N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms

BACKGROUND: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ.

METHODS: This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes.

DISCUSSION: This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine.

A randomized double-blind placebo-controlled crossover trial of sodium nitrate in patients with stable angina INAS

In an aging western population, a significant number of patients continue to suffer from angina once all revascularization and optimal medical treatment options are exhausted. Under experimental conditions, oral supplementation with inorganic nitrate was shown to exhibit a blood pressure-lowering effect, and has also been shown to promote angiogenesis, improve endothelial dysfunction and mitochondrial efficiency in skeletal muscle. It is unknown whether similar changes occur in cardiac muscle. In the current study, we investigate whether oral sodium nitrate treatment will improve myocardial ischemia in patients with stable angina.

The color blind test

Conceived as an investigation into theories and practices of visual perception, these prints explore the idea that artwork can be intentionally created to be experienced differently dependent on one's visual abilities. The software facilitates the embedding of messages revealed only to those with particular visual acuities or viewed using a smart device to digitally simulate those acuities.

Double blind test series

Braille is a communication tool in decline, in America by 80% since 1950, and in the UK to the extent that only 1% of blind people are now thought to read Braille.1, 2 There are a variety of causal factors, including the phasing out of Braille instruction due to the educational mainstreaming of blind children and the resistance to learning Braille by those who lose sight later in life.3Braille is a writing system of raised dots that allows blind people to read and write tactilely. Each Braille character comprises a cell of six potentially raised dots, two dots across and three dots down. It is designed only to communicate the message and does not convey the tonality provided by visual fonts.However, in his book Design Meets Disability, Graham Pullin, observes that: “Braille is interesting and beautiful, as abstract visual and tactile decoration, intriguing and indecipherable to the nonreader ” and continues; “…braille could be decorative for sighted people.”4I assert that the increasing abandonment of Braille frees it from its restrictive constraints, opening it to exploration and experimentation, and that this may result in Braille becoming dynamic expression for the sighted, as well as the partially sighted and blind.Printmaking is well suited for this exploration. Printmaking processes and techniques can result in prints aesthetically compelling to both senses of sight and touch. Established approaches, such as flocking, varnishes, puff-ink, embossing and die cut, combined with experiments in new techniques in laser cutting and 3D printing, create visually and texturally vibrant prints.In this paper I will detail my systematic investigation of sensually expressive printmaking concentrating on the issues surrounding Braille as a printmaking design element paying particular attention to the approaches and techniques used not only in producing its visual style but to those techniques used to keep it integrally tactile.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens

The aim is tassess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily (‘condensed’ regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily (‘conservative’ regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in (‘condensed’ vs. ‘conservative’) 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for ‘condensed’ vs. ‘conservative’; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/‘condensed’ vs. high-dose/‘conservative’ and 84.9% vs. 73.6% (P = 0.030) for low-dose/‘conservative’ vs. low-dose/‘condensed’. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

ANNUAL REPORT OF THE SOUTH CAROLINA COMMISSION FOR THE BLIND FOR THE FISCAL YEAR 1974-1975

The South Carolina Commission for the Blind reports to the Office of the Governor its annual report that includes summaries, financial statements, organizational charts, and directories.

