We examined the regulation of NF-kappaB in prostate cancer by estrogen receptor beta (ERbeta) based on the inverse correlation between p65 and ERbeta expression that exists in prostate carcinomas and reports that ERbeta can inhibit NF-kappaB activation, although the mechanism is not known. We demonstrate that ERbeta functions as a gate-keeper for NF-kappaB p65 signaling by repressing its expression and nuclear translocation. ERbeta regulation of NF-kappaB signaling is mediated by HIF-1. Loss of ERbeta or hypoxia stabilizes HIF-1alpha, which we found to be a direct driver of IKKbeta transcription through a hypoxia response element present in the promoter of the IKKbeta gene. The increase of IKKbeta expression in ERbeta-ablated cells correlates with an increase in phospho-IkappaBalpha and concomitant p65 nuclear translocation. An inverse correlation between the expression of ERbeta and IKKbeta/p65 was also observed in the prostates of ERbeta knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ERbeta prevents NF-kappaB activation and raise the exciting possibility that loss of ERbeta expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer.
Imaging single molecules in live cells in 4+ D (space, time and colors) is crucial for studying various biological processes, especially for observing the behavior of RNA molecules within the nuclear landscape . RNA molecules are known to serve a multitude of tasks such as being templates for protein translation or to act as enzymes for regulating countless reactions in the nucleus . Studying RNA kinetics in living cells can provide new information on RNA function or even human diseases, for instance caused by viruses such as the human immunodeficiency virus (HIV) . A challenge to imaging nuclear RNA function is that the nucleus as a whole undergoes major reformation during the cell cycle  but the time required to step through the sample limits the capability to image large numbers of rapidly moving particles in a 3D space.
Regulation of Nucleosome Architecture and Factor Binding Revealed by Nuclease Footprinting of the ESC Genome
Functional interactions between gene regulatory factors and chromatin architecture have been difficult to directly assess. Here, we use micrococcal nuclease (MNase) footprinting to probe the functions of two chromatin-remodeling complexes. By simultaneously quantifying alterations in small MNase footprints over the binding sites of 30 regulatory factors in mouse embryonic stem cells (ESCs), we provide evidence that esBAF and Mbd3/NuRD modulate the binding of several regulatory proteins. In addition, we find that nucleosome occupancy is reduced at specific loci in favor of subnucleosomes upon depletion of esBAF, including sites of histone H2A.Z localization. Consistent with these data, we demonstrate that esBAF is required for normal H2A.Z localization in ESCs, suggesting esBAF either stabilizes H2A.Z-containing nucleosomes or promotes subnucleosome to nucleosome conversion by facilitating H2A.Z deposition. Therefore, integrative examination of MNase footprints reveals insights into nucleosome dynamics and functional interactions between chromatin structure and key gene-regulatory factors.
Parental smoke exposure and the development of nicotine craving in adolescent novice smokers: the roles of DRD2, DRD4, and OPRM1 genotypes
BACKGROUND: Among adolescent novice smokers, craving is often the first, and is the most reported, symptom of nicotine dependence. Until now, little has been known about the development of craving symptoms in novice smokers. The aim of this study was to identify specific genetic (i.e., DRD2 Taq1A, DRD4 48 bp VNTR, and OPRM1 A118G polymorphisms) and environmental mechanisms that underlie the emergence of both cue-induced and cognitive craving among adolescent novice smokers.
METHOD: A five-wave longitudinal, genetically-informed survey study was conducted with intervals of four months. The sample included 376 early adolescent smokers (12-13 years of age at baseline). Self-report questionnaires were completed regarding smoking behavior, observed parental smoking behavior, and both cue-induced and cognitive craving.
RESULTS: Data were analyzed with a latent growth curve approach. For both cue-induced and cognitive craving, significant interaction effects were found for DRD2 Taq1A with parental smoke exposure. A1-allele carriers did not seem to be influenced by the environment with regard to craving development. Adolescents who are homozygous for the A2-allele and who are more exposed to parental smoking experience the highest levels of both types of craving over time. No significant interaction effects were found between parental smoke exposure and DRD4 48 bp VNTR or OPRM1 A118G.
