Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy.

Background and Purpose: Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS. Methods: Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes. Results: Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity. Conclusions: Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

Comparing Seizures Captured by Rapid Response EEG and Conventional EEG Recordings in a Multicenter Clinical Study.

Objective: A recent multicenter prospective study (DECIDE trial) examined the use of Ceribell Rapid Response EEG (Rapid-EEG) in the emergent evaluation and management of critically ill patients suspected to have non-convulsive seizures. We present a detailed, patient-level examination of seizures detected either on initial Rapid-EEG or subsequent conventional EEG within 24 h to investigate whether seizures were missed on Rapid-EEG due to the exclusion of midline/parasagittal coverage. Methods: We identified from 164 patients studied in the DECIDE trial those who had seizures detected on Rapid-EEG but not conventional EEG (n = 6), conventional EEG but not Rapid-EEG (n = 4), or both Rapid-EEG and conventional EEG (n = 9). We examined the electrographic characteristics of ictal and interictal findings on both devices, especially their detection in lateral or midline/parasagittal chains, and patient clinical histories to identify contributors toward discordant seizure detection. Results: Seizures detected on both EEG systems had similar electrographic appearance and laterality. Seizures detected only on conventional EEG (within 24 h following Rapid-EEG) were visible in the temporal chains, and external clinical factors (e.g., treatment with anti-seizure medications, sedation, and duration of recordings) explained the delayed presentation of seizures. Patients with seizures detected only by Rapid-EEG were treated with anti-seizure medications, and subsequent conventional EEG detected interictal highly epileptiform patterns with similar laterality. Conclusions: Our case series demonstrates that electrographic data obtained from initial Rapid-EEG and subsequent conventional EEG monitoring are largely concordant relative to morphology and laterality. These findings are valuable to inform future investigation of abbreviated EEG systems to optimize management of suspected non-convulsive seizures and status epilepticus. Future, larger studies could further investigate the value of Rapid-EEG findings for forecasting and predicting seizures in long-term EEG recordings.

Altered sense of self during seizures in the posteromedial cortex.

The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation-a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his "me" having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient's network anatomy at sites of interest using cortico-cortical-evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

Monitoring the Burden of Seizures and Highly Epileptiform Patterns in Critical Care with a Novel Machine Learning Method.

INTRODUCTION: Current electroencephalography (EEG) practice relies on interpretation by expert neurologists, which introduces diagnostic and therapeutic delays that can impact patients' clinical outcomes. As EEG practice expands, these experts are becoming increasingly limited resources. A highly sensitive and specific automated seizure detection system would streamline practice and expedite appropriate management for patients with possible nonconvulsive seizures. We aimed to test the performance of a recently FDA-cleared machine learning method (Claritγ, Ceribell Inc.) that measures the burden of seizure activity in real time and generates bedside alerts for possible status epilepticus (SE). METHODS: We retrospectively identified adult patients (n = 353) who underwent evaluation of possible seizures with Rapid Response EEG system (Rapid-EEG, Ceribell Inc.). Automated detection of seizure activity and seizure burden throughout a recording (calculated as the percentage of ten-second epochs with seizure activity in any 5-min EEG segment) was performed with Claritγ, and various thresholds of seizure burden were tested (≥ 10% indicating ≥ 30 s of seizure activity in the last 5 min, ≥ 50% indicating ≥ 2.5 min of seizure activity, and ≥ 90% indicating ≥ 4.5 min of seizure activity and triggering a SE alert). The sensitivity and specificity of Claritγ's real-time seizure burden measurements and SE alerts were compared to the majority consensus of at least two expert neurologists. RESULTS: Majority consensus of neurologists labeled the 353 EEGs as normal or slow activity (n = 249), highly epileptiform patterns (HEP, n = 87), or seizures [n = 17, nine longer than 5 min (e.g., SE), and eight shorter than 5 min]. The algorithm generated a SE alert (≥ 90% seizure burden) with 100% sensitivity and 93% specificity. The sensitivity and specificity of various thresholds for seizure burden during EEG recordings for detecting patients with seizures were 100% and 82% for ≥ 50% seizure burden and 88% and 60% for ≥ 10% seizure burden. Of the 179 EEG recordings in which the algorithm detected no seizures, seizures were identified by the expert reviewers in only two cases, indicating a negative predictive value of 99%. DISCUSSION: Claritγ detected SE events with high sensitivity and specificity, and it demonstrated a high negative predictive value for distinguishing nonepileptiform activity from seizure and highly epileptiform activity. CONCLUSIONS: Ruling out seizures accurately in a large proportion of cases can help prevent unnecessary or aggressive over-treatment in critical care settings, where empiric treatment with antiseizure medications is currently prevalent. Claritγ's high sensitivity for SE and high negative predictive value for cases without epileptiform activity make it a useful tool for triaging treatment and the need for urgent neurological consultation.

