Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.

Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.

CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (T TS ) cells during cancer development is still unclear. We demonstrate that CD4 T TS cells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 T TS cells and previously defined exhaustion programs, CD4 T TS cell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 T TS cell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 T TS cells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 T TS cells to favor tumor progression.

Parental-leave policies and perceptions of pregnancy during surgical residency training in North America: a scoping review.

BACKGROUND: The number of surgical residents experiencing childbearing during residency training is increasing, and there is an absence of clarity with respect to parental-leave, lactation and return-to-work policies in support of residents. The aim of this review was to examine parental-leave policies during residency training in surgery and the perceptions of these policies by residents, program directors and coresidents, as described in the literature. METHODS: We performed a scoping review of the literature based on the following themes: maternity or parental-leave policies; antepartum work-restriction policies and obstetric complications; accommodations for training absences; support for, and perceptions of, maternity or parental leave during residency training; and challenges upon return to work, namely resident performance and breastfeeding. RESULTS: Parental-leave policies during surgical residency training have historically lacked clarity and enforcement. Although recommendations for parental leave are now in place, this may have historically contributed to a lack of perceived support for surgical residents and may result in variable leave permitted to residents. Unclear policies may also contribute to career dissatisfaction among resident parents, which may deter qualified individuals from selecting surgical subspecialties. CONCLUSION: A call for a cultural shift is required to inform policies that would better support residents across all surgical specialties to pursue success in their dual roles as parents and surgeons. With increased awareness, progress in policy and guideline development is under way.

Simulating the IMA Recipient Site for DIEP Flap Surgery: A New Model for Dynamic Microsurgery Simulation with Real-Time Respiration and a Pilot Study.

BACKGROUND: Breast reconstruction (BR) using autologous free flaps has been shown to have numerous psychosocial and quality-of-life benefits. Unfortunately, the microsurgical learning curve is quite steep due to some unique operative challenges. Currently, there is no realistic simulation model that captures real-life respiratory excursion and the depth of internal mammary vessels within the compact recipient site. The purpose of this study was to delineate intraoperative measurements of depth and motion, describe the resulting simulation model, and conduct a pilot study evaluating the simulator as an educational resource. METHODS: This is a single-center, ethics-approved study. For the intraoperative measurements, all consecutive patients undergoing free flap BR using internal mammary vessels as recipients were recruited. Patient and intraoperative factors as well as intraoperative measurements were recorded. A dynamic model was developed based on intraoperative parameters. For the pilot study, plastic and reconstructive surgery trainees were recruited to complete a hand-sewn internal mammary artery (IMA) anastomosis using the new simulator and completed objective questionnaires pre- and postsimulation. Subjective feedback was recorded and themes determined. RESULTS: Fifteen operative sites were analyzed. Flap pocket was found to be between 4 and 5 cm in depth with vertical excursion of 3.7 ± 1.0mm and a respiratory rate of 9 to 14 breaths/minute. Previous radiation, rib space, body mass index (BMI), blood pressure, heart rate, tidal volume, and respiratory rate showed no correlation to vessel depth/excursion. Laterality, rib space, BMI, radiation, vitals, and tidal volume had no correlation with vessel movement. Twenty-two trainees were included in the pilot. An increase in confidence and mixed results for anxiety was reported. CONCLUSION: This study reports a novel microsurgical simulation model that provides a realistic deep inferior epigastric perforator free flap BR IMA anastomosis experience. It replicates movement of vessels in situ with real-time respiratory excursion and similar physical structures of the internal mammary system. This model shows promising results for increased use in microsurgical education.

The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity.

Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.

Improving Equity, Diversity, and Inclusion in Plastic, Reconstructive, and Aesthetic Surgery in Canada: A Call to Action.

The global COVID-19 pandemic has brought to light the significant inequities in the delivery of healthcare, vaccine inequity, and differential access to life-saving treatments, which have disproportionately impacted marginalized and racialized populations. In this article, we acknowledge and recognize the centuries-old legacies perpetuating inequity, injustice, and oppression, we discuss the principles of Equity, Diversity, and Inclusion (EDI) and we call our Canadian plastic surgery colleagues and trainees to action. We propose a plan for (1) Education, (2) Mitigating Disparities in the Clinical Setting, and (3) Policy, Societies, and Leadership Education.

La pandémie mondiale de COVID-19 a mis en lumière des iniquités importantes dans la prestation des soins, l'iniquité vaccinale et l'accès différentiel à des traitements salvateurs, qui ont touché démesurément les populations marginalisées et racisées. Dans le présent article, les auteurs reconnaissent les héritages séculaires qui perpétuent l'iniquité, l'injustice et l'oppression, ils abordent les principes d'équité, de diversité et d'inclusion et ils appellent à l'action leurs collègues et leurs stagiaires canadiens en chirurgie plastique. Ils proposent un plan en matière (1) d'éducation, (2) d'atténuation des disparités en milieu clinique et (3) de politique, de société et d'éducation au leadership.

Canadian Expert Opinion on Breast Reconstruction Access: Strategies to Optimize Care during COVID-19.

BACKGROUND: Breast reconstructive services are medically necessary, time-sensitive procedures with meaningful health-related quality of life benefits for breast cancer survivors. The COVID-19 global pandemic has resulted in unprecedented restrictions in surgical access, including access to breast reconstructive services. A national approach is needed to guide the strategic use of resources during times of fluctuating restrictions on surgical access due to COVID-19 demands on hospital capacity. METHODS: A national team of experts were convened for critical review of healthcare needs and development of recommendations and strategies for patients seeking breast reconstruction during the pandemic. Following critical review of literature, expert discussion by teleconference meetings, and evidenced-based consensus, best practice recommendations were developed to guide national provision of breast reconstructive services. RESULTS: Recommendations include strategic use of multidisciplinary teams for patient selection and triage with centralized coordinated use of alternate treatment plans during times of resource restrictions. With shared decision-making, patient-centered shifting and consolidation of resources facilitate efficient allocation. Targeted application of perioperative management strategies and surgical treatment plans maximize the provision of breast reconstructive services. CONCLUSIONS: A unified national approach to strategically reorganize healthcare delivery is feasible to uphold standards of patient-centered care for patients interested in breast reconstruction.

Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection.

Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.

Breast implant-associated EBV-positive diffuse large B-cell lymphoma: Two case reports and literature review.

Lymphomas associated with breast implants are mostly of the T-cell type. They are predominantly anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) characterized by CD30 positivity universally. Whilst the majority of primary breast lymphomas occurring in the absence of breast implants are of B-cell origin, there are few cases of implant-associated B-cell lymphomas reported to date in the literature, a subset of which are diffuse large B-cell lymphoma (DLBCL). Given the rarity of this entity, we describe two cases of breast implant-associated DLBCL. Both patients developed Epstein-Barr Virus (EBV)-positive large cell lymphoma of B-cell origin confined to the implant capsule with no evidence of systemic lymphoma. Considering the association with EBV, the activated B-cell phenotype and the presumed chronic inflammatory environment associated with the implant capsule, these might represent forms of DLBCL associated with chronic inflammation (DLBCL-CI) or fibrin-associated DLBCL (FA-DLBCL). Treatment included implant removal with total capsulectomy, and for one of the cases adjuvant systemic chemotherapy. Recognizing this rare type of breast implant-associated B-cell lymphoma could improve our understanding of this entity and hence develop appropriate management strategies.

State of Gender Diversity and Equity Policies within Plastic and Reconstructive Surgery in Canada.

