A randomized, double-blind phase 1b study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of the NLRP3 inhibitor selnoflast in patients with moderate to severe active ulcerative colitis.

BACKGROUND: The NLRP3 inflammasome drives release of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo-controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast. METHODS: Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL-1ß inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated. RESULTS: Selnoflast was well-tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post-dose. Mean plasma concentrations stayed above the IL-1ß IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 µg/mL and 2.66 µg/mL, respectively). At steady state, post-dose selnoflast concentrations in sigmoid colon (5-20 µg/g) were above the IC90 . Production of IL-1ß was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL-18 levels. There were no meaningful differences in the expression of an IL-1-related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers. CONCLUSIONS: Selnoflast was safe and well-tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL-1ß IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL-1ß in tissue. TRIAL REGISTRATION: ISRCTN16847938.

Pan-cancer population pharmacokinetics and exposure-safety and -efficacy analyses of atezolizumab in patients with high tumor mutational burden.

We retrospectively investigated the pharmacokinetics and exposure-efficacy/safety relationships of single-agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan-tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two-compartment intravenous-infusion population-pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high- and low-tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6-NE) months vs 15.9 (12.5-20.5) months for patients with high-tTMB vs low-tTMB tumors, respectively. A flat exposure-efficacy relationship was seen for ORR in patients with high-tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure-safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high-tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200-mg, every 3-week regimen in a tumor-agnostic high-tTMB population.

Additional Risk Minimisation Measures for Medicinal Products in the European Union: A Review of the Implementation and Effectiveness of Measures in the United Kingdom by One Marketing Authorisation Holder.

INTRODUCTION: Additional risk minimisation measures (aRMMs) for medicinal products are necessary to address specific important safety issues which may not be practically achieved through routine risk management measures alone. The implementation and determination of effectiveness for aRMMs can be a challenge as it involves multiple stakeholders. It is therefore important to have concise objectives to avoid undue burden on patients, healthcare professionals and the healthcare system. AIM: The aim of this study was to examine how aRMMs are implemented and how effectiveness is assessed in the European Union (EU) using practical examples from Roche Products Limited in the United Kingdom (UK) (referred to as the 'Company'). METHODS: Three centrally authorised products were selected from the Company's portfolio, each of which had aRMMs to address important safety concerns; specifically, teratogenicity, medication error and infections. The implementation of EU aRMMs, effectiveness checks and specific UK activities were analysed. Hard copy folders and electronic sites for Company aRMMs were used to assess process indicators. Periodic benefit-risk evaluation reports for specified time intervals and the Company safety database was used in checking safety outcomes for the selected products. For each product, the effectiveness of aRMMs was analysed based on specific process indicators and the subsequent safety outcomes. Literature searches were performed on scientific databases for the purposes of the broader study. RESULTS: The main process indicators in measuring effectiveness of Company aRMMs were distribution metrics for educational materials, assessment of awareness and clinical actions among healthcare professionals (HCPs). Case reports of pregnancy, medication errors and progressive multifocal leukoencephalopathy (PML) were the outcome indicators for Erivedge®â–¼, Kadcyla®â–¼ and MabThera® (the latter specifically in autoimmune indications: rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis) respectively. No pregnancy, one medication error and 10 confirmed PML cases were reported for Erivedge®â–¼, Kadcyla®â–¼ and MabThera® respectively. CONCLUSIONS: For the chosen products, a reasonable awareness of aRMMs amongst HCPs is a positive indicator of success in the use of educational materials. However, low response rates from surveys indicate that voluntary feedback may not always achieve the desired level of response in measuring effectiveness. There is a challenge in determining overall effectiveness of aRMMs due to a lack of defined success thresholds. Further regulatory guidance to outline the elements and desired outcomes of aRMMs will be useful for consistency in achieving successful outcomes.

Fracture risk calculation tool enhances dual-energy X-ray absorptiometry scan referral pathway in cirrhosis patients.

