Robust engraftment of fetal nonhuman primate CD34-positive cells in immune-deficient mice.

Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies. We found that adult rhesus macaque mobilized blood (AMb) CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) engrafted at low but persistent levels in immune-deficient mice harboring transgenes for human (NHP cross-reactive) GM-CSF and IL3, but did not in mice with wild-type murine cytokines lacking NHP cross-reactivity. To enhance engraftment, fetal liver-derived HSPCs were selected as the infusion product based on an increased CD34hi fraction compared with AMb and bone marrow. Coupled with cotransplantation of rhesus fetal thymic fragments beneath the mouse kidney capsule, fetal liver-derived HSPC infusion in cytokine-transgenic mice yielded robust multilineage lymphohematopoietic engraftment. The emergent immune system recapitulated that of the fetal monkey, with similar relative frequencies of lymphocyte, granulocyte, and monocyte subsets within the thymic, secondary lymphoid, and peripheral compartments. Importantly, while exhibiting a predominantly naïve phenotype, in vitro functional assays demonstrated robust cellular activation in response to nonspecific and allogenic stimuli. This primatized mouse represents a viable and translatable model for the study of hematopoietic stem cell physiology, immune development, and functional immunology in NHPs. Summary Sentence: Engraftment of rhesus macaque hematopoietic tissues in immune-deficient mice yields a robust BLT/NeoThy-type primatized mouse model for studying nonhuman primate hematopoiesis and immune function in vivo.

IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis.

BACKGROUND: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1ß antibody, canakinumab, in the treatment of AH. METHODS: This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of "improved" or "not improved". Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. DISCUSSION: This phase II study will explore the benefits of the IL-1ß antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1ß signalling may improve histology and survival for patients with AH. TRIAL REGISTRATION: EudraCT 2017-003724-79 . Prospectively registered on 13 April 2018.

B and T cell prolymphocytic leukaemia.

Prolymphocytic leukaemias B-PLL and T-PLL are rare disorders, typically with an aggressive clinical course and poor prognosis. Combining morphology, immunophenotyping, cytogenetic and molecular diagnostics reliably separates B-PLL and T-PLL from one another and other disorders. In T-PLL discovery of frequent mutations in the JAK-STAT pathway have increased understanding of disease pathogenesis. Alemtuzumab (anti-CD52) produces excellent response rates but long-term remissions are only achieved in a minority following consolidation with allogeneic stem cell transplant. Molecular abnormalities in B-PLL are less understood. Disruption of TP53 is a key finding, conveying chemotherapy resistance requiring novel therapies such as B-cell receptor inhibitors (BCRi). Both conditions require improved pathobiological knowledge to identify new treatment targets and guide therapy with novel pathway inhibitors.

Characterization of opioid consumption and disposal patterns after total knee arthroplasty.

AIMS: The aim of this study was to determine the general postoperative opioid consumption and rate of appropriate disposal of excess opioid prescriptions in patients undergoing primary unilateral total knee arthroplasty (TKA). PATIENTS AND METHODS: In total, 112 patients undergoing surgery with one of eight arthroplasty surgeons at a single specialty hospital were prospectively enrolled. Three patients were excluded for undergoing secondary procedures within six weeks. Daily pain levels and opioid consumption, quantity, and disposal patterns for leftover medications were collected for six weeks following surgery using a text-messaging platform. RESULTS: Overall, 103 of 109 patients (94.5%) completed the daily short message service (SMS) surveys. The mean oral morphine equivalents (OME) consumed during the six weeks post-surgery were 639.6 mg (sd 323.7; 20 to 1616) corresponding to 85.3 tablets of 5 mg oxycodone per patient. A total of 66 patients (64.1%) had stopped taking opioids within six weeks of surgery and had the mean equivalent of 18 oxycodone 5 mg tablets remaining. Only 17 patients (25.7%) appropriately disposed of leftover medications. CONCLUSION: These prospectively collected data provide a benchmark for general opioid consumption after uncomplicated primary unilateral TKA. Many patients are prescribed more opioids than they require, and leftover medication is infrequently disposed of appropriately, which increases the risk for illicit diversion. Cite this article: Bone Joint J 2019;101-B(7 Supple C):98-103.

Association of childhood adiposity measures with adulthood knee cartilage defects and bone marrow lesions: a 25-year cohort study.

