Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine-tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

Impact of Pharmacists to Improve Patient Care in the Critically Ill: A Large Multicenter Analysis Using Meaningful Metrics With the Medication Regimen Complexity-ICU (MRC-ICU) Score.

OBJECTIVES: Despite the established role of the critical care pharmacist on the ICU multiprofessional team, critical care pharmacist workloads are likely not optimized in the ICU. Medication regimen complexity (as measured by the Medication Regimen Complexity-ICU [MRC-ICU] scoring tool) has been proposed as a potential metric to optimize critical care pharmacist workload but has lacked robust external validation. The purpose of this study was to test the hypothesis that MRC-ICU is related to both patient outcomes and pharmacist interventions in a diverse ICU population. DESIGN: This was a multicenter, observational cohort study. SETTING: Twenty-eight ICUs in the United States. PATIENTS: Adult ICU patients. INTERVENTIONS: Critical care pharmacist interventions (quantity and type) on the medication regimens of critically ill patients over a 4-week period were prospectively captured. MRC-ICU and patient outcomes (i.e., mortality and length of stay [LOS]) were recorded retrospectively. MEASUREMENTS AND MAIN RESULTS: A total of 3,908 patients at 28 centers were included. Following analysis of variance, MRC-ICU was significantly associated with mortality (odds ratio, 1.09; 95% CI, 1.08-1.11; p < 0.01), ICU LOS (ß coefficient, 0.41; 95% CI, 00.37-0.45; p < 0.01), total pharmacist interventions (ß coefficient, 0.07; 95% CI, 0.04-0.09; p < 0.01), and a composite intensity score of pharmacist interventions (ß coefficient, 0.19; 95% CI, 0.11-0.28; p < 0.01). In multivariable regression analysis, increased patient: pharmacist ratio (indicating more patients per clinician) was significantly associated with increased ICU LOS (ß coefficient, 0.02; 0.00-0.04; p = 0.02) and reduced quantity (ß coefficient, -0.03; 95% CI, -0.04 to -0.02; p < 0.01) and intensity of interventions (ß coefficient, -0.05; 95% CI, -0.09 to -0.01). CONCLUSIONS: Increased medication regimen complexity, defined by the MRC-ICU, is associated with increased mortality, LOS, intervention quantity, and intervention intensity. Further, these results suggest that increased pharmacist workload is associated with decreased care provided and worsened patient outcomes, which warrants further exploration into staffing models and patient outcomes.

Determining presentation skills gaps among healthcare professionals.

Healthcare professionals frequently communicate complex medical information among colleagues and students. This paper aims to determine gaps in healthcare professionals' presentation skills and identify barriers to improving. Eighty-eight individuals at a Midwest Academic Medical Center completed a survey that consisted of three parts: (1) respondents' current presentation slide deck, (2) respondents' perceptions of their current presentation skills, and (3) barriers to and motivations for improving their presentation skills. A mixed-methods approach was used to collect and analyze data. Respondents used bullet points and text the most (74%), and videos the least in their presentations (51%). When assessing respondents' perceptions of their current presentation skills, they rated themselves the lowest as a storyteller (median = 6/10) and as an overall presenter (median = 6/10). The biggest barrier reported was "lack of training on best practices" (58%). Respondents reported "interested in improving" and "enhance opportunities" as their main motivations for improving presentation skills. Four themes emerged from the open-ended survey items: Practical tips and best practices, Ability to communicate effectively, Professional development, and Practice opportunities. Effective presentation skills should be included in every healthcare professionals faculty development curriculum. This is especially crucial for junior faculty members to ensure their continued success.

Signal-To-Noise Ratio Calculations to Validate Sensor Positioning for Facial Muscle Assessment Using Noninvasive Facial Electromyography.

The evaluation of neuromodulator treatment outcomes can be performed by noninvasive surface-derived facial electromyography (fEMG) which can detect cumulative muscle fiber activity deep to the skin. The objective of the present study is to identify the most reliable facial locations where the motor unit action potentials (MUAPs) of various facial muscles can be quantified during fEMG measurements. The study population consisted of five males and seven females (31.0 [12.9] years, body mass index of 22.15 [1.6] kg/m2). Facial muscle activity was assessed in several facial regions in each patient for their respective muscle activity utilizing noninvasive surface-derived fEMG. Variables of interest were the average root mean square of three performed muscle contractions (= signal) (µV), mean root mean square between those contraction with the face in a relaxed facial expression (= baseline noise) (µV), and the signal to noise ratio (SNR). A total of 1,709 processed fEMG signals revealed one specific reliable location in each investigated region based on each muscle's anatomy, on the highest value of the SNR, on the lowest value for the baseline noise, and on the practicability to position the sensor while performing a facial expression. The results of this exploratory study may help guiding future researchers and practitioners in designing study protocols and measuring individual facial MUAP when utilizing fEMG. The locations presented herein were selected based on the measured parameters (SNR, signal, baseline noise) and on the practicability and reproducibility of sensor placement.

