DOP28 Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort

Background Proteomic biomarkers have been linked to anti-TNF treatment failure, but previous studies have been insufficiently powered to stratify associations by drug level. The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a prospective UK-wide study investigating treatment failure in 1610 anti-TNF naïve patients. We aimed to identify proteomic markers of treatment failure. Methods We sampled patients with primary non-response (PNR) (n = 223) and remission (n = 219) who had a baseline CRP ≥4 mg/l and/or calprotectin >100 µg/g. PNR was defined at week 14 as ongoing steroids, or both of HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/l. Non-remission at week 54 was defined as HBI >4 and CRP >3 mg/l and no steroids. Targeted serum proteomic analysis of 180 proteins using Olink Inflammation and Immune Response panels were performed. Mann–Whitney U tests were used to identify baseline proteins that predicted PNR and non-remission. Sub-group analyses stratified by drug level were undertaken. Pharmacokinetic (PK) failure was defined as PNR with low drug level (infliximab level <2 mg/l, adalimumab level <6 mg/l) and pharmacodynamic (PD) failure as PNR despite adequate drug level. Significant proteins were entered into multivariable logistic regression models and Bayesian information criterion (BIC) with backward stepwise selection were used to build predictive models of treatment failure. We applied 10-fold cross-validation to test the models. P-values of < 0.05 were considered significant. Results Elevated fibroblast growth factor 21 (FGF21) (OR 1.3, CI 1.1–1.4, p = 3.4 × 10–5) and interleukin-10 receptor subunit α (IL10RA) (OR 1.6, CI 1.2–2.1, p = 6.3 × 10–4) predicted PNR (Figure 1). At week 14, FGF21 (OR 1.5, CI 1.3–1.9, p = 1.8 × 10–6) and IL10RA (OR 1.8, CI 1.3–2.3, p = 5.8 × 10–5) levels were also associated with PNR. graphic Sub-group analyses showed baseline FGF21 (OR 1.4, CI 1.2–1.7, p = 2.0 × 10–4) predicted PK failure and that IL10-RA (OR 1.6, CI 1.1–2.2, p = 6.7 × 10–3) predicted PD failure (Figure 2). graphic In separate models, non-remission at week 54 was predicted by baseline (FGF21; OR 1.3, CI 1.1–1.4, p = 1.4 × 10–4, IL10-RA; OR 1.5, CI 1.1–2.0, p = 3.6 × 10–3) and week 14 (FGF21; OR 1.4, CI 1.2–1.7, p = 3.6 × 10–4, IL10-RA; OR 1.7, CI 1.3–2.4, p = 1.7 × 10–4) FGF21 and IL10-RA levels. Model validation of baseline FGF21 and IL10-RA showed an area under the curve of 0.61 (CI 0.57–0.64) for PNR and 0.60 (CI 0.56–0.64) for non-remission at week 54. Conclusion Our study identified FGF-21 and IL10-RA as proteins of interest associated with PK and PD treatment failure, respectively. Functional studies to determine the molecular mechanism driving dysregulation of these proteins are required.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo), submitted versio

Antibacterial and antifungal activities of the extract and fractions of aerial parts of Heliotropium bacciferum

Background: H. bacciferum belonging to the family Boraginaceae is an important medicinal plant. The current research was carried out to investigate the medicinal properties of this plant.Methodology: The crude (methanol fraction) and n-hexane, ethyl acetate, butanol and aqueous fractions were subjected to antibacterial and antifungal activities by using standard methodology available in literature. Bacterial strains of Salmonella typhi, Escherichia coli, Pseudomonas Aeroginosa, Staphylococcus aureus, Erwinia carotovora, Klebsiella Pneumoniae, Bacillus subtilis and Bacillus atrophaeus were used for antibacterial activity.Results: All the fractions were active against different bacterial strains but n-hexane and ethyl acetate showed (Zone of inhibition ranged from 18-30 mm) highest activity. The fungal strains, Trichoderma longibrachiantum, Aspergillus flavus, Aspergillus niger, Fusarium solani and Candida albican were used for antifungal activity. Excellent inhibitory effect was observed against all fungal strains. The minimum inhibitory concentration (MIC) against various fungal strains was determined. The minimum inhibitory concentrations (MICs) of the investigated plant fractions ranged from 0.5- 2.00 mg/ml.Conclusion: The plant showed significant antibacterial and antifungal activities. All tested plant extracts exhibit activities against different fungal strains. The result against various microorganisms shows the therapeutic potential of the plant H. bacciferumKeywords: H. bacciferum, Medicinal Plant, crude fractions, Antimicrobial activities

Identification of common genetic markers of paroxysmal neurological disorders using a network analysis approach

Emerging data have established links between paroxysmal neurological disorders or psychiatric disorder, such as migraine, ataxia, movement disorders and epilepsy. Common gene signatures such as expression, protein interaction and the associated signalling pathways link genes in these associated disorders, with the object to predict unknown disease or risk genes. In this study, we used gene interaction networks to investigate common gene signatures associated with the above phenotypes. In total, 19 candidate genes were used for making an interaction network which further revealed 39 associated genes (including KCNA1, SCN2A, CACNA1A, KCNM4, KCNO3, SCN1B and CACNB4) implicated in paroxysmal neurological disorders development and progression. The meta-regression analysis showed the strongest association of SCN2A with genes involved in schizophrenia and neurodevelopmental disorders. Importantly, our analysis showed KCNMA1 as a common gene signature with a link to epilepsy, movement disorders and wide paroxysmal neurological presentations—with the greatest potential risk of being a disease gene in a paroxysmal or psychiatric disorder. Further gene interaction analysis is required to identify unidentified gene interactions which may be targets for future drugs development

Calcaneal fractures: an audit of radiological outcome.

