Cascade diagrams for depicting complex interventions in randomised trials

Clarity about how trial interventions are delivered is important for researchers and those who might want to use their results. A new graphical representation aims to help make complex interventions clearer. Many medical interventions—particularly non-pharmacological ones—are complex, consisting of multiple interacting components targeted at different organisational levels. Published descriptions of complex interventions often do not contain enough detail to enable their replication. Reports of behaviour change interventions should include descriptions of setting, mode, intensity, and duration, and characteristics of the participants. Graphical methods, such as that showing the relative timing of assessments and intervention components, may improve clarity of reporting. However, these approaches do not reveal the connections between the different “actors” in a complex intervention.8 Different audiences may want different things from a description of an intervention, but visualising relationships between actors can clarify crucial features such as the fidelity with which the intervention is passed down a chain of actors and possible routes of contamination between treatment arms. Here we describe a new graphical approach—the cascade diagram—that highlights these potential problems

Discontinuing financial incentives for adherence to antipsychotic depot medication: long-term outcomes of a cluster randomised controlled trial

Objectives: In a cluster randomised controlled trial, offering financial incentives improved adherence to antipsychotic depot medication over a 1-year period. Yet, it is unknown whether this positive effect is sustained once the incentives stop. Methods and analyses: Patients in the intervention and control group were followed up for 2 years after the intervention. Primary and secondary outcomes were assessed at 6 months and 24 months post intervention. Assessments were conducted between September 2011 and November 2014. Results: After the intervention period, intervention and control groups did not show any statistically significant differences in adherence, neither in the first 6 months (71% and 77%, respectively) nor in the following 18 months (68%, 74%). There were no statistically significant differences in secondary outcomes, that is, adherence ≥95% and untoward incidents either. Conclusions: It may be concluded that incentives to improve adherence to antipsychotic maintenance medication are effective only for as long as they are provided. Once they are stopped, adherence returns to approximately baseline level with no sustained benefit. Trial registration number: ISRCTN77769281

Effectiveness and cost-effectiveness of a novel, group self-management course for adults with chronic musculoskeletal pain: study protocol for a multicentre, randomised controlled trial (COPERS)

Introduction: Chronic musculoskeletal pain is a common condition that often responds poorly to treatment. Self-management courses have been advocated as a non-drug pain management technique, although evidence for their effectiveness is equivocal. We designed and piloted a self-management course based on evidence for effectiveness for specific course components and characteristics. Methods/analysis: COPERS (coping with persistent pain, effectiveness research into self-management) is a pragmatic randomised controlled trial testing the effectiveness and cost-effectiveness of an intensive, group, cognitive behavioural-based, theoretically informed and manualised self-management course for chronic pain patients against a control of best usual care: a pain education booklet and a relaxation CD. The course lasts for 15 h, spread over 3 days, with a –2 h follow-up session 2 weeks later. We aim to recruit 685 participants with chronic musculoskeletal pain from primary, intermediate and secondary care services in two UK regions. The study is powered to show a standardised mean difference of 0.3 in the primary outcome, pain-related disability. Secondary outcomes include generic health-related quality of life, healthcare utilisation, pain self-efficacy, coping, depression, anxiety and social engagement. Outcomes are measured at 6 and 12 months postrandomisation. Pain self-efficacy is measured at 3 months to assess whether change mediates clinical effect. Ethics/dissemination: Ethics approval was given by Cambridgeshire Ethics 11/EE/046. This trial will provide robust data on the effectiveness and cost-effectiveness of an evidence-based, group self-management programme for chronic musculoskeletal pain. The published outcomes will help to inform future policy and practice around such self-management courses, both nationally and internationally. Trial registration: ISRCTN24426731

Prevalence and impact of chronic widespread pain in the Bangladeshi and White populations of Tower Hamlets, East London

