Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer.

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

Hepatobiliary Infection after Transjugular Intrahepatic Portosystemic Shunt Creation in Patients with Prior Biliary Intervention: A Multi-Institution Retrospective Study.

PURPOSE: To estimate the risk of hepatobiliary infection, including endoTIPSitis, liver abscesses, and cholangitis, after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with prior biliary intervention. MATERIALS AND METHODS: This multi-institution, retrospective study identified 76 patients (n = 48 males; mean age, 54.9 years; mean Model for End-stage Liver Disease [MELD] score, 13.2; n = 45 for ascites and n = 23 for varices; n = 31 with prior liver transplantation) among 2,130 (3.6%) undergoing TIPS creation who had prior biliary intervention (n = 19 bilioenteric anastomoses, n = 35 sphincterotomies, n = 28 internal plastic stent placements, n = 4 internal metal stent placements, and n = 6 percutaneous biliary drain placements). The baseline risk of post-TIPS creation hepatobiliary infection was estimated from a control group of 1,202 TIPS creation procedures in patients without prior biliary intervention. RESULTS: Eleven (14.5%) of 76 patients developed hepatobiliary infection after TIPS creation, including 7 with endoTIPSitis, 4 with hepatic abscesses, and 2 with cholangitis. The 30-day risk of infection was 10.9% (95% confidence interval [CI], 3.5%-17.8%), significantly higher than the 0.4% risk (95% CI, 0.1%-0.8%) observed in patients without prior biliary intervention (hazard ratio [HR], 25.56; 95% CI, 8.36-78.13; P < .001). All types of biliary intervention were associated with increased risk of infection, with bilioenteric anastomoses conferring the highest risk. Paradoxically, among patients with prior biliary intervention, use of postprocedural antibiotic prophylaxis was associated with an increased infection risk (HR, 19.85; 95% CI, 2.44-161.50; P = .005). Microbial culture data showed high rates of Enterococcus, Klebsiella, and Candida species. CONCLUSIONS: Prior biliary intervention was associated with a 10.9% risk of hepatobiliary infection, including endoTIPSitis, liver abscess, and cholangitis, within 30 days after TIPS creation.

Outcomes of initial nonoperative treatment of traumatic full-thickness rotator cuff tears.

BACKGROUND: Nonsurgical management of chronic, degenerative rotator cuff tears (RCTs) can be an effective treatment strategy, but there is limited evidence to support conservative treatment of acute, traumatic RCTs. The objective of this study was to assess clinical outcomes and predictors of treatment success in patients with traumatic RCTs who elected for initial nonoperative treatment. METHODS: Patients from a single institution were retrospectively identified using diagnostic codes for traumatic RCTs followed by confirmed initial treatment with ≥2 months of physical therapy. The exclusion criteria included surgery within 2 months of injury and greater than grade I fatty infiltration on magnetic resonance imaging. At minimum 2-year follow-up, patients were contacted by telephone to collect interval surgical history and standardized patient-reported outcomes. Physical therapy was considered to have failed in all those who underwent surgical treatment and those with satisfaction ratings of "moderately dissatisfied" or "very dissatisfied." RESULTS: Follow-up outcomes were obtained in 40 of 49 patients (82%), with an average follow-up time of 4.2 years. Of the RCTs, 9 (22%) were small (<1 cm), 22 (54%) were medium (>1 cm to <3 cm), and 9 (22%) were large (>3 cm to <5 cm). Grade I fatty infiltration was seen on 25% of magnetic resonance imaging scans (n = 10). Rotator cuff repair was performed in 18 patients (45%) following an average of 6 months of nonoperative treatment (range, 3-12 months). Nonoperative treatment was determined to have failed in 23 of 40 patients (58%) in total. Conservative management was more likely to fail in patients with multiple tendons torn (P = .014). Tear size and retraction were not significantly different between patients who underwent surgery and those who did not. Patients who underwent surgical management had an 83% satisfaction rate at final follow-up compared with a 55% satisfaction rate for patients who did not undergo surgery (P = .054). There was no statistically significant difference in the American Shoulder and Elbow Surgeons score or visual analog scale score between these groups. Although patients who underwent surgery had a higher mean Single Alpha Numeric Evaluation score (86.3 vs. 75.1, P = .041), this difference was below the previously established minimal clinically important difference. CONCLUSION: Nonoperative treatment remains a viable option for certain patients with traumatic RCTs; however, the results of our study demonstrate a considerable early failure rate. This study further supports historical literature demonstrating reliably successful outcomes with surgical treatment of acute, traumatic RCTs.

