To see if a group course delivered by rheumatology teams using cognitive-behavioural approaches, plus usual care, reduced RA fatigue impact more than usual care alone.
Multicentre, 2-year randomised ...controlled trial in RA adults (fatigue severity
6/10, no recent major medication changes). RAFT (Reducing Arthritis Fatigue: clinical Teams using CB approaches) comprises seven sessions, codelivered by pairs of trained rheumatology occupational therapists/nurses. Usual care was Arthritis Research UK fatigue booklet. Primary 26-week outcome fatigue impact (Bristol RA Fatigue Effect Numerical Rating Scale, BRAF-NRS 0-10). Intention-to-treat regression analysis adjusted for baseline scores and centre.
308/333 randomised patients completed 26 week data (156/175 RAFT, 152/158 Control). Mean baseline variables were similar. At 26 weeks, the adjusted difference between arms for fatigue impact change favoured RAFT (BRAF-NRS Effect -0.59, 95% CI -1.11 to -0.06), BRAF Multidimensional Questionnaire (MDQ) Total -3.42 (95% CI -6.44 to -0.39), Living with Fatigue -1.19 (95% CI -2.17 to -0.21), Emotional Fatigue -0.91 (95% CI -1.58 to -0.23); RA Self-Efficacy (RASE, +3.05, 95% CI 0.43 to 5.66) (14 secondary outcomes unchanged). Effects persisted at 2 years: BRAF-NRS Effect -0.49 (95% CI -0.83 to -0.14), BRAF MDQ Total -2.98 (95% CI -5.39 to -0.57), Living with Fatigue -0.93 (95% CI -1.75 to -0.10), Emotional Fatigue -0.90 (95% CI -1.44, to -0.37); BRAF-NRS Coping +0.42 (95% CI 0.08 to 0.77) (relevance of fatigue impact improvement uncertain). RAFT satisfaction: 89% scored
8/10 vs 54% controls rating usual care booklet (p<0.0001).
Multiple RA fatigue impacts can be improved for 2 years by rheumatology teams delivering a group programme using cognitive behavioural approaches.
ISRCTN52709998.
Vitamin D receptor (VDR) gene variants have been variably associated with risk of colon cancer in epidemiologic studies. We sought to further clarify the relationship between colon cancer and three ...single-nucleotide polymorphisms (SNPs) in the VDR gene (Cdx-2, FokI and TaqI) in a population-based case–control study of 250 incident cases and 246 controls. Colon cancer cases were more frequently homozygous for the Cdx-2 A allele (9.2 versus 4.1%, P = 0.06). Cdx-2 AA homozygotes were at increased risk with an unadjusted odds ratio (OR) of 2.47 95% confidence interval (CI): 1.13–5.37, P = 0.022; adjustment for age, sex, body mass index (BMI), non-steroidal anti-inflammatory use and family history of colorectal cancer yielded an OR of 2.27 (CI: 0.95–5.41, P = 0.065). Carriers of the FokI TT genotype were also at increased risk with an adjusted OR of 1.87 (CI: 1.03–3.38, P = 0.038). Haplotype analyses showed significant increased colon cancer risk for carriers of the Cdx-2–FokI A-T haplotype and the FokI-TaqI T-G haplotype. The three-SNP Cdx-2–FokI–TaqI (A-T-G) haplotype showed a similar association with an adjusted OR of 3.63 (CI: 1.01–13.07). A strong positive association was observed for the Cdx-2 variant among individuals with low BMI or low waist circumference. Our results suggest that genetic variation at the VDR locus, in particular Cdx-2 and FokI SNPs, may influence colon cancer risk and these associations may be modified by adiposity.
To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications, is non-inferior to switching later.
This non-inferiority, parallel ...group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis.
Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%.
There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per protocol population. In total, 9 of 64 patients (14·1%) in the standard care arm met the primary endpoint, compared with 15 of 61 (24.6%) in the early switch arm, giving a risk difference of 10·5% (1-sided 95% CI, -∞% to 22%; P=0·14). In the per protocol population, 8 of the 60 patients (13·3%) in the standard care arm met the primary endpoint, compared with 9 of 53 (17%) in the intervention arm giving a risk difference of 3·7% (1-sided 95% CI, -∞% to 14·8%; P=0·59). Duration of hospital stay was shorter in the intervention arm (median 2 IQR 2,3 vs. 3 days IQR 2,4; P=0·002).
While non-inferiority of early oral switch was found in the per protocol population, the intervention was not non-inferior in the intent to treat population.
Colorectal cancer is a common malignancy that can be cured when detected early, but recurrence among survivors is a persistent risk. A field effect of cancer in the colon has been reported and could ...have implications for surveillance, but studies to date have been limited. A joint analysis of pooled transcriptomic data from all available bulk RNA-sequencing data sets of healthy, histologically normal tumor-adjacent, and tumor tissues was performed to provide an unbiased assessment of field effect.