BACKGROUND: Given the growing number of women in plastic and reconstructive surgery (PRS), it is imperative to evaluate the extent of gender diversity and equity policies among Canadian PRS programs to support female trainees and staff surgeons. METHODS: A modified version of the United Nations Women's Empowerment Principles (WEPs) Gender Gap Analysis tool was delivered to Canadian PRS Division Chairs (n = 11) and Residency Program Directors (n = 11). The survey assessed gender discrimination and equity policies, paid parental leave policies, and support for work/life balance. RESULTS: Six Program Directors (55% response rate) and ten Division Chairs (91% response rate) completed the survey. Fifty percent of respondents reported having a formal gender non-discrimination and equal opportunity policy in their program or division. Eighty-three percent of PRS residency programs offered paid maternity/paternity/caregiver leave; however, only 29% offered financial or non-financial support to its staff surgeons. Only 33% of programs had approaches to support residents as parents and/or caregivers upon return to work. Work/life balance was supported for most trainees (67%) but only few faculty members (14%). CONCLUSIONS: The majority of Canadian PRS programs have approaches rather than formal policies to ensure gender non-discrimination and equal opportunity among residents and faculty. Although residency programs support wellness, few have approaches for trainees as parents and/or caregivers upon return to work. At the faculty level, approaches and policies lack support for maternity/paternity/caregiver leave or work/life balance. This information can be used to develop policy for support of plastic surgery trainees and faculty.

Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection.

Chronic infection provokes alterations in inflammatory and suppressive pathways that potentially affect the function and integrity of multiple tissues, impacting both ongoing immune control and restorative immune therapies. Here we demonstrate that chronic lymphocytic choriomeningitis virus infection rapidly triggers severe thymic depletion, mediated by CD8 T cell-intrinsic type I interferon (IFN) and signal transducer and activator of transcription 2 (Stat2) signaling. Occurring temporal to T cell exhaustion, thymic cellularity reconstituted despite ongoing viral replication, with a rapid secondary thymic depletion following immune restoration by anti-programmed death-ligand 1 (PDL1) blockade. Therapeutic hematopoietic stem cell transplant (HSCT) during chronic infection generated new antiviral CD8 T cells, despite sustained virus replication in the thymus, indicating an impairment in negative selection. Consequently, low amounts of high-affinity self-reactive T cells also escaped the thymus following HSCT during chronic infection. Thus, by altering the stringency and partially impairing negative selection, the host generates new virus-specific T cells to replenish the fight against the chronic infection, but also has the potentially dangerous effect of enabling the escape of self-reactive T cells.

CD8+ T Cell Priming in Established Chronic Viral Infection Preferentially Directs Differentiation of Memory-like Cells for Sustained Immunity.

CD8+ T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8+ T cells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1+ cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished T cell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4+ T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8+ T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.

A shark attack treated in a tertiary care centre: Case report and review of the literature.

Although uncommon, shark attacks can lead to devastating outcomes for victims. Surgeons also face unique challenges during operative management such as exsanguination, shock, specific injury patterns and infections. This case report presents the management of a 39-year-old previously healthy female attacked by a shark while on vacation in Mexico. The patient sustained severe injuries to her left arm and her left thigh. She was transferred to a Canadian institution after ambiguous operative management in Mexico and presented with no clear antibiotic coverage and a Volkman's contracture of the left upper extremity. In total, the patient underwent four washouts of wounds, two split-thickness skin grafts, one free anterolateral thigh flap, and one free transverse rectus abdominus myocutaneous flap for the reconstruction and salvage of the left lower extremity. This article highlights the specifics of this case and describes important points in managing these devastating injuries.

Patient-Reported Outcomes following Breast Conservation Therapy and Barriers to Referral for Partial Breast Reconstruction.

