Network analysis reveals a major role for 14q32 cluster miRNAs in determining transcriptional differences between IGHV-mutated and unmutated CLL.

Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes with differing clinical behaviours, variable B cell receptor (BCR) signalling capacity and distinct transcriptional profiles. As it remains unclear how these differences reflect the tumour cells' innate pre/post germinal centre origin or their BCR signalling competence, we applied mRNA/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the MEG3 lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature. GAB1, a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the GAB1 3'UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.

Mid- to late-term follow-up of primary hip and knee arthroplasty: the UK SAFE evidence-based recommendations.

To review the evidence and reach consensus on recommendations for follow-up after total hip and knee arthroplasty. A programme of work was conducted, including: a systematic review of the clinical and cost-effectiveness literature; analysis of routine national datasets to identify pre-, peri-, and postoperative predictors of mid-to-late term revision; prospective data analyses from 560 patients to understand how patients present for revision surgery; qualitative interviews with NHS managers and orthopaedic surgeons; and health economic modelling. Finally, a consensus meeting considered all the work and agreed the final recommendations and research areas. The UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE) recommendations apply to post-primary hip and knee arthroplasty follow-up. The ten-year time point is based on a lack of robust evidence beyond ten years. The term 'complex cases' refers to individual patient and surgical factors that may increase the risk for arthroplasty failure. For Orthopaedic Data Evaluation Panel (ODEP) 10A* minimum implants, it is safe to disinvest in routine follow-up from one to years post-non-complex hip and knee arthroplasty provided there is rapid access to orthopaedic review. For ODEP 10A* minimum implants in complex cases, or non-ODEP 10A* minimum implants, periodic follow-up post-hip and knee arthroplasty may be required from one to ten years. At ten years post-hip and knee arthroplasty, clinical and radiological evaluation is recommended. After ten years post-hip and knee arthroplasty, frequency of further follow-up should be based on the ten-year assessment; ongoing rapid access to orthopaedic review is still required. Complex cases, implants not meeting the ODEP 10A* criteria, and follow-up after revision surgery are not covered by this recommendation.

GA4GH Phenopackets: A Practical Introduction.

The Global Alliance for Genomics and Health (GA4GH) is developing a suite of coordinated standards for genomics for healthcare. The Phenopacket is a new GA4GH standard for sharing disease and phenotype information that characterizes an individual person, linking that individual to detailed phenotypic descriptions, genetic information, diagnoses, and treatments. A detailed example is presented that illustrates how to use the schema to represent the clinical course of a patient with retinoblastoma, including demographic information, the clinical diagnosis, phenotypic features and clinical measurements, an examination of the extirpated tumor, therapies, and the results of genomic analysis. The Phenopacket Schema, together with other GA4GH data and technical standards, will enable data exchange and provide a foundation for the computational analysis of disease and phenotype information to improve our ability to diagnose and conduct research on all types of disorders, including cancer and rare diseases.

Association between outpatient follow-up and incidence of revision after knee and hip replacements: a population-based cohort study.

BACKGROUND: Follow-up visits 5 or 7 years after surgery were recommended for people having primary hip or knee replacement. The benefits of this practice to patients and the healthcare system, however, have not yet been specifically examined. The aim of this study was to investigate the association between long-term follow-up outpatient hospital visits and revision rates for patients who undergo primary knee or hip replacement surgery. METHODS: Cohorts were identified for patients undergoing knee or hip replacement surgery using medical records from primary care practices within the UK Clinical Practice Research Datalink (CPRD) GOLD dataset linked to hospital records from the English Hospital Episodes Statistics (HES) data. Two groups of patients were compared in terms of revision and mortality rates: those with at least one long-term (between five and 10 years since primary surgery) follow-up visit at the orthopaedic department ('Follow-up' group), and those without ('No follow-up' group). RESULTS: A total of 9856 (4349 in the Follow-up group) patients with knee replacement and 10,837 (4870 in the Follow-up group) with hip replacement were included in the analysis. For knee replacement, the incidence of revision was 3.6% for those followed-up and 0.6% for those not followed-up. An adjusted regression model confirmed the difference in the hazard ratio (HR) for revision was statistically significant (HR: 5.65 [95% CI 3.62 to 8.81]). Mortality at 4 years was lower for the Follow-up (17%) compared to the No follow-up group (21%), but this difference was not statistically significant (HR: 0.95 [0.84 to 1.07]). For hip replacement, the incidence of revision rates were 3.2 and 1.4% for the follow-up and not follow-up groups, respectively, the difference being statistically significant (HR: 2.34 [1.71 to 3.20]). Mortality was lower for the Follow-up (15%) compared to the No follow-up group (21%), but the difference was not statistically significant (HR: 0.91 [0.81 to 1.02]). CONCLUSION: Patients attending follow-up orthopaedic consultations show a higher risk of revision surgery compared to those who are not followed-up. A cause for this difference could not be identified in this study but a likely explanation is that surgeons play an effective role as ultimate arbitrators when identifying patients to be included in long-term follow-up lists.

Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment.

Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.

B-cell receptor dependent phagocytosis and presentation of particulate antigen by chronic lymphocytic leukemia cells.

Aim: T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated. Methods: The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation. Results: Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton's tyrosine kinase (BTK). Conclusions: CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens.

UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national datasets tell us about mid-late term revision risk after knee replacement?

OBJECTIVE: To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up. DESIGN: Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs)). PARTICIPANTS: Primary elective KRs aged ≥18 years. EVENT OF INTEREST: Revision surgery ≥5 years (mid-late term) postprimary KR. STATISTICAL METHODS: Cox regression modelling to ascertain risk factors of mid-late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision. RESULTS: NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995-2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0-8.8), with 1055 (0.6%) mid-late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02-18.3), with 352 (2.0%) mid-late term revisions.Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.No implant factors were identified. CONCLUSION: The risk of mid-late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality.

UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national data sets tell us about mid-late term revision risk after hip replacement? Retrospective cohort study.

OBJECTIVE: To identify patients at risk of mid-late term revision of hip replacement to inform targeted follow-up. DESIGN: Analysis of linked national data sets from primary and secondary care (Clinical Practice Research Datalink (CPRD-GOLD); National Joint Registry (NJR); English Hospital Episode Statistics (HES); Patient-Reported Outcome Measures (PROMs)). PARTICIPANTS: Primary elective total hip replacement (THR) aged≥18. EVENT OF INTEREST: Revision surgery≥5 years (mid-late term) after primary THR. STATISTICAL METHODS: Cox regression modelling to ascertain risk factors of mid-late term revision. HR and 95% CI assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision. RESULTS: NJR-HES-PROMs data were available from 2008 to 2011 on 142 275 THR; mean age 70.0 years and 61.9% female. CPRD GOLD-HES data covered 1995-2011 on 17 047 THR; mean age 68.4 years, 61.8% female. Patients had minimum 5 years postprimary surgery to end 2016. In NJR-HES-PROMS data, there were 3582 (2.5%) revisions, median time-to-revision after primary surgery 1.9 years (range 0.01-8.7), with 598 (0.4%) mid-late term revisions; in CPRD GOLD, 982 (5.8%) revisions, median time-to-revision 5.3 years (range 0-20), with 520 (3.1%) mid-late term revisions.Reduced risk of mid-late term revision was associated with older age at primary surgery (HR: 0.96; 95% CI: 0.95 to 0.96); better 6-month postoperative pain/function scores (HR: 0.35; 95% CI: 0.27 to 0.46); use of ceramic-on-ceramic (HR: 0.73; 95% CI: 0.56 to 0.95) or ceramic-on-polyethylene (HR: 0.76; 95% CI: 0.58 to 1.00) bearing surfaces.Increased risk of mid-late term revision was associated with the use of antidepressants (HR: 1.32; 95% CI: 1.09 to 1.59), glucocorticoid injections (HR: 1.33; 95% CI: 1.06 to 1.67) and femoral head size≥44 mm (HR: 2.56; 95% CI: 1.09 to 6.02)No association of gender, obesity or Index of Multiple Deprivation was observed. CONCLUSION: The risk of mid-late term THR is associated with age at primary surgery, 6-month postoperative pain and function and implant factors. Further work is needed to explore the associations with prescription medications observed in our data.

A comparative study of patients presenting for planned and unplanned revision hip or knee arthroplasty.

