Now showing items 21-40 of 2688

    • Germ cell determination and the developmental origin of germ cell tumors

      In each generation, the germline is tasked with producing somatic lineages that form the body, and segregating a population of cells for gametogenesis. During animal development, when do cells of the germline irreversibly commit to producing gametes? Integrating findings from diverse species, we conclude that the final commitment of the germline to gametogenesis - the process of germ cell determination - occurs after primordial germ cells (PGCs) colonize the gonads. Combining this understanding with medical findings, we present a model whereby germ cell tumors arise from cells that failed to undertake germ cell determination, regardless of their having colonized the gonads. We propose that the diversity of cell types present in these tumors reflects the broad developmental potential of migratory PGCs.
    • Advancing clinical and translational research in germ cell tumours (GCT): recommendations from the Malignant Germ Cell International Consortium

      Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes.
    • Effect of myopia management contact lens design on accommodative microfluctuations and eye movements during reading

      Ghorbani Mojarrad, Neema; Hussain, M.; Mankowska, Aleksandra; Mallen, Edward A.H.; Cufflin, Matthew P. (2024-02)
      Background: Soft contact lenses have been developed and licensed for reducing myopia progression. These lenses have different designs, such as extended depth of focus (EDOF) and dual focus (DF). In this prospective, doublemasked, cross-over study, different lens designs were investigated to see whether these had impact on accommodative microfluctuations and eye movements during reading. Methods: Participants were fitted with three lenses in a randomised order; a single vision (SV) design (Omafilcon A2; Proclear), a DF design (Omafilcon A2; MiSight), and an EDOF lens design (Etafilcon A; NaturalVue),. Accommodative microfluctuations were measured at 25 cm for at least 60s in each lens, using a Shin-Nippon SRW-5000 autorefractor adapted to continuously record accommodation at 22Hz. Eye movement data was collected with the Thomson Clinical Eye Tracker incorporating a Tobii Eye bar. Eye movements include fixations per row, fixations per minute, mean regressions per row, total number of regressions, and total rightward saccades. Accommodation data was analysed using power spectrum analysis. Differences between the lenses were compared using a related sample two-way Friedman test. Results: Twenty-three participants (18–29 years) were recruited to take part. The average mean spherical error was − 2.65D ± 1.42DS, with an average age of 23.4 ± 3.5 years. No significant difference for accommodative microfluctuations was found. Significant differences were found for fixations per row (P = 0.03), fixations per minute (P = 0.008), mean regressions per row (P = 0.002), and total number of regressions (P = 0.002), but not total rightward saccades (P = 0.10). Post-hoc analysis indicated the EDOF lens results were significantly different from the other lenses, with more regressive eye movements observed. Conclusions: Regressive saccades appear to increase when wearing EDOF lens designs, which may impact visual comfort. Further studies in children, over a longer period of adaptation are necessary to assess the potential impact of this finding on daily reading activities in children.
    • Adiponectin negatively regulates pigmentation, Wnt/β-catenin and HGF/c-Met signalling within human scalp hair follicles ex vivo

      Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated microdissected, organ-cultured HFs in the presence or absence of dWAT with a recombinant human adiponectin oligomer mix, or inhibited dWAT-derived adiponectin using a neutralizing antibody. Multiplex qPCR (Fluidigm) revealed that adiponectin oligomers downregulated pigmentation genes KITLG, PMEL and TYRP1 and Wnt genes AXIN2, LEF1 and WNT10B. In situ hybridization showed that adiponectin downregulated AXIN2 and LEF1, and up-regulated DKK1 within the dermal papilla (DP), a highly unusual transcriptional profile for a putative hair growth-promoting agent. Adiponectin oligomers also downregulated protein expression of the HGF receptor c-Met within the matrix and DP. However, adiponectin did not alter hair matrix keratinocyte proliferation within 48 h ex vivo, irrespective of the presence/absence of dWAT; HF pigmentation (Masson-Fontana histochemistry, tyrosinase activity) was also unchanged. In contrast, neutralizing adiponectin isoforms within HF + dWAT increased proliferation, melanin content and tyrosinase activity but resulted in fewer melanocytes and melanocytic dendrites, as assessed by gp100 immunostaining. These seemingly contradictory effects suggest that adiponectin exerts complex effects upon human HF biology, likely in parallel with the pro-pigmentation effects of dWAT- and DP-derived HGF. Our data suggest that dWAT-derived ratios of adiponectin isoforms and the cleaved, globular version of adiponectin may in fact determine how adiponectin impacts upon follicular pigmentation and growth.
    • Supramolecular chemistry enables vat photopolymerization 3D printing of novel water-soluble tablets

