Capturing RAS oligomerization on a membrane.

RAS GTPases associate with the biological membrane where they function as molecular switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize on membranes, and disrupting these assemblies represents an alternative therapeutic strategy. However, conflicting reports on RAS assemblies, ranging in size from dimers to nanoclusters, have brought to the fore key questions regarding the stoichiometry and parameters that influence oligomerization. Here, we probe three isoforms of RAS [Kirsten Rat Sarcoma viral oncogene (KRAS), Harvey Rat Sarcoma viral oncogene (HRAS), and Neuroblastoma oncogene (NRAS)] directly from membranes using mass spectrometry. We show that KRAS on membranes in the inactive state (GDP-bound) is monomeric but forms dimers in the active state (GTP-bound). We demonstrate that the small molecule BI2852 can induce dimerization of KRAS, whereas the binding of effector proteins disrupts dimerization. We also show that RAS dimerization is dependent on lipid composition and reveal that oligomerization of NRAS is regulated by palmitoylation. By monitoring the intrinsic GTPase activity of RAS, we capture the emergence of a dimer containing either mixed nucleotides or GDP on membranes. We find that the interaction of RAS with the catalytic domain of Son of Sevenless (SOScat) is influenced by membrane composition. We also capture the activation and monomer to dimer conversion of KRAS by SOScat. These results not only reveal the stoichiometry of RAS assemblies on membranes but also uncover the impact of critical factors on oligomerization, encompassing regulation by nucleotides, lipids, and palmitoylation.

Perfluorooctanesulfonic Acid Alters the Plant's Phosphate Transport Gene Network and Exhibits Antagonistic Effects on the Phosphate Uptake.

Per- and polyfluoroalkyl substances (PFASs), with significant health risks to humans and wildlife, bioaccumulate in plants. However, the mechanisms underlying plant uptake remain poorly understood. This study deployed transcriptomic analysis coupled with genetic and physiological studies using Arabidopsis to investigate how plants respond to perfluorooctanesulfonic acid (PFOS), a long-chain PFAS. We observed increased expressions of genes involved in plant uptake and transport of phosphorus, an essential plant nutrient, suggesting intertwined uptake and transport processes of phosphorus and PFOS. Furthermore, PFOS-altered response differed from the phosphorus deficiency response, disrupting phosphorus metabolism to increase phosphate transporter (PHT) transcript. Interestingly, pht1;2 and pht1;8 mutants showed reduced sensitivity to PFOS compared to that of the wild type, implying an important role of phosphate transporters in PFOS sensing. Furthermore, PFOS accumulated less in the shoots of the pht1;8 mutant, indicating the involvement of PHT1;8 protein in translocating PFOS from roots to shoots. Supplementing phosphate improved plant's tolerance to PFOS and reduced PFOS uptake, suggesting that manipulating the phosphate source in PFOS-contaminated soils may be a promising strategy for minimizing PFOS uptake by edible crops or promoting PFOS uptake during phytoremediation. This study highlighted the critical role of phosphate sensing and transport system in the uptake and translocation of PFOS in plants.

Density functional theory study of bulk properties of transition metal nitrides.

Density functional theory (DFT) calculations are performed to compute the lattice constants, formation energies and vacancy formation energies of transition metal nitrides (TMNs) for transition metals (TM) ranging from 3d-5d series. The results obtained using six different DFT exchange and correlation potentials (LDA, AM05, BLYP, PBE, rPBE, and PBEsol) show that the experimental lattice constants are best predicted by rPBE, while the values obtained using AM05, PBE, rPBE and PBEsol lie between the LDA and BLYP calculated values. A linear relationship is observed between the lattice constants and formation energies with the mean radii of TM and the difference in the electronegativity of TM and N in TMNs, respectively. Our calculated vacancy formation energies, in general, show that N-vacancies are more favorable than TM-vacancies in most TMNs. We observe that N-vacancy formation energies are linearly correlated with the calculated bulk formation energies indicating that TMNs with large negative formation energies are less susceptible to the formation of N-vacancies. Thus, our results from this extensive DFT study not only provide a systematic comparison of various DFT functionals in calculating the properties of TMNs but also serve as reference data for the computation-driven experimental design of materials.

