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Study objective This study identified the most important quality indicators for online educational resources such as blogs and podcasts. Methods A modified Delphi process that included 2 iterative surveys was used to build expert consensus on a previously defined list of 151 quality indicators divided into 3 themes: credibility, content, and design. Aggregate social media indicators were used to identify an expert population of editors from a defined list of emergency medicine and critical care blogs and podcasts. Survey 1 consisted of the quality indicators and a 7-point Likert scale. The mean score for each quality indicator was included in survey 2, which asked participants whether to "include" or "not include" each quality indicator. The cut point for consensus was defined at greater than 70% "include." Results Eighty-three percent (20/24) of bloggers and 90.9% (20/22) of podcasters completed survey 1 and 90% (18/20) of bloggers and podcasters completed survey 2. The 70% inclusion criteria were met by 44 and 80 quality indicators for bloggers and podcasters, respectively. Post hoc, a 90% cutoff was used to identify a list of 14 and 26 quality indicators for bloggers and podcasters, respectively. Conclusion The relative importance of quality indicators for emergency medicine blogs and podcasts was determined. This will be helpful for resource producers trying to improve their blogs or podcasts and for learners, educators, and academic leaders assessing their quality. These results will inform broader validation studies and attempts to develop user-friendly assessment instruments for these resources.

Copyright © 2015 by the article author(s). Introduction: The number of educational resources created for emergency medicine and critical care (EMCC) that incorporate social media has increased dramatically. With no way to assess their impact or quality, it is challenging for educators to receive scholarly credit and for learners to identify respected resources. The Social Media index (SMi) was developed to help address this. Methods: We used data from social media platforms (Google PageRanks, Alexa Ranks, Facebook Likes, Twitter Followers, and Google+ Followers) for EMCC blogs and podcasts to derive three normalized (ordinal, logarithmic, and raw) formulas. The most statistically robust formula was assessed for 1) temporal stability using repeated measures and website age, and 2) correlation with impact by applying it to EMCC journals and measuring the correlation with known journal impact metrics. Results: The logarithmic version of the SMi containing four metrics was the most statistically robust. It correlated significantly with website age (Spearman r=0.372; p

The purpose of this study was to assess the efficacy, specificity, and predictive value of a newly discovered biomarker, Zinc finger-like1 protein (referred to as neuroendocrine marker, NEM) for the detection of prostate cancer (PCa). We retrospectively analyzed banked plasma samples from 508 men, with a median age of 67 years (range 48-97), to compare the performance of NEM and PSA in predicting subsequent histologic PCa. The cohort consisted of four groups of patients visiting a urology clinic: (1) patients not diagnosed with either benign prostatic disease or prostate cancer (PCa) were defined as normal; (2) patients diagnosed with benign hyperplasia (BPH) but not PCa; (3) patients with confirmed PCa; and (4) patients with cancer other than PCa. The normal men displayed a mean NEM plasma level of 0.948 ± 0.051 ng/mL, which increased to 1.813 ± 0.315 ng/mL in men with BPH, 86.49 ± 15.51 ng/mL in men with PCa, and 10.47 ± 1.029 ng/mL in men with other Ca. The corresponding concentrations of prostate-specific antigen (PSA) in these subjects were 1.787 ± 0.135, 5.405 ± 0.699, 35.77 ± 11.48 ng/mL, and 8.036 ± 0.518, respectively. Receiver operating characteristic (ROC) curve analysis was performed to compare NEM and PSA performance, and the Jouden Index for each biomarker was calculated to determine cut-off points for each biomarker. The area under the ROC curve to predict PCa was 0.99 for NEM and 0.81 for PSA ( p < 0.0001). The cut-off for NEM was at 1.9 ng/mL, with sensitivity of 98% and specificity of 97%. The corresponding PSA values were 4.4 ng/mL, with sensitivity of 76% and specificity of 95%. The predictive value of each biomarker in a patient was matched with his pathologic data to determine the accuracy of each biomarker. NEM was more accurate than PSA in differentiating cancer from benign conditions, such as BPH or prostatitis. In conclusion, NEM was a better predictor of PCa than PSA in patients visiting urology clinics. NEM tests, either alone or in conjunction with other biomarkers, provide a reliable, non-invasive, and inexpensive test to remarkably reduce false positives and thereby reduce the number of diagnostic biopsies and associated painful procedures and the loss of quality of life.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Community surveillance surveys offer an opportunity to obtain important and timely public health information that may help local municipalities guide their response to public health threats. The objective of this paper is to present approaches, challenges, and solutions from SARS-CoV-2 surveillance surveys conducted in different settings by 2 research teams. For rapid assessment of a representative sample, a 2-stage cluster sampling design was developed by an interdisciplinary team of researchers at Oregon State University between April 2020 and June 2021 across 6 Oregon communities. In 2022, these methods were adapted for New York communities by a team of veterinary, medical, and public health practitioners. Partnerships were established with local medical facilities, health departments, COVID-19 testing sites, and health and public safety staff. Field staff were trained using online modules, field manuals describing survey methods and safety protocols, and in-person meetings with hands-on practice. Private and secure data integration systems and public awareness campaigns were implemented. Pilot surveys and field previews revealed challenges in survey processes that could be addressed before surveys proceeded. Strong leadership, robust trainings, and university-community partnerships proved critical to successful outcomes. Cultivating mutual trust and cooperation among stakeholders is essential to prepare for the next pandemic., (© 2024 The Authors.)

