Methodologies for data collection in congenital haemophilia with inhibitors (CHwI): critical assessment of the literature and lessons learned from recombinant factor VIIa.

AIMS: To systematically review the effectiveness of on-demand treatment with recombinant coagulation factor VIIa (rFVIIa) in congenital haemophilia with inhibitors and, if feasible, perform a meta-analysis of the data. MATERIALS AND METHODS: Publications from Embase® , MEDLINE® , MEDLINE® In-Process and the Cochrane Central Register of Controlled Trials were searched. Selected publications were reviewed for inclusion by two independent expert reviewers. Discrepancies were reconciled by a third independent reviewer. Data from selected studies were extracted using a predefined grid to ensure uniform and comparable results were captured. RESULTS: A systematic search (cut-off date of 2 May 2016) identified 20 studies (13 observational; seven randomized controlled trials). All studies were of sufficient quality to include in this analysis and comprised 1221 participants, with 5981 bleeds in 746 individuals treated with rFVIIa. Haemostatic overall effectiveness of the individual studies identified ranged from 68% to 100% at ≤12 hours, 86% to 96% at 13-24 hours and 76% to 99% at 24-48 hours with rFVIIa <100 µg/kg, with similar rates reported for the ≥250 µg/kg dose. However, heterogeneity between the studies precluded pooling of results. CONCLUSIONS: Data from the individual studies confirmed that rFVIIa is an effective therapy for the on-demand treatment of bleeds in congenital haemophilia with inhibitors. However, the high levels of heterogeneity between studies precluded pooling of results for a valid, reliable or precise summary measure. There remains a need to implement standardized clinical definitions and measurements for the effectiveness and safety of haemophilia therapies in future clinical trials.

Pain and Opioid Addiction: A Systematic Review and Evaluation of Pain Measurement in Patients with Opioid Dependence on Methadone Maintenance Treatment.

BACKGROUND: While chronic pain has been said to impact patient's response to methadone maintenance treatment for opioid dependence, the reported findings are inconsistent. These discrepancies may be a direct result of variations in the measurement of chronic pain or definitions of response to methadone treatment. The goal of this study is to evaluate the association between pain and substance use behaviour to determine the real impact of comorbid pain in the methadone population. We also aim to examine sources of variation across the literature with a specific focus on the measurement of pain. METHODS/DESIGN: We performed a systematic review using an electronic search strategy across CINAHL, MEDLINE, Web of Science, PsychINFO, EMBASE, and the Cochrane Library including Cochrane Reviews and the Cochrane Central Register of Controlled Trials databases. Title, abstract, as well as full text screening and extraction were performed in duplicate. Studies evaluating the association between chronic pain and methadone maintenance treatment response were eligible for inclusion in this review. Using a sample of 297 methadone patients from the Genetics of Opioid Addiction (GENOA) research collaborative, we assessed the reliability of patient self-reported pain and the validated Brief Pain Inventory (BPI) assessment tool. RESULTS: After screening 826 articles we identified five studies eligible for full text extraction, of which three showed a significant relationship between the presence of pain and the increase in substance abuse among patients on methadone for the treatment of opioid dependence. Studies varied largely in the definitions and measurement of both pain and response to treatment. Results from our validation of pain measurement in the GENOA sample (n=297) showed the use of a simple self-reported pain question is highly correlated to the use of the BPI. Simply asking patients whether they have pain showed a 44.2% sensitivity, 88.8% specificity, 84.4% PPV and 53.6% NPV to the BPI. The area under the ROC curve was 0.67 and the Pearson χ(2) was 37.3; (p<0.0001). DISCUSSION: The field of addiction medicine is at a lack of consensus as to the real effect of chronic pain on treatment response among opioid dependent patients. Whether it be the lack of a single "gold standard" measurement of response, or a lack of consistent measurement of pain, it is difficult to summarize and compare the results of these relatively small investigations. In comparison to the BPI, use of the simple self-reported pain has lower sensitivity for identifying patients with pain, suggesting the inconsistencies in these studies may result from differences in pain measurement. Future validation studies of pain measurement are required to address the predictive value of self-reported pain.

Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart failure.

OBJECTIVES: The purpose of this systematic review was to evaluate BNP and NT-proBNP to: (a) identify determinants, (b) establish their diagnostic performance in heart failure (HF) patients, (c) determine their predictive ability with respect to mortality and other cardiac endpoints, and (d) determine their value in monitoring HF treatment. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Central, and AMED from 1989 to February 2005 were searched for primary studies. REVIEW METHODS: Standard systematic review methodology, including meta-analysis, was employed. All study designs were included. Eligibility criteria included English-only studies and restricted the number of test methods to maximize generalizability. Outcomes for prognosis were limited to mortality and specific cardiac events. Further specific criteria were developed for each research question. RESULTS: Determinants: There were 103 determinants identified including age, gender, disease, treatment, as well as biochemical and physiological measures. Few studies reported independent associations and of those that did age, female gender and creatinine levels were positively associated with BNP and NT-proBNP. DIAGNOSIS: Pooled sensitivity and specificity values were 94 and 66 percent for BNP and 92 and 65 percent for NT-proBNP; there was minimal difference among settings (emergency, specialized clinics, and primary care). B-type natriuretic peptides also added independent diagnostic information above traditional measures for HF. PROGNOSIS: Both BNP and NT-proBNP were found to be independent predictors of mortality and other cardiac composite endpoints in patients with risk of coronary artery disease (CAD) (risk estimate range = 1.10 to 5.40), diagnosed CAD (risk estimate range = 1.50 to 3.00), and diagnosed HF patients (risk estimate range = 2.11 to 9.35). With respect to screening, the AUC values (range = 0.57 to 0.88) suggested poor performance. Monitoring Treatment: Studies showed therapy reduced BNP and NT-proBNP, however, relationship to outcome was limited and not consistent. CONCLUSIONS: Determinants: The importance of the identified determinants for clinical use is not clear. DIAGNOSIS: In all settings both BNP and NT-proBNP show good diagnostic properties as a rule out test for HF. PROGNOSIS: BNP and NT-proBNP are consistent independent predictors of mortality and other cardiac composite endpoints for populations with risk of CAD, diagnosed CAD, and diagnosed HF. There is insufficient evidence to determine the value of B-type natriuretic peptides for screening of HF. Monitoring Treatment: There is insufficient evidence to demonstrate that BNP and NT-proBNP levels show change in response to therapies to manage stable chronic HF patients.

Fluids and diuretics for acute ureteric colic.

BACKGROUND: Acute ureteric colic is a common cause of severe and debilitating pain. Theoretically, increasing fluid flow through the affected kidney might expedite stone passage, thereby improving symptoms more quickly. Unfortunately, for interventions such as high volume intravenous or oral fluids and diuretics that are aimed at doing this, the efficacy and safety is uncertain. OBJECTIVES: To look at the benefits and harms of diuretics and high volume (above maintenance) intravenous or oral fluid therapy for treating adult patients presenting with uncomplicated acute ureteric colic. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register (July 2004), the Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library, issue 3, 2004), MEDLINE (1966 - July 2004), EMBASE (1980 - July 2004) and handsearched reference lists of nephrology and urology textbooks, review articles, relevant trials, and abstracts from nephrology scientific meetings. We sent letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTS (including the first period of randomised cross-over studies) looking at diuretics or high volume intravenous or oral fluids for treating uncomplicated acute ureteric colic in adult patients presenting to the emergency department for the first time during that episode were to be included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes or weight mean difference (WMD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: One trial (60 participants) was identified. This study compared no fluids for six hours versus three litres of IV fluids received over a six hour period. There was no significant difference in pain at six hours (RR 1.06, 95% CI 0.71 to 1.57), surgical stone removal (RR 1.20, 95% CI 0.41 to 3.51) or manipulation by cystoscopy (RR 0.67, 95% CI 0.21 to 2.13). AUTHORS' CONCLUSIONS: Unfortunately, we could find no credible evidence in the literature regarding either of these two treatment modalities. Given their potential positive impact, the role of diuretics and high volume fluid therapy in acute ureteric colic should be examined to determine their safety and efficacy in facilitating stone passage.

