Failure to report protocol violations in clinical trials: a threat to internal validity?

<p>Abstract</p> <p>Background</p> <p>Excessive protocol violations (PV), which can be defined as preventable mistakes in study conduct, may result in patient harm and introduce errors into a clinical trial's results leading to flawed trial conclusions.</p> <p>The purpose of this project was to gain a better understanding of reported PVs, to describe current practice with regards to the use of methods for the reduction of PVs and to investigate relationships between clinical trial characteristics and PVs.</p> <p>Methods</p> <p>We reviewed 80 clinical trials conducted across a broad range of medical specialties published in four major general medical journals (The Lancet, NEJM, JAMA, BMJ). Eligible papers were identified using a PubMed search. For each included trial, two authors independently abstracted information on trial characteristics, PV reporting and PV rates and interventions used to reduce PVs. PVs were categorised into one of five distinct types: enrolment, randomisation, study intervention, patient compliance and data collection errors. Associations between PVs and study characteristics were investigated using logistic regression.</p> <p>Results</p> <p>Eighty clinical trials (20 from each journal) were identified from 101 consecutive PubMed abstracts. The median number of participants was 701 (range: 20 to 162, 367) and the median number of participating sites was 15 (range: 1 to 701). Nineteen percent (15/80) of included trials were single centre trials. The median study duration was 24 months (range: 5.81 - 127 months) and 74% (59/80) of included trials were primarily academic funded.</p> <p>Thirty two percent (26/80) of included trials failed to provide explicit reporting of any type of PV and none (0/80) of the trials provided explicit reporting of all five types of PVs. Larger clinical trials (more patients, more sites, longer duration, more complex management structure) were more likely to have more complete reporting of PV's.</p> <p>Only 9% (7/80) of trials reported the use of a specific study method to prevent PVs. Use of a run-in phase was the only method reported.</p> <p>Conclusions</p> <p>PVs are under-reported. Although the CONSORT statement provides guidance on the reporting of PVs, reporting requirements are not explicit for all types of PVs. As a first step towards improved reporting by authors, we recommend the CONSORT statement highlight the importance of PVs by making reporting requirements more explicit.</p

On the Interaction of a Racing Car Front Wing and Exposed Wheel

A numerical investigation of generic open-wheel racing car wing and wheel geometry has been conducted, using original sub-scale experimental data for validation. It was determined that there are three main interactions that may occur, identifiable by the path that the main and secondary wing vortices take around the wheel. Interaction ‘A’ occurs when the main and secondary wing vortices both travel outboard of the wheel; interaction ‘B’ is obtained when only the main wing vortex passes inboard of the wheel; while interaction ‘C’ sees both wing vortices travel inboard of the wheel. The different interactions are achieved when geometric changes to the wing affect the pressure distribution about the endplate, either by altering the magnitude of suction generated by the wing or by changing the locations of peak suction and vortices relative to the wheel’s stagnation regions. As a result, the influence that the wing and wheel have on each other – in comparison to the same bodies in isolation – varies, resulting in significant consequences for downforce and drag

Flow compressibility effects around an open-wheel racing car

A numerical investigation has been conducted into the influence of flow compressibility effects around an open-wheeled racing car. A geometry was created to comply with 2012 F1 regulations. Incompressible and compressible CFD simulations were compared-firstly with models which maintained Reynolds number as Mach number increased, and secondly allowing Mach number and Reynolds number to increase together as they would on track. Results demonstrated significant changes to predicted aerodynamic performance even below Mach 0·15. While the full car coefficients differed by a few percent, individual components (particularly the rear wheels and the floor/ diffuser area) showed discrepancies of over 10% at higher Mach numbers when compressible and incompressible predictions were compared. Components in close ground proximity were most affected due to the ground effect. The additional computational expense required for the more physically-realistic compressible simulations would therefore be an additional consideration when seeking to obtain maximum accuracy even at low freestream Mach numbers

Factors influencing the relationship between the dose of amlodipine required for blood pressure control and change in blood pressure in hypertensive cats

BACKGROUND: Hypertension is a common problem in elderly cats. In most cats, systolic blood pressure (SBP) of <160 mmHg is achieved in response to amlodipine besylate at either 0.625 or 1.25 mg q24h. The individual cat factors determining dose requirement dose have not been explored. AIMS: To determine whether individual cat factors influence the dose of amlodipine required to achieve adequate blood pressure control and to determine whether factors other than the prescribed dose of drug alter the achieved plasma amlodipine concentrations. METHODS: Fifty‐nine hypertensive cats that required 0.625 mg (A) and 41 cats that required 1.25 mg (B) amlodipine to reach a target SBP of <160 mmHg were identified, and plasma amlodipine concentrations were determined. Comparisons were made between groups, and multivariable linear regression models were performed to investigate predictors of antihypertensive response. RESULTS: Cats that required a greater dose of amlodipine had significantly higher SBP at diagnosis of hypertension (A: (median [25th, 75th percentile]) 182 [175,192] mmHg; B: 207 [194,217] mmHg, P < .001), but comparable blood pressure was achieved after treatment. Plasma amlodipine concentrations were directly related to the dose of amlodipine administered. At diagnosis, cats in group B had significantly lower plasma potassium concentration (A: 4.1 [3.8,4.5]; B: 3.8 [3.6,4.2] mEq/L, P < .01). Weight did not differ between groups. The decrease in SBP was directly and independently associated with the SBP at diagnosis and the plasma amlodipine concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with higher blood pressure at diagnosis might require a greater dose of amlodipine to control their blood pressure adequately. Differences in amlodipine pharmacokinetics between cats do not seem to play a role in the antihypertensive response

Competition between Diffusion and Fragmentation: An Important Evolutionary Process of Nature