Photoacoustic (PA) imaging can be used to monitor high-intensity focused ultrasound (HIFU) therapies because ablation changes the optical absorption spectrum of the tissue, and this change can be detected with PA imaging. Multi-wavelength photoacoustic (MWPA) imaging makes this change easier to detect by repeating PA imaging at multiple optical wavelengths and sampling the optical absorption spectrum more thoroughly. Real-time pixel-wise classification in MWPA imaging can assist clinicians in monitoring HIFU lesion formation and will be a crucial milestone towards full HIFU therapy automation based on artificial intelligence. In this paper, we present a deep-learning-based approach to segment HIFU lesions in MWPA images. Ex vivo bovine tissue is ablated with HIFU and imaged via MWPA imaging. The acquired MWPA images are then used to train and test a convolutional neural network (CNN) for lesion segmentation. Traditional machine learning algorithms are also trained and tested to compare with the CNN, and the results show that the performance of the CNN significantly exceeds traditional machine learning algorithms. Feature selection is conducted to reduce the number of wavelengths to facilitate real-time implementation while retaining good segmentation performance. This study demonstrates the feasibility and high performance of the deep-learning-based lesion segmentation method in MWPA imaging to monitor HIFU lesion formation and the potential to implement this method in real time.

The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10 -15 ), pleiotrophin (1.23 × 10 -9 ), and TIMP-1 (5.97 × 10 -8 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10 -7 ), CDON (2.38 × 10 -7 ), and SMOC1 (7.47 × 10 -7 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL)., Methods: Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality., Results: In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5-3.4, p=0.0001, and OR 2.6, 95% CI 1.4-4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (-767 bp, 95% CI 76-1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1-1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4-1.7, p=0.6, and HR 1.2, 95% CI 0.6-2.2, p=0.5, respectively)., Conclusion: ILA are associated with decreased MTL., Competing Interests: Conflict of interest: R.K. Putman reports grants from NIH/NHLBI, during the conduct of the study. Conflict of interest: G.T. Axelsson has nothing to disclose. Conflict of interest: S.Y. Ash reports grants from NHLBI (K08HL145118) and Pulmonary Fibrosis Foundation, during the conduct of the study; and is the owner of Quantitative Imaging Solutions, outside the submitted work. Conflict of interest: J.L. Sanders has commenced employment at Vertex Pharmaceuticals Inc. since the study was completed. Conflict of interest: A.A. Menon has nothing to disclose. Conflict of interest: T. Araki has nothing to disclose. Conflict of interest: M. Nishino reports personal fees for consultancy from Daiichi Sankyo and AstraZeneca, and grants from the Merck investigator studies programme, Canon Medical Systems, AstraZeneca and Daiichi Sankyo, outside the submitted work. Conflict of interest: M. Yanagawa reports travel expenses from Canon Medical Systems, outside the submitted work. Conflict of interest: E.F. Gudmundsson has nothing to disclose. Conflict of interest: D. Qiao has nothing to disclose. Conflict of interest: R. San José Estépar reports grants from Boehringer Ingelheim, Lung Biotechnology and Insmed, payment for lectures and travel expenses from Chiesi, and stock and/or stock options from Quantitative Imaging Solutions, outside the submitted work. Conflict of interest: J. Dupuis reports grants from NIH, during the conduct of the study. Conflict of interest: G.T. O'Connor reports grants from NIH, during the conduct of the study. Conflict of interest: I.O. Rosas has a patent 62/849,644 pending. Conflict of interest: G.R. Washko reports grants from Boehringer Ingelheim, consultancy for Pulmonx, Janssen Pharmaceuticals, Novartis and Vertex, and is founder and co-owner of Quantitative Imaging Solutions, outside the submitted work. Conflict of interest: S. El-Chemaly has nothing to disclose. Conflict of interest: B.A. Raby reports grants from NIH, outside the submitted work. Conflict of interest: V. Gudnason has nothing to disclose. Conflict of interest: D.L. DeMeo reports grants from Novartis and Bayer, during the conduct of the study. Conflict of interest: E.K. Silverman reports grants from GlaxoSmithKline and Bayer, during the conduct of the study. Conflict of interest: H. Hatabu reports grants from Canon Medical Systems Inc. and Konica-Minolta Inc., and personal fees for consultancy from Mitsubishi Chemical Inc. and Canon Medical Systems Inc., outside the submitted work. Conflict of interest: I. DeVivo has nothing to disclose. Conflict of interest: M.H. Cho reports grants from GlaxoSmithKline and Bayer, and consultancy and/or speaker fees from Genentech, AstraZeneca and Illumina, outside the submitted work. Conflict of interest: G. Gudmundsson has nothing to disclose. Conflict of interest: G.M. Hunninghake reports personal fees from Gerson Lehrman Group and Boehringer Ingelheim, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

This article presents an imaging probe with a 256-element ultrawideband (UWB) 1-D capacitive micromachined ultrasonic transducer (CMUT) array designed for acoustic angiography (AA). This array was fabricated on a borosilicate glass wafer with a reduced bottom electrode and an additional central plate mass to achieve the broad bandwidth. A custom 256-channel handheld probe was designed and implemented with integrated low-noise amplifiers and supporting power circuitry. This probe was used to characterize the UWB CMUT, which has a functional 3-dB frequency band from 3.5 to 23.5 MHz. A mechanical index (MI) of 0.33 was achieved at 3.5 MHz at a depth of 11 mm. These promising measurements are then combined to demonstrate AA. The use of alternate amplitude modulation (aAM) combined with a frequency analysis of the measured transmit signal demonstrates the suitability of the UWB CMUT for AA. This is achieved by measuring only a low level of unwanted high-frequency harmonics in both the transmit signal and the reconstructed image in the areas other than the contrast bubbles.