Key role of neuronal diversity in structured reservoir computing.

Chaotic time series have been captured by reservoir computing models composed of a recurrent neural network whose output weights are trained in a supervised manner. These models, however, are typically limited to randomly connected networks of homogeneous units. Here, we propose a new class of structured reservoir models that incorporates a diversity of cell types and their known connections. In a first version of the model, the reservoir was composed of mean-rate units separated into pyramidal, parvalbumin, and somatostatin cells. Stability analysis of this model revealed two distinct dynamical regimes, namely, (i) an inhibition-stabilized network (ISN) where strong recurrent excitation is balanced by strong inhibition and (ii) a non-ISN network with weak excitation. These results were extended to a leaky integrate-and-fire model that captured different cell types along with their network architecture. ISN and non-ISN reservoir networks were trained to relay and generate a chaotic Lorenz attractor. Despite their increased performance, ISN networks operate in a regime of activity near the limits of stability where external perturbations yield a rapid divergence in output. The proposed framework of structured reservoir computing opens avenues for exploring how neural microcircuits can balance performance and stability when representing time series through distinct dynamical regimes.

Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis.

Background and Purpose- Although aggressive medical therapy was superior to stenting in the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis), the stroke rate in the medical arm was still high. The aim of this study was to determine the association between hemodynamic markers (borderzone infarct pattern and impaired collateral flow on baseline imaging) and rates of recurrent stroke in patients treated medically in SAMMPRIS. Methods- This was a post hoc analysis of patients whose qualifying event for SAMMPRIS was an infarct in the territory of a stenotic middle cerebral artery or intracranial carotid artery. Infarcts were adjudicated as involving primarily internal or cortical borderzone territories, the core middle cerebral artery territory, or perforator territories, and collateral flow was assessed according to a standard scale (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology). Log-rank tests and χ2 tests were performed to assess associations of infarct patterns and collateral flow with rates of recurrent stroke. Results- Of 101 patients who qualified, 14 of 53 (26.4%) with borderzone infarcts, 2 of 24 (8.3%) with core middle cerebral artery infarcts, and 3 of 24 (12.5%) with perforator infarcts had a recurrent stroke in the territory (P=0.14 for comparing the 3 groups, P=0.052 for borderzone versus nonborderzone). Of 82 patients with collateral flow assessment, 30 of 43 (70%) with borderzone infarcts, 7 of 19 (37%) with core middle cerebral artery infarcts, and 11 of 20 (55%) with perforator infarcts had impaired collateral flow distal to the stenosis (P=0.049). Patients with borderzone infarcts and impaired collateral flow had the highest risk of recurrent stroke (37%). Conclusions- Borderzone infarcts and impaired collateral flow identify a subgroup of patients with intracranial stenosis who are at particularly high risk of recurrent stroke on medical treatment. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Impact of Baseline Features and Risk Factor Control on Cognitive Function in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial.

BACKGROUND: Cerebrovascular disease is an important cause of cognitive impairment. The aim of this study is to report the relationship between cognitive function and risk factors at baseline and during follow-up in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: Subjects in the SAMMPRIS trial were included in this study. In order to have an assessment of cognitive function independent of stroke, patients with a stroke as a qualifying event whose deficits included aphasia or neglect were excluded from these analyses as were those with a cerebrovascular event during follow-up. The Montreal Cognitive Assessment (MoCA) score was used to assess cognitive impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA < 26. A multivariate analysis was performed to determine what risk factors were independent predictors of cognitive function at baseline, 12 months and closeout. Among patients randomized to aggressive medical management only, the percentage of patients with cognitive impairment was compared between patients in versus out of target for each risk factor at 12 months and closeout. RESULTS: Of the 451 patients in SAMMPRIS, 371 patients met the inclusion criteria. MoCA < 26 was present in 55% at baseline. Older age and physical inactivity were associated with cognitive impairment at baseline. Older age, non-white race, lower baseline body mass index, and baseline cognitive impairment were associated with cognitive impairment at 12 months. In the aggressive medical management group, at 12 months, physical inactivity during follow-up was the strongest risk factor associated with cognitive impairment. CONCLUSION: Cognitive impairment is common in patients with severe symptomatic intracranial atherosclerosis. Physical inactivity at baseline and during follow-up is a strong predictor of cognitive impairment.

