Development of Highly Sensitive Fluorescent Sensors for Separation-Free Detection and Quantitation Systems of Pepsin Enzyme Applying a Structure-Guided Approach.

Two fluorescent molecularly imprinted polymers (MIPs) were developed for pepsin enzyme utilising fluorescein and rhodamine b. The main difference between both dyes is the presence of two (diethylamino) groups in the structure of rhodamine b. Consequently, we wanted to investigate the effect of these functional groups on the selectivity and sensitivity of the resulting MIPs. Therefore, two silica-based MIPs for pepsin enzyme were developed using 3-aminopropyltriethoxysilane as a functional monomer and tetraethyl orthosilicate as a crosslinker to achieve a one-pot synthesis. Results of our study revealed that rhodamine b dyed MIPs (RMIPs) showed stronger binding, indicated by a higher binding capacity value of 256 mg g-1 compared to 217 mg g-1 for fluorescein dyed MIPs (FMIPs). Moreover, RMIPs showed superior sensitivity in the detection and quantitation of pepsin with a linear range from 0.28 to 42.85 µmol L-1 and a limit of detection (LOD) as low as 0.11 µmol L-1. In contrast, FMIPs covered a narrower range from 0.71 to 35.71 µmol L-1, and the LOD value reached 0.34 µmol L-1, which is three times less sensitive than RMIPs. Finally, the developed FMIPs and RMIPs were applied to a separation-free quantification system for pepsin in saliva samples without interference from any cross-reactors.

Simulation study of a practical approach to enhance cadmium removal via biological treatment by controlling the concentration of MLSS.

The fate of cadmium at the Muharram Aisha wastewater treatment plant in Karbala governorate, Iraq was studied using the TOXCHEM model. Cadmium, a known carcinogen, and is considered one of the most dangerous heavy metals and high concentrations, greater than permissible limits, were found in the treated wastewater. The plant operates using an activated sludge system and this was modeled via TOXCHEM with a sensitivity analysis carried out on the extended aeration system. Prior to analysis, the model was calibrated and validated for cadmium, with the adjustments leading to a mean square error (RMSE) and correlation coefficient (R) of 0.0001 and 0.81, respectively. The mass balance of cadmium in the Muharram Aisha treatment plant was found to be 4832.44 g/day (37.1726%) in the treated wastewater and 8164.52 g/day (62.804%) in the sludge, which indicated that the mix liquor suspended solid (MLSS) was the most sensitive factor. The sensitivity to cadmium was analyzed via MLSS in the extended aeration system and the results o indicated that the higher the MLSS concentration (mg/L), the greater the removal of cadmium in the treated wastewater. It was found that increasing the MLSS through a biological treatment method reduced the concentration of cadmium without the need for additional of any (potentially harmful) chemical treatments. The plant was subsequently operated for a period of 5 months with the MLSS increased from 1500 to 4500 mg/L, and this reduced the concentration of cadmium in the wastewater from 0.36 to 0.01 mg/L as a consequence. This research demonstrates how the novel application of TOXCHEM can be a useful tool in the reduction of heavy metal contamination in the environment.

Anti-cancer drug waste disposal practices and wastewater management in hospitals: A Lebanese survey.

INTRODUCTION: To achieve continuous environmental sustainability and protect the population's health, healthcare waste (in liquid or solid form) needs appropriate management and suitable treatment strategies before its final disposal in the environment in order to reduce its adverse impacts. This study aims to identify disparities in the waste management of anti-cancer drugs and the wastewater generated in Lebanese hospitals. METHODS: Three questionnaires were designed to evaluate the level of knowledge, awareness and experience of hospital personnel regardless of their job levels. Data was collected in December 2019 from three departments of each participating hospital: pharmacy, oncology and maintenance departments. A descriptive analysis was conducted to summarise the survey results. RESULTS: The results revealed a lack of transparency and awareness of the participants, with a high frequency of 'prefer not to say' responses when asked about the disposal methods of anti-cancer drugs and with only 5.7% of the participants in the pharmacy department sharing their disposal procedures. The same perception was deduced regarding hospitals' wastewater treatment, where responses were often contradicting, preventing making assumptions about the fate of hospital wastewater. CONCLUSION: The results of this survey support the need to establish a more comprehensive waste management programme in Lebanon that would be maintained through regular training and supervision.

