The emergence of cerebral microbleeds (CMB) as common MR imaging findings raises the question of how MR imaging parameters influence CMB detection. To evaluate the effects of modified gradient ...recalled-echo (GRE) MR imaging methods, we performed an analysis of sequence, section thickness, and field strength on CMB imaging properties and detection in subjects with cerebral amyloid angiopathy (CAA), a condition associated with microhemorrhage.
Multiple MR images were obtained from subjects with probable CAA, with varying sequences (GRE versus susceptibility-weighted imaging SWI), section thicknesses (1.2-1.5 versus 5 mm), and magnetic field strengths (1.5T versus 3T). Individual CMB were manually identified and analyzed for contrast index (lesion intensity normalized to normal-appearing white matter signal intensity) and diameter. CMB counts were compared between 1.5T thick-section GRE and thin-section SWI for 3 subjects who underwent both protocols in the same scanning session.
With other parameters constant, use of SWI, thinner sections, and a higher field strength yielded medium-to-large gains in CMB contrast index (CI; Cohen d 0.71-1.87). SWI was also associated with small increases in CMB diameter (Cohen d <0.3). Conventional thick-section GRE identified only 33% of CMB (103 of 310) seen on thin-section SWI. Lesions prospectively identified on GRE had significantly greater CI and diameter measured on the GRE image than those not prospectively identified.
The examined alternatives to conventional GRE MR imaging yield substantially improved CMB contrast and sensitivity for detection. Future studies based on these techniques will most likely yield even higher prevalence estimates for CMB.
Background. The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine ...efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. Methods. Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. Results. The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. Conclusions. Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Advanced cerebrovascular β‐amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. ...We used T2*‐weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On coregistered positron emission tomography (PET) and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p = 0.002) and declined with increasing distance from the microbleed (p < 0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition. Ann Neurol 2010
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Small, asymptomatic microbleeds commonly accompany larger symptomatic macrobleeds. It is unclear whether microbleeds and macrobleeds represent arbitrary categories within a single continuum versus ...truly distinct events with separate pathophysiologies.
We performed 2 complementary retrospective analyses. In a radiographic analysis, we measured and plotted the volumes of all hemorrhagic lesions detected by gradient-echo MRI among 46 consecutive patients with symptomatic primary lobar intracerebral hemorrhage diagnosed as probable or possible cerebral amyloid angiopathy. In a second neuropathologic analysis, we performed blinded qualitative and quantitative examinations of amyloid-positive vessel segments in 6 autopsied subjects whose MRI scans demonstrated particularly high microbleed counts (>50 microbleeds on MRI, n=3) or low microbleed counts (<3 microbleeds, n=3).
Plotted on a logarithmic scale, the volumes of 163 hemorrhagic lesions identified on scans from the 46 subjects fell in a distinctly bimodal distribution with mean volumes for the 2 modes of 0.009 cm(3) and 27.5 cm(3). The optimal cut point for separating the 2 peaks (determined by receiver operating characteristics) corresponded to a lesion diameter of 0.57 cm. On neuropathologic analysis, the high microbleed-count autopsied subjects showed significantly thicker amyloid-positive vessel walls than the low microbleed-count subjects (proportional wall thickness 0.53+/-0.01 versus 0.37+/-0.01; P<0.0001; n=333 vessel segments analyzed).
These findings suggest that cerebral amyloid angiopathy-associated microbleeds and macrobleeds comprise distinct entities. Increased vessel wall thickness may predispose to formation of microbleeds relative to macrobleeds.
Summary
Background
Tumour necrosis factor (TNF)‐antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of ...anti‐drug antibodies (ADAs) may decrease their efficacy.
Aim
The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed.
Methods
The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies‐to‐infliximab.
Results
Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long‐term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence‐based manner and are probably not cost‐effective. Multiple TDM‐based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy.
Conclusions
Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post‐hoc analyses of randomised controlled trials.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Human immunodeficiency virus (HIV)—infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an ...improved safety profile would address this unmet medical need. Methods. The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4 + T-cell counts, ≥350 cells/mm 3 ) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects. Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola. Conclusions. MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile. Clinical Trials Registration. NCT00189904.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Invasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who are receiving chemotherapy for cancer.
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Early diagnosis of these infections is ...difficult, and persistent fever may be the only sign. A delay in treatment while a diagnosis is pursued may lead to increased morbidity and mortality.
As a standard of care, patients with persistent fever and neutropenia receive empirical antifungal therapy for the early treatment of clinically occult fungal infection or for the prevention of new fungal infections during neutropenia.
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In two randomized, placebo-controlled trials, the frequency of proved invasive fungal infections . . .
Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an ...option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.
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