Technical considerations and long-term results of endovascular venous stenting to control venous hypertension from meningiomas invading intracranial venous sinuses.

OBJECTIVE: Meningiomas invading the intracranial venous sinuses may cause intracranial venous hypertension, papilledema, and visual compromise. Sinus resection and graft reconstructions, however, add significant complexity to tumor surgery, with the potential for increased morbidity. In this study, the authors explored whether venous sinus stenting might provide an alternative means of controlling venous hypertension that would be sustainable over the long term. METHODS: The authors performed a retrospective review of all 16 patients with intracranial meningiomas who underwent stenting at their institution for venous sinus compromise. At presentation, all had headache and 9 had papilledema. Thirteen patients had 1 meningioma and 3 had 2 or more. Three patients had had previous tumor resection and radiotherapy. One patient had been treated with a lumboperitoneal shunt and radiotherapy. The median length of clinical follow-up was 8 years (range 4 months-18 years). RESULTS: Venous sinus narrowing was often not confined to the site of meningioma, and bilateral transverse sinus narrowing, reminiscent of that seen in idiopathic intracranial hypertension, was present in 7 patients with sagittal sinus meningiomas. Eleven patients had stents placed solely across sinus narrowing caused by meningioma. Five patients had additional stents placed at other sites of venous narrowing at the same time: in one of these patients, a stent was placed across a defect in the sagittal sinus caused by previous surgery, and in the 4 other patients, stents were placed across nontumor narrowings of the transverse sinuses. In 1 patient, the jugular vein was also stented. Nine patients developed symptomatic in-stent restenosis at the meningioma site. Eight had further stenting procedures with variable success in restoring the in-stent lumen. The remaining patient, with a late partial relapse, is being reinvestigated. Papilledema resolved in all patients after stenting. Six patients experienced prolonged and very substantial relief of all symptoms. Five patients had persistent headache despite restoration of the sinus lumen. Five had persistent symptoms associated with resistant in-stent stenosis. There were no significant complications from any of the diagnostic or therapeutic procedures. CONCLUSIONS: In patients who are symptomatic with meningiomas obstructing the venous sinuses, successful stenting of the affected segment can give a good outcome, especially in terms of relieving papilledema. However, further procedures are often necessary to maintain stent patency, other areas of venous compromise frequently coexist, and some patients remain symptomatic despite apparently successful treatment of the index lesion. Long-term surveillance is a requirement.

Case report: Post-traumatic Tourette syndrome resolving with treatment of jugular venous narrowing; reconciling organic brain dysfunction following whiplash trauma with the absence of direct brain injury.

We describe a man aged 33 years who developed multiple symptoms, personality change, and a severe tic disorder following a road traffic accident, which were undiminished for 3 years until jugular venous narrowing between the styloid process of the skull and the transverse process of the C1 vertebra was treated by surgical decompression. Immediately following surgery, his abnormal movements almost completely resolved, with no regression in 5 years of follow-up. Vigorously debated at the time was whether or not his condition represented a functional disorder. Unrecognized throughout his illness, however, was a complaint of intermittent, profuse discharge of clear fluid from his nose that began on the day of the accident and continued up to the time of surgery, after which it was substantially reduced. This outcome reinforces the idea that jugular venous narrowing can cause or perpetuate a cerebrospinal fluid leak. It suggests that the interaction between these two pathological defects may have a profound effect on brain function in the absence of any demonstrable brain lesion. It invites a reevaluation of normal head and neck venous anatomy. It should strike a cautionary note in the diagnosis of functional illness. It invites exploration of a remediable structural cause for Tourette syndrome.

Life changing response to successive surgical interventions on cranial venous outflow: A case report on chronic fatigue syndrome.