Cognitive Remediation in Bipolar (CRiB2): study protocol for a randomised controlled trial assessing efficacy and mechanisms of cognitive remediation therapy compared to treatment as usual.

BACKGROUND: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. METHODS: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30-40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. DISCUSSION: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. TRIAL REGISTRATION: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331 . Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting.

Temporal and spatial trends in lead levels in the blood and down of Black Stork nestlings in central Europe.

Young birds at an intensive growth stage are especially vulnerable to the deleterious effects of contaminants such as lead (Pb). This element negatively influences organs, development and even behavior, which can consequently lead to lower survival and reproductive success of the population. There was a suspicion that these mechanisms, along with other factors, retarded population growth of the Black Stork - still a heavily understudied species in respect to pollution, especially Pb. Therefore, we undertook a study concerning Pb concentrations in the down and blood of Black Stork nestlings from breeding grounds in central and southern Poland (Europe). To investigate the effects of Pb exposure on nestling condition, scale mass index and reduced glutathione levels were also studied, but results indicated that Pb did not influence either of these parameters. The highest blood Pb concentration reached 0.247 µg/g, while the highest down Pb concentrations was significantly higher reaching 4.95 µg/g. Concentrations in blood and down were not correlated with each other. Nest location and year of sampling were not influential for blood but were influential for down Pb concentrations. Relationships between Pb concentrations, habitat characteristics and proximity to emitters were not significant. Overall Pb concentrations in Black Stork nestlings were below the toxicity threshold and did not have negative effects on specimens studied. They were probably related to maternal exposure during migration, on stopover and breeding grounds as well as with food provided by parents.

CBT for difficult-to-treat depression: self-regulation model.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression but a significant minority of clients do not complete therapy, do not respond to it, or subsequently relapse. Non-responders, and those at risk of relapse, are more likely to have adverse childhood experiences, early-onset depression, co-morbidities, interpersonal problems and heightened risk. This is a heterogeneous group of clients who are currently difficult to treat. AIM: The aim was to develop a CBT model of depression that will be effective for difficult-to-treat clients who have not responded to standard CBT. METHOD: The method was to unify theory, evidence and clinical strategies within the field of CBT to develop an integrated CBT model. Single case methods were used to develop the treatment components. RESULTS: A self-regulation model of depression has been developed. It proposes that depression is maintained by repeated interactions of self-identity disruption, impaired motivation, disengagement, rumination, intrusive memories and passive life goals. Depression is more difficult to treat when these processes become interlocked. Treatment based on the model builds self-regulation skills and restructures self-identity, rather than target negative beliefs. A bespoke therapy plan is formed out of ten treatment components, based on an individual case formulation. CONCLUSIONS: A self-regulation model of depression is proposed that integrates theory, evidence and practice within the field of CBT. It has been developed with difficult-to-treat cases as its primary purpose. A case example is described in a concurrent article (Barton et al., 2022) and further empirical tests are on-going.

Voltammetric Determination of Hg2+, Zn2+, and Pb2+ Ions Using a PEDOT/NTA-Modified Electrode.

A novel electrochemical sensor for determining trace levels of Hg2+, Pb2+, and Zn2+ ions in water using square wave voltammetry (SWV) is reported. The sensor is based on a platinum electrode (Pt) modified by poly(3,4-ethylenedioxythiophene) and N α,N α-bis-(carboxymethyl)-l-lysine hydrate (NTA lysine) PEDOT/NTA. The modified electrode surface (PEDOT/NTA) was prepared via the introduction of the lysine-NTA group to a PEDOT/N-hydroxyphthalimide NHP electrode. The (PEDOT/NTA) was characterized via cyclic voltammetry (CV), Fourier transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). The effects of scan rates on the electrochemical properties of the polymer electrode were also investigated. The electrochemical results were used to estimate the coverage of the electrode polymer surface and its electrostability in background electrolyte solutions. Several analytical parameters, such as polymer film thickness, metal deposition time, and pH of the electrolyte, were examined. Linear responses to Hg2+, Pb2+, and Zn2+ ions in the concentration range of 5-100 µg L-1 were obtained. The limits of detection (LODs) for the determination of Hg2+, Pb2+, and Zn2+ ions were 1.73, 2.33, and 1.99 µg L-1, respectively. These promising results revealed that modified PEDOT/NTA films might well represent an important addition to existing electrochemical sensor technologies.