OBJECTIVES: Liver cirrhosis is associated with osteoporosis leading to an increased risk of fractures. We aimed to establish whether a risk stratification strategy using a fracture risk calculation tool (FRAX) to determine which patients should receive a dual-energy X-ray absorptiometry (DXA) scan is effective in reducing scan rates without compromising sensitivity for detecting osteoporosis. METHODS: A retrospective analysis of 252 patients with liver cirrhosis attending hepatoma surveillance clinics. Receiver operating characteristic analysis was performed to assess sensitivity and specificity at 10-year fracture risk thresholds of 5, 10 and 15%. RESULTS: DXA scans were performed among 252 patients. Mean age was 61.6±10.2 years, of which 53.2% were male. Cirrhosis aetiology was largely a result of alcohol excess (n=33.3%), chronic hepatitis C virus infection (n=20.2%) and nonalcoholic fatty liver disease (n=15.9%). The majority of patients were in good prognostic groups (87.4% Child-Pugh A, 11.3% Child-Pugh B, 1.3% Child-Pugh C). Osteoporosis was present in 19.0% of those who underwent DXA scanning. The optimum 10-year fracture risk threshold was found to be 10% using the FRAX tool. This retained a high sensitivity of 95.8%, specificity 64.7%, and negative predictive value 98.5%. Introduction of a 10% FRAX threshold would result in a reduction of the DXA scanning rate to 46.8% of the current rate. CONCLUSION: A risk stratification strategy for DXA scanning using a fracture risk assessment tool (FRAX) and a 10-year fracture risk threshold of 10% leads to a significant reduction in scan rates without compromising osteoporosis detection rates.

Detecting genotoxic effects of potential clastogens: an in vivo study using the transgenic lacZ plasmid and the MutaMouse model.

In the present paper the capacity of the pUR288 plasmid mouse model and the MutaMouse model to detect the clastogens bleomycin, m-AMSA, o-AMSA and camptothecin, was investigated. Ethylnitrosourea (ENU) served as a positive control, methylcellulose as a negative control. Only bleomycin induced a slight but significant increase in lacZ mutant frequency (MF) in bone marrow of pUR288 plasmid mice. Exposure to the other compounds did not result in an increase in the MF in bone marrow and liver in both mouse models. For the MutaMouse this result was expected, for the plasmid mouse an increase in MF after clastogen exposure was expected. The positive control ENU induced statistically significant increases in MF compared with the negative control in both models and in both tissues analyzed. Hybridisation of DNA of mutant colonies derived from plasmid mice with labelled total mouse DNA (Hybridisation Assay) demonstrated an increase in the percentage of colonies hybridised with total mouse DNA as compared with the negative control, which suggests that there was indeed a biological response associated with treatment. The latter results indicate that the plasmid mouse assay may still be a promising model for the detection of clastogens.

Computational study of the melting-freezing transition in the quantum hard-sphere system for intermediate densities. II. Structural features.

The structural features of the quantum hard-sphere system in the region of the fluid-face-centered-cubic-solid transition, for reduced number densities 0.45

Use of an open access spirometry service by general practitioners.

AIMS: To understand better which patients with which diagnoses or suspected diagnoses are referred for spirometry in primary care, and to assess whether all such referrals are appropriate. METHODS: 200 consecutive patient referrals to an open access spirometry service from ten local general practices were evaluated by perusing the request forms, and analysis of the spirometry results and the report sent to the general practitioner (GP). RESULTS: 51% of all referrals had suspected or stated COPD, but airway obstruction was demonstrated in only 53% of cases. A minority had a degree of reversibility which suggested an additional asthma component at least. Airway obstruction was rarely demonstrated in patients referred with stated or suspected asthma. 117 patients were referred with stated or suspected airway disease but had no evidence of airway narrowing on testing. 14.5% of these had an unexpected small lung (restrictive) disorder. Six of these had a BMI of more than 30. CONCLUSION: Most referrals with stated or suspected COPD were highly appropriate since spirometry is required in order to establish the correct diagnosis. Referral of patients with suspected asthma is less likely to be helpful, and a period of home peak flow monitoring may be more useful. Restrictive disorders can be confused with airway disorders, and obesity may be underestimated as a cause of breathlessness.

EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation.

Here we show that EGF and EGF receptor (EGFR) are trafficked through a subpopulation of multivesicular endosomes/bodies (MVBs) that are distinct from morphologically identical vacuoles that label for the late endosomal marker lyso-bisphosphatidic acid (LBPA). EGF stimulation increases both MVB biogenesis and inward vesiculation within EGFR-containing MVBs. Deletion of annexin 1, a substrate of EGFR tyrosine kinase, abolishes the effect of EGF stimulation on inward vesiculation. This phenotype is reversible by transfection with wild-type but not Y21F phosphorylation mutant annexin 1. Deletion of annexin 1 has no effect on EGF-stimulated MVB biogenesis, suggesting that MVB biogenesis and inward vesiculation within MVB are mediated by separate mechanisms. Loss or depletion of annexin 1 has no effect on EGF degradation and causes only a small delay in EGFR degradation, indicating that annexin 1 operates downstream of Hrs- and ESCRT-mediated sorting and is required solely for EGF-stimulated inward vesiculation. Annexin 1 accumulates on internal vesicles of MVB after EGF-stimulated inward vesiculation, suggesting that it may be required for a late stage in inward vesiculation.

