bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to quantify deaths averted derived from interrupted time-series analyses
Authors: Jiang Huan , Tran Alexander , Gmel Gerhard , Lange Shannon , Manthey Jakob , Room Robin , Rovira Pol , Štelemėkas Mindaugas , Telksnys Tadas , Rehm Jürgen 
Published: March 2021

AbstractBackgroundInterrupted time series (ITS) are an important tool for determining whether alcohol control policies, as well as other policy interventions, are successful over and above secular trends or chance. Subsequent to estimating whether a policy has had an effect, quantifying the key outcomes, such as the number of prevented deaths, is of primary practical importance. The current paper compares the results of two different methodological approaches to quantify deaths averted using different two standard populations.MethodsTime series methodologies were used to estimate the effect size in deaths averted of a substantial increase in excise taxation in Lithuania in 2017. We compare the impact of a) using ITS methodology vs. fitting the trend before the intervention to predict the following 12 months and comparing the predicted monthly estimates of deaths with the actual numbers; and b) adjusting the time series either using the World Health Organization standard or the age distribution of Lithuania in the month before the intervention. The effect was estimated by sex.ResultsThe increase in excise taxation was associated with a substantial decrease in all-cause mortality in all models considered. ITS methodology and using the age-distribution of Lithuania were consistently associated with higher estimates of deaths averted. Although confidence and prediction intervals were highly overlapping, the point estimates differed substantially. The taxation increase was associated with 1,155 deaths averted in the year following the intervention (95% prediction interval: 729, 1,582), corresponding to 2.80% of all deaths in Lithuania in the respective year, for the model selected as best for planning policy interventions in Lithuania.ConclusionsFitting a time series model for the time until the intervention, and then comparing the predicted time points with the actual mortality, standardizing to country-specific weights, was chosen as the best way to derive practically relevant effect sizes.
A New Causal Approach to Account for Treatment Switching in Randomized Experiments under a Structural Cumulative Survival Model
Authors: Ying Andrew , Tchetgen Tchetgen Eric J. 
Published: March 2021

AbstractBackgroundTreatment switching in a randomized controlled trial is said to occur when a patient randomized to one treatment arm switches to another treatment arm during follow-up. This can occur at the point of disease progression, whereby patients in the control arm may be offered the experimental treatment. It is widely known that failure to account for treatment switching can seriously dilute the estimated effect of treatment on overall survival. In this paper, we aim to account for the potential impact of treatment switching in a re-analysis evaluating the treatment effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) on a safety outcome (time to first severe or worse sign or symptom) in participants receiving a new antiretroviral regimen that either included or omitted NRTIs in the Optimized Treatment That Includes or Omits NRTIs (OPTIONS) trial.MethodsWe propose an estimator of a treatment causal effect under a structural cumulative survival model (SCSM) that leverages randomization as an instrumental variable to account for selective treatment switching. Unlike Robins’ accelerated failure time model often used to address treatment switching, the proposed approach avoids the need for artificial censoring for estimation. We establish that the proposed estimator is uniformly consistent and asymptotically Gaussian under standard regularity conditions. A consistent variance estimator is also given and a simple resampling approach provides uniform confidence bands for the causal difference comparing treatment groups over time on the cumulative intensity scale. We develop an R package named “ivsacim” implementing all proposed methods, freely available to download from R CRAN. We examine the finite performance of estimator via extensive simulations.Results357 participants in the OPTIONS trial were randomly assigned at baseline to add-NRTIs or omit-NRTIs treatment group; 93% subsequently completed a 48-week visit. Using the proposed methods, we found statistically significant evidence against the sharp null hypothesis of no treatment effect on the safety outcome (P value 0.034) and our SCSM estimator revealed an increased risk for a safety outcome in participants receiving a new antiretroviral regimen that included NRTIs when compared to participants receiving a regimen that omitted NRTIs. In fact, under an SCSM encoding a constant additive hazards model, we estimated a hazards difference equal to 0.0039 (95% CI 0.0002, 0.0075) over the 48-week follow-up.ConclusionsTreatment-experienced patients with HIV infection starting a new optimized regimen will experience a higher risk of severe or worse sign or symptom. Previous analyses concluded that treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Our analysis suggests that adding NRTIs is not only unnecessary to achieve optimal outcomes but may increase the risk for a safety outcome.
Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a fourplex real-time quantitative reverse transcription-PCR assays
Authors: Durand Mathieu , Thibault Philippe , Lévesque Simon , Brault Ariane , Carignan Alex , Valiquette Louis , Martin Philippe , Labbé Simon 
Published: March 2021