Cross-Modal Data Programming Enables Rapid Medical Machine Learning.

A major bottleneck in developing clinically impactful machine learning models is a lack of labeled training data for model supervision. Thus, medical researchers increasingly turn to weaker, noisier sources of supervision, such as leveraging extractions from unstructured text reports to supervise image classification. A key challenge in weak supervision is combining sources of information that may differ in quality and have correlated errors. Recently, a statistical theory of weak supervision called data programming has shown promise in addressing this challenge. Data programming now underpins many deployed machine-learning systems in the technology industry, even for critical applications. We propose a new technique for applying data programming to the problem of cross-modal weak supervision in medicine, wherein weak labels derived from an auxiliary modality (e.g., text) are used to train models over a different target modality (e.g., images). We evaluate our approach on diverse clinical tasks via direct comparison to institution-scale, hand-labeled datasets. We find that our supervision technique increases model performance by up to 6 points area under the receiver operating characteristic curve (ROC-AUC) over baseline methods by improving both coverage and quality of the weak labels. Our approach yields models that on average perform within 1.75 points ROC-AUC of those supervised with physician-years of hand labeling and outperform those supervised with physician-months of hand labeling by 10.25 points ROC-AUC, while using only person-days of developer time and clinician work-a time saving of 96%. Our results suggest that modern weak supervision techniques such as data programming may enable more rapid development and deployment of clinically useful machine-learning models.

Evaluating the Clinical Impact of Rapid Response Electroencephalography: The DECIDE Multicenter Prospective Observational Clinical Study.

OBJECTIVES: To measure the diagnostic accuracy, timeliness, and ease of use of Ceribell rapid response electroencephalography. We assessed physicians' diagnostic assessments and treatment plans before and after rapid response electroencephalography assessment. Primary outcomes were changes in physicians' diagnostic and therapeutic decision making and their confidence in these decisions based on the use of the rapid response electroencephalography system. Secondary outcomes were time to electroencephalography, setup time, ease of use, and quality of electroencephalography data. DESIGN: Prospective multicenter nonrandomized observational study. SETTING: ICUs in five academic hospitals in the United States. SUBJECTS: Patients with encephalopathy suspected of having nonconvulsive seizures and physicians evaluating these patients. INTERVENTIONS: Physician bedside assessment of sonified electroencephalography (30 s from each hemisphere) and visual electroencephalography (60 s) using rapid response electroencephalography. MEASUREMENTS AND MAIN RESULTS: Physicians (29 fellows or residents, eight attending neurologists) evaluated 181 ICU patients; complete clinical and electroencephalography data were available in 164 patients (average 58.6 ± 18.7 yr old, 45% females). Relying on rapid response electroencephalography information at the bedside improved the sensitivity (95% CI) of physicians' seizure diagnosis from 77.8% (40.0%, 97.2%) to 100% (66.4%, 100%) and the specificity (95% CI) of their diagnosis from 63.9% (55.8%, 71.4%) to 89% (83.0%, 93.5%). Physicians' confidence in their own diagnosis and treatment plan were also improved. Time to electroencephalography (median [interquartile range]) was 5 minutes (4-10 min) with rapid response electroencephalography while the conventional electroencephalography was delayed by several hours (median [interquartile range] delay = 239 minutes [134-471 min] [p < 0.0001 using Wilcoxon signed rank test]). The device was rated as easy to use (mean ± SD: 4.7 ± 0.6 [1 = difficult, 5 = easy]) and was without serious adverse effects. CONCLUSIONS: Rapid response electroencephalography enabled timely and more accurate assessment of patients in the critical care setting. The use of rapid response electroencephalography may be clinically beneficial in the assessment of patients with high suspicion for nonconvulsive seizures and status epilepticus.