Novel Temperature Responsive Films Impregnated with Silver Nano Particles (Ag-NPs) as Potential Dressings for Wounds.

Silver nanoparticles have attracted wide interest in medicine on account of their antibacterial activity. We report in this paper, the antibacterial activity and biocompatibility of a temperature responsive topical film fabricated from pullulan-g-pNIPAM and impregnated with two different concentrations (15 ppm and 30 ppm) of silver nanoparticles (Ag-NPs). The release of silver from the film under the influence of temperature above the LCST has been studied and the in vitro release profile of the films has been compared with a marketed silver nano formulation, 'Meganano gel'. The release of silver from the films has a distinctive profile characterized by a sustained release over a period of 48 hrs, which is comparable to the marketed formulation. The films exhibit excellent swelling properties, making them ideal materials for absorption of exudates from wounds. The antibacterial activity of the films has been established at physiological temperature against gram-positive S. aureus and gram-negative E. coli and compared with the marketed formulation. A cytotoxicity evaluation on HeK293 cells has demonstrated their biocompatibility. The nanocomposite films are thus a new therapeutic device for management of non-healing wounds being constructed from temperature responsive polymers that release Ag-NPs when the temperature of the wound exudate is slightly higher than normal.

Stability of Amoxicillin and Clavulanic Acid in Separate Containers for Administration via a Y-Site.

RATIONALE: With the discovery of new antibiotics diminishing, optimising the administration of existing antibiotics such as amoxicillin-clavulanic acid has become a necessity. At present, the optimal approach for enhancing the effectiveness of time-dependent antibiotics involves extending the time at which antibiotic concentrations are maintained above the minimal inhibitory concentration by prolonging the infusion time. This pharmacodynamic rationale cannot be applied to co-amoxiclav because of poor stability at room temperature. The aim of this study was to establish the shelf-life of amoxicillin and clavulanic acid prepared in separate containers to determine the feasibility of 24-hr continuous infusion therapy. METHODS: A previously developed and validated stability-indicating HPLC method was used to establish the shelf-life of reconstituted amoxicillin and clavulanic acid when prepared in separate containers. Stability at clinical concentration was evaluated at three temperatures. To establish whether there were significant differences at the level of both active ingredients and temperature, results were analysed using analysis of covariance (ANCOVA) to assess differences between the attained slopes of regression. RESULTS: Data obtained indicated amoxicillin and clavulanic acid stability superior to that previously proposed making it suitable for continuous infusion therapy. Analysis of regression slopes via ANCOVA showed that temperature significantly affected amoxicillin and clavulanic acid stability. Amoxicillin retained 90% of its initial concentration for 80.3 hrs when stored at 4°C, 24.8 hrs at 25°C and 9 hrs when incubated at 37°C. Clavulanic acid retained 90% of its initial concentration for 152 hrs when stored at 4°C, 26 hrs at 25°C and 6.4 hrs when incubated at 37°C. CONCLUSION: Amoxicillin and clavulanic acid are suitable for administration via continuous infusion when prepared, stored, and administered in separate containers. Results obtained from this study aid in ameliorating current dosing regimens to optimise antibiotic efficacy; however, more in-depth amoxicillin and clavulanic acid y-site compatibility studies are warranted.

Aquatic ecotoxicology of anticancer drugs: A systematic review.

Anticancer drugs in the aquatic environment have drawn a lot of attention in the last decade. Since wastewater treatment plants are inefficient at fully eliminating trace concentrations of anticancer drugs, these compounds are continuously discharged into the aquatic environment. Subsequently, non-target organisms such as the aquatic biota are directly exposed to a variety of anticancer drugs. To understand the potential impact on the aquatic organisms, a systematic review was conducted in compliance with the PRISMA guidelines. The results acquired from the 152 included studies were analysed and sorted into four categories: the impact of each included anticancer drug, the effect of metabolites, the effect of a mixture of drugs, and risk assessment. Findings showed that risk to the aquatic biota was unlikely to occur as the concentrations needed to induce effects were much higher than those detected in the environment. However, these data were based on acute toxicity and included only basic toxicity endpoints. The concentrations that produced significant effects were much lower when tested in the long-term or in multi-generational studies. Heterogeneity in results was also observed; this depended on the organism tested, the assessment adopted, and the endpoints selected. In this systematic review, an overall view of the research studies was generated by which all the variability factors to be considered were reported and recommendations to guide future studies were proposed.

