Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value

3D ultrasound reconstruction of sonographic callus:a novel imaging modality for early evaluation of fracture healing

AIMS: The aim of this study was to establish a reliable method for producing 3D reconstruction of sonographic callus. METHODS: A cohort of ten closed tibial shaft fractures managed with intramedullary nailing underwent ultrasound scanning at two, six, and 12 weeks post-surgery. Ultrasound capture was performed using infrared tracking technology to map each image to a 3D lattice. Using echo intensity, semi-automated mapping was performed to produce an anatomical 3D representation of the fracture site. Two reviewers independently performed 3D reconstructions and kappa coefficient was used to determine agreement. A further validation study was undertaken with ten reviewers to estimate the clinical application of this imaging technique using the intraclass correlation coefficient (ICC). RESULTS: Nine of the ten patients achieved union at six months. At six weeks, seven patients had bridging callus of ≥ one cortex on the 3D reconstruction and when present all achieved union. Compared to six-week radiographs, no bridging callus was present in any patient. Of the three patients lacking sonographic bridging callus, one went onto a nonunion (77.8% sensitive and 100% specific to predict union). At 12 weeks, nine patients had bridging callus at ≥ one cortex on 3D reconstruction (100%-sensitive and 100%-specific to predict union). Presence of sonographic bridging callus on 3D reconstruction demonstrated excellent reviewer agreement on ICC at 0.87 (95% confidence interval 0.74 to 0.96). CONCLUSION: 3D fracture reconstruction can be created using multiple ultrasound images in order to evaluate the presence of bridging callus. This imaging modality has the potential to enhance the usability and accuracy of identification of early fracture healing. Cite this article: Bone Joint Res 2021;10(12):759–766

Landscape, Memory, and the Shifting Regional Geographies of Northwest Bosnia-Herzegovina

Writing and arguing with older discourses that have informed the subdiscipline of regional geography and setting them against new ways of conceiving of the region, this article considers the northwest of Bosnia-Herzegovina as a site that calls for a newly animated form of regional study. Of particular concern here is the role that memory and commemorative practices play in such a spatial schema. The monumental landscapes of the Tito regime and its collective commemoration of World War II sit alongside and are troubled by the more recent traumas and spaces of unmarked death associated with the ethnic war in Bosnia during the early 1990s. Read together, northwest Bosnia-Herzegovina functions as a vivid exemplar for understanding traumatic historical mourning as a phenomenological process that is inseparable from the wider geopolitical landscape

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses

Spontaneous DNA damage to the nuclear genome promotes senescence,redox imbalance and aging

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/Δ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/Δ and aged WT mice. Chronic treatment of Ercc1-/Δ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline

Acute plate fixation of displaced midshaft clavicular fractures is not associated with earlier return of normal shoulder function when union is achieved

Aims: It is unclear whether acute plate fixation facilitates earlier return of normal shoulder function following a displaced mid-shaft clavicular fracture compared with nonoperative management when union occurs. The primary aim of this study was to establish whether acute plate fixation was associated with a greater return of normal shoulder function when compared with nonoperative management in patients who unite their fractures. The secondary aim was to investigate whether there were identifiable predictors associated with return of normal shoulder function in patients who achieve union with nonoperative management. Methods: Patient data from a randomized controlled trial were used to compare acute plate fixation with nonoperative management of united fractures. Return of shoulder function was based on the age- and sex-matched Disabilities of the Arm, Shoulder and Hand (DASH) scores for the cohort. Independent predictors of an early recovery of normal shoulder function were investigated using a separate prospective series of consecutive nonoperative displaced mid-shaft clavicular fractures recruited over a two-year period (aged ≥ 16 years). Patient demographics and functional recovery were assessed over the six months post-injury using a standardized protocol. Results: Data from the randomized controlled trial consisted of 86 patients who underwent operative fixation compared with 76 patients that united with nonoperative treatment. The recovery of normal shoulder function, as defined by a DASH score within the predicted 95% confidence interval for each respective patient, was similar between each group at six weeks (operative 26.7% vs nonoperative 25.0%, p = 0.800), three months (52.3% vs 44.2%, p = 0.768), and six months post-injury (86.0% vs 90.8%, p = 0.349). The mean DASH score and return to work were also comparable at each timepoint. In the prospective cohort, 86.5% (n = 173/200) achieved union by six months post-injury (follow-up rate 88.5%, n = 200/226). Regression analysis found that no specific patient, injury, or fracture predictor was associated with an early return of function at six or 12 weeks. Conclusion: Return of normal shoulder function was comparable between acute plate fixation and nonoperative management when union was achieved. One in two patients will have recovery of normal shoulder function at three months, increasing to nine out of ten patients at six months following injury when union occurs, irrespective of initial treatment

Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection

Socioeconomic Differences in the Association Between Competitive Food Laws and the School Food Environment

Schools of low socioeconomic status (SES) tend to sell fewer healthy competitive foods/beverages. This study examined whether state competitive food laws may reduce such disparities