Shared Decision-Making in Patients Seeking Surgery for Facial Trauma: The Role of Decisional Conflict and Perceived Discrimination.

Background: Shared decision-making (SDM) may facilitate challenging discussions between patients with facial trauma and reconstructive surgeons. Objective: To determine among patients seeking surgical evaluation for facial trauma, whether patient demographics, decisional conflict (DC), or experiences of discrimination in health care are associated with patient perceptions of SDM, as measured by scored responses on the CollaboRATE-10 questionnaire. Methods: English-speaking adults who presented to the offices of five facial trauma surgeons were contacted by telephone after their visit to complete a cross-sectional survey. Results: After screening 247 patients, 131 patients were recruited (53.0%). DC and history of discrimination were associated with lower perceived SDM (p < 0.001 and p = 0.048, respectively). After adjusting for age, sex, race, education, initial emergency department presentation, DC, and past discrimination, patients of older age (odds ratio [OR] 1.1, 95% confidence interval [CI] 1.02-1.09) and non-White race (OR 3.5, 95% CI 1.1-11.4) had higher perceptions of SDM; patients with DC (OR 0.52, 95% CI 0.01-0.20) reported less SDM. Conclusions: Patients who present to clinic for surgical evaluation after facial trauma feel that their physicians involve them less when deciding on a treatment plan if they have experienced discrimination in health care settings in the past, or if they have significant difficulty deciding between treatment options.

Time to Mohs Reconstruction: A Systematic Review Comparing Complication Rates between Immediate and Delayed Repair.

Several known factors affect outcomes of Mohs facial defect reconstruction; however, the effect of repair timing on outcomes is ill-defined. The aim of this study was to determine postoperative complication rates between immediate and delayed repair of Mohs facial defects. Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines were used. Articles were selected using PICO format-population: Mohs facial defect patients, intervention: defect repair, comparator: immediate (<24 hours), or delayed (>24 hours) repair, outcome: complication rate. PubMed/Medline (1946-2020), EMBASE (1947-2020), Scopus (1823-2020), Web of Science (1900-2020), Cochrane Library, and Clinicaltrials.gov were searched. Two independent reviewers screened abstracts; those in English with human subjects reporting repair timing and complication rates were included. Search criteria yielded 6,649 abstracts; 233 qualified for review. Data were gathered from six studies; they alone contained comparative data meeting inclusion criteria. While many well-written studies were encountered, reported results varied widely. A statistically sound meta-analysis could not be completed due to large heterogeneity between studies, biasing the analysis towards the largest weighted study. Clinically important differences may exist between immediate and delayed Mohs reconstruction, but small study numbers, large heterogeneity, and lack of standardized outcome measures limit definitive conclusions. More studies are needed to perform appropriate meta-analyses, including studies using standardized methods of reporting Mohs outcome data.

Evidence-Based Medicine for Midface/Orbit/Upper Facial Fracture Repair.

The face is one of the most common areas of traumatic injury, making up approximately 25% of all injuries in 2016. Assault, motor vehicle collision (MVC), fall, sports, occupational, and gunshot wounds (GSW) are all common causes of facial fractures, with MVC and GSW leading to significantly higher severity of injuries. Most facial fractures occur in the upper two-thirds of the face. Most facial fractures require timely assessment, diagnosis, and treatment for optimal restoration of facial structures and functions. Without proper initial management, significant complications including immediate complications such as airway compromise, massive bleeding, infection, intracranial hemorrhages, or even death, and long-term complications such as poor functional outcomes and aesthetic setbacks can occur. The goal of this review is to summarize the management of fractures of the upper face, orbit, and midface and provide an update about complications and their management.

Factors Shifting Preference Toward Telemedicine in the Delivery of Skin Cancer Reconstruction Care.