Genomic surveillance has emerged as a critical monitoring tool during the SARS-CoV-2 pandemic. Wastewater surveillance has the potential to identify and track SARS-CoV-2 variants in the community, including emerging variants. We demonstrate the novel use of multilocus sequence typing to identify SARS-CoV-2 variants in wastewater. Using this technique, we observed the emergence of the B.1.351 (Beta) variant in Linn County, Oregon, USA, in wastewater 12 days before this variant was identified in individual clinical specimens. During the study period, we identified 42 B.1.351 clinical specimens that clustered into 3 phylogenetic clades. Eighteen of the 19 clinical specimens and all wastewater B.1.351 specimens from Linn County clustered into clade 1. Our results provide further evidence of the reliability of wastewater surveillance to report localized SARS-CoV-2 sequence information.

Background: Positive correlations have been reported between wastewater SARS-CoV-2 concentrations and a community's burden of infection, disease or both. However, previous studies mostly compared wastewater to clinical case counts or nonrepresentative convenience samples, limiting their quantitative potential., Objectives: This study examined whether wastewater SARS-CoV-2 concentrations could provide better estimations for SARS-CoV-2 community prevalence than reported cases of COVID-19. In addition, this study tested whether wastewater-based epidemiology methods could identify neighborhood-level COVID-19 hotspots and SARS-CoV-2 variants., Methods: Community SARS-CoV-2 prevalence was estimated from eight randomized door-to-door nasal swab sampling events in six Oregon communities of disparate size, location, and demography over a 10-month period. Simultaneously, wastewater SARS-CoV-2 concentrations were quantified at each community's wastewater treatment plant and from 22 Newport, Oregon, neighborhoods. SARS-CoV-2 RNA was sequenced from all positive wastewater and nasal swab samples. Clinically reported case counts were obtained from the Oregon Health Authority., Results: Estimated community SARS-CoV-2 prevalence ranged from 8 to 1,687/10,000 persons. Community wastewater SARS-CoV-2 concentrations ranged from 2.9 to 5.1     log 10 gene copies per liter. Wastewater SARS-CoV-2 concentrations were more highly correlated (Pearson's r = 0.96 ; R 2 = 0.91 ) with community prevalence than were clinically reported cases of COVID-19 (Pearson's r = 0.85 ; R 2 = 0.73 ). Monte Carlo simulations indicated that wastewater SARS-CoV-2 concentrations were significantly better than clinically reported cases at estimating prevalence ( p < 0.05 ). In addition, wastewater analyses determined neighborhood-level COVID-19 hot spots and identified SARS-CoV-2 variants (B.1 and B.1.399) at the neighborhood and city scales., Discussion: The greater reliability of wastewater SARS-CoV-2 concentrations over clinically reported case counts was likely due to systematic biases that affect reported case counts, including variations in access to testing and underreporting of asymptomatic cases. With these advantages, combined with scalability and low costs, wastewater-based epidemiology can be a key component in public health surveillance of COVID-19 and other communicable infections. https://doi.org/10.1289/EHP10289.

A novel Enterocytozoon infection was identified in the intestines of sexually mature Chinook salmon. While microsporidian parasites are common across a diverse range of animal hosts, this novel species is remarkable because it demonstrates biological, pathological, and genetic similarity with Enterocytozoon bieneusi, the most common causative agent of microsporidiosis in AIDS patients. There are similarities in the immune and endocrine processes of sexually mature Pacific salmon and immunocompromised humans, suggesting possible common mechanisms of susceptibility in these two highly divergent host species. The discovery of Enterocytozoon schreckii n. sp. contributes to clarifying the phylogenetic relationships within family Enterocytozoonidae. The phylogenetic and morphological features of this species support the redescription of Enterocytozoon to include Enterospora as a junior synonym. Furthermore, the discovery of this novel parasite may have important implications for conservation, as it could be a sentinel of immune suppression, disease, and prespawning mortality in threatened populations of salmonids. IMPORTANCE In this work, we describe a new microsporidian species that infects the enterocytes of Chinook salmon. This novel pathogen is closely related to Enterocytozoon bieneusi, an opportunistic pathogen commonly found in AIDS patients and other severely immunocompromised humans. The discovery of this novel pathogen is of interest because it has only been found in sexually mature Chinook salmon, which have compromised immune systems due to the stresses of migration and maturation and which share similar pathological features with immunocompromised and senescent humans. The discovery of this novel pathogen could lead to new insights regarding how microsporidiosis relates to immunosuppression across animal hosts.