Ambulatory chemotherapy: Past, present, and future.

Ambulatory chemotherapy allows the delivery of short and extended chemotherapy infusions through a portable pump from the comfort of patients' homes. It is essential to offer it for suitable candidates to ensure both their safety and the success of the treatment session. This requires a delicate balance between clinical assessment and patient acceptance.The two main components of this treatment modality are the pump and the access device.There are several pump designs and mechanisms on the market, with the latest being the portable disposable elastomeric one.Clinicians along with a multidisciplinary medical team often decide upon the type of access device; patients are also involved whenever shared decision making is practiced.Despite some reports of pump programming errors or malfunctions, research is underway to find innovative solutions to support its use.

Consensus Recommendations for the Safe Handling of Cytotoxic Agents in Cytotoxic Academic Research Laboratories (CARL).

Cytotoxic agents, also called antineoplastic agents, are used in cancer treatment due to their inherent activity to inhibit cell growth or proliferation, or DNA, RNA and protein synthesis. They are, therefore, hazardous by nature in a non-selective manner leading to disruption of cell growth and function of both diseased and healthy cells of treated patients.While the benefits of receiving cytotoxic agents may outweigh the incurred risks for patients, the same cannot be said for exposed healthcare practitioners involved in the transport, preparation, administration, and resulting waste disposal of these agents.Consequently, many professional bodies around the world have set standards of practice to prevent occupational exposure of healthcare workers to cytotoxic agents, and hospitals have been active in defining strict policies in this concern.However, due to the variability of the practice and infrastructure in academic settings, some activities performed within the cytotoxic academic research laboratory often do not adhere to recommendations published by guidelines.The present recommendations were therefore set forward by members of a working group who are experts on the subject matter representing academic, clinical, and research backgrounds in an attempt to promote safe cytotoxic handling in academic institutions.The document maps out the trajectory of cytotoxic agents being investigated in academic research laboratories while providing recommendations on the delivery, storage, use and disposal of cytotoxic agents in university settings.

Comparing clinical outcomes of piperacillin-tazobactam administration and dosage strategies in critically ill adult patients: a systematic review and meta-analysis.

BACKGROUND: Recently, continuous administration of piperacillin-tazobactam has been proposed as a valuable alternative to traditional intermittent administration especially in critically ill patients. However, antibiotic dosing remains a challenge for clinicians as antibiotic dosing regimens are usually determined in non-critically ill hospitalized adult patients. The aim was to conduct a systematic review to identify and highlight studies comparing clinical outcomes of piperacillin tazobactam dosing regimens, continuous/prolonged infusion vs intermittent infusion in critically ill patients. Meta-analyses were performed to assess the overall effect of dosing regimen on clinical efficacy. METHODS: Studies were identified systematically through searches of PubMed and Science Direct, in compliance with PRISMA guidelines. Following the systematic literature review, meta-analyses were performed using Review Manager. RESULTS: Twenty-three studies were included in the analysis involving 3828 critically ill adult participants in total (continuous/prolonged infusion = 2197 and intermittent infusion = 1631) from geographically diverse regions. Continuous/prolonged resulted in significantly: higher clinical cure rates (Odds Ratio 1.56, 95% Confidence Interval 1.28-1.90, P = 0 .0001), lower mortality rates (Odds Ratio 0.68, 95% Confidence Interval 0.55-0.84, P = 0 .0003), higher microbiological success rates (Odds Ratio 1.52, 95% Confidence Interval 1.10-2.11, P = 0.01) and decreasing the length of hospital stay (Mean Difference - 1.27, 95% Confidence Interval - 2.45-0.08, P = 0.04) in critically ill patients. CONCLUSION: Results from this study show that there is a significant level of evidence that clinical outcome in critically ill patients is improved in patients receiving piperacillin-tazobactam via continuous/prolonged infusion. However, more rigorous scientific studies in critically ill patients are warranted to reach a sufficient level of evidence and promote further implementation of C/PI as a dosing strategy.