Relationship between Risk Factor Control and Compliance with a Lifestyle Modification Program in the Stenting Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis Trial.

BACKGROUND: Lifestyle modification programs have improved the achievement of risk factor targets in a variety of clinical settings, including patients who have previously suffered a stroke or transient ischemic attack and those with multiple risk factors. Stenting Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) was the first vascular disease prevention trial to provide a commercially available lifestyle modification program to enhance risk factor control. We sought to determine the relationship between compliance with this program and risk factor control in SAMMPRIS. METHODS: SAMMPRIS aggressive medical management included a telephonic lifestyle modification program provided free of charge to all subjects (n = 451) during their participation in the study. Subjects with fewer than 3 expected lifestyle-coaching calls were excluded from these analyses. Compliant subjects (n = 201) had greater than or equal to 78.5% of calls (median % of completed/expected calls). Noncompliant subjects (n = 200) had less than 78.5% of calls or refused to participate. Mean risk factor values or % in-target for each risk factor was compared between compliant versus noncompliant subjects, using t tests and chi-square tests. Risk factor changes from baseline to follow-up were compared between the groups to account for baseline differences. RESULTS: Compliant subjects had better risk factor control throughout follow-up for low-density lipoprotein, systolic blood pressure (SBP), hemoglobin A1c (HgA1c), non-high-density lipoprotein, nonsmoking, and exercise than noncompliant subjects, but there was no difference for body mass index. After adjusting for baseline differences between the groups, compliant subjects had a greater change from baseline than noncompliant subjects for SBP did at 24 months and HgA1c at 6 months. CONCLUSION: SAMMPRIS subjects who were compliant with the lifestyle modification program had better risk factor control during the study for almost all risk factors.

Nonprocedural Symptomatic Infarction and In-Stent Restenosis After Intracranial Angioplasty and Stenting in the SAMMPRIS Trial (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis).

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the frequency of symptomatic in-stent restenosis (ISR) and its contribution to nonprocedural symptomatic infarction in the SAMMPRIS trial (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis). METHODS: Patients without a periprocedural primary end point were followed up to determine the occurrence of any of the following events: ischemic stroke, cerebral infarct with temporary signs, or transient ischemic attack in the territory of the stented artery. Vascular imaging performed after these events was reviewed for ISR. Annual rates for symptomatic ISR were calculated using Kaplan-Meier estimates. RESULTS: Of 183 patients in the stenting group without a periprocedural primary end point, 27 (14.8%) had a symptomatic infarction (stroke or cerebral infarct with temporary signs) and 16 (8.7%) had transient ischemic attack alone in the territory during a median follow-up of 35.0 months. Of the 27 patients with infarctions, 17 (9.3%) had an ischemic stroke and 10 (5.5%) had a cerebral infarct with temporary signs alone. Adequate vascular imaging to evaluate ISR was available in 24 patients with infarctions (showing ISR in 16 [66.7%]) and in 10 patients with transient ischemic attack alone (showing ISR in 8 [80%]). The 1-, 2-, and 3-year rates (with 95% confidence limits) for symptomatic ISR in the SAMMPRIS stent cohort were 9.6% (6.1%-14.9%), 11.3% (7.5%-17.0%), and 14.0% (9.6%-20.2%), respectively. CONCLUSIONS: Symptomatic ISR occurred in at least 1 of 7 patients in SAMMPRIS by 3 years of follow-up and was likely responsible for the majority of nonprocedural cerebral infarctions. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00576693.