Recognition of similarities between chronic fatigue syndrome and idiopathic intracranial hypertension (IIH) has raised suggestions that they might be connected, with chronic fatigue syndrome representing a mild version of IIH, sharing many of its symptoms, but without the signature features of elevated intracranial pressure that characterize the complete syndrome. A further development of this idea factors in the effects of a cerebrospinal fluid leak, a known complication of IIH, to explain cases where symptoms seem out of proportion to the apparent physiological disturbance. Cranial venous outflow obstruction has been proposed as the pathological substrate. We describe a patient with multiple symptoms, including headache and disabling fatigue, in which this model guided investigation and treatment. Specifically, CT and catheter venography identified focal narrowings of both jugular and the left brachiocephalic veins. Treatment of brachiocephalic obstruction was not feasible. However, in separate surgical procedures, relief of jugular venous obstruction produced incremental and significant clinical improvements which have proven durable over the length of follow-up. We suggest that investigating chronic fatigue syndrome under this model might not only bring benefit to individual patients but also will provide new insights into IIH and its relationship with spontaneous intracranial hypotension.

Visual and cognitive demands of manual and voice-based driving mode implementations on smartphones.

Mobile phone apps and operating systems are increasingly adopting driving mode functions that attempt to reduce driver visual and cognitive demand by limiting functionality, using larger buttons and icons, and adding voice-based interactions. The present study assessed the visual and cognitive demands and the subjective level of distraction from two driving mode implementations (voice or manual) on an Android™ mobile phone using Google Assistant™, compared to a typical mobile phone operating system experience. While driving on a test track, participants performed several trials of five tasks on each of three interfaces: A mobile operating system interface, a manual driving mode interface, and a voice driving mode interface. Visual demand was measured with eye-gaze recordings, cognitive load was measured with the detection response task, and a Likert scale was used to rate the perceived level of distraction. The voice driving mode resulted in the lowest visual attention demand and lowest subjective ratings of distraction. The manual driving mode condition also reduced visual demand and subjective ratings of distraction relative to the mobile operating system condition. The cognitive load results were inconsistent across the task and interaction mode conditions. Overall, the results of this study provide positive evidence in support of voice-based driving mode implementations for reducing visual demand and subjective levels of distraction from mobile devices while driving. Moreover, the results suggest that manual driving mode implementations also have the potential to reduce visual demand and subjective levels of distraction, relative to the mobile operating system condition.

User-centered development process of an operating interface to couple a robotic glove with a virtual environment to optimize hand rehabilitation following a stroke.

Introduction: Task-specific neurorehabilitation is crucial to optimize hand recovery shortly after a stroke, but intensive neurorehabilitation remains limited in resource-constrained healthcare systems. This has led to a growing interest in the use of robotic gloves as an adjunct intervention to intensify hand-specific neurorehabilitation. This study aims to develop and assess the usability of an operating interface supporting such a technology coupled with a virtual environment through a user-centered design approach. Methods: Fourteen participants with hand hemiparesis following a stroke were invited to don the robotic glove before browsing through the operating interface and its functionalities, and perform two mobility exercises in a virtual environment. Feedback was collected for improving technology usability. Participants completed the System Usability Scale and ABILHAND questionnaires and their recommendations were gathered and prioritized in a Pugh Matrix. Results: The System Usability Scale (SUS) score for the operating interface was excellent (M = 87.0 SD = 11.6). A total of 74 recommendations to improve the user interface, calibration process, and exercise usability were identified. Conclusion: The application of a full cycle of user-centred design approach confirms the high level of usability of the system which is perceived by end users as acceptable and useful for intensifying neurorehabilitation.

Rare and declining bird species benefit most from designating protected areas for conservation in the UK.

There have been recent renewed commitments to increase the extent of protected areas to combat the growing biodiversity crisis but the underpinning evidence for their effectiveness is mixed and causal connections are rarely evaluated. We used data gathered by three large-scale citizen science programmes in the UK to provide the most comprehensive assessment to date of whether national (Sites of Special Scientific Interest) and European (Special Protection Areas/Special Areas of Conservation) designated areas are associated with improved state (occurrence, abundance), change (rates of colonization, persistence and trend in abundance), community structure and, uniquely, demography (productivity) on a national avifauna, while controlling for differences in land cover, elevation and climate. We found positive associations with state that suggest these areas are well targeted and that the greatest benefit accrued to the most conservation-dependent species since positive associations with change were largely restricted to rare and declining species and habitat specialists. We suggest that increased productivity provides a plausible demographic mechanism for positive effects of designation.

