Unveiling Syndesmotic Malreduction: A Proof-of-Concept towards Portable Ultrasound Detection.

Objectives: To evaluate the utility and diagnostic performance of portable handheld ultrasound for evaluating fibular rotation at the distal tibiofibular articulation after syndesmotic disruption. Methods: Four above-the-knee cadaveric specimens were included. Syndesmotic disruption was precipitated by transecting the Anterior Inferior Tibiofibular Ligament, Interosseous Ligament, and Posterior Inferior Tibiofibular Ligament. Thereafter, a proximal fibular osteotomy was performed, and three conditions were modeled at the distal syndesmosis: 1) reduced, 2) 5 degree internal rotation malreduction, and 3) 5 degree external rotation malreduction. Two blinded observers performed separate ultrasonographic examinations for each condition at the level of both the anterior and posterior distal tibiofibular articular surfaces. Syndesmotic gap penetrance, defined as the ability of the P-US to generate signal between the distal fibula and tibia at the level of the incisura, was graded positive if the sonographic waves penetrated between the distal tibiofibular joint and negative if no penetrating waves were detected. The accuracy measures of the anterior and posterior gap penetrance were evaluated individually. Results: Our preliminary results showed that posterior gap penetrance showed good performance when detecting either internal or external rotational malreduction of the fibula with very good specificity (87.5%) and PPV (90.0%). On the other hand, the anterior gap penetrance showed limited performance when detecting either form of rotational malreduction. Conclusion: We introduced a novel sign, the "gap penetrance sign", best measured from the posterior ankle, which can accurately detect syndesmotic malreduction using P-US in a manner that does not require specific quantitative measurements and is readily accessible to early P-US users.

Utility of three-dimensional printing in the surgical management of intra-articular distal humerus fractures: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Clinical outcomes after fixation of distal humerus intraarticular fractures are directly related to the quality of reduction. The use of three-dimensional (3D)-printed fracture models can benefit preoperative planning to ensure good reduction. This review aims to determine if surgery performed with 3D printing assistance are faster and result in fewer complications and improved clinical outcomes than conventional methods. We also outline the benefits and drawbacks of this novel technique in surgical management of distal humerus fractures. METHODS: A systematic literature search was carried out in various electronic databases. Search results were screened based on title and abstract. Data from eligible studies were extracted into spreadsheets. Meta-analysis was performed using appropriate computer software. RESULTS: Three randomized controlled trials with 144 cases were included in the final analysis. The 3D-printed group had significantly shorter mean operating time (mean difference, 16.25 minutes; 95% confidence interval [CI], 12.74-19.76 minutes; P<0.001) and mean intraoperative blood loss (30.40 mL; 95% CI, 10.45-60.36 mL; P=0.005) compared with the conventional group. The 3D-printed group also tended to have fewer complications and a better likelihood of good or excellent outcomes as per the Mayo elbow performance score, but this did not reach statistical significance. CONCLUSIONS: Three-dimensional-printing-assisted surgery in distal humerus fractures has several benefits in reduced operating time and lower blood loss, indirectly decreasing other complications such as infection and anemia-related issues. Future good-quality studies are required to conclusively demonstrate the benefits of 3D printing in improving clinical outcomes. Level of evidence: I.

Evaluation of the Stability of Internal Fixation Constructs in a Low Distal Tibia Extra-articular Cadaveric Fracture Model: A Comparative Biomechanical Study.