Myopic Shift 5 Years after Intraocular Lens Implantation in the Infant Aphakia Treatment Study.

PURPOSE: To report the myopic shift at 5 years of age after cataract surgery with intraocular lens (IOL) implantation for infants enrolled in the Infant Aphakia Treatment Study (IATS). METHODS: Refractions were performed at 1 month and every 3 months postoperatively until age 4 years and then at ages 4.25, 4.5, and 5 years. The change in refraction over time was estimated by linear mixed model analysis. RESULTS: Intraocular lens implantation was completed in 56 eyes; 43 were analyzed (median age, 2.4 months; range, 1.0-6.8 months). Exclusions included 11 patients with glaucoma, 1 patient with Stickler syndrome, and 1 patient with an IOL exchange at 8 months postoperatively. The mean rate of change in a myopic direction from 1 month after cataract surgery to age 1.5 years was 0.35 diopters (D)/month (95% confidence interval [CI], 0.29-0.40 D/month); after age 1.5 years, the mean rate of change in a myopic direction was 0.97 D/year (95% CI, 0.66-1.28 D/year). The mean refractive change was 8.97 D (95% CI, 7.25-10.68 D) at age 5 years for children 1 month of age at surgery and 7.22 D (95% CI, 5.54-8.91 D) for children 6 months of age at surgery. The mean refractive error at age 5 years was -2.53 D (95% CI, -4.05 to -1.02). CONCLUSIONS: After IOL implantation during infancy, the rate of myopic shift occurs most rapidly during the first 1.5 years of life. Myopic shift varies substantially among patients. If the goal is emmetropia at age 5 years, then the immediate postoperative hypermetropic targets should be +10.5 D at 4 to 6 weeks and +8.50 D from 7 weeks to 6 months. However, even using these targets, it is likely that many children will require additional refractive correction given the high variability of refractive outcomes.

Is There Benefit from Stenting on Cognitive Function in Intracranial Atherosclerosis?

BACKGROUND: Revascularization of stenotic cerebral arteries is hypothesized to improve cognition by increasing cerebral perfusion. AIMS: We compared cognition impairment among patients treated with percutaneous angioplasty and stenting (PTAS) and aggressive medical management (AMM) versus AMM alone in the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) Trial. METHODS: In SAMMPRIS, 451 patients with recent transient ischemic attack or stroke attributed to 70-99% intracranial stenosis were randomized to PTAS plus AMM or AMM alone. Patients who had stroke as the qualifying event with National Institutes of Health Stroke Scale indicating aphasia or neglect were excluded from these analyses. Patients with a cerebrovascular event (ischemic stroke, cerebral infarct with temporary signs or intracranial hemorrhage) during follow-up were excluded from follow-up visit analyses. The Montreal Cognitive Assessment (MoCA) score was used to assess cognition impairment at baseline, 4 months, 12 months and closeout. Cognitive impairment was defined as MoCA <26. Mean MoCA scores and the percentage of patients with cognitive impairment were compared between treatment groups at each time point using t tests and chi-square tests. Differences in MoCA mean at baseline and follow-up time points were compared using mixed model repeated measures ANOVA and Tukey-Kramer tests. RESULTS: There were no significant differences between the treatment groups for mean MoCA at any time point. Mean MoCA scores improved in both groups. The percentage of patients with cognitive impairment in the AMM versus PTAS groups was not significantly different at any time point. CONCLUSIONS: Revascularization with PTAS showed no improvement in cognitive impairment over AMM alone among patients who did not have recurrent cerebrovascular events during follow-up.

The Infant Aphakia Treatment Study Contact Lens Experience to Age 5 Years.

