MR Imaging of Pediatric Low-Grade Gliomas: Pretherapeutic Differentiation of BRAF V600E Mutation, BRAF Fusion, and Wild-Type Tumors in Patients without Neurofibromatosis-1.

BACKGROUND AND PURPOSE: The prognosis and treatment of pediatric low-grade gliomas is influenced by their molecular subtype. MR imaging remains the mainstay for initial work-up and surgical planning. We aimed to determine the relationship between imaging patterns and molecular subtypes of pediatric low-grade gliomas. MATERIALS AND METHODS: This was a retrospective bi-institutional study for patients diagnosed from 2004 to 2021 with pathologically confirmed pediatric low-grade gliomas molecularly defined as BRAF fusion, BRAF V600E mutant, or wild-type (which is neither BRAF V600E mutant nor BRAF fusion). Two neuroradiologists, blinded, independently reviewed imaging parameters from diagnostic MRIs, and discrepancies were resolved by consensus. Bivariate analysis was used followed by pair-wise comparison of the Dwass-Steel-Critchlow-Fligner method to compare the 3 molecular subtypes. Interreader agreement was assessed using κ. RESULTS: We included 70 patients: 30 BRAF fusion, 19 BRAF V600E mutant, and 21 wild-type. There was substantial agreement between the readers for overall imaging variables (κ = 0.75). BRAF fusion tumors compared with BRAF V600E and wild-type tumors were larger (P = .0022), and had a greater mass effect (P = .0053), increased frequency of hydrocephalus (P = .0002), and diffuse enhancement (p <.0001). BRAF V600E mutant tumors were more often hemispheric (P < .0001), appeared more infiltrative (P = .0002), and, though infrequent, were the only group demonstrating diffusion restriction (qualitatively; P = .0042) with a lower ADC ratio (quantitatively) (P = .003). CONCLUSIONS: BRAF fusion and BRAF V600E mutant pediatric low-grade gliomas have unique imaging features that can be used to differentiate them from each other and wild-type pediatric low-grade glioma using a standard radiology review with high interreader agreement. In the era of targeted therapy, these features can be useful for therapeutic planning before surgery.

Changes in primary care provider utilization by phase of care for women diagnosed with breast cancer: a CanIMPACT longitudinal cohort study.

BACKGROUND: Primary care providers (PCPs) have always played an important role in cancer diagnosis. There is increasing awareness of the importance of their role during treatment and survivorship. We examined changes in PCP utilization from pre-diagnosis to survival for women diagnosed with breast cancer, factors associated with being a high user of primary care, and variation across four Canadian provinces. METHODS: The cohorts included women 18+ years of age diagnosed with stage I-III invasive breast cancer in years 2007-2012 in British Columbia (BC), Manitoba (MB), Ontario (ON), and Nova Scotia (NS) who had surgery plus adjuvant chemotherapy and were alive 30+ months after diagnosis (N = 19,589). We compared the rate of PCP visits in each province across phases of care (pre-diagnosis, diagnosis, treatment, and survival years 1 to 4). RESULTS: PCP use was greatest during treatment and decreased with each successive survival year in all provinces. The unadjusted difference in PCP use between treatment and pre-diagnosis was most pronounced in BC where PCP use was six times higher during treatment than pre-diagnosis. Factors associated with being a high user of primary care during treatment included comorbidity and being a high user of care pre-diagnosis in all provinces. These factors were also associated with being a higher user of care during diagnosis and survival. CONCLUSIONS: Contrary to the traditional view that PCPs focus primarily on cancer prevention and early detection, we found that PCPs are involved in the care of women diagnosed with breast cancer across all phases of care.

Improving care for elderly patients living with polypharmacy: protocol for a pragmatic cluster randomized trial in community-based primary care practices in Canada.

