Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.

Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI: Composite Scores for Longitudinal and Cross-sectional Analysis.

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials. METHODS: Participants aged 18-65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0-5), and ≥1 short tau inversion recovery-positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4-12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed. RESULTS: Seventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36-85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = -0.71, ρ = -0.53; right arm: ρ = -0.61, ρ = -0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF <0.50) than in normal (MFI <0.10, MFF <0.50) muscles. DISCUSSION: We developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.

Quantitative muscle analysis in facioscapulohumeral muscular dystrophy using whole-body fat-referenced MRI: Protocol development, multicenter feasibility, and repeatability.

INTRODUCTION/AIMS: Functional performance tests are the gold standard to assess disease progression and treatment effects in neuromuscular disorders. These tests can be confounded by motivation, pain, fatigue, and learning effects, increasing variability and decreasing sensitivity to disease progression, limiting efficacy assessment in clinical trials with small sample sizes. We aimed to develop and validate a quantitative and objective method to measure skeletal muscle volume and fat content based on whole-body fat-referenced magnetic resonance imaging (MRI) for use in multisite clinical trials. METHODS: Subjects aged 18 to 65 years, genetically confirmed facioscapulohumeral muscular dystrophy 1 (FSHD1), clinical severity 2 to 4 (Ricci's scale, range 0-5), were enrolled at six sites and imaged twice 4-12 weeks apart with T1-weighted two-point Dixon MRI covering the torso and upper and lower extremities. Thirty-six muscles were volumetrically segmented using semi-automatic multi-atlas-based segmentation. Muscle fat fraction (MFF), muscle fat infiltration (MFI), and lean muscle volume (LMV) were quantified for each muscle using fat-referenced quantification. RESULTS: Seventeen patients (mean age ± SD, 49.4 years ±13.02; 12 men) were enrolled. Within-patient SD ranged from 1.00% to 3.51% for MFF and 0.40% to 1.48% for MFI in individual muscles. For LMV, coefficients of variation ranged from 2.7% to 11.7%. For the composite score average of all muscles, observed SDs were 0.70% and 0.32% for MFF and MFI, respectively; composite LMV coefficient of variation was 2.0%. DISCUSSION: We developed and validated a method for measuring skeletal muscle volume and fat content for use in multisite clinical trials of neuromuscular disorders.

Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.

AIMS: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). METHODS: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. RESULTS: PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited. CONCLUSION: Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. CLINICAL TRIAL REGISTRATION: Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.

Rituximab utilization for approved and off-label nononcology indications and patients' experiences with the Patient Alert Card.

This study used retrospective chart review and survey data to evaluate: (1) off-label use of rituximab (MabThera®/Rituxan®) in autoimmune conditions and (2) patients' receipt and knowledge of the Patient Alert Card (PAC), a risk minimization measure for progressive multifocal leukoencephalopathy (PML) and serious infections. Anonymized patient data were collected from infusion centers in Europe from December 2015 to July 2017. Adults receiving rituximab in the same centers were provided a self-administered survey. Outcomes included patterns of off-label rituximab use for nononcology indications, and evaluation of patients' receipt and knowledge of the PAC and its impact. Of 1012 patients in the retrospective chart review, 70.2% received rituximab for rheumatoid arthritis or granulomatosis with polyangiitis/microscopic polyangiitis, and 29.8% received rituximab off label. Among 524 survey participants, 32.8% reported receiving the PAC, 59.3% reported not receiving the PAC and 7.9% did not know whether they received the PAC. A total of 72.4% of patients reported that they were unaware that some patients receiving rituximab experience PML. A higher proportion of PAC recipients identified PML as a potential risk of rituximab than nonrecipients (37.8% vs 19.9%); 58.3% of PAC recipients had poor awareness of PML. Most PAC recipients (90.0%) and nonrecipients (85.5%) correctly answered that they should seek medical attention for infection symptoms. In conclusion, approximately 30% of patients received off-label rituximab. Most patients reported not receiving the PAC or having knowledge of PML but demonstrated understanding of the recommended action in the event of infection symptoms, regardless of PAC receipt.

Persistence of immunity after vaccination with a capsular group B meningococcal vaccine in 3 different toddler schedules.