PURPOSE: To describe our experience treating a cohort of unilateral aphakic infants with contact lenses in the Infant Aphakia Treatment Study (IATS). MATERIALS AND METHODS: Fifty-seven of the 114 infants in the IATS were randomized to contact lens wear; all were followed until age 5 years, although a few had lapses in care. An examination under anesthesia, including keratometry, was performed at the time of enrollment and at approximately 1 year of age; keratometry was performed again at 5 years of age. A traveling examiner assessed visual acuity at approximately 1 year of age and again at 4.5 years of age. RESULTS: Twenty-four treated eyes (46%) wore silicone elastomer (SE) contact lenses, 11 eyes (19%) rigid gas permeable (GP) contact lenses and 17 eyes (29%) wore both lens types at various points of time. Median logMAR visual acuity was +0.70 (interquartile range (IQR), +0.30 to 1.20) in the SE group and 2.03 (IQR, +0.20 to 2.28) in the GP group at age 4.5 years. The mean (±SD) keratometric power of the treated eyes was 46.3±2.8 diopter (D) at baseline, 44.6±2.3 D at 1 year of age, and 44.3±1.7 D at 5 years of age. Keratometric astigmatism of treated eyes was 1.98±1.37 D at baseline, 1.62±0.98 D at 1 year of age, and 2.00±1.00 D at 5 years of age. Thirteen contact lens-related adverse events occurred among 7 patients after age 1 year. CONCLUSIONS: A cohort of infants with unilateral aphakia successfully wore contact lenses with relatively few adverse events.

Impact of the New American Heart Association/American Stroke Association Definition of Stroke on the Results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial.

BACKGROUND: An American Heart Association/American Stroke Association (AHA/ASA) writing committee has recently recommended that tissue evidence of cerebral infarction associated with temporary symptoms (CITS) lasting <24 hours should be considered a stroke. We analyzed the impact of considering CITS as equivalent to stroke on the results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. METHODS: We compared outcomes in the medical (n = 227) and stenting (n = 224) groups in SAMMPRIS using the following primary end point (new components in bold): any stroke, CITS, or death within 30 days after enrollment or within 30 days after a revascularization procedure for the qualifying lesion during follow-up; or ischemic stroke or CITS in the territory of the qualifying artery beyond 30 days. We also compared the use of brain magnetic resonance imaging (MRI) after transient ischemic attacks (TIAs) in both treatment groups. RESULTS: By considering CITS as equivalent to stroke, the number of primary end points increased from 34 to 43 in the medical group and from 52 to 66 in the stenting group of SAMMPRIS. The Kaplan-Meier curves for the primary end points in the 2 groups were significantly different (P = .009). The percentage of patients with reported TIAs who underwent brain MRI was 69% in the medical group and 61% in the stenting group (P = .40). CONCLUSION: Using the AHA/ASA definition of stroke resulted in a substantially higher primary end point rate in both treatment groups and an even higher benefit from medical therapy over stenting than originally shown in SAMMPRIS. The higher rate of CITS in the stenting group was not due to ascertainment bias.

Do Patient Characteristics Explain the Differences in Outcome Between Medically Treated Patients in SAMMPRIS and WASID?

BACKGROUND AND PURPOSE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) medical group had a much lower primary end point rate than predicted from the preceding Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. This result has been attributed to the aggressive medical therapy used in SAMMPRIS, but an alternative hypothesis is that SAMMPRIS patients were at lower risk. We undertook analyses to evaluate these competing hypotheses. METHODS: Using proportional hazards regression, we compared the SAMMPRIS primary end point between SAMMPRIS medical patients and WASID patients meeting the same qualifying criteria adjusted for confounding baseline characteristics. RESULTS: The unadjusted comparison of the SAMMPRIS primary end point showed a significantly higher risk for WASID patients (P=0.009, logrank test) with 12 month Kaplan-Meier estimates of 21.9% in WASID and 12.6% in SAMMPRIS and hazard ratio 1.9 (95% confidence interval =1.2-3.0). The analyses identified the following confounding factors that varied between the studies and that conferred a higher risk: lack of statin use at enrollment (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.027) that was more prevalent among WASID patients (39% versus 14%, P<0.0001) and prior infarcts in the territory of the symptomatic vessel (hazard ratio =1.8, 95% confidence interval =1.1-2.9, P=0.023) that was more prevalent among SAMMPRIS patients (34% versus 22%, P=0.015).The hazard ratio for WASID versus SAMMPRIS adjusted for these 2 characteristics was 1.9 (95% confidence interval =1.1-3.2). CONCLUSIONS: After adjustment for confounding baseline characteristics, WASID patients had an almost 2-fold higher risk of the SAMMPRIS primary end point, which supports the hypothesis that the lower rate of the primary end point in the medical arm of SAMMPRIS compared with WASID patients was as a result of the aggressive medical management used in SAMMPRIS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis?