CONCLUSIONS: Previous studies identified DRD2 Taq1A A1-allele carriers as vulnerable to developing nicotine dependence. However, this study showed that parental smoking increased the chances of developing dependence more rapidly for early adolescents who are considered to be less sensitive to the rewarding effects of nicotine according to their DRD2 Taq1A genotype. It is thus especially important that these young people not be exposed to smoking in their social environment.
BACKGROUND: Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas.
METHODS: Patients with a pathologic diagnosis of meningioma from 2002-2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades.
RESULTS: Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi < 4, no CVA. 4. Postmenopausal, vi < 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas.
CONCLUSIONS: Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy.
Marginal structural models for the estimation of the risk of Diabetes Mellitus in the presence of elevated depressive symptoms and antidepressant medication use in the Women's Health Initiative observational and clinical trial cohorts
BACKGROUND: We evaluate the combined effect of the presence of elevated depressive symptoms and antidepressant medication use with respect to risk of type 2 diabetes among approximately 120,000 women enrolled in the Women's Health Initiative (WHI), and compare several different statistical models appropriate for causal inference in non-randomized settings.
METHODS: Data were analyzed for 52,326 women in the Women's Health Initiative Clinical Trials (CT) Cohort and 68,169 women in the Observational Study (OS) Cohort after exclusions. We included follow-up to 2005, resulting in a median duration of 7.6 years of follow up after enrollment. Results from three multivariable Cox models were compared to those from marginal structural models that included time varying measures of antidepressant medication use, presence of elevated depressive symptoms and BMI, while adjusting for potential confounders including age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.
RESULTS: Our results are consistent with previous studies examining the relationship of antidepressant medication use and risk of type 2 diabetes. All models showed a significant increase in diabetes risk for those taking antidepressants. The Cox Proportional Hazards models using baseline covariates showed the lowest increase in risk , with hazard ratios of 1.19 (95 % CI 1.06 - 1.35) and 1.14 (95 % CI 1.01 - 1.30) in the OS and CT, respectively. Hazard ratios from marginal structural models comparing antidepressant users to non-users were 1.35 (95 % CI 1.21 - 1.51) and 1.27 (95 % CI 1.13 - 1.43) in the WHI OS and CT, respectively - however, differences among estimates from traditional Cox models and marginal structural models were not statistically significant in both cohorts. One explanation suggests that time-dependent confounding was not a substantial factor in these data, however other explanations exist. Unadjusted Cox Proportional Hazards models showed that women with elevated depressive symptoms had a significant increase in diabetes risk that remained after adjustment for confounders. However, this association missed the threshold for statistical significance in propensity score adjusted and marginal structural models.
CONCLUSIONS: Results from the multiple approaches provide further evidence of an increase in risk of type 2 diabetes for those on antidepressants.
Host restriction factor TRIM5 inhibits retroviral transduction in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. But the restriction mechanism may not be that simple since TRIM5 E3 ubiquitin ligase activity, the proteasome, autophagy, and TAK1-dependent AP-1 signaling have been suggested to contribute to restriction. Here we show that, among a panel of seven primate and Carnivora TRIM5 orthologues, each of which has potential for potent retroviral restriction activity, all activated AP-1 signaling. In contrast, TRIM family paralogues most closely related to TRIM5 did not. While each primate species has a single TRIM5 gene, mice have at least seven TRIM5 homologues that cluster into two groups, Trim12a, b, and c, and Trim30a, b, c, and d. The three Trim12 proteins activated innate immune signaling, while the Trim30 proteins did not, though none of the murine Trim5 homologues restricted any of a panel of cloned retroviruses. To determine if any mouse TRIM5 homologues had potential for restriction activity each was fused to the HIV-1 CA binding protein cyclophilin A (CypA). The three Trim12-CypA fusions all activated AP-1 and restricted HIV-1 transduction, whereas the Trim30-CypA fusions did neither. AP-1 activation and HIV-1 restriction by the Trim12-CypA fusions was inhibited by disruption of TAK1. Overall then, these experiments demonstrate that there is a strong correlation between TRIM5 retroviral restriction activity and the ability to activate TAK1-dependent innate immune signaling.
