Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Informed consent in cluster randomised trials: a guide for the perplexed.

In a cluster randomised trial (CRT), intact groups-such as communities, clinics or schools-are randomised to the study intervention or control conditions. The issue of informed consent in CRTs has been particularly challenging for researchers and research ethics committees. Some argue that cluster randomisation is a reason not to seek informed consent from research participants. In fact, systematic reviews have found that, relative to individually randomised trials, CRTs are associated with an increased likelihood of inadequate reporting of consent procedures and inappropriate use of waivers of consent. The objective of this paper is to clarify this confusion by providing a practical and useful framework to guide researchers and research ethics committees through consent issues in CRTs. In CRTs, it is the unit of intervention-not the unit of randomisation-that drives informed consent issues. We explicate a three-step framework for thinking through informed consent in CRTs: (1) identify research participants, (2) identify the study element(s) to which research participants are exposed, and (3) determine if a waiver of consent is appropriate for each study element. We then apply our framework to examples of CRTs of cluster-level, professional-level and individual-level interventions, and provide key lessons on informed consent for each type of CRT.

Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees.

A novel Protocol Ethics Tool Kit ('Ethics Tool Kit') has been developed by a multi-stakeholder group of the Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard. The purpose of the Ethics Tool Kit is to facilitate effective recognition, consideration and deliberation of critical ethical issues in clinical trial protocols. The Ethics Tool Kit may be used by investigators and sponsors to develop a dedicated Ethics Section within a protocol to improve the consistency and transparency between clinical trial protocols and research ethics committee reviews. It may also streamline ethics review and may facilitate and expedite the review process by anticipating the concerns of ethics committee reviewers. Specific attention was given to issues arising in multinational settings. With the use of this Tool Kit, researchers have the opportunity to address critical research ethics issues proactively, potentially speeding the time and easing the process to final protocol approval.

Development of anterior inferior cerebellar artery pseudoaneurysm after gamma knife surgery for vestibular schwannoma. A case report and review of the literature.

Gamma knife surgery (GKS) is a well-established modality for controlling the progression of vestibular schwannomas. Adverse effects of this treatment are extremely rare but include cyst formation and malignant transformation. We report a case of anterior inferior cerebellar artery (AICA) pseudoaneurysm development rupture presenting as a poor WFNS grade subarachnoid haemorrhage. This is only the fourth case of aneurysm development (AICA aneurysm) following GKS reported but due to its serious nature we believe this potential complication warrants awareness in those offering this treatment.

Histopathological changes in cerebral arteriovenous malformations following Gamma Knife radiosurgery.

Histological, immunohistochemical and electron microscopic investigations were carried out in a series of surgical pathology material that was removed from 7 patients. They were harboring cerebral arteriovenous malformations (AVMs) that had been previously treated with Leksell Gamma Knife radiosurgery, and presented subsequent bleeding 10-52 months after treatment. Light microscopic studies revealed a spindle cell proliferation in the connective tissue stroma and in the subendothelial region of the irradiated AVM vessels. The histological, immunohistochemical and ultrastructural characteristics of the spindle cell population in the Leksell Gamma Knife-treated AVMs are similar to those designated as myofibroblasts in wound healing processes and pathological fibromatoses. Considering that similar cell modifications have not been demonstrated in control, nonirradiated AVM specimens, these myofibroblasts might contribute to the shrinking process and final occlusion of AVMs after radiosurgery.

Cerebral arteriovenous malformations: comparison of novel magnetic resonance angiographic techniques and conventional catheter angiography.

OBJECTIVE: To investigate the potential of novel magnetic resonance (MR) angiographic techniques for the assessment of cerebral arteriovenous malformations. METHODS: Forty patients who were about to undergo stereotactic radiosurgery were prospectively recruited. Three-dimensional, sliding-slab interleaved ky (SLINKY), time-of-flight acquisition was performed, as was a dynamic MR digital subtraction angiography (DSA) procedure in which single thick slices (6-10 cm) were obtained using a radiofrequency spoiled Fourier-acquired steady-state sequence (1 image/s). Sixty images were acquired, in two or three projections, during passage of a 6- to 10-ml bolus of gadolinium chelate. Subtraction and postprocessing were performed, and images were viewed in an inverted cine mode. SLINKY time-of-flight acquisition was repeated after the administration of gadolinium. Routine stereotactic conventional catheter angiography was performed after MR imaging. All images were assessed (in a blinded randomized manner) for Spetzler-Martin grading and determination of associated vascular pathological features. RESULTS: Forty-one arteriovenous malformations were assessed in 40 patients. Contrast-enhanced (CE) SLINKY MR angiography was the most consistent MR imaging technique, yielding a 95% correlation with the Spetzler-Martin classification defined by conventional catheter angiography; MR DSA exhibited 90% agreement, and SLINKY MR angiography exhibited 81% agreement. CE SLINKY MR angiography provided improved nidus delineation, compared with non-CE SLINKY MR angiography. Dynamic information from MR DSA significantly improved the observation of early-draining veins and associated aneurysms. CONCLUSION: CE SLINKY MR angiographic assessment of cerebral arteriovenous malformations offers significant advantages, compared with the use of non-CE SLINKY MR angiography, including improved nidus demonstration. MR DSA shows promise as a noninvasive method for dynamic angiography but is presently restricted by limitations in both temporal and spatial resolution.