We investigate systems of nature where the common physical processes diffusion and fragmentation compete. We derive a rate equation for the size distribution of fragments. The equation leads to a third order differential equation which we solve exactly in terms of Bessel functions. The stationary state is a universal Bessel distribution described by one parameter, which fits perfectly experimental data from two very different system of nature, namely, the distribution of ice crystal sizes from the Greenland ice sheet and the length distribution of alpha-helices in proteins.Comment: 4 pages, 3 figures, (minor changes

Clinical, Imaging and Neurogenetic Features of Patients with Gliomatosis Cerebri Referred to a Tertiary Neuro-Oncology Centre

Introduction: Gliomatosis cerebri describes a rare growth pattern of diffusely infiltrating glioma. The treatment options are limited and clinical outcomes remain poor. To characterise this population of patients, we examined referrals to a specialist brain tumour centre. Methods: We analysed demographic data, presenting symptoms, imaging, histology and genetics, and survival in individuals referred to a multidisciplinary team meeting over a 10-year period. Results: In total, 29 patients fulfilled the inclusion criteria with a median age of 64 years. The most common presenting symptoms were neuropsychiatric (31%), seizure (24%) or headache (21%). Of 20 patients with molecular data, 15 had IDH wild-type glioblastoma, with an IDH1 mutation most common in the remainder (5/20). The median length of survival from MDT referral to death was 48 weeks (IQR 23 to 70 weeks). Contrast enhancement patterns varied between and within tumours. In eight patients who had DSC perfusion studies, five (63%) had a measurable region of increased tumour perfusion with rCBV values ranging from 2.8 to 5.7. A minority of patients underwent MR spectroscopy with 2/3 (66.6%) false-negative results. Conclusions: Gliomatosis imaging, histological and genetic findings are heterogeneous. Advanced imaging, including MR perfusion, could identify biopsy targets. Negative MR spectroscopy does not exclude the diagnosis of glioma

The support and information needs of adolescents and young adults with cancer when active treatment ends

Background: The end of active treatment is a period of high stress for young people with cancer, but limited literature exists about their information and support needs during this phase. This study aimed to understand the needs of young people with cancer, how these needs are currently being met, and how best to provide information and support at the end of active treatment. Methods: This was a multi-stage, mixed methods study exploring the end of treatment experience from the perspectives of young people, and the healthcare professionals caring for them. Semi-structured interviews were undertaken with healthcare professionals, which informed a survey administered nationally. Subsequently, semi-structured interviews were conducted with young people. These combined results informed a co-design workshop to develop recommendations. Results: Telephone interviews were conducted with 12 healthcare professionals and 49 completed the online survey. A total of 11 young people aged 19–26 years (female = 8; 73%) were interviewed. The stakeholder workshop was attended by both healthcare professionals (n = 8) and young people (n = 3). At the end of treatment young people experience numerous ongoing physical issues including pain, fatigue and insomnia; in addition to a range of psychosocial and emotional issues including anxiety, fear of recurrence and isolation. The top three priorities for end of treatment care were: earlier provision and preparation around on-going impact of cancer and cancer treatment; standardised and continued follow-up of young people’s emotional well-being; and development of more information and resources specific to young people. Conclusion The access and availability of appropriate information and sources of support at the end of treatment is variable and inequitable. Young people’s needs would be more effectively met by timely, structured and accessible information, and support provision at the end of treatment to both prepare and enable adaptation across their transition to living with and beyond cancer. This will require both organisational and practical adjustments in care delivery, in addition to a renewed and updated understanding of what the ‘end of treatment’ transition process means

Rates of referable eye disease in the Scottish National Diabetic Retinopathy Screening Programme

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.Peer reviewedPublisher PD

Cotinine-assessed second-hand smoke exposure and risk of cardiovascular disease in older adults

Objectives: To examine whether second-hand smoke (SHS) exposure measured by serum cotinine is associated with increased coronary heart disease (CHD) and stroke risk among contemporary older British adults. Design: Prospective population-based study with self-reported medical history and health behaviours. Fasting blood samples were analysed for serum cotinine and cardiovascular disease (CVD) risk markers. Setting: Primary care centres in 25 British towns in 1998–2001. Patients: 8512 60–79-year-old men and women selected from primary care registers. Main outcome measures: Fatal and non-fatal myocardial infarction (MI; n=445) and stroke (n=386) during median 7.8-year follow-up. Main exposure: Observational study of serum cotinine assayed from fasting blood sample using liquid chromatography tandem mass spectrometry method, and self-reported smoking history. Results: Among 5374 non-smokers without pre-existing CVD, geometric mean cotinine was 0.15 ng/ml (IQR 0.05–0.30). Compared with non-smokers with cotinine ≤0.05 ng/ml, higher cotinine levels (0.06–0.19, 0.2–0.7 and 0.71–15.0 ng/ml) showed little association with MI; adjusted HRs were 0.92 (95% CI 0.63 to 1.35), 1.07 (0.73 to 1.55) and 1.09 (0.69 to 1.72), p(trend)=0.69. Equivalent HRs for stroke were 0.82 (0.55 to 1.23), 0.74 (0.48 to 1.13) and 0.69 (0.41 to 1.17), p(trend)=0.065. The adjustment for sociodemographic, behavioural and CVD risk factors had little effect on the results. The HR of MI for smokers (1–9 cigarettes/day) compared with non-smokers with cotinine ≤0.05 ng/ml was 2.14 (1.39 to 3.52) and 1.03 (0.52 to 2.04) for stroke. Conclusions: In contemporary older men and women, SHS exposure (predominantly at low levels) was not related to CHD or stroke risks, but we cannot rule out the possibility of modest effects at higher exposure levels