A viral-specific CD4 + T cell response protects female mice from Coxsackievirus B3 infection.

Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4 + T cell response that can protect female mice from mortality. We found that CVB3 can induce expansion of CD62L lo CD4 + T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4 + T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4 + T cells before infection increased mortality in female mice, indicating that CD4 + T cells play a protective role against CVB3 in our model. Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease outcomes.

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.

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection.

Background: Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality. Methods: We inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection. Results: We found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model. Conclusions: Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.

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.

CD4+ progenitor cells sustain helper responses during chronic infection.

How CD4+ T cell responses are maintained during chronic infection is unknown. In this issue of Immunity, Xia et al. (2022) identify a progenitor T cell subset that gives rise to effector and follicular helper T cells to sustain antiviral responses.

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.

Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection.

Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.

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.

A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract.

Many pathogens subvert intestinal immunity to persist within the gastrointestinal tract (GIT); yet, the underlying mechanisms that enable sanctuary specifically in this reservoir are unclear. Using mass cytometry and network analysis, we demonstrate that chronic LCMV infection of the GIT leads to dysregulated microbial composition, a cascade of metabolic alterations, increased susceptibility to GI disease, and a system-wide recalibration of immune composition that defines viral persistence. Chronic infection led to outgrowth of activated Tbet-expressing T reg cell populations unique to the GIT and the rapid erosion of pathogen-specific CD8 tissue-resident memory T cells. Mechanistically, T reg cells and coinhibitory receptors maintained long-term viral sanctuary within the GIT, and their targeting reactivated T cells and eliminated this viral reservoir. Thus, our data provide a high-dimensional definition of the mechanisms of immune regulation that chronic viruses implement to exploit the unique microenvironment of the GIT and identify T reg cells as key modulators of viral persistence in the intestinal tract.

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.

Efficacy and nontarget impact of zinc phosphide-coated cabbage as a ground squirrel management tool.

BACKGROUND: Effective management of ground squirrels relies on an integrated pest management (IPM) approach. Rodenticides may be included in an IPM program, but they must be efficacious with minimal impact on nontarget species. A zinc phosphide-coated green bait may meet these requirements. We established a study in northeastern California to test zinc phosphide-coated cabbage as a management tool for Belding's ground squirrels (Urocitellus beldingi). We specifically addressed factors that would influence the efficacy of a baiting program, as well as potential exposure risk to nontarget species. RESULTS: We found that prebaiting was an important application strategy, and efficacy increased as ground squirrel abundance increased. Efficacy was also greater in western portions of the study area, likely due to greater bait consumption at western sites. Belding's ground squirrels fed most heavily on cabbage during mid-morning and late afternoon; bait applications shortly before these time periods would increase bait consumption while minimizing nontarget risk. Bait uptake was greatest around burrow entrances. The only nontarget species observed feeding on cabbage was the California kangaroo rat (Dipodomys californicus), although they were never observed feeding on treated cabbage. CONCLUSION: Zinc phosphide-coated cabbage can be an efficacious tool for managing ground squirrels, but there will be limitations on where and how it can be used effectively. It posed a low risk to nontarget species present in our study area, but nontarget risk could vary regionally. The use of a zinc phosphide-coated green bait should only be one part of an IPM strategy for managing ground squirrels. © 2019 Society of Chemical Industry.

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.