Sustained endogenous glucose production, diminished lipolysis and non-esterified fatty acid appearance and oxidation in non-obese women at high risk of type 2 diabetes.

OBJECTIVE: To evaluate early defects in glucose production, lipolysis and fatty acid oxidation in non-obese, normally glucose tolerant women, who are nevertheless at risk of type 2 diabetes. METHODS: Ten women with previous gestational diabetes (pGDM) and ten controls were studied in two 4 h infusions of stable isotopes 6,6-(2)H(2)-glucose, 1-(13)C-palmitate, and 1,1,2,3,3-(2)H(5)-glycerol with and without infusion of adrenaline. Fatty acid oxidation was quantified using indirect calorimetry and (13)CO(2) measurements. Insulin sensitivity was evaluated using the short insulin tolerance test. RESULTS: The pGDM and control women were non-obese and carefully matched for body mass index and fat mass. Whole body insulin sensitivity and basal insulin concentrations did not differ significantly but basal glucose concentrations were increased in women with pGDM. During a 0.9% saline infusion, glucose appearance was not significantly different at the first (90-120 min) and second (210-240 min) steady states. However, glucose appearance decreased in controls but was maintained in the pGDM women (-0.33 +/- 0.02 vs -0.03 +/- 0.08 mg/kg per min; P = 0.004). Basal glycerol appearance (0.27 +/- 0.02 vs 0.38 +/- 0.03 mg/kg per min; P = 0.02), palmitate appearance (0.74 +/- 0.09 vs 1.05 +/- 0.09 mg/kg per min; P = 0.03) and palmitate oxidation (0.07 +/- 0.01 vs 0.10 +/- 0.01 mg/kg per min; P = 0.03) were lower in the pGDM women. During the adrenaline infusion, changes in glucose, glycerol and palmitate concentrations and kinetics were similar in both groups. CONCLUSIONS: Sustained glucose production during fasting is an early abnormality in non-obese subjects at risk of type 2 diabetes. Lipolysis and non-esterified fatty acid appearance and oxidation are diminished, suggesting an increased tendency to store fat. The observations are not readily attributable to differences in insulin or catecholamine sensitivity.

Delayed metabolic and thermogenic response to a mixed meal in normoglycemic European women with previous gestational diabetes.

We assessed postprandial thermogenesis (PPT) for 3 h following a mixed meal in 29 normoglycemic European women with previous gestational diabetes (GDM), compared with 37 control women. Given the potential role of catecholamines and insulin in the regulation of PPT, we assessed insulin and catecholamine responses to the meal. There was no significant difference between the two groups in resting energy expenditure, PPT (although lower in the GDM group), or catecholamine levels. However, we observed a difference in the shape of the PPT curve between groups, and by applying a mathematical model, there was a consistent delay in PPT, insulin, and noradrenaline responses to the meal in the GDM group (T: fitted time constant, geometric mean (95% confidence interval), T(PPT) 58 (47-72) vs. 42 (37-48) min, P = 0.006; T(ins) 32 (28-37) vs. 22 (19-27) min, P = 0.002; T(NA) 30 (23-38) vs. 18 (14-23) min, P = 0.01, respectively). Fidgeting activity during the study was assessed by a novel technique and was lower in the GDM group, resting [427 (381-477) vs. 511 (466-560) kJ/min, P = 0.02] but not postprandially. These delayed PPT, insulin, and noradrenaline responses to the meal in post-GDM women represent early metabolic changes. The decrease in fidgeting activity while resting, observed in the post-GDM group, may have physiological significance for energy balance.