AbstractThe early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is required to identify and isolate contagious patients to prevent further transmission of the coronavirus disease 2019 (COVID-19). In this study, we present a multitarget real-time TaqMan reverse transcription PCR (rRT-PCR) assay for the quantitative detection of SARS-CoV-2 and some of its circulating variants harboring mutations that give SARS-CoV-2 a selective advantage. Seven different primer-probe sets that included probes containing locked nucleic acid (LNA) nucleotides were designed to amplify specific wild-type and mutant sequences in Orf1ab, Envelope (E), Spike (S), and Nucleocapsid (N) genes. Furthermore, a newly developed primer-probe set targeted human β2-microglobulin (B2M) as a highly sensitive internal control for RT efficacy. All singleplex and fourplex assays detected ≤ 14 copies/reaction of quantified synthetic RNA transcripts, with a linear amplification range of 9 logarithmic orders. Primer-probe sets for detection of SARS-CoV-2 exhibited no false-positive amplifications with other common respiratory pathogens, including human coronaviruses NL63, 229E, OC43, and HKU-1. Given the emergence of SARS-CoV-2 variants and their rapid spread in some populations, fourplex rRT-PCR assay containing four primer-probe sets represents a reliable approach to detect multiple viral target sequences containing typical mutations of SARS-CoV-2 variants in a single reaction, allowing quicker detection of circulating relevant variants.
Mouth-rinses and SARS-CoV-2 viral load in saliva: A living systematic review
Authors: Hernández-Vásquez Akram , Barrenechea-Pulache Antonio , Comandé Daniel , Azañedo Diego 
Published: March 2021

ABSTRACTObjectiveTo conduct a living systematic review of the clinical evidence regarding the effect of different mouth-rinses on the viral load of SARS-CoV-2 in the saliva of infected patients. The viral load in aerosols, the duration of the reduction in viral load, viral clearance, SARS-CoV-2 cellular infectivity, and salivary cytokine profiles were also evaluated.Materials and methodsThis study was reported using the PRISMA guidelines. An electronic search was conducted in seven databases and in preprint repositories. We included human clinical trials that evaluated the effect of mouth-rinses with antiseptic substances on the viral load of SARS-CoV-2 in the saliva of children or adults that tested positive for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR). Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration number CRD42021240561.ResultsFour studies matching eligibility criteria were selected for evaluation (n=32 participants). Study participants underwent oral rinses with hydrogen peroxide (H2O2) at 1 %, povidone–iodine (PI) at 0.5% or 1%, chlorhexidine gluconate (CHX) at 0.2% or 0.12% or cetylpyridinium chloride (CPC) at 0.075%. Only one study included a control group with sterile water. Three of the studies identified a significant reduction in viral load up to 3, 4, and 6 hours after the use of mouthwashes with PI, CHX, and CPC or PI vs. sterile water, respectively, while one study did not identify a significant reduction in viral load after the use of H2O2 rinses.ConclusionsAccording to the present systematic review, the effect of the use of mouth-rinses on SARS-CoV-2 viral load in the saliva of COVID-19 patients remains uncertain. This is mainly due to the limited number of patients included and a high risk of bias present in the studies analyzed. Evidence from well-designed randomized clinical trials is required for further and more objective evaluation of this effect.
Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient
Authors: Klein Jonathan , Brito Anderson F. , Trubin Paul , Lu Peiwen , Wong Patrick , Alpert Tara , Peña-Hernández Mario A. , Haynes Winston , Kamath Kathy , Liu Feimei , Vogels Chantal B. F. , Fauver Joseph R. , Lucas Carolina , Oh Jieun , Mao Tianyang , Silva Julio , Wyllie Anne L. , Muenker M. Catherine , Casanovas-Massana Arnau , Moore Adam J. , Petrone Mary E. , Kalinich Chaney C. ,   Yale IMPACT Research Team, Cruz Charles Dela , Farhadian Shelli , Ring Aaron , Shon John , Ko Albert I. , Grubaugh Nathan D. , Israelow Benjamin , Iwasaki Akiko , Azar Marwan M. 
Published: March 2021

SummaryPrior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient’s immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.
Focal amplification of FAL1, an oncogenic enhancer lncRNA mapping to chromosome 1q is associated with dysregulated BMI1/p21 axis and an adverse event in intracranial ependymomas
Authors: Malgulwar Prit Benny , Pathak Pankaj , Sharma Vikas , Jha Pankaj , Nambirajan Aruna , Rajeshwari Madhu , Singh Manmohan , Suri Vaishali , Sarkar Chitra , Sharma Mehar Chand 
Published: March 2021

