Highlights • We review the contribution of plasticity in the dorsal horn to hypersensitivity following peripheral nerve injury. • Primary afferent neurons show spontaneous activity, phenotypic ...changes, and altered connectivity. • Dorsal horn neurons undergo activity-dependent plasticity, and show altered expression patterns and connectivity. • Descending controls to the dorsal horn are modulated which help to drive the neuropathic phenotype.
The
homeodomain transcription factor SHOOT MERISTEMLESS (STM) is crucial for shoot apical meristem (SAM) function, yet the components and structure of the STM gene regulatory network (GRN) are ...largely unknown. Here, we show that transcriptional regulators are overrepresented among STM-regulated genes and, using these as GRN components in Bayesian network analysis, we infer STM GRN associations and reveal regulatory relationships between STM and factors involved in multiple aspects of SAM function. These include hormone regulation, TCP-mediated control of cell differentiation, AIL/PLT-mediated regulation of pluripotency and phyllotaxis, and specification of meristem-organ boundary zones via CUC1. We demonstrate a direct positive transcriptional feedback loop between STM and CUC1, despite their distinct expression patterns in the meristem and organ boundary, respectively. Our further finding that STM activates expression of the CUC1-targeting microRNA
combined with mathematical modelling provides a potential solution for this apparent contradiction, demonstrating that these proposed regulatory interactions coupled with STM mobility could be sufficient to provide a mechanism for CUC1 localisation at the meristem-organ boundary. Our findings highlight the central role for the STM GRN in coordinating SAM functions.
In order to use environmental models effectively for management and decision-making, it is vital to establish an appropriate level of confidence in their performance. This paper reviews techniques ...available across various fields for characterising the performance of environmental models with focus on numerical, graphical and qualitative methods. General classes of direct value comparison, coupling real and modelled values, preserving data patterns, indirect metrics based on parameter values, and data transformations are discussed. In practice environmental modelling requires the use and implementation of workflows that combine several methods, tailored to the model purpose and dependent upon the data and information available. A five-step procedure for performance evaluation of models is suggested, with the key elements including: (i) (re)assessment of the model's aim, scale and scope; (ii) characterisation of the data for calibration and testing; (iii) visual and other analysis to detect under- or non-modelled behaviour and to gain an overview of overall performance; (iv) selection of basic performance criteria; and (v) consideration of more advanced methods to handle problems such as systematic divergence between modelled and observed values.
► Numerical, graphical and qualitative methods for characterising performance of environmental models are reviewed. ► A structured, iterative workflow that combines several evaluation methods is suggested. ► Selection of methods must be tailored to the model scope and purpose, and quality of data and information available.
Modified clay minerals on Mars
Sedimentary rocks exposed in Gale crater on Mars contain extensive clay minerals. Bristow
et al.
analyzed drill samples collected by the Curiosity rover as it climbed ...up sedimentary layers in the crater. They found evidence of past reactions with liquid water and sulfate brines, which could have percolated through the clay from an overlying sulfate deposit. Similar sulfate deposits are widespread across the planet and represent some of the last sedimentary rocks to form before the planet lost its surface liquid water, so the results inform our understanding of the geologic processes that occurred as Mars dried out.
Science, abg5449, this issue p.
198
Clay minerals examined by the Curiosity rover contain evidence of reactions with sulfate brines as Mars dried out.
Mars’ sedimentary rock record preserves information on geological (and potential astrobiological) processes that occurred on the planet billions of years ago. The
Curiosity
rover is exploring the lower reaches of Mount Sharp, in Gale crater on Mars. A traverse from Vera Rubin ridge to Glen Torridon has allowed
Curiosity
to examine a lateral transect of rock strata laid down in a martian lake ~3.5 billion years ago. We report spatial differences in the mineralogy of time-equivalent sedimentary rocks <400 meters apart. These differences indicate localized infiltration of silica-poor brines, generated during deposition of overlying magnesium sulfate–bearing strata. We propose that destabilization of silicate minerals driven by silica-poor brines (rarely observed on Earth) was widespread on ancient Mars, because sulfate deposits are globally distributed.
Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic ...hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.
IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the ...programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here.
The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay).
At a median of 45.3 months’ follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 95% confidence interval (CI) 0.78-1.28. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively.
Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months’ additional follow-up. Together, these findings support the positive benefit–risk profile of adjuvant atezolizumab in this setting.
•Atezolizumab significantly improved DFS versus BSC after resection and adjuvant chemo in PD-L1+ stage II-IIIA NSCLC.•Atezolizumab appears to extend OS versus BSC post resection and adjuvant chemo in PD-L1 TC ≥50% stage II-IIIA NSCLC.•Although OS was immature, a positive trend favouring atezolizumab that was greatest in the PD-L1 TC ≥50% stage II-IIIA group.
Previous research has explored the effectiveness of wearable activity trackers (wearables) for increasing child physical activity (PA) levels, but there have been mixed results. The use of ...theoretical frameworks and co-design techniques are recognised ways of increasing an intervention's acceptability and effectiveness.
This study aims to use co-design workshops and an evidence-based theoretical framework (the Behaviour Change Wheel) to develop a family-based PA intervention using wearables.
Three stages of intervention development outlined by the Behaviour Change Wheel were used. Co-design workshops with seven families (11 parents and 12 children) and seven PA experts were conducted where stakeholders discussed how to overcome previously identified barriers to families being active and using wearables. This resulted in the intervention's components being developed, with each component's mechanisms of action (e.g. intervention functions and behaviour change techniques) being retrospectively identified.
The ‘Move & Connect’ intervention was developed, which targets family PA and wearable use. The intervention takes a flexible approach and includes eight components, including wearable devices (Fitbit Alta HR), support resources, an introductory workshop, collective challenges, goal setting and reviewing, engagement prompts, social support and health-related resources (e.g. educational videos). The intervention incorporates six intervention functions targeting PA and wearable use: education, training, modelling, persuasion, incentivisation and environmental restructuring and 24 behaviour change techniques, including goal setting, social comparison, feedback on behaviour and graded task.
This is the first known study to use an evidence-based framework and co-design to develop a family-based wearable intervention. The identification of the intervention's mechanisms of action will prove useful when implementing and evaluating the ‘Move & Connect’ intervention and allow researchers to replicate its components.
Genome-wide transcript profiling was used to monitor signal transduction during yeast pheromone response. Genetic manipulations allowed analysis of changes in gene expression underlying pheromone ...signaling, cell cycle control, and polarized morphogenesis. A two-dimensional hierarchical clustered matrix, covering 383 of the most highly regulated genes, was constructed from 46 diverse experimental conditions. Diagnostic subsets of coexpressed genes reflected signaling activity, cross talk, and overlap of multiple mitogen-activated protein kinase (MAPK) pathways. Analysis of the profiles specified by two different MAPKs-Fus3p and Kss1p-revealed functional overlap of the filamentous growth and mating responses. Global transcript analysis reflects biological responses associated with the activation and perturbation of signal transduction pathways.
Chronic tinnitus during childhood/adolescence can be associated with impaired quality of life. Guidelines for managing paediatric tinnitus recommend assessment and interventions are often based upon ...the experiences and opinions of guideline committee members.
To examine patient response tools used for the assessment and management of childhood tinnitus and how interventions had been evaluated.
A structured scoping review (i) identifying and critically appraising patient response measures (PRMs) assessing tinnitus in children/adolescents, and (ii) critically appraising evidence supporting reported interventions. Original papers written in English, involving paediatric participants ≤19 years, reporting (i) application of established PRMs to assess the experience of chronic tinnitus or (ii) application and evaluation of tinnitus interventions were included.
Papers written in English, identifying, or assessing the experience of chronic tinnitus (>3 months) as a primary complaint during childhood/adolescence in participants ≤19 years of age using a PRM and studies evaluating the application of non-pharmaceutical interventions for tinnitus in children/adolescents.
Six studies involving the assessment of tinnitus during childhood/adolescence using a PRM were identified and evaluated. Three established (previously named, described, and published) PRMs were applied of which none were developed specifically for children/adolescents. Three behavioural tinnitus interventions and three combination intervention strategies (coupling of psychological intervention with sound enrichment) had been applied to and evaluated within paediatric populations.
Although clinicians are seeing children/adolescents with tinnitus, they are evaluating and managing children's distress without appropriate PRMs, and little evidence exists to support clinical interventions.
The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been ...recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range IQR, 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.
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