Comparative Molecular Characterization of Typical and Exceptional Responders in Glioblastoma

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer Genome Atlas were performed, and the results of these analyses were integrated via correlation studies and pathway analyses to assess the functional significance of the differential aberrations. Typical responders are characterized by upregulation of NF-κB signaling and of pro-inflammatory cytokines and their associated pathways, while exceptional responders are characterized by upregulation of Alzheimer’s and Parkinson’s disease pathways, as well as of genes involved in synaptic transmission and plasticity. The upregulated pathways and processes in typical responders are consistently associated with more aggressive tumor phenotypes, while those in the exceptional responders suggest a retained ability in tumor cells to undergo cell death

A New Rhesus Macaque Assembly and Annotation for Next-Generation Sequencing Analyses

BACKGROUND: The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses. RESULTS: We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies. CONCLUSIONS: The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates. REVIEWERS: This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova

Changes in Disease-Modifying Antirheumatic Drug Treatment for Patients With Rheumatoid Arthritis in the US During the COVID-19 Pandemic: A Three-Month Observational Study.

ObjectiveTo understand medication, lifestyle, and clinical care changes of persons with rheumatoid arthritis (RA) during the first months (March 2020 through May 2020) of the COVID-19 pandemic in the US.MethodsData were collected from adults with RA participating in FORWARD, The National Databank for Rheumatic Diseases observational registry, who answered COVID-19 web-based surveys in May 2020 and previously provided baseline characteristics and medication use prior to the US COVID-19 pandemic. We compared medication changes by disease-modifying antirheumatic drug (DMARD) exposure in logistic models that were adjusted for age, sex, comorbidities including pulmonary and cardiovascular diseases, education level, health insurance status, RA disease activity, fatigue, and polysymptomatic distress.ResultsOf 734 respondents, 221 (30%) reported medication changes. Among respondents who experienced a medication change, i.e., "medication changers/changers," glucocorticoids (GCs) were more commonly used compared to respondents who did not experience a medication change ("non-changers") (33% versus 18%). Non-hydroxychloroquine conventional DMARDs were less commonly used in changers compared to non-changers pre-COVID-19 (49% versus 62%), and changers reported more economic hardship during the COVID-19 pandemic compared to non-changers (23% versus 15%). While JAK inhibitor use was associated with the likelihood of a medication change, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.0, 3.4), only pre-COVID GC use remained a strong predictor for medication change in multivariable models (OR 3.0 [95% CI 1.9, 4.9]). Change in care was observed to have a significant association with pulmonary disease (OR 2.9 [95% CI 1.3, 6.5]), worse RA disease activity (OR 1.1 [95% CI 1.0, 1.1]), and GC use (OR 1.6 [95% CI 1.0, 2.5]). While the incidence of medication changes was the same before and after the American College of Rheumatology (ACR) guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic were first published in April 2020, self-imposed changes in medication were approximately twice as likely before publication of the guidelines, and physician-guided changes were more likely after publication.ConclusionPersons with RA in the US made substantial medication changes during the first three months of the COVID-19 pandemic, and changes among persons with RA after publication of the ACR guidance in April 2020 were made with increased physician guidance

Changes in Disease-Modifying Antirheumatic Drug Treatment for Patients With Rheumatoid Arthritis in the US During the COVID-19 Pandemic: A Three-Month Observational Study.