Background: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve., Methods: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography., Results: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; P =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; P =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] P =0.086) and 1.58 ([95% CI, 1.11-2.27] P =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; P <0.0001)., Conclusions: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.

This article presents a row-column (RC) capacitive micromachined ultrasonic transducer (CMUT) array fabricated using anodic bonding on a borosilicate glass substrate. This is shown to reduce the bottom electrode-to-substrate capacitive coupling. This subsequently improves the relative response of the elements when top or bottom electrodes are used as the "signal" (active) electrode. This results in a more uniform performance for the two cases. Measured capacitance and resonant frequency, pulse-echo signal amplitude, and frequency response are presented to support this. Biasing configurations with varying ac and dc arrangements are applied and subsequently explored. Setting the net dc bias voltage across an off element to zero is found to be most effective to minimize spurious transmission. To achieve this, a custom switching circuit was designed and implemented. This circuit was also used to obtain orthogonal B-mode cross-sectional images of a rotationally asymmetric target.

This study demonstrates, in detail, the potential of using capacitive micromachined ultrasonic transducers (CMUTs) for acoustic angiography of the microvasculature. It is known that when ultrasound contrast agents (microbubbles) are excited with moderate acoustic pressure around their resonance (2-4 MHz), they produce higher order harmonics (greater than third harmonic) due to their nonlinear behavior. To date, the fundamental challenge has been the availability of a transducer that can generate the transmit signals to excite the microbubbles at low frequencies and, in the same cycle, confocally detect harmonics in the higher frequencies. We present a novel device structure and dual-mode operation of a CMUT that operates with a center frequency of 4.3 MHz and 150% bandwidth in the conventional mode for transmitting and a center frequency of 9.8 MHz and a 125.5% bandwidth in collapse mode for receiving. Output pressure of 1.7 MPa pp is achieved on the surface of a single unfocused transducer. The mechanical index at the transducer surface is 0.56. FEM simulations are performed first to show the functionality of the proposed device, and then, the device fabrication is described in detail. Finally, we experimentally demonstrate the ability to detect the microbubble signals with good contrast, and the background reflection is adequately suppressed, indicating the feasibility of the presented approach for acoustic angiography.

Sudden cardiac death (SCD), or sudden loss of life-sustaining systemic and cerebral perfusion, is most often due to left ventricular (LV) dysfunction secondary to ischemic or structural cardiac disease or channelopathies. Degeneration of sinus rhythm into ventricular tachycardia and ultimately ventricular fibrillation is the final common pathway for most heart failure patients. Right ventricular (RV) dysfunction is recognized as an independent contributor to worsening heart failure. There is emerging evidence that RV dysfunction may also be an independent predictor of SCD. This review examines the role of RV dysfunction on modifying long term risk of SCD, and explores possible mechanisms that may underlie SCD. The RV has unique anatomy and physiology compared to the LV. Subsequently, we begin with a review of cardiac embryology, focusing on the chambers, valves, coronary arteries, and cardiac conduction system to understand the origins of RV dysfunction. Static and dynamic physiology of the RV is contrasted with that of the LV. Particular emphasis is placed on ventriculo-arterial coupling, mechanical cardiac constraint, and ventricular interdependence. The epidemiology of SCD is briefly reviewed to highlight how causes of SCD are age-specific. In turn, the age-specific causes of RV dysfunction are presented, including those which predominate in childhood and adolescence [arrhythmogenic RV dysplasia (ARVD) and hypertrophic cardiomyopathy (HCM)] and older adulthood (cardiac ischemia, chronic congestive heart failure and post-capillary pulmonary hypertension, and pulmonary hypertension). There is a clear need for additional studies on the independent contribution of RV dysfunction to overall functional capacity, SCD-associated mortality, and non-SCD-associated mortality. Discovery would be aided by the development of prospective cohorts with excellent RV phenotyping, coupled with deeper biologic measurements linking mechanisms to clinically relevant outcomes., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-450). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. Dr. MK served as the unpaid Guest Editors of the series. Dr. SR reports personal fees and other from Abbott, grants and personal fees from Actelion, personal fees from Acceleron, grants and personal fees from AstraZeneca, grants and personal fees from Bayer, personal fees from BMS, personal fees from Janssen, personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from United Therapeutics, personal fees from Vifor, outside the submitted work. Dr. BAM reports other from Acetelion, during the conduct of the study. The author has no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: ND-PAE, as a condition needing further study, requires validation. Few studies have assessed the validity of ND-PAE with none using a prospective sample., Methods: Fifty-eight children underwent multidisciplinary FASD assessments and were evaluated for ND-PAE using a prospective, clinical approach. Construct and factorial validity of ND-PAE were assessed, and associations between domains and symptoms described. Post hoc analysis assessed external validity of factors., Results: ND-PAE demonstrated weak construct validity with variable convergence and divergence within and between symptoms. Factor analysis revealed one strong factor consisting of abilities associated with adaptive behavior and general cognitive ability. Relative contribution of symptoms and domains were variable., Conclusion: This study provides an evidence-based approach to assessing ND-PAE symptoms and is a starting point to elucidating its neurobehavioral pattern.

