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1.  Simultaneous spatial frequency modulation imaging and micromachining with a femtosecond laser 
Optics letters  2016;41(2):265-268.
A Ti:Al2O3 chirped-pulse amplification system is used to simultaneously image and machine. By combining simultaneous spatial and temporal focusing (SSTF) with spatial frequency modulation for imaging (SPIFI), we are able to decouple the imaging and cutting beams to attain a resolution and a field-of-view that is independent of the cutting beam, while maintaining single-element detection. This setup allows for real-time feedback with the potential for simultaneous nonlinear imaging and imaging through scattering media. The novel SSTF machining platform uses refractive optics that, in general, are prohibitive for energetic, amplified pulses that might otherwise compromise the integrity of the focus as a result of nonlinear effects.
PMCID: PMC4773900  PMID: 26766690
2.  Higher Achieved Mean Arterial Pressure During Therapeutic Hypothermia is Not Associated with Neurologically Intact Survival Following Cardiac Arrest 
Resuscitation  2014;0:158-164.
Introduction
To determine if higher achieved mean arterial blood pressure (MAP) during treatment with therapeutic hypothermia (TH) is associated with neurologically intact survival following cardiac arrest.
Methods
Retrospective analysis of a prospectively collected cohort of 188 consecutive patients treated with TH in the cardiovascular intensive care unit of an academic tertiary care hospital.
Results
Neurologically intact survival was observed in 73/188 (38.8%) patients at hospital discharge and in 48/162 (29.6%) patients at a median follow up interval of 3 months. Patients in shock at the time of admission had lower baseline MAP at the initiation of TH (81 versus 87 mmHg; p=0.002), but had similar achieved MAP during TH (80.3 versus 83.7 mmHg; p=0.11). Shock on admission was associated with poor survival (18% versus 52%; p<0.001). Vasopressor use among all patients was common (84.6%) and was not associated with increased mortality. A multivariable analysis including age, initial rhythm, time to return of spontaneous circulation, baseline MAP and achieved MAP did not demonstrate a relationship between MAP achieved during TH and poor neurologic outcome at hospital discharge (OR 1.28, 95% CI 0.40–4.06; p=0.87) or at outpatient follow up (OR 1.09, 95% CI 0.32–3.75; p=0.976).
Conclusion
We did not observe a relationship between higher achieved MAP during TH and neurologically intact survival. However, shock at the time of admission was clearly associated with poor outcomes in our study population. These data do not support the use of vasopressors to artificially increase MAP in the absence of shock. There is a need for prospective, randomized trials to further define the optimum blood pressure target during treatment with TH.
doi:10.1016/j.resuscitation.2014.12.008
PMCID: PMC4330116  PMID: 25541429
3.  Patterns of hybridization among cutthroat trout and rainbow trout in northern Rocky Mountain streams 
Ecology and Evolution  2016;6(3):688-706.
Abstract
Introgressive hybridization between native and introduced species is a growing conservation concern. For native cutthroat trout and introduced rainbow trout in western North America, this process is thought to lead to the formation of hybrid swarms and the loss of monophyletic evolutionary lineages. Previous studies of this phenomenon, however, indicated that hybrid swarms were rare except when native and introduced forms of cutthroat trout co‐occurred. We used a panel of 86 diagnostic, single nucleotide polymorphisms to evaluate the genetic composition of 3865 fish captured in 188 locations on 129 streams distributed across western Montana and northern Idaho. Although introgression was common and only 37% of the sites were occupied solely by parental westslope cutthroat trout, levels of hybridization were generally low. Of the 188 sites sampled, 73% contained ≤5% rainbow trout alleles and 58% had ≤1% rainbow trout alleles. Overall, 72% of specimens were nonadmixed westslope cutthroat trout, and an additional 3.5% were nonadmixed rainbow trout. Samples from seven sites met our criteria for hybrid swarms, that is, an absence of nonadmixed individuals and a random distribution of alleles within the sample; most (6/7) were associated with introgression by Yellowstone cutthroat trout. In streams with multiple sites, upstream locations exhibited less introgression than downstream locations. We conclude that although the widespread introduction of nonnative trout within the historical range of westslope cutthroat trout has increased the incidence of introgression, sites containing nonadmixed populations of this taxon are common and broadly distributed.
doi:10.1002/ece3.1887
PMCID: PMC4739558  PMID: 26865958
cutthroat; hybridization; Oncorhynchus; SNP; swarm
4.  Increasing Access to Mental Health Care With Breathe, an Internet-Based Program for Anxious Adolescents: Study Protocol for a Pilot Randomized Controlled Trial 
JMIR Research Protocols  2016;5(1):e18.