OBJECTIVES: Identify which delivery modality for skin reconstruction care, face-to-face (FTF) in-person versus two telemedicine modalities, store-and-forward (S&F) and live video chat (LVC), is patient preferred and how cost, access, wait time, and demographics influence this preference. STUDY DESIGN: Cross-sectional survey. METHODS: A 16-question survey querying demographics and five scenario-specific preferences questions for the delivery of skin cancer reconstruction care was created and distributed via Amazon Mechanical Turk (MTurk), a crowdsourcing online marketplace, and in-person to Mohs micrographic surgery patients. RESULTS: 1394 MTurk and 55 in-person responses were included. While 82.1% of online respondents prefer FTF clinic visits, this decreases to 58.3% with an in-person visit cost (p < 0.01) and furthermore to a minority 43.5% with both an in-person visit cost and wait time (p < 0.01) despite 77.8% believing that usefulness to the surgeon would improve FTF. Both the MTurk and in-person cohorts demonstrated similar response patterns despite considerable demographic differences. Multivariable analyses revealed that telemedicine was preferred by MTurk respondents with Medicaid (adjusted OR [95% CI]: 1.97 [1.18-3.31]) or Medicare (1.69 [1.10-2.59]) versus private insurance, and prior skin cancer (2.01 [1.18-3.42]) and less preferred by those earning $140,000+ per year (0.49 [0.29-0.82]) compared to those earning <$20,000 per year. CONCLUSIONS: FTF visits are preferred for skin cancer reconstruction care; this shifts toward virtual care with a cost and wait time in spite of the perceived quality of care. Individuals with socioeconomic barriers to access prefer telemedicine. MTurk can be a valuable tool for behavioral research in FPRS. LEVEL OF EVIDENCE: NA Laryngoscope, 133:294-301, 2023.

Cheek Donor Site for Full-Thickness Skin Graft Repair of the Nasal Ala: Outcomes of a Retrospective Cohort Study.

BACKGROUND: Full-thickness skin grafts (FTSGs) are useful repairs for reconstructing nasal alar defects. Traditional donor sites include the preauricular, postauricular, and supraclavicular skin. OBJECTIVE: To evaluate esthetic outcomes and complications of nasal alar defects repaired with FTSGs from the medial cheek. MATERIALS AND METHODS: A retrospective chart review of Mohs surgery patients who had FTSG repair of the nasal ala between January 2015 and August 2020 was performed. Demographic, surgery, and follow-up visit data were reviewed. Cosmesis was rated by a facial plastic surgeon, a Mohs surgeon, and a plastic surgeon using baseline, defect, and follow-up visit photographs. RESULTS: Sixty-nine patients with FTSG repairs of nasal alar defects were identified. 51 of 69 patients (73.9%) had the cheek donor site, and 18 of 69 patients (26.1%) had a noncheek donor site. The mean (SD) rater visual analog score for both cohorts was good with no significant difference (cheek: 65.9 [13.8]; noncheek: 66.1 [15.3]; p = .96). A notable difference in the complication rate by donor site was observed (cheek: 6.9%, noncheek: 16.7%; p = .13), although it did not reach significance. CONCLUSION: The cheek is a reliable FTSG donor site for nasal alar defects after Mohs micrographic surgery, with a trend toward fewer complications.

Tailored Medication Adherence Incentives Using mHealth for Children With High-Risk Asthma (TAICAM): Protocol for a Randomized Controlled Trial.

BACKGROUND: Poor adherence to inhaled corticosteroid medications for children with high-risk asthma is both well documented and poorly understood. It has a disproportionate prevalence and impact on children of minority demographics in urban settings. Financial incentives have been shown to be a compelling method to engage those in a high-risk asthma population, but whether adherence can be maintained by offering financial incentives and how these incentives can be used to sustain high adherence are unknown. OBJECTIVE: The aim of this study is to determine the marginal effects of a financial incentive-based intervention on inhaled corticosteroid adherence, health care system use, and costs. METHODS: Participants include children aged 5 to 12 years who have had either at least two hospitalizations or one hospitalization and one emergency department visit for asthma in the year prior to their enrollment (and their caregivers). Participants are given an electronic inhaler sensor in order to track their medication use over a period of 7 months. After a 1-month period of observation, participants are randomized to 1 of 3 arms for a 3-month period. Participants in arm 1 receive daily text message reminders, feedback, and gain-framed, nominal financial incentives; participants in arm 2 receive daily text message reminders and feedback only, and participants in arm 3 receive no reminders, feedback, or incentives. All participants are subsequently observed for an additional 3-month period with no reminders, feedback, or incentives to assess whether any sustained effects are apparent. RESULTS: Study enrollment began in September 2019 with a target sample size of N=125 children. As of June 2020, 61 children have been enrolled. Data collection is estimated to be completed in June 2022, and analyses will be completed by June 2023. CONCLUSIONS: This study will provide data that will help to determine whether a financial incentive-based mobile health intervention for promoting inhaled corticosteroid use can be effective in patients with high-risk asthma over longer periods. TRIAL REGISTRATION: Clinicaltrial.gov NCT03907410; https://clinicaltrials.gov/ct2/show/NCT03907410. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16711.

Complications and Outcomes of Chimeric Free Flaps: A Systematic Review.