IMPORTANCE: The importance of retroviruses for the evolution of susceptible host organisms cannot be overestimated. 8% of the human genome is retrovirus sequence, fixed in the germline during past infection. Understanding how metazoa protect their genomes from mutagenic retrovirus infection is therefore of fundamental importance to biology. TRIM5 is a cellular protein that protects host genome integrity by disrupting the retroviral capsid as it transports viral nucleic acid to the host cell nucleus. Previous data suggest that innate immune signaling contributes to TRIM5-mediated restriction. Here we show that activation of innate immune signaling is conserved among primate and carnivore TRIM5 orthologues, and among 3 of the 7 mouse Trim5 homologues, and that such activity is required for TRIM5-mediated restriction activity.
Narratives to enhance smoking cessation interventions among African-American smokers, the ACCE project
BACKGROUND: Low-income, African-American smokers are less likely to have resources to aid in quitting smoking. Narrative communication may provide an enhancement to traditional smoking cessation interventions like NRT, medications, or behavioral treatments for this audience. After extensive pilot testing of stories and personal experiences with smoking cessation from African-Americans from a low-income community, we conducted a randomized control trial using stories to augment routine inpatient treatment among African-Americans at an urban Southern hospital (N = 300).
RESULTS: Differences in smoking cessation outcomes between the intervention (stories DVD + routine clinical treatment) and control (routine clinical treatment) arms were compared using self-report and carbon monoxide measurement at 6-months. Compared to control, individuals who viewed the intervention stories DVD reported greater intentions to quit. Although continuous quitting marginally favored the intervention, our main result did not reach statistical significance (p = 0.16).
CONCLUSION: Narrative communication via storytelling to promote smoking cessation among African-Americans in the South is one method to communicate smoking cessation. Results suggest this may not be sufficient as a stand-alone augmentation of routine clinical treatment for continuous smoking cessation. Smoking cessation efforts need to continually assess different means of communicating to smokers about quitting.
CLINICAL TRIALS REGISTRATION: The ClinicalTrials.gov Identifier is NCT00101491. This trial was registered January 10, 2005.
One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs. Using this assay, we screened the LOPAC (Sigma-Aldrich) Library of Pharmacologically Active Compounds and discovered that Guanabenz acetate (Wytensin), an FDA-approved drug formerly used as an antihypertensive agent, is capable of markedly increasing the cellular internalization and target mRNA silencing of hydrophobically modified siRNAs (hsiRNAs), yielding a approximately 100-fold decrease in hsiRNA IC50 (from 132 nM to 2.4 nM). This is one of the first descriptions of a high-throughput small-molecule screen to identify novel chemistries that specifically enhance siRNA intracellular efficacy, and can be applied toward expansion of the chemical diversity of ONTs.
The rhythm of life on earth is shaped by seasonal changes in the environment. Plants and animals show profound annual cycles in physiology, health, morphology, behaviour and demography in response to environmental cues. Seasonal biology impacts ecosystems and agriculture, with consequences for humans and biodiversity. Human populations show robust annual rhythms in health and well-being, and the birth month can have lasting effects that persist throughout life. This review emphasizes the need for a better understanding of seasonal biology against the backdrop of its rapidly progressing disruption through climate change, human lifestyles and other anthropogenic impact. Climate change is modifying annual rhythms to which numerous organisms have adapted, with potential consequences for industries relating to health, ecosystems and food security. Disconcertingly, human lifestyles under artificial conditions of eternal summer provide the most extreme example for disconnect from natural seasons, making humans vulnerable to increased morbidity and mortality. In this review, we introduce scenarios of seasonal disruption, highlight key aspects of seasonal biology and summarize from biomedical, anthropological, veterinary, agricultural and environmental perspectives the recent evidence for seasonal desynchronization between environmental factors and internal rhythms. Because annual rhythms are pervasive across biological systems, they provide a common framework for trans-disciplinary research.