Mechanisms underlying pulmonary arterial hypertension (PAH) remain elusive. Pulmonary arterial hypertension and exercise PH share similar physiologic consequences; it is debated whether they share biologic mechanisms and if exercise PH represents an early phase of pulmonary arterial hypertension. We conducted an observational study to test if there is a graded metabolic disturbance along the severity of PH, which may indicate shared or disparate pathophysiology. Individuals referred to an academic medical dyspnea center with unexplained exertional intolerance underwent invasive cardiopulmonary exercise testing. We identified controls with no hemodynamic exercise limitation, individuals with exercise PH (mean pulmonary arterial pressure (mPAP) < 25 mmHg at rest but ≥ 30 mmHg during exercise without pulmonary venous hypertension) and pulmonary arterial hypertension (mPAP > 25 mmHg at rest without pulmonary venous hypertension) ( n  = 26 in each group). Unbiased metabolomics with chromatography mass spectrometry was performed on pulmonary arterial blood at rest and peak exercise. Random forest analysis and hierarchical clustering were used to quantify metabolite prediction of group membership and rank metabolites which were significantly different between groups. Compared to controls, pulmonary arterial hypertension subjects exhibited perturbations in pathways involving glycolysis, TCA cycle, fatty acid and complex lipid oxidation, collagen deposition and fibrosis, nucleotide metabolism, and others. The metabolic signature of exercise PH was uniquely between that of control and pulmonary arterial hypertension subjects. Accuracy predicting control, exercise PH, and pulmonary arterial hypertension group was 96%, 90%, and 88%, respectively, using paired rest-exercise metabolic changes. Our data suggest the metabolic profile of exercise PH is between that of controls and patients with pulmonary arterial hypertension., (© The Author(s) 2019.)

Black versus white older Americans are more likely to experience frailty, a condition associated with adverse health outcomes. To reduce racial disparities in health, a complete understanding of the pathophysiology of frailty is needed. Metabolomics may further our understanding by characterizing differences in the body during a vigorous versus frail state. We sought to identify metabolites and biological pathways associated with vigor to frailty among 287 black men ages 70-81 from the Health, Aging, and Body Composition study. Using liquid chromatography-mass spectrometry, 350 metabolites were measured in overnight-fasting plasma. The Scale of Aging Vigor in Epidemiology (SAVE) measured vigor to frailty based on weight change, strength, energy, gait speed, and physical activity. Thirty-seven metabolites correlated with SAVE scores ( p < 0.05), while adjusting for age and site. Fourteen metabolites remained significant after multiple comparisons adjustment (false discovery rate < 0.30). Lower values of tryptophan, methionine, tyrosine, asparagine, C14:0 sphingomyelin, and 1-methylnicotinamide, and higher values of glucoronate, N-carbamoyl-beta-alanine, isocitrate, creatinine, C4-OH carnitine, cystathionine, hydroxyphenylacetate, and putrescine were associated with frailer SAVE scores. Pathway analyses identified nitrogen metabolism, aminoacyl-tRNA biosynthesis, and the citric acid cycle. Future studies need to confirm these SAVE-associated metabolites and pathways that may indicate novel mechanisms involved in the frailty syndrome.

The integration of intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging produces an imaging modality with high sensitivity and specificity which is particularly needed in interventional cardiology. Conventional side-looking IVUS imaging with a single-element ultrasound (US) transducer lacks forward-viewing capability, which limits the application of this imaging mode in intravascular intervention guidance, Doppler-based flow measurement, and visualization of nearly, or totally blocked arteries. For both side-looking and forward-looking imaging, the necessity to mechanically scan the US transducer limits the imaging frame rate, and therefore, array-based solutions are desired. In this paper, we present a low-cost, compact, high-speed, and programmable imaging system based on a field-programmable gate array suitable for dual-mode forward-looking IVUS/IVPA imaging. The system has 16 US transmit and receive channels and functions in multiple modes including interleaved photoacoustic (PA) and US imaging, hardware-based high-frame-rate US imaging, software-driven US imaging, and velocity measurement. The system is implemented in the register-transfer level, and the central system controller is implemented as a finite-state machine. The system was tested with a capacitive micromachined ultrasonic transducer array. A 170-frames-per-second (FPS) US imaging frame rate is achieved in the hardware-based high-frame-rate US imaging mode while the interleaved PA and US imaging mode operates at a 60-FPS US and a laser-limited 20-FPS PA imaging frame rate. The performance of the system benefits from the flexibility and efficiency provided by the low-level implementation. The resulting system provides a convenient backend platform for research and clinical IVPA and IVUS imaging.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Background: Bier blocks, or intravenous regional anesthesia (IVRA), are a method of anesthesia for upper extremity surgeries. This study reports our experience with tourniquet deflation prior to 20 minutes with upper extremity IVRA., Methods: This study was designed as a retrospective cohort analysis. Records, including intraoperative and immediate postoperative anesthesia notes, of 430 patients who underwent IVRA with an upper extremity Bier block and a corresponding tourniquet time of less than 20 minutes were reviewed. Patient demographics, procedure(s) performed, American Society of Anesthesiologists scores, volume of lidocaine used in Bier block, tourniquet time, and any complications were recorded., Results: This cohort consisted of 127 males and 303 females. The 3 most common procedures performed were carpal tunnel release (315), trigger finger release (47), and excision of masses (34). The average tourniquet time for this cohort was 16 minutes (range, 9-19 minutes), and the average volume of lidocaine (0.5% plain) injected was 44 mL (range, 30-70 mL). A tourniquet time of 17 minutes or less was observed in 339 patients, and 170 patients had tourniquet times of 15 minutes or less. Five complications were recorded: intraoperative vomiting, mild postoperative nausea/vomiting, severe postoperative nausea and vomiting, and transient postoperative hypotension that responded to a fluid bolus., Conclusions: No major complications were observed in our cohort of upper extremity IVRA and tourniquet times of less than 20 minutes. Several variables play a role in the safety of upper extremity IVRA.