ObjectiveTo understand medication, lifestyle, and clinical care changes of persons with rheumatoid arthritis (RA) during the first months (March 2020 through May 2020) of the COVID-19 pandemic in the US.MethodsData were collected from adults with RA participating in FORWARD, The National Databank for Rheumatic Diseases observational registry, who answered COVID-19 web-based surveys in May 2020 and previously provided baseline characteristics and medication use prior to the US COVID-19 pandemic. We compared medication changes by disease-modifying antirheumatic drug (DMARD) exposure in logistic models that were adjusted for age, sex, comorbidities including pulmonary and cardiovascular diseases, education level, health insurance status, RA disease activity, fatigue, and polysymptomatic distress.ResultsOf 734 respondents, 221 (30%) reported medication changes. Among respondents who experienced a medication change, i.e., "medication changers/changers," glucocorticoids (GCs) were more commonly used compared to respondents who did not experience a medication change ("non-changers") (33% versus 18%). Non-hydroxychloroquine conventional DMARDs were less commonly used in changers compared to non-changers pre-COVID-19 (49% versus 62%), and changers reported more economic hardship during the COVID-19 pandemic compared to non-changers (23% versus 15%). While JAK inhibitor use was associated with the likelihood of a medication change, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.0, 3.4), only pre-COVID GC use remained a strong predictor for medication change in multivariable models (OR 3.0 [95% CI 1.9, 4.9]). Change in care was observed to have a significant association with pulmonary disease (OR 2.9 [95% CI 1.3, 6.5]), worse RA disease activity (OR 1.1 [95% CI 1.0, 1.1]), and GC use (OR 1.6 [95% CI 1.0, 2.5]). While the incidence of medication changes was the same before and after the American College of Rheumatology (ACR) guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic were first published in April 2020, self-imposed changes in medication were approximately twice as likely before publication of the guidelines, and physician-guided changes were more likely after publication.ConclusionPersons with RA in the US made substantial medication changes during the first three months of the COVID-19 pandemic, and changes among persons with RA after publication of the ACR guidance in April 2020 were made with increased physician guidance

Rheumatic disease patient decision-making about COVID-19 vaccination: a qualitative analysis

Abstract Background Although patients with rheumatic and musculoskeletal diseases (RMDs) are at increased risk for adverse outcomes of COVID-19 illness compared to healthy controls, they also have lower rates of willingness to be vaccinated. Previous research has identified reasons for vaccine hesitancy among patients with RMDs (such as concerns about side effects and flares), but little is known about what these reasons mean in the context of patients’ lives, or how vaccine decision making is experienced from a patient perspective. Our objective was to describe decision-making about COVID-19 vaccination among RMD patients. Methods Participants in a RMD registry were invited to complete monthly online surveys regarding COVID-19 vaccination from March-June 2021. We qualitatively analyzed comments from two open-ended survey questions reporting general experiences with vaccination and side effects. Comments were coded for attitudes towards COVID-19 vaccination, vaccine access, rheumatologic medication management around vaccination, and vaccine side effects. Themes were identified for the process and context of COVID-19 vaccine decisions, patient motivations for receiving or avoiding vaccination, and consistency of peri-vaccine medication management with current ACR guidelines. Results We analyzed 710 comments from 537 respondents. Commenting respondents had a mean age of 64 years, were 87% female, 94% white, and 93% received/intended to receive ≥ 1 dose of a COVID-19 vaccine. Desire for protection and a return to normal routines motivated some commenters to get vaccinated, while concerns about vaccine side effects motivated others to delay or avoid vaccination. Several commenters reported disease flares following vaccination. Some commenters did not consult their providers about vaccination and failed to withhold immunomodulatory medications during vaccination, while others withheld medications more conservatively than recommended by current ACR guidelines, either on their own or directed by their provider. Conclusions While most commenters were vaccine-accepting, challenges to COVID-19 vaccine uptake in the RMD population may include fears of side effects, including worsened RMD symptoms, and perceptions that vaccination is unnecessary. Addressing these concerns and beliefs may be critical for promoting vaccination in this population

Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID-19 Pandemic.

ObjectivePatients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID-19. We set out to understand how the COVID-19 pandemic has impacted the lives of these patients in the United States.MethodsParticipants in a US-wide longitudinal observational registry responded to a supplemental COVID-19 questionnaire by e-mail on March 25, 2020, about their symptoms, COVID-19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free-text comment fields.ResultsOf the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID-19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID-19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine.ConclusionAfter 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID-19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases

Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID-19 Pandemic.

ObjectivePatients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID-19. We set out to understand how the COVID-19 pandemic has impacted the lives of these patients in the United States.MethodsParticipants in a US-wide longitudinal observational registry responded to a supplemental COVID-19 questionnaire by e-mail on March 25, 2020, about their symptoms, COVID-19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free-text comment fields.ResultsOf the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID-19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID-19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine.ConclusionAfter 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID-19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases

Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks