Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2002-1) contains supplementary material, which is available to authorized users.

The 'Getting to Know Me' programme was well received and had a significant impact on staff knowledge and confidence. Our findings add to a growing evidence base which will be strengthened by further robust studies, the exploration of the impact of staff training on direct patient outcomes, and further identification of ways in which to transfer principles of care from specialist dementia environments into general hospital settings.

BackgroundBreathlessness, cough and fatigue are distressing symptoms for patients with lung cancer. There is evidence that these three symptoms form a discreet symptom cluster. This study aimed to feasibly test a new non-pharmacological intervention for the management of the Respiratory Distress Symptom Cluster (breathlessness-cough-fatigue) in lung cancer.MethodThis was a multi-centre, randomised controlled non-blinded parallel group feasibility trial. Eligible patients (patients with primary lung cancer and ‘bothered’ by at least two of the three cluster symptoms) received usual care plus a multicomponent intervention delivered over two intervention training sessions and a follow-up telephone call or usual care only. Follow-up was for 12 weeks, and end-points included six numerical rating scales for breathlessness severity, Dyspnoea-12, Manchester Cough in Lung Cancer scale, FACIT-Fatigue scale, Hospital Anxiety and Depression scale, Lung Cancer Symptom Scale and the EQ-5D-3L, collected at baseline, week 4 and week 12.ResultsOne hundred seven patients were randomised over 8 months; however, six were removed from further analysis due to protocol violations (intervention group n = 50 and control group n = 51). Of the ineligible patients (n = 608), 29 % reported either not experiencing two or more symptoms or not being ‘bothered’ by at least two symptoms. There was 29 % drop-out by week 4, and by week 12, a further two patients in the control group were lost to follow-up. A sample size calculation indicated that 122 patients per arm would be needed to detect a clinically important difference in the main outcome for breathlessness, cough and fatigue.ConclusionsThe study has provided evidence of the feasibility and acceptability of a new intervention in the lung cancer population and warrants a fully powered trial before we reach any conclusions. The follow-on trial will test the hypothesis that the intervention improves symptom cluster of breathlessness, cough and fatigue better than usual care alone. Full economic evaluation will be conducted in the main trial.

Objective: To investigate the association between potential risk factors and falls in community-dwelling adults with rheumatoid arthritis (RA).Methods: We followed patients for 1 year of followup in a prospective cohort study with monthly falls calendars and telephone calls. Lower extremity muscle strength, postural stability, number of swollen and tender joints, functional status, history of falling, fear of falling, pain, fatigue, medication, and use of steroids were assessed as risk factors for falls.Results: A total of 386 women and 173 men with RA (n = 559) ages 18–88 years completed baseline assessments and 535 participants (96%) completed 1-year followup. Bivariate logistic regression showed that falls risk was not associated with age or sex. Multivariate logistic regression revealed that a history of multiple falls in the previous 12 months was the most significant predictive risk factor (odds ratio [OR] 5.3, 95% confidence interval [95% CI] 2.3–12.3). The most significant modifiable risk factors were swollen and tender lower extremity joints (OR 1.7, 95% CI 1.1–2.7), psychotropic medication (OR 1.8, 95% CI 1.1–3.1), and fatigue (OR 1.13, 95% CI 1.02–1.2).Conclusion: Adults with RA are at high risk of falls. In clinical practice, high-risk fall patients with RA can be identified by asking whether patients have fallen in the past year. Important risk factors highlighted in this study include swollen and tender lower extremity joints, fatigue, and use of psychotropic medications.