Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma

Purpose: The purpose of this study was to evaluate the power of trend-based visual field (VF) progression end points against long-term development of event-based end points accepted by the US Food and Drug Administration (FDA). Methods: One eye from 3352 patients with ≥10 24-2 VFs (median = 11 years) follow-up were analyzed. Two FDA-compatible criteria were applied to these series to label “true-progressed” eyes: ≥5 locations changing from baseline by more than 7 dB (FDA-7) or by more than the expected test-retest variability (GPA-like) in 2 consecutive tests. Observed rates of progression (RoP) were used to simulate trial-like series (2 years) randomly assigned (1000 times) to a “placebo” or a “treatment” arm. We simulated neuroprotec-tive “treatment” effects by changing the proportion of “true progressed” eyes in the two arms. Two trend-based methods for mean deviation (MD) were assessed: (1) linear mixed model (LMM), testing average difference in RoP between the two arms, and (2) time-to-progression (TTP), calculated by linear regression as time needed for MD to decline by predefined cutoffs from baseline. Power curves with 95% confidence intervals were calculated for trend and event-based methods on the simulated series. Results: The FDA-7 and GPA-like progression was achieved by 45% and 55% of the eyes in the clinical database. LMM and TTP had similar power, significantly superior to the event-based methods, none of which reached 80% power. All methods had a 5% false-positive rate. Conclusions: The trend-based methods can efficiently detect treatment effects defined by long-term FDA-compatible progression. Translational Relevance: The assessment of the power of trend-based methods to detect clinically relevant progression end points

The translation, validity and reliability of the German version of the Fremantle Back Awareness Questionnaire

Background: The Fremantle Back Awareness Questionnaire (FreBAQ) claims to assess disrupted self-perception of the back. The aim of this study was to develop a German version of the Fre-BAQ (FreBAQ-G) and assess its test-retest reliability, its known-groups validity and its convergent validity with another purported measure of back perception. Methods: The FreBaQ-G was translated following international guidelines for the transcultural adaptation of questionnaires. Thirty-five patients with non-specific CLBP and 48 healthy participants were recruited. Assessor one administered the FreBAQ-G to each patient with CLBP on two separate days to quantify intra-observer reliability. Assessor two administered the FreBaQ-G to each patient on day 1. The scores were compared to those obtained by assessor one on day 1 to assess inter-observer reliability. Known-groups validity was quantified by comparing the FreBAQ-G score between patients and healthy controls. To assess convergent validity, patient\u27s FreBAQ-G scores were correlated to their two-point discrimination (TPD) scores. Results: Intra- and Inter-observer reliability were both moderate with ICC3.1 = 0.88 (95%CI: 0.77 to 0.94) and 0.89 (95%CI: 0.79 to 0.94), respectively. Intra- and inter-observer limits of agreement (LoA) were 6.2 (95%CI: 5.0±8.1) and 6.0 (4.8±7.8), respectively. The adjusted mean difference between patients and controls was 5.4 (95%CI: 3.0 to 7.8, p\u3c0.01). Patient\u27s FreBAQ-G scores were not associated with TPD thresholds (Pearson\u27s r = -0.05, p = 0.79). Conclusions: The FreBAQ-G demonstrated a degree of reliability and known-groups validity. Interpretation of patient level data should be performed with caution because the LoA were substantial. It did not demonstrate convergent validity against TPD. Floor effects of some items of the FreBAQ-G may have influenced the validity and reliability results. The clinimetric properties of the FreBAQ-G require further investigation as a simple measure of disrupted self-perception of the back before firm recommendations on its use can be made

Detection of Central Visual Field Defects in Early Glaucomatous Eyes: comparison of Humphrey and Octopus perimetry