Suitability of Amoxicillin-Clavulanic Acid for Administration via Prolonged Infusion.

RATIONALE: Previously, we have been able to outpace bacterial mutation by replacing increasingly ineffective antibiotics with new agents. However, with the discovery of new antibiotics diminishing, optimising the administration of existing broad-spectrum antibiotics such as co-amoxiclav has become a necessity. METHODS: A stability indicating HPLC method was developed and validated in compliance with International Council for Harmonisation (ICH) guidelines. Stability of co-amoxiclav at clinical concentration was evaluated at three temperatures (4°C, ambient (23-25°C) and 37°C) in three diluents (water for injection (WFI), 0.9% w/v NaCl and Ringer's solution). To establish whether there were significant differences at the level of both diluent and temperature, results were analysed using analysis of covariance (ANCOVA) to assess differences between the attained slopes of regression. RESULTS: Data obtained indicated co-amoxiclav stability superior to that previously proposed making it suitable for extended infusion therapy. The degradation of amoxicillin appeared to follow a linear trend, with the rate of degradation elevated at higher temperatures, demonstrated by the magnitude of the regression slopes in these conditions. Analysis of regression slopes via ANCOVA demonstrated that diluent and temperature both significantly affected co-amoxiclav stability. Amoxicillin retained 90% of its initial concentration for 7.8 to 10 hrs when stored at 4°C, 5.9 to 8.8 hrs at ambient and 3.5 to 4.5 hrs when incubated at 37°C. CONCLUSION: Co-amoxiclav is suitable for administration via prolonged infusion. Findings from this study aid in ameliorating current dosing regimens to optimise antibiotic efficacy. Other valuable applications conferred from these findings include the ability to pre-prepare solutions for use in bolus administration, minimising preparation time and workload.

Differential antibiotic dosing in critical care: survey on nurses' knowledge, perceptions and experience.

BACKGROUND: With the discovery of new antibiotics diminishing, optimizing the administration of existing antibiotics has become a necessity. Critical care nurses play a crucial role in combating antimicrobial resistance and are involved in preparing and administering antibiotics as well as monitoring their effects on patients. A dosing strategy proposed to reduce the development of ever-evolving antimicrobial resistance involves differential dosing regimens such as prolonged/continuous infusions. OBJECTIVES: To assess critical care nurses' knowledge, perceptions, comfort and experience in relation to prolonged/continuous infusion antibiotics. METHODS: A descriptive cross-sectional study was conducted using an investigator-developed, self-administered survey consisting of open- and closed-ended questions. Obtained data were computed using SPSS. Descriptive and inferential statistics were used to analyse the data. RESULTS: Fifty-two critical care nurses participated in the survey. Data revealed that nurses have adequate levels of knowledge and comfort relating to the use of prolonged/continuous infusion antibiotics along with the ability to communicate effectively on the topic. Results indicate there is a need for further learning, especially in terms of multiplicity of methods for preparing and administering prolonged/continuous infusions and dose calculations. Overall, results are promising as nurses support the wider implementation of prolonged/continuous infusion treatment regimens in critical care. CONCLUSION: Although critical care nurses had a good understanding surrounding the use of prolonged/continuous infusion antibiotics, there is a need for further learning beyond information gained from nursing education courses. Findings from this study indicate that nurses are supportive of prolonged/continuous infusion antibiotics. However, further research is needed to determine the most effective mode of antibiotic administration.

The feasibility of low-intensity psychological therapy for depression co-occurring with autism in adults: The Autism Depression Trial (ADEPT) - a pilot randomised controlled trial.