BACKGROUND: Elders living with polypharmacy may be taking medications that do not benefit them. Polypharmacy can be associated with elevated risks of poor health, reduced quality of life, high care costs, and persistently complex care needs. While many medications could be problematic, this project targets medications that should be deprescribed for most elders and for which guidelines and evidence-based deprescribing tools are available. These are termed potentially inappropriate prescriptions (PIPs) and are as follows: proton pump inhibitors, benzodiazepines, antipsychotics, and sulfonylureas. Implementation strategies for deprescribing PIPs in complex older patient populations are needed. METHODS: This will be a pragmatic cluster randomized controlled trial in community-based primary care practices across Canada. Eligible practices provide comprehensive primary care and have at least one physician that consents to participate. Community-dwelling patients aged 65 years and older with ten or more unique medication prescriptions in the past year will be included. The objective is to assess whether the intervention reduces targeted PIPs for these patients compared with usual care. The intervention, Structured Process Informed by Data, Evidence and Research (SPIDER), is a collaboration between quality improvement (QI) and research programs. Primary care teams will form interprofessional Learning Collaboratives and work with QI coaches to review electronic medical record data provided by their regional Practice Based Research Networks (PBRNs), identify areas of improvement, and develop and implement changes. The study will be tested for feasibility in three PBRNs (Toronto, Montreal, and Edmonton) using prospective single-arm mixed methods. Findings will then guide a pragmatic cluster randomized controlled trial in five PBRNs (Calgary, Winnipeg, Ottawa, Montreal, and Halifax). Seven practices per PBRN will be recruited for each arm. The analysis will be by intention to treat. Ten percent of patients who have at least one PIP at baseline will be randomly selected to participate in the assessment of patient experience and self-reported outcomes. Qualitative methods will be used to explore patient and physician experience and evaluate SPIDER's processes. CONCLUSION: We are testing SPIDER in a primary care population with complex care needs. This could provide a widely applicable model for care improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03689049 ; registered September 28, 2018.

Disparities in breast cancer diagnosis for immigrant women in Ontario and BC: results from the CanIMPACT study.

BACKGROUND: In Canada, clinical practice guidelines recommend breast cancer screening, but there are gaps in adherence to recommendations for screening, particularly among certain hard-to-reach populations, that may differ by province. We compared stage of diagnosis, proportion of screen-detected breast cancers, and length of diagnostic interval for immigrant women versus long-term residents of BC and Ontario. METHODS: We conducted a retrospective cohort study using linked administrative databases in BC and Ontario. We identified all women residing in either province who were diagnosed with incident invasive breast cancer between 2007 and 2011, and determined who was foreign-born using the Immigration Refugee and Citizenship Canada database. We used descriptive statistics and bivariate analyses to describe the sample and study outcomes. We conducted multivariate analyses (modified Poisson regression and quantile regression) to control for potential confounders. RESULTS: There were 14,198 BC women and 46,952 Ontario women included in the study population, of which 11.8 and 11.7% were foreign-born respectively. In both provinces, immigrants and long-term residents had similar primary care access. In both provinces, immigrant women were significantly less likely to have a screen-detected breast cancer (adjusted relative risk 0.88 [0.79-0.96] in BC, 0.88 [0.84-0.93] in Ontario) and had a significantly longer median diagnostic interval (2 [0.2-3.8] days in BC, 5.5 [4.4-6.6] days in Ontario) than long-term residents. Women from East Asia and the Pacific were less likely to have a screen-detected cancer and had a longer diagnostic interval, but were diagnosed at an earlier stage than long-term residents. In Ontario, women from Latin America and the Caribbean and from South Asia were less likely to have a screen-detected cancer, had a longer median diagnostic interval, and were diagnosed at a later stage than long-term residents. These findings were not explained by access to primary care. CONCLUSIONS: There are inequalities in breast cancer diagnosis for Canadian immigrant women. We have identified particular immigrant groups (women from Latin America and the Caribbean and from South Asia) that appear to be subject to disparities in the diagnostic process that need to be addressed in order to effectively reduce gaps in care.

Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis.

PURPOSE: Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence. METHODS: Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients. RESULTS: In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients. CONCLUSIONS: Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.

Practice patterns in the care of acute Achilles tendon ruptures : is there an association with level I evidence?

AIMS: To determine whether the findings from a landmark Canadian trial assessing the optimal management of acute rupture of the Achilles tendon influenced the practice patterns of orthopaedic surgeons in Ontario, Canada. MATERIALS AND METHODS: Health administrative databases were used to identify Ontario residents ≥ 18 years of age with an Achilles tendon rupture from April 2002 to March 2014. The rate of surgical repair (per 100 cases) was calculated for each calendar quarter. A time-series analysis was used to determine whether changes in the rate were chronologically related to the dissemination of results from a landmark trial published in February 2009. Non-linear spline regression was then used independently to identify critical time-points of change in the surgical repair rate to confirm the findings. RESULTS: A total of 29 531 patients sustained an Achilles tendon rupture during the study period. Consistently, around 21 out of every 100 cases underwent surgical repair up to the first quarter of 2010. However, by the first quarter of 2014, only 6.5 cases per 100 had surgery. A statistically significant decrease in the rate of surgical repair was observed within one year of the presentation of landmark trial results in 2009 (p < 0.001). July 2009 was independently identified as a critical time at which the surgical repair rate began to significantly decline (p < 0.001). The dissemination of trial results was associated with a significant drop in the rate of surgical repair at non-teaching hospitals (p = 0.001). CONCLUSION: The current study demonstrates that large, well-designed randomised trials, have the potential to encourage significant changes in the practice patterns of orthopaedic surgeons. Cite this article: Bone Joint J 2017;99-B:1629-36.

A population-based assessment of primary care visits during adjuvant chemotherapy for breast cancer.

BACKGROUND: We used administrative health data to explore the impact of primary care physician (pcp) visits on acute-care service utilization by women receiving adjuvant chemotherapy for early-stage breast cancer (ebc). METHODS: Our population-based retrospective cohort study examined pcp visits and acute-care use [defined as an emergency room (er) visit or hospitalization] by women diagnosed with ebc between 2007 and 2009 and treated with adjuvant chemotherapy. Multivariate regression analysis was used to identify the effect of pcp visits on the likelihood of experiencing an acute-care visit. RESULTS: Patients receiving chemotherapy visited a pcp significantly more frequently than they had before their diagnosis [relative risk (rr): 1.48; 95% confidence interval (ci): 1.44 to 1.53; p < 0.001] and significantly more frequently than control subjects without cancer (rr: 1.51; 95% ci: 1.46 to 1.57; p < 0.001). More than one third of pcp visits by chemotherapy patients were related to breast cancer or chemotherapy-related side effects. In adjusted multivariate analyses, the likelihood of experiencing an er visit or hospitalization increased in the days immediately after a pcp visit (rr: 1.92; 95% ci: 1.76 to 2.10; p < 0.001). CONCLUSIONS: During chemotherapy treatment, patients visited their pcp more frequently than control subjects did, and they visited for reasons related to their breast cancer or to chemotherapy-related side effects. Visits to a pcp by patients receiving chemotherapy were associated with an increased frequency of er visits or hospitalizations in the days immediately after the pcp visit. Those results suggest an opportunity to institute measures for early detection and intervention in chemotherapy side effects.

Multigene expression profile testing in breast cancer: is there a role for family physicians?