BACKGROUND: The purpose of this study was to evaluate the self-reported aesthetic outcome of breast conservation therapy in a generalized sample of patients, and to describe potential barriers to referral for partial breast reconstruction. METHODS: Consecutive breast conservation therapy patients completing radiotherapy over a 1-year period at a regional cancer center were identified. Eligible patients were contacted by means of mail/e-mail and invited to participate. Participants completed the BREAST-Q breast conservation therapy module along with a questionnaire examining feelings about breast reconstruction. Multiple regression analysis was performed using the satisfaction with breasts scale as the dependent variable. RESULTS: Surveys were completed by 185 of 592 eligible participants (response rate, 31.3 percent; mean age, 61 years) an average of 38 months after lumpectomy. The mean score for the BREAST-Q satisfaction with breasts scale was 59 of 100. Younger age (p = 0.038), lumpectomy reexcision (p = 0.018), and lumpectomy at a nonacademic center (p = 0.026) were significantly associated with lower satisfaction. Bra size, months from lumpectomy, and tumor quadrant/size were not significantly associated with satisfaction (p > 0.05). The most common statements regarding reconstruction were "I don't feel the need for it" (60.0 percent), "I don't like the thought of having breast implants" (22.7 percent), and "I don't want any more surgeon/doctor visits" (22.2 percent). Before lumpectomy, only 1.6 percent had a consultation for reconstruction, and only 22.7 percent were aware of this option. If offered, 33.1 percent of patients would have attended this consultation. CONCLUSION: There is an unmet demand for partial breast reconstruction, with an opportunity to advocate and increase awareness on behalf of patients undergoing breast conservation therapy.

CD30 Is Dispensable for T-Cell Responses to Influenza Virus and Lymphocytic Choriomeningitis Virus Clone 13 but Contributes to Age-Associated T-Cell Expansion in Mice.

CD30 is a tumor necrosis factor receptor (TNFR) family member whose expression is associated with Hodgkin's disease, anaplastic large cell lymphomas, and other T and B lymphoproliferative disorders in humans. A limited number of studies have assessed the physiological role of CD30/CD30 ligand interactions in control of infection in mice. Here, we assess the role of CD30 in T-cell immunity to acute influenza and chronic lymphocytic choriomeningitis virus (LCMV) clone 13 infection, two viral infections in which other members of the TNFR superfamily are important for T-cell responses. We show that CD30 is expressed on activated but not resting CD4 and CD8 T cells in vitro, as well as on regulatory T cells and marginally on T helper 1 cells in vivo during influenza infection. Despite this, CD4 and CD8 T-cell expansion in response to influenza virus was comparable in CD30+/+ and CD30-/- littermates, with no discernable role for the pathway in the outcome of influenza infection. Similarly, during persistent infection with LCMV clone 13, CD30 plays no obvious role in CD4 or CD8 T-cell responses, the level of T-cell exhaustion or viral control. In contrast, in the steady state, we observed increased numbers of total CD4 and CD8 T cells as well as increased numbers of regulatory T cells in unimmunized older (~8 months) CD30+/+ but not in CD30-/- age-matched littermates. Naive T-cell numbers were unchanged in the aged CD30+/+ mice compared to their CD30-/- littermate controls, rather the T-cell expansions were explained by an increase in CD4+ and CD8+ CD44mid-hiCD62L- effector memory cells, with a similar trend in the central memory T-cell compartment. In contrast, CD30 did not impact the numbers of T cells in young mice. These data suggest a role for CD30 in the homeostatic regulation of T cells during aging, contributing to memory T-cell expansions, which may have relevance for CD30 expression in human T-cell lymphoproliferative diseases.

A Qualitative Assessment of the Journey to Delayed Breast Reconstruction.

BACKGROUND: Canada has low immediate breast reconstruction (IBR) rates compared to the United States and Europe. Breast cancer survivors live with mastectomy defects sometimes for years, and this represents an area for improvement in cancer care. PURPOSE: This study qualitatively assessed (1) information provided about breast reconstruction at the time of cancer diagnosis among women seeking delayed breast reconstruction (DBR) and (2) referral practices for plastic surgery consultation for DBR. METHODS: Fifty-two consecutive patients seen in consultation for DBR at a single Canadian tertiary care centre completed questionnaires regarding their experience in seeking breast reconstruction. Seven semi-structured interviews were conducted to further explore themes identified through questionnaires. Questionnaire responses and interview transcripts were analyzed for recurring themes using standard qualitative techniques. RESULTS: A significant portion of women (43%) was interested in reconstruction prior to mastectomy, yet IBR was infrequently discussed (14%) or discouraged by their oncologic surgeons (33%). Common patient reasons for not pursuing IBR were referring physician objection and not having adequate knowledge. Women expressed wanting to discuss reconstruction at the time of cancer diagnosis. Half of the patients had attended another consultation, but the initial plastic surgeon either did not offer procedures for which these women were candidates or had prohibitively long surgical wait times. CONCLUSION: Lack of information about reconstructive options at the time of cancer diagnosis and perceived access barriers to plastic surgeons may contribute to underutilization of IBR in Canada. Access to breast reconstruction can be improved by reducing inefficiencies in plastic surgery referrals.