BACKGROUND AND PURPOSE: Although the Stenting Versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial showed that medical therapy alone was superior to stenting plus medical therapy for preventing recurrent strokes in patients with symptomatic intracranial stenosis, we determined whether SAMMPRIS supported the use of stenting in any subpopulations of patients with symptomatic intracranial arterial stenosis. METHODS: The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared in those with and without baseline factors in the 2 treatment arms, percutaneous transluminal angioplasty and stenting (PTAS) plus aggressive medical therapy versus aggressive medical therapy alone. Baseline factors included sex, age, race, diabetes mellitus, hypertension, lipid disorder, smoking status, type of qualifying event, qualifying event hypoperfusion symptoms, use of antithrombotic or proton pump inhibitor at baseline, days to enrollment, old infarcts in the same territory, percent stenosis, other artery stenosis, and location of the symptomatic artery. RESULTS: A total of 451 patients were enrolled, 227 randomized to aggressive medical therapy and 224 to PTAS. Of all variables evaluated, the observed 2-year event rates were higher with PTAS than with aggressive medical therapy in the vast majority and the interaction with treatment was not statistically significant for any of the factors. CONCLUSIONS: The SAMMPRIS results do not provide evidence to support the use of PTAS using the Wingspan stent system compared with medical treatment in any examined subpopulation of patients with symptomatic intracranial stenosis, including those with qualifying event hypoperfusion symptoms. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial: subgroup analysis.

BACKGROUND AND PURPOSE: Stenting has been used as a rescue therapy in patients with intracranial arterial stenosis and a transient ischemic attack or stroke when on antithrombotic therapy (AT). We determined whether the stenting versus aggressive medical therapy for intracranial arterial stenosis (SAMMPRIS) trial supported this approach by comparing the treatments within subgroups of patients whose qualifying event (QE) occurred on versus off of AT. METHODS: The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared between (1) percutaneous transluminal angioplasty and stenting plus aggressive medical therapy (PTAS) versus aggressive medical management therapy alone (AMM) for patients whose QE occurred on versus off AT and between (2) patients whose QE occurred on versus off AT separately for the treatment groups. RESULTS: Among the 284/451 (63%) patients who had their QE on AT, the 2-year primary end point rates were 15.6% for those randomized to AMM (n=140) and 21.6% for PTAS (n=144; P=0.043, log-rank test). In the 167 patients not on AT, the 2-year primary end point rates were 11.6% for AMM (n=87) and 18.8% for PTAS (n=80; P=0.31, log-rank test). Within both treatment groups, there was no difference in the time to the primary end point between patients who were on or off AT (AMM, P=0.96; PTAS, P=0.52; log-rank test). CONCLUSIONS: SAMMPRIS results indicate that the benefit of AMM over PTAS is similar in patients on versus off AT at the QE and that failure of AT is not a predictor of increased risk of a primary end point. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial.

BACKGROUND: Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS: We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS: During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). INTERPRETATION: The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. FUNDING: National Institute of Neurological Disorders and Stroke (NINDS) and others.

Corneal Changes in Children after Unilateral Cataract Surgery in the Infant Aphakia Treatment Study.