BACKGROUND: Family physicians (fps) play a role in aspects of personalized medicine in cancer, including assessment of increased risk because of family history. Little is known about the potential role of fps in supporting cancer patients who undergo tumour gene expression profile (gep) testing. METHODS: We conducted a mixed-methods study with qualitative and quantitative components. Qualitative data from focus groups and interviews with fps and cancer specialists about the role of fps in breast cancer gep testing were obtained during studies conducted within the pan-Canadian canimpact research program. We determined the number of visits by breast cancer patients to a fp between the first medical oncology visit and the start of chemotherapy, a period when patients might be considering results of gep testing. RESULTS: The fps and cancer specialists felt that ordering gep tests and explaining the results was the role of the oncologist. A new fp role was identified relating to the fp-patient relationship: supporting patients in making adjuvant therapy decisions informed by gep tests by considering the patient's comorbid conditions, social situation, and preferences. Lack of fp knowledge and resources, and challenges in fp-oncologist communication were seen as significant barriers to that role. Between 28% and 38% of patients visited a fp between the first oncology visit and the start of chemotherapy. CONCLUSIONS: Our findings suggest an emerging role for fps in supporting patients who are making adjuvant treatment decisions after receiving the results of gep testing. For success in this new role, education and point-of-care tools, together with more effective communication strategies between fps and oncologists, are needed.

The epidemiology and trends in management of acute Achilles tendon ruptures in Ontario, Canada: a population-based study of 27 607 patients.

AIMS: The aims of this study were to establish the incidence of acute Achilles tendon rupture (AATR) in a North American population, to select demographic subgroups and to examine trends in the management of this injury in the province of Ontario, Canada. PATIENTS AND METHODS: Patients ≥ 18 years of age who presented with an AATR to an emergency department in Ontario, Canada between 1 January 2003 and 31 December 2013 were identified using administrative databases. The overall and annual incidence density rate (IDR) of AATR were calculated for all demographic subgroups. The annual rate of surgical repair was also calculated and compared between demographic subgroups. RESULTS: A total of 27 607 patients (median age, 44 years; interquartile range 26 to 62; 66.5% male) sustained an AATR. The annual IDR increased from 18.0 to 29.3 per 100 000 person-years between 2003 and 2013. The mean IDR was highest among men between the ages of 40 and 49 years (46.0/100 000 person-years). The annual rate of surgical repair dropped from 20.1 in 2003 to 9.2 per 100 AATRs in 2013. There was a noticeable decline after 2009. CONCLUSION: The incidence of AATR is increasing in Ontario, while the annual rate of surgical repair is decreasing. A sharp decline in the rate of surgical repair was noted after 2009. This coincided with the publication of several high-quality RCTs which showed similar outcomes for the 'functional' non-operative management and surgical repair. Cite this article: Bone Joint J 2017;99-B:78-86.

Pilot study on 18 F-FDG PET/CT for detection of inflammatory changes in blood-induced knee arthropathy in a rabbit model.

RATIONALE: 18 F-FDG-PET/CT has a potential role in the early detection of haemophilic arthritis, at a time when treatment may still avoid further joint degeneration. The purposes of this pilot study were to determine the ability of 18 F-FDG-PET/CT to detect inflammatory changes associated with blood-induced arthropathy in knees of a rabbit model. METHODS: Ten juvenile rabbits were imaged at baseline and weeks 5 and 17 post intraarticular autologous blood injections (ABI). Five rabbits in group 1 (G1) had ABI into the same knee joint every 2 weeks (total, eight injections). Five rabbits in group 2 (G2) had only two injections into the same knee, at weeks 5 and 17. Images were assessed visually and semi-quantitatively by measuring maximal standardized uptake values (SUVmax) and standardized uptake ratio (SUR = SUVmax in affected knee/SUVmax in non-affected knee). RESULTS: More rabbits in G1 than G2 presented with positive chronic inflammatory synovial scores at week 17. Mean iron staining scores in injected knees were greater for G1 than for G2 (P = 0.049). No increased uptake was identified in the injected knees in any of the rabbits at baseline or at week 5. At week 17, all G1 rabbits demonstrated increased uptake in their affected knees with higher mean SUVmax (1.5) than normal knees (1.0) (P < 0.02). None of the G2 rabbits showed asymmetric increased uptake. The SUR of G1 was higher at week 17 compared to baseline (P < 0.01) and week 5 (P < 0.01). The SUR at week 17 was higher for G1 than for G2 (1.13) rabbits (P < 0.01). CONCLUSION: 18 F-FDG-PET is able to detect the inflammatory changes associated with haemophilic arthropathy in this experimental model.