Background. The use of electronic hand hygiene reminder systems has been proposed as an approach to improve hand hygiene compliance among healthcare workers, although information on efficacy is limited. We prospectively assessed whether hand hygiene activities among healthcare workers could be increased using an electronic hand hygiene monitoring and reminder system.
Methods. A prospective controlled clinical trial was conducted in 2 medical intensive care units (ICUs) at an academic medical center with comparable patient populations, healthcare staff, and physical layout. Hand hygiene activity was monitored concurrently in both ICUs, and the reminder system was installed in the test ICU. The reminder system was tested during 3 administered phases including: room entry/exit chimes, display of real-time hand hygiene activity, and a combination of the 2.
Results. In the test ICU, the mean number of hand hygiene events increased from 1538 per day at baseline to 1911 per day (24% increase) with the use of a combination of room entry/exit chimes, real-time displays of hand hygiene activity, and manager reports (P < .001); in addition, the ratio of hand hygiene to room entry/exit events also increased from 26.1% to 36.6% (40% increase, P < .001). The performance returned to baseline (1473 hand hygiene events per day) during the follow-up phase. There was no significant change in hand hygiene activity in the control ICU during the course of the trial.
Conclusions. In an ICU setting, an electronic hand hygiene reminder system that provided real-time feedback on overall unit-wide hand hygiene performance significantly increased hand hygiene activity.
The current issue of the Journal of Global Radiology (JGR) covers a range of topics that fall within the sub-specialty of global radiology. Original articles, country reports, and a conference report have attempted to paint an informative picture of the practice, research, and educational opportunities for voluntary contributions and profitable business. These papers contribute, in one way or another, to the vision of the Journal of Global Radiology: Ensuring medical imaging access for all.
Liberia is a tropical country located south of the Sahara Desert in coastal West Africa. It lies at 6 °30’ North Latitude and 9° 30’ West Longitude and is bordered by Guinea, Cote d’Ivoire, Sierra Leone and the Atlantic Ocean. Liberia has three distinct topographical areas: 1) coastal plain, creeks, lagoons and mangrove swamps; 2) rolling, forested hills with elevations up to 500 feet that cover most of the country; and 3) low mountains and plateaus in the Northern highlands with elevations reaching 4,748 feet (Nimba Mountains). Liberia is home to approximately four million people and is roughly the size of the US state of Tennessee. Named after former US President James Monroe, Liberia’s capital Monrovia is a coastal city with a population of one million (1).
There are two major seasons in Liberia: dry and rainy. The dry season occurs between December and March, and is is characterized by warm days and cool nights, with risk of sand storms from the Sahara Desert (2). The rainy season occurs between mid-April and mid-November. The average annual rainfall is 200 inches on the coast and decreases to 80 inches in areas farthest inland, and the average temperature is 27 degrees Celsius (81 degrees Fahrenheit) (1). Liberia is a low-income country that relies heavily on foreign aid (3). Liberia is the seventh poorest nation in the world, ranking 31st among 46 sub-Sarahan African countries in national income. In 2013, Liberia’s per capita GDP was $900 US (3). Liberia’s economy depends heavily on natural resources, with mining and agriculture being the dominant industries. Iron exportation has grown and in 2013 overcame rubber as Liberia’s top export. According to the 2013 Central Bank of Liberia (CBL) Annual Report, iron ore and rubber represent 82% of Liberia’s total exports (4). Civil war destroyed much of Liberia’s economy, including critical infrastructure in and around Monrovia. Although conditions are favorable for agriculture, Liberia does not produce nearly enough food to meet the demands of its population. The country imports large quantities of food, with rice alone accounting for 10% of its overall imports (5).