Background
There is a demand to make first-line treatments, including cognitive behavioural therapy (CBT) for adolescent anxiety disorders, more widely available. Internet-based CBT is proposed to circumvent access and availability barriers and reduce health care system costs. Recent reviews suggest more evidence is needed to establish the treatment effects of Internet-based CBT in children and adolescents and to determine related economic impacts.
Objective
This pilot trial aims to collect the necessary data to inform the planning of a full-scale RCT to test the effectiveness of the Internet-based CBT program Breathe (Being Real, Easing Anxiety: Tools Helping Electronically).
Methods
We are conducting a 27-month, 2-arm parallel-group, pilot randomized controlled trial (RCT). Outcomes will inform the planning of a full-scale RCT aimed to test the effectiveness of Internet-based CBT with a population of adolescents with moderate to mild anxiety problems. In the pilot RCT we will: (1) define a minimal clinically important difference (MCID) for the primary outcome measure (total anxiety score using the Multidimensional Anxiety Scale for Children); (2) determine a sample size for the full-scale RCT; (3) estimate recruitment and retention rates; (4) measure intervention acceptability to inform critical intervention changes; (5) determine the use of co-interventions; and (6) conduct a cost-consequence analysis to inform a cost-effectiveness analysis in the full-scale RCT. Adolescents aged 13-17 years seeking care for an anxiety complaint from a participating emergency department, mobile or school-based crisis team, or primary care clinic are being screened for interest and eligibility. Enrolled adolescents are being randomly allocated to either 8 weeks of Internet-based CBT with limited telephone and e-mail support, or a control group with access to a static webpage listing anxiety resources. Adolescents are randomly assigned using a computer generated allocation sequence. Data are being collected at baseline, treatment completion, and at a 3-month follow-up.
Results
Currently, adolescents are being enrolled in the study. Enrolment is taking place between March 2014 and February 2016; data collection will conclude May 2016. We expect that analysis and results will be available by August 2016.
Conclusions
In many communities, the resources available for front-line anxiety treatment are outweighed by the need for care. This pilot RCT is an essential step to designing a robust RCT to evaluate the effectiveness of an Internet-based CBT program for adolescents with moderate to mild anxiety problems.
Trial Registration
Clinicaltrials.gov NCT02059226; http://clinicaltrials.gov/ct2/show/NCT02059226 (Archived by WebCite at http://www.webcitation.org/6epF8v7k4)
doi:10.2196/resprot.4428
PMCID: PMC4752691  PMID: 26825111
anxiety; etherapy; cognitive behavioral therapy; adolescents; mental health; Internet; intervention; pilot; randomized controlled trial
5.  Breast Cancer Risk in Relation to Ambient Air Pollution Exposure at Residences in the Sister Study Cohort 
Background
Some but not all past studies reported associations between components of air pollution and breast cancer, namely fine particulate matter ≤ 2.5 μm (PM2.5) and nitrogen dioxide (NO2). It is yet unclear whether risks differ according to estrogen receptor (ER) and progesterone receptor (PR) status.
Methods
This analysis includes 47,591 women from the Sister Study cohort enrolled from August 2003-July 2009, in whom 1,749 invasive breast cancer cases arose from enrollment to January 2013. Using Cox proportional hazards and polytomous logistic regression, we estimated breast cancer risk associated with residential exposure to NO2, PM2.5, and PM10.
Results
While breast cancer risk overall was not associated with PM2.5 (Hazards ratio [HR] = 1.03; 95% CI: 0.96–1.11), PM10 (HR = 0.99; 95% CI: 0.98–1.00), or NO2 (HR = 1.02; 95% CI: 0.97–1.07), the association with NO2 differed according to ER/PR subtype (p = 0.04). For an interquartile range (IQR) difference of 5.8 parts per billion (ppb) in NO2, the relative risk (RR) of ER+/PR+ breast cancer was 1.10 (95% CI: 1.02–1.19), while there was no evidence of association with ER−/PR− (RR=0.92; 95% CI: 0.77–1.09; pinteraction=0.04).