BACKGROUND: One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12-23 months, with a booster dose 12-24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12-24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children. METHODS: Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12-24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children. RESULTS: Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%-11% v. 1% (H44/76), 84%-100% v. 4% (5/99), 0%-18% v. 0% (NZ98/254) and 59%-60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%-100% (NZ98/254) and 90%-100% (M10713). INTERPRETATION: We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12-24 months, and doses at 12-24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. Trial registration: ClinicalTrials.gov, no. NCT01717638.

Persistence of bactericidal antibodies following booster vaccination with 4CMenB at 12, 18 or 24months and immunogenicity of a fifth dose administered at 4years of age-a phase 3 extension to a randomised controlled trial.

BACKGROUND: 4CMenB is immunogenic in infants and toddlers. We assessed persistence of human complement serum bactericidal activity (hSBA) following a fourth dose administered at 12, 18 or 24months and characterised the antibody response to a fifth dose administered at 4years of age. METHODS: A phase 3, open label, multi-centre extension to a randomised controlled trial conducted in four countries (number of centres): Czech Republic (nineteen), Italy (four), Spain (four) and the United Kingdom (four). Four-year-old children who were either 4CMenB-naïve or had previously received a variety of 3-dose infant priming schedules and a booster vaccine as toddlers (follow-on group) were recruited. Venous blood samples were obtained to determine hSBA against four reference strains; acting as targets to assess immunity to each of the vaccine antigens, NadA (5/99), fHbp (H44/76), PorA (NZ98/254), and NHBA (M10713) at baseline (prior to vaccination, all participants) and one month following a dose of 4CMenB for all vaccine-naïve and follow-on participants primed with the 2, 3, 4 schedule, and a third of follow-on participants primed with a 2, 4, 6month schedule. RESULTS: At baseline (prior to vaccination), the proportion of participants (n=468) with hSBA titers⩾5 was similar across all followon groups: 89-100% against 5/99; 12-35% for H44/76; 8-12% for NZ98/254 and 53-80% for M10713 compared with 5%, 0%, 0%; and 60% respectively, for the vaccine-naïve controls (n=206). Following a dose of 4CMenB at 4years of age, this increased to 100% (5/99), 97-100% (H44/76), 80-95 % (NZ98/254) and 84-100% (M10713) (n=210), compared with 89%, 70%, 24%, and 76% respectively for vaccine-naïve controls (n=192). CONCLUSION: Waning of protective antibodies occurred 24­36 months after toddler booster regardless of age at boost. This was least marked against target strains 5/99 and M10713. A robust memory response occurred after a booster dose given at 4 years of age.

Mentoring in biostatistics: some suggestions for reform.

Mentoring is routinely used as a tool to facilitate acquisition of skills by new professionals in fields like medicine, nursing, surgery, and business. While mentoring has been proposed as an effective strategy for knowledge and skills transfer in biostatistics and related fields, there is still much to be done to facilitate adoption by stakeholders, including academia and employers of biostatisticians. This is especially troubling given that biostatisticians play a key role in the success or otherwise of clinical research conducted for evidence-based decisions. In this paper, we offer suggestions on how mentoring can be applied in practice to advance the statistical training of future biostatisticians. In particular, we propose steps that academic statistics departments, professional statistical societies, and statistics organizations can take to advance the mentoring of young biostatisticians. Our suggestions also cover what mentors and mentees can do to facilitate a successful mentoring relationship.

Factors associated with discordance between absolute CD4 cell count and CD4 cell percentage in patients coinfected with HIV and hepatitis C virus.

BACKGROUND: Liver cirrhosis has been associated with decreased absolute CD4 cell counts but preserved CD4 cell percentage in human immunodeficiency virus (HIV)-negative persons. We evaluated factors associated with discordance between the absolute CD4 cell count and the CD4 cell percentage in a cohort of patients coinfected with HIV and hepatitis C virus (HCV). METHODS: Baseline data from 908 participants in a prospective, Canadian, multisite cohort of individuals with HIV-HCV coinfection were analyzed. Absolute CD4 cell count and CD4 cell percentage relationships were evaluated. We defined low and high discordance between absolute CD4 cell count/CD4 cell percentage relationships as CD4 cell percentages that differed from the expected CD4 cell percentage, given the observed absolute CD4 cell count, by ±7 percentage points; we defined very low and very high discordance as differences of ±14 percentage points. Factors associated with high or very high discordance, including either end-stage liver disease or aspartate transaminase to platelet ratio index (APRI) of >1.5, were analyzed using multivariate logistic regression models and compared to groups with concordant and low discordant results. RESULTS: High/very high discordance was seen in 31% (n = 286), while 35% (n = 321) had concordant values. Factors associated with very high discordance at baseline included history of end-stage liver disease (adjusted odds ratio [aOR], 6.52; 95% confidence interval [CI], 2.27-18.67) and APRI of >1.5 (aOR 4.69; 95% CI, 1.64-13.35). Compared with those with detectable HCV RNA, those who cleared HCV spontaneously were less likely to have very high discordance. CONCLUSIONS: Discordance between absolute CD4 cell count and CD4 cell percentage is common in an HIV/HCV-coinfected population and is associated with advanced liver disease and ongoing HCV replication.