Low-intensity cognitive behaviour therapy including behavioural activation is an evidence-based treatment for depression, a condition frequently co-occurring with autism. The feasibility of adapting low-intensity cognitive behaviour therapy for depression to meet the needs of autistic adults via a randomised controlled trial was investigated. The adapted intervention (guided self-help) comprised materials for nine individual sessions with a low-intensity psychological therapist. Autistic adults (n = 70) with depression (Patient Health Questionnaire-9 score ⩾10) recruited from National Health Service adult autism services and research cohorts were randomly allocated to guided self-help or treatment as usual. Outcomes at 10-, 16- and 24-weeks post-randomisation were blind to treatment group. Rates of retention in the study differed by treatment group with more participants attending follow-up in the guided self-help group than treatment as usual. The adapted intervention was well-received, 86% (n = 30/35) of participants attended the pre-defined 'dose' of five sessions of treatment and 71% (25/35) attended all treatment sessions. The findings of this pilot randomised controlled trial indicate that low-intensity cognitive behaviour therapy informed by behavioural activation can be successfully adapted to meet the needs of autistic people. Evaluation of the effectiveness of this intervention in a full scale randomised controlled trial is now warranted.

Occurrence of anticancer drugs in the aquatic environment: a systematic review.

Water contamination with pharmaceutical products is a well-studied problem. Numerous studies have demonstrated the presence of anticancer drugs in different water resources that failed to be eliminated by conventional wastewater treatment plants. The purpose of this report was to conduct a systematic review of anticancer drugs in the aquatic environment. The methodology adopted was carried out in compliance with the PRISMA guidelines. From the 75 studies that met the specific requirements for inclusion, data extracted showed that the most common anticancer drugs studied are cyclophosphamide, tamoxifen, ifosfamide and methotrexate with concentrations measured ranging between 0.01 and 86,200 ng/L. There was significant variation in the methodologies employed due to lack of available guidelines to address sampling techniques, seasonal variability and analytical strategy. The most routinely used technique for quantitative determination was found to be solid-phase extraction followed by LC-MS analysis. The lowest reported recovery percentage was 11%, and the highest limit of detection was 1700 ng/L. This indicated the inadequacy of some methods to analyse anticancer drugs and the failure to obtain reliable results. The significant heterogeneity within methodologies made it difficult to compare results and draw conclusions, nevertheless, this study aids in the extrapolation of proposed recommendations to guide future studies and reviews. Graphical abstract.

Guided self-help for depression in autistic adults: the ADEPT feasibility RCT.

BACKGROUND: Co-occurring depression frequently occurs in autism. Evidence-based psychological interventions have been successfully adapted to treat co-occurring anxiety, but there is little evidence about the usefulness of adapted cognitive-behavioural therapy for depression. To the authors' knowledge, to date there have been no randomised trials investigating the usefulness of low-intensity cognitive-behavioural therapy for depression in autism. OBJECTIVES: The objectives of the study were to (1) develop a low-intensity psychological intervention for depression adapted for autism, (2) assess the feasibility and patient and therapist acceptability of the intervention, (3) estimate the rates of recruitment and retention for a full-scale randomised controlled trial and (4) identify an appropriate measure of depression to be used in a full-scale randomised controlled trial. DESIGN: The study comprised a randomised controlled trial (n = 70) with a nested qualitative evaluation (n = 21). Seventy eligible and consenting participants were randomly allocated to guided self-help or to treatment as usual. SETTING: Adult autism services in two NHS regions. PARTICIPANTS: Adults with a diagnosis of autism spectrum disorder with depression, that is, a Patient Health Questionnaire-9 items score of ≥ 10. People who had attended more than six sessions of cognitive-behavioural therapy in the previous 6 months were excluded. INTERVENTIONS: The low-intensity intervention (guided self-help) comprised materials for nine individual sessions, based on behavioural activation adapted for autism, facilitated by therapist guides (coaches) who were graduate-level psychologists who attended training and regular supervision. Treatment as usual was standard NHS care for depression. MAIN OUTCOME MEASURES: Outcomes were measured 10, 16 and 24 weeks post randomisation using self-report and interview measures of depression, anxiety, obsessive-compulsive symptoms, social function and quality of life, and a health-care and service use questionnaire. As this was a feasibility study also designed to identify the most appropriate measure of depression, it was not possible to specify the primary outcome measure or outcome point a priori. RESULTS: The aims of the study were met in full. The guided self-help intervention was feasible and well received by participants and coaches. The majority of allocated participants attended the intervention in full. The most practical outcome point was determined to be 16 weeks. There were differential rates of attrition across the treatment groups: 86% of the guided self-help group remained in the study at 24 weeks, compared with 54% of treatment as usual group. The qualitative study suggested that guided self-help had enhanced credibility with participants at the point of randomisation. Inter-rater reliability of the interview measure of depression was less than adequate, limiting the conclusions that can be drawn from the prespecified sensitivity to change analyses. CONCLUSIONS: The intervention was feasible and well received. Although this feasibility study was not a fully powered trial, it provided some evidence that the guided self-help intervention was effective in reducing depressive symptoms. A full-scale clinical effectiveness and cost-effectiveness trial of the intervention is warranted. FUTURE WORK: Improvements to the intervention materials as a result of qualitative interviews. Stakeholder consultation to consider future trial design, consider strategies to improve retention in a treatment as usual arm and select a self-report measure of depression to serve as the primary outcome measure. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54650760. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 68. See the NIHR Journals Library website for further project information. This study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