Conclusions
Within the Sister Study cohort, we found no significant associations between air pollution and breast cancer risk overall. But we observed an increased risk of ER+/PR+ breast cancer associated with NO2.
Impact
Though these results suggest there is no substantial increased risk for breast cancer overall in relation to air pollution, NO2, a marker of traffic related air pollution, may differentially affect ER+/PR+ breast cancer.
doi:10.1158/1055-9965.EPI-15-0787
PMCID: PMC4686338  PMID: 26464427
Air pollution; Breast cancer risk; Particulate matter; Nitrogen dioxide; Cancer survival
6.  Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency 
Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0365-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0365-z
PMCID: PMC4683718  PMID: 26682746
Adenosine deaminase deficiency; SCID; Children; Pulmonary dysfunction; Impulse oscillometry; Spirometry
7.  Surviving the heat: heterogeneity of response in Saccharomyces cerevisiae provides insight into thermal damage to the membrane 
Environmental Microbiology  2015;17(8):2982-2992.
Environmental heat stress impacts on the physiology and viability of microbial cells with concomitant implications for microbial activity and diversity. Previously, it has been demonstrated that gradual heating of Saccharomyces cerevisiae induces a degree of thermal resistance, whereas a heat shock results in a high level of cell death. Here, we show that the impact of exogenous nutrients on acquisition of thermal resistance differs between strains.
Using single-cell methods, we demonstrate the extent of heterogeneity of the heat-stress response within populations of yeast cells and the presence of subpopulations that are reversibly damaged by heat stress. Such cells represent potential for recovery of entire populations once stresses are removed. The results show that plasma membrane permeability and potential are key factors involved in cell survival, but thermal resistance is not related to homeoviscous adaptation of the plasma membrane. These results have implications for growth and regrowth of populations experiencing environmental heat stress and our understanding of impacts at the level of the single cell. Given the important role of microbes in biofuel production and bioremediation, a thorough understanding of the impact of stress responses of populations and individuals is highly desirable.
doi:10.1111/1462-2920.12866
PMCID: PMC4676927  PMID: 25845620
8.  Illness Attitudes Associated with Seasonal Depressive Symptoms: An Examination Using a Newly Developed Implicit Measure 
The Dual Vulnerability Model of seasonal depression posits that seasonal vegetative symptoms are due to a physiological vulnerability, but cognitive and mood symptoms are the result of negative appraisal of vegetative changes. In addition, rumination may be associated with stronger negative attitudes toward vegetative symptoms. This is the first study to examine implicit attitudes toward vegetative symptoms. We hypothesized that illness attitudes about fatigue moderate the relationship between the severity of vegetative symptoms and the severity of cognitive symptoms and that the illness attitudes are associated with rumination. This study also developed an implicit method to assess the appraisal of fatigue as indicating illness. Results supported both hypotheses. Illness attitudes toward fatigue moderated the relationship between vegetative symptoms and cognitive symptoms. Ruminative response style was positively associated with implicit illness attitudes towards fatigue. The study provides support for the role of negative appraisals of vegetative symptoms in the development of cognitive and mood seasonal depressive symptoms.
doi:10.1155/2015/397076
PMCID: PMC4689914  PMID: 26783456
9.  A Tool for Multiple Targeted Genome Deletions that Is Precise, Scar-Free, and Suitable for Automation 
PLoS ONE  2015;10(12):e0142494.
Many advances in synthetic biology require the removal of a large number of genomic elements from a genome. Most existing deletion methods leave behind markers, and as there are a limited number of markers, such methods can only be applied a fixed number of times. Deletion methods that recycle markers generally are either imprecise (remove untargeted sequences), or leave scar sequences which can cause genome instability and rearrangements. No existing marker recycling method is automation-friendly. We have developed a novel openly available deletion tool that consists of: 1) a method for deleting genomic elements that can be repeatedly used without limit, is precise, scar-free, and suitable for automation; and 2) software to design the method’s primers. Our tool is sequence agnostic and could be used to delete large numbers of coding sequences, promoter regions, transcription factor binding sites, terminators, etc in a single genome. We have validated our tool on the deletion of non-essential open reading frames (ORFs) from S. cerevisiae. The tool is applicable to arbitrary genomes, and we provide primer sequences for the deletion of: 90% of the ORFs from the S. cerevisiae genome, 88% of the ORFs from S. pombe genome, and 85% of the ORFs from the L. lactis genome.
doi:10.1371/journal.pone.0142494
PMCID: PMC4668057  PMID: 26630677
11.  The Dual Challenges of Generality and Specificity When Developing Environmental DNA Markers for Species and Subspecies of Oncorhynchus 
PLoS ONE  2015;10(11):e0142008.