Purpose: To compare the detection rate of central visual field defect (CVFD) between the 30-degree Octopus G1 program (Dynamic strategy) and the HFA 10–2 SITA-Standard test in early glaucoma eyes not showing any CVFD on the HFA 24–2 SITA-Standard test. Methods: One eye of 41 early glaucoma patients without CVFD in the central 10 on HFA 24–2 test was tested with both the HFA 10–2 test and the Octopus G1 program 15 minutes apart, in random order. The primary outcome measure was the comparison of CVFD detection rates. Secondary outcome measures comprised the agreement in detecting CVFD, and the comparison of test durations and the numbers of depressed test points outside the central 10-degree area between the HFA 24–2 test and the Octopus G1 program. Results: The mean age of the population was 65.2±10.1 years, and the mean deviation with HFA 24–2 was -3.26±2.6 dB. The mean test duration was not significantly different between the tests (p = 0.13). A CVFD was present in 33 (80.4%) HFA 10–2 test and in 23 (56.0%) Octopus G1 tests (p = 0.002). The overall agreement between the HFA 10–2 and Octopus G1 examinations in classifying eyes as having or not having CVFD was moderate (Cohen’s kappa 0.47). The Octopus G1 program showed 69.6% sensitivity and 100% specificity to detect CVFD in eyes where the HFA 10–2 test revealed a CVFD. The number of depressed test points (p<5%) outside the central 10 area detected with the Octopus G1 program (19.68±10.6) was significantly higher than that detected with the HFA 24–2 program (11.95±5.5, p<0.001). Conclusion: Both HFA 10–2 and Octopus G1programs showed CVFD not present at HFA 24–2 test although the agreement was moderate. The use of a single Octopus G1 examination may represent a practical compromise for the assessment of both central and peripheral visual field up to 30 eccentricity without any additional testing and increasing the total investigation time

Differential Regional Immune Response in Chagas Disease

Following infection, lymphocytes expand exponentially and differentiate into effector cells to control infection and coordinate the multiple effector arms of the immune response. Soon after this expansion, the majority of antigen-specific lymphocytes die, thus keeping homeostasis, and a small pool of memory cells develops, providing long-term immunity to subsequent reinfection. The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of cell expansion and the homeostatic contraction to a stable number of memory cells. This straight correlation between the kinetics of T cell response and the dynamics of lymphoid tissue cell numbers is a constant feature in acute infections yielded by pathogens that are cleared during the course of response. However, the regional dynamics of the immune response mounted against pathogens that are able to establish a persistent infection remain poorly understood. Herein we discuss the differential lymphocyte dynamics in distinct central and peripheral lymphoid organs following acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. While the thymus and mesenteric lymph nodes undergo a severe atrophy with massive lymphocyte depletion, the spleen and subcutaneous lymph nodes expand due to T and B cell activation/proliferation. These events are regulated by cytokines, as well as parasite-derived moieties. In this regard, identifying the molecular mechanisms underlying regional lymphocyte dynamics secondary to T. cruzi infection may hopefully contribute to the design of novel immune intervention strategies to control pathology in this infection

Outcome of HIV-exposed uninfected children undergoing surgery

<p>Abstract</p> <p>Background</p> <p>HIV-exposed uninfected (HIVe) children are a rapidly growing population that may be at an increased risk of illness compared to HIV-unexposed children (HIVn). The aim of this study was to investigate the morbidity and mortality of HIVe compared to both HIVn and HIV-infected (HIVi) children after a general surgical procedure.</p> <p>Methods</p> <p>A prospective study of children less than 60 months of age undergoing general surgery at a paediatric referral hospital from July 2004 to July 2008 inclusive. Children underwent age-definitive HIV testing and were followed up post operatively for the development of complications, length of stay and mortality.</p> <p>Results</p> <p>Three hundred and eighty children were enrolled; 4 died and 11 were lost to follow up prior to HIV testing, thus 365 children were included. Of these, 38(10.4%) were HIVe, 245(67.1%) were HIVn and 82(22.5%) were HIVi children.</p> <p>The overall mortality was low, with 2(5.2%) deaths in the HIVe group, 0 in the HIVn group and 6(7.3%) in the HIVi group (p = 0.0003). HIVe had a longer stay than HIVn children (3 (2-7) vs. 2 (1-4) days p = 0.02). There was no significant difference in length of stay between the HIVe and HIVi groups. HIVe children had a higher rate of complications compared to HIVn children, (9 (23.7%) vs. 14(5.7%) (RR 3.8(2.1-7) p < 0.0001) but a similar rate of complications compared to HIVi children 34 (41.5%) (RR = 0.6 (0.3-1.1) p = 0.06).</p> <p>Conclusion</p> <p>HIVe children have a higher risk of developing complications and mortality after surgery compared to HIVn children. However, the risk of complications is lower than that of HIVi children.</p