New Ways of Working – Pharmacy and Medicines Management

Medicines play a key role in the treatment of most mental illnesses. The management of those medicines is of great importance to most mental health service users and also impacts on the daily professional life of many of those involved in caring, be they psychiatrists, nurses, pharmacists or others. The New Ways of Working (NWW) project began with a study of the potential to devolve many of the aspects of the dispensing of medicines within pharmacy departments from pharmacists to pharmacy technicians and then to pharmacy assistants. As this project evolved it became clear that perhaps the greatest impact of pharmacy staff and potential for NWW of medicines management was not just in the dispensary but within teams and wards. As further projects began to identify the potential for pharmacy staff to improve the way medicines are used across the whole spectrum of clinical care, it also became clear that medicines management and pharmacy had for many years been an area of neglect by Mental Health Trusts (MHTs) and for many to achieve safe and effective medicines use, would require significant investment. By the end of the programme a wide range of products associated with medicines management, involving pharmacy, service users, carers and others, had been developed (www.newwaysofworking.org.uk)

Establishing gold standard approaches to rapid tranquillisation: a review and discussion of the evidence on the safety and efficacy of medications currently used

Background: Rapid tranquillisation is used when control of agitation, aggression or excitement is required. Throughout the UK there is no consensus over the choice of drugs to be used as first line treatment. The NICE guideline on the management of violent behaviour involving psychiatric inpatients conducted a systematic examination of the literature relating to the effectiveness and safety of rapid tranquillisation (NICE, 2005). This paper presents the key findings from that review and key guideline recommendations generated, and discusses the implications for practice of more recent research and information. Aims: To examine the evidence on the efficacy and safety of medications used for rapid tranquillisation in inpatient psychiatric settings. Method: Systematic review of current guidelines and phase III randomised, controlled trials of medication used for rapid tranquillisation. Formal consensus methods were used to generate clinically relevant recommendations to support safe and effective prescribing of rapid tranquillisation in the development of a NICE guideline. Findings: There is a lack of high quality clinical trial evidence in the UK and therefore a ‘gold standard’ medication regime for rapid tranquillisation has not been established. Rapid tranquillisation and clinical practice: The NICE guideline produced 35 recommendations on rapid tranquillisation practice for the UK, with the primary aim of calming the service user to enable the use of psychosocial techniques. Conclusions and implications for clinical practice: Further UK specific research is urgently needed that provides the clinician with a hierarchy of options for the clinical practice of rapid tranquillisation

Spin polarized transport current in n-type co-doped ZnO thin films measured by Andreev spectroscopy

We use point contact Andreev reflection measurements to determine the spin polarization of the transport current in pulse laser deposited thin films of ZnO with 1% Al and with and without 2%Mn. Only films with Mn are ferromagnetic and show spin polarization of the transport current of up to 55 $\pm$ 0.5% at 4.2 K, in sharp contrast to measurements of the nonmagnetic films without Mn where the polarization is consistent with zero. Our results imply strongly that ferromagnetism in these Al doped ZnO films requires the presence of Mn.Comment: Published versio

A comparative analysis of algorithms for somatic SNV detection in cancer

Motivation: With the advent of relatively affordable high-throughput technologies, DNA sequencing of cancers is now common practice in cancer research projects and will be increasingly used in clinical practice to inform diagnosis and treatment. Somatic (cancer-only) single nucleotide variants (SNVs) are the simplest class of mutation, yet their identification in DNA sequencing data is confounded by germline polymorphisms, tumour heterogeneity and sequencing and analysis errors. Four recently published algorithms for the detection of somatic SNV sites in matched cancer–normal sequencing datasets are VarScan, SomaticSniper, JointSNVMix and Strelka. In this analysis, we apply these four SNV calling algorithms to cancer–normal Illumina exome sequencing of a chronic myeloid leukaemia (CML) patient. The candidate SNV sites returned by each algorithm are filtered to remove likely false positives, then characterized and compared to investigate the strengths and weaknesses of each SNV calling algorithm. Results: Comparing the candidate SNV sets returned by VarScan, SomaticSniper, JointSNVMix2 and Strelka revealed substantial differences with respect to the number and character of sites returned; the somatic probability scores assigned to the same sites; their susceptibility to various sources of noise; and their sensitivities to low-allelic-fraction candidates.Nicola D. Roberts, R. Daniel Kortschak, Wendy T. Parker, Andreas W. Schreiber, Susan Branford, Hamish S. Scott, Garique Glonek and David L. Adelso

Efficacy and safety of nilotinib 300mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study

Background Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. Methods This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. Results Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300mg bid. Conclusion Nilotinib 300mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses

De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways

Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fails to respond to Imatinib or to second generation inhibitors and progress to blast crisis. Limited improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis were achieved until now. We present here a massive parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls which reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells

Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, deep into each tumor, revealed unexpectedly heterogeneous patterns of methylation at the MLH1 promoter within a subset of endometrial tumors. This high-resolution analysis allowed us to measure the clonality of methylation in individual tumors and gain insight into the accumulation of aberrant promoter methylation on both alleles during tumorigenesis

Wordless intervention for epilepsy in learning disabilities (WIELD):study protocol for a randomized controlled feasibility trial

Epilepsy is the most common neurological problem that affects people with learning disabilities. The high seizure frequency, resistance to treatments, associated skills deficit and co-morbidities make the management of epilepsy particularly challenging for people with learning disabilities. The Books Beyond Words booklet for epilepsy uses images to help people with learning disabilities manage their condition and improve quality of life. Our aim is to conduct a randomized controlled feasibility trial exploring key methodological, design and acceptability issues, in order to subsequently undertake a large-scale randomized controlled trial of the Books Beyond Words booklet for epilepsy

Role of Spin-Orbit Coupling in the Electronic Structure of IrO₂

The delicate interplay of electronic charge, spin, and orbital degrees of freedom is in the heart of many novel phenomena across the transition metal oxide family. Here, by combining high- resolution angle resolved photoemission spectroscopy and first principles calculations (with and without spin-orbit coupling), the electronic structure of the rutile binary iridate, IrO$_2$ is investigated. The detailed study of electronic bands measured on a high-quality single crystalline sample, and use of a wide range of photon energy provide a huge improvement over the previous studies. The excellent agreement between theory and experimental results shows that the single-particle DFT description of IrO$_2$ band structure is adequate, without the need of invoking any treatment of correlation effects. Although many observed features point to a 3D nature of the electronic structure, clear surface effects are revealed. The discussion of the orbital character of the relevant bands crossing the Fermi level sheds light on spin orbit coupling-driven phenomena in this material, unveiling a spin-orbit induced avoided crossing, a property likely to play key role in its large spin Hall effect