Applying for regulatory approval of a clinical trial of a medical device in the UK - A practical guide.

Seeking regulatory and ethical approval is a significant task that must be completed before conducting a clinical trial of a medical device. Currently in the UK, the Integrated Research Application System (IRAS) is a unified system for preparing regulatory, ethical and governance applications for the relevant bodies that must approve health and social research. This article outlines key aspects in planning a clinical trial of a medical device and how applications for approval can be prepared using IRAS.

Professionalism and non-technical skills in Radiology in the UK: a review of the national curriculum.

OBJECTIVE: To drive quality and safe clinical practice, professional values and non-technical skills need to be explicit in all postgraduate medical curricula and appropriate assessment tools should be available for teachers to apply. We interrogate a national Radiology curriculum for content on professionalism and assessment tools, comparing it with the Royal College of Physicians' 2005 document. RESULTS: We found that whilst the knowledge for practising with professional values is embedded in the curriculum, the skills that have to be acquired have not been comprehensively developed. This is reflected in the restricted assessment tools that are mapped to each generic area. The terminology used in the Radiology curriculum was varied and the most frequently used descriptor for professionalism or behaviours pertaining to non-technical aspects was Good Medical Practice; a term used by our regulator, the General Medical Council, and to which our curriculum is mapped. If terminology is to be standardized in Britain collaboration with our regulator is key. We need standardized terminology to permit effective research and sharing of best practice. The Radiology curriculum encompasses all the values set out in the seminal document produced by the Royal College of Physicians in 2005, Doctors in society: medical professionalism in a changing world.

Uterine artery pulsatility and resistivity indices in pregnancy: Comparison of MRI and Doppler US.

OBJECTIVE: The aim of this work was to evaluate whether the uterine arteries (UtA) could be identified and their flow profiles measured during a fetal MRI examination. A comparison was performed against same day sonographic Doppler assessment. METHODS: 35 normal, healthy, singleton pregnancies at 28-32 weeks gestation underwent routine Doppler examination, followed by MRI examination. The resistivity index (RI) and pulsatility index (PI) of the left and right UtA were measured using phase contrast MRI. Bland Altman statistics were used to compare MRI and ultrasound results. RESULTS: Sixty-nine comparable vessels were analysed. Six vessels were excluded due to artefact or technical error. Bland-Altman analysis demonstrated the ultrasound indices were comparable, although systematically lower than the MRI indices; Right UtA RI bias -0.03 (95% limits of agreement (LOA) -0.27 to +0.20), and left UtA RI bias -0.06 (95% LOA -0.26 to +0.14); Right UtA PI bias -0.06 (95% LOA -0.50 to +0.38), Left UtA PI bias -0.11 (95% LOA -0.54 to +0.32). The inter-rater agreement for the MRI derived PI and RI analysis was good. CONCLUSION: This study demonstrates that in the majority of early third trimester pregnancies, the uterine arteries can be identified, and their flow profiles measured using MRI, and that the derived PI and RI values are comparable with Doppler ultrasound values.

Amniotic fluid volume: Rapid MR-based assessment at 28-32 weeks gestation.

OBJECTIVES: This work evaluates rapid magnetic resonance projection hydrography (PH) based amniotic fluid volume (AFV) estimates against established routine ultrasound single deepest vertical pocket (SDVP) and amniotic fluid index (AFI) measurements, in utero at 28-32 weeks gestation. Manual multi-section planimetry (MSP) based measurement of AFV is used as a proxy reference standard. METHODS: Thirty-five women with a healthy singleton pregnancy (20-41 years) attending routine antenatal ultrasound were recruited. SDVP and AFI were measured using ultrasound, with same day MRI assessing AFV with PH and MSP. The relationships between the respective techniques were assessed using linear regression analysis and Bland-Altman method comparison statistics. RESULTS: When comparing estimated AFV, a highly significant relationship was observed between PH and the reference standard MSP (R(2) = 0.802, p < 0.001). For the US measurements, SDVP measurement related most closely to amniotic fluid volume, (R(2) = 0.470, p < 0.001), with AFI demonstrating a weaker relationship (R(2) = 0.208, p = 0.007). CONCLUSION: This study shows that rapid MRI based PH measurement is a better predictor of AFV, relating more closely to our proxy standard than established US techniques. Although larger validation studies across a range of gestational ages are required this approach could form part of MR fetal assessment, particularly where poly- or oligohydramnios is suspected. KEY POINTS: • MR projection hydrography can be used to estimate amniotic fluid volume. • MR projection hydrography relies on the T2w signal from amniotic fluid. • Amniotic fluid volume (AFV) is more accurately assessed than with ultrasound.