Environmental DNA (eDNA) sampling is a powerful tool for detecting invasive and native aquatic species. Often, species of conservation interest co-occur with other, closely related taxa. Here, we developed qPCR (quantitative PCR) markers which distinguish westslope cutthroat trout (Oncorhynchus clarkii lewsi), Yellowstone cutthroat trout (O. clarkii bouvieri), and rainbow trout (O. mykiss), which are of conservation interest both as native species and as invasive species across each other’s native ranges. We found that local polymorphisms within westslope cutthroat trout and rainbow trout posed a challenge to designing assays that are generally applicable across the range of these widely-distributed species. Further, poorly-resolved taxonomies of Yellowstone cutthroat trout and Bonneville cutthroat trout (O. c. utah) prevented design of an assay that distinguishes these recognized taxa. The issues of intraspecific polymorphism and unresolved taxonomy for eDNA assay design addressed in this study are likely to be general problems for closely-related taxa. Prior to field application, we recommend that future studies sample populations and test assays more broadly than has been typical of published eDNA assays to date.
doi:10.1371/journal.pone.0142008
PMCID: PMC4633235  PMID: 26536367
12.  International survey of knowledge of food-induced anaphylaxis 
Background
Studies show that anaphylaxis is under-recognized and epinephrine (adrenaline) is under-used by medical personnel as well as patients and their families. This study assesses the knowledge of food-induced anaphylaxis diagnosis and management across different populations of providers and caregivers and other interested respondents.
Methods
An online survey embedded in a case discussion food-induced anaphylaxis was distributed by Medscape to registered members.
Results
7822 responders who started the activity chose to answer at least some of the questions presented (response rate 39.5%). Over 80% of responders in all groups correctly identified the case of anaphylaxis with prominent skin and respiratory symptoms, however, only 55% correctly recognized the case without skin symptoms as anaphylaxis. Only 23% of responders correctly selected risk factors for anaphylaxis, with physicians significantly more likely to choose the correct answers as compared to allied health, other health professionals and medical students (p<0.001). Ninety five perecnt selected epinephrine (adrenaline) as the most appropriate treatment for anaphylaxis, and 81% correctly indicated that there are no absolute contraindications for epinephrine (adrenaline) in the setting of anaphylaxis. When presented a case of a child with no documented history of allergies who has symptoms of anaphylaxis, more physicians than any other group chose to administer stock epinephrine (adrenaline) (73% vs 60%, p<0.001).
Conclusion
Specific knowledge deficits for food-induced anaphylaxis persist across all groups. Further educational efforts should be aimed not only at the medical community but also for the entire caregiver community and general public, to optimize care for food allergic individuals.
doi:10.1111/pai.12284
PMCID: PMC4302004  PMID: 25263184
allergy; anaphylaxis; epinephrine (adrenaline); food
13.  Dissociation Between History and Challenge in Patients with Physical Urticaria 
Background
Physical urticaria is a subtype of chronic urticaria induced by a physical stimulus.
Objective
To evaluate the consistency between a history of physical urticaria and results of challenge testing.
Methods
Seventy-six subjects, ages 3–77, were referred with the diagnoses of a physical urticaria and were evaluated using challenge testing directed toward the presenting diagnosis, yet included other stimuli based on history. The majority of subjects were tested to 3 or more stimuli, thus 294 provocation tests were performed. Fifty-seven subjects were surveyed for the status of their physical urticaria at least one year after initial evaluation.