PURPOSE: We report endothelial cell (EC) characteristics and central corneal thickness (CCT) from the Infant Aphakia Treatment Study (IATS) patients at the 5-year examination. DESIGN: Randomized, controlled trial of the treatment of unilateral cataract with aphakic contact lens (CL) versus primary intraocular lens (IOL) implant. PARTICIPANTS: A total of 114 infants with unilateral cataract. METHODS: The EC density, coefficient of variation (CV), and percent hexagonal cells were measured by noncontact specular microscopy. The CCT was measured using contact pachymetry. Fellow eyes served as controls. MAIN OUTCOME MEASURES: Mean differences between treated and fellow eyes of CL and IOL groups were compared with a paired t test. A 1-way analysis of variance model and the Tukey-Kramer multiple comparison procedure were used to assess the effect of a diagnosis of glaucoma or glaucoma suspect. RESULTS: A total of 105 subjects (52 with CLs, 53 with IOLs) had specular microscopy or corneal thickness data recorded. Mean EC densities were higher in aphakic eyes compared with fellow eyes (3921 vs. 3495 cells/mm2, P<0.0001). Mean CV was higher (27 vs. 24, P=0.0002) and mean percent hexagonal cells was lower (72% vs. 76%, P=0.002) in aphakic eyes compared with fellow eyes. Mean CCT of aphakic eyes was higher than in controls (637 vs. 563 µm, P<0.0001). There was no difference in EC density in eyes treated with IOLs compared with fellow eyes (3445 and 3487 cells/mm2, P=0.68). Means for CV (25 vs. 24, P=0.07) and percent hexagonal cells (74 vs. 76%, P=0.27) were also not significantly different. Mean CCT was higher in eyes with IOLs (605 vs. 571 µm, P<0.0001) compared with fellow eyes. Compared with treated eyes without glaucoma or glaucoma suspect, treated eyes with glaucoma had lower EC density (3289 vs. 3783 cells/mm2, P=0.03) and treated eyes with glaucoma suspect had greater mean corneal thickness (660 vs. 612 µm, P=0.0036). CONCLUSIONS: Cataract extraction during infancy with IOL implantation was not associated with a reduced EC count in treated compared with fellow eyes, although CCT was increased. Extended-wear aphakic CLs may cause corneal polymegathism with increased EC density and CCT. Glaucoma diagnosis was associated with reduced EC counts and increased CCT.

Comparison Among Methods of Retinopathy Assessment (CAMRA) Study: Smartphone, Nonmydriatic, and Mydriatic Photography.

PURPOSE: We compared smartphone fundus photography, nonmydriatic fundus photography, and 7-field mydriatic fundus photography for their abilities to detect and grade diabetic retinopathy (DR). DESIGN: This was a prospective, comparative study of 3 photography modalities. PARTICIPANTS: Diabetic patients (n = 300) were recruited at the ophthalmology clinic of a tertiary diabetes care center in Chennai, India. METHODS: Patients underwent photography by all 3 modalities, and photographs were evaluated by 2 retina specialists. MAIN OUTCOME MEASURES: The sensitivity and specificity in the detection of DR for both smartphone and nonmydriatic photography were determined by comparison with the standard method, 7-field mydriatic fundus photography. RESULTS: The sensitivity and specificity of smartphone fundus photography, compared with 7-field mydriatic fundus photography, for the detection of any DR were 50% (95% confidence interval [CI], 43-56) and 94% (95% CI, 92-97), respectively, and of nonmydriatic fundus photography were 81% (95% CI, 75-86) and 94% (95% CI, 92-96%), respectively. The sensitivity and specificity of smartphone fundus photography for the detection of vision-threatening DR were 59% (95% CI, 46-72) and 100% (95% CI, 99-100), respectively, and of nonmydriatic fundus photography were 54% (95% CI, 40-67) and 99% (95% CI, 98-100), respectively. CONCLUSIONS: Smartphone and nonmydriatic fundus photography are each able to detect DR and sight-threatening disease. However, the nonmydriatic camera is more sensitive at detecting DR than the smartphone. At this time, the benefits of the smartphone (connectivity, portability, and reduced cost) are not offset by the lack of sufficient sensitivity for detection of DR in most clinical circumstances.