Chondrocytic differentiation of mesenchymal stem cells sequentially exposed to transforming growth factor-beta1 in monolayer and insulin-like growth factor-I in a three-dimensional matrix.

This study evaluated chondrogenesis of mesenchymal progenitor stem cells (MSCs) cultured initially under pre-confluent monolayer conditions exposed to transforming growth factor-beta1 (TGF-beta1), and subsequently in three-dimensional cultures containing insulin-like growth factor I (IGF-I). Bone marrow aspirates and chondrocytes were obtained from horses and cultured in monolayer with 0 or 5 ng of TGF-beta 1 per ml of medium for 6 days. TGF-beta 1 treated and untreated cultures were distributed to three-dimensional fibrin disks containing 0 or 100 ng of IGF-I per ml of medium to establish four treatment groups. After 13 days, cultures were assessed by toluidine blue staining, collagen types I and II in situ hybridization and immunohistochemistry, proteoglycan production by [35S]-sulfate incorporation, and disk DNA content by fluorometry. Mesenchymal cells in monolayer cultures treated with TGF-beta1 actively proliferated for the first 4 days, developed cellular rounding, and formed cell clusters. Treated MSC cultures had a two-fold increase in medium proteoglycan content. Pretreatment of MSCs with TGF-beta1 followed by exposure of cells to IGF-I in three-dimensional culture significantly increased the formation of markers of chondrocytic function including disk proteoglycan content and procollagen type II mRNA production. However, proteoglycan and procollagen type II production by MSC's remained lower than parallel chondrocyte cultures. MSC pretreatment with TGF-beta1 without sequential IGF-I was less effective in initiating expression of markers of chondrogenesis. This study indicates that although MSC differentiation was less than complete when compared to mature chondrocytes, chondrogenesis was observed in IGF-I supplemented cultures, particularly when used in concert with TGF-beta1 pretreatment.

Measures of association: an overview with examples from Canadian emergency medicine research.

The authors of studies often report their results using abbreviated terms such as RR, OR, ARR, RRR and NNT. These terms are quantities that express the strength of association between the dependent and independent variables and are collectively referred to as measures of association. The similarity between these measures and the multiple terms by which each is referred can be confusing. The purpose of this article is to explain in a straightforward manner the purpose, derivation, and limitations of some of the more commonly used categorical measures of association, including relative risk, odds ratio, absolute and relative risk reduction and number needed to treat, using results from recent emergency medicine studies published by Canadian researchers.

Effect of transforming growth factor beta1 on chondrogenic differentiation of cultured equine mesenchymal stem cells.

OBJECTIVE: To determine the morphologic and phenotypic effects of transforming growth factor beta1 (TGFbeta1) on cultured equine mesenchymal stem cells (MSC) and articular chondrocytes. SAMPLE POPULATION: Bone marrow aspirates and articular cartilage samples from a 2-year-old and two 8-month-old horses. PROCEDURE: After initial isolation and culture, MSC and chondrocytes were cultured in Ham's F-12 medium supplemented with TGF-beta1 at a concentration of 0, 1, 5, or 10 ng/ml. Medium was exchanged on day 2, and cells were harvested on day 4. Medium was assayed for proteoglycan (PG) content. Total RNA was isolated from cell cultures, and expression of aggrecan, decrin, collagen type-I, and collagen type-II mRNA was assessed by means of Northern blot analyses. Cell cultures were stained with H&E or toluidine blue and examined histologically. Additional cultures were examined after immunohistochemical staining for type-I and -II collagen. RESULTS: MSC cultures exposed to TGF-beta1 had an increased cellular density with cell layering and nodule formation that was most pronounced in cultures treated with 5 ng of TGF-beta1/ml. Expression of collagen type-II mRNA in MSC cultures exposed to 5 ng of TGF-beta1/ml was 1.7 times expression in control cultures, and expression of collagen type-I mRNA was 2.8 times expression in control cultures. Treatment of MSC with TGF-beta1 led to dose-related increases in area and intensity of type-II collagen immunoreaction. CONCLUSION: Results suggest that TGF-beta1 enhances chondrogenic differentiation of bone marrow-derived MSC in a dose-dependent manner.

