prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.

Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM+ virions can also contribute to pathogenesis during primary DENV infections.

Is MRI Overutilized for Evaluation of Knee Pain in Veterans?

MRI is an essential diagnostic imaging modality for many knee conditions; however, it is not indicated in the setting of advanced knee arthritis. Inappropriate MRI imaging adds to health care costs and may delay definitive management for many patients. The primary purpose of this study was to ascertain the frequency of inappropriate MRI scans performed at one Veterans' Administration Medical Center (VAMC). We performed a retrospective chart review of all knee MRIs ordered over a 6-month period. Inappropriate MRI was defined as MRI performed prior to radiographs (XRs), or in the presence of XRs demonstrating severe osteoarthritis, without leading to a nonarthroplasty procedure of the knee. Of the 304 cases reviewed, 36.8% (112) of the MRIs were deemed inappropriate, 33 were ordered by orthopedists, and 79 were ordered by other health care providers. Of the 33 ordered by orthopedists, 25 were ordered by retired/nonsurgical orthopedists. Obtaining an MRI delayed care by an average of 29.2 days. Of the 252 cases that had XR prior to MRI, none included all four views in the standard knee XR series and only four had weightbearing images. Over a third of knee MRIs performed at this VAMC were inappropriate and delayed care. Additionally, no XRs in our study contained all the necessary views to properly assess knee arthritis. These concerning findings signify a potential opportunity for education in diagnostic strategies, to better patient care and resource utilization in the VAMC.

Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody-drug Conjugate Targeting ADAM9-expressing Tumors.

ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non-small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody-drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).

Moral decision making in adolescents: The effects of peer attachment, interpersonal affect, and gender.

INTRODUCTION: Sacrificial moral dilemmas are a useful tool for understanding how individuals reconcile concerns for aggregate welfare with the emotional aversion to deliberately, personally harming others. Yet little is known about how adolescents respond to such dilemmas, even though adolescence is a crucial period for moral development. The present study sought to investigate how adolescents respond to such dilemmas, with a focus on gender differences, age differences, and the role of two individual differences factors: peer attachment and dampened interpersonal affect. METHODS: For this cross-sectional study, 103 adolescents (mean age = 14.5, SD = 0.81, range = 12-16; 54% girls; 41% Black, 24% White, 15% multiracial, 9% Hispanic/Latin, 3% Other, 2% Asian/Pacific Islander, 1% Native American, 5% no response) were recruited from the local community (Brooklyn, NY, USA). Adolescents responded to a series of sacrificial moral dilemmas. Then, participants and their caregivers completed questionnaires to assess adolescents' callous-unemotional traits (e.g., lack of empathy) and the quality of their peer relationships. RESULTS: On average, participants endorsed committing personal harm for the greater good in 53% of their responses. Girls endorsed personal utilitarian sacrifice more than boys. Peer attachment, but not dampened interpersonal affect, was associated with increased endorsement of personal utilitarian sacrifice. Age and responses to dilemmas were not associated. CONCLUSIONS: Our results suggest that peer relationships are an important part of adolescent moral decision-making, for girls in particular. Our results also indicate that adolescents' utilitarian responses to conventional sacrificial moral dilemmas do not reflect a decreased aversion to interpersonal harm.

Predictors of PROMIS Physical Function at 2 Years following Knee Surgery.

The purpose of this study was to evaluate Patient-Reported Outcomes Measurement Information System physical function (PROMIS PF) 2 years following knee surgery, and identify preoperative factors associated with postoperative PROMIS PF. Three hundred and sixty-five patients, age 17 years and older, undergoing knee surgery at one institution were studied. Patients completed multiple questionnaires prior to surgery and again 2 years postoperatively including PROMIS PF, International Knee Documentation Committee (IKDC), joint and body numeric pain scales (NPS), Tegner's activity scale (TAS), and Marx's activity rating scale (MARS). Mean PROMIS PF improved from 41.4 to 50.9 at 2 years postoperatively (p < 0.001) and was strongly correlated with 2-year IKDC scores. Older age, female gender, non-Hispanic ethnicity, unemployment, lower income, government insurance, smoking, preoperative opioid use, having a legal claim, comorbidities, previous surgeries, higher body mass index (BMI), and knee arthroplasty were associated with worse 2-year PROMIS PF. Multivariable analysis confirmed that lower BMI, less NPS body pain, and higher MARS were independent predictors of greater 2-year PROMIS PF and better improvement in PROMIS PF. In this large, broad cohort of knee surgery patients, multiple preoperative factors were associated with PROMIS PF 2 years postoperatively. PROMIS PF scores improved significantly, but worse 2 year PROMIS PF scores and less improvement from baseline were independently predicted by higher BMI, greater NPS body pain, and lower MARS activity level. PROMIS PF can be implemented as an efficient means to assess outcomes after knee surgery.