The value of 18F-FDG PET in pediatric patients with post-transplant lymphoproliferative disorder at initial diagnosis.

PTLD is a serious complication of both solid organ and BMT. This study assessed whether (18) F-FDG PET, when added to CT scan, had additional value in the initial evaluation of PTLD in pediatric patients and whether PET/CT at baseline can reliably guide biopsy. This retrospective study evaluated 34 consecutive pediatric patients (14 female), aged 3.5-17.0 yr (mean age: 9.9 yr, s.d.: 4.9 yr), who had undergone (18) F-FDG PET/CT from May 2007 to December 2014 at initial diagnosis of PTLD following heart (n = 13), lung (n = 8), kidney (n = 4), liver (n = 3), liver and bowel (n = 3), and bone marrow (n = 3) transplantation. PTLD was diagnosed histopathologically in 33 patients and was based on clinical findings, elevated EBV, and imaging and follow-up results in one patient. On lesion-based analysis, (18) F-FDG PET showed more lesions than conventional CT scan (168 vs. 134), but CT revealed 22 lesions negative on PET. On per patient analysis, PET detected more lesions in 13 patients, CT identified more abnormalities in seven, and both showed the same number of lesions in 14. Adding (18) F-FDG PET to CT scans upstaged the disease in seven patients (20.5%). A combination of (18) F-FDG PET and CT was also useful in guiding biopsy, being positive in 36 of 39 samples (92.3%). These findings indicated that (18) F-FDG PET and CT are complementary at initial staging of pediatric PTLD and that (18) F-FDG PET/CT scanning can guide biopsies.

Longitudinal assessment of bone loss using quantitative ultrasound in a blood-induced arthritis rabbit model.

INTRODUCTION: Osteoporosis is common in haemophilic arthropathy. Quantitative ultrasound (QUS) can be a suitable alternative for dual-energy x-ray absorptiometry for diagnosing osteoporosis in haemophiliacs due to its lack of ionizing radiation, and ease to use. AIM: We investigated the intra- and inter-operator reliability of QUS, its responsiveness to bone growth, its ability to differentiate bone adjacent to blood-injected vs. control joints, and the effect of soft tissues on the speed of sound (SOS) QUS values in a juvenile white New Zealand rabbit model of blood-induced arthritis. METHODS: Eight of 16 rabbits were injected with autologous blood (0.1 mL kg(-1) ) 8 times over a 17-week period, the remaining eight rabbits served as controls. SOS was measured at baseline, weeks 8 and 17 in vivo and after the bones were excised on week 17. RESULTS: Intra- and inter-operator coefficients of variation for QUS data were <5% and intraclass correlation coefficients were >60% for 22/27 (81.5%) of bones assessed. The level of interval increase in SOS values from baseline to week 17 was significantly different in tibiae of injected, contralateral to injected and non-injected knee groups by anova (P = 0.01). In vivo (mean ± SD, 4147.17 ± 96.27 m s(-1) ) and postmortem (4457.85 ± 104.00 m s(-1) ) measurements on week 17 differed (P < 0.01) indicating an effect of soft tissues on SOS. CONCLUSION: In conclusion, QUS' acceptable reliability, its responsiveness to growth-related changes and its ability to discriminate injected and non-injected joints make this technique a plausible candidate as a diagnostic tool for osteoporosis in the paediatric haemophilic population if these results are confirmed upon animal-human translation.

Effect of specialized diagnostic assessment units on the time to diagnosis in screen-detected breast cancer patients.