OBJECTIVE: Ablations of locally advanced or recurrent head and neck cancer commonly result in large composite orofacial defects. Chimeric flaps represent a unique surgical option for these defects, as they provide diverse tissue types from a single donor site. The purpose of the study was to consolidate the literature on chimeric flaps with regard to postoperative complication rates to help inform surgical decision making. DATA SOURCES: The librarian created search strategies with a combination of keywords and controlled vocabulary in Ovid Medline (1946), Embase (1947), Scopus (1823), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrails.gov (1997). REVIEW METHODS: Candidate articles were independently reviewed by 2 authors familiar with the subject material, and inclusion/exclusion criteria were uniformly applied for article selection. Articles were considered eligible if they included patients who received a single chimeric flap for reconstruction of head and neck defects and if they provided data on complication rates. RESULTS: A total of 521 chimeric flaps were included in the study. The major complication rate was 22.6%, while the minor complication rate was 14.0%. There were 7 flap deaths noted in the series. Median operative time and harvest time were 15.0 and 2.5 hours, respectively. CONCLUSION: Chimeric flaps represent a viable option for reconstruction of complex head and neck defects and have complication rates similar to those of double free flaps and single free flaps with locoregional flap while only modestly increasing total operative time.

Perception of upper lip augmentation utilizing simulated photography.

BACKGROUND: No head to head comparison is available between surgical lip lifting and upper lip filler injections to decide which technique yields the best results in patients. Despite the growing popularity of upper lip augmentation, its effect on societal perceptions of attractiveness, successfulness and overall health in woman is unknown. METHODS: Blinded casual observers viewed three versions of independent images of 15 unique patient lower faces for a total of 45 images. Observers rated the attractiveness, perceived success, and perceived overall health for each patient image. Facial perception questions were answered on a visual analog scale from 0 to 100, where higher scores corresponded to more positive responses. RESULTS: Two hundred and seventeen random observers with an average age of 47 years (standard deviation, 15.9) rated the images. The majority of observers were females (n=183, 84%) of white race (n=174, 80%) and had at least some college education (n=202, 93%). The marginal mean score for perceived attractiveness from the natural condition was 1.5 points (95% confidence interval [CI], 0.9-2.18) higher than perceived attractiveness from the simulated upper lip filler injection condition, and 2.6 points higher (95% CI, 1.95-3.24) than the simulated upper lip lift condition. There was a moderate to strong correlation between the scores of the same observer. CONCLUSIONS: Simulated upper lip augmentation is amenable to social perception analysis. Scores of the same observer for attractiveness, successfulness, and overall health are strongly correlated. Overall, the natural condition had the highest scores in all categories, followed by simulated upper lip filler, and lastly simulated upper lip lift.

Postoperative Complications of Paramedian Forehead Flap Reconstruction.

IMPORTANCE: Paramedian forehead flaps are commonly used to reconstruct facial defects caused by skin cancers. Data are lacking on the complications from this procedure, postoperative outcomes, and association of cancer diagnosis with rate of deep venous thrombosis (DVT). OBJECTIVES: The primary objective was to determine complication rates after paramedian forehead flap reconstruction for defects resulting from resection of facial cancers; and the secondary objective was to determine patient factors and complications that are associated with readmission. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of patients who underwent paramedian forehead flap reconstruction for skin cancer reconstruction from January 1, 2007, through December 31, 2013. Data analysis took place between October 1, 2017, and June 1, 2018. MAIN OUTCOMES AND MEASURES: Complication rates including DVT, emergency department visits, and hospital readmissions. RESULTS: A total of 2175 patient were included in this study; mean (SD) age, 70.3 (13.4) years; 1153 (53.5%) were men. Postoperative DVT occurred in 10 or fewer patients (≤0.5%); postoperative bleeding in 30 (1.4%), and postoperative infection in 63 (2.9%). Most patients went home on the day of surgery (89.6%; n = 1949), while 10.4% stayed one or more days in the hospital (n = 226). Overnight admission was associated with tobacco use (odds ratio [OR], 1.65; 95% CI, 1.11-2.44), hypothyroidism (OR, 1.93; 95% CI, 1.10-3.39), hypertension (OR, 1.82; 95% CI, 1.29-2.57), ear cartilage graft (OR, 2.20; 95% CI, 1.51-3.21), and adjacent tissue transfer (OR, 1.88; 95% CI, 1.33-2.67). Risk factors strongly associated with immediate return to the emergency department or readmission within 48 hours of surgery included postoperative bleeding (OR, 13.05; 95% CI, 4.24-40.16), neurologic disorder (OR, 4.11; 95% CI, 1.12-15.09), and alcohol use (OR, 7.70; 95% CI, 1.55-38.21). CONCLUSIONS AND RELEVANCE: In this study, the most common complication of paramedian forehead flap reconstruction was infection. Risk factors for readmission included development of postoperative bleeding, having a neurologic disorder, and alcohol use. Deep venous thrombosis was a rare complication. Because bleeding is a more common complication in this patient population, discretion should be used when deciding to administer anticoagulation medication to low- to medium-risk patients prior to surgery. LEVEL OF EVIDENCE: NA.

