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.

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.

Finger millet (Eleusine coracana) enhancement through genomic resources and breeding methods: current implications and potential future interventions.

Finger millet (Eleusine coracana) is an essential staple crop in many regions of Africa and Asia, valued for its nutritional content and resilience in challenging agro-ecological conditions. The enhancement of finger millet through genomic resources and breeding methods represents a promising avenue for addressing food and nutritional security. Current efforts in this field have harnessed genomic technologies to decipher the crop's genetic diversity and identify key traits related to yield, disease resistance, and nutritional content. These insights have facilitated the development of improved varieties through selective breeding, accelerating the crop's adaptation to changing environmental conditions. In the future, continued advancements in genomics and breeding methodologies hold the potential to further enhance finger millet's resilience, nutritional value, and productivity, ultimately benefiting both farmers and consumers. This review article synthesizes the current state of research and development in finger millet enhancement through the integration of genomic resources and innovative breeding methods. The utilization of these insights in selective breeding has already yielded promising results in developing improved finger millet varieties that meet the evolving needs of farmers and consumers. Moreover, this article discusses potential future interventions, including the continued advancement of genomics, precision breeding, and sustainable agricultural practices. These interventions hold the promise of further enhancing finger millet's adaptability to changing climates, its nutritional quality, and its overall productivity, thereby contributing to food security and improved livelihoods in finger millet-dependent regions.

Pattern of Medical Device Adverse Events in a Tertiary Care Hospital in Northern India: An Ambispective Study.

BACKGROUND: Knowledge about the pattern of adverse events caused by medical devices (MDs) is limited in India. We aimed to assess the pattern of MD adverse events (MDAEs) in a tertiary hospital in Northern India. MATERIALS AND METHODS: This descriptive study was conducted ambispectively at various clinical departments of PGIMER, Chandigarh. We followed the guidelines edged by the Materiovigilance Program of India (MvPI) to conduct this study. The prospective study (PS) was done from January to December 2020, with a concurrent retrospective study (RS) proceeding to 3 years to learn more about the reporting culture, demographics, notification status, risk class of defective devices, and the type of adverse events. RESULTS: We received 224 MDAE in the PS and identified 413 MDAE in the RS. Reporting of adverse events to the national MvPI was negligible in the RS. In the PS, nurses reported the majority of MDAEs (65%), followed by doctors (30%). The occurrence of MDAE was higher in males (PS; 52%, RS; 57%) and age groups between 21 and 30 years (PS; 19.1%, RS; 23.2%) in both studies. MDAEs were frequent in low- to moderate-risk devices (class B: 66%) in the PS, while it was documented only for high-risk devices (class C: 51% and class D: 49%) in the RS. Most of the serious adverse events (SAEs) were reported among moderate to high-risk devices, and an increased frequency of SAE (60.4%) was observed among nonnotified MDs. The overall incidence of near-miss events was 14%. CONCLUSION: Knowledge of MDAEs and reporting of defective devices to regulatory authorities is essential to prevent further incidence. Adverse events caused by MDs are ubiquitous irrespective of their risk classification, notification status, and patient demographic factors. Accelerated reporting of MDAE by all cadre of healthcare professionals is urgently required to safeguard the health of Indians.

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.

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.

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.

Core decompression combined with intralesional autologous bone marrow derived cell therapies for osteonecrosis of the femoral head in adults: A systematic review and meta-analysis.

BACKGROUND: Core decompression (CD) is beneficial in the early stage of osteonecrosis of the femoral head (ONFH). Adjunctive bone marrow derived cell therapies (BMDCT) have been advocated which potentially aid the regenerative process. QUESTION/PURPOSE: This study was conducted to determine potential benefit of CD + BMDCT in ONFH, in terms of disease progression, conversion to arthroplasty (primary outcomes), and functional outcomes and complication rates (secondary outcomes). METHODS: A systematic review of literature was performed on 3 databases. Studies reporting CD + BMDCT (intralesional instillation) in ONFH, with a minimum follow up of 1 year and reporting the pre-defined outcome measures were included in the review. Meta-analysis consisted of two different arms: a comparative arm, to compare CD + BMDCT to CD alone, and a non-comparative meta-analysis arm, to determine pooled rates of disease progression, conversion to arthroplasty and complication rates. RESULTS: A total of 18 studies were included in the systematic review. CD + BMDCT had lower rates of disease progression (OR 0.19 [95% CI, 0.09, 0.40]) and conversion to arthroplasty (OR 0.20 [95% CI, 0.11, 0.40]) as compared to CD alone. Functional score (MD = -7.07 [95% CI, -12.28, -1.86]) and visual analog scale also showed better improvement with the use of CD + BMAC (MD = -10.39 [95% CI, -12.87, -7.90]). Increasing age and post-collapse stage at presentation were noted to have an adverse effect on the outcomes. CONCLUSION: CD + BMDCT was found to decrease disease progression and conversion to arthroplasty, and was noted to have better functional outcome scores as compared to CD alone.

Outcomes and complications of the INFIX technique for unstable pelvic ring injuries with high-velocity trauma: a systematic review and meta-analysis.

BACKGROUND: The pelvic INFIX technique has been proposed as a useful alternative to symphyseal plating for management of unstable pelvic ring injuries. The minimally invasive nature of the procedure, shorter operative time and less perioperative blood loss have been purported as potential advantages. QUESTIONS/PURPOSES: This systematic review and meta-analysis were conducted to determine the outcomes and complications of the INFIX technique for unstable pelvic ring injuries. METHODS: A systematic review of literature was performed on the PubMed, EMBASE and Scopus databases. Prospective and retrospective studies in all languages, whether comparative or non-comparative, pertaining to the use of INFIX in pelvic fractures were included. Studies which did not evaluate INFIX, case reports, conference abstracts and those with less than 10 cases were excluded. Cadaveric studies, technique papers and studies that did not describe the prespecified outcome measures were also excluded. Meta-analysis consisted of two different arms: a comparative arm, to compare INFIX to symphyseal plating, and a non-comparative meta-analysis arm, to determine pooled rates of outcomes and complications. Risk of bias was determined by the Methodological Index for Non-Randomised Studies (MINORS) tool. RESULTS: A total of 22 studies were included in the systematic review, of which 7 were comparative and 15 were non-comparative. 746 patients were included for qualitative analysis and pooled analysis done for 589 patients. The average follow-up of these studies ranged from a minimum of 5.4 months to a maximum of 54 months. Comparative meta-analysis (n = 3 studies) of plating and INFIX showed significantly lesser blood loss (mean difference = 176.46 mL; 95% CI - 207.54 to - 145.38) and shorter operative time (mean difference = 26.43 min, 95% CI - 31.79 to - 21.07) with INFIX, but no significant difference in the overall complication rates (OR 1.59, 95% CI 0.83-3.05) and functional outcome scores (mean difference = - 2.51, 95% CI - 5.73 to 0.71). Pooled analysis showed overall good radiological (mean percentage of excellent to good reduction = 91.4%, 95% CI 0.860-0.969) and functional outcomes (mean Majeed score = 86.48, 95% CI 83.34-89.61) with INFIX. The most common complications were lateral femoral cutaneous nerve (LFCN) injury (overall rate 28%, 95% CI 15.1-41%) and heterotopic ossification (HO) (overall rate 9.4%, 95% CI 5.5-13.3%); rates of other complications were low. Significant heterogeneity was noted in the pooled analysis of blood loss, operative time, functional outcome, HO and LFCN injury. The overall strength of evidence was found to be weak. CONCLUSION: The INFIX technique can be considered as a viable alternative to symphyseal plating for unstable pelvic ring injuries. It has the advantages of shorter operative times and less blood loss, along with comparable functional outcomes, when compared to plating. Overall, good functional outcomes can be expected. However, well-designed, multi-center randomized controlled trials are needed to conclusively prove the benefit of this technique.

Influence of posterior malleolar fragment morphology on the outcomes of trimalleolar fractures: A systematic review and meta-analysis.

BACKGROUND: Trimalleolar fractures are generally considered to have inferior outcomes among ankle injuries. Historically, emphasis was placed on the size of the posterior malleolar fracture (PMF) to guide surgical decision-making and predict outcomes. Recent studies have suggested that the morphology of the PMF fragment is more important than its size. The aim of this systematic review was to determine if the outcomes of trimalleolar fractures depend on the morphology of the PMF as per the Haraguchi classification system after surgical fixation. METHODS: A systematic literature search was conducted in the electronic databases of PubMed, Embase, Scopus, and Ovid. Title and abstracts were screened, and data from eligible studies were extracted. Meta-regression and pooled analysis was performed using appropriate computer software. RESULTS: 11 studies with 597 patients were included in the final analysis. Pooled mean AOFAS score was 87.43 (95% CI 84.24-90.62) after a mean follow-up of 31.6 months. Univariate and multivariate meta-regression analysis demonstrated that as the percentage of Haraguchi type 1 patients increased, there was a statistically significant improvement in outcome scores. A similar trend was noted for Haraguchi type 3 fractures, and a reverse trend was observed for Haraguchi type 2 injuries, although neither were statistically significant. CONCLUSION: Our review suggests that the outcomes of trimalleolar fractures after surgical fixation may depend on the morphology of the PMF, with Haraguchi type 1 fractures having overall superior functional outcomes than Haraguchi type 2 and 3 injuries. Future studies need to done to conclusively prove or refute these findings.

Fibular Strut Arthrodesis for Salvage of Campanacci Grade III Giant Cell Tumor of the Hallucal Proximal Phalanx: A Case Report.

Involvement of toe phalanges by giant cell tumor (GCT) is extremely rare; tumors in these locations tend to be aggressive. Whereas aggressive GCTs of the distal phalanx may be managed successfully by en-bloc resection without reconstruction or amputation, management of these lesions, when they involve the proximal phalanx, can be challenging. We present a Campannaci grade III GCT of the hallucal proximal phalanx in a 14-year old girl that had breached into the dorsal soft tissues and the metatarso-phalangeal joint. Wide local resection of the proximal phalanx along with reconstruction arthrodesis with an autologous, non-vascularized fibular strut graft was performed. There was no recurrence at 3 years of follow-up. The patient had an excellent functional outcome. To the best of our knowledge, this is the first case reporting the outcomes of fibular strut arthrodesis for salvage of GCT of the hallucal proximal phalanx.

Proximal femoral nailing is superior to hemiarthroplasty in AO/OTA A2 and A3 intertrochanteric femur fractures in the elderly: a systematic literature review and meta-analysis.

INTRODUCTION: Unstable intertrochanteric femoral fractures in the elderly require either fixation or joint sacrificing surgery; proximal femoral nail (PFN) and bipolar hemiarthroplasties (BPH) are the most common interventions. PFN is considered to be the ideal construct for these fractures; however, the usage of hemiarthroplasties to facilitate earlier mobilization has been on a rise. Currently there is no consensus on the superiority of one of these two techniques over the other and the present review was done to determine this. RESEARCH QUESTION: Is PFN a better alternative to BPH for unstable intertrochanteric femur fractures in the elderly? OBJECTIVE: The present systematic review and meta-analysis was conducted to determine the superiority of PFN over BPH by comparing the primary outcomes like mortality, Harris Hip scores (HHS), complications, and re-operations. Additionally, secondary outcomes like blood loss, duration of surgery, and period of hospital stays were also compared. METHODOLOGY: Three databases of PubMed, EMBASE, and SCOPUS were searched for relevant articles that directly compared PFN and BPH in unstable intertrochanteric femur fractures in the elderly. RESULTS: We analyzed a total of seven studies published between the years 2005 to 2017. There were four retrospective and three prospective randomized controlled studies. The number of patients in these studies ranged from 53 to 303. PRIMARY OUTCOMES: There was a significant difference in HHS between two groups with standard mean difference of - 0.51 (range - 0.67 to -0.36), favouring the PFN group. The rate of mortality was higher in the BPH group with odds ratio of 2.07 (range 1.40-3.08). Implant-related complications like fractures and subsidence were more in BPH group but this was not significant. SECONDARY OUTCOMES: Mean surgical time (standard mean difference 2.19) and blood loss (3.75) were significantly less in the PFN group. The duration of hospital stay was also found to be significantly less in the PFN group (2.66). CONCLUSION: Proximal femoral nails are superior to bipolar hemiarthroplasties for unstable intertrochanteric femoral fractures in the elderly. PFN imparts better functional outcomes and has lower rates of overall mortality. Additionally it is faster surgery, with lesser blood loss contributing to better results.