BACKGROUND: The duration of the cancer diagnostic process has considerable influence on patients' psychosocial well-being. Breast diagnostic assessment units (DAUs) in Ontario, Canada are designed to improve the quality and timeliness of care during a breast cancer diagnosis. We compared the diagnostic duration of patients diagnosed through a DAU vs usual care (UC). METHODS: Retrospective population-based cohort study of 2499 screen-detected breast cancers (2011) using administrative health-care databases linked to the Ontario Cancer Registry. The diagnostic interval was measured from the initial screen to cancer diagnosis. Diagnostic assessment unit use was based on the biopsy and/or surgery hospital. We compared the length of the diagnostic interval between the DAU groups using multivariable quantile regression. RESULTS: Diagnostic assessment units had a higher proportion of patients diagnosed within the 7-week target compared with UC (79.1% vs 70.2%, P<0.001). The median time to diagnosis at DAUs was 26 days, which was 9 days shorter compared with UC (95% CI: 6.4-11.6). This effect was reduced to 8.3 days after adjusting for all study covariates. Adjusted DAU differences were similar at the 75th and 90th percentiles of the diagnostic interval distribution. CONCLUSIONS: Diagnosis through an Ontario DAU was associated with a reduced time to diagnosis for screen-detected breast cancer patients, which likely reduces the anxiety and distress associated with waiting for a diagnosis.

Ultrasound and magnetic resonance imaging of healthy paediatric ankles and knees: a baseline for comparison with haemophilic joints.

The study was undertaken to document cartilage and soft tissue changes/findings in ankles and knees of normal children of different age groups to be used for comparison in the assessment of children with haemophilia. Cartilage thickness and soft tissue changes were recorded at predetermined sites of ankles/knees on both US and MRI in healthy boys in three age groups: 7-9; 10-14; and 15-18 years. To assess the validity of the ultrasound and MRI measurements, an ex vivo study was done using agar phantoms with techniques and scanners similar to those applied in vivo. Twenty (48%) knees and 22 (52%) ankles of 42 boys, were evaluated. There was a reduction in the thickness of joint cartilage with age. A difference in cartilage measurements was noted in most sites between the age groups on both US and MRI (P < 0.05 each), but such difference was not noted for joint fluid in ankles or knees (P = 0.20, P = 0.68 or P = 0.75, P = 0.63 for US, MRI, respectively). Although cartilage measurements were smaller on US than on MRI for both ankles and knees (P < 0.05 each), this observation was not recorded for fluid in knees (P = 0.02). For diminutive measurements (2 mm) mean US measurements were smaller than corresponding phantom's measurements, P = 0.02. Age-related measurements were noted for cartilage thickness on US and MRI in ankles and knees. US measurements were smaller than corresponding MRI measurements at most joint sites, which were supported by results on small-diameter phantoms.

USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood-induced arthritis: a pilot study.

Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 µmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post-USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation.

Bone healing and the effect of implant surface topography on osteoconduction in hyperglycemia.

Dental implant failures that occur clinically for unknown reasons could be related to undiagnosed hyperglycemia. The exact mechanisms that underlie such failures are not known, but there is a general consensus that bone growth is compromised in hyperglycemia. Nevertheless, contradictory findings exist related to peri-implant bone healing in hyperglycemia. We hypothesized that hyperglycemia delays early bone healing by impeding osteoconduction, and that the compromised implant integration due to hyperglycemia could be abrogated by using nanotopographically complex implants. Thus we undertook two parallel experiments, an osteotomy model and a bone in-growth chamber model. The osteotomy model tracked temporal bone healing in the femora of euglycemic and hyperglycemic rats using micro computed tomography (microCT) analysis and histology. The bone in-growth chamber model used implant surfaces of either micro- or nanotopographical complexity and measured bone-implant contact (BIC) using backscattered electron imaging in both metabolic groups. Quantitative microCT analyses on bone volume, trabeculae number and trabeculae connectivity density provided clear evidence that bone healing, both reparative trabecular bone formation and remodeling, was delayed in hyperglycemia, and the reparative bone volume changed with time between metabolic groups. Furthermore, fluorochrome labeling showed evidently less mineralized bone in hyperglycemic than euglycemic animals. An increased probability of osteoconduction was seen on nano-compared with microtopographically complex surfaces, independent of metabolic group. The nanotopographically complex surfaces in hyperglycemia outperformed microtopographically complex surfaces in euglycemic animals. In conclusion, the compromised implant integration in hyperglycemia is abrogated by the addition of nanotopographical features to an underlying microtopographically complex implant surface.

Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada.

BACKGROUND/OBJECTIVES: Tailored primary prophylaxis (TPP) is a reduced-intensity treatment program for hemophiliacs with the goal of preventing arthropathy. Our primary aim was to evaluate the joint outcomes of treated subjects using magnetic resonance imaging (MRI) and physical examination as outcome measures. METHODS: Ankles, elbows and knees (index joints) of 24 subjects (median [range] age at start of therapy, 1.6 [1-2.5] years) with severe hemophilia A enrolled in the Canadian Hemophilia Primary Prophylaxis Study (CHPS) were examined by MRI at a median age of 8.8 years (range 6.2-11.5 years). Subjects were treated with TPP using a recombinant factor VIII concentrate, starting once weekly and escalating in frequency and dose according to frequency of bleeding. RESULTS: Osteochondral changes (cartilage loss/subchondral bone damage) were detected in 9% (13/140) of the index joints and 50% (12/24) of study subjects. Osteochondral changes were restricted to joints with a history of clinically reported joint bleeding. Soft tissue changes were detected in 31% (20/65) of index joints with no history of clinically reported bleeding (ankles 75% (12/16); elbows 19% (6/32); and knees 12% (2/17)). In these apparently 'bleed free' index joints hemosiderin deposition was detected by MRI in 26% (17/65) of joints (ankles 63% (10/16); elbows 16% (5/32), and knees 12% (2/17)). CONCLUSION: TPP did not completely avoid the development of MRI-detected structural joint changes in hemophilic boys in this prospective study. A longer period of follow-up is required for assessment of the longitudinal course of these early changes in hemophilic arthropathy, detected using a sensitive imaging technique (MRI).

An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group.

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria.

AIMS: Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation. METHODS: Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups. RESULTS: At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01). CONCLUSIONS: Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Immigrants' duration of residence and adverse birth outcomes: a population-based study.

OBJECTIVE: This study aimed to examine preterm and small-for-gestational-age (SGA) births among immigrants, by duration of residence, and to compare them with the Canadian-born population. DESIGN: Population-based cross-sectional study with retrospective assessment of immigration. SETTING: Metropolitan areas of Ontario, Canada. POPULATION: A total of 83 233 singleton newborns born to immigrant mothers and 314 237 newborns born to non-immigrant mothers. METHODS: We linked a database of immigrants acquiring permanent residence in Ontario, Canada, in the period 1985-2000 with mother-infant hospital records (2002-2007). Duration of residence was measured as completed years from arrival to Canada to delivery/birth. Logistic regression models were used to estimate the effects of duration of residence with adjusted odds ratios and 95% confidence intervals. In analyses restricted to immigrants only, hierarchical models were used to account for the clustering of births into maternal countries of birth. MAIN OUTCOME MEASURES: Preterm birth (PTB) and SGA birth. RESULTS: Recent immigrants (<5 years) had a lower risk of PTB (4.7%) than non-immigrants (6.2%), but those with > or =15 years of stay were at higher risk (7.4%). Among immigrants, a 5-year increase in Canadian residence was associated with an increase in PTB (AOR 1.14, 95% CI 1.10-1.19), but not in SGA birth (AOR 0.99, 95% CI 0.96-1.02). CONCLUSIONS: Time since migration was associated with increases in the risk of PTB, but was not associated with an increase in SGA births. Ignoring duration of residence may mask important disparities in preterm delivery between immigrants and non-immigrants, and between immigrant subgroups categorised by their duration of residence.