AIMS: The aim of this study was to conduct a cross-sectional, observational cohort study of patients presenting for revision of a total hip, or total or unicompartmental knee arthroplasty, to understand current routes to revision surgery and explore differences in symptoms, healthcare use, reason for revision, and the revision surgery (surgical time, components, length of stay) between patients having regular follow-up and those without. METHODS: Data were collected from participants and medical records for the 12 months prior to revision. Patients with previous revision, metal-on-metal articulations, or hip hemiarthroplasty were excluded. Participants were retrospectively classified as 'Planned' or 'Unplanned' revision. Multilevel regression and propensity score matching were used to compare the two groups. RESULTS: Data were analyzed from 568 patients, recruited in 38 UK secondary care sites between October 2017 and October 2018 (43.5% male; mean (SD) age 71.86 years (9.93); 305 hips, 263 knees). No significant inclusion differences were identified between the two groups. For hip revision, time to revision > ten years (odds ratio (OR) 3.804, 95% confidence interval (CI) (1.353 to 10.694), p = 0.011), periprosthetic fracture (OR 20.309, 95% CI (4.574 to 90.179), p < 0.001), and dislocation (OR 12.953, 95% CI (4.014 to 41.794), p < 0.001), were associated with unplanned revision. For knee, there were no associations with route to revision. Revision after ten years was more likely for those who were younger at primary surgery, regardless of route to revision. No significant differences in cost outcomes, length of surgery time, and access to a health professional in the year prior to revision were found between the two groups. When periprosthetic fractures, dislocations, and infections were excluded, healthcare use was significantly higher in the unplanned revision group. CONCLUSION: Differences between characteristics for patients presenting for planned and unplanned revision are minimal. Although there was greater healthcare use in those having unplanned revision, it appears unlikely that routine orthopaedic review would have detected many of these issues. It may be safe to disinvest in standard follow-up provided there is rapid access to orthopaedic review. Cite this article: Bone Joint J 2022;104-B(1):59-67.

Blood culture negative infective endocarditis in adult congenital heart disease patients with prosthetic grafts: a case series.

BACKGROUND: Blood culture negative infective endocarditis (BCNIE) is often a diagnostic challenge in adult congenital heart disease patients leading to misdiagnosis, treatment delay and associated high mortality. Studies of BCNIE in adult congenital heart disease patients repaired with prosthetic cardiovascular grafts are limited. CASE SUMMARY: We report two cases of BCNIE where serology testing, multiple polymerase chain reaction testing of explanted valve material and multi-modality imaging including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were utilized not only to confirm the diagnosis but also to guide management strategy and inform prognosis. Both patients were treated successfully with cardiac surgery and prolonged anti-microbial therapy. DISCUSSION: Clinical presentation of BCNIE in repaired CHD patients is highly variable. The symptoms are often non-specific with subacute or chronic presentation. This may mislead initial diagnosis and subsequent management. Multi-modality imaging including PET/CT should be considered to support the diagnosis, define the extent of infection, decide the management strategy and inform prognosis in patients. A thorough history of animal exposure, and consideration of serology and multiple molecular testing to identify the causative organism, is critical in the management of BCNIE.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Pilot study: Is a long-term follow-up service beneficial for patients undergoing revision hip replacement surgery?

PURPOSE: Total hip arthroplasty (THA) is highly successful but some patients will require later revision surgery. This pilot study evaluates the effects of long-term follow-up for patients undergoing revision hip replacement. METHODS: Consecutive patients undergoing aseptic revision of THA were recruited from a large orthopaedic unit to a single centre, observational study. Primary outcomes were changes in patient-reported scores from pre-revision to 12 months post-surgery. Secondary outcomes were costs during hospital stay up to 6 months post-revision. Participants were retrospectively allocated to two groups-those with regular orthopaedic review prior to revision (Planned revision) or those without (Unplanned revision). RESULTS: 52 patients were recruited, 7 were unrevised, one incomplete baseline questionnaires. There were 25 planned and 19 unplanned revisions with no significant differences between groups at baseline. At 12 months, 34 complete data sets were available for analysis, 17 in each group. Change scores were analysed with Mann-Whitney U test; none reached statistical significance. There was a significant difference for length of stay: Planned group 5 days (2-22), Unplanned 11 days (3-86) (Mann-Whitney U test, p = 0.023). No significant differences found for theatre time or component costs. Resource costs post-revision surgery are presented. CONCLUSION: This pilot study indicates that some change in methods would be required for future work. The results show that there may be some financial benefit from providing long-term follow-up of THA but a larger study is needed to explore these findings and to discuss the impact on recommended guidelines.