Blind nasogastric tube advancement following sleeve gastrectomy: an animal model.

BACKGROUND: Sleeve gastrectomy is an effective surgical treatment for morbid obesity. The major technical risk of this procedure is staple line dehiscence. Some surgeons are reluctant to place a nasogastric tube (NGT) blindly due to the perceived risk of damage to the staple line. We sought to determine whether such concern was warranted. METHODS: A porcine tissue model (Animal Technologies, Inc., Tyler, TX) was used. Sleeve gastrectomy was performed using a flexible gastroscope as a guide for the Endo GIA stapler (Covidien, New Haven, CT) in an identical fashion used in our patients. The specimen was then placed in a plastic model of the thorax (VATS Trainers, LLC. Lansing, MI). The NGT was blindly advanced to 55 cm for a total of 50 passes, and to 75 cm for another 50 passes. Endoscopy with water submersion was performed to evaluate for injury or leak. RESULTS: After multiple passes of the NGT, no significant injuries, leaks, or perforations were observed to the gastric model, except for several small petechiae of the gastric mucosa, the largest measuring approximately 3 mm. None were of full thickness or penetrated the mucosa. The staple line showed no evidence of trauma. CONCLUSION: In this porcine model, blind NGT placement was not associated with significant mucosal injury or any damage to the sleeve gastrectomy staple line.

Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5).

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Collectively, our results firmly establish the significance of C-terminal phosphorylation in regulating ERK5 function. The post-translational modification of ERK5 on its C-terminal tail might be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated.

Prospective memory intervention using visual imagery in individuals with brain injury.

Prospective memory deficits are common after brain injury and can create impediments to independent living. Most approaches to management of such deficits are compensatory, such as the use of notebooks or electronic devices. While these can be effective, a restorative approach, in theory, could lead to greater generalisation of treatment. In the current study a metacognitive technique, using visual imagery, was employed under conditions of rote repetition and spaced retrieval. Treatment was provided in an AB-BA crossover design with A as the active treatment and B as a no-treatment attention control to 20 individuals with brain injury. A group of 20 healthy participants served to control for effects of re-testing. Individuals with brain injury demonstrated improvement on the main outcome measure of prospective memory, the Memory for Intentions Screening Test, only after the active treatment condition. In addition, some generalisation of treatment was measured in daily life. Moreover, treatment gains were maintained for one year after treatment was completed.

Gene signatures of postoperative atrial fibrillation in atrial tissue after coronary artery bypass grafting surgery in patients receiving ß-blockers.

Atrial tissue gene expression profiling may help to determine how differentially expressed genes in the human atrium before cardiopulmonary bypass (CPB) are related to subsequent biologic pathway activation patterns, and whether specific expression profiles are associated with an increased risk for postoperative atrial fibrillation (AF) or altered response to ß-blocker (BB) therapy after coronary artery bypass grafting (CABG) surgery. Right atrial appendage (RAA) samples were collected from 45 patients who were receiving perioperative BB treatment, and underwent CABG surgery. The isolated RNA samples were used for microarray gene expression analysis, to identify probes that were expressed differently in patients with and without postoperative AF. Gene expression analysis was performed to identify probes that were expressed differently in patients with and without postoperative AF. Gene set enrichment analysis (GSEA) was performed to determine how sets of genes might be systematically altered in patients with postoperative AF. Of the 45 patients studied, genomic DNA from 42 patients was used for target sequencing of 66 candidate genes potentially associated with AF, and 2,144 single-nucleotide polymorphisms (SNPs) were identified. We then performed expression quantitative trait loci (eQTL) analysis to determine the correlation between SNPs identified in the genotyped patients, and RAA expression. Probes that met a false discovery rate<0.25 were selected for eQTL analysis. Of the 17,678 gene expression probes analyzed, 2 probes met our prespecified significance threshold of false discovery rate<0.25. The most significant probe corresponded to vesicular overexpressed in cancer - prosurvival protein 1 gene (VOPP1; 1.83 fold change; P=3.47×10(-7)), and was up-regulated in patients with postoperative AF, whereas the second most significant probe, which corresponded to the LOC389286 gene (0.49 fold change; P=1.54×10(-5)), was down-regulated in patients with postoperative AF. GSEA highlighted the role of VOPP1 in pathways with biologic relevance to myocardial homeostasis, and oxidative stress and redox modulation. Candidate gene eQTL showed a trans-acting association between variants of G protein-coupled receptor kinase 5 gene, previously linked to altered BB response, and high expression of VOPP1. In patients undergoing CABG surgery, RAA gene expression profiling, and pathway and eQTL analysis suggested that VOPP1 plays a novel etiological role in postoperative AF despite perioperative BB therapy.

Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia-Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats.

BACKGROUND: Hibernation is an adaptation to extreme environments known to provide organ protection against ischemia-reperfusion (I/R) injury. An unbiased systems approach was utilized to investigate hibernation-induced changes that are characteristic of the hibernator cardioprotective phenotype, by comparing the myocardial proteome of winter hibernating arctic ground squirrels (AGS), summer active AGS, and rats subjected to I/R, and further correlating with targeted metabolic changes. METHODS: In a well-defined rodent model of I/R by deep hypothermic circulatory arrest followed by 3 or 24 h of reperfusion or sham, myocardial protein abundance in AGS (hibernating summer active) and rats (n = 4 to 5/group) was quantified by label-free proteomics (n = 4 to 5/group) and correlated with metabolic changes. RESULTS: Compared to rats, hibernating AGS displayed markedly reduced plasma levels of troponin I, myocardial apoptosis, and left ventricular contractile dysfunction. Of the 1,320 rat and 1,478 AGS proteins identified, 545 were differentially expressed between hibernating AGS and rat hearts (47% up-regulated and 53% down-regulated). Gene ontology analysis revealed down-regulation in hibernating AGS hearts of most proteins involved in mitochondrial energy transduction, including electron transport chain complexes, acetyl CoA biosynthesis, Krebs cycle, glycolysis, and ketogenesis. Conversely, fatty acid oxidation enzymes and sirtuin-3 were up-regulated in hibernating AGS, with preserved peroxisome proliferator-activated receptor-α activity and reduced tissue levels of acylcarnitines and ceramides after I/R. CONCLUSIONS: Natural cardioprotective adaptations in hibernators involve extensive metabolic remodeling, featuring increased expression of fatty acid metabolic proteins and reduced levels of toxic lipid metabolites. Robust up-regulation of sirtuin-3 suggests that posttranslational modifications may underlie organ protection in hibernating mammals.

Lucy's back: Reassessment of fossils associated with the A.L. 288-1 vertebral column.

The Australopithecus afarensis partial skeleton A.L. 288-1, popularly known as "Lucy" is associated with nine vertebrae. The vertebrae were given provisional level assignments to locations within the vertebral column by their discoverers and later workers. The continuity of the thoracic series differs in these assessments, which has implications for functional interpretations and comparative studies with other fossil hominins. Johanson and colleagues described one vertebral element (A.L. 288-1am) as uniquely worn amongst the A.L. 288-1 fossil assemblage, a condition unobservable on casts of the fossils. Here, we reassess the species attribution and serial position of this vertebral fragment and other vertebrae in the A.L. 288-1 series. When compared to the other vertebrae, A.L. 288-1am falls well below the expected size within a given spinal column. Furthermore, we demonstrate this vertebra exhibits non-metric characters absent in hominoids but common in large-bodied papionins. Quantitative analyses situate this vertebra within the genus Theropithecus, which today is solely represented by the gelada baboon but was the most abundant cercopithecoid in the KH-1s deposit at Hadar where Lucy was discovered. Our additional analyses confirm that the remainder of the A.L. 288-1 vertebral material belongs to A. afarensis, and we provide new level assignments for some of the other vertebrae, resulting in a continuous articular series of thoracic vertebrae, from T6 to T11. This work does not refute previous work on Lucy or its importance for human evolution, but rather highlights the importance of studying original fossils, as well as the efficacy of the scientific method.

Effects of lower limb neurodynamic mobilization on intraneural fluid dispersion of the fourth lumbar nerve root: an unembalmed cadaveric investigation.

