Citations

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Purpose: The availability of an objective outcome measure for facial reconstructive surgery remains elusive. Evaluations submitted by external raters or by patient self-report are subjective, and may unreliably convey how one is perceived by others. We are interested in observers’ instantaneous responses to the human face. The goal of modern facelift and associated procedures for facial rejuvenation are to achieved subtle differences that lead to the perception of youth and attractiveness, yet the observer cannot pinpoint what exactly have been done to the patient’s face. We explored the visual markers that lead to differential perception of patients before and after facial rejuvenation surgery (high SMAS facelift, neck lift, fat grafting, brow lifts and blepharoplasty). Methods: 40 images were obtained which portrayed pre and post operative photos of patients who underwent high SMAS facelift, fat grafting, and browlifts and blepharoplasty for facial rejuvenation. Photographs were obtained before and after surgical correction (>3 months postop). 40 observers examined the images while an infrared eye-tracking camera recorded their eye movements. The observers were then asked to rate the image for character attributes (attractiveness, trustworthiness, sociability, healthy, and capability, 1-7 scale, and also estimate the age of the patient). Results: (i) The surgical intervention was found to decrease observers’ attention to the cervical region, but did not change how other areas are perceived significantly.(ii) The surgical intervention was found to significantly increase the character ratings for all five attributes compared to pre op controls: (sociable 3.53 to 4.18, trustworthy 3.85 to 4.20, attractive 3.34 to 3.3.90, health 4.07 to 4.61, capable 3.91 to 4.43.(iii) Average age estimate of the photos decreased significantly from 54 years (SD 6) to 48.6 years (SD 5.2), with true average age of 57.4 (7.6). Conclusion: We provide data illustrating a novel and objective technique to evaluate the effect of reconstructive intervention for facial rejuvenation. Consistent with the goals of subtle facial rejuvenation, the observers did not detect any particular areas of difference post operatively, but gain a more favorable impression of the person, and also perceived them as younger by a decade compared to their true age.

Purpose: Examining the outcomes and progression of face transplants has expanded to include the recent advancements in artificial intelligence. This novel methodology has allowed for the objective exploration of emotional expression. To our knowledge, this examined emotional expression has yet to be correlated to the hypothesized functioning of the allograft. We have combined the result of the AI software with a software analyzing smile excursion; demonstrating the progression of the allograft in our face transplant patient. This study helps illuminate the software possibilities for objective measures in transplant progression. Methods: Images were analyzed from our face transplant patient post-operatively at approximately 6-month intervals for four years. The still images for each time interval include both a neutral facial expression and a full-face smile with teeth. The images were taken from video clips of the patient and then analyzed using the FACEgram software (Hadlock & Urban, 2012). The measurements of the smile excursion were standardized based off of the pupil diameter and excursion was measured relative to the neutral expression of each time period. The emotional expression data was acquired using FaceReader AI software from Noldus Information Technology (Wageningen, The Netherlands). The emotional analysis was done on 2 second clips from clinical videos of the patient, the same videos used for the still images. This data was correlated with the smile excursion measurements. Results: The post-operative smile excursion analysis from 6 to 49 months demonstrated a near double in smile excursion from 3.58mm to 6.04mm. The smile excursion data has a squared correlation of 0.705; a strong upward linear trend of excursion. From 6 to 35 months, the happy emotion increased gradually from 0% to 15.8% (49-month data unavailable). Performed correlative analysis showed a positive correlation coefficient of 0.63. This moderate to strong correlation demonstrates the intuitive relationship of happy emotion and lip excursion during full face smiling. The findings also substantiate the AI software’s detection of increasing activity in the lip corner puller action unit from zero to 3/5 intensity over the same period. Conclusion: This study demonstrates the correlation of smile excursion to happy emotional expression in our face transplant patient. The correlation square of the lip excursion shows a trend of increased functioning of the allograft over time; substantiating the AI’s finding. This data provides evidence for the use of artificial intelligence as a measure of transplant strength progression. The conjoined analysis of patient images and videos has supported proof for the ability to analyze transplant healing progression and efficacy in an objective form. Hadlock, T. A., & Urban, L. S. (2012). Toward a Universal, Automated Facial Measurement Tool in Facial Reanimation. Archives of Facial Plastic Surgery,14(4). doi:10.1001/archfacial.2012.111

Purpose: Exceptional functional results can be obtained with toe to thumb transfers; however objective measures to evaluate the aesthetic outcome of a toe to thumb transfers remains elusive. Aesthetic evaluation of a reconstruction when performed by external raters or the patient, may be influenced by expert knowledge, emotional antecedent, or ethnic or regional bias. In this study, we were interested in determining the observers’ instantaneous, reflexive responses to the toe to thumb transfer as determined by eye-tracking analysis. Methods: 13 patients with unilateral great toe to thumb transfers were photographed using a standardized technique. None had undergone secondary procedures that changed the appearance of the transferred toe. Both hands were photographed side by side in each image. A dorsal and palmar image was taken, producing 26 photos in total. 40 observers (Average age 41.39, 14-65 yo, 18 males, 22 females), blinded to the procedure, were asked to evaluate each image for symmetry between the hands. An infrared eye-tracking camera continuously recorded their eye movements. Participants were allowed to evaluate each image for 6 seconds. Data was evaluated to determine the percent of time that was devoted to evaluating each portion of the photograph. The percent time spent in each of the lookzones was recorded. Results: i) Observers spent an average of 17.7% of their time evaluating the reconstructed thumb compared to the entire bilateral hand. This was on average 63% more time looking at the reconstructed thumb compared to the normal control thumb. (p value<0.01) ii) Observers spent 43.9% of the time looking at the reconstructed thumb compared to the entire hand of the same side. They spent 31.6% of the time looking at the normal control thumb compared to the entire hand of the same side (p value<0.01, mean 0.36 seconds on the abnormal thumb (SD 0.439)), vs. mean 0.22 seconds on normal control thumb (SD 0.305); mean 0.82 seconds on abnormal hand (SD 0.45), mean 0.69 seconds on normal contralateral hand (SD 0.423); mean 0.74 on entirely normal bilateral hand (SD 0.41)). iii) Areas of significant attention as visualized by heatmaps representing where observers focus their attention include abnormal nailbed and scar tissue at the junction between the toe and native hand skin. Conclusion: The technique described above may represent a novel and objective technique for quantifying observers’ gaze with respect to toe to thumb reconstructions and the un-altered contralateral thumb. It could be applied to other areas of hand reconstruction to help determine aesthetic outcomes. The present pilot suggests that symmetric nail size may be an area of importance for creating the sense of aesthetic success. Incorporation of this data into surgical counseling may assist the patient and medical team focus on surgical-decision making priorities.

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

AbstractBackgroundAdipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival.MethodsPlasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided.ResultsWe found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index &gt;30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P &lt; .001), in men vs women (median = 8185 vs 11 567 ng/mL; P &lt; .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P &lt; .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (&lt;30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS.ConclusionsLower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.