Predictors of two-year patient satisfaction following elective knee surgery.

BACKGROUND: Patient satisfaction metrics are increasingly being utilized as tools to evaluate the quality of healthcare and affect reimbursements. The objectives of this study were to (1) identify factors associated with two-year patient satisfaction after elective knee surgery, (2) compare the Surgical Satisfaction Questionnaire-8 (SSQ-8) and a numeric satisfaction scale (NSS), and (3) determine if two-year patient satisfaction can be predicted based on preoperative factors. METHODS: A total of 365 patients undergoing elective knee surgery at a single center were administered questionnaires to assess demographics, medical history, and various patient-reported outcomes preoperatively and at two years postoperatively. Patient satisfaction was measured at two years postoperatively with SSQ-8 and NSS. Bivariate and multivariate statistical analyses were performed to identify significant associations and independent predictors of satisfaction. RESULTS: SSQ-8 and NSS scores were significantly correlated (rs = 0.68, P < 0.0001). Lower SSQ-8 and NSS scores were associated with black race, higher BMI, more comorbidities, unemployment, smoking, higher ASA score, and greater Met Expectations (P < 0.05). Better scores on patient-based outcome measures and better improvement from baseline were significantly correlated with higher satisfaction on both SSQ-8 and NSS. Multivariable analysis identified greater Met Expectations and higher two-year Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference scores as independent predictors of greater SSQ-8 scores (adjusted r2 = .52). Greater Met Expectations and better two-year PROMIS Social Satisfaction scores were independent predictors of NSS score (adjusted r2 = .41). In contrast, when only preoperative variables were considered, the multivariable regression model accounted for only 14% of the variance in SSQ-8 and 6% of the variance in NSS. CONCLUSION: While there are multiple preoperative factors that are associated with two-year patient satisfaction after knee surgery, those factors contribute relatively little to satisfaction. Meeting expectations and better patient-based outcomes at two years are more important.

Current surgical practice for septic arthritis of the knee in the United States.

For septic arthritis of the knee, we attempted to determine: the preferred surgical technique in the United-States (US), the believed "gold-standard" treatment among others. This was performed by an electronic-survey distributed to all academic orthopaedic faculty throughout the US. The preferred method was arthroscopy (69.8%). Arthroscopy is believed to be the gold-standard in 27.0%, arthrotomy in 29.4%, while 43.5% believe no gold-standard exists. In conclusion the majority of surgeons prefer arthroscopy when managing a native, septic knee in an adult patient. However, there is no national consensus on a gold-standard treatment or the role of synovectomy.

Single-Sided Reciprocating Saw for Tibial Component Removal During Revision Total Knee Arthroplasty.

Revision total knee arthroplasty often necessitates removing well-fixed components. Tibial tray removal is challenging becaue of 1) physical barriers posed by the component pegs, keel, or stem in accessing the implant-bone interface circumferentially and 2) proximity of vulnerable structures including the patellar tendon, collateral ligaments, popliteal artery, and distal femur. In this report, we present a step-by-step technique for removal of a well-fixed tibial component using a single-sided reciprocating saw.

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. OBJECTIVE: To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. DESIGN, SETTING, AND PARTICIPANTS: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. INTERVENTIONS: Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. MAIN OUTCOMES AND MEASURES: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. RESULTS: A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02492711.

Glenoid bony morphology of osteoarthritis prior to shoulder arthroplasty: what the surgeon wants to know and why.