Post-mortem skeletal surveys in suspected non-accidental injury.

AIM: To evaluate potential differences between live (LSS) and post-mortem skeletal surveys (PMSS) in cases of non-accidental injury (NAI). MATERIALS AND METHODS: All skeletal surveys (SS) performed for suspected NAI over a 5 year period were retrospectively reviewed. Demographic details, injuries obtained, artefacts, and radiographic difficulties encountered during LSS and PMSS were recorded. RESULTS: Of 195 surveys performed, there were significantly fewer positive PMSS (11/128; 8.6%) than LSS (16/67; 23.8%), but no difference between the actual injuries encountered. Of those who had a positive SS, dead children were significantly younger (mean age 2.6 ± 3.4 months old) than live children (7.8 ± 6.9 months old; p < 0.05). Thirty-six percent of all contemporary digital radiographs contained artefacts, particularly in PMSS (599/1504; 39.8%) compared to LSS (269/904: 29.7%; p < 0.001), which were mostly patient identification labels (55.1 versus 21.6%; p < 0.001). PMSS demonstrated death-related radiographic complications in 10.6% of cases. CONCLUSION: Radiographic imaging in deceased children is not easy, and yields significant artefacts, which may hamper image interpretation. A technique for obtaining multiple views of a limb in fixed flexion deformity to maximize the diagnostic potential is described. Careful consideration of these factors would maximize the diagnostic yield in this unique patient population.

Nutcracker and SMA syndromes: What is the normal SMA angle in children?

OBJECTIVE: The nutcracker and superior mesenteric artery (SMA) syndromes are rare conditions where the left renal vein or duodenum may be compressed by an unusually acute angle between the SMA and aorta, although the normal angle in children is unknown. We measured the SMA angle to define the normal range in children. METHODS: We retrospectively measured SMA angles, left renal vein (LRV) distance, and duodenal distance (DD) in 205 consecutive pediatric abdominal CT. Total and visceral intra-abdominal fat at the level of the umbilicus were also assessed. RESULTS: Mean SMA angle was 45.6±19.6° (range 10.6-112.9°), mean LRV distance was 8.6±3.9mm (range 2.0-28.6mm) and mean DD was 11.3±4.8mm (range 3.6-35.3mm). There was a significant but weak correlation between %visceral fat volume (%VF) and SMA angle (R=0.30; p<0.001), LRV distance (R=0.37, p<0.001) and DD (R=0.32; p<0.001). CONCLUSION: There is a wide range of SMA angle, LRV and DD in normal children, which correlated weakly with visceral fat volume. Using a definition of SMA angle <25° would diagnose 9.3% of asymptomatic children with nutcracker syndrome, and using a DD definition of <8mm would diagnose 20% with SMA compression. Our findings suggest exercising caution when attributing these rare syndromes to an absolute SMA angle.

Use of small bowel MRI enteroclysis in the management of paediatric IBD.

