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Background The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. Methods Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I–III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. Results A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). Conclusion Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.

Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes.We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics.Baseline plasma arginine, threonine, α-aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes.These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

The authors will present examples of how revising base layer control strategies have resulted in improved compressor operation in a mature deep-water asset. The revised control strategies have resulted in improved production and capacity whilst reducing greenhouse gas production. Existing control schemes were in place for multiple compressors at the asset; Vapor Recovery (VRU), Gas Lift (GLC) and Field Gas Compression (FGC). In the case of the VRU, process dynamics exceeded the ability of the control scheme to provide good control and a new valve position control scheme was designed and implemented. Further gains were realized through automated surveillance techniques which identified controller induced disturbances which when removed increased useable capacity by 16%. For the Gas Lift compressor, the initial control scheme would not work under low gas lift demand conditions. The control scheme was dealing with upstream disturbances, resulting in frequent trips and higher than expected energy consumption. Finally the FGC control scheme was adjusted to allow recycle to be minimized at all times without compromising process control. Through the use of new control strategies existing compressors are being operated in new and more efficient ways. This has led to direct results to the business in terms of additional oil and gas production whilst also reducing energy intensity in line with the business strategy. Furthermore, the changes have resulted in reduced recycling meaning the compressors are capable of greater useable throughput. The wear to control valves has also been reduced. The field examples presented show how advanced surveillance tools and strategy adjustments can lead to meaningful and cost-effective improvements even for control schemes that were initially meeting expectations. With the focus on energy efficiency being renewed by the oil and gas industry the examples given may extend to other production facilities.

The vestibular lamina (VL) forms the oral vestibule, creating a gap between the teeth, lips and cheeks. In a number of ciliopathies, formation of the vestibule is defective, leading to the creation of multiple frenula. In contrast to the neighbouring dental lamina, which forms the teeth, little is known about the genes that pattern the VL. Here, we establish a molecular signature for the usually non-odontogenic VL in mice and highlight several genes and signalling pathways that may play a role in its development. For one of these, the Sonic hedgehog (Shh) pathway, we show that co-receptors Gas1, Cdon and Boc are highly expressed in the VL and act to enhance the Shh signal from the forming incisor region. In Gas1 mutant mice, expression of Gli1 was disrupted and the VL epithelium failed to extend due to a loss of proliferation. This defect was exacerbated in Boc/Gas1 double mutants and could be phenocopied using cyclopamine in culture. Signals from the forming teeth, therefore, control development of the VL, coordinating the development of the dentition and the oral cavity.

The tear test is widely used to measure the fracture toughness of thin rubber sheets and polymer films. More recently, the tear test has been applied to polymer materials produced by melt extrusion additive manufacturing to measure the fracture toughness of a single weld between two printed (extruded) filaments. This paper presents a finite element modeling study of the tearing of a weld between two printed filaments to investigate the mechanics of the tear test and the effects of geometry and material properties on the measured tear energy. The mechanical behavior of the printed filaments was described by a viscoplastic model for glassy polymers and the weld was represented using cohesive surface elements and the Xu–Needleman traction–separation relationship. The geometric model and the material parameters were chosen based on experimental measurements. The tear energy varied with the specimen dimensions, the curvature of the printed filaments, the yield stress relative to the cohesive strength of the weld, and the post-yield stress drop. The effects of the hardening modulus were small. These factors altered the viscoplastic dissipation in the material ahead of the propagating crack tip. The results showed that viscoplastic dissipation could constitute a large fraction of the tear energy and is strongly affected by the specimen dimensions and the geometry and material properties of the printed filament. There was also considerable mode mixty in the tear energy. The findings can be used to design tear tests to measure the intrinsic fracture toughness of the weld.

Worldwide, falls and accompanying injuries are increasingly common, making their prevention and management a critical global challenge. The wealth of evidence to support interventions to prevent falls has recently (2022) been distilled in the first World Falls Guideline for Prevention and Management for Older Adults. The core of falls prevention includes (i) risk assessment and stratification; (ii) general recommendations on optimising physical function and mobility for all and (iii) offering a holistic, multidomain intervention to older adults at high risk of falls, in which the older adult’s priorities, beliefs and resources are carefully considered. In recent decades, sustainable and adequately resourced falls prevention has proved challenging, although evidence suggests that suboptimal implementation of falls prevention is ineffective. Future research should focus on understanding the most successful approaches for implementation. To further optimise falls prevention, recent developments include technological innovation to identify and prevent falls, including exergaming. Further work is warranted to understand how to best incorporate the concepts of frailty and sarcopenia in falls prevention and management. This themed collection includes key articles in the field of falls prevention, covering several topics including risk factors, effective interventions, older adult’s views, implementation issues and future perspectives.

Background our aim was to assess the effectiveness of medication review and deprescribing interventions as a single intervention in falls prevention. Methods Design systematic review and meta-analysis. Data sources Medline, Embase, Cochrane CENTRAL, PsycINFO until 28 March 2022. Eligibility criteria randomised controlled trials of older participants comparing any medication review or deprescribing intervention with usual care and reporting falls as an outcome. Study records title/abstract and full-text screening by two reviewers. Risk of bias Cochrane Collaboration revised tool. Data synthesis results reported separately for different settings and sufficiently comparable studies meta-analysed. Results forty-nine heterogeneous studies were included. Community meta-analyses of medication reviews resulted in a risk ratio (RR) of 1.05 (95% confidence interval, 0.85–1.29, I2 = 0%, 3 studies(s)) for number of fallers, in an RR = 0.95 (0.70–1.27, I2 = 37%, 3 s) for number of injurious fallers and in a rate ratio (RaR) of 0.89 (0.69–1.14, I2 = 0%, 2 s) for injurious falls. Hospital meta-analyses assessing medication reviews resulted in an RR = 0.97 (0.74–1.28, I2 = 15%, 2 s) and in an RR = 0.50 (0.07–3.50, I2 = 72% %, 2 s) for number of fallers after and during admission, respectively. Long-term care meta-analyses investigating medication reviews or deprescribing plans resulted in an RR = 0.86 (0.72–1.02, I2 = 0%, 5 s) for number of fallers and in an RaR = 0.93 (0.64–1.35, I2 = 92%, 7 s) for number of falls. Conclusions the heterogeneity of the interventions precluded us to estimate the exact effect of medication review and deprescribing as a single intervention. For future studies, more comparability is warranted. These interventions should not be implemented as a stand-alone strategy in falls prevention but included in multimodal strategies due to the multifactorial nature of falls. PROSPERO registration number: CRD42020218231

Aim Antidepressants are well-established fall-risk increasing drugs(FRIDs) and therefore falls should be considered an important adverse drug event(ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry(LC-MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration, or concentration change over time (delta) and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor(SSRI) and 41 antidepressant(TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07-5.87, crude model). Adjusted there were no significant associations between concentrations of SSRIs and fall risk. Also, for delta concentrations there was no association with fall risk in users. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, replication in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.