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This study challenges Samuel Huntington’s well-known clash of civilizations paradigm based on a philosophical reasoning of cognitive proofs. The authors propose the clash of perceptions, an alternative paradigm that better reflects the complexity of individual and collective interactions. Building on case studies and recent cognitive science and informatics research, this paradigm offers greater insight into the dynamics of international relations. In the first section, the authors explain the conceptual and methodological limits of Huntington’s paradigm before proposing in the second section a new approach geared toward individual and group phenomena aiming to model the clash of perceptions. New concepts such as percepts, misperception, misconception and perception prototypes are introduced in order to explain this complex process. These concepts help better understand the complexity of conflict among individuals, groups and nation states.

The Maryland Route 30 Bypass at Hampstead, Carroll County, Maryland is a long awaited 4.5 mile $27 million safety and congestion relief project proposed by the Maryland State Highway Administration (MD SHA). However, an unanticipated problem arose during the final stages of design and prior to the submittal of state and federal environmental permits. Late in 1997, the northern population of a small turtle (Clemmys muhlenbergi), the bog turtle, was listed as a threatened species under the Endangered Species Act. The rural residential and agricultural lands surrounding Hampstead provide essential habitat for this rare turtle. While many saw this as potential threat to the project, others saw this as an opportunity for a creative approach for habitat and species protection.

The case report will present some novel techniques for using a “staged” protocol utilizing strategic periodontally involved teeth as transitional abutments in combination with CBCT guided implant surgery. Staging the case prevented premature loading of the grafted sites during the healing phase. A CBCT following a tenting screw guided bone regeneration procedure ensured adequate bone to place an implant fixture. Proper assessment of the CBCT allowed the surgeon to do an osteotome internal sinus lift in an optimum location. The depth of the bone needed for the osteotome sinus floor elevation was planned. The staged appliance allowed these sinus-augmented sites to heal for an extended period of time compared to implants, which were uncovered and loaded at an earlier time frame. The staged protocol and CBCT analysis enabled the immediate implants to be placed in proper alignment to the adjacent fixture. After teeth were extracted, the osseointegrated implants were converted to abutments for the transitional appliance. Finally, the staged protocol allowed for soft tissue enhancement in the implant and pontic areas prior to final insertion of the prosthesis.

Context: Breakthrough pain (BTP) is common in cancer and other conditions yet there is a lack of validated BTP measurement tools.Objectives: We aimed to identify all tools assessing or characterising BTP in patients of any age with any condition, and to critically appraise their psychometric properties.Methods: The Cochrane Library, PROSPERO, Embase, CINAHL, Medline, PsycINFO, Web of Science, Google Scholar, ProQuest, Evidence Search and OpenGrey were searched to identify all available tools used to assess BTP. A second search identified studies that had evaluated psychometric properties of tools identified in Search 1. Databases were searched from inception to November 2020. Studies were assessed using COSMIN criteria and GRADE guidelines.Results: Search 1 found 51 tools used to assess BTP. Search 2 found six tools that had a development study and/or a study evaluating a tool psychometric property. No tool had more than one study evaluating psychometric properties so a meta-analysis could not be conducted. Studies were of inadequate to very good quality. Only the Breakthrough Pain Assessment Tool (BAT) had sufficient content validity and at least low-quality evidence for sufficient internal consistency.Conclusion: The BAT is recommended to characterise BTP in adults with cancer; its applicability to other conditions is unknown. The remaining tools need further evaluation. Only the Breakthrough Pain Questionnaire for Children was designed for children with cancer, but no psychometric properties were evaluated. There is a need for a tool to assess and characterise BTP in children with non-cancer diagnoses and those who cannot self-report. [ABSTRACT FROM AUTHOR]

Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival., Methods: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m 2 on day 1 of cycle 1 and at 500 mg/m 2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m 2 per day orally on day 1-5, cyclophosphamide 150 mg/m 2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete., Findings: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group., Interpretation: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder., Funding: Cancer Research UK and Janssen., Competing Interests: Declaration of interests PH reports funding for the study and provision of investigational medicinal products from Janssen and AbbVie; personal consulting fees from Janssen, AbbVie, and AstraZeneca; personal speaker fees from Janssen, AbbVie, AstraZeneca, and BeiGene; institutional support of clinical trials from Janssen, AbbVie, Gilead Sciences, and F Hoffman-La Roche. AP reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. ABl reports speaker fees from Janssen and AbbVie and support for conference attendance from AbbVie. ABr reports personal payment for presentations from Janssen-Cilag and AstraZeneca and personal payment for attending meetings from AbbVie. BK reports personal payment or honoraria for lectures from AbbVie and AstraZeneca and a voluntary unpaid role as CLL Support Associate Trustee. RW reports payment for lectures from AbbVie, AstraZeneca, Janssen, and BeiGene; support for attending meetings from AbbVie and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, Janssen, SecuraBio, and AbbVie. MF reports travel support for conference attendance from AbbVie and remunerated participation on an advisory board for AstraZeneca. GP reports honoraria for delivering educational sessions from Janssen-Cilag and Roche. NM reports payment or honoraria for presentations from Amgen and Kite Gilead; support for attending meetings or travel from Takeda; and participation on a data safety monitoring board or advisory board for Kite Gilead, Amgen, and AbbVie. KC reports personal speakers fees from Roche, Takeda, Kite, Gilead, and Incyte; support for travel and registration for meetings from Roche, Takeda, Kite, and BMS; and participation on a data safety monitoring board or advisory board for Roche, Takeda, Celgene, Atara, Gilead, Kite, Janssen, and Incyte. AS reports receipt of part of her salary from the Oxford Biomedical Research Centre; grants from Janssen and AstraZeneca; honoraria for presentations from Roche, AbbVie, Janssen, BeiGene, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Illumina, Oxford Nanopore Technology, and Adaptive Biotechnology. FF reports grants from Cancer Research UK and AbbVie; consulting fees from BC Platform; payment or honoraria for presentations from AbbVie, Janssen-Cilag, Acerta, and BeiGene; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for BeiGene. NE reports personal speaker payments from AstraZeneca and Roche and support for attending meetings and travel from AbbVie. SP reports personal honoraria for presentations from Gilead, AstraZeneca, AbbVie, BeiGene, and Takeda. CPF reports personal consultancy fees from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead–Kite, Incyte, Lilly, Morphosys, Ono, Roche, and Takeda; payment for educational events from Janssen, Incyte, and Roche; institution research funding from BeiGene; support for attending meetings or travel from Roche; and participation on trial steering committees for GenMab, Morphosys, and Roche. DRH is employed by Roche and holds stock or stock options from Roche. AH reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and receipt of a speaker fee from AbbVie. JMB reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. DAC reports unrestricted educational grants to his institution from Janssen, Pharmacyclics, and AbbVie; payment to institution for educational lectures from Janssen; participation on a data safety monitoring board for an academically led investigator-initiated CLL study and personal payment for meeting attendance and report preparation from University Hospital Cologne. SJ reports receipt of unrestricted educational grants to her institution from Janssen, Pharmacyclics and AbbVie. NG reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and participation on an advisory board for AbbVie. PEMP reports grants from Roche and Gilead; payment or honoraria for presentations from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for AbbVie, BeiGene, and Novartis. DA reports receipt of part of his salary from the National Institute for Health and Care Research and Medical Research Council and support to attend meetings from CSL Behring. AR reports grants to his institution from AbbVie, Janssen, Pharmacyclics, and Roche; consulting fees from BeiGene and Pharmacyclics paid to a company of which AR is a director; payment or honoraria for presentations from AbbVie, Beckman Coulter, BD Biosciences, BeiGene, and Janssen paid to a company of which AR is a director; support for attending meetings or travel from Janssen; participation on a data safety monitoring board or advisory board from AbbVie and Janssen; and receipt of equipment from Beckman Coulter. TM reports payment for lectures and presentations from Janssen, AbbVie, and AstraZeneca; support for attending conferences from Janssen, AbbVie, and AstraZeneca; and participation on advisory boards for Janssen, AbbVie, AstraZeneca, Lilly, BeiGene, and Morphosys. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Chronic stimulation of CD8 + T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.

Current declines in terrestrial insect biomass and abundance have raised global concern for the fate of insects and the ecosystem services they provide. However, the ecological and economic contributions of many insects have yet to be quantified. Carrion-specializing invertebrates are important mediators of carrion decomposition; however, the role of their reproductive activities in facilitating this nutrient pulse into ecosystems is poorly understood. Here, we investigate whether insects that sequester carrion belowground for reproduction alter soil biotic and abiotic properties in North American temperate forests. We conducted a field experiment that measured soil conditions in control, surface carrion alone, and beetle-utilized carrion treatments. Our data demonstrate that Nicrophorus beetle reproduction and development results in changes in soil characteristics which are consistent with those observed in surface carrion decomposition alone. Carrion addition treatments increase soil labile C, DON and DOC, while soil pH and microbial C:N ratios decrease. This study demonstrates that the decomposition of carrion drives soil changes but suggests that the behaviors of insect scavengers play an important role in the release of carrion nutrients directly into the soil by sequestering carrion resources in the ecosystem where they were deposited.