Amphibian

Amphibian is an 10’00’’ musical work which explores new musical interfaces and approaches to hybridising performance practices from the popular music, electronic dance music and computer music traditions. The work is designed to be presented in a range of contexts associated with the electro-acoustic, popular and classical music traditions. The work is for two performers using two synchronised laptops, an electric guitar and a custom designed gestural interface for vocal performers - the e-Mic (Extended Mic-stand Interface Controller). This interface was developed by one of the co-authors, Donna Hewitt. The e-Mic allows a vocal performer to manipulate the voice in real time through the capture of physical gestures via an array of sensors - pressure, distance, tilt - along with ribbon controllers and an X-Y joystick microphone mount. Performance data are then sent to a computer, running audio-processing software, which is used to transform the audio signal from the microphone. In this work, data is also exchanged between performers via a local wireless network, allowing performers to work with shared data streams. The duo employs the gestural conventions of guitarist and singer (i.e. 'a band' in a popular music context), but transform these sounds and gestures into new digital music. The gestural language of popular music is deliberately subverted and taken into a new context. The piece thus explores the nexus between the sonic and performative practices of electro acoustic music and intelligent electronic dance music (‘idm’). This work was situated in the research fields of new musical interfacing, interaction design, experimental music composition and performance. The contexts in which the research was conducted were live musical performance and studio music production. The work investigated new methods for musical interfacing, performance data mapping, hybrid performance and compositional practices in electronic music. The research methodology was practice-led. New insights were gained from the iterative experimental workshopping of gestural inputs, musical data mapping, inter-performer data exchange, software patch design, data and audio processing chains. In respect of interfacing, there were innovations in the design and implementation of a novel sensor-based gestural interface for singers, the e-Mic, one of the only existing gestural controllers for singers. This work explored the compositional potential of sharing real time performance data between performers and deployed novel methods for inter-performer data exchange and mapping. As regards stylistic and performance innovation, the work explored and demonstrated an approach to the hybridisation of the gestural and sonic language of popular music with recent ‘post-digital’ approaches to laptop based experimental music The development of the work was supported by an Australia Council Grant. Research findings have been disseminated via a range of international conference publications, recordings, radio interviews (ABC Classic FM), broadcasts, and performances at international events and festivals. The work was curated into the major Australian international festival, Liquid Architecture, and was selected by an international music jury (through blind peer review) for presentation at the International Computer Music Conference in Belfast, N. Ireland.

A reflective model for colour studies learning

In a university context how should colour be taught in order to engage students? Entwistle states, ‘What we learn depends on how we learn, and why we have to learn it.’ Therefore, there is a need to address the accumulating evidence that highlights the effects of learning environments on the quality of student learning when considering colour education. It is necessary to embrace the contextual demands while ensuring that the student knowledge of colour and the joy of discovering its characteristics in practice are enhanced. Institutional policy is forcing educators to re-evaluate traditional studio’s effectiveness and the intensive 'hands-on' interactive approach that is embedded in such an approach. As curriculum development involves not only theory and project work, the classroom culture and physical environment also need to be addressed. The increase in student numbers impacting the number of academic staff/student ratio, availability of teaching support as well as increasing variety of student age, work commitments, learning styles and attitudes have called for positive changes to how we teach. The Queensland University of Technology’s restructure in 2005 was a great opportunity to re-evaluate and redesign the approach to teaching within the design units of Interior Design undergraduate program –including colour. The resultant approach “encapsulates a mode of delivery, studio structure, as well as the learning context in which students and staff interact to facilitate learning”1 with a potential “to be integrated into a range of Interior Design units as it provides an adaptive educational framework rather than a prescriptive set of rules”.

What is that place? Observations of the impact of environment colour through photographic analysis

Isolating the impact of a colour, or a combination of colours, is extremely difficult to achieve because it is difficult to remove other environmental elements such as sound, odours, light, and occasion from the experience of being in a place. In order to ascertain the impact of colour on how we interpret the world in day to day situations, the current study records participant responses to achromatic scenes of the built environment prior to viewing the same scene in colour. A number of environments were photographed in colour or copied from design books; and copies of the images saved as both colour and black/grey/white. An overview of the study will be introduced by firstly providing examples of studies which have linked colour to meaning and emotions. For example, yellow is said to be connected to happiness1 ; or red evokes feelings of anger2 or passion. A link between colour and the way we understand and/or feel is established however, there is a further need for knowledge of colour in context. In response to this need, the current achromatic/chromatic environmental study will be described and discussed in light of the findings. Finally, suggestions for future research are posed. Based on previous research the authors hypothesised that a shift in environmental perception by participants would occur. It was found that the impact of colour includes a shift in perception of aspects such as its atmosphere and youthfulness. Through studio-class discussions it was also noted that the predicted age of the place, the function, and in association, the potential users when colour was added (or deleted) were often challenged. It is posited that the ability of a designer (for example, interior designer, architect, or landscape architect) to design for a particular target group—user and/or clients will be enhanced through more targeted studies relating colour in situ. The importance of noting the perceptual shift for the participants in our study, who were young designers, is the realisation that colour potentially holds the power to impact on the identity of an architectural form, an interior space, and/or particular elements such as doorways, furniture settings, and the like.