Introduction Despite the recent advances in implant design, the choice of an internal fixation modality for extra-articular distal tibia fractures remains controversial, and there is sparse literature comparing the stability of intramedullary nails and locked plates for such fractures. Hence, we conducted a biomechanical study on an AO type 43A3 tibia fracture cadaveric model stabilized by four different constructs, viz., intramedullary (IM) interlocking nail, anteromedial plate, anterolateral plate, and posterior plate. An AO type 43A3 fracture is defined as an extra-articular fracture of the distal tibia with metaphyseal comminution. Methods A biomechanical comparative study on formalin-preserved human cadaveric tibiae was undertaken; a total of four groups were tested, with eight bones in each group. Out of the 32 cadaveric tibiae, 19 bones belonged to male cadavers, and 13 bones belonged to female cadavers. All bones were dissected from age-appropriate cadavers and fixed with an implant, followed by the creation of a 1 cm osteotomy to simulate an AO type 43A3 fracture. All fixation constructs were subjected to three-point bending tests in the anteroposterior (AP) and mediolateral (ML) planes. Three parameters, viz., bending stiffness, peak fracture gap angle, and neutral zone, were evaluated on the load-displacement curves. A fixation construct was deemed biomechanically stable if it had a high bending stiffness, a low neutral zone (inherent toggle in the construct by its weight), and a low peak fracture gap angle. Results Out of the four implants tested, locked IM nails exhibited the maximum biomechanical stability in terms of higher bending stiffness, smaller peak fracture gap angle, and smaller neutral zones. The IM nail exhibited the highest bending stiffness in the AP plane, and the anterolateral plate had the lowest bending stiffness, and the difference was statistically significant (p= 0.032). In the AP plane, the anterolateral plate exhibited a bending stiffness of 1.51 ± 0.69 Nm/degree, whereas the intramedullary nail exhibited a bending stiffness of 2.34 ± 0.81 Nm/degree, and the posterior locked plate had a bending stiffness of 1.57 ± 0.44 Nm/degree. In the ML plane, the anterolateral plate exhibited the highest neutral zone as compared to the intramedullary nail, which had the lowest neutral zone, and the difference was statistically significant (p = 0.019). The intramedullary nail exhibited the lowest neutral zone of 0.46 ± 0.31 degrees, whereas the posterior locked plate exhibited a neutral zone of 0.78 ± 0.43 degrees in the ML plane. The anterolateral plate exhibited a neutral zone of 1.43 ± 1.00 (expressed as mean ± SD) degrees in the mediolateral plane. Conclusion Our biomechanical study supports the recommendations of using a locked intramedullary nail for AO type 43A3 fractures. We concluded that the anterolateral plate construct exhibited the least biomechanical stability, in terms of lower AP bending stiffness and higher neutral zone. If the surgeon must choose a locked plating technique for any reason, the anterolateral locking plate should be avoided. If plating is at all required, we can recommend both anteromedial and posterior locked plating as biomechanically sound options.

Repositioning the Early Pathology of Type 1 Diabetes to the Extraislet Vasculature.

Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.

Ankle fractures with Chaput fragment: A new classification system with insights into morphology and relation to surgical treatment.

BACKGROUND: The Chaput fragment, a bony avulsion of the anterolateral margin of the distal tibia, is a less commonly discussed fracture pattern in ankle injuries. Its significance in ankle fractures and the optimal fixation technique remains unclear due to limited literature. This study aims to describe the morphology of ankle fractures with Chaput fragment and introduce a new classification system. MATERIALS AND METHODS: We retrospectively analyzed 33 patients with ankle fractures with associated Chaput fragment treated at our institute over a 3-year period. Data on patient demographics, fracture classification, surgical approach, and fixation method were collected, and a novel classification system for Chaput fragments was proposed. RESULTS: Four distinct morphological types of Chaput fragment were identified (types 1-4), and three newer variants of trimalleolar fractures were identified (anterior, lateral, and medial variants). Type 1 refers to a small avulsion fragment attached to the anterior-inferior tibiofibular ligament; Type 2 is an anterolateral oblique type; Type 3 refers to an anterolateral fragment with extension into the medial malleolus and Type 4 is a comminuted Chaput fragment. Type 1 Chaput fragment was the most prevalent (60.6%), followed by Type 2 (24.3%), Type 4 (9.1%), and Type 3 (6.1%). The fixation methods ranged from screw fixation, plate fixation, and suture fixation to combinations of these techniques or even indirect stabilization with syndesmotic screws. CONCLUSION: Our new classification system based on morphology includes all possible variants of Chaput fracture. This preliminary data needs to be corroborated by more studies and validated by a larger number of observers.