Digital imaging is now firmly ensconced in the developed world. Its widespread adoption has enabled instant access to images, remote viewing, remote consultation, and the end of lost or misplaced film. Unfortunately, the current paradigm of Picture Archiving and Communication System (PACS), with advanced technology inseparable from high complexity, high purchase costs, and high maintenance costs, is not suited for the low-income developing world. Like the simple, easy to repair, 1950’s American cars still running on the streets of Havana, the developing world requires a PACS (DW-PACS) that can perform basic functions and survive in a limited-resource environment. The purpose of this article is to more fully describe this concept and to present a blueprint for PACS tailored to the needs and resources of the developing world. This framework should assist both users looking for a vendor-supplied or open-source solutions and developers seeking to address the needs of this emerging market.
Maternal and child health conditions, many of which can be detected by ultrasound, represent the highest burden of disease in Uganda. Imaging the World (ITW) is a not-for-profit organization which integrates high quality, affordable ultrasound services into rural health facilities. Of all the challenges faced with implementation of ITW programs in Uganda, lack of sensitization to ultrasound represented the greatest barrier. The Village Health Team (VHT) is an existing public health “train the trainer” model sponsored by the Uganda Ministry of Health which provides public health training to community volunteers. Trained VHT members were recruited to help with ultrasound community outreach and education. These VHT members were successful in achieving dramatic community acceptance and increased utilization of ultrasound services in rural communities. This has led to significant contributions in improving population health in low-resource settings.
A Systematic Review of Oral Health Interventions to Reduce Disparities in Adults with Intellectual Disability: Results of a Novel Approach
Research consistently shows that people with I/DD experience poorer oral hygiene, higher prevalence and severity of periodontal disease, and higher incidence of untreated caries when compared to the general population. In a systematic review funded by the Centers for Disease Control (NCBDD), researchers rigorously evaluated evidence for a wide range of interventions that offer the potential to reduce those disparities. More than 4,000 titles/abstracts were identified from a literature search that included peer reviewed as well as gray literature. After criteria were applied to identify the I/DD population and intervention-studies only, the number of full text reviews was reduced to 125, and intervention categories were identified as follows: 1) sedation, appropriate use in the population; 2) education and behavioral interventions for treatment and prevention directed at individuals, caregivers and providers; 3) prevention strategies such as fluoride and chlorhexidine; and 4) access issues related to financing and funding. Researchers completed data extraction using a structured on-line tool, the Systematic Review Data Repository. The broad range of topic areas required researchers to include clinical experts in the structured review providing valuable input into the interpretation of findings, providing a measure of external validity for each reported study. A research methodologist accomplished a separate review of the studies’ internal validity, including design and statistical analyses. Results of the complimentary examinations of validity were included in the overall measure of the quality of each study and used in assigning a level of evidence to each study that was included for each topic.
Interventions to Improve Access and Health Behaviors in Individuals with Intellectual and Developmental Disability: A National Resource for Oral Health
The presentation will describe the process by which the systematic review, designed to uncover interventions to reduce oral health disparities in individuals with intellectual and developmental disability, was conducted, along with the search strategy, interventions and outcomes measured. The presentation will convey the evidence base and promising practices for access, behavior, and prevention to generate discussion among researchers, clinicians and policy makers, about future study topics.
Pediatric sudden unexplained deaths are rare and tragic events that should be evaluated with all the tools available to the medical community. The current state of genetic testing is an excellent resource that improves our ability to diagnose cardiovascular disorders that can lead to sudden cardiac arrest. Post-mortem genetic testing is not typically a covered benefit of health insurance and may not be offered to families in the setting of a negative autopsy. This unusual case includes two separate cardiovascular disorders that highlight the use of genetic testing and its role in diagnosis, screening, and risk stratification. The insurance company's decision to cover post-mortem testing demonstrated both compassion as well as an understanding of the long-term cost effectiveness.