Background: Diagnostic criteria have recently been introduced in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). The purpose of this study is to assess the classification of this condition using the Canadian fetal alcohol spectrum disorder (FASD) multidisciplinary diagnostic guidelines as the standard of comparison. First, classification of ND-PAE was compared with Canadian FASD diagnoses of fetal alcohol syndrome (FAS), partial FAS and alcohol-related neurodevelopmental disorder. Second, classification of ND-PAE was compared with FAS and pFAS only, a criterion for which includes facial features highly predictive of prenatal alcohol exposure and effects., Methods: Eighty-two patients underwent multidisciplinary clinical evaluations using the Canadian FASD diagnostic guidelines between 2011 and 2015. Two clinicians independently reviewed patient files for evidence of diagnostic criteria for ND-PAE when applying an impairment cut-off level of 2 or more standard deviations below the mean, or clinically significant impairment in the absence of standardized norm-referenced measures., Results: Good interrater reliability was established between clinicians (κ = 0.79). Classifications of ND-PAE and Canadian FASD diagnoses, including alcohol-related neurodevelopmental disorder, were moderately correlated (Cramer V [82] = 0.44, p < 0.01). However, ND-PAE possessed low sensitivity in FASD identification. Further, there was no correlation between ND-PAE and FAS/pFAS classifications (Cramer V [82] = 0.05, p > 0.05)., Interpretation: Although there is considerable overlap between both sets of criteria, ND-PAE was less likely to identify patients with FASD. Although the neurobehavioral domains assessed by ND-PAE are supported in research, its diagnostic structure restricts the identification of FASD at the impairment threshold of 2 or more standard deviations. A disconnect remains with regard to impairment thresholds between FASD, which relies on neurodevelopmental data, and ND-PAE, which relies on clinical judgment., Competing Interests: Competing interests: None declared.

Important safety concerns have recently emerged regarding the use of sodium polystyrene sulfonate (Kayexalate), a cation-exchange resin commonly used for the treatment of hyperkalemia. We implemented an electronic alert system at a tertiary care academic medical center to warn providers of the safety concerns of Kayexalate. We assessed the number of Kayexalate prescriptions per month, as well as the number of grams of Kayexalate ordered per month, one year before versus one year after implementing the alert. The mean (±SD) number of Kayexalate orders decreased from 123 (±12) to 76 (±14) orders/month (38% absolute reduction, p < 0.001) after implementing the alert. Additionally, the mean (±SD) amount of Kayexalate prescribed decreased from 3332 (±329) to 1885 (±358) g/month (43% absolute reduction, p < 0.001). We conclude that an electronic alert is an effective tool to decrease Kayexalate ordering.

Background: Multimorbidity is a major driver of physical and cognitive impairment, but rates of decline are also related to ageing. We sought to determine trajectories of decline in a large cohort by disease status, and examined their correspondence with biomarkers of ageing processes including growth hormone, sex steroid, inflammation, visceral adiposity and kidney function pathways., Methods: We have followed the 5888 participants in the Cardiovascular Health Study (CHS) for healthy ageing and longevity since 1989-90. Gait speed, grip strength, modified mini-mental status examination (3MSE) and the digit symbol substitution test (DSST) were assessed annually to 1998-99 and again in 2005-06. Insulin-like growth hormone (IGF-1), dehydroepiandrosterone sulphate (DHEAS), interleukin-6 (IL-6), adiponectin and cystatin-C were assessed 3-5 times from stored samples. Health status was updated annually and dichotomized as healthy vs not healthy. Trajectories for each function measure and biomarker were estimated using generalized estimating equations as a function of age and health status using standardized values., Results: Trajectories of functional decline showed strong age acceleration late in life in healthy older men and women as well as in chronically ill older adults. Adiponectin, IL-6 and cystatin-C tracked with functional decline in all domains; cystatin-C was consistently associated with functional declines independent of other biomarkers. DHEAS was independently associated with grip strength and IL-6 with grip strength and gait speed trajectories., Conclusions: Functional decline in late life appears to mark a fundamental ageing process in that it occurred and was accelerated in late life regardless of health status. Cystatin C was most consistently associated with these functional declines., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Introduction: Growing evidence supports emergency physician (EP)-performed point-of-care ultrasound (PoC US). However, there is a utilization gap between academic emergency departments (ED) and other emergency settings. We elucidated barriers to PoC US use in a multistate sample of predominantly non-academic EDs to inform future strategies to increase PoC US utilization, particularly in non-academic centers., Methods: In 2010, we surveyed ED directors in five states (Arkansas, Hawaii, Minnesota, Vermont, and Wyoming; n=242 EDs) about general ED characteristics. In four states we determined barriers to PoC US use, proportion of EPs using PoC US, use privileges, and whether EPs can bill for PoC US., Results: Response rates were >80% in each state. Overall, 47% of EDs reported PoC US availability. Availability varied by state, from 34% of EDs in Arkansas to 85% in Vermont. Availability was associated with higher ED visit volume, and percent of EPs who were board certified/board eligible in emergency medicine. The greatest barriers to use were limited training (70%), expense (39%), and limited need (perceived or real) (32%). When PoC US was used by EPs, 50% used it daily, 44% had privileges not requiring radiology confirmation, and 34% could bill separately for PoC US. Only 12% of EPs used it ≥80% of the time when placing central venous lines., Conclusion: Only 47% of EDs in our five-state sample of predominantly non-academic EDs had PoC US immediately available. When available, the greatest barriers to use were limited training, expense, and limited need. Recent educational and technical advancements may help overcome these barriers.