Diagnostic Value of Electroencephalography with Ten Electrodes in Critically Ill Patients.

BACKGROUND: In critical care settings, electroencephalography (EEG) with reduced number of electrodes (reduced montage EEG, rm-EEG) might be a timely alternative to the conventional full montage EEG (fm-EEG). However, past studies have reported variable accuracies for detecting seizures using rm-EEG. We hypothesized that the past studies did not distinguish between differences in sensitivity from differences in classification of EEG patterns by different readers. The goal of the present study was to revisit the diagnostic value of rm-EEG when confounding issues are accounted for. METHODS: We retrospectively collected 212 adult EEGs recorded at Massachusetts General Hospital and reviewed by two epileptologists with access to clinical, trending, and video information. In Phase I of the study, we re-configured the first 4 h of the EEGs in lateral circumferential montage with ten electrodes and asked new readers to interpret the EEGs without access to any other ancillary information. We compared their rating to the reading of hospital clinicians with access to ancillary information. In Phase II, we measured the accuracy of the same raters reading representative samples of the discordant EEGs in full and reduced configurations presented randomly by comparing their performance to majority consensus as the gold standard. RESULTS: Of the 95 EEGs without seizures in the selected fm-EEG, readers of rm-EEG identified 92 cases (97%) as having no seizure activity. Of 117 EEGs with "seizures" identified in the selected fm-EEG, none of the cases was labeled as normal on rm-EEG. Readers of rm-EEG reported pathological activity in 100% of cases, but labeled them as seizures (N = 77), rhythmic or periodic patterns (N = 24), epileptiform spikes (N = 7), or burst suppression (N = 6). When the same raters read representative epochs of the discordant EEG cases (N = 43) in both fm-EEG and rm-EEG configurations, we found high concordance (95%) and intra-rater agreement (93%) between fm-EEG and rm-EEG diagnoses. CONCLUSIONS: Reduced EEG with ten electrodes in circumferential configuration preserves key features of the traditional EEG system. Discrepancies between rm-EEG and fm-EEG as reported in some of the past studies can be in part due to methodological factors such as choice of gold standard diagnosis, asymmetric access to ancillary clinical information, and inter-rater variability rather than detection failure of rm-EEG as a result of electrode reduction per se.

In Vivo Glycan Engineering via the Mannosidase I Inhibitor (Kifunensine) Improves Efficacy of Rituximab Manufactured in Nicotiana benthamiana Plants.

N-glycosylation has been shown to affect the pharmacokinetic properties of several classes of biologics, including monoclonal antibodies, blood factors, and lysosomal enzymes. In the last two decades, N-glycan engineering has been employed to achieve a N-glycosylation profile that is either more consistent or aligned with a specific improved activity (i.e., effector function or serum half-life). In particular, attention has focused on engineering processes in vivo or in vitro to alter the structure of the N-glycosylation of the Fc region of anti-cancer monoclonal antibodies in order to increase antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we applied the mannosidase I inhibitor kifunensine to the Nicotiana benthamiana transient expression platform to produce an afucosylated anti-CD20 antibody (rituximab). We determined the optimal concentration of kifunensine used in the infiltration solution, 0.375 µM, which was sufficient to produce exclusively oligomannose glycoforms, at a concentration 14 times lower than previously published levels. The resulting afucosylated rituximab revealed a 14-fold increase in ADCC activity targeting the lymphoma cell line Wil2-S when compared with rituximab produced in the absence of kifunensine. When applied to the cost-effective and scalable N. benthamiana transient expression platform, the use of kifunensine allows simple in-process glycan engineering without the need for transgenic hosts.