A comparison of outcomes of locking versus non-locking plate fixation for the distal fibula fractures: a systematic review and meta-analysis.

PURPOSE: A locking plate (LP) or non-locking plate (NLP) can be used for distal fibula fracture fixation. However, the advantages of LP over NLP in patients with distal fibula fractures are not clear. In terms of indications, the role of the two plates probably differs; however, to draw comparative conclusions, we conceptualized this systematic review and meta-analysis of studies that directly compared the two plates, wherein both groups' indications and baseline parameters were similar. METHODS: An electronic literature search was performed using PubMed/Medline, Embase, Scopus, and Cochrane Library databases for studies comparing the LP versus NLP fixation for the lateral malleolus fracture. A total of 18 studies were included in qualitative and quantitative analysis. A subgroup analysis was performed for patients aged < 55 years and patients aged > 55 years. The statistical analysis was performed by Review Manager Software version 5.4.1. RESULTS: A meta-analysis of 4243 fractures was performed across 18 studies. The rate of fracture union and overall complication rates did not differ between the two fixation groups with an OR of 0.71 (95% CI 0.26, 1.96, p = 0.51 and 1.11 (95% CI 0.84, 1.47, p = 0.47, respectively. There is no difference in the reoperation rate due to minor or major complications between the two groups. There was no difference in functional outcome (MD -0.85, with 95% CI -5.63, 3.93, p = 0.73), but NLP has a shorter surgical duration (MD 3.0, with 95% CI 0.26, 5.75, p = 0.03). A leave-one-out sensitivity analysis performed for overall complications affected the final outcome of the meta-analysis. CONCLUSION: This meta-analysis demonstrates no clear benefit in selecting LP over NLP for the fixation of lateral malleolus fractures.

Comparison between achilles tendon reinsertion and dorsal closing wedge calcaneal osteotomy for the treatment of insertional achilles tendinopathy: A meta-analysis.

BACKGROUND: The debridement and Achilles tendon reinsertion (DATR) have been the most common surgical approach for the treatment of Insertional Achilles Tendinopathy (IAT), while dorsal closing wedge calcaneal osteotomy (DCWCO) has recently gained popularity as an alternative surgical option. This study aimed to systematically review the published literature on both surgical techniques and compare their clinical outcomes and complication rates. METHODS: A systematic review was performed according to the PRISMA guidelines using Medline, Embase, and Scopus databases. The inclusion criteria encompassed clinical studies reporting functional outcomes and complications, with a minimum of 10 patients and at least 12 months of follow-up. RESULTS: Seven studies (n = 169) were included for the analysis of DATR, and eight studies (n = 227) were included for the analysis of open DCWCO. Both groups showed a similar improvement in AOFAS score. The overall complication rates were 16.6% in the DATR group and 9.2% in the DCWCO group, but the difference was not statistically significant. However, there was a significantly higher incidence of wound complications in the DATR group (10.1%, 95% C.I.: 4.7-15.6) compared to the DCWCO group (2.5%, 95% C.I.: 0.6-4.4) as the confidence intervals did not overlap. CONCLUSIONS: Clinical outcomes and overall complication rates of both techniques were comparable, although DCWCO had a lower incidence of wound complications. Further research should be focused on prospective studies comparing the two techniques to corroborate the current findings. LEVEL OF EVIDENCE: Level IV; meta-analysis.

Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.

Inter- and Intra-observer Reliability of a New Classification System for Calcaneus Fracture Malunions: The ADEINS Classification.