INTRODUCTION: Children with inflammatory bowel disease (IBD) frequently present with small bowel involvement at some stage of their disease. Hence, reliable assessment of the entire small bowel is required in order to adjust treatment accordingly. Recently, magnetic resonance imaging (MRI) of the small bowel in combination with luminal contrast agent delivered via a naso-jejunal tube (MR enteroclysis) is an emerging technique demonstrating good results in adult patients. However, data on its use and benefits in children is limited. AIMS: In this study we report our experience on performing small bowel MR enteroclysis (MRE) in children with IBD. Specifically, we reviewed indications, MR findings, advantages and disadvantages of the technique in a tertiary unit. METHODS: A total of 34 MRE studies (29 paediatric IBD patients) were retrospectively analysed. All patients underwent upper and lower endoscopy under general anaesthetic (GA) the day before MR imaging was performed. Nasojejunal (NJ)-tube was placed during endoscopy. RESULTS: Frequently detected findings included small and large bowel wall thickening, small bowel strictures and intestinal lymph node enlargement. Importantly, in all our clinical cases, MRE results were key to making a clinical decision in the given scenario regardless of whether MRE findings were positive or negative. CONCLUSIONS: Within our setup, MR enteroclysis is a well-tolerated, sensitive technique for small bowel imaging, providing detailed information at crucial clinical decision points. Moreover, accurate information then allows appropriate clinical decisions to be made.

More harm than good? The anatomy of misguided shielding of the ovaries.

OBJECTIVE: Popular gonad shield designs aim to provide coverage of the true pelvis, which is presumed to be the probable location of the ovaries. Shields are frequently placed inaccurately, especially in children, obscuring important orthopaedic landmarks on pelvic radiographs. We aimed to identify the position of the ovaries and asses how this may vary with age and the degree of bladder filling. We aimed to identify the position of the ovaries and asses how this may vary with age and the degree of bladder filling. METHODS: Using MRI examinations of the pelvis in women and children, we located 594 ovaries in 306 female patients aged from birth to 59 years. RESULTS: This study provides new evidence that bladder filling affects ovary position. A lower than expected number of patients had both ovaries within the pelvis if the bladder contained more than a moderate volume of urine. Bladder emptying should be achieved wherever practical if a shield is used. In children under the age of 7 years, more than half (19/37) had at least one ovary outside the true pelvis. There was a significant association between age and ovary position, with the percentage of patients with one or both ovaries outside the true pelvis decreasing with age (χ(2), p<0.0001). CONCLUSION: The embryological descent of the ovaries into the pelvis would appear to continue after birth, well into childhood. Current popular shield designs are therefore inappropriate for use in young children. Given the high risk of obscuring critical landmarks, coupled with the new evidence that even accurate placement will not necessarily protect the ovaries, the use of pelvic shields in girls should be reconsidered.

Minimally-invasive fetal autopsy using magnetic resonance imaging and percutaneous organ biopsies: clinical value and comparison to conventional autopsy.

OBJECTIVES: Autopsy is an important investigation following fetal death or termination for fetal abnormality. Postmortem magnetic resonance imaging (MRI) can provide macroscopic information of comparable quality to that of conventional autopsy in the event of perinatal death. It does not provide tissue for histological examination, which may limit the quality of counseling for recurrence risks and elucidation of the cause of death. We sought to examine the comparability and clinical value of a combination of postmortem MRI and percutaneous fetal organ biopsies (minimally invasive autopsy (MIA)) with conventional fetal autopsy. METHODS: Forty-four fetuses underwent postmortem MRI and attempted percutaneous biopsy (using surface landmarks) of major fetal organs (liver, lung, heart, spleen, kidney, adrenal and thymus) following fetal death or termination for abnormality, prior to conventional autopsy, which was considered the 'gold standard'. We compared significant findings of the two examinations for both diagnostic information and clinical significance. Ancillary investigations (such as radiographs and placental histology) were regarded as common to the two forms of autopsy. RESULTS: In 21 cases conventional autopsy provided superior diagnostic information to that of MIA. In two cases the MIA provided superior diagnostic information to that of conventional autopsy, when autolysis prevented detailed examination of the fetal brain. In the remaining 21 cases, conventional autopsy and MIA provided equivalent diagnostic information. With regard to clinical significance, however, in 32 (72.7%) cases, the MIA provided information of at least equivalent clinical significance to that of conventional autopsy. In no case did the addition of percutaneous biopsies reveal information of additional clinical significance. CONCLUSIONS: Although in some cases MRI may provide additional information, conventional perinatal autopsy remains the gold standard for the investigation of fetal death. The utility of adding percutaneous organ biopsies, without imaging guidance, to an MRI-based fetal autopsy remains unproven. Postmortem MRI, combined with ancillary investigations such as placental histology, external examination by a pathologist, cytogenetics and plain radiography provided information of equivalent clinical significance in the majority of cases.