OBJECTIVE: To describe the associations between childhood adiposity measures and adulthood knee cartilage defects and bone marrow lesions (BMLs) measured 25 years later. METHODS: 327 participants from the Australian Schools Health and Fitness Survey (ASHFS) of 1985 (aged 7-15 years) were followed up 25 years later (aged 31-41 years). Childhood measures (weight, height and skinfolds) were collected in 1985. Body mass index (BMI), overweight status and fat mass were calculated. Participants underwent 1.5 T knee magnetic resonance imaging (MRI) during 2008-2010, and cartilage defects and BMLs were scored from knee MRI scans. Log binomial regressions were used to examine the associations. RESULTS: Among 327 participants (47.1% females), 21 (6.4%) were overweight in childhood. Childhood adiposity measures were associated with the increased risk of adulthood patellar cartilage defects (Weight relative risk (RR) 1.05/kg, 95% confidence interval (CI) 1.01-1.09; BMI 1.10/kg/m2, 1.01-1.19; Overweight 2.22/yes, 1.21-4.08; fat mass 1.11/kg, 1.01-1.22), but not tibiofemoral cartilage defects. Childhood adiposity measures were not significantly associated with adulthood knee BMLs except for the association between childhood overweight status and adulthood patellar BMLs (RR 2.87/yes, 95% CI 1.10-7.53). These significant associations persisted after adjustment for corresponding adulthood adiposity measure. CONCLUSION: Childhood adiposity measures were associated with the increased risk of adulthood patellar cartilage defects and, to a lesser extent, BMLs, independent of adulthood adiposity measures. These results suggest that adiposity in childhood has long-term effects on patellar structural abnormalities in young adults.

The Synergy cementless femoral stem in primary total hip arthroplasty at a minimum follow-up of 15 years.

AIMS: We report on the outcome of the Synergy cementless femoral stem with a minimum follow-up of 15 years (15 to 17). PATIENTS AND METHODS: A retrospective review was undertaken of a consecutive series of 112 routine primary cementless total hip arthroplasties (THAs) in 102 patients (112 hips). There were 60 female and 42 male patients with a mean age of 61 years (18 to 82) at the time of surgery. A total of 78 hips in the 69 patients remain in situ; nine hips in eight patients died before 15 years, and 16 hips in 16 patients were revised. Clinical outcome scores and radiographs were available for 94 hips in 85 patients. RESULTS: In all, four stems were revised. One stem was revised for aseptic loosening; two stems because of deep infection; and one because of periprosthetic femoral fracture. There was a significant improvement in all components of the Western Ontario and McMaster Universities Osteoarthritis Index score at the final follow-up (total: p < 0.001, pain: p < 0.001, stiffness: p < 0.001, function: p < 0.001). The mean Harris Hip Scores improved from 47 points (27 to 59) pre-operatively to 89 points (65 to 100) at the latest follow-up (p < 0.001). Kaplan-Meier survivorship, with stem revision for aseptic loosening as the endpoint, was 98.9% at 15 years (95% confidence interval (CI) 96.9 to 100, number at risk at 15 years: 90) and with stem revision for any reason was 95.7% (95% CI 91.7 to 99.8, number at risk at 15 years: 90). CONCLUSION: The Synergy cementless femoral stem demonstrates excellent survivorship and functional outcomes at 15 years. Cite this article: Bone Joint J 2017;99-B:29-36.

Favorable outcome in children and adolescents with a high proportion of advanced phase disease using single/multiple autologous or matched/mismatched allogeneic stem cell transplantations.

We determined the indication, outcome, and risk factors of single and multiple hematopoietic stem cell transplantation(s) (HSCT) in children and adolescents mostly with advanced disease. Forty-one out of 483 patients (8.5 %; median age 9 years) diagnosed at the University of Leipzig with hematological and oncological diseases required HSCT from 1999 to 2011. Patients had overall survival (OS) of 63 ± 10 and 63 ± 16 %, event-free survival (EFS) of 57 ± 10 and 42 ± 16 %, relapse incidence (RI) of 39 ± 10 and 44 ± 18 % and nonrelapse mortality (NRM) of 4 ± 4 and 13 ± 9 % at 10 years after one or more allogeneic and autologous HSCT, respectively. One patient in CR1 and five with advanced disease received two HSCT. Four of the six patients maintained/achieved CR for a median of 13 months. Three died of progression and one of NRM. Two patients had a third HSCT and one survived in CR +231 days after HSCT. Risk factors for OS and EFS were disease stage at HSCT and EBMT risk score. Center (pediatric or JACIE accredited pediatric/adult) was not a determinant for survival. Pediatric single and multiple HSCT are important curative approaches for high-risk malignant diseases with low NRM. Efforts to reduce high RI remain the major aim.

Alignment and fixation in total knee arthroplasty: changing paradigms.