      Ong, J.J.; Chow, Y.L.; Gaisford, S.; Cook, M.T.; Swift, Thomas; Telford, Richard; Rimmer, Stephen; Qin, Y.; Mai, Y.; Goyanes, A.; et al. (2023-08-25)
      Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate …
    • Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer

      Presa, Daniela; Khurram, S.A.; Zubir, A.Z.A.; Swaroop, Sneha; Cooper, Patricia A.; Morais, Goreti R.; Sadiq, Maria; Sutherland, Mark; Loadman, Paul; McCaul, Jim; et al. (2021-09)
      Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.
    • Exploring Radio Frequency Techniques for Bone Fracture Detection: A Comprehensive Review of Low Frequency and Microwave Approaches

      This comprehensive review paper examines bone fracture detection techniques based on time-domain low-frequency and microwave radiofrequency (RF). Early and accurate diagnosis of bone fractures remains critical in healthcare, as it can significantly improve patient outcomes. This review focuses on the potential of low-frequency and microwave RF methods, particularly their combination and application of time-domain analysis for enhanced fracture detection. We begin by providing an overview of the fundamental concepts of RF techniques and then by examining biological tissues' dielectric properties. We then compare the advantages and limitations of various bone fracture detection techniques, such as low-frequency RF methods, microwave RF methods, ultrasonography, X-ray, and CT scans. The discussion then shifts to hybrid approaches that combine low-frequency and microwave techniques, emphasising the advantages of such combinations in fracture detection. Machine learning techniques, their applications in bone fracture detection, and the role of time-domain analysis in hybrid approaches are also investigated. Finally, we examine the accuracy and reliability of simulated models for bone fracture detection. We discuss recent advancements and future directions, such as novel sensor technologies, improved signal processing techniques, integration with medical imaging modalities, and personalised fracture detection approaches. This review aims to comprehensively understand the landscape and future potential of time-domain analysis in low-frequency and microwave RF techniques for bone fracture detection.
    • Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol

      There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. Methods and analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. Ethics and dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. Trial registration number NCT03428477.
    • Current approaches to soft contact lens handling training - Global perspectives

      All neophyte contact lens wearers require training on how to handle contact lenses. Currently, almost no published information exists describing the most common approaches used by those involved in such training in soft contact lens wearers. This study aimed to gather information on the approaches taken by those conducting this training worldwide. An online survey was created in English and translated to Spanish and distributed internationally via social media, conference attendees, and professional contacts. The anonymous survey included information on workplace setting of respondents, information about the typical approaches used for application and removal of soft contact lenses, length of the appointment, and success rate with their approach. Survey responses were received between May 2021 and April 2022. A total of 511 individuals completed the survey and responses were received from 31 countries with 48.7% from the UK. The most common approach taught for application was to have the patient hold the upper eyelashes (84.7%) and to hold the lower eyelid with the same hand as the lens (89.4%). Lenses were applied directly to the cornea by 57.7% of the respondents. The most common approach taught for lens removal was to drag the lens inferiorly from the cornea prior to removal (49.3%). Most respondents did not use videos to aid the teaching appointment (62.0%); however, they felt that their approach was successful in most cases (90). Application and removal training sessions lasted a median of 30 min and contact lenses were typically dispensed after the instructor witnessing successful application and removal three times. Various methods are adopted globally for training of application and removal of soft contact lenses, with many advising a patient-specific approach is required for success. The results of this survey provide novel insights into soft contact lens handling training in clinical practice.
    • Clinical investigation of flat pack toric contact lenses and wearer attitudes to environmental impact

      Objectives: To investigate the performance of a novel flat pack toric daily disposable contact lens compared with traditionally packaged toric lenses in a randomized, crossover study. Environmental attitudes to contact lens wear were also explored. Methods: Habitual contact lens wearers were recruited to wear a hioxifilcon A (Miru 1 day Flat Pack Toric, Menicon, Nagoya, Japan) test lens and a control lens: either nelfilcon A (Dailies AquaComfort Plus, Alcon, Geneva, Switzerland) or etafilcon A (1-Day Acuvue Moist, Johnson & Johnson, New Brunswick, NJ). Objective lens performance was assessed at fitting, and participants wore lenses in a randomized order for three consecutive days. Subjective measures of lens performance (comfort, vision, and handling) were then assessed by a questionnaire, with further questions on overall lens preference and environmental perceptions. Results: Objective measures of lens fit were similar for the test and control lenses, except for distance VA which was better with the control lenses (P<0.05; difference of two logMAR letters). End of day comfort was greater with the test lens, but this did not reach significance. Both lenses demonstrated similar scores for overall satisfaction. 87.5% of participants indicated the environmental impact of contact lenses to be important/extremely important to them, with 100% of participants identifying the flat pack packaging as having a smaller environmental impact. Conclusion: Overall, the lenses used in the study performed to similar levels. Environmental credentials are important to contact lens wearers, which may contribute to overall lens preference.
    • Myokines, Measurement, and Technical Considerations

