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Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3 + CD4 + Tregs are well established, much of CD8 + Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8 + T cells have been named “CD8 + Treg” and mainly focus on CD122 hi Ly49 + CD8 + Tregs present in naïve mice. CD122 hi Ly49 + CD8 + Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-β (Transforming growth factor-β) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8 + Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8 + Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4 + T FR (follicular regulatory T cells) and CD8 + Tregs.

TGF-β signaling is necessary for CD8 + T cell differentiation into tissue resident memory T cells (T RM ). Although higher frequency of CD8 + T RM cells in the tumor microenvironment is associated with better prognosis, TGF-β−blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8 + T cells differentiate into T RM s in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8 + T cells are maintained in a stem-like state, but a proportion of cells lost T RM status and differentiate into CX3CR1 + effector CD8 + T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8 + T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent T RM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade. TGF-β has been shown to regulate stem-like CD8 + T cell differentiation into tissue resident memory T cells in chronic infection. Here authors show that in tumour-bearing mice, a similar TGF-βdependent CD8 + T cell differentiation program is carried out in the draining lymph nodes, which impedes generation of anti-tumor migratory effector T cells upon future vaccination.

Since the development of an Accreditation Council of Graduate Medical Education (ACGME)-accredited emergency medical services (EMS) fellowship, there has been little published literature on effective methods of content delivery or training modalities. Here we explore a variety of innovative approaches to the development and revision of the EMS fellowship curriculum. Three academic, university-based ACGME-accredited EMS fellowship programs each implemented an innovative change to their existing training curricula. These changes included the following: a novel didactic curriculum delivery modality and evaluation; implementation of a distance education program to improve EMS fellows' rural EMS experiences; and modification of an existing EMS fellowship curriculum to train a non-emergency medicine physician. Changes made to each of the above EMS fellowship programs addressed unique challenges, demonstrating areas of success and promise for more generalized implementation of these curricula. Obstacles remain in tailoring the described curricula to the needs of each unique institution and system. Three separate curricula and program changes were implemented to overcome specific challenges and achieve educational goals. It is our hope that our shared experiences will enable others in addressing common barriers to teaching the EMS fellowship core content and share similar innovative approaches to educational challenges.

Gingival bleeding is a relatively uncommon chief complaint in the pediatric population. The differential diagnosis is broad, and both the patient's clinical presentation and medical history must be taken into account when formulating a differential diagnosis. The following is a case of a child with trisomy 21 who presented to the emergency department with oral bleeding in the setting of a normal complete blood count and coagulation studies. The patient underwent a workup for coagulopathies, malignancy, and nutritional deficiencies and was found to have vitamin C deficiency, also known as scurvy. This case illustrates a rare cause of gingival bleeding that occurs primarily in developing countries but may also occur in developed countries in children with underlying medical conditions such trisomy 21 or developmental delay.

Purpose: The purpose of this study is to assess the efficacy and safety of intracameral mydriatic solution, as compared to preoperative topical mydriatics, in patients undergoing manual small incision cataract surgery (MSICS) under peribulbar anesthesia. To assess the sustainability of intracameral mydriasis in MSICS by monitoring pupil size at specific junctures during the surgery. Methods: This trial recruited 127 patients, who underwent MSICS under peribulbar block. Mydriasis in topical group was achieved with preoperative topical dilating drops while patients in intracameral group were taken up for surgery without dilation, and mydriasis was achieved intraoperatively with intracameral solution. Pupil sizes were measured serially, at six different junctures during surgery. Time duration of surgery, any intraoperative complications and first postoperative day visual acuity, corneal edema score, and anterior chamber inflammation score were noted in all patients. Results: Mean pupil size just before peribulbar block was 7.3 mm in topical group and 3.3 mm in intracameral group (P < 0.001). Mean pupil size in intracameral group increased to 7.3 mm 30 s after injecting intracameral dilating solution. Mean pupil size in both groups progressively reduced, reaching 5.5 mm (topical group) and 6.2 mm (intracameral group) just before intraocular lens implantation (P = 0.001), and measured 5.1 mm and 5.5 mm, respectively, at the end of surgery (P = 0.048). On first postoperative day, there was no significant difference in distribution of corneal edema scores, AC inflammation scores, and in median logMAR visual acuity between the two groups. Conclusions: MSICS can be performed effectively and safely utilizing intracameral mydriatic solution, without the use of preoperative dilating drops. Trial registration: CTRI/2016/06/007036

Using the pediatric version of the Simple Triage and Rapid Treatment (JumpSTART) algorithm for the triage of pediatric patients in a mass-casualty incident (MCI) requires assessing the results of each step and determining whether to move to the next appropriate action. Inappropriate application can lead to performance of unnecessary actions or failure to perform necessary actions. Hypothesis/Problem To report overall accuracy and time required for triage, and to assess if the performance of unnecessary steps, or failure to perform required steps, in the triage algorithm was associated with inaccuracy of triage designation or increased time to reach a triage decision. Medical students participated in an MCI drill in which they triaged both live actors portraying patients and computer-based simulated patients to the four triage levels: minor, delayed, immediate, and expectant. Their performance was timed and compared to intended triage designations and a priori determined critical actions. Thirty-three students completed 363 scenarios. The overall accuracy was 85.7% and overall mean time to assign a triage designation was 70.4 seconds, with decreasing times as triage acuity level decreased. In over one-half of cases, the student omitted at least one action and/or performed at least one action that was not required. Each unnecessary action increased time to triage by a mean of 8.4 seconds and each omitted action increased time to triage by a mean of 5.5 seconds. Discussion Increasing triage level, performance of inappropriate actions, and omission of recommended actions were all associated with increasing time to perform triage.