Neuromodulation - Science and Practice in Epilepsy: Vagus Nerve Stimulation, Thalamic Deep Brain Stimulation, and Responsive NeuroStimulation.

Introduction: Neuromodulation devices can be safe and effective for the treatment of drug-resistant epilepsy. A body of scientific work supports peripheral, subcortical and cortical targets, each with different fundamental methods of action. Areas covered: High-quality evidence is available for vagal nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Mechanistic research in animals and human studies are reviewed, along with key data from VNS, DBS, and RNS clinical trials. Specifically, the authors review some of the science behind the most frequently used medical devices for neuromodulation, the evidence that lead to their adoption, a delineation of the populations that often benefit from these devices, and perspectives on clinical practice to optimize benefit in treatment of seizures. Expert Commentary: Neuromodulation is increasingly used to complement medical management of refractory epilepsy. Device preference will be made on the basis of patient preference, physician familiarity and other individualized factors. Right now, the field is very new and decision-making will improve with experience.

Repetitive transcranial magnetic stimulation directed to a seizure focus localized by high-density EEG: A case report.

We demonstrate feasibility of using high-density EEG to map a neocortical seizure focus in conjunction with delivery of magnetic therapy. Our patient had refractory seizures affecting the left leg. A five-day course of placebo stimulation followed a month later by active rTMS was directed to the mapped seizure dipole. Active rTMS resulted in reduced EEG spiking, and shortening of seizure duration compared to placebo. Seizure frequency, however, improved similarly in both placebo and active treatment stages. rTMS-evoked EEG potentials demonstrated that a negative peak at 40 ms - believed to represent GABAergic inhibition - was enhanced by stimulation.

Association Between Carotid Artery Function and Structure in the Northern Manhattan Study.

BACKGROUND AND PURPOSE: Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD. METHODS: We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area). RESULTS: The mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm2. STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque. CONCLUSION: Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.

Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities: The Northern Manhattan Study.

BACKGROUND AND PURPOSE: Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort. METHODS: We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors. RESULTS: In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21-0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (ß=0.046 per SD cIMT; P=0.04). Age and race/ethnicity were significant modifiers (P for age, 0.02; and P for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (ß=0.088 per SD cIMT; P=0.01) and among Hispanics (ß=0.084 per SD cIMT; P=0.003). CONCLUSIONS: Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline.

Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity.

Circadian repression of CLOCK-BMAL1 by PERIOD and CRYPTOCHROME (CRY) in mammals lies at the core of the circadian timekeeping mechanism. CRY repression of CLOCK-BMAL1 and regulation of circadian period are proposed to rely primarily on competition for binding with coactivators on an α-helix located within the transactivation domain (TAD) of the BMAL1 C terminus. This model has, however, not been tested in vivo. Here, we applied CRISPR/Cas9-mediated mutagenesis in the monarch butterfly (Danaus plexippus), which possesses a vertebrate-like CRY (dpCRY2) and an ortholog of BMAL1, to show that insect CRY2 regulates circadian repression through TAD α-helix-dependent and -independent mechanisms. Monarch mutants lacking the BMAL1 C terminus including the TAD exhibited arrhythmic eclosion behavior. In contrast, mutants lacking the TAD α-helix but retaining the most distal C-terminal residues exhibited robust rhythms during the first day of constant darkness (DD1), albeit with a delayed peak of eclosion. Phase delay in this mutant on DD1 was exacerbated in the presence of a single functional allele of dpCry2, and rhythmicity was abolished in the absence of dpCRY2. Reporter assays in Drosophila S2 cells further revealed that dpCRY2 represses through two distinct mechanisms: a TAD-dependent mechanism that involves the dpBMAL1 TAD α-helix and dpCLK W328 and a TAD-independent mechanism involving dpCLK E333. Together, our results provide evidence for independent mechanisms of vertebrate-like CRY circadian regulation on the BMAL1 C terminus and the CLK PAS-B domain and demonstrate the importance of a BMAL1 TAD-independent mechanism for generating circadian rhythms in vivo.

Relationship between carotid arterial properties and cerebral white matter hyperintensities.