Naturally Occurring Subclinical Endotoxemia in Humans Alters Adaptive and Innate Immune Functions through Reduced MAPK and Increased STAT1 Phosphorylation.

Multiple studies have shown correlates of immune activation with microbial translocation and plasma LPS during HIV infection. It is unclear whether this activation is due to LPS, residual viral replication, or both. Few studies have addressed the effects of persistent in vivo levels of LPS on specific immune functions in humans in the absence of chronic viral infection or pathological settings such as sepsis. We previously reported on a cohort of HIV-negative men with subclinical endotoxemia linked to alterations in CD4/CD8 T cell ratio and plasma cytokine levels. This HIV-negative cohort allowed us to assess cellular immune functions in the context of different subclinical plasma LPS levels ex vivo without confounding viral effects. By comparing two samples of differing plasma LPS levels from each individual, we now show that subclinical levels of plasma LPS in vivo significantly alter T cell proliferative capacity, monocyte cytokine release, and HLA-DR expression, and induce TLR cross-tolerance by decreased phosphorylation of MAPK pathway components. Using this human in vivo model of subclinical endotoxemia, we furthermore show that plasma LPS leads to constitutive activation of STAT1 through autocrine cytokine signaling, suggesting that subclinical endotoxemia in healthy individuals might lead to significant changes in immune function that have thus far not been appreciated.

HIV-1 infection impairs regulatory T-cell suppressive capacity on a per-cell basis.

The impact of CD4+ regulatory T cells (Tregs) on human immunodeficiency virus type 1 (HIV-1) pathogenesis remains incompletely understood. Although it has been shown that Tregs can be infected with HIV-1, the consequences of infection on a per-cell basis are still unknown. In vitro HIV-GFP infected and noninfected Tregs were isolated by flow-based cell-sorting to investigate Treg suppressive capacity and gene expression profiles. Our data show that HIV-1-infected Tregs were significantly less suppressive than noninfected Tregs and demonstrated down-regulation of genes critical to Treg function. This impaired function may have detrimental consequences for the control of generalized immune activation and accelerate HIV disease progression.

PCT as a Prognostic Marker in Cardiac Patients with Neutropenic Sepsis: Two Case Reports.

Procalcitonin (PCT) is an innovative and highly specific marker for diagnosis of clinically relevant bacterial infection and sepsis. PCT supports early diagnosis and Clinical decision making. A retrospective study of two classical cases of neutropenic sepsis with elevated PCT levels in cardiac ICU was done. PCT was analyzed using Elecsys Brahms PCT kit. Serum PCT levels <0.5 ng/ml and ANC <1,000/mm(3) was taken as cutoff. The first patient had initial high levels of PCT 100 ng/ml, TLC 13,600/mm(3) and ANC 12,250/mm(3). It was followed by drop with subsequent rise in PCT levels and drop in TLC 1,000/mm(3) and ANC 70/mm(3). The second patient had normal PCT 0.116 ng/ml, TLC 5,600/mm(3) and ANC 4,420/mm(3) levels followed with sharp increase in all the values with subsequent drop in TLC 2,000/mm(3) and ANC 880 cells/mm(3). Both the patients died of neutropenic sepsis with multiorgan failure. The case reports showed the correlation of PCT with TLC and ANC levels in predicting the mortality of patients with neutropenic sepsis in cardiac ICU.

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.