The current study explores the potential of eugenol as a therapeutic agent for bone regeneration through an integrative approach combining in silico and in vitro analyses. Network pharmacology and molecular docking was employed to investigate the molecular targets and pathways associated with eugenol in the context of bone-related diseases, revealing its multi-targeted therapeutic potential. Based on these findings, composite biomaterials were fabricated using Sodium Alginate, Chitosan, and β-Tricalcium phosphate, infused with Eugenol, to develop a bioactive scaffold for bone tissue engineering. The fabricated scaffolds were characterized using Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Thermogravimetric Analysis, Scanning Electron Microscopy, and compression testing to evaluate their physicochemical and mechanical properties. Additionally, porosity, swelling behaviour, in vitro degradation and bio-mineralization were assessed to determine the scaffold’s suitability for bone regeneration. The porous structure, swelling ratio, and controlled degradation profile indicated favourable properties for cell infiltration and tissue integration. Cytocompatibility of the scaffolds was evaluated using the MTT assay on MG-63 osteoblastic cell lines, demonstrating high cell viability and biocompatibility. Overall, the Eugenol-infused Alginate/Chitosan/β-Tricalcium phosphate composite scaffold exhibits promising potential as a multifunctional biomaterial for bone tissue engineering applications. Graphical Abstract

Aging is tightly associated with reduced immune protection but increased risk of autoimmunity and inflammatory conditions. Regulatory T cells are one of the key cells to maintaining immune homeostasis. The age‐dependent changes in CD4+Foxp3+ regulatory T cells (Tregs) have been well documented. However, the nonredundant Foxp3−CD8+ Tregs were never examined in the context of aging. This study first established clear distinctions between phenotypically overlapping CD8+ Tregs and virtual memory T cells. Then, we elucidated the dynamics of CD8+ Tregs across the lifespan in mice and further extended our investigation to human peripheral blood mononuclear cells (PBMCs). In mice, we discovered a bi‐phasic dynamic shift in the frequency of CD8+CD44hiCD122hiLy49+ Tregs, with a steady increase in young adults and a notable peak in middle age followed by a decline in older mice. Transcriptomic analysis revealed that mouse CD8+ Tregs upregulated a selected set of natural killer (NK) cell‐associated genes, including NKG2D, with age. Importantly, NKG2D might negatively regulate CD8+ Tregs. Additionally, by analyzing a scRNA‐seq dataset of human PBMC, we found a distinct CD8+ Treg‐like subset (Cluster 10) with comparable age‐dependent frequency changes and gene expression, suggesting a conserved aging pattern in CD8+ Treg across mice and humans. In summary, our findings highlight the importance of CD8+ Tregs in immune regulation and aging. The biology of Ly49+CD8+ regulatory T cells (Tregs) during aging is unknown. Here, we demonstrate that CD8+ Tregs exhibit unique bi‐phasic population dynamics during aging, with a gradual increase until middle age followed by a progressive loss. This age‐dependent pattern is highly conserved between mice and humans.

Objectives Firearm injuries to children and adolescents remain an important cause of morbidity and mortality in the USA. The objectives of this study were to describe the prevalence of and epidemiologic risk factors associated with firearm injuries to children and adolescents evaluated in a nationally representative sample of US emergency departments and ambulatory care centres. Study design We performed a retrospective cross-sectional analysis of data from the National Hospital Ambulatory Medical Care Survey from 2001 to 2010. Firearm injury-related visits in patients 0–19 years old were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification firearm injury codes. The primary outcome was the prevalence of firearm-related injuries. We used multivariate logistic regression to analyse demographic risk factors associated with these injuries. Results From 2001 to 2010, there were a total of 322 730 927 (95% CI 287 462 091 to 357 999 763) paediatric US outpatient visits; 198 969 visits (0.06%, 95% CI 120 727 to 277 211) were for firearm injuries. Fatal firearm injuries accounted for 2% of these visits; 36% were intentionally inflicted. There were increased odds of firearm injuries to men (OR 10.2, 95% CI 5.1 to 20.5), black children and adolescents (0–19 years) (OR 3.2, 95% CI 1.5 to 6.7) and adolescents 12–19 years old (all races) (OR 16.6, 95% CI 6.3 to 44.3) on multivariable analysis. Conclusions Firearm injuries continue to be a substantial problem for US children and adolescents, with non-fatal rates 24% higher than previously reported. Increased odds for firearm-related visits were found in men, black children and those 12–19 years old.

Multiple modalities for simulating mass-casualty scenarios exist; however, the ideal modality for education and drilling of mass-casualty incident (MCI) triage is not established. Hypothesis/Problem Medical student triage accuracy and time to triage for computer-based simulated victims and live moulaged actors using the pediatric version of the Simple Triage and Rapid Treatment (JumpSTART) mass-casualty triage tool were compared, anticipating that student performance and experience would be equivalent. The victim scenarios were created from actual trauma records from pediatric high-mechanism trauma presenting to a participating Level 1 trauma center. The student-reported fidelity of the two modalities was also measured. Comparisons were done using nonparametric statistics and regression analysis using generalized estimating equations. Thirty-three students triaged four live patients and seven computerized patients representing a spectrum of minor, immediate, delayed, and expectant victims. Of the live simulated patients, 92.4% were given accurate triage designations versus 81.8% for the computerized scenarios (P=.005). The median time to triage of live actors was 57 seconds (IQR=45-66) versus 80 seconds (IQR=58-106) for the computerized patients (P<.0001). The moulaged actors were felt to offer a more realistic encounter by 88% of the participants, with a higher associated stress level. While potentially easier and more convenient to accomplish, computerized scenarios offered less fidelity than live moulaged actors for the purposes of MCI drilling. Medical students triaged live actors more accurately and more quickly than victims shown in a computerized simulation.