Shoulder arthroplasty is performed with increasing frequency, and osteoarthritis is the most common indication for this procedure. However, the glenoid side of the joint is widely recognized as a limiting factor in the long-term durability of shoulder replacement, and osteoarthritis leads to characteristic bony changes at the glenoid which can exacerbate this challenge by reducing the already limited glenoid bone stock, by altering biomechanics, and by interfering with operative exposure. This article reviews the Walch classification system for glenoid morphology. Several typical findings of osteoarthritis at the glenoid are discussed including central bone loss, posterior bone loss, retroversion, biconcavity, inclination, osteophyte formation, subchondral bone quality, and bone density. The three primary types of shoulder arthroplasty are reviewed, along with several techniques for addressing glenoid deformity, including eccentric reaming, bone grafting, and the use of augmented glenoid components. Ultimately, a primary objective at shoulder arthroplasty is to correct glenoid deformity while preserving bone stock, which depends critically on characterizing the glenoid at pre-operative imaging. Understanding the surgical techniques and the implications of glenoid morphology on surgical decision-making enables the radiologist to provide the morphologic information needed by the surgeon.

Preclinical Development of MGC018, a Duocarmycin-based Antibody-drug Conjugate Targeting B7-H3 for Solid Cancer.

B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody-drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vc-seco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg.

Use of a custom website by orthopaedic sports medicine surgical patients: If you build it, will they come?

BACKGROUND: Internet use is nearly ubiquitous, and orthopaedic patients are increasingly utilizing the Internet for medical information. The quality of resources available to patients is variable, and patients may benefit from physician guidance. A recent study showed only 11% of orthopaedic trauma patients accessed a custom-designed website developed by a physician. The purpose of this study was to determine whether orthopaedic sports medicine patients would use a custom-designed website and what factors would be associated with website use. METHODS: A prospective study was conducted of patients undergoing eight common orthopaedic sports medicine procedures from April 2017 to December 2017.108 patients were enrolled and provided access to the website that allowed tracking of each patient's website use. The sports medicine cohort was compared to a previously published trauma cohort using the same methodology in a similar population at the same institution. The custom-designed website was replicated from the previous trauma study, but with the patient information now focused on sports medicine conditions and procedures. Patients' access to the website, tracking of website use, data collection, and analysis was identical to the previous trauma cohort. Bivariate and multivariate analyses were performed to determine which patient factors were associated with website use. RESULTS: 33 orthopaedic sports medicine patients (31%) accessed the website, and of those, 96% found the website helpful or very helpful. Orthopaedic sports medicine patients were nearly 3 times more likely to use the designated website than orthopaedic trauma patients (31% vs. 11%; p = 0.0004). Higher education predicted website use (p = 0.006). Age, gender, race, employment status, and household income were not predictive of use (p = 0.49, 0.27, 0.23, 0.15, 0.58; respectively). Anterior cruciate ligament (ACL) reconstruction was associated with website use as compared to meniscus and cartilage surgery (42% vs. 20%; p = 0.037). Nominal logistic regression analysis confirmed higher level of education (p = 0.00001) and ACL reconstruction (p = 0.0005) independently predicted website use. CONCLUSION: Orthopaedic sports medicine surgical patients are more likely to use a custom-designed informational website than orthopaedic trauma patients. However, only 31% of sports medicine patients accessed the website. Inherent differences between groups may account for the differences in website use. Higher level of education is predictive of website use, as is ACL reconstruction for knee surgery patients. Physicians should work to direct patients to high quality Internet resources given the vast amount of potentially unreliable information available.

Can Liposomal Bupivacaine Be Safely Utilized in Elective Spine Surgery?

STUDY DESIGN: Single-blinded prospective randomized control trial. OBJECTIVES: To compare the incidence of adverse events (AEs) and hospital length of stay between patients who received liposomal bupivacaine (LB) versus a single saline injection, following posterior lumbar decompression and fusion surgery for degenerative spondylosis. METHODS: From 2015 to 2016, 59 patients undergoing posterior lumbar decompression and fusion surgery were prospectively enrolled and randomized to receive either 60 mL injection of 266 mg LB or 60 mL of 0.9% sterile saline, intraoperatively. Outcome measures included the incidence of postoperative AEs and hospital length of stay. RESULTS: The most common AEs in the treatment group were nausea (39.3%), emesis (18.1%), and hypotension (18.1%). Nausea (23%), constipation (19.2%), and urinary retention (15.3%) were most common in the control group. Patients who received LB had an increased risk of developing nausea (relative risk [RR] = 1.7; 95% confidence interval [CI] = 0.75-3.8), emesis (RR = 2.3; 95% CI = 0.51-10.7), and headaches (RR = 2.36; 95% CI = 0.26-21.4). Patients receiving LB had a decreased risk of developing constipation (RR = 0.78; 95% CI = 0.25-2.43), urinary retention (RR = 0.78; 95% CI = 0.21-2.85), and pruritus (RR = 0.78; 95% = 0.21-2.8) postoperatively. Relative risk values mentioned above failed to reach statistical significance. No significant difference in the hospital length of stay between both groups was found (3.9 vs 3.9 days; P = .92). CONCLUSION: Single-dose injections of LB to the surgical site prior to wound closure did not significantly increase or decrease the incidence or risk of developing AEs postoperatively. Furthermore, no significant difference was found in the hospital length of stay between both groups.