OBJECTIVES: Manual and physical therapists incorporate neurodynamic mobilisation (NDM) to improve function and decrease pain. Little is known about the mechanisms by which these interventions affect neural tissue. The objective of this research was to assess the effects of repetitive straight leg raise (SLR) NDM on the fluid dynamics within the fourth lumbar nerve root in unembalmed cadavers. METHODS: A biomimetic solution (Toluidine Blue Stock 1% and Plasma) was injected intraneurally, deep to the epineurium, into the L4 nerve roots of seven unembalmed cadavers. The initial dye spread was allowed to stabilise and measured with a digital calliper. Once the initial longitudinal dye spread stabilised, an intervention strategy (repetitive SLR) was applied incorporating NDMs (stretch/relax cycles) at a rate of 30 repetitions per minute for 5 minutes. Post-intervention calliper measurements of the longitudinal dye spread were measured. RESULTS: The mean experimental posttest longitudinal dye spread measurement (1.1 ± 0.9 mm) was significantly greater (P = 0.02) than the initial stabilised pretest longitudinal dye spread measurement. Increases ranged from 0.0 to 2.6 mm and represented an average of 7.9% and up to an 18.1% increase in longitudinal dye spread. DISCUSSION: Passive NDM in the form of repetitive SLR induced a significant increase in longitudinal fluid dispersion in the L4 nerve root of human cadaveric specimen. Lower limb NDM may be beneficial in promoting nerve function by limiting or altering intraneural fluid accumulation within the nerve root, thus preventing the adverse effects of intraneural oedema.

Effects of simulated neural mobilization on fluid movement in cadaveric peripheral nerve sections: implications for the treatment of neuropathic pain and dysfunction.

BACKGROUND AND PURPOSE: Neural mobilization techniques are used clinically to treat neuropathic pain and dysfunction. While selected studies report efficacy of these techniques, the mechanisms of benefit are speculative. The purpose of this study was to evaluate the effects of in vitro simulated stretch/relax neural mobilization cycles on fluid dispersion within sections of unembalmed cadaveric peripheral nerve tissue. METHODS: Bilateral sciatic nerve sections were harvested from six cadavers. Matched pairs of nerve sections were secured in a tissue tester and injected with a plasma/Toluidine Blue dye solution. Once the initial dye spread stabilized, the experimental nerve sections underwent 25 stretch/relaxation cycles (e.g. simulated neural mobilization) produced by a mechanical tissue tester. Post-test dye spread measurements were compared to pre-test measurements as well as control findings (no simulated mobilization). Data were analyzed using paired t-tests. RESULTS: Individual dye spread measurements were reliable [ICC(3,1) = 0·99]. The post-test intraneural fluid movement (dye spread) in the experimental section increased significantly with simulated neural mobilization compared to pre-test measurements (3·2±2·1 mm; P = 0·015) and control measurements (3·3±2·7 mm; P = 0·013). CONCLUSION: Repetitive simulated neural mobilization, incorporating stretch/relax cycles, of excised cadaveric peripheral nerve tissue produced an increase in intraneural fluid dispersion. Neural mobilization may alter nerve tissue environment, promoting improved function and nerve health, by dispersing tissue fluid and diminishing intraneural swelling and/or pressure.

Computed Tomography Scan Versus Saline Load Test in the Detection of Traumatic Arthrotomies of the Ankle: A Cadaveric Study.

OBJECTIVE: To evaluate the sensitivity and ability of computed tomography (CT) scan for diagnosing traumatic ankle arthrotomies compared with that of the saline load test (SLT). METHODS: Eleven cadaveric ankles were included in this study. Before intervention, a CT scan was obtained to confirm the absence of intra-articular air. Arthrotomies were created at the anterolateral, posterolateral, anteromedial, and posteromedial aspects of the ankle under fluoroscopic visualization. A postarthrotomy and postrange of motion CT scan was obtained to evaluate for the presence of intra-articular air. Each ankle then underwent a SLT with 60 mL of saline, where volumes provoking extravasation were recorded. RESULTS: Of the 11 included ankles, intra-articular air was detected in all 11 ankles by CT scan. All 11 ankles also demonstrated extravasation of saline through the arthrotomy site during SLT. Thus, the sensitivity for both CT scan and SLT for detecting ankle traumatic arthrotomy was 100%. The mean volume of saline needed for extravasation was 7.7 mL, with a range of 3-22 mL and a SD of 5.4. CONCLUSIONS: Given that CT scan was equally as sensitive to the SLT, this study presents good evidence that CT scan may be used for the detection of ankle traumatic arthrotomies.