AbstractGain of chromosome 1q locus is a common cytogenetic feature associated with intracranial ependymomas; however, candidate non-coding RNAs on this locus have not been identified. Recent studies have reported somatic copy number alterations for long non coding RNA (lncRNA) FAL1/FALEC residing on chromosome 1q to stabilize BMI1, an epigenetic repressor and PRC1 component, leading with to downregulation of p21/CDKN1A tumor suppressor gene. We aimed to study the role of FAL1 in ependymomas, its association with 1q gain, BMI1/p21 regulatory axis and clinicopathological parameters. Using SNP array analysis (GSE32101), 31% (discovery cohort) and 63.8% (in-house cohort) showed amplification/gain of FAL1 locus with higher prevalence in intracranial tumors. Copy number gain of FAL1 locus was significantly associated with increased FAL1 (p=0.003) and BMI1 (p=0.007) levels, and reduced p21 (p=0.001) expressions. Interestingly, gain of FAL1 locus and FAL1 transcripts did not show any association with 1q gain or RELA fusions. Subcellular localization reported FAL1 to be expressed in nuclear compartment in ependymomas. Chromatin immunoprecipitation-qPCR demonstrated in-vivo binding of BMI1 at p21 promoter locus with BMI1 target genes to be enriched in cell architecture related pathways. A 3-tier survival analysis between FAL1 gain and increased expression levels of FAL1 and BMI1 correlated with poor outcome in our cohort. Ours is the first study demonstrating gain of FAL1 locus and its interplay with the BMI1/p21 axis in intracranial ependymomas. Further studies into this epigenetic regulatory mechanism will unravel novel driver mutations in intracranial ependymomasHighlightsSomatic variations in enhancer long non-coding RNA has been recently attributed for various clinical malignancies including cancers. Gain of 1q locus is a common cytogenetic variation observed in intracranial ependymomas. Our study has demonstrated, focal amplification of enhancer lncRNA mapping to Chromosome 1q, FAL1/FALEC, to be involved in oncogenicity/ progression of ependymomas. Moreover, our data suggests a positive association with BMI1 (a PRC1 component) with FAL1 levels, indicating downregulation of BMI1 target gene involved in cell cycle, p21. Furthermore, a 3-tier prognosis analysis (between FAL1 gain, FAL1 and BMI1 expressions) suggests a negative survival outcome. Our study highlights the importance of somatic variation in non-coding genome with ependymoma survival.
Public Opinion about the UK Government during COVID-19 and Implications for Public Health: A Topic Modelling Analysis of Open-Ended Survey Response Data
Authors: Wright Liam , Burton Alexandra , McKinlay Alison , Steptoe Andrew , Fancourt Daisy 
Published: March 2021

AbstractConfidence in the central UK Government has declined since the beginning of the COVID-19 pandemic, and while this may be linked to specific government actions to curb the spread of the virus, understanding is still incomplete. Examining public opinion is important, as research suggests that low confidence in government increases the extent of non-compliance with infection-dampening rules (for instance, social distancing); however, the detailed reasons for this association are still unclear. To understand public opinion on the central UK government during COVID-19, we used structural topic modelling, a text mining technique, to extract themes from over 4000 free-text survey responses, collected between 14 October and 26 November 2020. We identified eleven topics, among which were topics related to perceived government corruption and cronyism, complaints about inconsistency in rules and messaging, lack of clear planning, and lack of openness and transparency. Participants reported that elements of the government’s approach had made it difficult to comply with guidelines (e.g., changing rules) or were having impacts on mental wellbeing (e.g., inability to plan for the future). Results suggested that consistent, transparent communication and messaging from the government is critical to improving compliance with measures to contain the virus, as well as protecting mental health during health emergencies.
Understanding and Addressing Vaccine Hesitancy in the Context of COVID-19: Development of a Digital intervention
Authors: Knight Holly , Jia Ru , Ayling Kieran , Bradbury Katherine , Baker Katherine , Chalder Trudie , Morling Joanne R , Durrant Lindy , Avery Tony , Ball Jonathan , Barker Caroline , Bennett Robert , McKeever Tricia , Vedhara Kavita 
Published: March 2021