The National Institute for Health Research commissioned research to investigate whether or not NHS psychological treatment for depression could be adapted for autistic people. Psychological treatment for anxiety can be helpful for autistic people if it is adapted to meet their needs, but there has been less research into such treatment for depression. We developed a treatment called guided self-help, which comprised materials for nine individual sessions and a manual to help the therapist guides work alongside autistic people. Two autistic people helped us to improve the session materials we had developed. The guides attended 2 days of training on how to deliver guided self-help. Seventy adults with a diagnosis of autism spectrum disorder and depression agreed to take part in the study. They were randomly allocated to guided self-help or to treatment as usual. Treatment as usual means whatever treatment would usually be available. We asked these adults to complete measures of depression, anxiety and other psychological symptoms, as well as their use of health and social care services, before treatment. We asked them to complete these measures again 10, 16 and 24 weeks later. We also invited them to take part in interviews about their experiences of the study. People who had guided self-help attended the treatment to the end and said that they found it acceptable and helpful. They suggested ways to improve the treatment materials. More people in the guided self-help group than in the treatment-as-usual group completed the 16- and 24-week follow-ups. Just over half of the people in the treatment-as-usual group did not attend the 16- and 24-week follow-ups. This would be a problem in a larger trial because we would not have enough information about the treatment-as-usual group to know if people in this group were doing better or worse than those in the guided self-help group. The findings of this study suggest that a larger trial to find out if guided self-help is effective in treating depression in autism would be helpful.

Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations.

The reactivity of hydrogen peroxide and catalytic hydroiodic acid toward 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane.

Stability of Meropenem After Reconstitution for Administration by Prolonged Infusion.

Objective: Meropenem is a parenteral carbapenem antibiotic which has a broad spectrum of activity against aerobes and anaerobes. Meropenem's bactericidal activity is determined by the time during which meropenem concentration remains above the minimal inhibition concentration (MIC) during the dosing interval. Thus, prolonged infusion is the optimal way to maximize the time-dependant activity. However, studies to date have shown that carbapenems and in particular, meropenem, are relatively unstable in solution. The aims of this study were therefore (1) to establish the effects of temperature on the concentration of a generic brand reconstituted meropenem solution and (2) to determine whether 24-hour continuous infusion is possible without concentrations dropping below the recommended 90%. Method: Preliminary examination was carried out by the means of nuclear magnetic resonance (NMR) spectroscopy. Meropenem was subsequently assayed using high-performance liquid chromatography (HPLC). The method was developed and validated in compliance with International Council for Harmonisation (ICH) guidelines. Meropenem's stability was examined at two temperatures 22°C and 33°C to mimic average and high temperature in hospital wards. Solutions were prepared aseptically at the clinically relevant concentration. Results: NMR results obtained showed an increase in open ring methyl groups peak intensity, indicating that meropenem begins to degrade upon dissolution (d=1.05 and 1.25). Results obtained from quantitative HPLC confirm that meropenem concentrations dropped to 90% of initial concentration at 7.4 hours and 5.7 hours at 22°C and 33°C, respectively. Conclusion: Although results obtained indicate that meropenem should not be continuously infused over 24 hours, it is possible that meropenem could be continuously infused for at least 7 hours if temperature does not exceed 22°C and for 5 hours if temperature does not exceed 33°C.