Abstract
BACKGROUND
Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor ...lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and
METHODS
Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results.
RESULTS
331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine.
CONCLUSION
Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.
Wolbachia bacteria are maternally inherited symbionts that commonly infect terrestrial arthropods. Many Wolbachia reach high frequencies in their hosts by manipulating their reproduction, for example ...by causing reproductive incompatibilities between infected male and uninfected female hosts. However, not all strains manipulate reproduction, and a key unresolved question is how these non‐manipulative Wolbachia persist in their hosts, often at intermediate to high frequencies. One such strain, wSuz, infects the invasive fruit pest Drosophila suzukii, spotted‐wing drosophila. Here, we tested the hypothesis that wSuz infection provides a competitive benefit when resources are limited. Over the course of one season, we established population cages with varying amounts of food in a semi‐field setting and seeded them with a 50:50 mixture of flies with and without Wolbachia. We predicted that Wolbachia‐infected individuals should have higher survival and faster development than their uninfected counterparts when there was little available food. We found that while food availability strongly impacted fly fitness, there was no difference in development times or survival between Wolbachia‐infected and uninfected flies. Interestingly, however, Wolbachia infection frequencies changed dramatically, with infections either increasing or decreasing by as much as 30% in a single generation, suggesting the possibility of unidentified factors shaping Wolbachia infection over the course of the season.
We do not have a good understanding of how Wolbachia and other facultative inherited bacterial symbionts that do not manipulate host reproduction persist in their hosts; we addressed this question in a strain of Wolbachia that infects spotted‐wing drosophila, D. suzukii. To test the hypothesis that Wolbachia infection provides a competitive benefit when resources are limited, we established cages with varying amounts of food and seeded them with a 50:50 mixture of flies with or without Wolbachia. We found that although food availability did not affect Wolbachia prevalence, symbiont infection frequencies changed dramatically, either increasing or decreasing by as much as 30% in a single generation.
We report the presence of two Asian species of larval parasitoids of spotted wing Drosophila,
Drosophila suzukii
(Matsumura) (Diptera: Drosophilidae), in northwestern North America.
Leptopilina ...japonica
Novkovic & Kimura and
Ganaspis brasiliensis
(Ihering) (Hymenoptera: Figitidae) were found foraging near and emerging from fruits infested by
D. suzukii
at several locations across coastal British Columbia, Canada in the summer and fall of 2019. While
G. brasiliensis
was found in British Columbia for the first time in 2019, re-inspection of previously collected specimens suggests that
L. japonica
has been present since at least 2016. Additionally, we found a species of
Asobara
associated with
D. suzukii
in British Columbia that is possibly
Asobara rufescens
(Förster) (known only from the Palearctic Region) based on COI DNA barcode data. These findings add to the list of cases documenting adventive establishment of candidate classical biological control agents outside of their native ranges. The findings also illustrate the need for revisiting species concepts within
Asobara
, as well as host and geographic distribution data due to cryptic and/or misidentified species.
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•Meta-analysis of HLA-DRB1 alleles with cervical cancer in diverse ancestry population.•A total of 36 case-control studies were included in this meta-analysis.•HLA-DRB1*04:01, ...DRB1*09, DRB1*10:01, DRB1*11:01, DRB1*15, DRB1*15:01, & DRB1*15:02 increased cervical cancer risk.•HLA-DRB1*04:06, DRB1*12:02, DRB1*13, DRB1*13:01, DRB1*13:02 & DRB1*14:4 exerted a protective effect.
Human leukocyte antigens (HLA) are encoded by closely linked genetic loci, and are important in cervical carcinogenesis. The association between HLA-DRB1 alleles with cervical cancer has been studied extensively, but results reported thus far have been inconsistent. Hence, we performed a meta-analysis to precisely assess this association.
A literature search was conducted in various online databases to identify suitable articles. Case-control studies investigating the association between HLA-DRB1 alleles and cervical cancer were included in this study. Fixed and random-effect models were used to calculate the pooled odds ratio (OR) and 95% confidence intervals (CIs).
A total of 6645 cases and 9095 controls from 36 case-control studies were included. Of the 13 HLA-DRB1 family alleles, DRB1*09 (OR = 1.30) and DRB1 *15 (OR = 1.60) were associated with cervical cancer risk, whilst DRB1*13 (OR = 0.66) exerted a protective effect. Among the 44 HLA-DRB1 specific alleles, DRB1*04:01 (OR = 1.25), DRB1*10:01 (OR = 1.45), DRB1*11:01 (OR = 1.32), DRB1*15:01 (OR = 1.21) and DRB1*15:02 (OR = 1.55) were associated with an increased risk of cervical cancer. However, DRB1*04:06 (OR = 0.52), DRB1*12:02 (OR = 0.61), DRB1*13:01 (OR = 0.62), DRB1*13:02 (OR = 0.57), and DRB1*14:04 (OR = 0.37) were associated with a decreased risk of cervical cancer. Subgroup analysis also revealed that HLA-DRB1 alleles are associated with cervical cancer in Asian, Caucasian, Hispanic or Latin American and black sub-Saharan Africa populations.
