revealed an aromatic cage composed of Tyr-362, Ser-369, and Trp-385 that accommodate the tri-methylated side chain of H3K4. Mutational analysis confirmed the critical importance of Tyr-362 and Trp-385 in mediating the ING3PHD-H3K4me3 interaction. Finally, the biological relevance of ING3PHD-H3K4me3 binding was demonstrated by the failure of ING3PHD mutant proteins to enhance ING3-mediated DNA damage-dependent cell death. Together, our results reveal the molecular mechanism of H3K4me3 selection by the ING3PHD and suggest that this interaction is important for mediating ING3 tumor suppressive activities.

Minimum 10-Year Follow-Up of Cementless Total Hip Arthroplasty Using a Contemporary Triple-Tapered Titanium Stem.

BACKGROUND: There is extensive variation in design and insertion technique of cementless tapered femoral stems. The purpose of our study was to evaluate a consecutive series of contemporary tapered cementless femoral stems inserted with a ream-and-broach technique at a minimum 10-year follow-up in patients undergoing total hip arthroplasty (THA). METHODS: One hundred consecutive THAs (88 patients) performed by a single surgeon were followed for a minimum of 10 years. Hips were evaluated clinically for revision status, Western Ontario and McMaster Universities Osteoarthritis Index, 36-item Short Form Health Survey, Harris Hip Score, and University of California, Los Angeles, and Tegner Activity Scores. Radiographic evaluation included assessment for loosening, osteolysis, and stress shielding. Kaplan-Meier survivorship analysis included end points for revision and radiographic evidence of femoral component loosening. RESULTS: At minimum 10-year follow-up, 66 patients (74 hips) were living, 20 patients (24 hips) were deceased, and 2 patients (2 hips) were lost to follow-up. Four hips required reoperation, but no femoral components were revised for aseptic loosening. One femoral component (1%) was revised due to a postoperative periprosthetic fracture. Radiographic evaluation demonstrated bone ingrowth of all stems without evidence of component loosening and 1 case of severe stress shielding. Kaplan-Meier survivorship at 10 years was 100% for the end points of femoral revision for loosening or femoral radiographic loosening. CONCLUSION: This contemporary, cementless titanium-tapered femoral component inserted with ream-and-broach technique demonstrated excellent results in terms of outcomes and clinical durability as well as osteointegration on radiographs at minimum 10-year follow-up. This study corroborates, with level 2 and level 3 data, level 1 data reported in national registries.

Curcumin and dimethoxycurcumin induced epigenetic changes in leukemia cells.

PURPOSE: Curcumin is an ideal chemopreventive and antitumor agent characterized by poor bioavailability and low stability. The development of synthetic structural analogues like dimethoxycurcumin (DMC) could overcome these drawbacks. In this study we compared the cytotoxicity, metabolism and the epigenetic changes induced by both drugs in leukemia cells. METHODS: Apoptosis and cell cycle analysis were analyzed by flow cytometry. Real-time PCR was used for gene expression analysis. DNA methylation was analyzed by DNA pyrosequencing. The metabolic stability was determined using human pooled liver microsomes. Chromatin Immunoprecipitation was used to quantify histone methylation. RESULTS: Clinically relevant concentration of curcumin and DMC were not cytotoxic to leukemia cells and induced G2/M cell cycle arrest. DMC was more metabolically stable than curcumin. Curcumin and DMC were devoid of DNA hypomethylating activity. DMC induced the expression of promoter methylated genes without reversing DNA methylation and increased H3K36me3 mark near the promoter region of hypermethylated genes. CONCLUSION: DMC is a more stable analogue of curcumin that can induce epigenetic changes not induced by curcumin. DMC induced the expression of promoter methylated genes. The combination of DMC with DNA methyltransferase inhibitors could harness their combined induced epigenetic changes for optimal re-expression of epigenetically silenced genes.

The MOZ histone acetyltransferase in epigenetic signaling and disease.

The monocytic leukemic zinc finger (MOZ) histone acetyltransferase (HAT) plays a role in acute myeloid leukemia (AML). It functions as a quaternary complex with the bromodomain PHD finger protein 1 (BRPF1), the human Esa1-associated factor 6 homolog (hEAF6), and the inhibitor of growth 5 (ING5). Each of these subunits contain chromatin reader domains that recognize specific post-translational modifications (PTMs) on histone tails, and this recognition directs the MOZ HAT complex to specific chromatin substrates. The structure and function of these epigenetic reader modules has now been elucidated, and a model describing how the cooperative action of these domains regulates HAT activity in response to the epigenetic landscape is proposed. The emerging role of epigenetic reader domains in disease, and their therapeutic potential for many types of cancer is also highlighted.

NP vs. PA: what is the difference?

The recent passage of the Affordable Care Act (ACA) has highlighted the need for more primary care providers. One solution to increase the primary care provider base is the increased utilization of nurse practioners (NPs) and physician's assistants (PAs). Differences exist in the educational background, board examinations and licensing requirements of NPs and PAs. In addition, their practice patterns, recertification and types of supervision are different. Moreover, changes in the NP educational pathway leading to a doctoral degree will create new challenges regarding collaboration agreements currently required by South Dakota statute. This paper discusses the differences and similarities of NPs and PAs to gain a better understanding of these professions.

