The STAR care pathway for patients with pain at 3 months after total knee replacement:a multicentre, pragmatic randomised controlled trial

BACKGROUND: Approximately 20% of people experience chronic pain after total knee replacement, but effective treatments are not available. We aimed to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for chronic pain after total knee replacement. METHODS: We did an unmasked, parallel group, pragmatic, superiority, randomised, controlled trial at eight UK National Health Service (NHS) hospitals. People with chronic pain at 3 months after total knee replacement surgery were randomly assigned (2:1) to the Support and Treatment After Replacement (STAR) care pathway plus usual care, or to usual care alone. The STAR intervention aimed to identify underlying causes of chronic pain and enable onward referrals for targeted treatment through a 3-month post-surgery assessment with an extended scope practitioner and telephone follow-up over 12 months. Co-primary outcomes were self-reported pain severity and pain interference in the replaced knee, assessed with the Brief Pain Inventory (BPI) pain severity and interference scales at 12 months (scored 0–10, best to worst) and analysed on an as-randomised basis. Resource use, collected from electronic hospital records and participants, was valued with UK reference costs. Quality-adjusted life-years (QALYs) were calculated from EQ-5D-5L responses. This trial is registered with ISRCTN, ISRCTN92545361. FINDINGS: Between Sept 6, 2016, and May 31, 2019, 363 participants were randomly assigned to receive the intervention plus usual care (n=242) or to receive usual care alone (n=121). Participants had a median age of 67 years (IQR 61 to 73), 217 (60%) of 363 were female, and 335 (92%) were White. 313 (86%) patients provided follow-up data at 12 months after randomisation (213 assigned to the intervention plus usual care and 100 assigned to usual care alone). At 12 months, the mean between-group difference in the BPI severity score was −0·65 (95% CI −1·17 to −0·13; p=0·014) and the mean between-group difference in the BPI interference score was −0·68 (−1·29 to −0·08; p=0·026), both favouring the intervention. From an NHS and personal social services perspective, the intervention was cost-effective (greater improvement with lower cost), with an incremental net monetary benefit of £1256 (95% CI 164 to 2348) at £20 000 per QALY threshold. One adverse reaction of participant distress was reported in the intervention group. INTERPRETATION: STAR is a clinically effective and cost-effective intervention to improve pain outcomes over 1 year for people with chronic pain at 3 months after total knee replacement surgery. FUNDING: National Institute for Health Research

Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM):pragmatic, parallel group, open label, randomised controlled trial

OBJECTIVES: To determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures. DESIGN: Pragmatic, parallel group, open label, randomised controlled trial. SETTING: High volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018. PARTICIPANTS: 140 adults (aged ≥18 years) with a prosthetic joint infection of the hip who required revision (65 randomly assigned to single stage and 75 to two stage revision). INTERVENTIONS: A computer generated 1:1 randomisation list stratified by hospital was used to allocate participants with prosthetic joint infection of the hip to a single stage or a two stage revision procedure. MAIN OUTCOME MEASURES: The primary intention-to-treat outcome was pain, stiffness, and functional limitations 18 months after randomisation, measured by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included surgical complications and joint infection. The economic evaluation (only assessed in UK participants) compared quality adjusted life years and costs between the randomised groups. RESULTS: The mean age of participants was 71 years (standard deviation 9) and 51 (36%) were women. WOMAC scores did not differ between groups at 18 months (mean difference 0.13 (95% confidence interval -8.20 to 8.46), P=0.98); however, the single stage procedure was better at three months (11.53 (3.89 to 19.17), P=0.003), but not from six months onwards. Intraoperative events occurred in five (8%) participants in the single stage group and 20 (27%) in the two stage group (P=0.01). At 18 months, nine (14%) participants in the single stage group and eight (11%) in the two stage group had at least one marker of possible ongoing infection (P=0.62). From the perspective of healthcare providers and personal social services, single stage revision was cost effective with an incremental net monetary benefit of £11 167 (95% confidence interval £638 to £21 696) at a £20 000 per quality adjusted life years threshold (£1.0; $1.1; €1.4). CONCLUSIONS: At 18 months, single stage revision compared with two stage revision for prosthetic joint infection of the hip showed no superiority by patient reported outcome. Single stage revision had a better outcome at three months, fewer intraoperative complications, and was cost effective. Patients prefer early restoration of function, therefore, when deciding treatment, surgeons should consider patient preferences and the cost effectiveness of single stage surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN10956306.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Unknow

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications.

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Discovering cancer genes by integrating network and functional properties

<p>Abstract</p> <p>Background</p> <p>Identification of novel cancer-causing genes is one of the main goals in cancer research. The rapid accumulation of genome-wide protein-protein interaction (PPI) data in humans has provided a new basis for studying the topological features of cancer genes in cellular networks. It is important to integrate multiple genomic data sources, including PPI networks, protein domains and Gene Ontology (GO) annotations, to facilitate the identification of cancer genes.</p> <p>Methods</p> <p>Topological features of the PPI network, as well as protein domain compositions, enrichment of gene ontology categories, sequence and evolutionary conservation features were extracted and compared between cancer genes and other genes. The predictive power of various classifiers for identification of cancer genes was evaluated by cross validation. Experimental validation of a subset of the prediction results was conducted using siRNA knockdown and viability assays in human colon cancer cell line DLD-1.</p> <p>Results</p> <p>Cross validation demonstrated advantageous performance of classifiers based on support vector machines (SVMs) with the inclusion of the topological features from the PPI network, protein domain compositions and GO annotations. We then applied the trained SVM classifier to human genes to prioritize putative cancer genes. siRNA knock-down of several SVM predicted cancer genes displayed greatly reduced cell viability in human colon cancer cell line DLD-1.</p> <p>Conclusion</p> <p>Topological features of PPI networks, protein domain compositions and GO annotations are good predictors of cancer genes. The SVM classifier integrates multiple features and as such is useful for prioritizing candidate cancer genes for experimental validations.</p

