Arthroscopic Shaver-based Harvest of Minced Cartilage Results in Reduced Chondrocyte Viability and Reduced Quality of Cartilaginous Repair Tissue Compared With Open Harvest and Conventional Fragmentation.

PURPOSE: To characterize and compare the quality of regenerative cartilage tissue (ReCT) after conventional minced cartilage (CMC) and arthroscopic minced cartilage (AMC), in terms of cell viability, gene expression, and matrix synthesis and to investigate the influence of different shaver types. METHODS: Chondral tissue was harvested from the knees of 8 porcine donors. Porcine specimens were euthanized one day before harvest. AMC was created with 2 shaver blades in 2 operating modes (oscillating vs forward) and compared with a scalpel-fragmented CMC control. Before histologic analysis, 50% of the tissue was digested to prevent dedifferentiation of chondrocytes to fibroblasts. Cells were cultured and analyzed for cell viability, gene expression of cartilage-specific markers (aggrecan [ACAN], collagen type II, alpha1 [COL2A1], collagen type I, alpha1 [COL1A1], fibronectin-1 [FN1]), and matrix synthesis (Alcian-blue). RESULTS: AMC tissue contained fewer viable chondrocytes (41%-54% vs 91%; P = .001-.048) compared with CMC. After culture, CMC showed greater expressions of ACAN (27 virtual copy numbers [VCN]/housekeeping gene) and COL2A1 (30 VCN) compared with AMC (ACAN 2-9 VCN, COL2A1 2-7 VCN, P = .001-.039). AMC presented greater expressions of COL1A1 (9-21 VCN) and FN1 (12-17 VCN) than CMC (1 and 6 VCN, P = .001-.050). The signal intensity of the cartilage matrix formed by CMC (86/mm2) was greater than by AMC (7-10 mm2, P = .001-.032). CONCLUSIONS: CMC contained high numbers of viable chondrocytes, resulting in high-quality, hyaline-like ReCT. In contrast, AMC showed impaired chondrocyte quantity and viability, showing greater expressions of fibroblast markers and a decreased formation of mature cartilage matrix in porcine samples. The high chondrogenic potential of CMC to form hyaline-like ReCT was not confirmed for AMC. CLINICAL RELEVANCE: On the basis of our findings, arthroscopic harvest of minced cartilage leads to reduced chondrocyte viability and ReCT quality. Accordingly, CMC and AMC cannot be regarded as synonymous techniques, as arthroscopic techniques seem to be less efficacious.

The emerging role of tranexamic acid and its principal target, plasminogen, in skeletal health.

The worldwide burden of skeletal diseases such as osteoporosis, degenerative joint disease and impaired fracture healing is steadily increasing. Tranexamic acid (TXA), a plasminogen inhibitor and anti-fibrinolytic agent, is used to reduce bleeding with high effectiveness and safety in major surgical procedures. With its widespread clinical application, the effects of TXA beyond anti-fibrinolysis have been noticed and prompted renewed interest in its use. Some clinical trials have characterized the effects of TXA on reducing postoperative infection rates and regulating immune responses in patients undergoing surgery. Also, several animal studies suggest potential therapeutic effects of TXA on skeletal diseases such as osteoporosis and fracture healing. Although a direct effect of TXA on the differentiation and function of bone cells in vitro was shown, few mechanisms of action have been reported. Here, we summarize recent findings of the effects of TXA on skeletal diseases and discuss the underlying plasminogen-dependent and -independent mechanisms related to bone metabolism and the immune response. We furthermore discuss potential novel indications for TXA application as a treatment strategy for skeletal diseases.

Calcitonin treatment for osteoarthritis and rheumatoid arthritis - a systematic review and meta-analysis of preclinical data.

Purpose: The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new stabilized CT formulations are currently being introduced. Methods: A comprehensive and systemic literature search was conducted in PubMed/MEDLINE and Embase databases to identify articles with original data on CT treatment of preclinical OA and RA. Methodological quality was assessed using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool for animal intervention studies. To provide summary estimates of efficacy, a meta-analysis was conducted for outcomes reported in four or more studies, using a random-effects model. Subgroup analyses were employed to correct for study specifics. Results: Twenty-six studies were ultimately evaluated and data from 16 studies could be analyzed in the meta-analysis, which included the following outcomes: bone mineral density, bone volume, levels of cross-linked C-telopeptide of type I collagen, histopathological arthritis score, and mechanical allodynia. For all considered outcome parameters, CT-treated groups were significantly superior to control groups (P = 0.002; P = 0.01; P < 0.00001; P < 0.00001; P = 0.04). For most outcomes, effect sizes were significantly greater in OA than in RA (P ≤ 0.025). High in-between study heterogeneity was detected. Conclusion: There is preclinical evidence for an antioxidant, anti-inflammatory, antinociceptive, cartilage- and bone-protective effect of CT in RA and OA. Given these effects, CT presents a promising agent for the treatment of both diseases, although the potential seems to be greater in OA.