A novel bulk RNA-sequencing data set from biopsies of nondiseased colon from screening colonoscopy along with published data sets from the Genomic Data Commons and Sequence Read Archive were considered for inclusion. Analyses were limited to samples with a quantified read depth of at least 10 million reads. Transcript abundance was estimated with Salmon, and downstream analysis was performed in R.
A total of 1,139 samples were analyzed in 3 cohorts. The primary cohort consisted of 834 independent samples from 8 independent data sets, including 462 healthy, 61 tumor-adjacent, and 311 tumor samples. Tumor-adjacent gene expression was found to represent an intermediate state between healthy and tumor expression. Among differentially expressed genes in tumor-adjacent samples, 1,143 were expressed in patterns similar to tumor samples, and these genes were enriched for cancer-associated pathways.
Novel insights into the field effect in colorectal cancer were generated in this mega-analysis of the colorectal transcriptome. Oncogenic features that might help explain metachronous lesions in cancer survivors and could be used for surveillance and risk stratification were identified.
Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no ...approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs.
The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 μg, 30 μg, or 60 μg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603.
Between April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 53% female participants and 14 47% male participants). Six groups of five participants each received 6 μg, 30 μg, or 60 μg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 73% of 30) and malaise (15 50% of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 μg, 30 μg, and 60 μg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 μg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 μg plus alum group (PRNT
geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 83% of 29 for EEEV; 26 90% of 29 for VEEV; 27 93% of 29 for WEEV; and 22 76% of 29 for EEEV, VEEV, and WEEV combined).
The favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials.
The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product.
The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes ...implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource.
We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses.
We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application.
We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.
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The Genome Sequence of the SARS-Associated Coronavirus Marra, Marco A.; Steven J. M. Jones; Astell, Caroline R. ...
Science (American Association for the Advancement of Science),
05/2003, Letnik:
300, Številka:
5624
Journal Article
Recenzirano
Odprti dostop
We sequenced the 29,751-base genome of the severe acute respiratory syndrome (SARS)-associated coronavirus known as the Tor2 isolate. The genome sequence reveals that this coronavirus is only ...moderately related to other known coronaviruses, including two human coronaviruses, HCoV-OC43 and HCoV-229E. Phylogenetic analysis of the predicted viral proteins indicates that the virus does not closely resemble any of the three previously known groups of coronaviruses. The genome sequence will aid in the diagnosis of SARS virus infection in humans and potential animal hosts (using polymerase chain reaction and immunological tests), in the development of antivirals (including neutralizing antibodies), and in the identification of putative epitopes for vaccine development.
Resistance to HIV infection in a small group of Kenyan sex workers is associated with CD8+-lymphocyte responses to HIV cytotoxic T-lymphocyte (CTL) epitopes. Eleven prostitutes meeting criteria for ...HIV resistance seroconverted between 1996 and 1999. The occurrence and specificity of preexisting HIV-1 epitope-specific responses were examined using the IFN-gamma enzyme-linked immunospot assay, and any epitopes recognized were cloned and sequenced from the infecting viral isolate. Immunologic and behavioral variables were compared between late seroconverters and persistently uninfected sex worker controls. HIV-1 CTL epitope responses were present in four of six cases, 5-18 months before seroconversion, and their presence was confirmed by bulk CTL culture. A possible viral escape mutation was found in one of six epitopes. The key epidemiologic correlate of late seroconversion was a reduction in sex work over the preceding year. In persistently uninfected controls, a break from sex work was associated with a loss of HIV-specific CD8+ responses. Late seroconversion may occur in HIV-1-resistant sex workers despite preceding HIV-specific CD8+ responses. Seroconversion generally occurs in the absence of detectable CTL escape mutations and may relate to the waning of HIV-specific CD8+ responses due to reduced antigenic exposure.
People around the world are looking to marine ecosystems to provide additional benefits to society. As they consider expanding current uses and investing in new ones, new management approaches are ...needed that will sustain the delivery of the diverse benefits that people want and need. An ecosystem services framework provides metrics for assessing the quantity, quality, and value of benefits obtained from different portfolios of uses. Such a framework has been developed for assessments on land, and is now being developed for application to marine ecosystems. Here, we present marine Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST), a new tool to assess (i.e., map, model, and value) multiple services provided by marine ecosystems. It allows one to estimate changes in a suite of services under different management scenarios and to investigate trade-offs among the scenarios, including implications of drivers like climate. We describe key inputs and outputs of each of the component ecosystem service models and present results from an application to the West Coast of Vancouver Island, British Columbia, Canada. The results demonstrate how marine InVEST can be used to help shape the dialogue and inform decision making in a marine spatial planning context.
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