Background: Currently, two classification systems, namely Stephens and Sanders, based on axial CT images, and Zwipp and Rammelt, which consider deformities, are used for calcaneus malunions. Existing classifications have limitations due to their pure anatomical basis, and the complexity of the problem, involving both bone and soft tissues. As a solution, the senior author proposed a novel ADIENS classification system for calcaneal malunion, based on pain generators. This study aimed to introduce and evaluate the inter- and intra-observer reliability of a new classification system for calcaneal malunions. Methods: This retrospective cohort study included adult cases with post-traumatic calcaneus malunion. Three experienced foot and ankle surgeon volunteers underwent training session on the classification system, which classifies malunions based on A arthritis, D deformity, E exostosis, I implant issues, N nerve issues, and S soft tissue issues. Post-training, two rounds of classification exercises were conducted. Inter-rater and intra-rater agreements were determined using Gwet's AC coefficient. Results: Out of 15 cases, 6 were of Stephen and Sanders types, and 8 were of Zwipp and Rammelt types, the rest fell out of these classifications. Inter-rater agreement for ADEINS classification was noted to be 'very good' for all six domains. Intra-observer agreements were 'very good' for four out of six domains of classification and 'fair' for two domains of classification. Conclusion: Pain generators-based new ADEINS classification has demonstrated good intra- and inter-observer reliability and seemed user-friendly. However, results need to be replicated in a larger, multicentric cohort before wider clinical applicability. Level of Evidence: Level IV, retrospective study.

Efficacy of undenatured collagen in knee osteoarthritis: review of the literature with limited meta-analysis.

BACKGROUND: Early knee osteoarthritis (OA) treatment is multimodal, with physical therapy and pharmacotherapy commonly used. Although popular, oral supplements like glucosamine and diacerein have not been reported to have high efficacy. Undenatured collagen type II (UC-II) has been introduced for therapy in early OA; it helps in cartilage repair and preservation. The present review was done to ascertain its efficacy in pain relief and knee function. MATERIALS AND METHODS: A systematic literature search was performed on MEDLINE (PubMed), Embase, Scopus, and Cochrane Library for published literature; studies comparing the outcome of UC-II supplementation with placebo/control in adult humans with early knee OA were included. The outcomes evaluated were VAS Score, quality of life - Western Ontario and McMaster Universities (WOMAC-score), Knee function, Knee range of motion, and any complications during the course of treatment. RESULTS: A total of 293 results were obtained after a primary search; 8 randomized control trials (RCT) were finally included. A total of 243 patients received UC-II supplementation (91 men and 152 women). The overall mean age range for the intervention group was 53.5±0.99 to 68.7±5.3 years across all included studies, and the mean follow-up duration was 3 to 6 months. Outcome measures like WOMAC and VAS scores showed better outcomes with UC-II in comparison to placebo. Walking measurements improved significantly from the baseline, reflected in improved timed up-and-go and 6-minute walk tests (6MWT). The overall complications were similar to other supplements. CONCLUSION: With limited literature, UC-II has shown promise as a potent supplement in early knee OA with good pain relief and improved function. However, further large-scale studies are needed to substantiate these findings.

Extruded talus injuries are associated with significant complications: A double center series with minimum 1-year follow up.

BACKGROUND: Extruded talus (ET) injuries are rare, but high-energy open pantalar dislocations. Literature on these injuries is sparse and optimal treatment protocols are ill defined. The current study documents the clinical and radiological outcomes in cases seen at 2 centers, in an attempt to determine whether surgeons should choose primary reimplantation or primary talectomy and fusion for these injuries. METHODS: Patients with ET injuries were identified from the database of two hospitals. Baseline demographics and treatment details were evaluated, and patients were called for follow-up. Radiological evaluation was conducted, and function was evaluated by the AOFAS hindfoot score. Outcomes and complications were compared between patients who had undergone primary talectomy versus primary reimplantation. Predictors of poor functional outcomes were determined. RESULTS: Of 23 patients seen by us, 15 were available for follow-up at 45.7 ± 22.2 months. Of these 19 had undergone reimplantation and 4 had talectomy with tibio-calcaneal arthrodesis. The mean percentage AOFAS score was 66.2 ± 14.6 at follow up. AVN was noted in 5, ankle arthrosis in 10, subtalar arthrosis in 4 and infection in 4 cases; no patient needed salvage arthrodesis during this time. There was no difference in baseline demographics, range of motion, AOFAS scores or complication rates between patients undergoing primary reimplantation versus primary talectomy. The number of complications per patient showed a negative, moderate correlation with the AOFAS score (Pearson's correlation coefficient 0.6, P value = 0.02). CONCLUSION: Despite best treatment, ET injuries result in significant impairment of functional outcomes and complications. Within the numbers available, no difference in outcomes or complication rates was noted between primary reimplantation or talectomy. However, we recommend reimplantation as the treatment of first choice as this offers the chance to salvage the ankle joint and preserves bone stock for future fusion or arthroplasty.