Anatomical variation in the position of the brachiocephalic trunk (innominate artery) with respect to the trachea: a computed tomography-based study and literature review of Innominate Artery Compression Syndrome.

Respiratory compromise due to tracheal compression by the brachiocephalic trunk (BT), a condition first labeled as Innominate Artery Compression Syndrome (IACS), has been controversially attributed to an anomalous origin of this vessel to the left of, and hence crossing, the trachea. The aim of this study was to establish the normal relationship between the BT and trachea in infants, children, and young adults without obstructive respiratory symptoms. One hundred and eighty-one computed tomography (CT) examinations of the thorax, in three age groups, were reviewed. In axial cross section, the origin of the BT from the aortic arch was identified. The BT origin, with respect to the trachea, was recorded as for a clock face, approximated to the nearest half hour. There were 62 CTs in Group 1 (1 day to 3 years of age), 48 CTs in Group 2 (10-15 years), and 71 examinations in Group 3 (20-40 years). In 96.8% of Group 1, 91.7% of Group 2, and 74.6% of Group 3 the BT origin was to the left of the trachea, between the half past twelve and 3 o'clock positions. The BT origin occurred more the left in Group 1 when compared with the other two groups (P < 0.001). An origin of the BT to the left of the trachea is a normal finding in children and young adults without obstructive respiratory symptoms. There is a tendency for the origin to become progressively more rightward with age.

The toddler refusing to weight-bear: a revised imaging guide from a case series.

BACKGROUND: The previously mobile child who refuses to walk or weight-bear is a common presentation to the accident and emergency department, for which there are a number of causes. One uncommon cause is discitis, an inflammatory process of the intervertebral disc, which is easily diagnosed with spinal magnetic resonance imaging (MRI). A case series of three patients is presented of non-weight-bearing children in whom there was a delay in making the diagnosis of lumbosacral discitis. None presented with back pain, spinal symptoms or abnormal neurological findings, and a full range of movement of both hips was found. METHODS: All patients underwent conventional radiography and ultrasound, but diagnoses were made on spinal MRI, with two patients undergoing bone scintigraphy before this. RESULTS: The mean delay was 15.6 days (range 13-20) from presentation at the hospital to MRI. All three patients made a good clinical recovery with intravenous antibiotics. CONCLUSION: These cases are presented in order to heighten the awareness of this disease entity and its imaging findings, and suggest new guidelines for the appropriate radiological investigations in this clinical setting.

Evaluation of image quality and radiation dose in adolescent thoracic imaging: 64-slice is preferable to 16-slice multislice CT.

There is a constant drive for radiology departments to acquire newer and improved CT machines in order to facilitate faster procedures and a greater repertoire of examinations. However, it is unclear whether the newer technology provides significantly improved image quality, or carries radiation dose implications for patients during everyday clinical practice. We assessed image quality and radiation dose in 15 children and young adults aged 9.3-19.5 years who underwent thoracic imaging on both 16-slice (16CT) and 64-slice (64CT) CT machines. Images were assessed for image quality on a visual analogue scale (1 = unacceptable; 5 = perfect) and preferred image set. All datasets were diagnostically acceptable (scores of 3 or more). The scores for 64CT datasets were significantly better than for 16CT datasets (mean scores of 4.5 and 4.0, respectively; p<0.05). The mean dose-length product (DLP) given was significantly higher during 16CT examinations at 152 mGy cm (effective dose, 2.1 mSv) than for 64CT examinations at 136 mGy cm (1.9 mSv; p<0.05). On average, 64CT examination DLPs were 16 mGy cm (or 9%) lower than the equivalent 16CT examination DLPs. In the context of childhood and adolescent thoracic CT imaging, and using the same software from the same manufacturers, 64CT examinations provide better image quality and give a lower effective dose than do 16CT examinations. If the choice were available, it would be pertinent to use 64CT for this patient group.