HISTORIQUE: Le taux de reconstructions mammaires immédiates (RMI) est faible au Canada par rapport aux États-Unis et à l'Europe. Les survivantes du cancer du sein vivent parfois avec une mastectomie pendant des années, ce qui représente un secteur à améliorer dans les soins du cancer. OBJECTIF: La présente étude était une analyse qualitative 1) de l'information transmise au sujet de la reconstruction mammaire au moment du diagnostic de cancer chez les femmes qui souhaitent une reconstruction mammaire tardive (RMT) et 2) des pratiques d'orientation vers une consultation en chirurgie plastique en vue d'une RMT. MÉTHODOLOGIE: Cinquante-deux patientes consécutives vues en consultation pour subir une RMT dans un seul centre canadien de soins tertiaries ont rempli des questionnaires sur leur expérience dans l'obtention d'une reconstruction mammaire. Les chercheurs ont organisé sept entrevues semi-structurées pour explorer les thèmes colligés grâce aux questionnaires. Ils ont utilisé des techniques qualitatives standards pour analyser les réponses aux questionnaires et les entrevues transcrites et relever des thèmes récurrents. RÉSULTATS: Avant la mastectomie, une forte proportion de femmes (43 %) souhaitait subir une reconstruction, mais leur chirurgien oncologue abordait rarement la RMI (14 %) ou la déconseillait (33 %). Les raisons fréquentes pour ne pas demander une RMI étaient l'objection du médecin traitant et le manque de connaissances suffisantes. Les femmes indiquaient vouloir parler de reconstruction au moment de leur diagnostic de cancer. La moitié des patientes avait participé à une autre consultation, mais le premier plasticien n'avait pas offert d'interventions auxquelles ces femmes étaient candidates ou présentait une trop longue liste d'attente avant l'opération. CONCLUSION: Le manque d'information sur les possibilités de reconstruction au moment du diagnostic de cancer et les obstacles perçus à l'accès aux plasticiens peuvent contribuer à une sous-utilisation de la RMI au Canada. Pour améliorer l'accès à la reconstruction mammaire, on peut réduire les inefficacités en matière de demande de consultation auprès des plasticiens.

Type I Interferon in Chronic Virus Infection and Cancer.

Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases.

Surgeon-Reported Needs for Improved Training in Identifying and Managing Free Flap Compromise.

Background This study examined the need for improved training in the identification and management of free flap (FF) compromise and assessed a potential role for simulated scenario training. Methods Online needs assessment surveys were completed by plastic surgeons and a subsample with expertise in microsurgery education participated in focus groups. Data were analyzed using descriptive statistics and mixed qualitative methods. Results In this study, 77 surgeons completed surveys and 11 experts participated in one of two focus groups. Forty-nine (64%) participants were educators, 65 and 45% of which reported having an insufficient volume of FF cases to adequately teach the management and identification of compromise, respectively. Forty-three percent of educators felt that graduating residents are not adequately prepared to manage FF compromise independently. Exposure to normal and abnormal FF cases was felt to be critical for effective training by focus group participants. Experts identified low failure rates, communication issues, and challenging teaching conditions as current barriers to training. Most educators (74%) felt that simulated scenario training would be "very useful" or "extremely useful" to current residents. Focus groups highlighted the need for a widely accepted algorithm for re-exploration and salvage on which to base the development of a training adjunct consisting of simulated scenarios. Conclusion Trainee exposure to FF compromise is inadequate in existing plastic surgery programs. Early exposure, high case volume, and a standardized algorithmic approach to management with a focus on decision making may improve training. Simulated scenario training may be valuable in addressing current barriers.

Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence.

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.