Visual Improvement Despite Macular Pucker After Inverted Internal Limiting Membrane Flap Technique for Idiopathic Macular Hole.

Purpose: To report a case of a macular pucker forming after macular hole (MH) repair with the inverted internal limiting membrane (ILM) flap technique, with resolution after secondary inverted ILM flap peeling. Methods: A single case was evaluated. Results: A 76-year-old woman presented with reduced central vision (28 letters) in the right eye. Optical coherence tomography (OCT) identified an idiopathic full-thickness MH measuring 629 µm in diameter. The patient had pars plana vitrectomy with inverted ILM flap formation. One month postoperatively, the visual acuity (VA) in the right eye was 47 letters and OCT confirmed MH closure. However, the patient developed deterioration in the central vision 10 months postoperatively. A macular pucker in the inverted ILM flap region was found on OCT. Repeat vitrectomy with inverted ILM flap peeling was performed. Postoperatively, the VA in the right eye improved to 60 letters and OCT showed resolution of the macular pucker. Conclusions: A complication of the inverted ILM flap technique for MH is formation of a macular pucker in the region of the inverted ILM flap. Secondary inverted ILM flap peeling results in resolution of the macular pucker.

Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Critical aspects in dissolution testing of nanomaterials in the oro-gastrointestinal tract: the relevance of juice composition for hazard identification and grouping.

The dissolution of a nanomaterial (NM) in an in vitro simulant of the oro-gastrointestinal (OGI) tract is an important predictor of its biodurability in vivo. The cascade addition of simulated digestive juices (saliva, stomach and intestine), including inorganic/organic biomacromolecules and digestive enzymes (complete composition, referred to as "Type 1 formulation"), strives for realistic representation of chemical composition of the OGI tract. However, the data robustness requires consideration of analytical feasibility, such as the use of simplified media. Here we present a systematic analysis of the effects exerted by different digestive juice formulations on the dissolution% (or half-life values) of benchmark NMs (e.g., zinc oxide, titanium dioxide, barium sulfate, and silicon dioxide). The digestive juices were progressively simplified by removal of components such as organic molecules, enzymes, and inorganic molecules (Type 2, 3 and 4). The results indicate that the "Type 1 formulation" augments the dissolution via sequestration of ions by measurable factors compared to formulations without enzymes (i.e., Type 3 and 4). Type 1 formulation is thus regarded as a preferable option for predicting NM biodurability for hazard assessment. However, for grouping purposes, the relative similarity among diverse nanoforms (NFs) of a NM is decisive. Two similarity algorithms were applied, and additional case studies comprising NFs and non NFs of the same substance were included. The results support the grouping decision by simplified formulation (Type 3) as a robust method for screening and grouping purposes.

Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice.

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP-/- and CALCA-/- mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA-/- mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP-/- and WT mice. Osteophyte formation is reduced to the same extent in CALCA-/- and αCGRP-/- mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development.

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Tranexamic Acid Attenuates the Progression of Posttraumatic Osteoarthritis in Mice.

BACKGROUND: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression. PURPOSE: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice. STUDY DESIGN: Controlled laboratory study. METHODS: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro-computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically. RESULTS: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed. CONCLUSION: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery. CLINICAL RELEVANCE: TXA might be beneficial in patients with posttraumatic OA of the knee.

I like it because it hurts you: On the association of everyday sadism, sadistic pleasure, and victim blaming.

Past research on determinants of victim blaming mainly concentrated on individuals' just-world beliefs as motivational process underlying this harsh reaction to others' suffering. The present work provides novel insights regarding underlying affective processes by showing how individuals prone to derive pleasure from others' suffering-individuals high in everyday sadism-engage in victim blaming due to increased sadistic pleasure and reduced empathic concern they experience. Results of three cross-sectional studies and one ambulatory assessment study applying online experience sampling method (ESM; overall N = 2,653) document this association. Importantly, the relation emerged over and above the honesty-humility, emotionality, extraversion, agreeableness, conscientiousness, and openness personality model (Study 1a), and other so-called dark traits (Study 1b), across different cultural backgrounds (Study 1c), and also when sampling from a population of individuals frequently confronted with victim-perpetrator constellations: police officers (Study 1d). Studies 2 and 3 highlight a significant behavioral correlate of victim blaming. Everyday sadism is related to reduced willingness to engage in effortful cognitive activity as individuals high (vs. low) in everyday sadism recall less information regarding victim-perpetrator constellations of sexual assault. Results obtained in the ESM study (Study 4) indicate that the relation of everyday sadism, sadistic pleasure, and victim blaming holds in everyday life and is not significantly moderated by interpersonal closeness to the blamed victim or impactfulness of the incident. Overall, the present article extends our understanding of what determines innocent victims' derogation and highlights emotional mechanisms, societal relevance, and generalizability of the observed associations beyond the laboratory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