Kava Anxiety Depression Spectrum Study (KADSS): a mixed methods RCT using an aqueous extract of Piper methysticum

Objectives: To report on the design, significance and potential impacts of the first documented human clinical trial assessing the anxiolytic and thymoleptic efficacy of an aqueous monoextract of Piper methysticum (kava). The significance of the qualitative element of our clinical trial is also explored. The Kava Anxiety Depression Spectrum Study (KADSS) is a 3-week placebocontrolled, double-blind, cross-over trial involving 60 adult participants (18—65) with elevated stable anxiety and varying levels of depressive symptoms. Aims: The aims of KADSS are: (1) to determine whether an aqueous standardised extract of kava is effective for the treatment of anxiety; (2) to assess the effects of kava on differing levels of depression; and (3) to explore participants’ experience of taking kava via qualitative research. The study also provides preliminary assessment of the safety of an aqueous extract of kava in humans. Conclusion: If results reveal that the aqueous kava preparation exerts significant anxiolytic effects and appears safe, potentially beneficial impacts may occur. Data supporting a safe and effective kava extract may encourage a re-introduction of kava to Europe, UK and Canada. This may provide a major socioeconomic benefit to Pacific Island nations, and to sufferers of anxiety disorders.

Mailed treatment to augment primary care for alcohol disorders : a randomised controlled trial

Introduction and Aims: Remote delivery of interventions is needed to address large numbers of people with alcohol use disorders who are spread over large areas. Previous correspondence trials typically examined its effects as stand-alone treatment. This study aimed to test whether adding postal treatment to general practitioner (GP) support would lower alcohol use more than GP intervention alone. Design and Methods: A single-blind, randomised controlled trial with a crossover design was conducted over 12 months on 204 people with alcohol use disorders. Participants in an immediate correspondence condition received treatment over the first 3 months; those receiving delayed treatment received it in months 3–6. Results: Few participants were referred from GPs, and little intervention was offered by them. At 3 months, 78% of participants remained in the study. Those in immediate treatment showed greater reductions in alcohol per week, drinking days, anxiety, depression and distress than those in the delayed condition. However, post-treatment and follow-up outcomes still showed elevated alcohol use, depression, anxiety and distress. Greater baseline anxiety predicted better alcohol outcomes, although more mental distress at baseline predicted dropout. Discussion and Conclusions: The study gave consistent results with those from previous research on correspondence treatments, and showed that high levels of participant engagement over 3 months can be obtained. Substantial reductions in alcohol use are seen, with indications that they are well maintained. However, many participants continue to show high-risk alcohol use and psychological distress.

A brief motivational intervention for substance misuse in recent-onset psychosis

Substance misuse is common in early psychosis, and impacts negatively on outcomes. Little is known about effective interventions for this population. We report a pilot study of brief intervention for substance misuse in early psychosis (Start Over and Survive: SOS), comparing it with Standard Care (SC). Twenty-five in-patients aged 18-35 years with early psychosis and current misuse of non-opioid drugs were allocated randomly to conditions. Substance use and related problems were assessed at baseline, 6 weeks and 3, 6 and 12 months. Final assessments were blind to condition. All 13 SOS participants who proceeded to motivational interviewing reported less substance use at 6 months, compared with 58% (7/12) in SC alone. Effects were well maintained to 12 months. However, more SOS participants lived with a relative or partner, and this also was associated with better outcomes. Engagement remained challenging: 39% (16/41) declined participation and 38% (5/13) in SOS only received rapport building. Further research will increase sample size, and address both engagement and potential confounds.

Ethyl-eicosapentaenoic acid in first-episode psychosis : a 1H-MRS study

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12=6.1, p=0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20=4.4, p=0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r=-0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.