Comprehensive Algorithm for Nasal Ala Reconstruction: Utility of the Auricular Composite Graft.

Defects of the nasal ala are challenging to reconstruct, given its complex three-dimensional structure. Successful repair of these defects needs to provide aesthetic symmetry and preserve nasal function. A wide variety of reconstructive options have been described for nasal ala defects, ranging from skin grafts to locoregional flaps, and also includes the auricular composite graft. However, there are currently no comprehensive guidelines for nasal ala repair, and the versatile role of the auricular composite graft has not been well defined. In this review, we aim to provide a comprehensive algorithm to guide repair of nasal ala defects. Additionally, we compare our experience using the auricular composite graft with the available literature to better define its utility in nasal ala repair.

Complications and Reoperations in Mandibular Angle Fractures.

IMPORTANCE: Mandible angle fractures can be repaired in a variety of ways, with no consensus on the outcomes of complications and reoperation rates. OBJECTIVES: To analyze patient, injury, and surgical factors, including approach to the angle and plating technique, associated with postoperative complications, as well as the rate of reoperation with regard to mandible angle fractures. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study analyzing the surgical outcomes of patients with mandible angle fractures between January 1, 2000, and December 31, 2015, who underwent open reduction and internal fixation. Patients were eligible if they were aged 18 years or older, had 3 or less mandible fractures with 1 involving the mandibular angle, and had adequate follow-up data. Patients with comminuted angle fractures, bilateral angle fractures, and multiple surgical approaches were excluded. A total of 135 patients were included in the study. All procedures were conducted at a single, large academic hospital located in an urban setting. MAIN OUTCOMES AND MEASURES: Major complications and reoperation rates. Major complications included in this study were nonunion, malunion, severe malocclusion, severe infection, and exposed hardware. RESULTS: Of 135 patients 113 (83.7%) were men; median age was 29 years (range, 18-82 years). Eighty-seven patients (64.4%) underwent the transcervical approach and 48 patients (35.6%) received the transoral approach. Fifteen (17.2%) patients in the transcervical group and 9 (18.8%) patients in the transoral group experienced major complications (difference, 1%; 95% CI, -8% to 10%). Thirteen (14.9%) patients in the transcervical group and 8 (16.7%) patients in the transoral group underwent reoperations (difference, 2%; 95% CI, -13% to 17%). Active smoking had a significant effect on the rate of major complications (odds ratio, 4.04; 95% CI, 1.07 to 15.34; P = .04). CONCLUSIONS AND RELEVANCE: During repair of noncomminuted mandibular angle fractures, both of the commonly used approaches-transcervical and transoral-can be used during treatment with equal rates of complication and risk of reoperation. For a patient undergoing surgery for mandibular angle fracture, smoking status is more likely to predict surgical outcomes rather than how the surgeon chooses to approach and fixate the fracture. LEVEL OF EVIDENCE: 3.

Complications of double free flap and free flap combined with locoregional flap in head and neck reconstruction: A systematic review.

BACKGROUND: The purpose of this clinical review was to assess the feasibility of reconstructing complex head and neck defects with 2 or more free flaps simultaneously. METHODS: A total of 38 articles were reviewed. The patient population included those who received 2 or more free flaps or a single free flap plus a locoregional flap. The primary outcome assessed was rate of complications. RESULTS: Among double flaps, the minor complication rate was 6.96% and the major complication rate was 20.0%. In comparison, the free flap plus locoregional flap group had higher rates of minor and major complications of 30.4% and 29.5%, respectively. The median operating time was 660 minutes for double flaps and 602 minutes for free flap plus locoregional flap (P = .828). CONCLUSION: Compared to the single free flap plus locoregional flap, double free flaps are relatively reliable without increasing surgical complications or decreasing flap survival, while only modestly increasing operating times.