Elevated HbA1c is not associated with reoperation following arthroscopic rotator cuff repair in patients with diabetes mellitus.

BACKGROUND: Hyperglycemia is a known risk factor for tendon degeneration due to oxidative stresses from production of advanced glycosylation end products. In patients with diabetes mellitus (DM), analysis of glycated hemoglobin (HbA1c) provides a 3-month window into a patient's glucose control. No guidelines exist for ideal preoperative HbA1c and glucose control prior to arthroscopic rotator cuff repair. This study evaluated if a critical HbA1c level is associated with reoperation following arthroscopic rotator cuff repair. METHODS: We retrospectively evaluated patients with DM who underwent primary arthroscopic rotator cuff repair from January 2014 to December 2018 at a single institution. Patients required a preoperative HbA1c within 3 months of surgery. Medical records were queried to evaluate for reoperation and identify the subsequent procedures performed. Univariate statistical analysis was performed to assess factors associated with reoperation (P < .05 considered significant). Threshold, area under the curve (AUC), analysis was performed to assess if a critical HbA1c value was associated with reoperation. RESULTS: A total of 402 patients met inclusion criteria. Patients had an average age of 65.5 years (range 40-89) at time of surgery; 244 (60.6%) patients were male; and average body mass index was 32.96 ± 5.81. Mean HbA1c was 7.36 (range 5.2-12). Thirty-three patients (8.2%) underwent subsequent reoperation. Six patients (1.5%) underwent capsular release and lysis of adhesions, 20 patients (5.0%) underwent a revision rotator cuff surgery, combination revision rotator cuff repair and lysis of adhesions, graft-augmented revision repair, or superior capsular reconstruction, and 7 patients (1.7%) underwent revision to reverse shoulder arthroplasty (1.7%). There were no cases of reoperation for infection. On AUC analysis, no critical HbA1c value was identified to predispose to reoperation. Interestingly, elevated preoperative American Society of Anesthesiologists (ASA) physical status classification score (2.8 vs. 2.28, P = .001) was associated with a higher reoperation rate. DISCUSSION: In patients with DM, preoperative HbA1c is not a predictive factor for surgical failure requiring reoperation. Stable glycemic control is important to a patient's overall health and may play a role in minimizing postoperative medical complications, but an elevated preoperative HbA1c should not be a strict surgical contraindication for arthroscopic rotator cuff repair. In patients with DM, an elevated ASA score is associated with an increased rate of subsequent reoperation; diabetic patients should be counseled accordingly.

High failure rate of 2-stage revision for the infected total elbow arthroplasty: a single institution's experience.

BACKGROUND: Despite 2-stage revision being a common treatment for elbow prosthetic joint infection (PJI), failure rates are high. The purpose of this study was to report on a single institution's experience with 2-stage revisions for elbow PJI and determine risk factors for failed eradication of infection. The secondary purpose was to determine risk factors for needing allograft bone at the second stage of revision in the setting of compromised bone stock. METHODS: We retrospectively analyzed all 2-stage revision total elbow arthroplasties (TEAs) performed for infection at a single institution between 2006 and 2020. Data collected included demographics and treatment course prior to, during, and after 2-stage revision. Radiographs obtained after explantation and operative reports were reviewed to evaluate for partial component retention and incomplete cement removal. The primary outcome was failed eradication of infection, defined as the need for repeat surgery to treat infection after the second-stage revision. The secondary outcome was the use of allograft for compromised bone stock during the second-stage revision. Risk factors for both outcomes were determined. RESULTS: Nineteen patients were included. Seven patients (37%) had either the humeral or ulnar component retained during the first stage, and 10 (53%) had incomplete removal of cement in either the humerus or ulna. Nine patients (47%) had allograft strut used during reimplantation and reconstruction. Nine patients (47%) failed to eradicate the infection after 2-stage revision. Demographic data were similar between the repeat-infection and nonrepeat-infection groups. Six patients (60%) with retained cement failed compared with 3 patients (33%) with full cement removal (P = .370). Two patients (29%) with a retained component failed compared to 7 patients (58%) with full component removal (P = .350). Allograft was used less frequently when a well-fixed component or cement was retained, with no patients with a retained component needing allograft compared to 9 with complete component removal (P = .003). Three patients (30%) with retained cement needed allograft, compared with 6 patients (67%) who had complete cement removal (P = .179). CONCLUSION: Nearly half of the patients failed to eradicate infection after 2-stage revision. The data did not demonstrate a clear association between retained cement or implants and risk of recurrent infection. Allograft was used less frequently when a component and cement were retained, possibly serving as a proxy for decreased bone loss during the first stage of revision. Therefore, the unclear benefit of removing well-fixed components and cement need to be carefully considered as it likely leads to compromised bone stock that complicates the second stage of revision.