Abstract OBJECTIVE: To assess radiological outcome of management of calcaneal fractures. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised data of calcanealfractures managed between February , 2008 and February, 2014 Cases were identified through medical records, and X-rays were reviewed through digital radiology archive. Bohler\\u27s angle, Gissane\\u27s angle, calcaneal height and width were assessed digitally on pre-operative and post-operative X-ray images. RESULTS: Of the27 patients, only 1(3.7%) was female. The cause of fracture was fall from height 15(56%), road traffic accidents 7(26%) and bomb blasts5(19%). Tongue type fractures were 16(59%) and 11(41%) were joint depression type. There was a significant mean increase in Bohler\\u27s angle (p0.05 each). CONCLUSIONS: Measurable improvement in anatomical parameters is possible with surgery, which is a prerequisite for good functional results

Stem Cell Organoids in Primary Cultures of Human Non-Malignant and Malignant Colon

YesA sub-population of cells named cancer stem cells (CSCs) that initiate and promote tumour growth have been demonstrated to exist in several malignancies including colon carcinoma. The objective of our pilot study was to isolate CD133+CD26+CD44+ CSCs from patient colon tumours, culture spheres or organoids and observe their proliferation in primary cultures. Parallel cultures of non-cancer controls from colon normal lining and nonadenomatous polyps were set up. Magnetic activated cell sorting was used to isolate CD133+CD26+CD44+ cell populations followed by primary cell culturing under stem cell culture conditions. Number, cells/organoid and daughter generations of organoids were calculated using phase contrast microscope. Trypan blue exclusion method was used to test the viability of the cells. Both colon tumour and colon non-adenomatous polyp formed floating organoids in suspension; however non-adenomatous polyp cultures did not show self-renewal properties for more than 1 passage. Normal colon singlecell suspension did not create organoids. Metastatic colon tumours rapidly produce cancer cell organoids in less than 24 hours in larger numbers compared to non-metastatic colon tumours (1-3 weeks). Metastatic colon tumour organoids have the ability for proliferation for upto five daughter generations in primary culture compared to three generations for those grown from non-metastatic tumours. This in vitro CSC organoid model will help study colon cancer biology, in particular providing a valuable source of primary cell-derived tissue for studying personalized molecular profiling using ‘omics strategies to direct therapeutic intervention

Spearmint (\u3cem\u3el\u3c/em\u3e-carvone) Oil and Wintergreen (methyl salicylate) Oil Emulsion is an Effective Immersion Anesthetic of Fishes

This study evaluates the effects of a spearmint (/-carvone) and wintergreen oil (methyl salicylate) emulsion (CMSE) on age 1 landlocked Atlantic salmon Salmo salar sebago (hereafter salmon). Salmon were immersed in either 257 µl/L CMSE or 75 mg/L tricaine methanesulfonate (MS-222) to induce anesthesia (stage 4), useful for emersion and noninvasive husbandry procedures, and then salmon were recovered in fresh water. Induction was quicker in the CMSE group; however, recovery was quicker in the MS-222 group. A second experiment was conducted in which salmon were immersed in 257 µl/L CMSE for 8.5 min, or 75 mg/L MS-222 for 8.5 min in order to compare electrocardiographs during deeper anesthesia (stage 5) between salmon continuously immersed in CMSE to those continuously immersed in MS-222. Because salmon remained sedated longer after CMSE exposure than after MS-222 exposure, a third group of salmon was immersed in 257 µl/L CMSE for just 2.5 min before undergoing the 6-min electrocardiograph procedure. Anesthesia induction rates, recovery rates, and electrocardiographs of salmon anesthetized with CMSE were comparable to salmon anesthetized with MS-222. Salmon anesthetized with CMSE and then transferred immediately to fresh water had more stable heart rates than salmon anesthetized with either MS-222 or CMSE continuously. Salmon bathed continuously in CMSE showed clinical signs of increasing anesthetic depth including decreasing heart rate, decreasing respiration rate and electrocardiograph abnormalities. The CMSE, with its mint and wintergreen concentrations less than in household products such as chewing gum, toothpaste, and mouthwash, is a potent, rapid-acting immersion fish anesthetic comparable to MS-222 for stages 4 and 5 anesthesia

A novel comprehensive analysis of the refinements of Hermite-Hadamard type integral inequalities involving special functions

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Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

A SWOT Analysis approach for the development of Photovoltaic (PV) energy in Northern Nigeria

This research employs a comprehensive Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis to investigate the advancement of photovoltaic (PV) energy in Northern Nigeria. The study delves into the intricacies of introducing PV systems within the context of economic challenges, including issues such as currency volatility and inflation, which amplify costs and impede capital investments. Environmental factors, such as dust and sandstorms, are identified as obstacles diminishing the efficiency of solar panels. Additionally, security concerns in remote areas elevate operational costs and influence investment decisions. This paper proposes effective mitigation strategies, encompassing widespread public awareness campaigns to augment market engagement, the establishment of mini-grid systems for enhanced energy distribution, customised on-the-job training programs to foster local expertise in PV technology, and the utilisation of micro-grid systems as experimental grounds for regulatory and policy testing. By synthesising these components, the study offers a comprehensive overview of the prerequisites essential for the successful proliferation of PV energy in Northern Nigeria. Emphasis is placed on the potential for solar energy to significantly contribute to the region's sustainable development and achieve energy independence when the identified strength, and opportunities are exploited. The key strength identified are the average Global horizontal irradiance (GHI) of 5.436kWh/m2, Direct Normal Irradiance (DNI) of 1534-1680kWh/m2, Levelised Cost of Electricity (LCoE) of $0.1, and an opportunity to fully utilise the over$ 7.88 million grant authorised by the African Development Bank (AfDB) from the Sustainable Energy Fund for Africa