Exploring the Value of Improvisational Theater in Medical Education for Advancing the Doctor-Patient Relationship and Health Equity.

PURPOSE: Health care inequities persist, and it is difficult to teach health professions students effectively about implicit bias, structural inequities, and caring for patients from underrepresented or minoritized backgrounds. Improvisational theater (improv), where performers create everything in a spontaneous and unplanned manner, may help teach health professions trainees about advancing health equity. Core improv skills, discussion, and self-reflection can help improve communication; build trustworthy relationships with patients; and address bias, racism, oppressive systems, and structural inequities. METHOD: Authors integrated a 90-minute virtual improv workshop using basic exercises into a required course for first-year medical students at University of Chicago in 2020. Sixty randomly chosen students took the workshop and 37 (62%) responded to Likert-scale and open-ended questions about strengths, impact, and areas for improvement. Eleven students participated in structured interviews about their experience. RESULTS: Twenty-eight (76%) of 37 students rated the workshop as very good or excellent, and 31 (84%) would recommend it to others. Over 80% of students perceived their listening and observation skills improved, and that the workshop would help them take better care of patients with experiences different than their own. Six (16%) students experienced stress during the workshop but 36 (97%) felt safe. Eleven (30%) students agreed there were meaningful discussions about systemic inequities. Qualitative interview analysis showed that students thought the workshop helped develop interpersonal skills (communication, relationship building, empathy); helped personal growth (insights into perception of self and others, ability to adapt to unexpected situations); and felt safe. Students noted the workshop helped them to be in the moment with patients and respond to the unexpected in ways more traditional communication curricula have not. The authors developed a conceptual model relating improv skills and equity teaching methods to advancing health equity. CONCLUSIONS: Improv theater exercises can complement traditional communication curricula to advance health equity.

Measurement of the gluteal compartment pressures: A cadaveric study describing safety and reproducibility of two methods.

INTRODUCTION: Gluteal compartment syndrome is an uncommon entity and physicians may use intracompartmental pressure measurements for confirmation of the clinical diagnosis, or in cases where the physical exam is indeterminate. However, there is a paucity of literature describing a safe and reproducible technique to measure gluteal intracompartmental pressures during the diagnosis of gluteal compartment syndrome. The purpose of this cadaveric study is to evaluate the sole previous technique described in the literature to measure gluteal intracompartmental pressures and provide a modified technique which can be safely and reliably utilized clinically. METHODS: A cadaveric study with three phases was performed in 16 gluteal regions in 8 cadavers. In the first phase, the previously described technique was assessed. In the second phase, a modified set of techniques was created and evaluated. In the third phase, inter-user reliability of the modified set of techniques was assessed and calculated using Cohen's ĸ coefficient. In all three phases, methylene blue was injected through pressure monitoring needles into the gluteus maximus (GMax), gluteus medius/minimus (GMM), and the tensor fascia lata (TFL) compartments. Following dissection, rate of successful penetration into each targeted compartment and distance from the neurovascular structures was recorded. RESULTS: The previously described set of techniques was found to be variable. The modified set of techniques was effective, successfully reaching the GMax, GMM, and TFL compartments in 100%, 100%, and 81% of attempts, respectively. Inter-user reliability was excellent (ĸ = 1) for the techniques to reach both the GMax and GMM compartments, and moderate (ĸ = 0.54) for the technique to reach the TFL compartment. Within the GMax, the pressure monitoring needle was at a mean of 5.4±0.6 cm, 4.1±0.7 cm, 6.4±0.5 cm from the sciatic nerve (SN), superior gluteal nerve (SGN), and inferior gluteal nerve (IGN), respectively. Within the GMM, the pressure monitoring needle was at a mean of 9.7±1.4 cm, 7.4±1.3 cm, 11.1±1.7 cm from the SN, SGN, and IGN, respectively. CONCLUSION: The modified set of techniques presented allows the three gluteal compartments to be safely and reproducibly reached to measure intracompartmental pressures during the diagnosis of gluteal compartment syndrome.

Computed Tomography Scan Versus Saline Load Test for Detection of Traumatic Shoulder Arthrotomy: A Cadaveric Study.