The prevalence and impact of chronic pain differ between ethnic groups. We report a study of the comparative prevalence and impact of chronic pain in Bangladeshi, British Bangladeshi and White British/Irish people. We posted a short questionnaire to a random sample of 4,480 patients registered with 16 general practices in the London Borough of Tower Hamlets and conducted a longer questionnaire with patients in the waiting areas at those practices. We distinguished between Bangladeshi participants who were born in the UK or had arrived in the UK at the age of 14 or under (British Bangladeshi) and those who arrived in UK at the age of over 14 (Bangladeshi). We obtained 1,223/4,480 (27 %) responses to the short survey and 600/637 (94 %) to the long survey. From the former, the prevalence of chronic pain in the White, British Bangladeshi and Bangladeshi groups was 55, 54 and 72 %, respectively. The corresponding figures from the long survey were 49, 45 and 70 %. Chronic widespread pain was commoner in the Bangladeshi (16 %) than in the White (10 %) or British Bangladeshi (9 %) groups. People with chronic pain experienced poorer quality of life (odds ratio for scoring best possible health vs. good health (or good vs. poor health) 5.6 (95 % confidence interval 3.4 to 9.8)), but we found no evidence of differences between ethnic groups in the impact of chronic pain on the quality of life. Chronic pain is commoner and, of greater severity, in Bangladeshis than in Whites. On most measures in this study, British Bangladeshis resembled the Whites more than the Bangladeshis

A convenient and efficient synthesis of (S)-lysine and (S)-arginine homologues via olefin cross-metathesis

A convenient five step synthesis of (S)-homolysine, incorporating a key olefin cross-metathesis step in the chain extension methodology, has been developed, together with a six step related synthesis of a new homologue of arginine, (S)-bishomoarginine

An Arbitrary Two-qubit Computation In 23 Elementary Gates

Quantum circuits currently constitute a dominant model for quantum computation. Our work addresses the problem of constructing quantum circuits to implement an arbitrary given quantum computation, in the special case of two qubits. We pursue circuits without ancilla qubits and as small a number of elementary quantum gates as possible. Our lower bound for worst-case optimal two-qubit circuits calls for at least 17 gates: 15 one-qubit rotations and 2 CNOTs. To this end, we constructively prove a worst-case upper bound of 23 elementary gates, of which at most 4 (CNOT) entail multi-qubit interactions. Our analysis shows that synthesis algorithms suggested in previous work, although more general, entail much larger quantum circuits than ours in the special case of two qubits. One such algorithm has a worst case of 61 gates of which 18 may be CNOTs. Our techniques rely on the KAK decomposition from Lie theory as well as the polar and spectral (symmetric Shur) matrix decompositions from numerical analysis and operator theory. They are related to the canonical decomposition of a two-qubit gate with respect to the ``magic basis'' of phase-shifted Bell states, published previously. We further extend this decomposition in terms of elementary gates for quantum computation.Comment: 18 pages, 7 figures. Version 2 gives correct credits for the GQC "quantum compiler". Version 3 adds justification for our choice of elementary gates and adds a comparison with classical library-less logic synthesis. It adds acknowledgements and a new reference, adds full details about the 8-gate decomposition of topC-V and stealthily fixes several minor inaccuracies. NOTE: Using a new technique, we recently improved the lower bound to 18 gates and (tada!) found a circuit decomposition that requires 18 gates or less. This work will appear as a separate manuscrip

Nanoflow-nanospray mass spectrometry metabolomics reveals disruption of the urinary metabolite profiles of HIV-positive patients on combination antiretroviral therapy

Background: The use of combination antiretroviral therapy (cART) has substantially improved the outlook for patients with HIV infection. However, lifelong exposure to cART is also associated with adverse metabolic changes and an enhanced risk of renal, hepatic and cardiovascular dysfunction. This study investigated disruptions of the urinary metabolome of cART-exposed patients, thereby furthering our understanding of some of the side effects of pharmaceutical intervention. Methods: HIV-positive patients were recruited from an HIV clinic and divided into cART-naive and cART-exposed groups. HIV-negative patients were recruited from a sexual health clinic. All 89 subjects were white males. Targeted biochemistry analyses were performed on plasma samples. Urine samples were collected following an overnight fast and analysed with a highly sensitive untargeted metabolomic method using nanoflow/nanospray liquid chromatography-time of flight mass spectrometry. Datasets were analysed using projection modelling to detect metabolite markers of cART exposure. Results: Metabolites or parent compounds of all cART drugs were detected in urine extracts of all but one of the cART-exposed patients confirming adherence to the pharmaceutical regimen. Analysis of urine samples from patients on cART revealed significant reductions in selected bile acids, lipid, nucleoside and androgen metabolites. However, plasma concentrations of free or conjugated testosterone were unchanged indicating possible disruption of androgen transport or excretion in urine of patients on cART. Conclusions: Discovery-based metabolomics reveals the potential to identify novel markers of cART intervention and metabolite disruption in HIV-positive patients, which may enable the efficacy, compliance and side effects of these pharmaceutical mixtures to be investigated