Diverged subpopulations in tropical Urochloa (Brachiaria) forage species indicate a role for facultative apomixis and varying ploidy in their population structure and evolution.

BACKGROUND: Urochloa (syn. Brachiaria) is a genus of tropical grasses sown as forage feedstock, particularly in marginal soils. Here we aimed to clarify the genetic diversity and population structure in Urochloa species to understand better how population evolution relates to ploidy level and occurrence of apomictic reproduction. METHODS: We explored the genetic diversity of 111 accessions from the five Urochloa species used to develop commercial cultivars. These accessions were conserved from wild materials collected at their centre of origin in Africa, and they tentatively represent the complete Urochloa gene pool used in breeding programmes. We used RNA-sequencing to generate 1.1 million single nucleotide polymorphism loci. We employed genetic admixture, principal component and phylogenetic analyses to define subpopulations. RESULTS: We observed three highly differentiated subpopulations in U. brizantha, which were unrelated to ploidy: one intermixed with U. decumbens, and two diverged from the former and the other species in the complex. We also observed two subpopulations in U. humidicola, unrelated to ploidy; one subpopulation had fewer accessions but included the only characterized sexual accession in the species. Our results also supported a division of U. decumbens between diploids and polyploids, and no subpopulations within U. ruziziensis and U. maxima. CONCLUSIONS: Polyploid U. decumbens are more closely related to polyploid U. brizantha than to diploid U. decumbens, which supports the divergence of both polyploid groups from a common tetraploid ancestor and provides evidence for the hybridization barrier of ploidy. The three differentiated subpopulations of apomictic polyploid U. brizantha accessions constitute diverged ecotypes, which can probably be utilized in hybrid breeding. Subpopulations were not observed in non-apomictic U. ruziziensis. Sexual Urochloa polyploids were not found (U. brizantha, U. decumbens) or were limited to small subpopulations (U. humidicola). The subpopulation structure observed in the Urochloa sexual-apomictic multiploidy complexes supports geographical parthenogenesis, where the polyploid genotypes exploit the evolutionary advantage of apomixis, i.e. uniparental reproduction and clonality, to occupy extensive geographical areas.

Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human.

[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (Cmax of 7.1 µM), JNJ-2482272 had plasma concentrations beneath the lower limit of quantification (3 ng/ml) after 6 consecutive days of dosing. To determine if JNJ-2482272 is an autoinducer in rats, plated rat hepatocytes were treated with JNJ-2482272 for 2 days. The major hydroxylated metabolites of JNJ-2482272 were isolated and characterized by mass spectrometry and NMR analyses. Compared with the vehicle-treated cells, a concentration-dependent increase was observed in the formation of phase I- and II-mediated metabolites coinciding with greater expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in rat hepatocytes. CYP1A1, CYP1A2, CYP1B1, and UGT1A6 transcripts were predominantly induced, suggesting that JNJ-2482272 is an activator of the aryl hydrocarbon receptor (AhR). In a human AhR reporter assay, JNJ-2482272 demonstrated potent AhR activation with an EC50 value of 0.768 nM, a potency more comparable to the strong AhR activator and toxin 2,3,7,8-tetrachloro-dibenzodioxin than to weaker AhR activators 3-methylcholanthrene, ß-naphthoflavone, and omeprazole. In plated human hepatocytes, JNJ-2482272 induced CYP1A1 gene expression with an EC50 of 20.4 nM and increased CYP1A activity >50-fold from basal levels. In human recombinant P450s, JNJ-2482272 was exclusively metabolized by the CYP1 family of enzymes and most rapidly by CYP1A1. The summation of these in vitro findings bridges the in vivo conclusion that JNJ-2482272 is a strong autoinducer in rats and potentially in humans through potent AhR activation. SIGNIFICANCE STATEMENT: Drugs that induce their own metabolism (autoinducers) can lack sustained exposures for pharmacology and safety assessment hindering their development. JNJ-2482272 is demonstrated herein as a strong aryl hydrocarbon receptor (AhR) activator and CYP1A autoinducer, explaining its near complete loss of exposure after repeat administration in rat, which is likely translatable to human (if progressed further) considering its nanomolar potency comparable to "classical" AhR ligands like 2,3,7,8-tetrachloro-dibenzo-dioxin despite bearing a "nonclassical" drug structure.