Recovery-oriented service provision and clinical outcomes in assertive community treatment.

OBJECTIVE: While the term "recovery" is routinely referenced in clinical services and health policy, few studies have examined the relationship between recovery-oriented service provision and client outcomes. The present study was designed to examine the relationship between recovery-orientation of service provision for persons with severe mental illnesses and outcomes in Assertive Community Treatment (ACT). METHODS: Client, family, staff, and manager ratings of service recovery-orientation and outcomes across a range of service utilization and community functioning indicators were examined among 67 ACT teams in Ontario, Canada. RESULTS: Significant associations were found between ratings of recovery-oriented service provision and better outcomes in the domains of legal involvement, hospitalization days, education involvement, and employment. Results were not uniformly positive or consistent, however, across stakeholder Recovery Self-Assessment (RSA) ratings or outcomes. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These findings provide some preliminary support for an association between recovery-oriented service delivery for persons with severe mental illnesses and better outcomes. In line with the current practice commentary, this association would suggest the importance of evaluating and cultivating recovery-oriented values and practices in ACT contexts. This is a particularly salient point given that ACT standards minimally address key domains of recovery-oriented service provision. Further study is required, however, to determine if these findings apply to the implementation of ACT in other jurisdictions or generalize to other community support programs.

Impact of hepatitis C viral replication on CD4+ T-lymphocyte progression in HIV-HCV coinfection before and after antiretroviral therapy.

OBJECTIVE: HIV is known to have a negative impact on the progression of hepatitis C virus (HCV) infection, whereas the reverse remains unclear. We examined the impact of spontaneous clearance of HCV on CD4(+) T-lymphocyte count progression before and after initiation of antiretroviral therapy (ART) in HIV-HCV coinfected adults. METHODS: Data were analysed from participants in a Canadian, multisite prospective cohort of HIV-infected adults with serologic evidence of HCV infection. The rate of CD4(+) T-lymphocyte change was determined using multivariate mixed linear regression comparing chronically HCV RNA+ with spontaneous clearers (persistently HCV RNA- without HCV therapy). RESULTS: Baseline characteristics of the 271 participants analysed did not differ between individuals whose HCV RNA cleared (n = 35) and those whose HCV RNA persisted (n = 236) except with respect to markers of liver disease. HCV RNA+ individuals had on average seven-times slower recovery of CD4(+) T-cells on chronic ART compared with HCV RNA-: (adjusted change in absolute CD4 cell T-lymphocyte count per year: 4 (95% confidence interval, -0.6 to 8) cells/microl vs. 26 (95% confidence interval, 12 to 41) cells/microl; P < 0.001. Analyses restricted to individuals initiating ART showed similar results. There was also a trend to greater CD4 decline prior to ART initiation among those HCV RNA+, although this did not reach statistical significance. CONCLUSION: We found that CD4 cell progression is negatively affected by the presence of ongoing HCV replication in coinfected individuals initiating ART which persisted throughout stable ART suggesting active HCV infection affects immune restoration even after years of ART exposure.

Parenting-by-gender interactions in child psychopathology: attempting to address inconsistencies with a Canadian national database.

BACKGROUND: Research has shown strong links between parenting and child psychopathology. The moderating role of child gender is of particular interest, due to gender differences in socialization history and in the prevalence of psychiatric disorders. Currently there is little agreement on how gender moderates the relationship between parenting and child psychopathology. This study attempts to address this lack of consensus by drawing upon two theories (self-salience vs. gender stereotyped misbehaviour) to determine how child gender moderates the role of parenting, if at all. METHODS: Using generalized estimating equations (GEE) associations between three parenting dimensions (hostile-ineffective parenting, parental consistency, and positive interaction) were examined in relationship to child externalizing (physical aggression, indirect aggression, and hyperactivity-inattention) and internalizing (emotional disorder-anxiety) dimensions of psychopathology. A sample 4 and 5 year olds from the National Longitudinal Survey of Children and Youth (NLSCY) were selected for analysis and followed over 6 years (N = 1214). Two models with main effects (Model 1) and main effects plus interactions (Model 2) were tested. RESULTS: No child gender-by-parenting interactions were observed for child physical aggression and indirect aggression. The association between hostile-ineffective parenting and child hyperactivity was stronger for girls, though this effect did not reach conventional levels of statistical significance (p = .059). The associations between parenting and child emotional disorder did vary as a function of gender, where influences of parental consistency and positive interaction were stronger for boys. DISCUSSION: Despite the presence of a few significant interaction effects, hypotheses were not supported for either theory (i.e. self-salience or gender stereotyped misbehaviour). We believe that the inconsistencies in the literature regarding child gender-by-parenting interactions is due to the reliance on gender as an indicator of a different variable which is intended to explain the interactions. This may be problematic because there is likely within-gender and between-sample variability in such constructs. Future research should consider measuring and modelling variables that are assumed to explain such interactions when conducting gender-by-parenting research.

Tips on overlapping confidence intervals and univariate linear models.

In randomised controlled trials, an overlap of confidence intervals is often cited as evidence of 'no statistically significant difference' between intervention groups. This paper illustrates the limitations of this strategy and compares different univariate linear regression models with baseline and follow-up response measures. The researchers also demonstrate that using 'change in response' or exit score as a function of the baseline response in clinical studies leads to the same results. Further, using a model that includes baseline response as covariate leads to more precise estimates. The implications for future trials are discussed.

Comparison of brachial and carotid artery ultrasound for assessing extent of subclinical atherosclerosis in HIV: a prospective cohort study.

BACKGROUND: Non-invasive surrogate measures which are valid and responsive to change are needed to study cardiovascular risks in HIV. We compared the construct validity of two noninvasive arterial measures: carotid intima medial thickness (IMT), which measures anatomic disease; and brachial flow-mediated vasodilation (FMD), a measure of endothelial dysfunction. METHODS: A sample of 257 subjects aged 35 years or older, attending clinics in five Canadian centres, were prospectively recruited into a study of cardiovascular risk among HIV subjects. The relationship between baseline IMT or FMD and traditional vascular risk factors was studied using regression analysis. We analyzed the relationship between progression of IMT or FMD and risk factors using fixed-effects models. We adjusted for use of statin medication and CD4 count in both models. RESULTS: Baseline IMT was significantly associated with age (p < 0.001), male gender (p = 0.034), current smoking status (p < 0.001), systolic blood pressure (p < 0.001) and total:HDL cholesterol ratio (p = 0.004), but not statin use (p = 0.904) and CD4 count (p = 0.929). IMT progression was significantly associated with age (p < 0.001), male gender (p = 0.0051) and current smoking status (p = 0.011), but not statin use (p = 0.289) and CD4 count (p = 0.927). FMD progression was significantly associated with current statin use (p = 0.019), but not CD4 count (p = 0.84). Neither extent nor progression of FMD was significantly associated with any of the examined vascular risk factors. CONCLUSION: IMT correlates better than FMD with established cardiovascular risk factors in this cohort of HIV patients. Standardization of protocols for FMD and IMT will facilitate the comparison of results across studies.

Has the incidence of deep vein thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of randomized controlled trials.

BACKGROUND: There is a perception in the orthopaedic and thromboembolism community that the incidence of deep vein thrombosis (DVT) has decreased in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA). OBJECTIVES: To assess the incidence of DVT with warfarin thromboprophylaxis over time in patients undergoing elective TKA or THA. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched to October 2006, supplemented by a manual search of reference lists. Two reviewers independently extracted data on study characteristics, quality and the frequency of total, symptomatic and proximal DVT. RESULTS: Fourteen studies (4,423 patients) were included. Total and proximal DVT after TKA declined over time (r=-0.75, p=0.031; r=-0.86, p=0.007 respectively). Total and proximal DVT after THA did not change. The risk of developing DVT after TKA was significantly higher than after THA (OR 1.85, 95% CI 1.6-2.14; p<0.0001). The risk of developing symptomatic DVT after THA was significantly higher than after TKA (OR 2.18, 95% CI 1.11-4.27; p=0.012). CONCLUSIONS: The incidence of DVT in patients undergoing elective TKA appears to have declined in patients receiving warfarin thromboprophylaxis.