Amyotrophic lateral sclerosis: analysis of ALS cases in a predominantly admixed population of Ecuador
Recent studies suggest amyotrophic lateral sclerosis (ALS) prevalence, incidence, and age of onset are heterogeneous across populations. These include studies from South America (SA) where lower prevalence, earlier onset, and reduced survival time of ALS are reported. However, the scarcity of epidemiological and clinical data confounds effective comparison. To investigate ALS incidence in the predominantly admixed population of Ecuador, we analyzed patient data. We analyzed case data from two major hospitals. To confirm diagnosis, we evaluated clinical and EMG examinations in a cohort of patients. For 2000-2012, we found 116 patients with ALS diagnosis in the two hospitals. Crude incidence was 0.2-0.6 per 100,000. Median age of onset was 54.3 (+ 15.06 SD). Clinical re-evaluation found misdiagnosis in three cases in the cohort. In conclusion, ALS incidence in the Ecuadorian hospital population is in accord with rates reported in recent studies for other admixed populations, and lower than that in the United States and Europe. Our study found that appropriate EMG administration and interpretation for the purposes of supporting a diagnosis of ALS with current consensus guidelines prevent adequate use of this test as an essential tool in the evaluation and diagnosis of ALS. Training for required standardization in Ecuador is recommended.
The systolic blood pressure difference between arms and cardiovascular disease in the Framingham Heart Study
BACKGROUND: An increased interarm systolic blood pressure difference is an easily determined physical examination finding. The relationship between interarm systolic blood pressure difference and risk of future cardiovascular disease is uncertain. We described the prevalence and risk factor correlates of interarm systolic blood pressure difference in the Framingham Heart Study (FHS) original and offspring cohorts and examined the association between interarm systolic blood pressure difference and incident cardiovascular disease and all-cause mortality.
METHODS: An increased interarm systolic blood pressure difference was defined as >/= 10 mm Hg using the average of initial and repeat blood pressure measurements obtained in both arms. Participants were followed through 2010 for incident cardiovascular disease events. Multivariable Cox proportional hazards regression analyses were performed to investigate the effect of interarm systolic blood pressure difference on incident cardiovascular disease.
RESULTS: We examined 3390 (56.3% female) participants aged 40 years and older, free of cardiovascular disease at baseline, mean age of 61.1 years, who attended a FHS examination between 1991 and 1994 (original cohort) and from 1995 to 1998 (offspring cohort). The mean absolute interarm systolic blood pressure difference was 4.6 mm Hg (range 0-78). Increased interarm systolic blood pressure difference was present in 317 (9.4%) participants. The median follow-up time was 13.3 years, during which time 598 participants (17.6%) experienced a first cardiovascular event, including 83 (26.2%) participants with interarm systolic blood pressure difference > /= 10 mm Hg. Compared with those with normal interarm systolic blood pressure difference, participants with an elevated interarm systolic blood pressure difference were older (63.0 years vs 60.9 years), had a greater prevalence of diabetes mellitus (13.3% vs 7.5%,), higher systolic blood pressure (136.3 mm Hg vs 129.3 mm Hg), and a higher total cholesterol level (212.1 mg/dL vs 206.5 mg/dL). Interarm systolic blood pressure difference was associated with a significantly increased hazard of incident cardiovascular events in the multivariable adjusted model (hazard ratio 1.38; 95% CI, 1.09-1.75). For each 1-SD-unit increase in absolute interarm systolic blood pressure difference, the hazard ratio for incident cardiovascular events was 1.07 (95% CI, 1.00-1.14) in the fully adjusted model. There was no such association with mortality (hazard ratio 1.02; 95% CI 0.76-1.38).
CONCLUSIONS: In this community-based cohort, an interarm systolic blood pressure difference is common and associated with a significant increased risk for future cardiovascular events, even when the absolute difference in arm systolic blood pressure is modest. These findings support research to expand clinical use of this simple measurement.