Humeral stem loosening is not always prosthetic joint infection.

BACKGROUND: Aseptic humeral stem loosening is an uncommon complication of shoulder arthroplasty, and its presence has been considered a highly specific predictor of prosthetic joint infection (PJI). Literature on aseptic humeral stem loosening is sparse. The primary purpose of this study was to determine the rate of aseptic humeral loosening in revision shoulder arthroplasty. Secondarily, we sought to identify predictors of septic and aseptic humeral loosening. METHODS: Our institutional revision shoulder arthroplasty database was reviewed. Inclusion criteria were patients with humeral stem loosening as indicated in the operative report. Patient demographics, index surgery and indication, revision surgery and indication, and operative data were recorded. Charts were manually reviewed, and PJI scores were calculated using the International Consensus Meeting scoring criteria. International Consensus Meeting classifications of PJI "unlikely" and "possible" were considered aseptic, and PJI "probable" and "definite" were considered septic. Statistical analysis was performed to determine associations between the abovementioned variables and aseptic humeral loosening. RESULTS: Forty-six patients with 48 shoulders were included in our analysis. Ten cases (21%) were classified as definite PJI, 13 cases (27%) were classified as probable PJI, 4 cases (8%) were classified as possible PJI, and 21 cases (44%) were classified as PJI unlikely. On analysis of stem design, there were no statistically significant associations with aseptic loosening; although, a lack of proximal porous ingrowth surface trended toward higher rates of aseptic loosening in all patients and in anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) subgroup analyses. In the index RTSA subgroup, aseptic loosening was associated with female sex (P = .005). Seventeen of 39 shoulders (44%) that underwent either index ATSA or RTSA demonstrated concomitant glenoid loosening. The absence of glenoid loosening was associated with aseptic humeral loosening in index ATSA and RTSA (P < .001). CONCLUSION: Fifty-two % of revision shoulder arthroplasty cases with humeral loosening performed at our institution were aseptic. There appear to be distinct demographic and radiographic factors that are more commonly associated with aseptic as opposed to septic humeral loosening. Our data demonstrate that demographic predictors of aseptic loosening of RTSA include female sex. The absence of glenoid component loosening is associated with aseptic humeral loosening and concomitant glenoid loosening is associated with septic humeral loosening. Understanding of these factors can guide the preoperative index of suspicion for PJI in the setting of humeral stem loosening.

Kick-Starting Wound Healing: A Review of Pro-Healing Drugs.

Cutaneous wound healing consists of four stages: hemostasis, inflammation, proliferation/repair, and remodeling. While healthy wounds normally heal in four to six weeks, a variety of underlying medical conditions can impair the progression through the stages of wound healing, resulting in the development of chronic, non-healing wounds. Great progress has been made in developing wound dressings and improving surgical techniques, yet challenges remain in finding effective therapeutics that directly promote healing. This review examines the current understanding of the pro-healing effects of targeted pharmaceuticals, re-purposed drugs, natural products, and cell-based therapies on the various cell types present in normal and chronic wounds. Overall, despite several promising studies, there remains only one therapeutic approved by the United States Food and Drug Administration (FDA), Becaplermin, shown to significantly improve wound closure in the clinic. This highlights the need for new approaches aimed at understanding and targeting the underlying mechanisms impeding wound closure and moving the field from the management of chronic wounds towards resolving wounds.

Mechanistic Assessment of Metabolic Interaction between Single Oral Commensal Cells by Scanning Electrochemical Microscopy.

