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HIV reservoirs and production of viral antigens are not eliminated in chronically infected participants treated with combination antiretroviral therapy (cART). Novel therapeutic strategies aiming at viral reservoir elimination are needed to address chronic immune dysfunction and non-AIDS morbidities that exist despite effective cART. The HIV envelope protein (Env) is emerging as a highly specific viral target for therapeutic elimination of the persistent HIV-infected reservoirs via antibody-mediated cell killing. Dual-Affinity Re-Targeting (DART) molecules exhibit a distinct mechanism of action via binding the cell surface target antigen and simultaneously engaging CD3 on cytotoxic T lymphocytes (CTLs). We designed and evaluated Env-specific DARTs (HIVxCD3 DARTs) derived from known antibodies recognizing diverse Env epitopes with or without broadly neutralizing activity. HIVxCD3 DARTs derived from PGT121, PGT145, A32, and 7B2, but not VRC01 or 10E8 antibodies, mediated potent CTL-dependent killing of quiescent primary CD4 T cells infected with diverse HIV isolates. Similar killing activity was also observed with DARTs structurally modified for in vivo half-life extension. In an ex vivo model using cells isolated from HIV-infected participants on cART, combinations of the most potent HIVxCD3 DARTs reduced HIV expression both in quiescent and activated peripheral blood mononuclear cell cultures isolated from HIV-infected participants on suppressive cART. Importantly, HIVxCD3 DARTs did not induce cell-to-cell virus spread in resting or activated CD4 T cell cultures. Collectively, these results provide support for further development of HIVxCD3 DARTs as a promising therapeutic strategy for targeting HIV reservoirs.

Purpose Locked plating (LP) of distal femoral fractures has become very popular. Despite technique suggestions from anecdotal and some early reports, knowledge about risk factors for failure, nonunion (NU), and revision is limited. The purpose of this study was to analyze the complications and clinical outcomes of LP treatment for distal femoral fractures. Materials and methods From two trauma centers, 243 consecutive surgically treated distal femoral fractures (AO/OTA 33) were retrospectively identified. Of these, 111 fractures in 106 patients (53.8% female) underwent locked plate fixation. They had an average age of 54 years (range 18 to 95 years): 34.2% were obese, 18.9% were smokers, and 18.9% were diabetic. Open fractures were present in 40.5% with 79.5% Gustilo type III. Fixation constructs for plate length, working length, and screw concentration were delineated. Nonunion and/or infection, and implant failure were used as outcome complication variables. Outcome was based on surgical method and addressed according to Pritchett for reduction, range of motion, and pain. Results Eighty-three (74.8%) of the fractures healed after the index procedure. Twenty (18.0%) of the patients developed a NU. Four of 20 (20%) resulted in a recalcitrant NU. Length of comminution did not correlate to NU ( p  = 0.180). Closed injuries had a higher tendency to heal after the index procedure than open injuries ( p  = 0.057). Closed and minimally open (Gustilo/Anderson types I and II) fractures healed at a significantly higher rate after the index procedure compared to type III open fractures (80.0% versus 61.3%, p  = 0.041). Eleven fractures (9.9%) developed hardware failure. Fewer nonunions were found in the submuscular group (10.7%) compared to open reduction (32.0%) ( p  = 0.023). Fractures above total knee arthroplasties had a significantly greater rate of failed hardware ( p  = 0.040) and worse clinical outcome according to Pritchett ( p  = 0.040). Loss of fixation was related to pain ( F  = 3.19, p  = 0.046) and a tendency to worse outcome ( F  = 2.43, p  = 0.071). No relationship was found between nonunion and working length. Conclusion Despite modern fixation techniques, distal femoral fractures often result in persistent disability and worse clinical outcomes. Soft tissue management seems to be important. Submuscular plate insertion reduced the nonunion rate. Preexisting total knee arthroplasty increased the risk of hardware failure. Further studies determining factors that improve outcome are warranted.

The final differentiation or maturation of dendritic cells (DCs) in response to environmental stimuli influences their ability to both initiate immunity and determine the quality of the response to antigens. Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for inadvertent DC activation in the steady state and during autoimmunity. Here, we show that selective blockade of the inhibitory Fcγ receptor (FcγR) FcγRIIb with recently developed monoclonal antibodies leads to maturation of human monocyte-derived DCs, which depends on the presence of IgG in normal human plasma. Plasma, in the presence of an FcγRIIb blockade, caused the DCs to up-regulate the expression of costimulatory molecules and to produce the inflammatory mediator IL-12p70. FcγRIIb blockade of DCs loaded with tumor cells led to increased tumor-specific T cell immunity without the need for exogenous stimuli other than human plasma. Therefore, the activation status of DCs in the presence of normal human serum depends on the balance between activating and inhibitory FcγRs and can be enhanced by new antibodies that react selectively with FcγRIIb. These data suggest an approach for modifying this balance to enhance immunity to immune complexes and antibody-coated tumor cells and to silence DC activation by immune complexes in autoimmune states.

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.