Automated Adherence Reminders for High Risk Children With Asthma: A Research Protocol.

BACKGROUND: The use of inhaled corticosteroid (ICS) medications has been shown to improve asthma control and reduce asthma-related morbidity and mortality. Two recent randomized trials demonstrated dramatic improvements in ICS adherence by monitoring adherence with electronic sensors and providing automated reminders to participants to take their ICS medications. Given their lower levels of adherence and higher levels of asthma-related emergency department (ED) visits, hospitalizations, and death, urban minority populations could potentially benefit greatly from these types of interventions. OBJECTIVE: The principal objective of this study will be to evaluate the feasibility, acceptability, and limited efficacy of a text message (short message service, SMS) reminder intervention to enhance ICS adherence in an urban minority population of children with asthma. We will also assess trajectories of ICS adherence in the 2 months following asthma hospitalization. METHODS: Participants will include 40 children aged 2-13 years, who are currently admitted to the Children's Hospital of Philadelphia (CHOP) for asthma, and their parent or legal guardian. Participants will be assigned to intervention and control arms using a 1:1 randomization scheme. The intervention arm will receive daily text message reminders for a 30-day intervention phase following hospitalization. This will be followed by a 30-day follow-up phase, in which all participants may choose whether or not to receive the text messages. Feasibility will be assessed by measuring (1) retention of the participants through the study phases and (2) perceived usefulness, acceptability, and preferences regarding the intervention components. Limited efficacy outcomes will include percent adherence to prescribed ICS regimen measured using Propeller Health sensors and change in parent-reported asthma control. We will perform an exploratory analysis to assess for discrete trajectories of adherence using group-based trajectory modeling (GBTM). RESULTS: Study enrollment began in December 2015 and the intervention and follow-up phases are ongoing. Results of the data analysis are expected to be available by December 2016. CONCLUSIONS: This study will add to the literature by providing foundational feasibility data on which elements of a mobile health text-message reminder intervention may need to be modified to suit the needs and constraints of high-risk urban minority populations. TRIAL REGISTRATION: Clinicaltrials.gov NCT02615743; https://www.clinicaltrials.gov/ct2/show/study/NCT02615743 (Archived with WebCite at http://www.webcitation.org/6ji59rAXN).

Titanium Mesh Nasal Repair without Nasal Lining.

The objective of this study was to describe outcomes for patients who underwent titanium mesh reconstruction of full-thickness nasal defects without internal lining repair. This is a retrospective cohort study. Patients with through-and-through nasal defects were identified at a single academic institution between 2008 and 2016. Nasal reconstruction was performed with either titanium mesh and external skin reconstruction without repair of the intranasal lining or traditional three-layer closure. Five patients underwent titanium mesh reconstruction and 11 underwent traditional three-layer repair. Median follow-up was 11 months (range, 2-66 months). The only significant difference between groups was older age in patients undergoing titanium reconstruction (mean, 81 vs. 63 years; difference of 18; 95% confidence interval [CI], 4-32 years). Defect extent including overall size and structures removed was similar between groups (p > 0.05). Paramedian forehead flap was the most common external reconstruction in both groups (100% for titanium mesh and 73% for three-layer closure). Time under anesthesia was significantly shorter for titanium mesh reconstruction (median, 119 vs. 314 minutes; difference of 195; 95% CI, 45-237). Estimated blood loss and length of hospital stay were similar between groups (p > 0.05). Complication rates were substantial although not significantly different, 40 and 36% in titanium and three-layer reconstruction, respectively (p > 0.05). All patients with complications after titanium reconstruction had prior or postoperative radiotherapy. Titanium mesh reconstruction of through-and-through nasal defects can successfully be performed without reconstruction of the intranasal lining, significantly decreasing operative times. This reconstructive technique may not be suitable for patients who undergo radiotherapy.

Electronic Adherence Monitoring in a High-Utilizing Pediatric Asthma Cohort: A Feasibility Study.