Pythiosis with bone lesions in a pregnant mare.

A 9-year-old pregnant mare was referred for evaluation of a nonhealing wound of 8 weeks' duration on the lateral aspect of the left forelimb. A soft tissue mass encircled the proximal two thirds of the metacarpus; radiography revealed a moderate periosteal reaction affecting metacarpal bone i.v. Histologic and immunohistochemical examinations revealed eosinophilic granulomatous inflammation and Pythium sp in the soft tissues. The mare was treated for 12 days with antimicrobials, medicated wound dressings, debridement, and i.v. administration of sodium iodide; radiography revealed progression of the bone lesions. The mare was treated by regional arterial perfusion with miconazole and excision of affected soft tissues and the distal two thirds of metacarpal bone i.v. The mare recovered without complications and gave birth to a healthy foal. Regional perfusion of antifungal agents provides high concentrations in soft and osseous tissues and permits use of low dosages of agents administered by other routes, which reduces cost, adverse effects, and teratogenic effects.

Effects of external thermal manipulation on laminar temperature and perfusion scintigraphy of the equine digit.

AIMS: To assess the effects of external thermal manipulation on the soft-tissue and vascular perfusion of the equine digit using nuclear scintigraphy and documented tissue temperatures. METHODS: Six horses were used in a randomised crossover design. Each horse was treated with external heat (47 degrees C) or external cold (4 degrees C) applied to a digit for 30 minutes. The opposite front foot was untreated and used for control measurements. Nuclear scintigraphy was performed before, during, and after therapy to assess vascular and soft-tissue perfusion to the digit in response to therapy. Dorsal hoof wall laminar-tissue temperatures were recorded before, during, and after therapy using a thermistor. RESULTS: Treatment with topical cold therapy significantly decreased soft-tissue perfusion of the digit to 80.5% of the pre-cooled values. Conversely, the application of external heat significantly increased soft-tissue perfusion of the digit 25.1% above the pre-heated values. Vascular perfusion showed similar, but not statistically significant trends. External cold application to the digit caused a significant mean decrease in laminar-tissue temperatures of 11.6 degrees C during therapy, while external heat application to the digit caused a significant mean increase in laminar-tissue temperatures of 3.9 degrees C. CONCLUSION: The external application of heat and cold to the normal equine foot could effectively alter soft-tissue perfusion and laminar-tissue temperatures within 30 minutes of treatment. The application of hot water and ice water to the digit was a safe, well-tolerated, and economical therapy. CLINICAL RELEVANCE: Cooling the foot could decrease enzymatic reactions associated with laminitis, and warming could increase local perfusion when desired.

Alteration in adrenocortical function in horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively.