The use of tissue adhesive as an adjunct to wound closure in knee arthroplasty does not reduce wound ooze.

INTRODUCTION: Persistent wound ooze has been associated with prolonged length of hospital stay and increased risk of infection. Recently, the use of tissue adhesive after hip and knee arthroplasty has been described. We believe that knee arthroplasty wounds exhibit different behavior compared to hip arthroplasty due to the increased wound-margin tension associated with knee flexion. PATIENTS AND METHODS: Forty-three patients undergoing total knee arthroplasty (TKA) by a single surgeon were studied. All wounds were closed using staples with or without tissue adhesive. Post-operatively, the wounds were reviewed daily for ooze. Dressings were changed only if soaked > 50% or if there was persistent wound discharge of more than 2 × 2 cm at 72 h. RESULTS: There were 21 patients in the tissue adhesive (group 1), 22 in the non-tissue adhesive (group 2) with the average age for group 1 of 72.2 years and for group 2 of 69.3 years. The median length of stay for both groups was 4 days (range of 3-7 days for group 1 and 2-6 days for group 2) (P = 0.960). The tissue adhesive group showed a statistically significant reduction in wound ooze on day 1 (P = 0.019); however, the difference was not significant on the following days. The median for the number of dressing changes for group 1 was zero changes and for group 2, one change. This was not statistically significant (P = 0.112). No complications were observed in both groups and there were no reactions to the tissue adhesive. CONCLUSION: The data from this case series suggest that the use of tissue adhesive may reduce wound ooze on day 1 only. The latter is most likely due to significant tensile forces to which the knee arthroplasty wound is subjected in the immediate post-operative rehabilitation. Further, the cost of tissue adhesive is not offset by reduced dressing changes or length of hospital stay.

Doxycycline-Induced Antinuclear Antibody and Antineutrophil Cytoplasmic Antibody Associated Vasculitis: A Case Report and Literature Review.

Drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has been increasingly recognized in the literature with numerous medications listed as causative agents in disease pathology. Doxycycline is a commonly prescribed medication within the United States which is a synthetic, broad-spectrum antibiotic with antimicrobial properties and at low doses exhibits anti-inflammatory effects. In this report, we describe a case of doxycycline-induced ANCA-associated vasculitis with laboratory and biopsy findings supporting the diagnosis, which to the best of our knowledge is the first described case of doxycycline-induced AAV in the literature. The patient was started on doxycycline for treatment of potential Lyme disease. She began to develop progressively worsening myasthenia, erythematous macular rash, anorexia, anemia, and fatigue for several weeks following the course of doxycycline with initial concern of a paraneoplastic process. Ultimately, the patient was discovered to be positive for antinuclear antibody (ANA), perinuclear antineutrophil cytoplasmic antibody (pANCA), and myeloperoxidase (MPO) antibody for which she was treated with a course of prednisone leading to complete remission of disease. A brief review of the pathogenesis of ANCA vasculitides will also be discussed within this article.

Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells.

PURPOSE: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS: Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.

Mid inter-epicondyle trochlea intersection (MIELTI): Proposal of a new index for identifying the deepest part of the trochlea.