BACKGROUND: Inner-city, minority children with asthma have the highest rates of morbidity and death from asthma and the lowest rates of asthma controller medication adherence. Some recent electronic medication monitoring interventions demonstrated dramatic improvements in adherence in lower-risk populations. The feasibility and acceptability of such an intervention in the highest-risk children with asthma has not been studied. OBJECTIVE: Our objective was to assess the feasibility and acceptability of a community health worker-delivered electronic adherence monitoring intervention among the highest utilizers of acute asthma care in an inner-city practice. METHODS: This was a prospective cohort pilot study targeting children with the highest frequency of asthma-related emergency department and hospital care within a local managed care Medicaid plan. The 3-month intervention included motivational interviewing, electronic monitoring of controller and rescue inhaler use, and outreach by a community health worker for predefined medication alerts. We measured acceptability by using a modified technology acceptability model and changes in asthma control using the Asthma Control Test (ACT). Given prominent feasibility issues, we describe qualitative patterns of medication use at baseline only. RESULTS: We enrolled 14 non-Hispanic black children with a median age of 3.5 years. Participants averaged 7.8 emergency or hospital visits in the year preceding enrollment. We observed three distinct patterns of baseline controller use: 4 patients demonstrated sustained use, 5 patients had periodic use, and 5 patients lapsed within 2 weeks. All participants initiated use of the electronic devices; however, no modem signal was transmitted for 5 or the 14 participants after a mean of 45 days. Of the 9 (64% of total) caregivers who completed the final study visit, all viewed the electronic monitoring device favorably and would recommend it to friends, and 5 (56%) believed that the device helped to improve asthma control. ACT scores improved by a mean of 2.7 points (P=.05) over the 3-month intervention. CONCLUSIONS: High-utilizer, minority families who completed a community health worker-delivered electronic adherence intervention found it generally acceptable. Prominent feasibility concerns, however, such as recruitment, data transmission failure, and lost devices, should be carefully considered when designing interventions in this setting.

Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.

Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T-cell-intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8(+) T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8(+) T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8(+) T-cell effector differentiation under otherwise tolerizing conditions.

Inflammation programs self-reactive CD8+ T cells to acquire T-box-mediated effector function but does not prevent deletional tolerance.

CD8(+) T cells must detect foreign antigens and differentiate into effector cells to eliminate infections. But, when self-antigen is recognized instead, mechanisms of peripheral tolerance prevent acquisition of effector function to avoid autoimmunity. These distinct responses are influenced by inflammatory and regulatory clues from the tissue environment, but the mechanism(s) by which naive T cells interpret these signals to generate the appropriate immune response are unclear. The identification of the molecules operative in these cell-fate decisions is crucial for developing new treatment options for patients with cancer or autoimmunity, where manipulation of T cell activity is desired to alter the course of disease. With the use of an in vivo murine model to examine CD8(+) T cell responses to healthy self-tissue, we correlated self-tolerance with a failure to induce the T-box transcription factors T-bet and Eomes. However, inflammation associated with acute microbial infection induced T-bet and Eomes expression and promoted effector differentiation of self-reactive T cells under conditions that normally favor tolerance. In the context of a Listeria infection, these functional responses relied on elevated T-bet expression, independent of Eomes. Alternatively, infection with LCMV induced higher Eomes expression, which was sufficient in the absence of T-bet to promote effector cytokine production. Our results place T-box transcription factors at a molecular crossroads between CD8(+) T cell anergy and effector function upon recognition of peripheral self-antigen, and suggest that inflammation during T cell priming directs these distinct cellular responses.

The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1.

The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy- induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1ß). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/ neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration- approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients.

Controlling murine and rat chronic pain through A3 adenosine receptor activation.

Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A(3) adenosine receptor (A(3)AR) agonism as a new target-based therapeutic strategy. The development of mechanoallodynia in a well-characterized mouse model of neuropathic pain following chronic constriction injury of the sciatic nerve was rapidly and dose-dependently reversed by the A(3)AR agonists: IB-MECA, its 2-chlorinated analog (Cl-IB-MECA), and the structurally distinct MRS1898. These effects were naloxone insensitive and thus are not opioid receptor mediated. IB-MECA was ≥1.6-fold more efficacious than morphine and >5-fold more potent. In addition, IB-MECA was equally efficacious as gabapentin (Neurontin) or amitriptyline, but respectively >350- and >75-fold more potent. Besides its potent standalone ability to reverse established mechanoallodynia, IB-MECA significantly increased the antiallodynic effects of all 3 analgesics. Moreover, neuropathic pain development in rats caused by widely used chemotherapeutics in the taxane (paclitaxel), platinum-complex (oxaliplatin), and proteasome-inhibitor (bortezomib) classes was blocked by IB-MECA without antagonizing their antitumor effect. A(3)AR agonist effects were blocked with A(3)AR antagonist MRS1523, but not with A(1)AR (DPCPX) or A(2A)AR (SCH-442416) antagonists. Our findings provide the scientific rationale and pharmacological basis for therapeutic development of A(3)AR agonists for chronic pain.