Working with Chronic Musculoskeletal Disorders : Good Practice Advice Report

This report takes an in-depth look at working with chronic musculoskeletal disorders (MSDs) and makes a clear case for the benefits of enabling those with chronic conditions to remain in work. It highlights the importance of designing inclusive workplaces and sets out principles for managing chronic MSDs, with prevention, early intervention, and effective, participative rehabilitation and return-to-work planning being identified as key. Good practice examples detail a wide range of workplace adjustments made to accommodate individuals with MSDs, from offering flexitime to providing the right tools and ergonomic equipment. This comprehensive practical advice is complemented by broader recommendations for policy-makers

First large-scale study of antimicrobial susceptibility data, and genetic resistance determinants, in Fusobacterium necrophorum highlighting the importance of continuing focused susceptibility trend surveillance

Objectives: The objective of the study was to explore antimicrobial resistance gene determinant, and phenotypic antibiotic susceptibility, data for Fusobacterium necrophorum from a collection of UK strains. In addition, antimicrobial resistance genes detected in publicly available assembled whole genome sequences were investigated for comparison.Methods: Three hundred and eighty five F. necrophorum strains (1982-2019) were revived from cryovials (Prolab). Subsequent to sequencing (Illumina) and quality checking, 374 whole genomes were available for analysis. These genomes, in addition to publicly available assembled F. necrophorum genetic data, were interrogated using BioNumerics (bioMérieux; v 8.1), for the presence of known antimicrobial resistance genes (ARGs). Agar dilution susceptibility results for 313 F. necrophorum isolates (2016-2021) were also examined.Results: The phenotypic antibiotic test data for the 313 contemporary strains demonstrated potential resistance to penicillin, without increased dosing, in only three isolates. Otherwise, all strains were susceptible to ceftriaxone, clindamycin, co-amoxiclav, meropenem, metronidazole, penicillin and piperacillin/tazobactam, using EUCAST (v 11.0) interpretive guidance. The tet(O), tet(M), tet(40), aph(3’)-III, ant(6)-la and blaOXA-85 ARGs were present in publicly available assembled genomes. tet(M), tet(32), erm(A) and erm(B) were found within the UK strains, with correspondingly raised clindamycin and tetracycline minimum inhibitory concentrations.Conclusions: Current antibiotics recommended for the treatment of infections caused by F. necrophorum, including Lemierre’s disease, are likely to be effective in most cases. However, with evidence of potential ARG transmission from oral bacteria, and the detection of a transposon-mediated beta-lactamase resistance determinant in F. necrophorum, surveillance of both phenotypic and genotypic antimicrobial susceptibility trends must continue, and increase.<br/

Painted flowers: Eluta generates pigment patterning in Antirrhinum

*In the early 1900s, Erwin Baur established Antirrhinum majus as a model system, identifying and characterising numerous flower colour variants. This included Picturatum /Eluta, which restricts the accumulation of magenta anthocyanin pigments, forming bullseye markings on the flower face. *We identified the gene underlying the Eluta locus by transposon-tagging, using an Antirrhinum line that spontaneously lost the non-suppressive el phenotype. A candidate MYB repressor gene at this locus contained a CACTA transposable element. We subsequently identified plants where this element excised, reverting to a suppressive Eluta phenotype. El alleles inhibit expression of anthocyanin biosynthetic genes, confirming it to be a regulatory locus. The modes of action of Eluta were investigated by generating stable transgenic tobacco lines, biolistic transformation of Antirrhinum petals and by promoter activation/repression assays. *Eluta competes with MYB activators for promoter cis-elements, and also by titrating essential co-factors (bHLH proteins) to reduce transcription of target genes. Eluta restricts the pigmentation established by the R2R3-MYB factors, Rosea and Venosa, with greatest repression on those parts of the petals where Eluta is most highly expressed. *Baur questioned the origin of heredity units determining flower colour variation in cultivated A. majus. Our findings support introgression from wild species into cultivated varieties. <br/

Anti-tumour necrosis factor therapy for Dupuytren's Disease: a randomised dose response proof of concept phase 2a clinical trial

Background Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Methods Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. Interpretation In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease

The low-resolution version of HadGEM3 GC3.1: development and evaluation for global climate

A new climate model, HadGEM3 N96ORCA1, is presented that is part of the GC3.1 configuration of HadGEM3. N96ORCA1 has a horizontal resolution of ~135 km in the atmosphere and 1° in the ocean and requires an order of magnitude less computing power than its medium-resolution counterpart, N216ORCA025, while retaining a high degree of performance traceability. Scientific performance is compared both to observations and the N216ORCA025 model. N96ORCA1 reproduces observed climate mean and variability almost as well as N216ORCA025. Patterns of biases are similar across the two models. In the north-west Atlantic, N96ORCA1 shows a cold surface bias of up to 6K, typical of ocean models of this resolution. The strength of the Atlantic meridional overturning circulation (16 to 17 Sv) matches observations. In the Southern Ocean, a warm surface bias (up to 2K) is smaller than in N216ORCA025 and linked to improved ocean circulation. Model El Niño/Southern Oscillation and Atlantic Multidecadal Variability are close to observations. Both the cold bias in the Northern hemisphere (N96ORCA1) and the warm bias in the Southern hemisphere (N216ORCA025) develop in the first few decades of the simulations. As in many comparable climate models, simulated interhemispheric gradients of top-of-atmosphere radiation are larger than observations suggest, with contributions from both hemispheres. HadGEM3 GC3.1 N96ORCA1 constitutes the physical core of the UK Earth System Model (UKESM1) and will be used extensively in the Coupled Model Intercomparison Project 6 (CMIP6), both as part of UKESM1 and as a stand-alone coupled climate model

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead