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DNA methylation is an important epigenetic modification that is widely conserved across animal genomes. It is widely accepted that DNA methylation patterns can change in a context-dependent manner, including in response to changing environmental parameters. However, this phenomenon has not been analyzed in animal livestock yet, where it holds major potential for biomarker development. Building on the previous identification of population-specific DNA methylation in clonal marbled crayfish, we have now generated numerous base-resolution methylomes to analyze location-specific DNA methylation patterns. We also describe the time-dependent conversion of epigenetic signatures upon transfer from one environment to another. We further demonstrate production system-specific methylation signatures in shrimp, river-specific signatures in salmon and farm-specific signatures in chicken. Together, our findings provide a detailed resource for epigenetic variation in animal livestock and suggest the possibility for origin tracing of animal products by epigenetic fingerprinting.

Objective: The management of inflammatory bowel disease (IBD) patients on complex medications such as biologic disease-modifying anti-rheumatic drugs (DMARD) requires close supervision. At East Sussex NHS Healthcare Trust (ESHT), the multi-disciplinary team (MDT) already looking after these patients could benefit from the additional knowledge and support from a specialist pharmacist (SP). Methods: To assess if the MDT could benefit from an SP, all IBD patients on the DMARD adalimumab were identified. The patient records were screened for patient demographic data, clinical assessment and investigations, treatment, and follow-up clinics. Results: 162 patients at ESHT were identified as being on adalimumab treatment for either Crohn’s Disease (77%) or Ulcerative Colitis (23%). Disease activity scores, a clinical measure of IBD severity, were infrequently recorded (1%) on patient letters. Evidence of a biologic screen, a series of investigations to ensure safety in a biologic treatment, was only evident in one-third of patients. Clinic review of patients recently started on adalimumab and annual review of stable patients occurred 43% and 26% respectively. Conclusion: The results indicate that there is a need for an additional member to support the IBD MDT in managing this cohort of patients. An SP is uniquely positioned to fill this gap. They have extensive knowledge in drug indication, therapeutic drug monitoring, and side-effect profiles. Similar studies have been identified that support SP in this role.

AimsIt is currently unclear which approach to staff management during Covid-19 disruption allows clinical practice optimization whilst ensuring junior doctor resilience. Our project aimed to provide an optimised surge rota at East Sussex Healthcare Trust during the second Covid-19 surge to improve workforce experience and to allow us to prepare for future surges while ensuring patient safety.MethodsA novel surge rota was developed alongside a diverse group of representatives with backgrounds in medical education, hospital management and general medicine. The new rota was more flexible and built on the regular 2016 Junior Doctor contract with the addition of supportive staffing and environmental changes. These included a variety of changes informed by the previous discussions regarding the rota used during the first surge. Improvement was measured during feedback sessions with individual doctors. Furthermore, qualitative and quantitative questionnaire data was gathered and analysed using descriptive statistics for presentation and summary.ResultsOur results suggest the novel surge rota was an improvement upon other rotas used during the first Covid-19 surge. The main factors that affected this were: more senior and specialist support, timely consultant assessment of newly admitted patients, and extra locum cover. The novel rota facilitated more flexible workforce distribution, translating into improved overall junior doctor wellbeing throughout the surge.ConclusionsThe identified rota tactics are recommended for future disruption and more can be understood on this topic. Open communication through hierarchies and disciplines is pertinent when synthesising diverse stakeholder opinions. A well-received surge rota is possible and rewarding, with improvements to be seen nationally. Moving forward, it is important to develop surge rota designs to improve resilience to chronic disruption, reduce burnout, and most importantly improve patient safety.

Introduction Biosimilars of adalimumab are now used throughout the National Health Service (NHS). Patients who switch to biosimilars may develop adverse effects such as cutaneous reactions or disease flares, and are sometimes switched back (reverse switching) to the originator. There is limited information about the outcomes of these switchbacks, particularly in the event of disease flares. At East Sussex NHS Trust (ESHT), clinical information regarding switchback patients was collected and the outcomes analysed to gain a better understanding of the effects of reverse switching. Methods This was a retrospective review of a database of all IBD patients who underwent switching from the originator (Humira®) to biosimilar adalimumab (Imraldi®) at ESHT. Patients who encountered adverse events post-switch were discussed at the IBD multi-disciplinary meeting and a consensus decision was made whether a switchback was appropriate. Data was collected on Harvey Bradshaw Index (HBI), Simple Colitis Activity Index (SCCAI),C reactive protein, faecal calprotectin (FC) and adverse event reports. Disease flare for this study was defined as symptoms suggestive of a flare in conjunction with a rise in HBI/SCCAI. Patients who were switched back were followed up by the IBD specialist nurse and clinical outcomes post-switchback were documented. Results At ESHT, 113 IBD patients were switched to Imraldi®(Biogen). There were in total 17 switchbacks (12 female, 5 male) to the originator Humira®(Abbvie). 11 of the switchbacks were due to cutaneous reactions/severe pain on injection/joint pain. These 11 patients continue to remain on Humira®. 6 of the switchbacks were due to disease flare (3 patients on weekly dosing, 3 patients on fortnightly dosing). Of these 6 switchbacks, only 4 patients remain on the originator to date. 1 patient was assessed further with tests and her symptoms were found to be functional in nature. 1 patient was switched to vedolizumab. 1 patient had a further hospital admission for a Crohn’s flare that required steroids but remains on Humira®. The rate of capture of clinical response was 50% if the switchback was due to a disease flare. Conclusions As more NHS Trusts engage in switches to adalimumab biosimilars, they will increasing also face patients where a switchback may be considered. Our local experience shows that switchbacks instigated due to a disease flare should be considered with caution as the rate of clinical response is low. More research is required to ascertain the true effects of switchbacks on patient clinical outcomes to devise appropriate treatment algorithms for such situations.

Dyspepsia is a common symptom and the priority is to identify alarm signals that necessitate endoscopy referral. Our Drug review discusses its investigation, management and some new drug developments, followed by sources of further information.

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers and KRAS mutation occurs in 25-30% of NSCLC. Therapeutics directly targeting KRAS mutant proteins are currently not available. We developed a novel siRNA therapeutic against Glutathione S-Transferase P (GSTP), a gene target that is highly expressed in KRAS mutant NSCLC and is also involved in modulating RAS signaling pathway proteins. GSTP has been known as a Phase II detoxification enzyme and a modulator of MAP kinase-related cell-signaling pathways. Therefore, developing a GSTP inhibiting siRNA may be an effective therapeutic approach to treat KRAS mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle (LNP) with a size of less than 70 nm, comprising GSTP siRNA (NDT-05-1040) and a novel ionizable, non-immunogenic, biodegradable lipid developed to target tumors in the lung. Our studies evaluated biodistribution and in vivo antitumor activities of NBF-006 in KRAS mutant NSCLC xenograft models. NBF-006 delivered siRNA molecules favorably to the lungs and tumor as compared to other tissues, with 70-80% of tumor cells showing siRNA uptake. Significant tumor growth inhibition (P *These authors contributed equally. Citation Format: Zhihong O'Brien*, Li Wang*, Bharat Majeti*, Jeanpierre Clamme, Robiel Baclig, James Chu, Steven Fong, Jens Harborth, Jose Ibarra, Haiqing Yin, Jing Yu, Clayton Zhang, Roger Adami, Sonya Zabludoff, Wenbin Ying. A novel lipid nanoparticle (NBF-006) encapsulating glutathione S-transferase P (GSTP) siRNA for the treatment of KRAS-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5917.

We have successfully integrated an embedded Flash technology into a 65-nm leading-edge logic technology. We have also optimized the logic transistor characteristics to achieve an extremely low standby current suitable for consumer applications.

Background New medications for treating HIV/AIDS are effective, but expensive, and funding shortfalls have led many state AIDS Drug Assistance Programs (ADAPs) to ration these drugs. Little is known about the views of those most directly affected by rationing policies. This study explores attitudes of patients with HIV and the general public toward specific rationing strategies. Methods A Likert-style, self-administered questionnaire about rationing expensive HIV medications in the context of a budget shortfall was administered to patients with HIV and shopping mall patrons in central Pennsylvania. Subjects were asked how much they agreed or disagreed with seven drug rationing policies. Results In all, 100 patients and 101 shoppers completed the survey (response rate = 89%). A majority in both groups "strongly" or "somewhat" disagreed with six of the seven rationing policies described, and patients more strongly disagreed with the policies than did the public. The five policies actually used by state ADAPs (first come first serve, limiting expensive medicines, limiting new patient enrollment, giving the expensive medicines to the sickest, using a spending cap) lacked support in either group. Conclusions HIV drug rationing policies currently in use do not reflect the preferences of patients and the public. Integrating the views of those affected by the rationing decisions would raise difficult challenges to current programs.

We have successfully integrated an embedded flash technology into a 90 nm leading edge logic technology to realize superior FPGA products with only 10% additional process steps. The stacked gate memory cell is completely compatible with Cu and a low-k interconnection and has excellent flash reliability. Achieving the same logic performance as the non-embedded technology maximizes the utilization of design resources between the non-embedded technology and the embedded flash technology.

Cystamine together with colchicine markedly enhanced the uptake of [3H]-thymidine into DNA of quiescent cultures of insulin-stimulated Swiss 3T3 mouse fibroblasts. Flow cytofluorometric analyses showed an increased rate of transition of cells from G0/G1----S + G2 in response to combinations of insulin, colchicine, and cystamine. Cystamine, the most effective of several thiol compounds, gave maximal augmentation at 200 microM and was toxic at 300-500 microM. Amplification of DNA synthesis by cystamine was also obtained with epidermal growth factor, vasopressin, and 0.5% fetal bovine serum. Combinations of cystamine and other microtubule-disrupting agents such as nocodazole, maytansine, and podophyllotoxin enhanced DNA synthesis in insulin-stimulated cells. In experiments involving sequential addition of agents, significant enhancement of DNA synthesis was observed when the addition of colchicine to cystamine-treated cells was delayed or conversely when the addition of cystamine to colchicine-treated cultures was delayed. This reciprocal interaction between cystamine and colchicine suggests that a prereplicative intermediate accumulates in response to the action of these dissimilar compounds. We consider the possibility that cystamine may act by forming mixed disulfides with thiol groups of unknown protein(s) that regulate DNA replication.

The phenotype of fibroblasts repopulating experimental wounds in vivo has been shown to influence both wound healing responses and clinical outcome. Recent studies have demonstrated that the human homeobox gene PRX-2 is strongly upregulated in fibroblasts within fetal, but not adult, mesenchymal tissues during healing. Differential homeobox gene expression by fibroblasts may therefore be important in mediating the scarless healing exhibited in early fetal wounds. RNase protection analysis demonstrated that murine Prx-2 expression was involved in fetal but not adult wound healing responses in vitro. Using fibroblasts established from homozygous mutant (Prx-2-/-) and wild-type (Prx-2+/+) murine skin tissues it was demonstrated that Prx-2 affected a number of fetal fibroblastic responses believed to be important in mediating scarless healing in vivo; namely cellular proliferation, extracellular matrix reorganization, and matrix metalloproteinase 2 and hyaluronic acid production. These data demonstrate how Prx-2 may contribute to the regulation of fetal, but not adult, fibroblasts and ultimately the wound healing phenotype. This study provides further evidence for the importance of homeobox transcription factors in the regulation of scarless wound healing. A further understanding of these processes will, it is hoped, enable the targeting of specific therapies in wound healing, both to effect scarless healing and to stimulate healing in chronic, nonhealing wounds such as venous leg ulcers.