Beyond the Boundary: A Bibliometric Analysis of the Published Research on Injuries in Cricket.

Background: Cricket, a sport immensely popular in the Indian subcontinent and Commonwealth countries, boasts a staggering global following of over 1 billion enthusiasts. However, injuries in cricket are prevalent, resulting in detrimental effects on player performance and leading to substantial absenteeism from the game. In recent times, there has been a surge in interest on the epidemiology, biomechanics, and prevention of cricket-related injuries. To gain comprehensive insights into the existing research landscape, we present a bibliometric analysis of the published research on cricket injuries. Materials: The Web of Science database was searched using a well-defined search strategy. Original research articles looking at any aspect of injuries in cricket were included. Search results were imported into the R Bibliometrix package for analysis. Analysis of bibliometric parameters included top authors, journals, countries and keywords. Co-occurrence networks were generated and thematic mapping was performed to identify emerging research topics. Observations: 423 publications from 126 journals were included. An increasing trend in publications was noted. JW Orchard was the highest published author; Australia was the highest published country and the Journal of Science and Sport in Medicine had the highest number of publications. Fast bowlers were the most extensively researched and the major research was noted to focus on three niche areas, i.e., epidemiology, consensus definitions and spinal issues in fast bowlers. Research on batsmen, wicketkeepers and fielders was relatively sparse. Furthermore, we observed limited representation of research from the Indian subcontinent, despite cricket's immense popularity in the region. Conclusions: Our study findings highlight that majority of the cricket injury research stems from developed countries. The primary research areas include epidemiology, injury prevention, and biomechanics, with a particular focus on fast bowlers. However, much more has to be done to encourage research publications, focused on batsmen, wicketkeeper and fielders, as well as cricket in the developing world. These insights are essential for researchers seeking to delve into cricket-related studies and organizations aiming to advance injury prevention research in cricket.

Congenital epulis: a rare diagnosis of newborn.

Congenital epulis is a rare benign soft tissue lesion that occurs exclusively in neonates and usually develops from the alveolar mucosa at the frontal region of the maxilla. Lesions may be sessile or pedunculated, normal in color or reddish and vary in size from a few millimeters to a few centimeters. Although spontaneous regression has also been reported, surgical excision is indicated for large tumors that may obstruct the airway and make feeding the child difficult. In this case report, we present a rare case of congenital epulis involving the right side of the maxillary alveolar mucosa in a neonate delivered vaginally at Dhulikhel Hospital, Kavreplanchok, Nepal. The lesion was surgically removed by electrocautery, and histologic examination confirmed the clinical diagnosis of congenital epulis. No complications occurred after surgery, and when the child was examined 6 months later, no evidence of recurrence noticed.

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Comparison of Outcomes of Long Versus Short Cephalomedullary Nails for the Fixation of Intertrochanteric Femur Fractures: A Systematic Review and Meta-analysis of 14,547 Patients.