      Skeletal muscle has long been established as a highly multifunctional organ, playing a vital role in locomotion, whole-body metabolic and energy homeostasis, and thermoregulation. More recently, emergent evidence has highlighted a potent secretory role for muscle, producing and releasing “myokine” molecules that act in autocrine, paracrine, or endocrine fashion to govern muscle physiology and regulate whole-body homeostasis via multi-tissue cross talk mechanisms. Myokines represent promising therapeutic targets in health and disease, with their discovery, measurement, and functional importance being a hotbed of research across numerous physiological contexts. Here, we provide an overview of myokines and summarize current understanding of their biological role(s). We also outline primary approaches for myokine analysis, including detailed methodology for performing omics-driven myokine prediction, while further appraising both method-specific and general technical considerations to provide an evidence-based approach for designing and conducting myokine experiments.
    • Spaceflight Induces Strength Decline in Caenorhabditis elegans

      Background: Understanding and countering the well-established negative health consequences of spaceflight remains a primary challenge preventing safe deep space exploration. Targeted/personalized therapeutics are at the forefront of space medicine strategies, and cross-species molecular signatures now define the 'typical' spaceflight response. However, a lack of direct genotype-phenotype associations currently limits the robustness and, therefore, the therapeutic utility of putative mechanisms underpinning pathological changes in flight. Methods: We employed the worm Caenorhabditis elegans as a validated model of space biology, combined with 'NemaFlex-S' microfluidic devices for assessing animal strength production as one of the most reproducible physiological responses to spaceflight. Wild-type and dys-1 (BZ33) strains (a Duchenne muscular dystrophy (DMD) model for comparing predisposed muscle weak animals) were cultured on the International Space Station in chemically defined media before loading second-generation gravid adults into NemaFlex-S devices to assess individual animal strength. These same cultures were then frozen on orbit before returning to Earth for next-generation sequencing transcriptomic analysis. Results: Neuromuscular strength was lower in flight versus ground controls (16.6% decline, p
    • Adaptability to eccentric exercise training is diminished with age in female mice

      The ability of skeletal muscle to adapt to eccentric contractions has been suggested to be blunted in older muscle. If eccentric exercise is to be a safe and efficient training mode for older adults, preclinical studies need to establish if older muscle can effectively adapt and if not, determine the molecular signatures that are causing this impairment. The purpose of this study was to quantify the extent age impacts functional adaptations of muscle and identify genetic signatures associated with adaptation (or lack thereof). The anterior crural muscles of young (4 mo) and older (28 mo) female mice performed repeated bouts of eccentric contractions in vivo (50 contractions/wk for 5 wk) and isometric torque was measured across the initial and final bouts. Transcriptomics was completed by RNA-sequencing 1 wk following the fifth bout to identify common and differentially regulated genes. When torques post eccentric contractions were compared after the first and fifth bouts, young muscle exhibited a robust ability to adapt, increasing isometric torque 20%-36%, whereas isometric torque of older muscle decreased up to 18% (P ≤ 0.047). Using differential gene expression, young and older muscles shared some common transcriptional changes in response to eccentric exercise training, whereas other transcripts appeared to be age dependent. That is, the ability to express particular genes after repeated bouts of eccentric contractions was not the same between ages. These molecular signatures may reveal, in part, why older muscles do not appear to be as adaptive to exercise training as young muscles.NEW & NOTEWORTHY The ability to adapt to exercise training may help prevent and combat sarcopenia. Here, we demonstrate young mouse muscles get stronger whereas older mouse muscles become weaker after repeated bouts of eccentric contractions, and that numerous genes were differentially expressed between age groups following training. These results highlight that molecular and functional plasticity is not fixed in skeletal muscle with advancing age, and the ability to handle or cope with physical stress may be impaired.
    • VEGF stimulates activation of ERK5 in the absence of C-terminal phosphorylation preventing nuclear localization and facilitating AKT activation in endothelial cells

      Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.
    • Talking about falls: a qualitative exploration of spoken communication of patients' fall risks in hospitals and implications for multifactorial approaches to fall prevention.