The human oral microbiome heavily influences the status of oral and systemic diseases through different microbial compositions and complex signaling between microbes. Recent evidence suggests that investigation of interactions between oral microbes can be utilized to understand how stable communities are maintained and how they may preserve health. Herein, we investigate two highly abundant species in the human supragingival plaque, Streptococcus mitis and Corynebacterium matruchotii, to elucidate their real-time chemical communication in commensal harmony. Specifically, we apply nanoscale scanning electrochemical microscopy (SECM) using a submicropipet-supported interface between two immiscible electrolyte solutions as an SECM probe not only to image the permeability of S. mitis and C. matruchotii membranes to tetraethylammonium (TEA+) probe ions but also to real-time visualize the metabolic interaction between two microbes via lactate production/consumption at a single-cell level. The metabolic relationship between two strains is quantitatively assessed by determining (1) the passive permeability of both bacterial membranes of 2.4 × 10-4 cm/s to the free diffusion of TEA+, (2) 0.5 mM of the lactate concentration produced by a single S. mitis strain at a rate of 2.7 × 10-4 cm/s, and (3) a lactate oxidation rate ≥5.0 × 106 s-1 by an individual C. matruchotii strain. Significantly, this study, for the first time, describes a mechanism of in situ metabolic interaction between oral commensals at the single-cell level through quantitative analysis, which supports the observed in vivo spatial arrangements of these microbes.

Ambulatory shoulder arthroplasty provides a mild reduction in overall cost compared with inpatient shoulder arthroplasty cost of ambulatory shoulder arthroplasty.

HYPOTHESIS: The purpose of this study was to determine the relative cost difference of inpatient vs. ambulatory total shoulder arthroplasty (TSA) procedures. METHODS: A retrospective case series was performed to identify a consecutive series of patients who underwent primary anatomic or reverse TSA at 2 orthopedic specialty hospitals between September 2015 and August 2020. Those undergoing surgery for fracture or revision were excluded. Itemized facility costs were analyzed with a time-driven activity-based costing model and compared between ambulatory and non-ambulatory procedures. Ambulatory patients were defined as those admitted and discharged on the same calendar day. All other patients were considered non-ambulatory. RESULTS: A total of 1027 patients were analyzed, comprising 38 ambulatory patients (3.7%) and 989 non-ambulatory patients (96.3%). There was a higher proportion of anatomic TSA than reverse shoulder arthroplasty in the ambulatory group (81.6% vs. 51.7%, P < .0001). Overall, there was no difference in cost between the 2 groups ($8832 vs. $8841, P = .97). However, personnel costs were greater in the non-same-day group ($1895 vs. $2743, P < .0001) whereas supply costs were less ($6937 vs. $6097, P < .0003). When implant costs were excluded, outpatient shoulder arthroplasty provided a cost savings of $745. CONCLUSION: Ambulatory shoulder arthroplasty provides a mild cost savings of $745 after controlling for fixed costs. This is much less dramatic than previously reported and should raise concern as shoulder arthroplasty continues to be targeted by payers as a potential for cost savings through decreased reimbursement.

Traumatic Elbow Instability: How to Fix It and When to Phone a Friend.

Traumatic elbow instability is a difficult condition to manage. Many surgeons consider the elbow a perplexing black box and evaluating damaged structures in the setting of pain and swelling a diagnostic challenge. Injury most commonly occurs from a fall onto an outstretched hand but also results from elbow dislocation, direct trauma, and sporting activities. The injury can initiate on the medial or lateral side, depending on forearm position at the time of injury, and usually follows a predictable pattern, with progressive instability caused by soft-tissue disruption and fractures of the medial or lateral column. Primary medial instability, lateral instability, and combined injury patterns have been described and discussed. Simple elbow dislocations and certain fractures can be managed nonsurgically, whereas complex patterns of instability and fracture-dislocations routinely require surgery. Stiffness and nerve injury are the most common complications and occur from both surgical and nonsurgical management. This chapter describes the diagnosis and management of traumatic elbow instability and the management of its sequela.

Identifying surgeon and institutional drivers of cost in total shoulder arthroplasty: a multicenter study.

