Anona Thorne

Association of Biomarkers With Pre-Radiographically Defined and Radiographically Defined Knee Osteoarthritis in a Population-Based Study

OBJECTIVE To evaluate 10 biomarkers in magnetic resonance imaging (MRI)-determined, pre-radiographically defined osteoarthritis (pre-ROA) and radiographically defined OA (ROA) in a population-based cohort of subjects with symptomatic knee pain. METHODS Two hundred one white subjects with knee pain, ages 40-79 years, were classified into OA subgroups according to MRI-based cartilage (MRC) scores (range 0-4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0-4): no OA (MRC score 0, K/L grade<2), pre-ROA (MRC score>or=1, K/L grade<2), or ROA (MRC score>or=1, K/L grade>or=2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C-telopeptide of type II collagen (uCTX-II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N-telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C-propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index. RESULTS The risk of ROA versus no OA increased with increasing levels of uCTX-II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35-7.21), uC2C (OR 2.13, 95% CI 1.04-4.37), and uC1,2C (OR 2.07, 95% CI 1.06-4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30-0.94). The risk of pre-ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05-4.01) and uC1,2C (OR 2.06, 95% CI 1.12-3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX-II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34-9.03) and a risk of pre-ROA versus no OA of 2.56 (95% CI 1.03-6.40). CONCLUSION Different cartilage degradation markers are associated with pre-ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.

Clindamycin with Primaquine vs. Trimethoprim-Sulfamethoxazole Therapy for Mild and Moderately Severe Pneumocystis carinii Pneumonia in Patients with AIDS: A Multicenter, Double-Blind, Randomized Trial (CTN 004)

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of > or = 60 kg or 240 mg/1,200 mg q.i.d. if weight of < 60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of > 70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 of < or = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

Association of clinical findings with pre–radiographic and radiographic knee osteoarthritis in a population‐based study

To determine the prevalence of pre–radiographic osteoarthritis (ROA) and ROA of the knee in a symptomatic population‐based cohort, and to evaluate the clinical correlates of pre‐ROA and ROA.

Immunogenicity Is Not Improved by Increased Antigen Dose or Booster Dosing of Seasonal Influenza Vaccine in a Randomized Trial of HIV Infected Adults

Introduction The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. Methods A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. Results 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥40 = 31–58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. Conclusion Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. Trial Registration ClinicalTrials.gov NCT00764998

Vitamin D supplementation does not increase immunogenicity of seasonal influenza vaccine in HIV-infected adults.

Abstract The influence of vitamin D on influenza vaccine immunogenicity in HIV was assessed using data from a phase 3, randomized trial conducted during the 2011–2009 influ-enza season. Thirty–three percent of participants were on supplemental vitamin D at baseline. Neither seroconversion nor seroprotection were predicted by vitamin D use for any of the 3 vaccine strains. There is no evidence of improved influenza vaccine immunogenicity with vitamin D supplementation in this HIV-positive population.

Natural history of cartilage damage and osteoarthritis progression on magnetic resonance imaging in a population-based cohort with knee pain.

OBJECTIVES To determine the natural history of cartilage damage and of osteoarthritis (OA) progression using magnetic resonance imaging (MRI); to evaluate whether OA progression varies by stage of disease. METHODS A population-based cohort with knee pain was assessed clinically, with X-ray (Kellgren-Lawrence [KL] grading) and MRI. Cartilage was graded 0-3 on six joint surfaces. Frequency of cartilage damage change was determined for each joint site. Progression of OA was defined as a worsening of MRI cartilage damage by ≥1 grade in at least two joint sites or ≥2 grades in at least one joint site. The association of KL grade with OA progression was evaluated using parametric lifetime regression analysis. RESULTS 163 subjects were assessed at baseline and follow-up (mean 3.2 years). KL grade ≥2 was present in 39.4% at baseline. An increase in cartilage damage by ≥1 grade was seen in 8.0-14.1% of subjects at different joint sites. OA progression on MRI was present in 15.5%. Baseline KL grade was a significant predictor of OA progression with hazard ratio (HR) of 6.5 (95% confidence interval [CI] 1.4-30.7), 6.1 (95% CI 1.3-28.9), and 9.2 (95% CI 1.9-44.9) for KL grades 1, 2 and ≥3, respectively. CONCLUSION A low OA progression rate was seen over 3 years in this population-based symptomatic cohort. Radiographic severity, including KL grade 1, was a significant predictor of OA progression. Future interventions aimed at reducing progression will need to target not only radiographic OA, but also those with early abnormalities suggestive of pre-radiographic OA.

Leukocyte Telomere Length in HIV-Infected and HIV-Exposed Uninfected Children: Shorter Telomeres with Uncontrolled HIV Viremia

Objectives Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging. Methods In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV -1-infected (HIV+) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV−) control children (n = 104) aged 0–19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV+/HEU children only, and c) HIV+ children only. Results After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV+ group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007). Conclusions In this large study, group rates of LTL attrition were similar for HIV+, HEU and HIV− children. No associations between children’s LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.