Characterization of buried interfaces using Ga Kα hard X-ray photoelectron spectroscopy (HAXPES).

The extension of X-ray photoelectron spectroscopy (XPS) to measure layers and interfaces below the uppermost surface requires higher X-ray energies and electron energy analysers capable of measuring higher electron kinetic energies. This has been enabled at synchrotron radiation facilities and by using lab-based instruments which are now available with sufficient sensitivity for measurements to be performed on reasonable timescales. Here, we detail measurements on buried interfaces using a Ga Kα (9.25 keV) metal jet X-ray source and an EW4000 energy analyser (ScientaOmicron GmbH) in the Henry Royce Institute at the University of Manchester. Development of the technique has required the calculation of relative sensitivity factors (RSFs) to enable quantification analogous to Al Kα XPS, and here we provide further substantiation of the Ga Kα RSF library. Examples of buried interfaces include layers of memory and energy materials below top electrode layers, semiconductor heterostructures, ions implanted in graphite, oxide layers at metallic surfaces, and core-shell nanoparticles. The use of an angle-resolved mode enables depth profiling from the surface into the bulk, and is complemented with surface-sensitive XPS. Inelastic background modelling allows the extraction of information about buried layers at depths up to 20 times the photoelectron inelastic mean free path.

Split staphylectomy to address soft palate thickness in brachycephalic dogs: 75 cases (2016-2018).

OBJECTIVES: Describe the split staphylectomy procedure to address soft palate thickness and assess the complications and long-term outcome of this procedure as a part of multi-level surgery for brachycephalic obstructive airway syndrome. To consider whether same-day discharge following this surgery can be recommended. MATERIALS AND METHODS: Medical records of dogs treated for brachycephalic obstructive airway syndrome using the split staphylectomy were reviewed. Owners were contacted to complete a questionnaire assessing initial postoperative concerns, the long-term outcome and the effect of surgery on their dog's quality of life. RESULTS: Seventy-five dogs underwent split staphylectomy during the study period. The overall complication rate was 8.3%, of which 2.7% were considered major. No life-threatening complications occurred, and no complications were related to the staphylectomy. The questionnaire was completed by 66.7% of owners (median follow-up 459 days), of which 88% felt that surgery had improved the quality of life for their dog. The majority (88%) of dogs were discharged from hospital on the day of surgery. Of the surveyed owners, 14% sought veterinary attention between their dog leaving the hospital and the scheduled postoperative reassessment 2 weeks after surgery. Four dogs were presented for veterinary intervention during this time period, but no intervention was related to the staphylectomy or for a life-threatening condition. CLINICAL SIGNIFICANCE: The split staphylectomy offers a safe, straightforward method of addressing both excess thickness and length of soft palate in dogs with brachycephalic obstructive airway syndrome. Dogs can be discharged on the same day as brachycephalic obstructive airway syndrome surgery including split staphylectomy without an increased risk of complications.

COVID-19 lockdowns' effects on the quality of life, perceived health and well-being of healthy elderly individuals: A longitudinal comparison of pre-lockdown and lockdown states of well-being.

PURPOSE: . The concept of lockdown in relation to COVID-19 is thought to have an indirect impact on the quality of life and well-being of the elderly due to its consequences on the physical, psychological, and cognitive health of individuals. However, previous published studies on this subject are limited in terms of methodological approach used, including the absence of pre-confinement status and the type of experimental design, which is often cross-sectional. The present study proposes a longitudinal design with pre-confinement measures. It assesses changes in quality of life, perceived health, and well-being by comparing the period before lockdown (T1 = December 2019), three months after the start of the first lockdown (T2 = June 2020), and during the second lockdown (T3 = January 2021) due to COVID-19. MATERIALS AND METHODS: . This study is conducted with a group of 72 healthy elderly persons. They completed an electronic (online) survey assessing personal factors, activities, and participation as well as responding to the EuroQol-5D and Warwick-Edinburgh Mental Well-being Scale. RESULTS: . A decrease in quality of life, perceived health and well-being was observed between T1 and T2 and between T1 and T3, but no difference was reported between the two lockdown periods. The variables associated with these changes included energy level, level of happiness, physical activity, change in medical condition, memory difficulties, level of perceived isolation and age. CONCLUSION: . This study will help to target variables that may have a deleterious effect on older adults for consideration in future confinement settings and for preventive purposes.