OBJECTIVE: Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants. METHODS: Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors. RESULTS: In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (ß = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race-ethnicity, STRAIN (ß = -1.78, p = 0.002) and DD (ß = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants. CONCLUSIONS: Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These associations suggest a potential important pathophysiologic role of extracranial large artery remodeling in the burden of WMH.

Genomic Access to Monarch Migration Using TALEN and CRISPR/Cas9-Mediated Targeted Mutagenesis.

The eastern North American monarch butterfly, Danaus plexippus, is an emerging model system to study the neural, molecular, and genetic basis of animal long-distance migration and animal clockwork mechanisms. While genomic studies have provided new insight into migration-associated and circadian clock genes, the general lack of simple and versatile reverse-genetic methods has limited in vivo functional analysis of candidate genes in this species. Here, we report the establishment of highly efficient and heritable gene mutagenesis methods in the monarch butterfly using transcriptional activator-like effector nucleases (TALENs) and CRISPR-associated RNA-guided nuclease Cas9 (CRISPR/Cas9). Using two clock gene loci, cryptochrome 2 and clock (clk), as candidates, we show that both TALENs and CRISPR/Cas9 generate high-frequency nonhomologous end-joining (NHEJ)-mediated mutations at targeted sites (up to 100%), and that injecting fewer than 100 eggs is sufficient to recover mutant progeny and generate monarch knockout lines in about 3 months. Our study also genetically defines monarch CLK as an essential component of the transcriptional activation complex of the circadian clock. The methods presented should not only greatly accelerate functional analyses of many aspects of monarch biology, but are also anticipated to facilitate the development of these tools in other nontraditional insect species as well as the development of homology-directed knock-ins.

Performance trends in large 10-km road running races in the United States.

Our study examines the current trends of runners participating in 10-km road races in the United States. Finish times and ages of all runners participating in 10 of the largest 10-km running races in the United States between 2002-2005 and 2011 were recorded. Linear regression analysis was performed to examine the trends for age, sex, and finishing time for all participants completing the course in <1 hour. A total of 408,296 runners were analyzed. There was a significant annual decrease in the ratio of men to women finishers (p < 0.001, r = 0.976). The average finishing time of the top 10 (men, p ≤ 0.05), 100 (men and women, p ≤ 0.05), and 1,000 (men and women, p < 0.01) significantly decreased annually. The total number of subhour finishers increased annually across all races (194 men per year, r = 0.584, p = 0.045; 161 women per year, r = 0.779, p = 0.008), whereas the percentage of overall finishers completing the course in less than an hour significantly declined for men and women (p ≤ 0.003). There was a significant trend toward younger men in all top groups except for the single fastest runner (p ≤ 0.017). Our study demonstrates that for large 10-km U.S. races: the top men and women seem to be getting faster; there are more subhour finishers, with increasingly more women accomplishing this feat compared with men; an increasingly lower percentage of overall finishers is finishing in <1 hour; and the fastest men are also increasingly younger.

Diet soft drink consumption is associated with an increased risk of vascular events in the Northern Manhattan Study.

BACKGROUND: Diet and regular soft drinks have been associated with diabetes and the metabolic syndrome, and regular soft drinks with coronary heart disease. OBJECTIVE: To determine the association between soft drinks and combined vascular events, including stroke. DESIGN: A population-based cohort study of stroke incidence and risk factors. PARTICANTS: Participants (N= 2564, 36% men, mean age 69 ± 10, 20% white, 23% black, 53% Hispanic) were from the Northern Manhattan Study. MAIN MEASURES: We assessed diet and regular soft drink consumption using a food frequency questionnaire at baseline, and categorized: none (<1/month, N = 1948 diet, N = 1333 regular), light (1/month-6/week, N = 453 diet, N = 995 regular), daily (≥1/day, N = 163 diet, N = 338 regular). Over a mean follow-up of 10 years, we examined the association between soft drink consumption and 591 incident vascular events (stroke, myocardial infarction, vascular death) using Cox models. KEY RESULTS: Controlling for age, sex, race/ethnicity, education, smoking, physical activity, alcohol consumption, BMI, daily calories, consumption of protein, carbohydrates, total fat, saturated fat, and sodium, those who drank diet soft drinks daily (vs. none) had an increased risk of vascular events, and this persisted after controlling further for the metabolic syndrome, peripheral vascular disease, diabetes, cardiac disease, hypertension, and hypercholesterolemia (HR = 1.43, 95% CI = 1.06-1.94). There was no increased risk of vascular events associated with regular soft drinks or light diet soft drink consumption. CONCLUSIONS: Daily diet soft drink consumption was associated with several vascular risk factors and with an increased risk for vascular events. Further research is needed before any conclusions can be made regarding the potential health consequences of diet soft drink consumption.