Specialist educational intervention for acute inpatient mental health nursing staff: service user views and effects on nursing quality.

AIM: This paper reports a study to evaluate the impact of an innovative 18-day educational intervention for acute ward-based mental healthcare nursing staff on documented quality of nursing care and on service user views of that care. BACKGROUND: There are grave concerns internationally about the quality of inpatient mental health care for people with acute psychiatric problems. It is claimed that specialist educational courses are needed to improve these services. However, whilst such courses may lead to positive learning outcomes for participants, the impact on the actual care of service users is unknown. METHOD: An uncontrolled before-and-after evaluation of three acute mental health wards from different United Kingdom National Health Service trusts was carried out. Quality of nursing care was evaluated by extracting documentary evidence from service user records, assessed by two independent researchers according to predefined quality criteria. The views of a purposive sample of mental health service users, currently receiving services from the three designated wards, were ascertained by semi-structured interview. RESULTS: Both documentary evidence and service user views revealed some important baseline deficiencies in the quality of care offered at the study sites. Following the educational intervention, statistically significant improvements were observed in the quality of care planning, initial assessments and the provision of therapeutic care. No statistically significant changes were observed in the quality of risk assessments, medication management or external agency involvement. CONCLUSIONS: Education can have an impact on nursing care but may not be sufficient alone to change mental healthcare practices on acute inpatient wards in the radical manner demanded by policymakers and service user lobby groups. Educational interventions need to be implemented in conjunction with organizational changes that are specifically designed to maximize the opportunities presented by a newly skilled and positive workforce.

Specialist educational intervention for mental health nursing staff: delivery, content and personal impact.

AIM: This paper reports a study to ascertain the views of acute ward-based mental health nursing staff on the delivery, content and personal impact of an innovative 18-day, whole team educational intervention in acute mental health care. BACKGROUND: There are grave concerns internationally about the quality of inpatient mental health care for people with acute psychiatric problems. Educational courses are needed to improve these services. However, existing schemes are often selective, hard to access and limited to developing highly specialist skills for senior nurses. They have also been criticized for making no difference to clinical practice. There is little evidence to guide the development of these or alternative team-based courses. METHOD: Qualitative data were collected over a 6-week period using 12 focus group interviews and individual questionnaires. RESULTS: Four themes were identified. The joint education of nursing staff from different organizations was welcomed and reduced feelings of ward isolation. Mixing qualified and unqualified staff was not regarded positively. In terms of course content and learning themes, unqualified staff were more likely to report positive learning outcomes for knowledge, skills, attitude, morale and personal development; qualified nurses were more likely to indicate positive outcomes in anonymized data from questionnaires than from focus groups. Both groups reported little chance of knowledge implementation without changes in the organization of care. CONCLUSION: Whilst it may be desirable to educate whole nursing teams, more benefit might be gained from shared education between several organizations and separating the education of qualified and unqualified staff before combining these groups in team education. Participants remained pessimistic about their chances of implementing new knowledge and skills in current acute inpatient mental health environments.

The decay of pair correlations in quantum hard-sphere fluids.

A study of the asymptotic decay of the pair radial correlations in the bare quantum hard-sphere (QHS) fluid and in the quantum hard-sphere Yukawa (QHSY) fluid is presented. The conditions explored are far from quantum exchange and are contained within the region (0.1

Contribution of the ADP-ribosylating and receptor-binding properties of cholera-like enterotoxins in modulating cytokine secretion by human intestinal epithelial cells.

When epithelial cells first encounter cholera toxin (Ctx) produced by Vibrio cholerae they secrete not only chloride ions responsible for causing diarrhoea, but also a number of cytokines that may contribute to the toxin's potent immunomodulatory properties. Much less is known about the ability of the heat-labile enterotoxin of Escherichia coli (Etx), a close homologue of Ctx, to elicit cytokine secretion by epithelial cells. This study shows that treatment of human intestinal epithelial T84 cells with Etx induces expression of IL-6, IL-10, IL-1R antagonist, as well as IL-1alpha and IL-1beta and low levels of IL-8. Such induction was totally dependent on the intrinsic ADP-ribosylating activity of the toxin A-subunit, and could be mimicked by cAMP-elevating agents, such as forskolin and dibutyryl cAMP. By comparison, neither an enzymically inactive mutant of Etx nor EtxB was able to induce cytokine secretion. The behaviour of Ctx and CtxB was very similar to that of Etx and EtxB, respectively. The spectrum of cytokines released by Etx and Ctx indicates that the toxins may create a local microenvironment that strongly biases the immune response towards an anti-inflammatory and a polarized Th2 response.