Results
Of the 76 subjects with a positive history of a physical urticaria, 38 %(N=29) were challenge negative to the presenting diagnosis. Eight patients within the challenge negative group reacted positively to additional testing, thus 28 % (N=21) remained negative to all challenge testing, allowing discontinuation of medications and avoidance behavior. A negative challenge result was less likely in subjects presenting with cold induced urticaria (25 %), delayed pressure urticaria (25 %) and dermatographism (29 %), yet more common in cholinergic (65 %) and solar urticaria (67 %). A one-year follow-up survey of 57 subjects was consistent with initial results. Nineteen of this sub-group were rechallenged for the presenting diagnosis and the outcome was unchanged in 17 patients and in two patients the urticaria had resolved.
Conclusions
The diagnosis by history of a physical urticaria should be verified by testing whenever possible; and particularly if the condition is judged as severe and thus requires both significant life-style changes and pharmacologic intervention.
doi:10.1016/j.jaip.2014.07.008
PMCID: PMC4254441  PMID: 25439372
Urticaria; physical urticaria; challenge testing; cold; cholinergic; dermatographism; delayed pressure
14.  A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity 
Stem Cell Reports  2015;5(5):763-775.
Summary
Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells. The potential impact of the atlas was demonstrated via cellular reprogramming efforts where candidate core TFs proved capable of converting human fibroblasts to retinal pigment epithelial-like cells. These results suggest that candidate core TFs from the atlas will prove a useful starting point for studying transcriptional control of cell identity and reprogramming in many human cell types.
Graphical Abstract
Highlights
•Core transcription factors (TFs) are predicted for >200 cell types/tissues•Predicted TFs for retinal pigment epithelial (RPE) cells can reprogram fibroblasts•These reprogrammed RPE-like cells are functionally similar to primary RPE•The sets of predicted factors may facilitate studies of control of cell identity
Small sets of core transcription factors establish gene expression programs that determine cellular function. Young, Lee, and colleagues have generated an atlas of candidate core transcription factors for over 200 human cell types. Candidate core transcription factors proved capable of reprogramming cells, suggesting this atlas may facilitate studies of transcriptional regulation and reprogramming for clinically important cell types.
doi:10.1016/j.stemcr.2015.09.016
PMCID: PMC4649293  PMID: 26603904
15.  Ambient Air Pollution Exposure and Incident Adult Asthma in a Nationwide Cohort of U.S. Women 
Rationale: Limited prior data suggest an association between traffic-related air pollution and incident asthma in adults. No published studies assess the effect of long-term exposures to particulate matter less than 2.5 μm in diameter (PM2.5) on adult incident asthma.
Objectives: To estimate the association between ambient air pollution exposures (PM2.5 and nitrogen dioxide, NO2) and development of asthma and incident respiratory symptoms.
Methods: The Sister Study is a U.S. cohort study of risk factors for breast cancer and other health outcomes (n = 50,884) in sisters of women with breast cancer (enrollment, 2003–2009). Annual average (2006) ambient PM2.5 and NO2 concentrations were estimated at participants’ addresses, using a national land-use/kriging model incorporating roadway information. Outcomes at follow-up (2008–2012) included incident self-reported wheeze, chronic cough, and doctor-diagnosed asthma in women without baseline symptoms.
Measurements and Main Results: Adjusted analyses included 254 incident cases of asthma, 1,023 of wheeze, and 1,559 of chronic cough. For an interquartile range (IQR) difference (3.6 μg/m3) in estimated PM2.5 exposure, the adjusted odds ratio (aOR) was 1.20 (95% confidence interval [CI] = 0.99–1.46, P = 0.063) for incident asthma and 1.14 (95% CI = 1.04–1.26, P = 0.008) for incident wheeze. For NO2, there was evidence for an association with incident wheeze (aOR = 1.08, 95% CI = 1.00–1.17, P = 0.048 per IQR of 5.8 ppb). Neither pollutant was significantly associated with incident cough (PM2.5: aOR = 0.95, 95% CI = 0.88–1.03, P = 0.194; NO2: aOR = 1.00, 95% CI = 0.93–1.07, P = 0.939).
Conclusions: Results suggest that PM2.5 exposure increases the risk of developing asthma and that PM2.5 and NO2 increase the risk of developing wheeze, the cardinal symptom of asthma, in adult women.
doi:10.1164/rccm.201403-0525OC
PMCID: PMC4299575  PMID: 25172226
asthma incidence; particulate matter; PM2.5; nitrogen dioxide; NO2
16.  The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants 
Purpose
The development of photoreceptor replacement therapy for retinal degenerative disorders requires the identification of the optimal cell source and immunosuppressive regimen in a large animal model. Allotransplants are not acutely rejected in swine subretinal space, although it is not known if survival can be improved with immunosuppression. Here we investigated the survival and integration of expanded pig retinal progenitor cells (pRPCs) in normal recipients with and without transient anti-inflammatory suppression.