BACKGROUND: Despite rapid increases in the demand for total shoulder arthroplasty, data describing cost trends are scarce. We aim to (1) describe variation in the cost of shoulder arthroplasty performed by different surgeons at multiple hospitals and (2) determine the driving factors of such variation. METHODS: A standardized, highly accurate cost accounting method, time-driven activity-based costing, was used to determine the cost of 1571 shoulder arthroplasties performed by 12 surgeons at 4 high-volume institutions between 2016 and 2018. Costs were broken down into supply costs (including implant price and consumables) and personnel costs, including physician fees. Cost parameters were compared with total cost for surgical episodes and case volume. RESULTS: Across 4 institutions and 12 surgeons, surgeon volume and hospital volume did not correlate with episode-of-care cost. Average cost per case of each institution varied by factors of 1.6 (P = .47) and 1.7 (P = .06) for anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RSA), respectively. Implant (56% and 62%, respectively) and personnel costs from check-in through the operating room (21% and 17%, respectively) represented the highest percentages of cost and highly correlated with the cost of the episode of care for TSA and RSA. CONCLUSIONS: Variation in episode-of-care total costs for both TSA and RSA had no association with hospital or surgeon case volume at 4 high-volume institutions but was driven primarily by variation in implant and personnel costs through the operating room. This analysis does not address medium- or long-term costs.

Radiographic humeral head restoration after total shoulder arthroplasty: does the stem make a difference?

BACKGROUND: Humeral stem designs for total shoulder arthroplasty have varied over the years, with a recent trend toward shorter stems. The purpose of this study was to examine the impact of humeral component stem length on the ability to restore the native humeral head anatomy. METHODS: We performed a retrospective review including patients who underwent total shoulder arthroplasty for primary osteoarthritis between 2007 and 2017 with complete operative reports and adequate radiographs. Surgical data including stem design were collected. Preoperative and postoperative radiographic measurements of the center of rotation (COR), humeral head height (HH), and neck-shaft angle were performed. Restoration of the native humeral anatomy was deemed "acceptable" based on postoperative differences in the COR ≤ 3 mm, HH ≤ 5 mm, and neck-shaft angle > 130°. Deviations between preoperative and postoperative measurements were compared across stem types. All available 2-year stemless implant radiographs were also analyzed. RESULTS: In total, 261 patients were included, with 31 stemless, 43 short-stem, and 187 standard-stem implants. There was no significant difference in COR restoration in the x-axis direction (P = .060) or y-axis direction (P = .579). There was no significant difference in restoration of acceptable HH by stem type (P = .339). Stemless arthroplasty implants were more likely to be placed in varus (22.6%) compared with short-stem (7.0%) and standard-stem (3.7%) designs (P < .001). CONCLUSION: Restoration of humeral anatomic parameters occurred significantly less with stemless implants than with short- and standard-stem implants. The stem of a shoulder arthroplasty implant aids surgeons in accurately restoring patient-specific anatomy.

Low-dose aspirin and the rate of symptomatic venous thromboembolic complications following primary shoulder arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) events are infrequent but potentially catastrophic complications following orthopedic surgery. There is currently a paucity of evidence regarding the role of chemoprophylaxis with low-dose aspirin (acetylsalicylic acid [ASA]) after shoulder arthroplasty. METHODS: We conducted a retrospective review of prospectively collected complications occurring within 90 days of 2394 primary shoulder arthroplasties performed over a 3-year period at a single institution. Patients preoperatively underwent risk stratification into medically high risk, moderate risk, or low risk as part of a standardized navigated-care pathway. For chemoprophylaxis, 81 mg of ASA (low dose) was routinely used once daily for 6 weeks unless alternative medications were deemed necessary by the medical team. Baseline demographic information, medical comorbidities, and postoperative VTE prophylaxis, as well as rates of clinically symptomatic VTE, were assessed. RESULTS: Symptomatic VTE occurred after 0.63% of primary shoulder arthroplasties (15 of 2394). There were 9 patients with deep vein thromboses and 6 with pulmonary embolisms. Eighty-one milligrams of ASA was used in 2141 patients (89.4%), resulting in an overall VTE rate of 0.56%. Medically high-risk patients were significantly more likely to have a VTE (P = .018). Patients with a history of deep vein thrombosis, asthma, and cardiac arrhythmia were significantly more likely to have a VTE (P < .05). Complications occurred in 4 patients (0.19%) associated with low-dose ASA and 1 patient (0.63%) associated with a novel oral anticoagulant medication. CONCLUSION: Routine use of low-dose ASA results in a very low risk of VTE and medication-associated complications following primary shoulder arthroplasty. Preoperative medical risk stratification can potentially identify patients at high risk of postoperative VTE.

Early repair of traumatic rotator cuff tears improves functional outcomes.