We used (1)H nuclear magnetic resonance spectroscopy to describe key metabolites of the polar metabolome of the freshwater mussel, Elliptio complanata. Principal components analysis documented variability across tissue types and river of origin in mussels collected from two rivers in North Carolina (USA). Muscle, digestive gland, mantle and gill tissues yielded identifiable but overlapping metabolic profiles. Variation in digestive gland metabolic profiles between the two mussel collection sites was characterized by differences in mono- and disaccharides. Variation in mantle tissue metabolomes appeared to be associated with sex. Nuclear magnetic resonance spectroscopy is a sensitive means to detect metabolites in the tissues of E. complanata and holds promise as a tool for the investigation of freshwater mussel health and physiology.

Introduction: While medical schools strive to foster students' lifelong learning, motivational theories have not played an explicit role in curricular design. Self-determination Theory is a prominent motivational theory. It posits that perceived autonomy, competence and relatedness foster intrinsic motivation. This study explores the effects of autonomy on intrinsic motivation in medical students participating in high-fidelity mannequin simulation., Methods: A non-randomised crossover trial compared first-year medical students participating in (1) required simulation sessions with predetermined learning objectives and (2) extracurricular simulation sessions with student-directed learning objectives. An adapted Intrinsic Motivation Inventory (IMI) was used to assess intrinsic motivation, perceived autonomy, competence and relatedness. Each participant completed the IMI survey after each type of session. Variables were compared with signed-rank tests., Results: All 22 participants completed the IMI after both types of session. Perceived autonomy was significantly higher during extracurricular simulation (p<0.001), but intrinsic motivation, competence and relatedness were not. Intrinsic motivation correlated with autonomy (RS=0.57 and extracurricular simulation, ES=0.52), competence (RS=0.46 and ES=0.15) and relatedness (RS=0.51 and ES=0.64). The IMI subscales had good internal consistency (Cronbach's α=0.84, 0.90, 0.90 and 0.76 for intrinsic motivation, autonomy, competence and relatedness, respectively)., Conclusions: Extracurricular sessions increased students' perceived autonomy, but they were highly intrinsically motivated in both settings. Further study is needed to understand the relationship between perceived autonomy and intrinsic motivation in medical education learning activities. The IMI shows promise as a measurement tool for this work., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Calcium-dependent protein kinases (CDPKs) are conserved in plants and apicomplexan parasites. In Toxoplasma gondii, TgCDPK3 regulates parasite egress from the host cell in the presence of a calcium-ionophore. The targets and the pathways that the kinase controls, however, are not known. To identify pathways regulated by TgCDPK3, we measured relative phosphorylation site usage in wild type and TgCDPK3 mutant and knock-out parasites by quantitative mass-spectrometry using stable isotope-labeling with amino acids in cell culture (SILAC). This revealed known and novel phosphorylation events on proteins predicted to play a role in host-cell egress, but also a novel function of TgCDPK3 as an upstream regulator of other calcium-dependent signaling pathways, as we also identified proteins that are differentially phosphorylated prior to egress, including proteins important for ion-homeostasis and metabolism. This observation is supported by the observation that basal calcium levels are increased in parasites where TgCDPK3 has been inactivated. Most of the differential phosphorylation observed in CDPK3 mutants is rescued by complementation of the mutants with a wild type copy of TgCDPK3. Lastly, the TgCDPK3 mutants showed hyperphosphorylation of two targets of a related calcium-dependent kinase (TgCDPK1), as well as TgCDPK1 itself, indicating that this latter kinase appears to play a role downstream of TgCDPK3 function. Overexpression of TgCDPK1 partially rescues the egress phenotype of the TgCDPK3 mutants, reinforcing this conclusion. These results show that TgCDPK3 plays a pivotal role in regulating tachyzoite functions including, but not limited to, egress.

Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes-TERC, MYNN, and OBFC1-were significantly associated with leukocyte telomere length at p empirical < 0.05.