Determining the accuracy of zero-flux and ingestible thermometers in the peri-operative setting

Accurately monitoring peri-operative core temperature is a cornerstone of good practice. Relatively invasive devices such as oesophageal temperature probes and pulmonary artery catheters facilitate this, but are inappropriate for many patients. There remains a need for accurate monitors of core temperature that can be used in awake patients. This study compared the accuracy of two core temperature thermometers that can be used for this purpose: the 3M Bair Hugger™ Temperature Monitoring System Zero Flux Thermometer and the CorTempR™ Wireless Ingestible Temperature Sensor. Readings were compared with the oesophageal probe, the current intraoperative standard. Thirty patients undergoing elective surgical procedures under general anaesthesia were recruited. The ingestible sensor was ingested prior to induction of anaethesia, and post induction, the zero-flux electrode attached above the right eyebrow and oesophageal probe inserted. During surgery, the temperature on each device was recorded every minute. Measurements were compared using Bland–Altman analysis. The ingestible sensor experienced interference from use of diathermy and fluoroscopy in the operating theatre, rendering 39% of its readings unusable. These were removed from analysis. With remaining readings the bias compared with oesophageal probe was + 0.42 °C, with 95% limits of agreement − 2.4 °C to 3.2 °C. 75.4% of readings were within ± 0.5 °C of the OTP reading. The bias for the zero flux electrode compared to oesophageal probe was + 0.02 °C with 95% limits of agreement − 0.5 °C to 0.5 °C. 97.7% of readings were within ± 0.5 °C of the oesophageal probe. The study findings suggest the zero-flux thermometer is sufficiently accurate for clinical use, whereas the ingestible sensor is not

Implications of the problem orientated medical record (POMR) for research using electronic GP databases: a comparison of the Doctors Independent Network Database (DIN) and the General Practice Research Database (GPRD).

Background The General Practice Research Database (GPRD) and Doctor's Independent Network Database (DIN), are large electronic primary care databases compiled in the UK during the 1990s. They provide a valuable resource for epidemiological and health services research. GPRD (based on VAMP) presents notes as a series of discrete episodes, whereas DIN is based on a system (MEDITEL) that used a Problem Orientated Medical Record (POMR) which links prescriptions to diagnostic problems. We have examined the implications for research of these different underlying philosophies. Methods Records of 40,183 children from 141 practices in DIN and 76,310 from 464 practices in GRPD who were followed to age 5 were used to compare the volume of recording of prescribing and diagnostic codes in the two databases. To assess the importance and additional value of the POMR within DIN, the appropriateness of diagnostic linking to skin emollient prescriptions was investigated. Results Variation between practices for both the number of days on which prescriptions were issued and diagnoses were recorded was marked in both databases. Mean number of "prescription days" during the first 5 years of life was similar in DIN (19.5) and in GPRD (19.8), but the average number of "diagnostic days" was lower in DIN (15.8) than in GPRD (22.9). Adjustment for linkage increased the average "diagnostic days" to 23.1 in DIN. 32.7% of emollient prescriptions in GPRD appeared with an eczema diagnosis on the same day compared to only 19.4% in DIN; however, 86.4% of prescriptions in DIN were linked to an earlier eczema diagnosis. More specifically 83% of emollient prescriptions appeared under a problem heading of eczema in the 121 practices that were using problem headings satisfactorily. Conclusion Prescribing records in DIN and GPRD are very similar, but the usage of diagnostic codes is more parsimonious in DIN because of its POMR structure. Period prevalence rates will be underestimated in DIN unless this structure is taken into account. The advantage of the POMR is that in 121 of 141 practices using problem headings as intended, most prescriptions can be linked to a problem heading providing a specific reason for their issue