Background Tofacitinib is a partially selective Janus kinase inhibitor approved for the treatment of refractory moderate to severe ulcerative colitis [UC]. We sought to define the effectiveness and adverse effects of tofacitinib in a real-world cohort. Methods We conducted a retrospective observational cohort study of 134 patients with UC [64% male; median age 37 years [range 16–81]; 83% of patients had previously received at least one biologic] treated with tofacitinib from October 2018 to October 2019 in four UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index [SCCAI] or partial Mayo score [PMS], depending on study site. Response and remission were defined as a reduction in SCCAI or PMS of ≥3and SCCAI ≤2 or a PMS ≤1, respectively. Results Overall, 74% (88/119; 95 confidence interval [CI] 65–81%] patients responded to tofacitinib at Week 8 and steroid-free remission was observed in 44% [47/108; 95% CI 3453%] patients at Week 26. Primary non-response was independently associated with younger age [p = 0.014] and higher C-reactive protein [CRP] levels at baseline [p = 0.004]. Only 23% [3/13] of patients who continued tofacitinib in the setting of primary non-response were in steroid-free remission at Week 26. Prior biologic exposure did not influence response or remission rates. Dose escalation, however, recaptured response in approximately half of patients who had lost response. Dyslipidaemia was observed in 20% [27/134; 95% CI 1428%] of patients, but adverse events necessitating drug withdrawal were uncommon and no venous thromboembolic events occurred. Conclusions In this multicentre real-world cohort, tofacitinib was well tolerated and clinically effective in a treatment-refractory UC population.

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HighlightsWe investigated the mechanisms of lipid bioaccessibility from almond muffins.An in vitro dynamic gastric model was used to simulate human digestion.A pilot ileostomy study was performed to define the rate of lipid release.Microstructural analysis proved that some lipid remained encapsulated within matrix.The cell-wall is the main factor regulating the lipid bioaccessibility.

ABSTRACT-The prevalence of obesity is rising worldwide, with the UK having the highest prevalence in Europe. Obesity is associated with significant morbidity and has substantial healthcare implications, with current projections estimating that by 2030 obesity will cost the NHS approximately £2 billion each year. Lifestyle modification remains the cornerstone of antiobesity treatment, but drugs can be introduced as adjuncts to assist and maintain weight loss. Some 1.45 million obesityrelated prescriptions were dispensed in 2009, highlighting the high demand for obesity pharmacotherapy. At present, the lipase inhibitor orlistat (Xenical) is the only UK-approved longterm medical therapy for obesity. Double-blind clinical trials have shown that orlistat significantly increases weight loss compared to placebo, but the array of adverse side effects associated with orlistat limits its tolerability. The need for more effective and better-tolerated anti-obesity medications is clear and six therapies have reached phase-III trials. KEY WORDS: Obesity, pharmacotherapy BackgroundThe incidence of obesity is rising worldwide and the UK is amongst the worst-affected countries, with 30% of adults in the UK being obese. In addition, 30% of UK children aged 2 to 15 are overweight or obese. 1 The prevalence of obesity in the UK population is projected to reach 50% by 2050 (Fig 1), 2,3 with the cost of this condition and its associated co-morbidities predicted to cost the NHS some £2 billion per year by 2030. 3 The terms 'overweight' and 'obese' are defined as having a body mass index (BMI) greater than 25 kg/m 2 and 30 kg/m 2 , respectively. These values should, however, be used with caution as BMI is not a direct measure of adiposity. The National Institute of Clinical Excellence (NICE) recommends that waist circumference (above 88 cm for women or 102 cm for men being considered raised) is used in conjunction with BMI when describing the extent of obesity and predicting the extent of associated health risks. 4 The development of obesity is characterised by the interplay of nature and nurture. Genetic factors that are known to predispose individuals to obesity were probably once advantageous in resourcedeficient environments, where energy-conservation was essential for survival. With modern environments providing cheap energydense foods combined with increasingly sedentary lifestyles, these adaptive responses result in unnecessary retention of energy-rich adipose tissue. 5 This increased mass, and the released chemokines, are deemed responsible for obesity-related morbidity and mortality from conditions such as type 2 diabetes, cardiovascular and liver disease, and cancers. 4 A growing body of evidence suggests that maternal obesity might increase the offspring's propensity to obesity in adulthood through epigenetic alteration of fetal physiology. 6 This is especially important in the UK, where about one in five women of reproductive age are obese, 7 as failure to address maternal obesity might be leading to developmental progr...

These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.

Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and b-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine b-hydroxylasedeficient mice (Dbh 2/2 ), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the b-adrenoceptor agonist, isoproterenol (ISO), or the b-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/b-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh 2/2 mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP1ISO-treated mice to other APAPinjured mice improved AILI, an effect antagonized by DKK1. Conclusion: SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para-and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI. (HEPATOLOGY 2014;60:1023-1034 A cetaminophen (APAP) overdose, deliberate or unintentional, can lead to fulminant liver failure (FLF) 1 and is a major health problem. This is despite the presence of N-acetylcysteine (NAC) as an antidote (which has rapidly diminishing benefits if its administration is delayed).2 FLF may result in death if a suitable liver for transplantation cannot be found, with approximately 450 and 250 such deaths

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ObjectivesEmerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock - molecular core circadian genes (CCG) in the generation of NAFPD.DesignFemale C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined.ResultsOffspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (−4.818, p<0.01), REV-ERB-α (−1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (−0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG.ConclusionsFetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.