Our meta-analysis revealed that multiple HLA-DRB1 alleles are associated with cervical cancer in women of diverse ancestry populations.
Background and Aim The emergence of direct-to-consumer hearing devices has introduced confusion in making appropriate choices, highlighting the need for users to be well-informed for optimal device ...selection. Currently, no established metric offers insights into the sound performance of these devices. This study aimed to introduce and assess a novel consumer-centric metric (i.e., SoundScore) for hearing device audio performance. Method The SoundScore metric was created based on five dimensions of hearing device audio performance (i.e., speech benefit in quiet and moderate, speech benefit in loud, own voice perception, feedback control, streamed music sound quality). Tests were conducted under lab conditions with an acoustic manikin using two fitting protocols meant to approximate (1) real-world default device settings for a mild-to-moderate sloping hearing loss (“Initial Fit”) and (2) an audiological best-practices approach (“Tuned Fit”). A total of 41 hearing devices comprising 10 prescription hearing aids (Rx-HA), 10 self-fitting over-the-counter hearing aids (OTC-SF), 8 pre-set based over-the-counter hearing aids (OTC-PS), and 13 personal sound amplification systems (PSAPs) were evaluated. Results SoundScore varied significantly between device classifications with Rx-HA yielding the highest average scores and PSAPs the lowest. SoundScore also varied with fitting method, whereby preset based devices scored lower on average than devices programmable by fitting software. Performance across the five composite sound performance metrics generally improved between “Initial” and “Tuned” fits for Rx-HA. However, this was not observed with OTC-SF. Also, no significant difference in SoundScore was found between devices of different form factors (i.e., BTE vs. ITE). Conclusions Initial findings suggest that the SoundScore can effectively distinguish between the audio performance of different hearing aids, offering consumers a valuable decision-making tool. Future studies should examine the relationship between the SoundScore and consumer hearing aid benefit/satisfaction.
Summary
Xanthomonas campestris pv. campestris (Xcc) is a vascular pathogen that invades the xylem of Brassica crops. Current chemical and antibiotics‐based control measures for this bacterium are ...unsustainable and inefficient. After establishing a representative collection of Xcc strains, we isolated and characterized bacteriophages from two clades of phages to assess their potential in phage‐based biocontrol. The most promising phages, FoX2 and FoX6, specifically recognize (lipo) polysaccharides, associated with the wxc gene cluster, on the surface of the bacterial cell wall. Next, we determined and optimized the applicability of FoX2 and FoX6 in an array of complementary bioassays, ranging from seed decontamination to irrigation‐ and spray‐based applications. Here, an irrigation‐based application showed promising results. In a final proof‐of‐concept, a CaCl2‐formulated phage cocktail was shown to control the outbreak of Xcc in the open field. This comprehensive approach illustrates the potential of phage biocontrol of black rot disease in Brassica and serves as a reference for the broader implementation of phage biocontrol in integrated pest management strategies.
Xanthomonas is an important phytopathogenic bacterial species, causing losses in crop production. Controlling its infection is therefore essential for a sustainable agriculture. Here, we describe the in‐depth molecular characterization and implementation of bacteriophages within the framework of integrated pest management. We developed tailored bioassays and showed that our phages perform well during seed steeping and that they limit the effects of the bacterium on seedling germination significantly. In greenhouse conditions, one of our phages outperforms the other in an irrigation‐based bioassay, resulting in a full disease control. Additional spray applications also demonstrate the potential of our phage to be used in this setting. Finally, we could demonstrate that a formulation of two phages significantly impacts infection in field conditions.
Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in ...healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available.
We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572.
In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0).
RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections.
Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.
Abstract
Background
Respiratory syncytial virus (RSV) surveillance is heavily dependent on the influenza-like illness (ILI) case definition from the World Health Organization (WHO). Because ILI ...includes fever in its syndromic case definition, its ability to accurately identify acute respiratory tract infections (ARTI) caused by RSV in older adults is uncertain.
Methods
The accuracy of the WHO ILI and a modified ILI (requiring only self-reported fever) case definitions in identifying patients with PCR-confirmed RSV-ARTI was evaluated in community-dwelling older adults (≥60 years) from the prospective European RESCEU cohort study.
Results
Among 1040 participants, 750 ARTI episodes were analyzed including 36 confirmed RSV-ARTI. Due to a general lack of fever, sensitivity for RSV-ARTI was 33% for modified ILI and 11% for ILI. The area under the curve for both ILI definitions was 0.52 indicating poor discrimination for RSV. RSV-ARTI could not be distinguished from all other ARTI based on clinical symptoms.
Conclusions
The use of ILI underestimated the occurrence of RSV-ARTI in community-dwelling older adults up to 9-fold (11% sensitivity). Because worldwide RSV surveillance depends largely on ILI, there is an urgent need for a better approach to measure the occurrence of RSV disease and the impact of future RSV vaccine introduction.
Clinical Trials Registration. NCT03621930.
Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised ...within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.
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