Purpose: Intertrochanteric Femur Fractures (IFF) fixation could be done with short or long Cephalomedullary Nails (CMNs). Nevertheless, despite several studies in the literature, there has been a continued lack of consensus on which design of CMN is better than the other. Hence, the current review aimed to evaluate the evidence about short versus long CMNs for the fixation of IFF. Methodology: PRISMA guidelines were followed, and the protocol for the study was registered to PROSPERO. Four databases, Medline/PubMed, Embase, Scopus, and Cochrane Library, were searched. A total of 31 studies with 6 randomized trials (RCTs) and 25 non-randomized studies were included. Demographic data, follow-up period, and primary and secondary outcomes were extracted and evaluated from each of the included studies; statistical analysis was done by Review Manager Software version 5.4.1. Results: Fourteen thousand five hundred forty-seven patients were included in this review. Primary Outcomes: Long CMNs showed statistically significant lower rates of ipsilateral shaft femur refracture (OR 1.60, 95% CI 1.14, 2.24, p = 0.007); however, the difference was not statistically significant between the two groups for mortality at 30 days and within 1 year. Secondary Outcomes: Statistically significant shorter duration of surgery (MD-17.83 (95% CI - 22.03, - 13.63, p < 0.05), less intra-operative blood loss (MD - 62.65, 95% CI - 97.13 to - 28.17, p = < 0.05), and lower blood transfusion rates (OR 0.71, 95% CI 0.62, 0.83, p < 0.05) for short CMNs; no statistically significant difference for the length of hospital stay, implant-related complications, overall complications, re-operation rates, fluoroscopy time, and functional outcome between two groups of CMNs was seen. Conclusion: With shorter operative time, lesser intra-operative blood loss, and lower postoperative transfusion rates for short CMNs, they have certain benefits over longer CMNs. However, more distal shaft femur fractures were seen in the shorter version of nail, which should be considered before offering these nails to a patient; careful and individualized postoperative weight-bearing protocol could minimize the same. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-023-00915-5.

Total temporomandibular joint replacement in recurrent temporomandibular joint ankylosis: a case report.

Total temporomandibular joint replacement (TMJR) is a surgical procedure in which end-stage temporomandibular joint disorders are replaced with an alloplastic prosthesis between the mandible and the base of the skull when autogenous grafts are inadvisable. These alloplastic prostheses may be available as stock or custom-made prostheses consisting of the mandibular condyle and glenoid fossa components. Although the first total temporomandibular joint prosthesis was used in the 1960s, we present the case of a 20-year-old female patient, probably the first case of total temporomandibular joint arthroplasty in Nepal, performed at Dhulikhel Hospital in Kavrepalanchok. The patient underwent bilateral TMJR with a custom joint prosthesis for recurrent TMJ ankylosis. Postoperatively, the patient noticed significant improvements in mouth opening, chewing ability, facial esthetics and, most importantly, her self-esteem and confidence.

Measuring anti-islet autoimmunity in mouse and human by profiling peripheral blood antigen-specific CD4 T cells.

The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell-dependent disease. Here, peptide-major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and humans. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish the absence of autoimmunity versus disease progression. Activated anti-insulin CD4 T cell were detected not only at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen-specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the preclinical phase of anti-islet autoimmunity.

Transcriptional activation of Jun and Fos members of the AP-1 complex is a conserved signature of immune aging that contributes to inflammaging.

Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains. ATAC-seq data analyses showed that the chromatin around these genes was more accessible with age and there were significantly more binding sites for these TFs with age across all studied tissues, targeting pro-inflammatory molecules including Il6. Age-related increases in binding sites of JUN and FOS factors were also conserved in human peripheral blood ATAC-seq data. Single-cell RNA-seq data from the mouse aging cell atlas Tabula Muris Senis showed that the expression of these genes increased with age in B, T, NK cells, and macrophages, with macrophages from old mice expressing these molecules more abundantly than other cells. Functional data showed that upon myeloid cell activation via poly(I:C), the levels of JUN protein and its binding activity increased more significantly in spleen cells from old compared to young mice. In addition, upon activation, old cells produced more IL6 compared to young cells. In sum, we showed that the aging-related transcriptional activation of Jun and Fos family members in AP-1 complex is conserved across immune tissues and long- and short-living mouse strains, possibly contributing to increased inflammation with age.