Citations

Abstract CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

PURPOSE The purpose of this study was to determine if dose de-escalation from 60 to 66 Gy to 30 to 36 Gy of adjuvant radiotherapy (RT) for selected patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma could maintain historical rates for disease control while reducing toxicity and preserving swallow function and quality of life (QOL). PATIENTS AND METHODS MC1273 was a single-arm phase II trial testing an aggressive course of RT de-escalation after surgery. Eligibility criteria included patients with p16-positive oropharyngeal squamous cell carcinoma, smoking history of 10 pack-years or less, and negative margins. Cohort A (intermediate risk) received 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks along with 15 mg/m 2 docetaxel once per week. Cohort B included patients with extranodal extension who received the same treatment plus a simultaneous integrated boost to nodal levels with extranodal extension to 36 Gy in 1.8-Gy fractions twice per day. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. RESULTS Accrual was from September 2013 to June 2016 (N = 80; cohort A, n = 37; cohort B, n = 43). Median follow-up was 36 months, with a minimum follow-up of 25 months. The 2-year locoregional tumor control rate was 96.2%, with progression-free survival of 91.1% and overall survival of 98.7%. Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. Swallowing function improved slightly between pre-RT and 12 months post-RT, with one patient requiring temporary feeding tube placement. CONCLUSION Aggressive RT de-escalation resulted in locoregional tumor control rates comparable to historical controls, low toxicity, and little decrement in swallowing function or QOL.

Background: Anterior cruciate ligament (ACL) tears and concomitant medial collateral ligament (MCL) injuries are known to occur during dynamic athletic tasks that place combinatorial frontal and transverse plane loads on the knee. A mechanical impact simulator that produces clinical presentation of ACL injury allows for the quantification of individual loading contributors leading to ACL failure. Purpose/Hypothesis: The objective was to delineate the relationship between knee abduction moment, anterior tibial shear, and internal tibial rotation applied at the knee and ACL strain during physiologically defined simulations of impact at a knee flexion angle representative of initial contact landing from a jump. The hypothesis tested was that before ACL failure, abduction moment would induce greater change in ACL strain during landing than either anterior shear or internal rotation. Study Design: Controlled laboratory study. Methods: Nineteen cadaveric specimens were subjected to simulated landings in the mechanical impact simulator. During simulations, external knee abduction moment, internal tibial rotation moment, and anterior tibial shear loads were derived from a previously analyzed in vivo cohort and applied to the knee in varying magnitudes with respect to injury risk classification. Implanted strain gauges were used to track knee ligament displacement throughout simulation. Kruskal-Wallis tests were used to assess strain differences among loading factors, with Wilcoxon each pair post hoc tests used to assess differences of magnitude within each loading. Results: Each loading factor significantly increased ACL strain ( P < .005). Within factors, the high-risk magnitude of each factor significantly increased ACL strain relative to the baseline condition ( P≤ .002). However, relative to knee abduction moment specifically, ACL strain increased with each increased risk magnitude ( P≤ .015). Conclusion: Increased risk levels of each load factor contributed to increased levels of ACL strain during a simulated jump landing. The behavior of increased strain between levels of increased risk loading was most prevalent for changes in knee abduction moment. This behavior was observed in the ACL and MCL. Clinical Relevance: Knee abduction moment may be the predominant precursor to ACL injury and concomitant MCL injury. As knee abduction occurs within the frontal plane, primary preventative focus should incorporate reduction of frontal plane knee loading in landing and cutting tasks, but secondary reduction of transverse plane loading could further increase intervention efficacy. Constraint of motion in these planes should restrict peak ACL strain magnitudes during athletic performance.

Purpose To evaluate for appearance-based discrimination in the selection of radiology residents. Method A deception study simulating the resident selection process examined the impact of attractiveness and obesity on resident selection. Seventy-four core faculty from 5 academic radiology departments reviewed mock residency applications in September and October 2017. Each application included demographic information and a photograph, representing a prespecified distribution of facial attractiveness and obesity, combined with randomized academic and supporting variables. Reviewers independently scored applications for interview desirability. Reviewer scores and application variables were compared using linear mixed fixed- and random-effects models. Results Reviewers evaluated 5,447 applications (mean: 74 applications per reviewer). United States Medical Licensing Examination Step 1 scores were the strongest predictor of reviewer rating (B = 0.35 [standard error (SE) = 0.029]). Applicant facial attractiveness strongly predicted rating (attractive vs unattractive, B = 0.30 [SE = 0.056]; neutral vs unattractive, B = 0.13 [SE = 0.028]). Less influential but still significant predictors included race/ethnicity (B = 0.25 [SE = 0.059]), preclinical class rank (B = 0.25 [SE = 0.040]), clinical clerkship grades (B = 0.23 [SE = 0.034]), Alpha Omega Alpha membership (B = 0.21 [SE = 0.032]), and obesity (vs not obese) (B = −0.14 [SE = 0.024]). Conclusions Findings provide preliminary evidence of discrimination against facially unattractive and obese applicants in radiology resident selection. Obesity and attractiveness were as influential in applicant selection for interview as traditional medical school performance metrics. Selection committees should invoke strategies to detect and manage appearance-based bias.