Ethnic differences in carotid artery diameter and stiffness: the Northern Manhattan Study.

OBJECTIVE: Race/ethnic differences in carotid arterial function and structure exist among those with cerebrovascular disease, but whether differences persist among healthy populations is unknown. Our objective was to investigate differences in carotid artery diameter and stiffness between race/ethnic groups, and examine whether these race/ethnic differences were age-dependent. METHODS: Carotid diameters were assessed by B-mode ultrasound among 1536 participants from the Northern Manhattan Study (NOMAS), and carotid stiffness metrics were calculated. We used multivariable linear regression models to determine the relationship between race/ethnicity and both carotid arterial stiffness and carotid diastolic diameter. RESULTS: Mean participant age was 70 ± 9 years (Hispanics = 68 ± 8, blacks = 72 ± 9, and whites = 74 ± 9, p < 0.0001). Mean DDIAM was 6.2 ± 1.0mm (Hispanics = 6.2 ± 0.9 mm, blacks = 6.3 ± 1.0 mm, and whites = 6.3 ± 1.0 mm, p < 0.005) and mean STIFF was 8.7 ± 6.3 (Hispanics = 8.5 ± 5.7, blacks = 9.2 ± 6.2 and whites = 8.9 ± 6.9, p < 0.02). In a model that adjusted for sociodemographics and vascular risk factors including hypertension, diabetes, dislipidemia, renal function, physical acticity and a history of known coronary artery diseases; age was positively associated with greater DDIAM in Hispanics (p < 0.0001) but not among blacks or whites. Older age was associated with greater stiffness among Hispanics (p < 0.0001) and blacks (p < 0.003), but not among whites. CONCLUSIONS: We found race/ethnic differences in the association between age and arterial stiffness and diameter, including age-dependent arterial dilation observed in Hispanics that was not observed among blacks or whites.

Predictive value of BI-RADS classification for breast imaging in women under age 50.

In this study, we assessed the positive-predictive value (PPV) of mammography and/or ultrasonography in women age 50 based on recommendations for biopsies and final pathology results. We performed a retrospective analysis of all mammography and ultrasonography reports issued from 9/2005 to 1/2007 resulting in biopsy among women aged 18-50 at a large county hospital. Data included demographics, imaging modality, breast density, type of finding, BI-RADS, and final pathology. Results were compared to women aged >50 at the same institution. Four hundred and seventy-five biopsies in 395 patients were reviewed. The PPV of BI-RADS 3 (n = 11) was 9.1%, BI-RADS 4 (n = 440) 5.9%, and BI-RADS 5 (n = 24) 66.7%. Forty three (9%) were malignant, of which 31 (6.5%) were invasive carcinomas and 12 (2.5%) were noninvasive. None of the biopsies on patients aged <30 were malignant. Recommended biopsies based on mammography alone were malignant in 20.2% (20/99) compared to 3.4% (7/205) for ultrasonography alone, and 8.9% (15/168) for both mammography and ultrasonography. Suspicious calcifications were malignant in 25% compared to 6.8% for masses/nodules and 3.6% for cysts. Lesions larger than 2 cm are more likely to be malignant (11.8%) than lesions between 1 and 2 cm (3.6%) or below 1 cm (4.3%). The PPV of the current screening modalities diminishes markedly in women under the age of 50 and even more below the age of 40. Calcifications and masses larger than 2 cm should be biopsied, but the current BI-RADS criteria may benefit from revision for other findings in young patients.