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1.  Ensuring Quality Cancer Care: A Follow-Up Review of the Institute of Medicine’s Ten Recommendations for Improving the Quality of Cancer Care in America 
Cancer  2011;118(10):2571-2582.
Responding to growing concerns regarding the safety, quality, and efficacy of cancer care in the United States, the Institute of Medicine (IOM) of the National Academy of Sciences commissioned a comprehensive review of cancer care delivery in the US healthcare system in the late 1990s. The National Cancer Policy Board (NCPB), a twenty-member board with broad representation, performed this review. In its review, the NCPB focused on the state of cancer care delivery at that time, its shortcomings, and ways to measure and improve the quality of cancer care. The NCPB described an ideal cancer care system, where patients would have equitable access to coordinated, guideline-based care and novel therapies throughout the course of their disease. In 1999, the IOM published the results of this review in its influential report, Ensuring Quality Cancer Care. This report outlined ten recommendations, which, when implemented, would: 1) improve the quality of cancer care; 2) increase our understanding of quality cancer care; and, 3) reduce or eliminate access barriers to quality cancer care.
Despite the fervor generated by this report, there are lingering doubts regarding the safety and quality of cancer care in the United States today. Increased awareness of medical errors and barriers to quality care, coupled with escalating healthcare costs, has prompted national efforts to reform the healthcare system. These efforts by healthcare providers and policymakers should bridge the gap between the ideal state described in Ensuring Quality Cancer Care and the current state of cancer care in the United States.
PMCID: PMC3272132  PMID: 22045610
Oncology Service; Hospital; Quality of Health Care; Benchmarking; Guideline Adherence; Medically Uninsured; Palliative Care; Comparative Effectiveness Research
3.  Prescription of Psychiatric Medications and Polypharmacy in the LAMS Cohort 
This study evaluated demographic and clinical correlates and predictors of polypharmacy at baseline assessment in the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a cohort of children age six to 12 years at their first outpatient mental health visit at university-affiliated clinics.
Use of medications in four classes (mood stabilizers, antidepressants, antipsychotics, and stimulants) was assessed, and the Service Assessment for Children and Adolescents classified lifetime and current use of various services. Analyses examined correlates of the number of medications prescribed and odds of polypharmacy, defined as use of two or more concurrent medications.
In the total sample, 201 of 698 participants (29%) were prescribed two or more medications. These participants had lower Children's Global Assessment Scale scores, more comorbid disorders, and higher baseline parent-reported mood symptoms than those prescribed no or one medication. White youths were three times as likely as nonwhite youths to be receiving two or more psychotropics, even after adjustment for other demographic and clinical characteristics. Of 262 participants (38% of sample) not being treated with medications, 252 (96%) had a diagnosis of at least one psychiatric disorder (74% had two or more).
Findings suggest that patients with greater severity and comorbidity were more likely to receive two or more medications. However, 38% of these children with serious disorders were not receiving psychotropic medication at the time of this assessment. Results counter findings suggesting overtreatment with medications of children with psychiatric disorders in the community.
PMCID: PMC3977739  PMID: 23852186
4.  Reduction of Aedes aegypti Vector Competence for Dengue Virus under Large Temperature Fluctuations 
Diurnal temperature fluctuations can fundamentally alter mosquito biology and mosquito-virus interactions in ways that impact pathogen transmission. We investigated the effect of two daily fluctuating temperature profiles on Aedes aegypti vector competence for dengue virus (DENV) serotype-1. A large diurnal temperature range of 18.6°C around a 26°C mean, corresponding with the low DENV transmission season in northwestern Thailand, reduced midgut infection rates and tended to extend the virus extrinsic incubation period. Dissemination was first observed at day 7 under small fluctuations (7.6°C; corresponding with high DENV transmission) and constant control temperature, but not until Day 11 for the large diurnal temperature range. Results indicate that female Ae. aegypti in northwest Thailand are less likely to transmit DENV during the low than high transmission season because of reduced DENV susceptibility and extended virus extrinsic incubation period. Better understanding of DENV transmission dynamics will come with improved knowledge of temperature effects on mosquito-virus interactions.
PMCID: PMC3617853  PMID: 23438766
5.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
PMCID: PMC3973018  PMID: 23563607
6.  Head Impact Exposure Sustained by Football Players on Days of Diagnosed Concussion 
This study compares the frequency and severity of head impacts sustained by football players on days with and without diagnosed concussion and to identify the sensitivity and specificity of single impact severity measures to diagnosed injury.