AbstractBackgroundSevere Acute Respiratory Coronavirus 2 (SARS-CoV-2) was identified in late 2019, spreading to over 200 countries and resulting in almost two million deaths worldwide. The emergence of safe and effective vaccines provides a route out of the pandemic, with vaccination uptake of 75-90% needed to achieve population protection. Vaccine hesitancy is problematic for vaccine rollout; global reports suggest only 73% of the population may agree to being vaccinated. As a result, there is an urgent need to develop equitable and accessible interventions to address vaccine hesitancy at the population level.MethodWe report the development of a scalable digital intervention seeking to address COVID-19 vaccine hesitancy and enhance uptake of COVID-19 vaccines. Guided by motivational interviewing (MI) principles, the intervention includes a series of therapeutic dialogues addressing 10 key concerns of vaccine hesitant individuals. Development of the intervention occurred linearly across four stages. During stage 1, we identified common reasons for COVID-19 vaccine hesitancy through analysis of existing survey data, a rapid systematic literature review, and public engagement workshops. Stage 2 comprised qualitative interviews with medical, immunological, and public health experts. Rapid content and thematic analysis of the data provided evidence-based responses to common vaccine concerns. Stage 3 involved the development of therapeutic dialogues through workshops with psychological and digital behaviour change experts. Dialogues were developed to address concerns using MI principles, including embracing resistance and supporting self-efficacy.Finally, stage 4 involved digitisation of the dialogues and pilot testing with members of the public.DiscussionThe digital intervention provides an evidence-based approach to addressing vaccine hesitancy through MI principles. The dialogues are user-selected, allowing exploration of relevant issues associated with hesitancy in a non-judgmental context. The text-based content and digital format allow for rapid modification to changing information and scalability for wider dissemination.
The gut microbiome and rotavirus vaccine immunogenicity in rural Zimbabwean infants
Authors: Robertson Ruairi C. , Church James A. , Edens Thaddeus J. , Mutasa Kuda , Geum Hyun Min , Baharmand Iman , Gill Sandeep K. , Ntozini Robert , Chasekwa Bernard , Carr Lynnea , Majo Florence D. , Kirkpatrick Beth D. , Lee Benjamin , Moulton Lawrence H. , Humphrey Jean H. , Prendergast Andrew J. , Manges Amee R. ,   SHINE Trial Team
Published: March 2021

ABSTRACTBackgroundOral rotavirus vaccine (RVV) immunogenicity is considerably lower in low-versus high-income populations; however, the mechanisms underlying this remain unclear. Previous evidence suggests that the gut microbiota may contribute to differences in oral vaccine efficacy.MethodsWe performed whole metagenome shotgun sequencing on stool samples and measured anti-rotavirus immunoglobulin A in plasma samples from a subset of infants enrolled in a cluster randomized 2×2 factorial trial of improved water, sanitation and hygiene and infant feeding in rural Zimbabwe (SHINE trial: NCT01824940). We examined taxonomic and functional microbiome composition using random forest models, differential abundance testing and regression analyses to explored associations with RVV immunogenicity.ResultsAmong 158 infants with stool samples and anti-rotavirus IgA titres, 34 were RVV seroconverters. The median age at stool collection was 43 days. The infant microbiome was dominated by Bifidobacterium longum. The gut microbiome differed significantly between early (≤42 days) and later samples (>42 days) however, we observed no meaningful differences in alpha diversity, beta diversity, species composition or functional metagenomic composition by RVV seroconversion status. Bacteroides thetaiotaomicron was the only species associated with anti-rotavirus IgA titre. Random forest models poorly classified seroconversion status by both composition and functional microbiome variables.ConclusionsRVV immunogenicity is low in this rural Zimbabwean setting, however it is not explained by the composition or function of the early-life gut microbiome. Further research is warranted to examine the mechanisms of poor oral RVV efficacy in low-income countries.
DNA methylation signatures and the contribution of age-associated methylomic drift to carcinogenesis in early-onset colorectal cancer
Authors: Joo Jihoon E. , Clendenning Mark , Wong Ee Ming , Rosty Christophe , Mahmood Khalid , Georgeson Peter , Winship Ingrid M. , Preston Susan G. , Win Aung Ko , Dugué Pierre-Antoine , Jayasekara Harindra , English Dallas , Macrae Finlay A. , Hopper John L. , Jenkins Mark A. , Milne Roger L. , Giles Graham G. , Southey Melissa C. , Buchanan Daniel D. 
Published: March 2021

AbstractBackgroundThe role of DNA methylation (DNAm) in the carcinogenesis of colorectal cancer (CRC) diagnosed <50years of age (early-onset CRC or EOCRC) is currently unknown. We investigated aberrant DNAm changes and the contribution of ageing-associated methylomic drift, and age acceleration to EOCRC carcinogenesis.MethodsGenome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: 1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and 2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2.ResultsCommon to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p=3.7×10−16) and young people without CRC (p=5.8×10−6).ConclusionEOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. We found accelerated ageing in normal mucosa from people with EOCRC, as evidenced by a faster stem-cell division rate, potentially contributing to EOCRC carcinogenesis.