RHEGMATOGENOUS RETINAL DETACHMENT AFTER INJECTION OF TISSUE PLASMINOGEN ACTIVATOR AND GAS FOR SUBMACULAR HEMORRHAGE SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The purpose of this study was to describe the rate, clinical characteristics, and outcomes of rhegmatogenous retinal detachment (RRD) after injection of tissue plasminogen activator (TPA) and gas for submacular hemorrhage displacement. METHODS: Retrospective analysis of consecutive cases developing RRD after TPA injection and gas for submacular hemorrhage displacement. The rate of RRD was calculated, and a description of RRD clinical characteristics was performed. Anatomic and visual outcomes after RRD repair were analyzed. RESULTS: Ninety eyes of 90 patients were analyzed. Tissue plasminogen activator was given intravitreally in 53 eyes (59%) and subretinally in 37 eyes (41%). RRD occurred in 6 of 90 eyes (7%). Of these, one had intravitreal TPA and five had vitrectomy with subretinal TPA ( P = 0.04). The mean age was 75 (64-93) years. The median time of RRD occurrence was 42 (1-134) days. All cases had macular involvement. Two cases had PVR at presentation. Vitrectomy was performed in all cases and silicone oil used in five, all of which resulted in permanent silicone oil retention. One case (17%) achieved primary single surgery success. The median final visual acuity was 1.8 logMAR (20/1,260 Snellen). CONCLUSION: The RRD rate after submacular hemorrhage displacement was 7% in our case series. Rhegmatogenous retinal detachment occurred more commonly after vitrectomy with subretinal TPA injection. The visual and anatomic outcomes were poor, with a high rate of retained silicone oil and recurrent RRD.

Nesting behavior is associated with body weight and grip strength loss in mice suffering from experimental arthritis.

Objective animal health evaluation is essential to determine welfare and discomfort in preclinical in vivo research. Body condition scores, body weight, and grimace scales are commonly used to evaluate well-being in murine rheumatoid arthritis (RA) and osteoarthritis experiments. However, nest-building, a natural behavior in mice, has not yet been evaluated in wild type (WT) or genetically modified rodents suffering from collagen antibody-induced arthritis (CAIA). To address this, we analyzed nesting behavior in WT mice, calcitonin gene-related peptide alpha-deficient (αCGRP-/-) mice, and calcitonin receptor-deficient (Calcr-/-) mice suffering from experimental RA compared to healthy control (CTRL) groups of the same genotypes. CAIA was induced in 10-12-week-old male mice, and clinical parameters (body weight, grip strength, clinical arthritis score, ankle size) as well as nesting behavior were assessed over 10 or 48 days. A slight positive association between the nest score and body weight and grip strength was found for animals suffering from CAIA. For the clinical arthritis score and ankle size, no significant associations were observed. Mixed model analyses confirmed these associations. This study demonstrates that clinical effects of RA, such as loss of body weight and grip strength, might negatively affect nesting behavior in mice. Assessing nesting behavior in mice with arthritis could be an additional, non-invasive and thus valuable health parameter in future experiments to monitor welfare and discomfort in mice. During severe disease stages, pre-formed nest-building material may be provided to animals suffering from arthritis.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

BACKGROUND: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. METHODS: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP-/-CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. RESULTS: WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP-/-aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. CONCLUSIONS: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

On the social signal function of emotional crying: Broadening the perspective to social interactions in daily life.

Emotional crying is a potent signal that can influence how social interactions unfold. Although the social signal function of crying has been mostly studied in experimental approaches involving hypothetical scenarios with strangers as targets, we propose that daily social interactions should be considered to address aspects of external validity. We conducted three retrospective studies (total N = 2,277; convenience samples; Studies 2 and 3 were preregistered; data were collected in 2022 and 2023) and found that individuals primarily observed close others crying in their daily lives; a boundary condition that was hardly reflected in former studies. Crying episodes were typically characterized by tears and changes in facial expression, vocalizations, and gestures, whereas isolated emotional tears, were rarely reported. Participants indicated that they frequently helped close others, but that helping strangers was the exception. The level of familiarity with the target also influenced the form of help provided. Furthermore, the crying person was rated as less warm and less competent when crying (vs. in general or in a neutral situation). Additional analyses suggest that question order effects and recall biases are no plausible alternative explanations of our findings. Taken together, these results call into question the validity of the experimental approaches used in this line of research. We discuss strategies for future study of the social signal function of crying in nonhypothetical scenarios with reference to the "generalizability crisis" of psychological science. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Increased local bone turnover in patients with chronic periprosthetic joint infection.