Decompression Versus Fusion for Grade I Degenerative Spondylolisthesis: A Meta-Analysis.

STUDY DESIGN: Meta-analysis of evidence level I to IV studies. OBJECTIVE: To compare decompression alone versus decompression plus fusion in the treatment of grade I degenerative spondylolisthesis (DS). METHODS: Following established guidelines, we systematically reviewed 3 electronic databases to assess studies evaluating patients with grade I DS. We stratified all patients into 2 cohorts; the first cohort underwent a decompression-type surgery, and the second cohort underwent decompression plus fusion. We noted clinical outcomes, complications, reoperations, and surgical details such as blood loss. Descriptive statistics and random-effects models were used to determine the specified outcome metrics with 95% confidence intervals (CIs). RESULTS: In both cohorts, the pain (legs and lower back) significantly decreased and the physical component of the Short Form 36 showed better patient clinical outcomes. The decompression cohort had a 5.8% complication rate (95% CI = 1.7-2.1), and the decompression plus fusion cohort had an 8.3% complication rate (95% CI = 5.5-11.6). The reoperation rate was higher in the decompression-only cohort (8.5%; 95% CI = 2.9-17.0) compared with the decompression plus fusion cohort (4.9%; 95% CI = 2.5-7.9). CONCLUSIONS: There does not appear to be any advantage of one procedure over the other. Patients undergoing decompression alone tended to be older with a higher percentage of leg pain, whereas patients additionally undergoing fusion tended to be younger with more lower back pain. The decompression-only cohort had fewer complications but a higher revision rate.

Biomechanical evaluation of lumbar lateral interbody fusion for the treatment of adjacent segment disease.

BACKGROUND CONTEXT: Adjacent segment disease (ASD) is a well-known complication after lumbar fusion. Lumbar lateral interbody fusion (LLIF) may provide an alternative method of treatment for ASD while avoiding the morbidity associated with revision surgery through a traditional posterior approach. This is the first biomechanical study to evaluate the stability of lateral-based constructs for treating ASD in existing multilevel fusion model. PURPOSE: We aimed to evaluate the biomechanical stability of anterior column reconstruction through the less invasive lateral-based interbody techniques compared with traditional posterior spinal fusion for the treatment of ASD in existing multilevel fusion. STUDY DESIGN/SETTING: Cadaveric biomechanical study of laterally based interbody strategies for treating ASD. METHODS: Eighteen fresh-frozen cadaveric specimens were nondestructively loaded in flexion, extension, and lateral bending. The specimens were randomized into three different groups according to planned posterior spinal instrumented fusion (PSF): group 1: L5-S1, group 2: L4-S1, and group 3: L3-S1. In each group, ASD was considered the level cranial to the upper-instrumented vertebrae (UIV). After testing the intact spine, each specimen underwent PSF representing prior fusion in the ASD model. The adjacent segment for each specimen then underwent (1) Stand-alone LLIF, (2) LLIF + plate, (3) LLIF + single screw rod (SSR) anterior instrumentation, and (4) LLIF + traditional posterior extension of PSF. In all conditions, three-dimensional kinematics were tracked, and range of motion (ROM) was calculated for the comparisons. RESULTS: ROM results were expressed as a percentage of the intact spine ROM. LLIF effectively reduces ROM in all planes of ROM. Supplementation of LLIF with plate or SSR provides further stability as compared with stand-alone LLIF. Expansion of posterior instrumentation provides the most substantial stability in all planes of ROM (p <.05). All constructs demonstrated a consistent trend of reduction in ROM between all the groups in all bending motions. CONCLUSIONS: This biomechanical study suggests potential promise in exploring LLIF as an alternative treatment of ASD but reinforces previous studies' findings that traditional expansion of posterior instrumentation provides the most biomechanically stable construct.