Fulminant intracranial hypertension as a result of otological surgery: case report and discussion of management.

BACKGROUND: Dural venous sinus injury is a rare complication of otological surgery that can lead to life-threatening sequelae, the management of which is complex and poorly described. CASE REPORT: This paper describes the case of a 40-year-old female who underwent routine right myringoplasty complicated by sigmoid sinus laceration. The patient subsequently developed right-sided lateral sinus thrombosis leading to fulminant intracranial hypertension. The patient underwent successful emergency management by surgical reconstruction of the sigmoid sinus, followed by endovascular thrombolysis, catheter balloon angioplasty and endovascular stenting. CONCLUSION: Torrential haemorrhage following otological procedures is uncommon and rarely requires packing of a bleeding venous sinus. This case highlights that injury to a highly dominant venous sinus can lead to venous outflow obstruction and life-threatening intracranial hypertension. To our knowledge, the development of this complication following otological surgery and its management has not been reported previously.

A paradigm for chronic fatigue syndrome: caught between idiopathic intracranial hypertension and spontaneous intracranial hypotension; caused by cranial venous outflow obstruction.

Background: Clinical similarities between chronic fatigue syndrome and idiopathic intracranial hypertension, supported by measurements of intracranial pressure, invite suggestions that they may be connected, the first representing a mild version of the second. Yet, if this is to be the basis for a structural explanation for chronic fatigue syndrome, it already seems incomplete, failing to explain cases where disability seems disproportionate. Is there some other confounding variable? Purpose: To refine, in this theoretical paper, an earlier model connecting chronic fatigue syndrome with idiopathic intracranial hypertension to allow for a cerebrospinal fluid (CSF) leak. Model: In this model, the primary structural problem is acquired obstruction to cranial venous outflow. This obstruction can take different forms, may be intermittent and subtle, and even be mistaken for normal venous anatomy, yet would be the driving force behind a tendency towards increased intracranial pressure. This chronic elevation of intracranial pressure stresses the dural membrane maintaining the integrity of the subarachnoid space, which can rupture at a weak point, allowing CSF to leak away and intracranial pressure to fall. The clinical manifestation of this disorder is the product of the severity of cranial venous outflow compromise and of the competing forces on intracranial pressure. In some instances, a CSF leak will mitigate the effects of venous compromise, in others it will compound it, producing a disease spectrum ranging through idiopathic intracranial hypertension, chronic fatigue syndrome, fibromyalgia, and spontaneous intracranial hypotension. Conclusion: In chronic fatigue syndrome a normal intracranial pressure does not exclude significant physiological disturbance.

Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation.

Directed differentiation of human pluripotent stem cells to kidney organoids brings the prospect of drug screening, disease modelling and the generation of tissue for renal replacement. Currently, these applications are hampered by organoid variability, nephron immaturity, low throughput and limited scale. Here, we apply extrusion-based three-dimensional cellular bioprinting to deliver rapid and high-throughput generation of kidney organoids with highly reproducible cell number and viability. We demonstrate that manual organoid generation can be replaced by 6- or 96-well organoid bioprinting and evaluate the relative toxicity of aminoglycosides as a proof of concept for drug testing. In addition, three-dimensional bioprinting enables precise manipulation of biophysical properties, including organoid size, cell number and conformation, with modification of organoid conformation substantially increasing nephron yield per starting cell number. This facilitates the manufacture of uniformly patterned kidney tissue sheets with functional proximal tubular segments. Hence, automated extrusion-based bioprinting for kidney organoid production delivers improvements in throughput, quality control, scale and structure, facilitating in vitro and in vivo applications of stem cell-derived human kidney tissue.

Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300.

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Brain Network Disruption in Whiplash.

