Citations

Abstract The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2− patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

Introduction Globally, the use of telestroke programmes for acute care is expanding. Currently, a standardised set of variables for enabling reliable international comparisons of telestroke programmes does not exist. The aim of the study was to establish a consensus-based, minimum dataset for acute telestroke to enable the reliable comparison of programmes, clinical management and patient outcomes. Methods An initial scoping review of variables was conducted, supplemented by reaching out to colleagues leading some of these programmes in different countries. An international expert panel of clinicians, researchers and managers ( n = 20) from the Australasia Pacific region, USA, UK and Europe was convened. A modified-Delphi technique was used to achieve consensus via online questionnaires, teleconferences and email. Results Overall, 533 variables were initially identified and harmonised into 159 variables for the expert panel to review. The final dataset included 110 variables covering three themes (service configuration, consultations, patient information) and 12 categories: (1) details about telestroke network/programme ( n = 12), (2) details about initiating hospital ( n = 10), (3) telestroke consultation ( n = 17), (4) patient characteristics ( n = 7), (5) presentation to hospital ( n = 5), (6) general clinical care within first 24 hours ( n = 10), (7) thrombolysis treatment ( n = 10), (8) endovascular treatment ( n = 13), (9) neurosurgery treatment ( n = 8), (10) processes of care beyond 24 hours ( n = 7), (11) discharge information ( n = 5), (12) post-discharge and follow-up data ( n = 6). Discussion The acute telestroke minimum dataset provides a recommended set of variables to systematically evaluate acute telestroke programmes in different countries. Adoption is recommended for new and existing services.

Mice expressing the H2b haplotype are resistant to infection with Theiler's murine encephalomyelitis virus (TMEV), which causes chronic demyelination in susceptible mice. The prominent cytolytic T-lymphocyte (CTL) response to the VP2 antigen encoded by TMEV led us to the identification of a class I-binding peptide derived from the VP2 antigen. Escherichia coli transformants overexpressing a series of 11 overlapping VP2 protein fragments were subjected to lysis and alkali digestion, and the resultant peptide pools were tested for their abilities to sensitize RMA-S targets for lysis by CTLs. The source of effector CD8+ T cells for the assays was either freshly harvested central nervous system-infiltrating lymphocytes (CNS-IL) or CNS-IL-derived VP2-specific CTL clones and lines. A 10-residue peptide at VP2 positions 121 to 130 (VP2(121-130)) (FHAGSLLVFM) was identified that sensitized targets for lysis and formed stable complexes with H2Db class I molecules. The VP2(121-130) peptide sensitized target cells for lysis by freshly harvested CNS-IL CTLs at femtomolar concentrations. Despite its relative high level of biological activity, the VP2(121-130) peptide is distinguished from other Db-binding peptides by its lack of an asparagine residue at position five, which had been previously proposed to be a requirement for Db-peptide complexing.

The Plus Aerobic/F resin bottle of the BACTEC 9240 automated blood culture system (Becton Dickinson Diagnostic Instrument Systems, Sparks, Md.) was compared with aerobic culture of the Isolator system (Wampole Laboratories, Cranbury, N.J.) for the detection of bloodstream microorganisms from 6,145 blood cultures collected from adult patients with suspected septicemia. The BACTEC resin bottles were incubated for 7 days, and the sediment from the Isolator tube was inoculated to sheep blood and chocolate agars which were incubated for 72 h and to inhibitory mold, brain heart infusion, and Sabouraud agars which were incubated for 21 days. A total of 622 microorganisms were recovered from 583 blood cultures. The BACTEC resin bottle recovered statistically significantly more pathogens overall than the Isolator system (P = 0.0006). When individual pathogens isolated from either system for a 7-day study period were assessed, it was determined that the BACTEC resin bottle detected statistically significantly more isolates of Staphylococcus aureus (P = 0.0113) and coagulase-negative Staphylococcus spp. (P = 0.0029) than the Isolator system. The BACTEC resin bottle also detected statistically significantly more bloodstream infections (septic episodes) caused by coagulase-negative Staphylococcus spp. (P = 0.0146). The Isolator system recovered statistically significantly more contaminants overall (P < 0.0001), and among this group of microorganisms, recovered statistically significantly more Bacillus spp. (P < 0.0001), coagulase-negative Staphylococcus spp. (P < 0.0001), and viridans group Streptococcus spp. (P = 0.0156). The Isolator system detected statistically significantly more isolates of Histoplasma capsulatum (P = 0.004), but all of these isolates were detected at > or = 7 days of incubation of fungal plates, i.e., after the system to system comparison study period (7 days). In blood culture sets which produced growth of the same pathogen in both systems, there was a statistically significant difference in median time to detection for all pathogens combined favoring the BACTEC resin bottle over the Isolator tube (P < 0.05). When assessing individual microorganisms, the median times for detection of S. aureus, Enterococcus spp., and Pseudomonas spp. were all statistically significantly less for the BACTEC system (P < 0.05). The BACTEC instrument had 79 (1.3%) false positive signals. The BACTEC system required less processing time than the Isolator system and eliminates the hands-on time for detection of positive cultures required with the Isolator system.