BACKGROUND: Tibial tuberosity trochlear groove distance (TT-TG) is an important radiological measurement in patellofemoral instability (PFI). Where instability is recurrent, a value ≥20 mm is considered an indication for tubercle medialisation. Trochlear dysplasia commonly accompanies PFI. It can make identification of the deepest part of the trochlea difficult, which makes the TT-TG difficult or impossible to assess. To address this, we propose a new method of identifying the deepest part of trochlea based on the femoral epicondyles. It is named the tibial tuberosity mid inter-epicondyle trochlea intersection distance (TT-MIELTI). METHODS: The TT-TG and TT-MIELTI of 30 consecutive non-dysplastic knee MRIs were compared, excluding 96 knees with dysplasia, sulcus angles ≥135°, a tibial tuberosity anterior cortex which was not fully demonstrated, artefact, fracture, or Osgood Schlatter's disease. To assess inter-observer reliability three blinded researchers measured the TT-TG and the TT-MIELTI of all 30 knees. To assess intra-observer repeatability one researcher repeated the measurements after six weeks. RESULTS: The intraclass correlation coefficient (ICC) test demonstrated good to excellent values for all measurements (TT-TG and TT-MIELTI correlation ICC 0.94-0.97; TT-TG inter-observer reliability ICC = 0.85, intra-observer repeatability ICC = 0.90; TT-MIELTI inter-observer reliability ICC = 0.86, intra-observer repeatability ICC = 0.89. All p values < .001.) CONCLUSIONS: In non-dysplastic knees the mid inter-epicondyle trochlea intersection (MIELTI) accurately identifies the deepest part of the trochlea, and TT-MIELTI is a reliable alternative to the TT-TG. Re-assessment in dysplastic knees would be of benefit to establish its usefulness in the clinical setting.

Metastatic malignancy masquerading as neurocysticercosis.

Cystic brain lesions are a common clinical dilemma facing infectious disease providers. A broad differential diagnosis is required in the proper evaluation and care of patients facing such an illness. Here the authors describe the case of a 29-year-old woman who presented with seizures and was found to have multiple cystic brain lesions, with risk factors for neurocysticercosis. Ultimately, she was found to have a metastatic neuroendocrine malignancy. The authors review the ideal imaging and testing modalities in the diagnosis and exclusion of neurocysticercosis. This case serves as guidance for clinicians caring for patients with cystic brain lesions that may be infectious or non-infectious in etiology.

Towards UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): protocol for an evaluation of the requirements for arthroplasty follow-up, and the production of consensus-based recommendations.

INTRODUCTION: Hip and knee arthroplasties have revolutionised the management of degenerative joint diseases and, due to an ageing population, are becoming increasingly common. Follow-up of joint prostheses is to identify problems in symptomatic or asymptomatic patients due to infection, osteolysis, bone loss or potential periprosthetic fracture, enabling timely intervention to prevent catastrophic failure at a later date. Early revision is usually more straight-forward surgically and less traumatic for the patient. However, routine long-term follow-up is costly and requires considerable clinical time. Therefore, some centres in the UK have curtailed this aspect of primary hip and knee arthroplasty services, doing so without an evidence base that such disinvestment is clinically or cost-effective. METHODS: Given the timeline from joint replacement to revision, conducting a randomised controlled trial (RCT) to determine potential consequences of disinvestment in hip and knee arthroplasty follow-up is not feasible. Furthermore, the low revision rates of modern prostheses, less than 10% at 10 years, would necessitate thousands of patients to adequately power such a study. The huge variation in follow-up practice across the UK also limits the generalisability of an RCT. This study will therefore use a mixed-methods approach to examine the requirements for arthroplasty follow-up and produce evidence-based and consensus-based recommendations as to how, when and on whom follow-up should be conducted. Four interconnected work packages will be completed: (1) a systematic literature review; (2a) analysis of routinely collected National Health Service data from five national data sets to understand when and which patients present for revision surgery; (2b) prospective data regarding how patients currently present for revision surgery; (3) economic modelling to simulate long-term costs and quality-adjusted life years associated with different follow-up care models and (4) a Delphi-consensus process, involving all stakeholders, to develop a policy document which includes a stratification algorithm to determine appropriate follow-up care for an individual patient. ETHICS AND DISSEMINATION: Favourable ethical opinion has been obtained for WP2a (RO-HES) (220520) and WP2B (220316) from the National Research Ethics Committee. Following advice from the Confidentiality Advisory Group (17/CAG/0122), data controllers for the data sets used in WP2a (RO-HES) - NHS Digital and The Phoenix Partnership - confirmed that Section 251 support was not required as no identifiable data was flowing into or out of these parties. Application for approval of WP2a (RO-HES) from the Independent Group Advising on the Release of Data (IGARD) at NHS Digital is in progress (DARS-NIC-147997). Section 251 support (17/CAG/0030) and NHS Digital approval (DARS-NIC-172121-G0Z1H-v0.11) have been obtained for WP2a (NJR-HES-PROMS). ISAC (11_050MnA2R2) approval has been obtained for WP2a (CPRD-HES).