OBJECTIVE: To determine alteration in adrenocortical function in horses with recurrent airway obstruction (heaves) after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively. ANIMALS: 6 horses with inducible and reversible heaves. PROCEDURE: Episodes of heaves were induced by exposure to moldy hay and straw for 7 days (natural challenge). Horses then underwent treatment (aerosolized beclomethasone, parenterally administered dexamethasone, and aerosolized propellant) for 7 days. Horses remained in the mold-contaminated environment for 7 days after discontinuation of drugs. Adrenocortical function was determine by serial evaluation of cortisol concentration in serum obtained on days 0, 7, 9, 12, 14, 16, 19, and 21. Adrenocorticotropic hormone stimulation testing was performed in 4 horses/treatment group on days 0, 7, 14, and 21. RESULTS: Endogenous cortisol production was suppressed in beclomethasone- and dexamethasone-treated horses within 2 days of treatment but recovered to values similar to those in propellant-treated horses approximately 2 and 4 days after discontinuation of drugs. Serum cortisol concentration in propellant-treated horses gradually decreased during the study and was significantly lower than baseline on days 14, 16, 19, and 21. Mean increase in serum cortisol concentration in response to ACTH stimulation testing after beclomethasone and dexamethasone administration did not differ significantly from the response observed in propellant-treated horses. CONCLUSIONS: Aerosol and parenteral administration of beclomethasone and dexamethasone, respectively, suppressed adrenocortical function; however, endogenous cortisol production resumed approximately 2 and 4 days after discontinuation of drugs. Responsiveness to ACTH stimulation testing was not affected by the 7-day treatment period.

Willingness to follow breast cancer. Survey of family physicians.

OBJECTIVE: To identify the experience and willingness of family physicians to accept follow-up care of patients treated for stage I breast cancer. DESIGN: Mailed questionnaire. PARTICIPANTS: One hundred eighty-nine family physicians in southwestern Ontario with oversampling of female physicians and physicians practising more than 20 km from a cancer clinic. MAIN OUTCOME MEASURE: Willingness to follow breast cancer patients and time after treatment family physicians would be willing to begin follow-up care. RESULTS: We had an 81.5% response rate. Of the 154 respondents, 53% had been involved previously in the 5-year, follow-up care of a patient with breast cancer and 77.1% believed it appropriate for family physicians to assume responsibility for follow-up care in all or most cases. If asked by a patient, the family, or an oncologist to provide follow-up care, 90.1% of family physicians reported they would accept this responsibility. Willingness to follow breast cancer patients was not associated with sex, years in practice, proximity to a cancer clinic, or certification status but was associated with having previously provided such care (P = .043). Of those willing to care for these patients, almost 90% would prefer to start within 1 year of treatment. CONCLUSION: Although only half the respondents had experience in providing follow-up care to breast cancer patients, most were willing to take on this role, especially if asked.

Who provides follow-up care for patients with early breast cancer?

OBJECTIVE: To assess how often family physicians are involved in posttreatment care of their stage I breast cancer patients and to identify factors associated with family physicians providing follow-up care. DESIGN: A retrospective cohort study with a 5-year follow up by chart review. PARTICIPANTS: All cases of breast cancer seen at the London Regional Cancer Centre between 1982 and 1987 were reviewed to identify 183 stage I cancer patients alive at 5 years. MAIN OUTCOME MEASURES: Whether a physician (other than an oncologist) was involved in the follow-up care of patients, and whether the physician was a family physician or a surgeon. RESULTS: Follow-up care during the 5-year postoperative period was provided in most cases by oncologists alone (66.7%); family physicians and surgeons were involved in 17.5% and 15.8% of cases, respectively. Surgeons became involved in follow-up care much earlier (12 months) than family physicians did (23 months) (P = 0.01) and were more likely to provide care for patients who received radiation treatment (P = 0.04) and for patients who lived in London (P = 0.004). Most malignant breast lesions (77.5%) were discovered by patients themselves (P = 0.0001). CONCLUSIONS: Currently, family physicians are infrequently involved in follow-up care of their patients with early breast cancer.

Cholangiographic appearances of ductular rejection of ABO-incompatible liver transplants.

Two patients, after ABO-incompatible liver transplant, developed a picture of chronic cholestasis that was associated with unique ductular appearances within the donor graft on retrograde cholangiography. We believe that the appearance of progressive ductular ectasia within liver grafts indicates a specific immunologically mediated injury to ductular epithelium, probably because of ductular epithelial expression of ABH antigens.