Purpose: To quantify the amount of strain across an anterior cruciate ligament reconstruction (ACLR) before and after a lateral meniscus (LM) posterior root complex tear and determine whether a meniscal root repair effectively protects the ACLR against excessive strain., Methods: Fresh-frozen cadaveric knees were tested with an 88-N anterior drawer force and an internal and external torque of 5-Nm applied at 0°, 15°, 30°, 60°, and 90° of flexion. A simulated pivot shift was also applied at 0, 15, and 30° of flexion. Rotation and translation of the tibia, and strain across the ACL graft were recorded. Testing was repeated for the following four conditions: ACL-intact, ACLR with intact LM, ACLR with LM posterior root complex tear, and ACLR with root repair., Results: The kinematic data from 12 fresh frozen cadaveric knees underwent analysis. Only 11 specimens had usable strain data. Sectioning the meniscofemoral ligaments and the LM posterior root increased rotational and translational laxity at 30° of knee flexion. ACLR graft strain significantly increased when an anterior load and internal torque were applied. Repair of the LM posterior root reduced strain when the knee was internally rotated but was unable to normalize strain when an anterior force was applied., Conclusions: This cadaveric biomechanical study suggests injury to the LM posterior root complex increases rotational and anterior laxity of the knee and places increased strain across reconstructed ACL grafts. Subsequent root repair did not result in a statistically significant reduction in strain., Clinical Relevance: This study provides quantitative data on the implications of a LM posterior root injury in the setting of an ACL reconstruction to help guide clinical decision-making., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier Inc.)

Background: The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success., Methods: FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial., Results: The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres., Conclusions: FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community., Trial Registration: ISRCTN Registry ISRCTN01844152 . Registered on August 08, 2014.

Resource niche partitioning mediates the coexistence of similar species by reducing the chance of competitive encounters. For co-occurring species that share an ephemeral resource, contrasting activity in space and time may facilitate their persistence. Burying beetles (Silphidae: Nicrophorus) depend entirely on small vertebrate carcasses to reproduce. Given the unpredictability of this resource, and its value to congeners and other scavenger species, burying beetles likely endure intense competition to secure a carcass. Here, contrasting spatial and temporal niche patterns are explored as resource allocation strategies among five sympatric species of burying beetles (N. americanus, N. marginatus, N. pustulatus, N. orbicollis, and N. tomentosus). Specifically, the space-use and daily activity patterns are measured, at a fine scale, across species pairs to extrapolate contrasting niche-use patterns within a nicrophorine-rich grassland community in North-Central Oklahoma, USA. The results of this study reveal an important interplay between space-use and daily temporal activity in mediating the scramble competition associated with carrion resources. Where spatial or temporal overlap between burying beetle species is high, direct competition is mediated along an alternative niche dimension. For instance, N. americanus and N. orbicollis, a species dyad thought to be in direct competition, do overlap temporally but were found to have segregated space-use patterns. Our findings provide key insights into the competitive interactions within a necrophilous community and further inform our broader understanding of the spatial and temporal resource dimensions that drive the ecological niche.

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT., (© 2019 by The American Society of Hematology.)

Background: Extensor mechanism disruption after total knee arthroplasty is a serious complication leading to notable patient morbidity. The purpose of this study is to compare the outcomes of extensor mechanism allograft with synthetic graft reconstruction., Methods: We retrospectively identified all patients who underwent extensor mechanism reconstruction using either allograft or synthetic graft from two high-volume academic arthroplasty institutions between 2006 and 2017. We collected extensor lag, need for ambulatory aids, and patient-reported outcome measures, as well as the incidence of postoperative complications and revision surgeries. We evaluated cost differences, considering both material cost and the need for revision surgery., Results: We identified 27 cases. A significantly greater postoperative extensor lag was found in the allograft group (P = 0.05). Graft failure after synthetic reconstruction was zero, with an overall revision surgery rate of 15%. Graft failure was 21%, and the revision surgery rate was 43% after allograft reconstruction. The allograft cost was significantly higher compared with the synthetic graft cost (P = 0.001). The mean total cost was 4,733.08 CAD for the synthetic group and 24,050.40 CAD for the allograft group (P = 0.17)., Discussion: Synthetic reconstruction for extensor mechanism disruption shows benefit in postoperative extensor lag, graft failure, revision surgery, and cost when compared with allograft., Level of Evidence: Level III.