An algorithm for the evaluation and treatment of sacroiliac joint dysfunction.

Approximately 90 percent of adults experience an episode of low back pain in their lifetime. Sacroiliac joint (SIJ) dysfunction has been shown to cause approximately 13-30 percent of LBP in the adult population. SIJ fusion is becoming an increasingly popular treatment alternative for SIJ dysfunction. This paper presents a literature-based algorithm to assist the clinician in the evaluation and treatment of patients with suspected SIJ dysfunction.

A Comprehensive Review of Solriamfetol to Treat Excessive Daytime Sleepiness.

Purpose of Review: This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic approaches to treating excessive daytime sleepiness, the management of common comorbidities, and the existing evidence investigating the use of Solriamfetol for this purpose. Recent Findings: Excessive daytime sleepiness leads to worse quality of life, a medical sequela and significant economic cost. There are multiple phenotypes of excessive daytime sleepiness depending on the comorbidity making treatment challenging. Due to the complexity of etiology there is not a cure for this ailment. Solriamfetol is a norepinephrine/dopamine dual reuptake antagonist that can be used to manage daytime sleepiness. Solriamfetol was first approved by the FDA in 2018 for use in excessive daytime sleepiness associated with obstructive sleep apnea and narcolepsy. Ongoing literature has proved this drug to be a safe and effective alternative pharmacotherapy. Summary: Recent epidemiological data estimate up to one-third of the general adult population suffers from excessive daytime sleepiness. There is no cure to daytime somnolence and current pharmacotherapeutic regimens have worrisome side effect profiles. Solriamfetol is a new class of drug that offers a safe and effective alternative option for clinical providers treating excessive daytime sleepiness.

A Comprehensive Review of Lemborexant to Treat Insomnia.

Purpose of Review: This is a comprehensive review of the literature regarding Lemborexant for the treatment of insomnia. It covers the background and management of insomnia and then reviews the body of existing evidence evaluating the use of Lemborexant for this purpose. Recent Findings: Insomnia leads to significant decreased in quality of life and economic burden due to decreased workplace performance and increased health care costs. Insomnia manifests as a single common pathway of hyperarousal due to a highly complex network of interactions between activation of the sympathetic system and the endocrine system. Lemborexant is a dual orexin 1/2 antagonist that blocks cortical arousal and promotes sleep state transition. Lemborexant was approved by the FDA in 2019 for use in insomnia. It belongs to a class of orexin neuropeptide inhibitors that is growing in popular clinical application. Summary: Insomnia is a crippling disorder of the sleep wake cycle that drives significant morbidity and mortality in the United States. It carries a high societal and economic toll due to direct and indirect effects to the healthcare system. Lemborexant is a new addition to the orexin antagonist class of drugs that already includes Almorexant and Suvorexant that has superior pharmacokinetic properties. While Lemborexant does have a mild side effect profile, its clinical safety and efficacy make it a promising insomnia drug of the future.

Prevalence of groin pain after primary dual-mobility total hip arthroplasty.

BACKGROUND: Instability remains a challenging problem following total hip arthroplasty (THA). Dual-mobility (DM) components are used with increasing frequency to mitigate this potential complication. As has been shown with larger metal-on-metal (MoM) THA, the larger size femoral head may pose an increased risk of groin pain. This study aims to evaluate the prevalence of groin pain following primary DM THA compared to other THA constructs. METHODS: We identified 190 primary THAs (183 patients) performed with DM components at a single academic institution from 2008 to 2017. We retrospectively reviewed standardised patient questionnaires and the electronic medical record to determine the prevalence of groin pain. DM patients were compared to historical controls of 39 MoM hip resurfacing, 26 large-head MoM THA, and 217 conventional THA. Mean age was 64 years, 58% were female, mean body mass index was 30 kg/m2, and mean follow-up was 3.5 years (range 2-8 years). RESULTS: The prevalence of groin pain in patients with DM components was 5%, similar to the prevalence reported by patients with conventional THA (7%). There was a decreased prevalence of groin pain in DM patients compared to hip resurfacing (18%) and MoM THA (15%). Among the 9 DM patients with groin pain, 1 was treated with iliopsoas injection, and 1 underwent radiofrequency ablation of the articular nerve. CONCLUSIONS: This study documents a relatively low prevalence of groin pain among primary DM THA patients. This is comparable with historical controls of conventional THA and decreased compared to hip resurfacing and large head MoM THA.

Supporting the right ventricle in postcardiotomy renal dysfunction: A case series.

Postcardiotomy RV dysfunction is an under-recognized cause of acute kidney injury (AKI). Insertion of a percutaneous right ventricular assist device (RVAD) reduces central venous hypertension and congestive nephropathy by augmenting cardiac output. In selected patients, percutaneous RVAD insertion may improve renal function and obviate the need for long-term dialysis.