The ESP 80A aerobic blood culture of the ESP automated blood culture system (Difco Laboratories. Detroit, Mich.) was compared with two manual aerobic blood culture systems, the Isolator (Wampole Laboratories, Cranbury, N.J.) and the Septi-Chek (Becton Dickinson, Cockeysville, Md.) systems, for the detection of bloodstream microorganisms from 5,845 blood samples for culture collected from adult patients with suspected septicemia. The bottles were incubated for 7 days, and the sediment from the Isolator tube was inoculated onto solid medium and this medium was incubated for 72 h. A total of 609 microorganisms were recovered from 546 blood cultures. There was no statistically significant difference in the total recovery of microorganisms for the ESP 80A system when compared with that for the Septi-Chek system (P = 0.083); however, the Isolator system recovered significantly more microorganisms overall than either the ESP 80A (P < 0.001) or the Septi-Chek (P < 0.001) system. When assessing individual probable pathogens, the Isolator system detected statistically significantly more Staphylococcus aureus and Candida spp. than either the ESP 80A or the Septi-Chek system (P < 0.05). Similarly, the Isolator system detected statistically significantly more bloodstream infections (septic episodes) caused by S. aureus and Candida spp. than either the ESP 80A or the Septi-Chek system (P < 0.05). In blood culture sets which produced growth of the same probable pathogens in the ESP 80A and the Isolator systems, there was no statistically significant difference in the median times to detection for all pathogens combined (P = 0.067). However, a similar comparison showed the Isolator and the ESP 80A systems to have statistically significantly shorter median detection times for all pathogens combined (P < 0.001) when they were independently compared with the Septi-Chek system. The ESP 80A system had 29 (0.5%) false-positive signals. The ESP system required less processing time than the Isolator system and eliminates the hands-on time for the detection of positive cultures required by the manual systems.

ABSTRACT Eighty-four cerebrospinal fluid (CSF) samples from different children who presented with signs and symptoms of meningitis were evaluated for the presence of Mycobacterium tuberculosis complex organisms by the Gen-Probe Amplified Mycobacterium tuberculosis Direct Test (MTD; Gen-Probe, San Diego, Calif.). All CSF samples had negative acid-fast smears by the Ziehl-Neelsen staining method. M. tuberculosis was recovered from five samples. M. tuberculosis did not grow from 19 additional samples, but the samples were from patients who fulfilled specific clinical and laboratory criteria for probable tuberculous meningitis (TBM). The remaining samples ( n = 60) were from patients with other infections or noninfectious causes of meningitis. The results of the MTD were interpreted as positive or negative on the basis of recommended cutoff values for respiratory specimens. These results were interpreted as true or false positives or true or false negatives on the basis of the results of M. tuberculosis culture or whether the patient fulfilled criteria for probable TBM. The Gen-Probe MTD was 33% sensitive and 100% specific for detecting M. tuberculosis complex organisms in these 84 CSF samples. If the cutoff values for positive results were decreased for the MTD (≥11,000 versus ≥30,000 relative light units), the sensitivity increased to 83% and the specificity remained 100%. These results for the MTD are encouraging considering that TBM is a highly fatal disease and difficult to diagnose by conventional laboratory techniques.

Abstract Context Vitamin D (VD) deficiency in pregnancy and the neonatal period has impacts on childhood outcomes. Maternal VD sufficiency is crucial for sufficiency in the neonate, though the effect of early versus late pregnancy 25-hydroxy-vitamin D (25(OH)D) levels on neonatal levels is unknown. Furthermore, chemiluminescence immunoassays (CLIAs) are widely used, though their validity in measuring 25(OH)D specifically in cord blood specimens has not been established. Objective To assess the validity of a CLIA in the measurement of cord blood 25(OH)D and to evaluate maternal determinants of neonatal 25(OH)D, including early versus late pregnancy 25(OH)D levels. Design This is an ancillary analysis from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized, double-blinded, placebo-controlled study. Participants and Intervention A total of 881 pregnant women at high risk of having offspring asthma were randomized to receive VD supplementation or placebo. Serum samples were collected from mothers in early and late pregnancy and from offspring cord blood at birth. 25(OH)D levels were assayed by CLIA in all maternal and offspring samples and by LC-MS/MS in all offspring samples and a subset of 200 maternal third trimester samples. Results Cord blood 25(OH)D levels were higher as measured by CLIA (mean 37.13 ng/mL [SD 18.30]) than by LC-MS/MS (mean 23.54 ng/mL [SD 11.99]), with a mean positive bias of 13.54 ng/mL (SD 12.92) by Bland-Altman analysis. This positive bias in measurement by CLIA was not observed in maternal samples. Third trimester 25(OH)D was a positive determinant of neonatal 25(OH)D levels. Conclusion Chemiluminescence immunoassays overestimate 25(OH)D levels in human cord blood samples, an effect not observed in maternal blood samples. The quantification of 25(OH)D by CLIA should therefore not be considered valid when assayed in cord blood samples. Third trimester, but not first trimester, maternal 25(OH)D is one of several determinants of neonatal 25(OH)D status.