BACKGROUND: The impact of surgical timing on outcomes involving traumatic rotator cuff tears (RCTs) remains uncertain. The purpose of this study was to determine how functional outcomes are affected by surgical timing in traumatic RCTs. METHODS: We performed a retrospective review of patients with repair of traumatic full-thickness RCTs. Preoperative magnetic resonance imaging scans were evaluated by 2 blinded reviewers to measure RCT area and muscular atrophy. Functional outcomes were assessed via the American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE) score, Simple Shoulder Test score, and visual analog scale (VAS) pain score. Patients were divided into 4 groups based on the time from injury to surgery: 0-2 months (group 1), 2-4 months (group 2), 4-6 months (group 3), and 6-12 months (group 4). Multivariate analysis was performed to assess the impact of surgical timing on functional outcomes. A subanalysis was performed to assess outcomes in patients who underwent surgery within 3 weeks of injury. RESULTS: The study included 206 patients (150 men and 56 women) with a mean age of 60.0 ± 9.7 years and a minimum of 24 months' clinical follow-up (mean, 35.5 months; range, 24-54.4 months). The average tear area was 8.4 ± 6.3 cm2 in group 1 (66 patients), 5.8 ± 5.1 cm2 in group 2 (76 patients), 5.1 ± 4.6 cm2 in group 3 (29 patients), and 3.7 ± 3.1 cm2 in group 4 (35 patients) (P < .001). There were significant differences between the 4 cohorts in the final postoperative ASES score (P = .030) and VAS pain score (P = .032). The multivariate regression demonstrated that patients who underwent surgery within 4 months of injury had estimated improvements of 10.3 points in the ASES score (P = .008), 1.8 points in the Simple Shoulder Test score (P = .001), 8.6 points in the SANE score (P = .033), and 0.93 points in the VAS pain score (P = .028) compared with patients who underwent surgery later. The subanalysis demonstrated that patients who underwent surgery within 3 weeks of injury (n = 13) had significantly better VAS (P = .003), ASES (P = .008), and SANE (P = .019) scores than patients who underwent surgery at between 3 weeks and 4 months after injury (n = 129). CONCLUSIONS: This study demonstrates that surgical repair of traumatic RCTs results in significant improvements in functional outcomes for all patients; however, patients who undergo surgery within 3 weeks can expect the best functional outcomes, with a drop in function in patients who undergo surgery >4 months after injury.

Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry.

Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggers withdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence.SIGNIFICANCE STATEMENT This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., "e-cigarettes") likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder.

Interobserver reliability of the rotator cable and its relationship to rotator cuff congruity.

BACKGROUND: This study evaluated the presence of the rotator cable intraoperatively and compared its prevalence according to both patient age and rotator cuff integrity. The study hypothesis was that the cable would be more prevalent in older patients and patients with partial-thickness tears. METHODS: Patients who were undergoing shoulder arthroscopy and were aged at least 16 years were included in this study, whereas those who had a cuff tear of more than 1 tendon or who had a video with poor visualization of the rotator cuff insertion were excluded. Intraoperative videos were collected, deidentified, and distributed to 7 orthopedic surgeons to define rotator cable and cuff tear characteristics. RESULTS: A total of 58 arthroscopic videos (average patient age, 46 years; range, 16-75 years) were evaluated. The observers were in the most agreement on identifying the presence of a cable, with a κ coefficient of 0.276. Patients with the rotator cable were significantly older than those without it (mean age, 52.1 years vs. 42.5 years; P = .008), and a positive and significant correlation was found between rotator cable presence and increasing patient age (r = 0.27, P = .04). A significant association was noted between tear degree and cable presence (P = .002). There was no significant association with cable presence in patients with a full-thickness tear. CONCLUSIONS: In this study, an intraoperative analysis was performed to define the presence of the rotator cable and correlate this with both patient age and rotator cuff integrity. The hypothesis was confirmed in that patients older than 40 years had a significantly higher rotator cable prevalence.

Quantitative ultrahigh-molecular-weight polyethylene wear in total elbow retrievals.