BACKGROUND AND PURPOSE: Whiplash-associated disorders frequently develop following motor vehicle collisions and often involve a range of cognitive and affective symptoms, though the neural correlates of the disorder are largely unknown. In this study, a sample of participants with chronic whiplash injuries were scanned by using resting-state fMRI to assess brain network changes associated with long-term outcome metrics. MATERIALS AND METHODS: Resting-state fMRI was collected for 23 participants and used to calculate network modularity, a quantitative measure of the functional segregation of brain region communities. This was analyzed for associations with whiplash-associated disorder outcome metrics, including scales of neck disability, traumatic distress, depression, and pain. In addition to these clinical scales, cervical muscle fat infiltration was quantified by using Dixon fat-water imaging, which has shown promise as a biomarker for assessing disorder severity and predicting recovery in chronic whiplash. RESULTS: An association was found between brain network structure and muscle fat infiltration, wherein lower network modularity was associated with larger amounts of cervical muscle fat infiltration after controlling for age, sex, body mass index, and scan motion (t = -4.02, partial R 2 = 0.49, P < .001). CONCLUSIONS: This work contributes to the existing whiplash literature by examining a sample of participants with whiplash-associated disorder by using resting-state fMRI. Less modular brain networks were found to be associated with greater amounts of cervical muscle fat infiltration suggesting a connection between disorder severity and neurologic changes, and a potential role for neuroimaging in understanding the pathophysiology of chronic whiplash-associated disorders.

Spontaneous Intracranial Hypotension Complicated by Subdural Effusions Treated by Surgical Relief of Cranial Venous Outflow Obstruction.

Spontaneous intracranial hypotension describes the clinical syndrome brought on by a cerebrospinal fluid (CSF) leak. Orthostatic headache is the key symptom, but others include nausea, vomiting, and dizziness, as well as cognitive and mood disturbance. In severe cases, the brain slumps inside the cranium and subdural collections develop to replace lost CSF volume. Initial treatment is by bed rest, but when conservative measures fail, attention is focused on finding and plugging the leak, although this can be very difficult and some patients remain bedbound for months or years. Recently, we have proposed an alternative approach in which obstruction to cranial venous outflow would be regarded as the driving force behind a chronic elevation of CSF pressure, which eventually causes dural rupture. Instead of focusing on the site of rupture, therefore, investigation and treatment can be directed at locating and relieving the obstructing venous lesion, allowing intracranial pressure to fall, and the dural defect to heal. The case we describe illustrates this idea. Moreover, since there was a graded clinical response to successive interventions relieving venous obstruction, and eventual complete resolution, it also provides an opportunity to consider particular symptoms in relation to cerebral venous insufficiency in its own right.

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Diffusion Properties of Normal-Appearing White Matter Microstructure and Severity of Motor Impairment in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The effect of white matter hyperintensities as measured by FLAIR MR imaging on functional impairment and recovery after ischemic stroke has been investigated thoroughly. However, there has been growing interest in investigating normal-appearing white matter microstructural integrity following ischemic stroke onset with techniques such as DTI. MATERIALS AND METHODS: Fifty-two patients with acute ischemic stroke and 36 without stroke were evaluated with a DTI and FLAIR imaging protocol and clinically assessed for the severity of motor impairment using the Motricity Index within 72 hours of suspected symptom onset. RESULTS: There were widespread decreases in fractional anisotropy and increases in mean diffusivity and radial diffusivity for the acute stroke group compared with the nonstroke group. There was a significant positive association between fractional anisotropy and motor function and a significant negative association between mean diffusivity/radial diffusivity and motor function. The normal-appearing white matter ROIs that were most sensitive to the Motricity Index were the anterior/posterior limb of the internal capsule in the infarcted hemisphere and the splenium of the corpus callosum, external capsule, posterior limb/retrolenticular part of the internal capsule, superior longitudinal fasciculus, and cingulum (hippocampus) of the intrahemisphere/contralateral hemisphere. CONCLUSIONS: The microstructural integrity of normal-appearing white matter is a significant parameter to identify neural differences not only between those individuals with and without acute ischemic stroke but also correlated with the severity of acute motor impairment.