OBJECTIVES: Traumatic shoulder arthrotomy (TSA) is a rare injury that is commonly detected through saline load test (SLT). There are no studies that have studied the ability of computed tomography (CT) scan to detect a TSA. The purpose of this study is to determine the ability of CT scan to detect a TSA and compare it with the SLT. METHODS: Twelve cadaveric shoulders were included in the study. Before intervention, a CT scan was conducted to determine presence of intra-articular air. After confirmation that no air was present, an arthrotomy was made at the anterior or posterior portal site. A CT was obtained postarthrotomy to evaluate for intra-articular air. Each shoulder then underwent an SLT to assess the sensitivity of SLT and the volume needed for extravasation. RESULTS: Twelve shoulders were included after a pre-intervention CT scan. Six shoulders received an arthrotomy through the anterior portal and six shoulders received an arthrotomy through the posterior portal. After the arthrotomy, air was visualized on CT scan in 11 of the 12 shoulders (92%). All 12 shoulders demonstrated extravasation during SLT. The mean volume of saline needed for extravasation was 29 mL with an SD of 10 and range of 18-50 mL. CONCLUSIONS: CT scan is a sensitive modality (sensitivity of 92%) for detection of TSA. In comparison, SLT is more sensitive (sensitivity of 100%) and outperforms CT scan for the diagnosis of TSA in a cadaveric model. Further research is needed to solidify the role that CT imaging has in the diagnosis of TSAs.

Intralabial Lip Compartments and their Potential Clinical Relevance.

BACKGROUND: Aesthetic soft tissue filler injections for lip enhancement are highly popular and are performed throughout the world. When injecting lips with cannulas, as the cannula is advanced, resistance is perceived in consistent locations potentially indicating boundaries between intralabial compartments. OBJECTIVE: To investigate whether intra-labial compartments exist and (if so) to describe their volumes, location, boundaries, and dimensions. METHODS: This cadaveric study investigated a total of n = 20 (13 males, 7 females) human body donors with a mean age at death of 61.9 (23.9) years and a mean body mass index of 24.3 (3.7) kg/m 2. The investigated cohort included n = 11 Caucasian, n = 8 Asian, and n = 1 African American donors. Dye injections simulating minimally invasive lip treatments were conducted. RESULTS: Independent of gender or race, 6 anterior and 6 posterior compartments in the upper and lower lip were identified, for a total of 24 lip compartments. Compartment boundaries were formed by vertically oriented septations that were found in consistent locations. The anterior compartments had volumes ranging from 0.30 - 0.39 cc whereas the posterior compartment volume ranged from 0.44 - 0.52 cc. Centrally, the compartment volumes were larger and decreased gradually towards the oral commissure. CONCLUSION: The volume and the size of each of the 24 compartments contribute to the overall appearance and shape of the lips. To achieve a natural and lip-shape preserving aesthetic outcome it may be preferable to administer the volumizing product using a compartment-respecting injection approach.

Clinical Factors Impacting Outcomes From Failed Trabeculectomy Leading to Glaucoma Drainage Device Implantation and Subsequent Penetrating Keratoplasty.

PRCIS: We evaluated the factors that impacted time from glaucoma drainage implant (GDI) surgery to penetrating keratoplasty (PK) in eyes with previously clear corneas (ie, GDI-first sequence), and that specifically underwent a trabeculectomy before GDI surgery for intraocular pressure (IOP) control. PURPOSE: To describe through an event-triggered data collection method the clinical course and the long-term outcomes of 2 procedures that are commonly performed sequentially in complex clinical situations: GDI surgery and PK. The study investigates the clinical factors associated with the progression to PK and determines the GDI success rate and graft survival. METHODS: A single, tertiary-care center retrospective interventional cases series including patients with a sequential history of trabeculectomy, GDI surgery, and PK from 1999 to 2009. Outcome measures included IOP, visual acuity, graft failure, GDI failure, and time from GDI to PK. RESULTS: Of the eyes, 56% had primary open angle glaucoma. The time from the last trabeculectomy to GDI was 66.5 ± 66.7 months. Of the eyes, 84% received a Baerveldt GDI. Time from GDI to PK was 36.4 ± 28.4 months. IOP at the time of PK was between 5 mm Hg and 21 mm Hg in 90% of eyes. At the last follow-up, 48% of grafts were clear. At 5 years post-PK, 33% of corneal grafts remained clear, whereas 81% of tubes remained functional. CONCLUSIONS: Nearly half of the corneal grafts are clear at the last long-term follow-up. Graft failure occurs at a higher rate than tube failure suggesting that IOP control is only one and possibly not the most important factor in graft survival in eyes with prior glaucoma surgery.

PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models.

Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.