Hypothesizing that members of families enriched for longevity delay morbidity compared to population controls and approximate the health-span of centenarians, we compared the health-spans of older generation subjects of the Long Life Family Study (LLFS) to controls without family history of longevity and to centenarians of the New England Centenarian Study (NECS) using Bayesian parametric survival analysis. We estimated hazard ratios, the ages at which specific percentiles of subjects had onsets of diseases, and the gain of years of disease-free survival in the different cohorts compared to referent controls. Compared to controls, LLFS subjects had lower hazards for cancer, cardiovascular disease, severe dementia, diabetes, hypertension, osteoporosis, and stroke. The age at which 20% of the LLFS siblings and probands had one or more age-related diseases was approximately 10 years later than NECS controls. While female NECS controls generally delayed the onset of age-related diseases compared with males controls, these gender differences became much less in the older generation of the LLFS and disappeared amongst the centenarians of the NECS. The analyses demonstrate extended health-span in the older subjects of the LLFS and suggest that this aging cohort provides an important resource to discover genetic and environmental factors that promote prolonged health-span in addition to longer life-span.

Direct transmission from parents to offspring, referred to as vertical transmission, occurs within essentially all major groups of pathogens. Several microsporidia (Phylum Microsporidia) that infect arthropods employ this mode of transmission, and various lines of evidence have suggested this might occur with certain fish microsporidia. The microsporidium, Pseudoloma neurophilia, is a common pathogen of the laboratory zebrafish, Danio rerio. We previously verified that this parasite is easily transmitted horizontally, but previous studies also indicated that maternal transmission occurs. We report here direct observation of Pseudoloma neurophilia in the progeny of infected zebrafish that were reared in isolation, including microscopic visualization of the parasite in all major stages of development. Histological examination of larval fish reared in isolation from a group spawn showed microsporidian spores in the resorbing yolk sac of a fish. Infections were also observed in three of 36 juvenile fish. Eggs from a second group spawn of 30 infected fish were examined using a stereomicroscope and the infection was observed from 4 to 48 hours post-fertilization in two embryos. Intraovum infections were detected in embryos from 4 of 27 pairs of infected fish that were spawned based on qPCR detection of P. neurophilia DNA. The prevalence of intraovum infections from the four spawns containing infected embryos was low (∼1%) based on calculation of prevalence using a maximum likelihood analysis for pooled samples. Parasite DNA was detected in the water following spawning of 11 of the infected pairs, suggesting there was also potential for extraovum transmission in these spawning events. Our study represents the first direct observation of vertical transmission within a developing embryo of a microsporidian parasite in a vertebrate. The low prevalence of vertical transmission in embryos is consistent with observations of some other fish pathogens that are also readily transmitted by both vertical and horizontal routes.

Background: Despite agreement that handwashing decreases hospital-acquired infections (HAIs), physician hand hygiene remains suboptimal. Interventions to empower patients to discuss handwashing have had variable success., Objective: To understand patient perceived barriers to discussing physician hand hygiene and to determine whether patients prefer electronic alerts over printed information as an intervention to discuss physician handwashing., Design: Cross-sectional study of 250 medical/surgical patients at an academic medical center., Results: Ninety-six percent of patients had heard of HAIs. Ninety-six percent of patients thought it was important for physicians to clean their hands before touching anything in a patient's room. The majority of patients (78%) believed patients should remind physicians to clean their hands. Thirty-two percent of patients observed physician hand hygiene noncompliance. In multivariate analysis, predictors of not speaking up regarding physician hand hygiene included never having worked in health care (odds ratio [OR], 2.8 [95% confidence interval (CI), 1.5-5.1]), not observing a physician clean hands before touching the patient (OR, 2.4 [95% CI, 1.3-4.4]), and not thinking patients should have to remind physicians to clean hands (OR, 5.5 [95% CI, 2.4-12.7]). Ninety-three percent of patients favored electronic device reminders over printed information as an intervention to encourage patients to discuss hand hygiene with their doctors., Conclusions: The strongest predictor of not challenging a doctor to clean their hands was not believing it was the patient's role to do so. Patients prefer electronic device reminders to printed information as an aid in overcoming barriers to discussing hand hygiene with physicians.

Optical tweezers are exciting tools with which to explore liquid crystal (LC) systems; the motion of particles held in laser traps through LCs is perhaps the only approach that allows a low Ericksen number regime to be accessed. This offers a new method of studying the microrheology associated with micrometre-sized particles suspended in LC media--and such hybrid systems are of increasing importance as novel soft-matter systems. This paper describes the microrheology experiments that are possible in nematic materials and discusses the sometimes unexpected results that ensue. It also presents observations made in the inverse system; micrometre-sized droplets of LC suspended in an isotropic medium.

Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional studies, researchers have investigated whether leukocyte telomere length (LTL) is associated with demographic, behavioral, and health variables. In prospective studies, baseline LTL has been used to predict mortality and occasionally other adverse health outcomes. Conflicting data have generated heated debate about the value of LTL as a biomarker of overall aging. In this review, we address the epidemiologic data on LTL and demonstrate that shorter LTL is associated with older age, male gender, Caucasian race, and possibly atherosclerosis; associations with other markers of health are equivocal. We discuss the reasons for discrepancy across studies, including a detailed review of methods for measuring telomere length as they apply to epidemiology. Finally, we conclude with questions about LTL as a biomarker of aging and how epidemiology can be used to answer these questions., (© The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)