BACKGROUND: The purpose of this study was to evaluate ultrahigh-molecular-weight polyethylene (UHMWPE) wear and damage from retrieved total elbow arthroplasty components and compare in vivo wear with wear produced in vitro. METHODS: Explanted total elbow components were collected at revision surgery. UHMWPE damage was characterized visually, whereas penetration and wear were quantified using micro-computed tomography and gas pycnometry. Volumetric wear rates were compared with historical hip data, and wear data were compared with reported in vitro wear test data. RESULTS: Humeral bushing damage primarily occurred in the form of burnishing, scratching, and pitting at the articular face in the region of contact with the ulnar component. Wear of the ulnar bushings was concentrated on the edge of the component at the point of contact with the axis pin. Pitting and embedded debris were dominant damage modes, in addition to burnishing and delamination. Backside wear was negligible. The median linear penetration rates of the lateral, medial, and ulnar bushings were 0.14 mm/yr (range, 0.01-0.78 mm/yr), 0.12 mm/yr (range, 0.03-0.55 mm/yr), and 0.11 mm/yr (range, 0.01-0.69 mm/yr), respectively. The volumetric wear rates of the lateral, medial, and ulnar bushings were 5.5 mm3/yr (range, 0.7-37.2 mm3/yr), 5.9 mm3/yr (range, 0.6-25.5 mm3/yr), and 5.5 mm3/yr (range, 1.2-51.2 mm3/yr), respectively. CONCLUSIONS: The observed wear rates were similar to those reported in well-functioning total hip replacement patients with conventional UHMWPE bearings. We found limitations in reported in vitro testing resulting in wear that was not consistent with our retrieval data. We recommend further investigation to clinically validate in vitro simulation to provide appropriate loading protocols for elbow wear simulation.

Revision total elbow arthroplasty failure rates: the impact of primary arthroplasty failure etiology on subsequent revisions.

BACKGROUND: The number of primary total elbow arthroplasties (TEAs) performed is increasing annually, necessitating a rise in the number of revision procedures. No studies exist to illustrate reliable indications for revision arthroplasty. The purpose of this study was to determine the impact of the etiology of primary TEA failure on the failure rate of revision surgery. METHODS: We retrospectively analyzed the patient charts of all revision TEAs performed at a single institution between 2006 and 2016. The primary outcome was revision failure, defined as the need for a second revision surgical procedure. Patients were organized into cohorts by etiology of primary implant failure. Failure rates, time to second revision, and average number of additional revisions were compared among cohorts. RESULTS: A total of 46 patients with a mean age of 62.7 years and minimum 2-year follow-up were included. The etiologies of failure identified were infection (n = 20), aseptic loosening (n = 17), periprosthetic fracture (n = 6), and bushing wear (n = 3). All noninfectious etiologies were grouped into an additional cohort. Patients who underwent revision for infection demonstrated a significantly greater failure rate and greater number of additional revisions per patient than those with aseptic loosening, those with periprosthetic fracture, and the noninfectious group, as well as a shorter time to failure than the noninfectious group. CONCLUSION: Patients in whom primary TEA fails because of infection are more likely to experience revision failure and require a greater number of subsequent operations than patients with other etiologies of primary TEA failure. These data question the efficacy of revision surgery in the treatment of infected TEAs.

ΔNp63α represses anti-proliferative genes via H2A.Z deposition.

ΔNp63α is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because ΔNp63α and p53 bind virtually identical DNA sequence motifs, it has been proposed that ΔNp63α functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress ΔNp63α and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by ΔNp63α that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of ΔNp63α status but fails to transactivate genes repressed by ΔNp63α. We found that ΔNp63α associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of ΔNp63α-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by ΔNp63α and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by ΔNp63α knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of ΔNp63α.

Understanding Transcriptional Networks Regulating Initiation of Cutaneous Wound Healing.

The epidermis has an essential function in creating a barrier against the external environment to retain proper fluid balance and block the entry of pathogens. When damage occurs to this barrier, the wound must quickly be sealed to avoid fluid loss, cleared of invading pathogens, and then keratinocytes must re-form an intact barrier. This requires complex integration of temporally and spatially distinct signals to execute orderly closure of the wound, and failure of this process can lead to chronic ulceration. Transcription factors serve as a key integration point for the myriad of information coming from the external environment, allowing for an orderly process of re-epithelialization. Importantly, transcription factors engage with and alter the chromatin structure around key target genes through association with different chromatin-modifying complexes. In this review, we will discuss the current understanding of how transcription is regulated during the initiation of re-epithelialization, and the exciting technological advances that will allow for a more refined mechanistic understanding of the re-epithelialization process.