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.

There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with <10% remaining double positive. We also demonstrated the potential of the CSLC to differentiate to multi-lineage structures with branching lung morphology expressing bronchial, alveolar and neuroendocrine markers in vitro. Taken together the properties of these ASC-derived CSLC suggests that ASC may arise from a primitive lung stem cell distinct from the bronchial-alveolar or basal stem cells.

Humans infected with West Nile virus (WNV) may clinically present with symptoms that are suggestive of neurological infection. Nearly all treatments of WNV disease have been effective in animal models only if administered before or soon after viral challenge. Here, we evaluated whether a potent neutralizing anti-WNV humanized monoclonal antibody (MAb), hE16, could improve the course of disease in a hamster model when administered after the virus had infected neurons in the brain. Five days after viral injection, WNV was detected in the brains of hamsters by cytopathic assay, quantitative reverse-transcription polymerase chain reaction, and immunohistochemical staining of WNV envelope in neurons. Notably, 80%–90% of the hamsters treated 5 days after viral injection by intraperitoneal injection with hE16 survived the disease, compared with 37% of the placebo-treated hamsters (P⩽.001). The hamsters that received hE16 directly in the brain also exhibited markedly improved survival rates, compared with those in the placebo-treated hamsters. In prospective experiments, hamsters with high levels of infectious WNV in their cerebrospinal fluid were also protected by hE16 when administered 5 days after viral injection. These experiments suggest that humanized MAbs with potent neutralizing activity are a possible treatment for human patients after WNV has infected neurons in the central nervous system

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.

Psychopathy is characterized by impulsivity, antisocial behavior, and deficient affect, and it has also been associated with attention deficits. However, studies of the relationship between psychopathy and the underlying neurophysiology of attention have yielded mixed results, which may be due to the heterogeneous nature of psychopathy as well as the failure to account for the influence of a history of traumatic brain injury (TBI). This study investigated whether the neurophysiology of attention is differentially associated with individual psychopathic traits, and whether a history of TBI may change these associations. Psychopathic traits were assessed among college students (age = 18–26 years; 63% male) with (n = 20) and without (n = 23) a history of mild TBI. Brain activation in bilateral middle frontal gyri (MFG) was measured with functional near-infrared spectroscopy (fNIRS) during a block-designed (rest and task blocks) visual sustained attention task. Relative to non-TBI controls, participants with a history of TBI showed significantly more activation in the right MFG in response to the task. In participants without a history of TBI, self-centered impulsivity was positively associated with activation in the right MFG during the rest blocks, while coldheartedness was negatively associated with activation in the left MFG during the task. No relationships between psychopathic traits and MFG activation were found in those with a history of TBI. These findings indicate that MFG hypoactivation and hyperactivation may contribute to the affective coldness and impulsivity of psychopathy, respectively, and highlight the importance of assessing TBI in psychopathy research.

Category: Ankle, Ankle Arthritis, Hindfoot, Midfoot/Forefoot Introduction/Purpose: There has been in increased interest in foot and ankle arthritis in the literature in recent years. A significant focus of the literature has been which operative techniques are best for managing these problems. Some work has been done analogizing disability due to ankle arthritis to more familiar joints such as the hip. There is little data explaining how much patient reported disability is associated with each type of isolated foot and ankle arthritis. Various clinical rating scales have proven how debilitating foot and ankle arthritides can be to patients. The purpose of our study was to use Functional Foot Index (FFI) and Short Form-12 (SF-12) rating scales to compare the patient reported disability associated with ankle, hindfoot, midfoot, and hallux metatarsalphalangeal (MTP) arthritides. Methods: We retrospectively reviewed the FFI and SF-12 (both Physical Component Scores (PCS) and Mental Component Scores (MCS)) of patients who presented to a high volume orthopaedic foot and ankle practice between 2010 and 2016 with either ankle, hindfoot, midfoot or hallux MTP arthritis. We included patients between 18-65 years of age who underwent a surgical procedure for arthritis within 6 months of their initial presentation. We excluded patients with any medical or surgical co-morbidities known to affect disability scores. A total of 214 FFI and 195 SF-12 data sets were included. Results: Study population SF-12 PCS scores for all patients with ankle or foot arthritis were significantly lower than US age-based norms. Patients with ankle arthritis had the highest disability (FFI score 46.5, SF-12 PCS 32.3). Patients with midfoot and hindfoot arthritis had intermediate disability (Midfoot FFI score 34.9, SF-12 PCS 34.5; Hindfoot FFI score 44.3, SF-12 PCS 34.5). Patients with hallux MTP arthritis had the lowest disability (FFI score 32.9, SF-12 PCS 40.7). All FFI and SF-12 PCS scores were statistically significant. SF 12 MCS were not statistically significant. Conclusion: All patients with foot and ankle arthritis had increased disability compared to US age-based norms. Patients with ankle arthritis experience the most self-reported disability and patients with hallux MTP arthritis experience the least self- reported disability of the isolated types of arthritis in orthopaedic foot and ankle.