Methods
pRPCs were derived from the neural retina of E60 GFP transgenic pigs, expanded for six passages, characterized, and transplanted into the subretinal space of 12 pigs. Six recipients received a single intravitreal injection of rapamycin and dexamethasone.
Results
pRPCs expressed the photoreceptor development genes Sox2, Pax6, Lhx2, Crx, Nrl, and Recoverin in vitro. Transplanted cells were identified in 9 out of 12 recipients 4 weeks after the injection. pRPCs integrated primarily into the photoreceptor inner segment layer and outer nuclear layer with single cells present in the inner nuclear layer. Donor cells remained recoverin-positive and acquired rhodopsin. We did not observe any signs of graft proliferation. The immunosuppression did not affect the survival or distribution of grafts. No macrophage infiltration or loss of retinal structure was observed in either group.
Conclusions
Local immunosuppression with rapamycin and dexamethasone does not improve the outcome of pRPC allotransplantation into the subretinal space.
Translational Relevance
Survival and integration of pRPC together with the lack of graft proliferation suggests that allogeneic RPC transplantation without transient immunosuppression is a favorable approach for photoreceptor cell replacement.
doi:10.1167/tvst.4.5.6
PMCID: PMC4585327  PMID: 26425402
retina; photoreceptors; retinal progenitor cells; cell therapy; rapamycin
17.  Young’s postulate 
doi:10.1503/cmaj.140744
PMCID: PMC4162792  PMID: 25183724
18.  Training Tolerance to Delay Using the Escalating Interest Task 
The Psychological record  2014;64(3):423-431.
The present study examined the lasting effects of exposure to reinforcement that increased in magnitude as a function of time between responses in a first-person shooter video game preparation of the escalating interest task. When reinforcement density increased as a function of time, it encouraged participants to wait longer between responses (shots of a weapon). Participants exposed to such contingencies waited significantly longer to fire their weapons than participants who were exposed to linear growth, where long inter-response times were not differentially reinforced. Those with experience in conditions where reinforcement density increased as a function of time showed persistently longer wait times when the contingencies changed in the latter portion of the game where the disincentive to fire quickly was removed. The potential utility of such contingencies for training tolerance to delay of reinforcement and the broader implications of training self-control are discussed.
doi:10.1007/s40732-014-0045-8
PMCID: PMC4191859  PMID: 25309001
Delay discounting; temporal discounting; self-control; impulsivity; tolerance to delay
19.  Increased myocardial extracellular volume in active idiopathic systemic capillary leak syndrome 
Background
The Systemic Capillary Leak Syndrome (SCLS) is a rare disorder of unknown etiology presenting as recurrent episodes of shock and peripheral edema due to leakage of fluid into soft tissues. Insights into SCLS pathogenesis are few due to the scarcity of cases, and the etiology of vascular barrier disruption in SCLS is unknown. Recent advances in cardiovascular magnetic resonance (CMR) allow for the quantitative assessment of the myocardial extracellular volume (ECV), which can be increased in conditions causing myocardial edema. We hypothesized that measurement of myocardial ECV may detect myocardial vascular leak in patients with SCLS.
Methods
Fifty-six subjects underwent a standard CMR examination at the NIH Clinical Center from 2009 until 2014: 20 patients with acute intermittent SCLS, six subjects with chronic SCLS, and 30 unaffected controls. Standard volumetric measurements; late gadolinium enhancement imaging and pre- and post-contrast T1 mapping were performed. ECV was calculated by calibration of pre- and post-contrast T1 values with blood hematocrit.