Impact of missing data due to dropouts on estimates of the treatment effect in a randomized trial of antiretroviral therapy for HIV-infected individuals

PURPOSE To evaluate the impact of missing data due to nonrandom dropout on estimates of the effect of treatment on the CD4 count in a clinical trial of antiretroviral therapy for HIV infected individuals. METHODS The effect of treatment on CD4 counts in a recent study of continued ZDV versus ddI in HIV-infected individuals was estimated from the observed data and after imputing missing CD4 counts for patients who dropped out of the study. Imputation methods studied were (a) carrying forward the last observed CD4 count, (b) predicting missing CD4 counts from regression models, and (c) assuming that CD4 counts of patients who dropped out declined at a rate of 100 cells per year. RESULTS Of the 245 patients enrolled in the study, 52% completed the planned 48 weeks of follow-up. Patients with lower CD4 counts were more likely to drop out of the study (RR = 1.77; p = 0.0001). Patients receiving ZDV had a greater tendency to drop out than patients receiving ddI (p = 0.07). Mean CD4 counts calculated after imputing missing data were lower than those obtained from the observed data at all follow-up times for both treatment groups. Imputing CD4 counts with regression models yielded higher estimates of the effect of treatment than were obtained using the observed data. CONCLUSION Missing outcome data due to dropouts can result in an underestimation of the treatment effect and overly optimistic statements about the outcome of participants on both treatment arms due to the selective dropout of participants with lower or decreasing CD4 counts. When there are significant dropout rates in randomized trials, imputation is a useful technique to assess the range of plausible values of the treatment effect.

Frequency of Bone Marrow Lesions and Association with Pain Severity: Results from a Population-based Symptomatic Knee Cohort

Objective. To evaluate the prevalence of bone marrow lesions (BML) and their association with pain severity in a population-based cohort of symptomatic early knee osteoarthritis (OA). Methods. Subjects with knee pain (n = 255), age 40–79 years, were evaluated by radiograph and magnetic resonance imaging (MRI) and classified into OA stages: no OA (NOA), preradiographic OA (PROA), and radiographic OA (ROA). BML were graded 0–3 (none, mild, moderate, severe) in 6 regions and defined as (1) BMLsum = the sum of 6 scores; and (2) BMLmax = the worst score at any region. Pain was assessed by the Western Ontario and McMaster Universities OA Index (WOMAC). Linear regression analysis was completed to assess the association of Total WOMAC Pain (primary outcome) versus BMLsum or BMLmax. Secondary outcomes were WOMAC Pain on Walking and WOMAC Pain on Climbing Stairs. All analyses were adjusted for age, sex, body mass index, OA stage, joint effusion, and meniscal damage. Results. BML were present in 11% of NOA, 38% of PROA, and 71% of ROA subjects (p < 0.001). No association was seen for BMLsum or BMLmax versus Total WOMAC Pain or Pain on Walking. However, BMLsum was associated with Pain on Climbing Stairs [regression coefficients (RC) = 0.09, 95% CI 0.00–0.18]. BMLmax was associated with Pain on Climbing Stairs, with the strongest association for severe BML (RC 0.60, 95% CI 0.04–1.17). Conclusion. BML were present in 38% of PROA and 71% of ROA subjects in this symptomatic knee cohort. BML were significantly associated with Pain on Climbing Stairs but not Total WOMAC or Pain on Walking.

The relationship between subchondral sclerosis detected with MRI and cartilage loss in a cohort of subjects with knee pain: the knee osteoarthritis progression (KOAP) study

PURPOSE To assess the association between subchondral sclerosis detected at baseline with MRI and cartilage loss over time in the same region of the knee in a cohort of subjects with knee pain. METHODS 163 subjects with knee pain participated in a longitudinal study to assess knee osteoarthritis progression (KOAP). Subjects received baseline knee radiographs as well as baseline and 3-year follow-up MRI examinations. Baseline subchondral sclerosis and bone marrow lesions (BMLs) were scored semiquantitatively on MRI in each region from 0 to 3. Cartilage morphology at baseline and follow-up was scored semiquantitatively from 0 to 4. The association between baseline subchondral sclerosis and cartilage loss in the same region of the knee was evaluated using logistic regression, adjusting the results for age, gender, body mass index, and the presence of concomitant BMLs. RESULTS The prevalence of subchondral sclerosis detected by MRI in the regions of the knee varied between 1.6% (trochlea) and 17% (medial tibia). The occurrence of cartilage loss over time in regions varied between 6% (lateral tibia) and 13.1% (medial femur). The prevalence of radiographically-detected subchondral sclerosis in compartments varied from 2.9% (patellofemoral) to 14.2% (medial tibiofemoral). In logistic regression models, there were no significant associations between baseline subchondral sclerosis detected by MRI and cartilage loss in the same region of the knee. CONCLUSION Baseline subchondral sclerosis as detected by MRI did not increase the risk of cartilage loss over time.