Quality of reporting of randomized controlled trials in general endocrinology literature.

CONTEXT: The reporting quality of randomized controlled trials (RCTs) is poor in general medicine and several areas of specialization but unknown in endocrinology. OBJECTIVE: Our aim was to assess the reporting quality of RCTs in general endocrinology. A secondary objective was to identify predictors for better reporting quality. DESIGN AND SETTING: We systematically reviewed RCTs published in three general endocrinology journals between January 2005 and December 2006. PARTICIPANTS: We included parallel-design RCTs that addressed a question of treatment or prevention. Article selection and data abstraction were conducted by two reviewers independently, and disagreements were resolved by consensus. MAIN OUTCOMES: There were two main outcomes: 1) a 15-point overall reporting quality score (OQS) based on the Consolidated Standards for Reporting Trials (CONSORT); and 2) a 3-point key score, based on allocation concealment, blinding, and use of intention-to-treat analysis. RESULTS: Eighty nine RCTs were included. The median OQS was 10 (interquartile range = 2). Allocation concealment, blinding, and analysis by intention to treat were reported in 10, 20, and 16 of the 89 RCTs, respectively. A multivariable regression analysis showed that complete industrial funding [incidence rate ratio (IRR) = 1.014; 95% confidence interval (CI), 1.010-1.018], journal of publication (IRR = 1.068; 95% CI, 1.007-1.132), and sample size (IRR = 1.048; 95% CI, 1.026-1.070) were significantly associated with a slightly better OQS. CONCLUSIONS: The quality of RCT reporting in general endocrine literature is suboptimal. We discuss our results, highlight the areas where improvements are needed, and provide some recommendations.

Comparison of generalized estimating equations and quadratic inference functions using data from the National Longitudinal Survey of Children and Youth (NLSCY) database.

BACKGROUND: The generalized estimating equations (GEE) technique is often used in longitudinal data modeling, where investigators are interested in population-averaged effects of covariates on responses of interest. GEE involves specifying a model relating covariates to outcomes and a plausible correlation structure between responses at different time periods. While GEE parameter estimates are consistent irrespective of the true underlying correlation structure, the method has some limitations that include challenges with model selection due to lack of absolute goodness-of-fit tests to aid comparisons among several plausible models. The quadratic inference functions (QIF) method extends the capabilities of GEE, while also addressing some GEE limitations. METHODS: We conducted a comparative study between GEE and QIF via an illustrative example, using data from the "National Longitudinal Survey of Children and Youth (NLSCY)" database. The NLSCY dataset consists of long-term, population based survey data collected since 1994, and is designed to evaluate the determinants of developmental outcomes in Canadian children. We modeled the relationship between hyperactivity-inattention and gender, age, family functioning, maternal depression symptoms, household income adequacy, maternal immigration status and maternal educational level using GEE and QIF. Basis for comparison include: (1) ease of model selection; (2) sensitivity of results to different working correlation matrices; and (3) efficiency of parameter estimates. RESULTS: The sample included 795, 858 respondents (50.3% male; 12% immigrant; 6% from dysfunctional families). QIF analysis reveals that gender (male) (odds ratio [OR] = 1.73; 95% confidence interval [CI] = 1.10 to 2.71), family dysfunctional (OR = 2.84, 95% CI of 1.58 to 5.11), and maternal depression (OR = 2.49, 95% CI of 1.60 to 2.60) are significantly associated with higher odds of hyperactivity-inattention. The results remained robust under GEE modeling. Model selection was facilitated in QIF using a goodness-of-fit statistic. Overall, estimates from QIF were more efficient than those from GEE using AR (1) and Exchangeable working correlation matrices (Relative efficiency = 1.1117; 1.3082 respectively). CONCLUSION: QIF is useful for model selection and provides more efficient parameter estimates than GEE. QIF can help investigators obtain more reliable results when used in conjunction with GEE.