Patients' Use and Perception of Internet-Based Orthopaedic Sports Medicine Resources.

BACKGROUND: Current research is sparse regarding how patients with orthopaedic injuries perceive and use internet-based information resources. HYPOTHESIS: The majority of patients use the internet to research their orthopaedic condition and are receptive to guidance from their provider. STUDY DESIGN: Cross-sectional study. METHODS: A total of 213 patients attending a sports medicine clinic on the East Coast of the United States were asked to complete a questionnaire regarding their use of internet-based information. Data from 185 patients were available for analysis. Bivariate and multivariate statistical analyses were used to determine the significance of identified associations. RESULTS: Overall, 54% of patients used the internet to find information about their orthopaedic condition prior to their consultation. A higher percentage of internet users were women (P = .01), were white (P = .03), and had internet access at home (P = .02). Multivariable analysis found home internet access to be the only significant independent factor predictive of patients using internet-based information sources (P < .01). The majority of patients (61%) were neutral toward orthopaedic information found online, and only 32% of patients trusted the orthopaedic information they found online. The majority of patients (83%) reported they would be receptive to providers' guidance on which internet resources to use. CONCLUSION: Only half of patients use the internet to research their orthopaedic condition. Most patients were either neutral toward or did not trust the internet-based information that they found and may forgo internet sources altogether. To help patients avoid misleading information, sports medicine providers should understand how patients are using the internet and guide patients in selecting high-quality, peer-reviewed sources of information. Doing so allows physicians to proactively educate their patients even after the clinic visit.

Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer.

We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 µg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33-expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD-1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 µg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together, MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Mol Cancer Ther; 17(8); 1761-72. ©2018 AACR.

Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair.

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.

The Effect of Level I Evidence on Surgical Decision Making in the United States Versus Canada.

BACKGROUND: In this study, we examined the difference that randomized trials favoring either surgery or nonsurgical treatment had on the surgical indications of American versus Canadian surgeons. METHODS: One randomized trial favoring surgical management of clavicle fractures and another one favoring nonsurgical management of Achilles tendon ruptures were used. American and Canadian orthopaedic surgeons were surveyed regarding their surgical indications for these injuries. RESULTS: More than 2000 US and 200 Canadian responses were received. For clavicles, 57% of US respondents indicated that the trial changed their practice, with 64% operating on more fractures, compared with Canadians at 78% and 68%, respectively. For Achilles, 37% of US respondents indicated that the trial changed their practice, with 29% operating on fewer ruptures, compared with Canadians at 72% and 67%, respectively. CONCLUSION: American surgeons seem more willing to alter their practice to "evidence-based" indications for a trial that favors surgery rather than one that does not.

Glucocorticoid-associated blood glucose response and MS relapse recovery.

OBJECTIVE: To determine the relationship between MS relapse recovery and blood glucose (BG) response to IV methylprednisolone (IVMP) treatment. METHODS: We retrospectively identified 36 patients with MS admitted for IVMP treatment of acute relapse who had adequate data to characterize BG response, relapse severity, and recovery. The relationship between glucocorticoid-associated nonfasting BG (NFBG) and relapse recovery was assessed. RESULTS: Highest recorded nonfasting BG (maximum NFBG [maxNFBG]) values were significantly higher in patients with MS without relapse recovery compared with those with recovery (271 ± 68 vs 209 ± 48 mg/dL, respectively; p = 0.0045). After adjusting for relapse severity, MS patients with maxNFBG below the group median were 6 times (OR = 6.01; 95% CI, 1.08-33.40; p = 0.040) more likely to experience relapse recovery than those with maxNFBG above the group median. In a multiple regression model adjusting for age, sex, and relapse severity, a 1-mg/dL increase in the maxNFBG was associated with 4.5% decrease in the probability of recovery (OR = 0.955; 95% CI, 0.928-0.983; p = 0.002). CONCLUSIONS: These findings suggest that higher glucocorticoid-associated NFBG values in acutely relapsing patients with MS are associated with diminished probability of recovery. This relationship could reflect steroid-associated hyperglycemia and/or insulin resistance, defects in non-steroid-associated (e.g., prerelapse) glucose metabolism, or both. This study included only those admitted for an MS relapse, and it is this subset of patients for whom these findings may be most relevant. A prospective study to evaluate glucose regulation and MS relapse recovery in a broader outpatient MS population is under way.