Results
Demographics and cardiac parameters were similar in both groups. There was no significant valvular disorder in either group. Subjects with chronic SCLS had higher pre-contrast myocardial T1 compared to healthy controls (T1: 1027 ± 44 v. 971 ± 41, respectively; p = 0.03) and higher myocardial ECV than patients with acute intermittent SCLS or controls: 33.8 ± 4.6, 26.9 ± 2.6, 26 ± 2.4, respectively; p = 0.007 v. acute intermittent; P = 0.0005 v. controls). When patients with chronic disease were analyzed together with five patients with acute intermittent disease who had just experienced an acute SCLS flare, ECV values were significantly higher than in subjects with acute intermittent SCLS in remission or age-matched controls and (31.2 ± 4.6 %, 26.5 ± 2.7 %, 26 ± 2.4 %, respectively; p = 0.01 v. remission, p = 0.001 v. controls). By contrast, T1 values did not distinguish these three subgroups (1008 ± 40, 978 ± 40, 971 ± 41, respectively, p = 0.2, active v. remission; p = 0.06 active v. controls). Abundant myocardial edema without evidence of acute inflammation was detected in cardiac tissue postmortem in one patient.
Conclusions
Patients with active SCLS have significantly higher myocardial ECV than age-matched controls or SCLS patients in remission, which correlated with histopathological findings in one patient.
doi:10.1186/s12968-015-0181-6
PMCID: PMC4551171  PMID: 26310790
Systemic capillary leak syndrome; Mycocardial edema; Cardiovascular magnetic resonance
20.  Electrical Stimulation via a Biocompatible Conductive Polymer Directs Retinal Progenitor Cell Differentiation 
The goal of this study was to simulate in vitro the spontaneous electrical wave activity associated with retinal development and investigate if such biometrically designed signals can enhance differentiation of mouse retinal progenitor cells (mRPC). To this end, we cultured cells on an electroconductive transplantable polymer, polypyrrole (PPy) and measured gene expression and morphology of the cells. Custom-made 8-well cell culture chambers were designed to accommodate PPy deposited onto indium tin oxide-coated (ITO) glass slides, with precise control of the PPy film thickness. mRPCs were isolated from post-natal day 1 (P1) green fluorescent protein positive (GFP+) mice, expanded, seeded onto PPY films, allowed to adhere for 24 hours, and then subjected to electrical stimulation (100 μA pulse trains, 5 s in duration, once per minute) for 4 days. Cultured cells and non-stimulated controls were processed for immunostaining and confocal analysis, and for RNA extraction and quantitative PCR. Stimulated cells expressed significantly higher levels of the early photoreceptor marker cone-rod homebox (CRX, the earliest known marker of photoreceptor identity), and protein kinase-C (PKC), and significantly lower levels of the glial fibrillary acidic protein (GFAP). Consistently, stimulated cells developed pronounced neuronal morphologies with significantly longer dendritic processes and larger cell bodies than non-stimulated controls. Taken together, the experimental evidence shows that the application of an electrical stimulation designed based on retinal development can be implemented to direct and enhance retinal differentiation of mRPCs, suggesting a role for biomimetic electrical stimulation in directing progenitor cells toward neural fates.
doi:10.1109/EMBC.2013.6609828
PMCID: PMC4480863  PMID: 24110015
22.  Assessing the Feasibility of a Virtual Tumor Board Program: A Case Study 
Executive Summary
Multidisciplinary tumor boards involve various providers (e.g., oncology physicians, nurses) in patient care. Although many Community Hospitals have local tumor boards that review all types of cases, many providers, particularly in rural areas and smaller institutions, still lack access to tumor boards specializing in a particular type of cancer (e.g., breast, gastrointestinal, hematologic). Videoconferencing technology can connect providers across geographic locations and institutions; however, virtual tumor board (VTB) programs using this technology are uncommon.
In this study, we evaluated the feasibility of a new VTB program at UNC Lineberger Comprehensive Cancer Center, which connects community-based clinicians to UNC tumor boards. We used an embedded case study design with UNC VTB as the overarching case, comprised of multiple tumor boards representing different cancer types, each with individual clinician participants (our primary unit of analysis). Methods included observations, interviews, and surveys.
Our findings suggest that participants were generally satisfied with the VTB. Cases presented at VTB were appropriate, sufficient information was available for discussion, and technology problems were not common. UNC clinicians viewed the VTB as a service to patients and colleagues and an opportunity for clinical trial recruitment. Community-based clinicians presenting at VTB valued the discussion, even if it simply confirmed their original treatment plan or did not yield consensus recommendations. However, barriers to participation for community-based clinicians included timing of the VTB and lack of reimbursement. To maximize benefits of the VTB, barriers to participation should be addressed, scheduling and preparation processes optimized, and appropriate measures for evaluating impact identified.