Aims: The management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI. Methods: Periprosthetic femoral trabecular bone specimens were obtained from patients suffering from chronic PJI of the hip and knee (n = 20). Microbiological analysis was performed on preoperative joint aspirates and tissue specimens obtained during revision surgery. Microstructural and cellular bone parameters were analyzed in bone specimens by histomorphometry on undecalcified sections complemented by tartrate-resistant acid phosphatase immunohistochemistry. Data were compared with control specimens obtained during primary arthroplasty (n = 20) and aseptic revision (n = 20). Results: PJI specimens exhibited a higher bone volume, thickened trabeculae, and increased osteoid parameters compared to both control groups, suggesting an accelerated bone turnover with sclerotic microstructure. On the cellular level, osteoblast and osteoclast parameters were markedly increased in the PJI cohort. Furthermore, a positive association between serum (CRP) but not synovial (white blood cell (WBC) count) inflammatory markers and osteoclast indices could be detected. Comparison between different pathogens revealed increased osteoclastic bone resorption parameters without a concomitant increase in osteoblasts in bone specimens from patients with Staphylococcus aureus infection, compared to those with detection of Staphylococcus epidermidis and Cutibacterium spp. Conclusion: This study provides insights into the local bone metabolism in chronic PJI, demonstrating osteosclerosis with high bone turnover. The fact that Staphylococcus aureus was associated with distinctly increased osteoclast indices strongly suggests early surgical treatment to prevent periprosthetic bone alterations.

The selective norepinephrine reuptake inhibitor reboxetine promotes late-stage fracture healing in mice.

Impaired fracture healing is of high clinical relevance, as up to 15% of patients with long-bone fractures display non-unions. Fracture patients also include individuals treated with selective norepinephrine reuptake inhibitors (SNRI). As SNRI were previously shown to negatively affect bone homeostasis, it remained unclear whether patients with SNRI are at risk of impaired bone healing. Here, we show that daily treatment with the SNRI reboxetine reduces trabecular bone mass in the spine but increases cortical thickness and osteoblast numbers in the femoral midshaft. Most importantly, reboxetine does not impair bone regeneration in a standardized murine fracture model, and even improves callus bridging and biomechanical stability at late healing stages. In sum, reboxetine affects bone remodeling in a site-specific manner. Treatment does not interfere with the early and intermediate stages of bone regeneration and improves healing outcomes of the late-stage fracture callus in mice.

Performance and Hypothetical Impact on Joint Infection Management of the BioFire Joint Infection Panel: a Retrospective Analysis.

Pathogen identification is key in septic arthritis. Culture-based techniques are challenging, especially when patients have been pretreated with antibiotics or when difficult-to-culture bacteria are encountered. The BioFire joint infection assay (BJA) is a multiplex PCR panel which detects 31 of the most prevalent bacterial and fungal pathogens causing septic arthritis. Here, 123 cryoconserved contemporary synovial fluid samples from 120 patients underwent BJA analysis. Results were compared to those of culture-based diagnostics (standard of care [SOC]). Clinical data were collected, and the possible impact of the molecular diagnostic application on patient management was evaluated. Fifteen of 123 synovial fluid cultures grew bacterial pathogens. All on-panel pathogens (9/15) were correctly identified by the BJA. The BJA identified four additional bacterial pathogens in four SOC-negative cases. BJA sensitivity and specificity were 100% (95% confidence interval [CI], 69.2% to 100%) and 100% (95% CI, 96.8% to 100%), respectively. Compared to the SOC, the BJA would have resulted in faster provision of species identification and molecular susceptibility data by 49 h and 99 h, respectively. Clinical data analysis indicates that in BJA-positive cases, faster species ID could have led to timelier optimization of antibiotic therapy. This retrospective study demonstrates high sensitivity and specificity of the BJA to detect on-panel organisms in bacterial arthritis. The usefulness of the BJA in prosthetic-joint infections is limited, as important pathogens (i.e., coagulase negative staphylococci and Cutibacterium acnes) are not covered. Evidence from patient data analysis suggests that the assay might prove valuable for optimizing patient management in acute arthritis related to fastidious organisms or for patients who received antibiotics prior to specimen collection.

Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability.

Notch signaling regulates cell fate in multiple tissues including the skeleton. Hajdu-Cheney-Syndrome (HCS), caused by gain-of-function mutations in the Notch2 gene, is a rare inherited disease featuring early-onset osteoporosis and increased risk for fractures and non-union. As the impact of Notch2 overactivation on fracture healing is unknown, we studied bone regeneration in mice harboring a human HCS mutation. HCS mice, displaying high turnover osteopenia in the non-fractured skeleton, exhibited only minor morphologic alterations in the progression of bone regeneration, evidenced by static radiological and histological outcome measurements. Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers. These observations were accompanied by inferior biomechanical stability of healed femora in HCS mice. Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization.

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.