Introduction: The clinical success and longevity of a primary total knee arthroplasty (TKA) in large part depend on our ability to control coronal alignment. However, controversy exists regarding which radiographs to use for the most accurate interpretation. The study assesses the accuracy of coronal alignment measurements using a single short knee radiograph (SKR) in comparison with full-length radiographs (FLRs)., Methods: Using our institutional database, we retrieved radiographs of all patients who have had pre- and postoperative FLRs for their primary TKA in 2014. The following measurements were obtained on both short and long radiographs: femoral-tibial angle (FTA), anatomic lateral distal femoral angle, medial proximal tibial angle, condylar-plateau angle, and condylar-plateau distance. A reliability analysis was conducted between the pre- and postoperative SKRs and FLRs using the intraclass correlation coefficient (ICC)., Results: Radiographs of 236 limbs were included in the analysis. The FTA showed an ICC of 0.84 and 0.69 on the pre- and postoperative radiographs, respectively. Good ICC was seen in the lateral distal femoral angle in both the pre- and postoperative radiographs; these were 0.70 and 0.67, respectively. Also, the medial proximal tibial angle showed good to excellent correlation, with an ICC of 0.83 on the preoperative and 0.66 on the postoperative radiographs., Conclusion: This study illustrates that SKRs could be an appropriate substitute for FLRs for the evaluation of primary TKA coronal alignment, especially in the postoperative assessment of these patients., Level of Evidence: Level III.

Background: Hamstring tendons are commonly harvested as autograft for ulnar collateral ligament reconstruction. There is no consensus in the literature whether the hamstring tendon should be harvested from the ipsilateral (drive) leg or contralateral (landing) leg of baseball pitchers undergoing ulnar collateral ligament reconstruction. Hamstring injuries commonly occur in baseball players, but there are no reports on their incidence specifically among Major League Baseball (MLB) pitchers, nor are there reports on whether they occur more commonly in the drive leg or the landing leg., Hypothesis: Hamstring injuries occur more commonly in the landing legs of MLB pitchers., Study Design: Descriptive epidemiology study., Methods: MLB pitchers who sustained hamstring injuries requiring time spent on the disabled list were identified from publicly available sources over 10 seasons. Demographics of the pitchers and injury and return-to-sport data were collected. Hamstring injuries to the drive leg were compared with injuries to the landing leg., Results: Sixty-five pitchers had 78 disabled list stints due to hamstring injuries over 10 seasons. The landing leg was injured in 67.9% of cases, and the most common mechanism of injury was pitching. There were no significant differences in demographics between pitchers who sustained drive leg and landing leg injuries. There was no significant difference in mechanism of injury or time to return to sport between pitchers who sustained drive leg and landing leg injuries., Conclusion: The landing leg is more commonly injured than the drive leg among MLB pitchers who sustain hamstring injuries. There is no difference in time to return to sport between pitchers who sustain drive leg and landing leg injuries. More research is required to determine whether there is a difference in performance or future injury between hamstring tendons harvested from the drive leg and the landing leg for ulnar collateral ligament reconstruction among pitchers.

Acquisition of T-cell central tolerance involves distinct pathways of self-antigen presentation to thymocytes. One pathway termed indirect presentation requires a self-antigen transfer step from thymic epithelial cells (TECs) to bone marrow-derived cells before the self-antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context-dependent, potentially due to variation in self-antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane-bound transgenic self-antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow-derived antigen-presenting cells, insHEL-mediated thymocyte deletion was abolished, whereas thyroHEL-mediated deletion occurred at a later stage of thymocyte development and Foxp3 + regulatory T-cell differentiation increased. Indirect presentation increased the strength of T-cell receptor signalling that both self-antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self-reactive thymocytes., (© 2018 John Wiley & Sons Ltd.)

Objectives: In vitro culture studies have shown that miR-363 is enriched in extracellular vesicles from chronic lymphocytic leukaemia cells. We wondered whether miR-363 was detectable in plasma, which is an essential precondition for further studies to assess its usefulness as a biomarker. Using samples from two clinical trials: one enrolling patients with advanced disease and the other asymptomatic patients with early stage disease, we determined plasma miR-363 levels and secondly investigated the distribution of this miRNA between plasma and particle bound fractions in patients and normal subjects., Results: Advanced disease (n = 95) was associated with higher levels of miR-363 than early stage disease (n = 45) or normal subjects (n = 11) but there was no association with markers of prognosis. The distribution of specific miRNA between particle bound and plasma protein fractions was investigated using size exclusion chromatography on plasma from patients (n = 4) and normal subjects (n = 3). ~ 20% of total miR-16 and miR-363 is particle bound in patients while there was no detectable particle bound material in normal subjects. Our work demonstrates that miR-363 levels are raised in chronic lymphocytic leukaemia patients and raises the possibility that distribution of circulating miRNA between plasma fractions differs in health and disease.