Variation in carbon and nitrogen concentrations among peatland categories at the global scale

Publisher Copyright: © 2022 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.Peatlands account for 15 to 30% of the world's soil carbon (C) stock and are important controls over global nitrogen (N) cycles. However, C and N concentrations are known to vary among peatlands contributing to the uncertainty of global C inventories, but there are few global studies that relate peatland classification to peat chemistry. We analyzed 436 peat cores sampled in 24 countries across six continents and measured C, N, and organic matter (OM) content at three depths down to 70 cm. Sites were distinguished between northern (387) and tropical (49) peatlands and assigned to one of six distinct broadly recognized peatland categories that vary primarily along a pH gradient. Peat C and N concentrations, OM content, and C:N ratios differed significantly among peatland categories, but few differences in chemistry with depth were found within each category. Across all peatlands C and N concentrations in the 10-20 cm layer, were 440 ± 85.1 g kg-1 and 13.9 ± 7.4 g kg-1, with an average C:N ratio of 30.1 ± 20.8. Among peatland categories, median C concentrations were highest in bogs, poor fens and tropical swamps (446-532 g kg-1) and lowest in intermediate and extremely rich fens (375-414 g kg-1). The C:OM ratio in peat was similar across most peatland categories, except in deeper samples from ombrotrophic tropical peat swamps that were higher than other peatlands categories. Peat N concentrations and C:N ratios varied approximately two-fold among peatland categories and N concentrations tended to be higher (and C:N lower) in intermediate fens compared with other peatland types. This study reports on a unique data set and demonstrates that differences in peat C and OM concentrations among broadly classified peatland categories are predictable, which can aid future studies that use land cover assessments to refine global peatland C and N stocks.Peer reviewe

GFI1 proteins regulate stem cell formation in the AGM

In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that Gfi1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells.We thank the staff at the Advanced Imaging, animal facility, Molecular Biology Core facilities and Flow Cytometry of CRUK Manchester Institute for technical support and Michael Lie-A-Ling and Elli Marinopoulou for initiating the DamID-PIP bioinformatics project. We thank members of the Stem Cell Biology group, the Stem Cell Haematopoiesis groups and Martin Gering for valuable advice and critical reading of the manuscript. Work in our laboratory is supported by the Leukaemia and Lymphoma Research Foundation (LLR), Cancer Research UK (CRUK) and the Biotechnology and Biological Sciences Research Council (BBSRC). SC is the recipient of an MRC senior fellowship (MR/J009202/1).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb327

Guided, internet based, cognitive behavioural therapy for post-traumatic stress disorder: pragmatic, multicentre, randomised controlled non-inferiority trial (RAPID)

Objective To determine if guided internet based cognitive behavioural therapy with a trauma focus (CBT-TF) is non-inferior to individual face-to-face CBT-TF for mild to moderate post-traumatic stress disorder (PTSD) to one traumatic event. Design Pragmatic, multicentre, randomised controlled non-inferiority trial (RAPID). Setting Primary and secondary mental health settings across the UK’s NHS. Participants 196 adults with a primary diagnosis of mild to moderate PTSD were randomised in a 1:1 ratio to one of two interventions, with 82% retention at 16 weeks and 71% retention at 52 weeks. 19 participants and 10 therapists were purposively sampled and interviewed for evaluation of the process. Interventions Up to 12 face-to-face, manual based, individual CBT-TF sessions, each lasting 60-90 minutes; or guided internet based CBT-TF with an eight step online programme, with up to three hours of contact with a therapist and four brief telephone calls or email contacts between sessions. Main outcome measures Primary outcome was the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) at 16 weeks after randomisation (diagnosis of PTSD based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, DSM-5). Secondary outcomes included severity of PTSD symptoms at 52 weeks, and functioning, symptoms of depression and anxiety, use of alcohol, and perceived social support at 16 and 52 weeks after randomisation. Results Non-inferiority was found at the primary endpoint of 16 weeks on the CAPS-5 (mean difference 1.01, one sided 95% confidence interval −∞ to 3.90, non-inferiority P=0.012). Improvements in CAPS-5 score of more than 60% in the two groups were maintained at 52 weeks, but the non-inferiority results were inconclusive in favour of face-to-face CBT-TF at this time point (3.20, −∞ to 6.00, P=0.15). Guided internet based CBT-TF was significantly (P<0.001) cheaper than face-to-face CBT-TF and seemed to be acceptable and well tolerated by participants. The main themes of the qualitative analysis were facilitators and barriers to engagement with guided internet based CBT-TF, treatment outcomes, and considerations for its future implementation. Conclusions Guided internet based CBT-TF for mild to moderate PTSD to one traumatic event was non-inferior to individual face-to-face CBT-TF and should be considered a first line treatment for people with this condition