Many aspects of total knee arthroplasty have changed since its inception. Modern prosthetic design, better fixation techniques, improved polyethylene wear characteristics and rehabilitation, have all contributed to a large change in revision rates. Arthroplasty patients now expect longevity of their prostheses and demand functional improvement to match. This has led to a re-examination of the long-held belief that mechanical alignment is instrumental to a successful outcome and a focus on restoring healthy joint kinematics. A combination of kinematic restoration and uncemented, adaptable fixation may hold the key to future advances.

Comparable outcome after single-antigen-mismatched versus matched unrelated donor haematopoietic cell transplantation.

PURPOSE: Allogeneic haematopoietic stem cell transplantation (HSCT) is a proven treatment for patients with haematological malignancies. In this retrospective analysis, the impact of donor matching on outcome of unrelated HSCT was analysed in patients transplanted at the University of Leipzig. METHODS: From 2000 to 2009, 206 patients were transplanted from unrelated donors, of which 51 were mismatched (39 in 1 and 12 in ≥ 2 HLA-antigens), using peripheral blood or bone marrow grafts after total body irradiation and cyclophosphamide or busulfan and cyclophosphamide preparative regimens in combination with ATG. For graft-versus-host disease (GvHD) prophylaxis cyclosporine and MTX were administered. RESULTS: After a median follow-up of 49 months, outcome at 5 years in recipients of HLA-identical grafts was comparable to that of patients transplanted from HLA-incompatible donors with an overall survival (OS) of 52 % (95 % CI 43-61) versus 48 % (95 % CI 34-63), respectively (p = 0.48). Results were also comparable for event-free survival at 5 years [47 % (95 % CI 38-56) vs. 39 % (95 % CI 25-54); p = 0.44], relapse incidence (RI) [29 % (95 % CI 20-38) vs. 41 (95 % CI 25-57); p = 0.22] and non-relapse mortality [24 % (95 % CI 16-33) vs. 20 % (95 % CI 8-33); p = 0.84] in the matched versus mismatched groups. Incidence of acute and chronic GvHD was similar in both groups. Advanced disease (p = 0.02) and low-resolution typing (p = 0.04) are risk factors for OS and RI in univariate and multivariate analysis. CONCLUSIONS: Donors with one antigen mismatch are an acceptable option for patients with malignant disease for whom no fully matched donor is available.

The functional and financial impact of isolated and recurrent dislocation after total hip arthroplasty.

The aims of this study were to determine the functional impact and financial burden of isolated and recurrent dislocation after total hip arthroplasty (THA). Our secondary goal was to determine whether there was a difference between patients who were treated non-operatively and those who were treated operatively. We retrospectively reviewed 71 patients who had suffered dislocation of a primary THA. Their mean age was 67 years (41 to 92) and the mean follow-up was 3.8 years (2.1 to 8.2). Because patients with recurrent dislocation were three times more likely to undergo operative treatment (p < 0.0001), they ultimately had a significantly higher mean Harris Hip Score (HHS) (p = 0.0001), lower mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores (p = 0.001) and a higher mean SF-12 score (p < 0.0001) than patients with a single dislocation. Likewise, those who underwent operative treatment had a higher mean HHS (p < 0.0001), lower mean WOMAC score (p < 0.0001) and a higher mean SF-12 score (p < 0.0001) than those who were treated non-operatively. Recurrent dislocation and operative treatment increased costs by 300% (£11 456; p < 0.0001) and 40% (£5217; p < 0.0001), respectively. The operative treatment of recurrent dislocation results in significantly better function than non-operative management. Moreover, the increase in costs for operative treatment is modest compared with that of non-operative measures.

Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.

Utility of percutaneous joint aspiration and synovial biopsy in identifying culture-positive infected hip arthroplasty.

PURPOSE: Percutaneous synovial biopsy has recently been reported to have a high diagnostic value in the preoperative identification of periprosthetic infection of the hip. We report our experience with this technique in the evaluation of patients undergoing revision hip arthroplasty, comparing results of preoperative synovial biopsy with joint aspiration in identifying an infected hip arthroplasty by bacteriological analysis. MATERIALS AND METHODS: We retrospectively reviewed the results of the 110 most recent revision hip arthroplasties in which preoperative synovial biopsy and joint aspiration were both performed. Revision surgery for these patients occurred during the period from September 2005 to March 2012. Using this study group, results from preoperative cultures were compared with preoperative laboratory studies and the results of intraoperative cultures. Synovial aspiration was done using an 18- or 20-gauge spinal needle. Synovial biopsy was done coaxially following aspiration using a 22-gauge Chiba needle or 21-gauge Sure-Cut needle. Standard microbiological analysis was performed on preoperative synovial fluid aspirate and synovial biopsy. Intraoperative tissue biopsy bacteriological analysis results at surgical revision were accepted as the "gold standard" for the presence or absence of infection. RESULTS: Seventeen of 110 (15 %) of patients had intraoperative culture-positive periprosthetic infection. Of these 17 cases, there were ten cases where either the synovial fluid aspiration and/or the synovial biopsy were true positive (sensitivity of 59 %, specificity of 100 %, positive predictive value of 100 % and accuracy of 94 %). There were seven cases where aspiration and biopsy results were both falsely negative, but no false-positive results. Similar results were found for synovial fluid aspiration alone. The results of synovial biopsy alone resulted in the identification of seven infected joints with no false-positive result (sensitivity of 41 %, specificity of 100 %, positive predictive value of 100 %, and accuracy of 91 %). CONCLUSIONS: Standard microbiological analyses performed on percutaneous synovial biopsy specimen during the preoperative evaluation of patients undergoing revision hip arthroplasty did not improve detection of culture-positive periprosthetic infection as compared to synovial fluid aspiration alone.