      McVey, Lynn; Alvarado, Natasha; Healey, F.; Montague, Jane; Todd, C.; Zaman, Hadar; Dowding, D.; Lynch, A.; Issa, B.; Randell, Rebecca (2024-03)
      Inpatient falls are the most common safety incident reported by hospitals worldwide. Traditionally, responses have been guided by categorising patients' levels of fall risk, but multifactorial approaches are now recommended. These target individual, modifiable fall risk factors, requiring clear communication between multidisciplinary team members. Spoken communication is an important channel, but little is known about its form in this context. We aim to address this by exploring spoken communication between hospital staff about fall prevention and how this supports multifactorial fall prevention practice. Data were collected through semistructured qualitative interviews with 50 staff and ethnographic observations of fall prevention practices (251.25 hours) on orthopaedic and older person wards in four English hospitals. Findings were analysed using a framework approach. We observed staff engaging in 'multifactorial talk' to address patients' modifiable risk factors, especially during multidisciplinary meetings which were patient focused rather than risk type focused. Such communication coexisted with 'categorisation talk', which focused on patients' levels of fall risk and allocating nursing supervision to 'high risk' patients. Staff negotiated tensions between these different approaches through frequent 'hybrid talk', where, as well as categorising risks, they also discussed how to modify them. To support hospitals in implementing multifactorial, multidisciplinary fall prevention, we recommend: (1) focusing on patients' individual risk factors and actions to address them (a 'why?' rather than a 'who' approach); (2) where not possible to avoid 'high risk' categorisations, employing 'hybrid' communication which emphasises actions to modify individual risk factors, as well as risk level; (3) challenging assumptions about generic interventions to identify what individual patients need; and (4) timing meetings to enable staff from different disciplines to participate.
    • Pottery

      An interim report on pottery recovered during underwater surveys undertaken around a series of artificial islets on the islands of North and South Uist in 2022.
    • Pottery

      Copper, Michael (2022-08)
      An interim report on pottery excavated at the Neolithic islet of Loch Bhorgastail, Isle of Lewis, Scotland, in 2021.
    • The effect of aspirin and eicosapentaenoic acid on urinary biomarkers of prostaglandin E2 synthesis and platelet activation in participants of the seAFOod polyp prevention trial

      Sun, G.; Fuller, H.; Fenton, H.; Race, Amanda D.; Downing, A.; Williams, E.A.; Rees, C.J.; Brown, L.C.; Loadman, Paul; Hull, M.A. (2024-03)
      Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤ .001] and 8% [P ≤ .05] reduction in median 11-d-TXB2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation.
    • Polymorphisms in Cyclooxygenase, Lipoxygenase and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial

      Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 single nucleotide polymorphisms (SNPs) in oxylipin metabolism genes such as cyclooxygenase [PTGS] and lipoxygenase [ALOX], as well as 7 SNPs already associated with colorectal cancer (CRC) risk reduction by aspirin (eg. TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomised 2x2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. Five hundred and forty-two (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (IRR 0.69 [95%CI 0.53,0.90]; q=0.06), rs2745557 (PTGS2) compound heterozygote-rare homozygotes (IRR 0.60 [0.41,0.88]; q=0.06), rs7090328 (ALOX5) rare homozygotes (IRR 0.27 [0.11,0.64]; q=0.05), rs2073438 (ALOX12) common homozygotes (IRR 0.57 [0.41,0.80]; q=0.05), and rs104522 (TP53) rare homozygotes (IRR 0.37 [0.17,0.79]; q=0.06). No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalised, predictive models of CRC chemoprevention by aspirin.
    • Pottery from BHO16; Pottery from LAN16/17; and The pottery

      This interim report covers archaeological work undertaken at two Neolithic islet sites or crannogs, Loch Bhorgastail and Loch Langabhat, on the Isle of Lewis, Outer Hebrides, from 15-29 July 2017 (Figure 1). Fieldwork in 2017 included photogrammetric survey of both stone-built islets (under and above water), palaeoenvironmental coring of both loch beds, excavation at Loch Langabhat and vegetation clearance at Loch Bhorgastail. This work followed on directly from fieldwork carried out in 2016; the present report should therefore be read in conjunction with that report (Garrow, Sturt & Copper 2017). Our main results for fieldwork in 2017 included: • Construction of detailed 3D photogrammetric models of both sites • A better understanding of the construction techniques used in the creation of both islets • Recovery of c. 0.60m of core material from each loch for palaeoenvironmental assessment • The identification and excavation of occupation deposits and a small structure at Loch Langabhat