PMCID: PMC4116610  PMID: 24988672
videoconferencing; health services accessibility; oncology service; hospital; interdisciplinary communication; patient care management
23.  Low-Oxygen Culture Conditions Extend the Multipotent Properties of Human Retinal Progenitor Cells 
Tissue Engineering. Part A  2014;20(9-10):1465-1475.
Purpose: Development of an effective cell-based therapy is highly dependent upon having a reproducible cell source suitable for transplantation. One potential source, isolated from the developing fetal neural retina, is the human retinal progenitor cell (hRPC). One limiting factor for the use of hRPCs is their in vitro expansion limit. As such, the aim of this study was to determine whether culturing hRPCs under 3% O2 would support their proliferative capacity while maintaining multipotency.
Methods: To determine the effect of low oxygen on the ability of hRPCs to self-renew, rates of proliferation and apoptosis, telomerase activity, and expression of proliferative, stemness, and differentiation markers were assessed for hRPCs cultured in 3% and 20% oxygen conditions.
Results: Culture under 3% oxygen increases the proliferation rate and shifts the proliferation limit of hRPCs to greater 40 divisions. This increased capacity for proliferation is correlated with an upregulation of Ki67, CyclinD1, and telomerase activity and a decrease in p53 expression and apoptosis. Increased expression of cMyc, Klf4, Oct4, and Sox2 in 3% O2 is correlated with stabilization of both HIF1α and HIF2α. The eye field development markers Pax6, Sox2, and Otx2 are present in hRPCs up to passage 16 in 3% O2. Following in vitro differentiation hRPCs expanded in the 3% O2 were able to generate specialized retinal cells, including rods and cones.
Conclusions: Low-oxygen culture conditions act to maintain both multipotency and self-renewal properties of hRPCs in vitro. The extended expansion limits permit the development of a clinical-grade reagent for transplantation.
doi:10.1089/ten.tea.2013.0361
PMCID: PMC4251088  PMID: 24320879
24.  Cardiopulmonary resuscitation among mechanically ventilated patients 
Intensive care medicine  2014;40(4):556-563.
Purpose
To evaluate the outcomes, including long term survival, after CPR in mechanically ventilated patients.
Methods
We analyzed Medicare data from 1994-2005 to identify beneficiaries who underwent in-hospital CPR. We then identified a subgroup receiving CPR one or more days after mechanical ventilation was initiated (defined by ICD-9 procedure code for intubation [96.04] or mechanical ventilation [96.7x] one or more days prior to procedure code for CPR [99.60 or 99.63]).
Results
We identified 471,962 patients who received in-hospital CPR with an overall survival to hospital discharge of 18.4% (95% confidence interval [CI] 18.3-18.5%). Of those, 42,163 received CPR one or more days after mechanical ventilation initiation. Survival to hospital discharge after CPR in ventilated patients was 10.1% (95% CI 9.8%-10.4%), compared to 19.2% (95% CI 19.1%-19.3%) in non-ventilated patients (p<0.001). Among this group, older age, race other than white, higher burden of chronic illness, and admission from a nursing facility were associated with decreased survival in multivariable analyses. Among all CPR recipients, those who were ventilated had 52% lower odds of survival (OR 0.48, 95% CI 0.46-0.49, p<0.001). Median long term survival in ventilated patients receiving CPR who survived to hospital discharge was 6.0 months (95% CI 5.3-6.8 months), compared to 19.0 months (95% CI 18.6-19.5 months) among the non-ventilated survivors (p=<0.001 by logrank test). Of all patients receiving CPR while ventilated, only 4.1% were alive at one year.
Conclusions
Survival after in-hospital CPR is decreased among ventilated patients compared to those who are not ventilated. This information is important for clinicians, patients, and family members when discussing CPR in critically ill patients.
doi:10.1007/s00134-014-3247-2
PMCID: PMC4005593  PMID: 24570267
Cardiopulmonary arrest; Outcome; Predictors; Survival; Quality of life
25.  Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases 
Journal of the Royal Society Interface  2015;12(104):20141289.
There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.
doi:10.1098/rsif.2014.1289
PMCID: PMC4345494  PMID: 25652463
drug design; artificial intelligence; quantitative structure activity relationship

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