Managing femoral bone loss in revision total hip replacement: fluted tapered modular stems.

If a surgeon is faced with altered lesser trochanter anatomy when revising the femoral component in revision total hip replacement, a peri-prosthetic fracture, or Paprosky type IIIb or type IV femoral bone loss, a modular tapered stem offers the advantages of accurately controlling femoral version and length. The splines of the taper allow rotational control, and improve the fit in femoral canals with diaphyseal bone loss. In general, two centimetres of diaphyseal contact is all that is needed to gain stability with modular tapered stems. By allowing the proximal body trial to rotate on a well-fixed distal segment during trial reduction, appropriate anteversion can be obtained in order to improve intra-operative stability, and decrease the dislocation risk. However, modular stems should not be used for all femoral revisions, as implant fracture and corrosion at modular junctions can still occur.

The removal of acetabular bone in hip resurfacing and cementless total hip replacement: a comparison using the ratio of the size of the acetabular component to the diameter of the native femoral head.

The purpose of this study was to compare the amount of acetabular bone removed during hip resurfacing (HR) and cementless total hip replacement (THR), after controlling for the diameter of the patient's native femoral head. Based on a power analysis, 64 consecutive patients (68 hips) undergoing HR or THR were prospectively enrolled in the study. The following data were recorded intra-operatively: the diameter of the native femoral head, the largest reamer used, the final size of the acetabular component, the size of the prosthetic femoral head and whether a decision was made to increase the size of the acetabular component in order to accommodate a larger prosthetic femoral head. Results were compared using two-sided, independent samples Student's t-tests. A statistically significant difference was seen in the mean ratio of the size of the acetabular component to the diameter of the native femoral head (HR: 1.05 (SD 0.04) versus THR: 1.09 (SD 0.05); p < 0.001) and largest acetabular reamer used to the diameter of the native femoral head (HR: 1.03 (SD 0.04) versus THR: 1.09 (SD 0.05); p < 0.001). The ratios varied minimally when the groups were subdivided by gender, age and obesity. The decision to increase the size of the acetabular component to accommodate a larger femoral head occurred more often in the THR group (27% versus 9%). Despite the emphasis on avoiding damage to the femoral neck during HR, the ratio of the size of the acetabular component to the diameter of the native femoral head was larger in cementless THR than in HR.

Physical activity parenting: a systematic review of questionnaires and their associations with child activity levels.

Insufficient physical activity (PA) is considered a critical contributor to childhood overweight. Parents are a key in influencing their child's PA through various mechanisms of PA parenting, including support, restriction of PA and facilitation of enrolment in PA classes or activities. However, study findings are difficult to compare because instruments vary in terms of constructs, psychometric assessment and type of PA assessed. The goal of the current review was to identify existing PA parenting questionnaires and report on the validation of these measures through findings of their psychometric performance and correlation to youth's PA. The search of eligible studies was restricted to instruments with multiple items. Eleven unique PA parenting questionnaires were identified, and 46 studies that used these instruments were included. Extracted data include sample characteristics, as well as type and assessment methods of parental influence and PA. Findings highlight the tremendous variation in the conceptualization and measurement of PA parenting, common use of non-validated instruments and lack of comprehensive measures. The development of theory-based PA parenting measures (preferably multidimensional) should be prioritized to guide the study of the parental role in promoting child's PA as well as the design of family-based PA interventions.

A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture.

An 81-year-old woman presented with a fracture in the left femur. She had well-fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures.

Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning.

Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34(+) sorted cells and Wilms' tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n=84) or without (n=4) fludarabine 3 × 30 mg/m(2), followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34(+) sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34(+) DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82-91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34(+) DC kinetics. Monitoring of WT1 expression and CD34(+) DC predict relapse of AML and MDS after RIC-HCT.