Feasibility of percutaneous organ biopsy as part of a minimally invasive perinatal autopsy.

To determine the feasibility of percutaneous fetal organ biopsies in the context of a 'minimally invasive' perinatal autopsy after stillbirth and termination for abnormality is the aim of this study. We assessed successful biopsy rate and the proportion adequate for histological examination in 30 fetuses undergoing organ sampling before autopsy. The relationship between gestational age, body weight, death-biopsy interval, operator experience and successful biopsy rate was investigated. Significant findings from conventional block histology were compared with corresponding percutaneous biopsies. Of 210 organ biopsies attempted from seven target organs, 107 were obtained, of which 94 were adequate for pathological comment. The median delivery-autopsy interval was 4 (range 2-11) days. Adequate samples were obtained from the lung in 86% cases (95% CI 68, 96%), liver 76% (95% CI 56, 90%) and less frequently for the myocardium, kidney, adrenal, thymus and spleen. There was no relationship between biopsy success and time to biopsy, gestational age, body weight and user experience. No histological abnormalities found at autopsy were diagnosed from needle biopsies. Although targeted percutaneous biopsies appear feasible for some organs, fewer than 50% of all biopsies are adequate for histological examination. This technique cannot be considered to provide useful clinical information as part of a 'minimally invasive' perinatal autopsy.

Use of a confidence scale in reporting postmortem fetal magnetic resonance imaging.

OBJECTIVES: Postmortem magnetic resonance imaging (MRI) may be an alternative to conventional autopsy. However, it is unclear how confident radiologists are in reporting such studies. We sought to determine the confidence with which radiologists report on various fetal organs by developing a scale to express their confidence of normality and abnormality, and to place this in the context of a pathological diagnosis of whether the organ was in fact normal or abnormal. METHODS: Thirty fetuses, aged 16-39 gestational weeks and weighing 61-3270 g, underwent postmortem MRI prior to conventional autopsy. MRI studies were reported by two radiologists with access to the clinical and sonographic history: a neuroradiologist, reporting head and neck, and a pediatric radiologist, reporting thorax, abdomen and pelvis. Radiologists used a scale (0 = definitely abnormal, 100 = definitely normal, 50 = unable to comment) to indicate their confidence of anatomical structures being normal or abnormal, using a checklist. Conventional autopsies were performed by pediatric pathologists blinded to the MRI findings, and these were considered the reference standard. RESULTS: Most normal fetal organs had high scores on postmortem MRI, with median confidence scores above 80. However, the atrioventricular valves, duodenum, bowel rotation and pancreas proved more difficult to assess, with median scores of 50, 60, 60 and 62.5, respectively. Abnormal cardiac atria and ventricles, kidneys, cerebral hemispheres and corpus callosum were always detected with high or moderate degrees of confidence (median scores of 2.5, 5, 0, 0 and 30 respectively). However, in two cases with abnormal cardiac outflow tracts, both cases scored 50. Kappa values, assessing agreement between MRI diagnoses of abnormality and autopsy, were high for the brain (0.83), moderate for the lungs (0.56) and fair for the heart (0.33). CONCLUSIONS: This scoring system represents an attempt to define the confidence of radiologists to report varying degrees of normality and abnormality following z ex-utero fetal MRI. While most fetal anatomy is clearly visualized on postmortem MRI, radiologists may lack confidence reporting such studies and there are particular problems with assessment of some cardiac and gastrointestinal structures, both normal and abnormal.

The accuracy of antenatal ultrasound in the detection of facial clefts in a low-risk screening population.

OBJECTIVES: To evaluate the accuracy of prenatal ultrasound in the detection of facial clefts in a low-risk screening population and to report on the outcome of these pregnancies. DESIGN: We retrospectively reviewed antenatal ultrasound records from the obstetric ultrasound department, postnatal records from the regional craniofacial unit and autopsy reports of fetuses over 16 weeks' gestational age from the regional pathology department over a 5-year period (1993-97). Cross-referencing between the three data sets identified all cases of facial clefts. RESULTS: Out of 23 577 live and still births, 30 had facial clefts; four were excluded from the study. Of the remaining 26 cases, 10 had associated major anomalies. There were 19 live births and seven terminations. Six of the seven terminations had other major abnormalities. Our detection rate for cleft lip and palate was 93% and the detection rate for isolated cleft palate was 22%. Isolated cleft lip was detected in 67% of cases. The overall detection rate for facial clefts was 65%. CONCLUSION: From our results and a review of the literature it is clear that before standards can be set we need to define which facial clefts are sonographically demonstrable. Our data provide information for effective counseling and setting of standards for clinical practice.

