Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19–affected lung tissue. We applied correlation network–based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies

Increased density and periosteal expansion of the tibia in young adult men following short-term arduous training

Purpose: Few human studies have reported early structural adaptations of bone to weight-bearing exercise, which provide a greater contribution to improved bone strength than increased density. This prospective study examined site- and regional-specific adaptations of the tibia during arduous training in a cohort of male military (infantry) recruits to better understand how bone responds in vivo to mechanical loading. Methods: Tibial bone density and geometry were measured in 90 British Army male recruits (ages 21 + 3 y, height 1.78 ± 0.06 m, body mass 73.9 + 9.8 kg) in weeks 1 (Baseline) and 10 of initial military training. Scans were performed at the 4%, 14%, 38% and 66% sites, measured from the distal end plate, using pQCT (XCT2000L, Stratec Pforzheim, Germany). Customised software (BAMPack, L-3 ATI) was used to examine whole bone cross-section and regional sectors. T-tests determined significant differences between time points (P<0.05). Results: Bone density of trabecular and cortical compartments increased significantly at all measured sites. Bone geometry (cortical area and thickness) and bone strength (i, MMi and BSI) at the diaphyseal sites (38 and 66%) were also significantly higher in week 10. Regional changes in density and geometry were largely observed in the anterior, medial-anterior and anterior-posterior sectors. Calf muscle density and area (66% site) increased significantly at week 10 (P<0.01). Conclusions: In vivo mechanical loading improves bone strength of the human tibia by increased density and periosteal expansion, which varies by site and region of the bone. These changes may occur in response to the nature and distribution of forces originating from bending, torsional and shear stresses of military training. These improvements are observed early in training when the osteogenic stimulus is sufficient, which may be close to the fracture threshold in some individuals

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Novel bile acid therapeutics for the treatment of chronic liver diseases

Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases

Phospholipase activity of Acyloxyacyl Hydrolase induces IL‐22‐producing CD1a‐autoreactive T cells in individuals with psoriasis

Psoriasis is a chronic inflammatory skin disease characterised by T helper 17 responses. Recent evidence has identified Langerhans cells as having a key role in disease pathogenesis, with constitutive high expression of CD1a and capacity to present lipid antigens to T cells. Phospholipase A2 enzymes generate neo-lipid antigens for recognition by CD1a-reactive T cells, however the broader enzymatic pathways of CD1a lipid ligand generation have not been thoroughly investigated. In this study, we used immunofluorescence of skin and ELISpot analyses of CD1a-reactive T cells to investigate the role of the lipase acyloxyacyl hydrolase (AOAH) in CD1a ligand generation with relevance to the pathogenesis of psoriasis. We found that the PLA2 activity of rAOAH leads to the activation of circulating CD1a auto-reactive T cells, leading to the production of IFN-γ and IL-22. Circulating AOAH-responsive CD1a-reactive T cells from patients with psoriasis show elevated IL-22 production. We observed that AOAH is highly expressed in psoriatic lesions compared to healthy skin. Overall, these data present a role for AOAH in generating antigens that activate circulating lipid-specific CD1a-restricted T cells and thus contribute to psoriatic inflammation. These findings suggest that inhibition of PLA2 activity of AOAH may have therapeutic potential for individuals with psoriasis