Platelet dopamine receptors and oxidative stress parameters as markers of manganese toxicity.

The present study has been undertaken to investigate whether neurotoxic effects of manganese (Mn) are reflected in platelets in rats to monitor the usefulness of platelet as peripheral model. Exposure of rats to Mn (10 or 15 mg/kg bw, i.p.) for 45 days caused a significant increase in membrane fluidity as evidenced by decrease in fluorescence polarisation in platelets (11% and 14%) and striatum (9% and 13%). These rats exhibited a significant increase in superoxide dismutase activity both in platelets (24% and 37%) and striatum (31% and 42%), respectively, in comparison to controls. Exposure of rats to Mn for 45 days (15 mg/kg bw, i.p.) caused a significant decrease in reduced glutathione content (platelets 20%, striatum 24%) and catalase activity (platelets 35%, striatum 44%) compared to control rats. Rats exposed to Mn (10 or 15 mg/ kg bw, i.p.) for 15 days exhibited a significant increase in dopamine receptors both in platelets (55% and 40%) and striatum (38% and 31%). The results suggest that exposure to Mn may alter the membrane functions and impair the anti-oxidant defense mechanism both in platelets and brain. The study also suggests that dopaminergic mechanisms are impaired following Mn exposure and such changes are reflected in platelets. Interestingly, parallel changes both in striatum and platelets, as observed in the present study, strengthen the usefulness of platelets as a peripheral neuronal model.

Persistent value of air-augmented radiograph in neonatal high gastrointestinal obstruction, despite more modern techniques.

Air is a safe and effective natural contrast agent in neonatal high gastrointestinal (GIT) obstruction. Successful early decompression often results in plain abdominal radiographs of low diagnostic yield. We present a series of neonates with high GIT obstruction in whom air-augmented abdominal radiographs (AAAR) were performed instead. Fourteen neonates presented with suspected high GIT obstruction. In 12 sick babies, obstruction was confirmed and the level of obstruction was determined. The other two neonates required additional positive contrast upper GIT studies. These confirmed small bowel malrotation. For neonatal high GIT obstruction an AAAR can provide a rapid and accurate diagnosis. Positive contrast agent studies should be performed when the AAAR is non-diagnostic.

Ultrasound, CT and colonoscopy of colonic cancer.

Barium enema and colonoscopy are commonly used for the investigation of suspected colonic cancer. These techniques are relatively invasive and both the investigation and the preceding bowel preparation are demanding, particularly in the elderly. A prospective, blinded trial was conducted to compare ultrasound (US) and CT with colonoscopy. CT and colonoscopy were performed on 50 patients with symptoms suggesting colonic cancer. Both radiological investigations were performed prior to the bowel preparation for colonoscopy. US was performed without any preparation and oral contrast medium was the only preparation used for CT. Colonoscopy detected six cancers, all of which were diagnosed by both US and CT. In addition, US and CT diagnosed a further cancer not seen on colonoscopy due to an incomplete study. US had a sensitivity and specificity of 100% and CT a sensitivity of 100% and a specificity of 84%. US and CT were poor at diagnosing polyps. If the detection of polyps greater than 2 cm is included then US sensitivity falls to 67% and CT sensitivity falls to 89% and specificity rises to 88%. In conclusion, both US and CT are possible alternatives to colonoscopy in the investigation of symptomatic patients with suspected colonic cancer. The use of these techniques could markedly reduce the need for colonoscopy in this patient population with attendant cost savings. Non-invasive imaging has particular advantages in the elderly who cope poorly with both the bowel preparation and the procedure.