1,208 players from eight collegiate and six high school football teams wore instrumented helmets to measure head impacts during all team sessions, of which 95 players were diagnosed with concussion. Eight players sustained two injuries and one three, providing 105 injury cases. Measures of head kinematics (peak linear and rotational acceleration, Gadd Severity Index (GSI), Head Injury Criteria (HIC15), change in head velocity (Δv)) and the number of head impacts sustained by individual players were compared between days with and without diagnosed concussion. Receiver operator characteristic curves were generated to evaluate the sensitivity and specificity of each kinematic measure to diagnosed concussion using only those impacts that directly preceded diagnosis.
Players sustained a higher frequency of impacts and impacts with more severe kinematic properties on days of diagnosed concussion than on days without diagnosed concussion. Forty-five injury cases were immediately diagnosed following head impact. For these cases, peak linear acceleration and HIC15 were most sensitive to immediately diagnosed concussion (AUC = 0.983). Peak rotational acceleration was less sensitive to diagnosed injury than all other kinematic measures (p = 0.01) which are derived from linear acceleration (peak linear, HIC15, GSI, and Δv).
Players sustain more impacts and impacts of higher severity on days of diagnosed concussion than on days without diagnosed concussion. Additionally, of historical measures of impact severity, those associated with peak linear acceleration are the best predictors of immediately diagnosed concussion.
PMCID: PMC3605215  PMID: 23135363
HIT System; Sport; impact biomechanics; MTBI; TBI; injury threshold
7.  Timing of Concussion Diagnosis is Related to Head Impact Exposure Prior to Injury 
Concussions are commonly undiagnosed in an athletic environment because the post-injury signs and symptoms may be mild, masked by the subject, or unrecognized. This study compares measures of head impact frequency, location and kinematic response prior to cases of immediate and delayed concussion diagnosis.
Football players from eight collegiate and six high school teams wore instrumented helmets during play (n=1,208), of which ninety-five were diagnosed with concussion (105 total cases). Acceleration data recorded by the instrumented helmets was reduced to five kinematic metrics: peak linear and rotational acceleration, GSI, HIC15, and change in head velocity (Δv). Additionally, each impact was assigned to one of four general location regions (Front, Back, Side, and Top), and the number of impacts sustained prior to injury was calculated over two time periods (one and seven days).
All head kinematic measures associated with injury, except peak rotational acceleration (p = 0.284), were significantly higher for cases of immediate diagnosis than delayed diagnosis (p<0.05). Players with delayed diagnosis sustained a significantly higher number of head impacts on the day of injury (32.9 ±24.9; p < 0.001) and within seven days of injury (69.7 ±43.3; p = 0.006) than players with immediate diagnosis (16.5 ±15.1 and 50.2 ±43.6). Impacts associated with concussion occurred most frequently to the Front of the head (46%) followed by the Top (25%), Side (16%), and Back (13%) with the number of impacts by location independent of temporal diagnosis (χ2(3) = 4.72; p = 0.19).
Concussions diagnosed immediately after an impact event are associated with the highest kinematic measures, while those characterized by delayed diagnosis are preceded by a higher number of impacts.
PMCID: PMC3605273  PMID: 23135364
HIT System; impact biomechanics; MTBI; TBI; injury threshold; symptomatology
8.  Animal models for highly pathogenic emerging viruses 
Current opinion in virology  2013;3(2):205-209.
Exotic and emerging viral pathogens associated with high morbidity and mortality in humans are being identified annually with recent examples including Lujo virus in southern Africa, Severe fever with Thrombocytopenia virus in China and a SARS-like coronavirus in the Middle East. The sporadic nature of these infections hampers our understanding of these diseases and limits the opportunities to design appropriate medical countermeasures against them. Due to this, animal models are utilized to gain insight into the pathogenesis of disease with the overall goal of identifying potential targets for intervention and evaluating specific therapeutics and vaccines. For these reasons it is imperative that animal models of disease recapitulate the human condition as closely as possible in order to provide the best predictive data with respect to the potential efficacy in humans. In this article we review the current status of disease models for highly pathogenic and emerging viral pathogens.
PMCID: PMC3644300  PMID: 23403208
9.  Soluble P-selectin for the diagnosis of lower extremity deep venous thrombosis 
Although duplex ultrasound is the standard for the diagnosis of lower extremity deep venous thrombosis (LE-DVT), imaging is not always available. The use of D-dimer can exclude (high-sensitivity), but not rule in (low-specificity) LE-DVT. Previously, we demonstrated that soluble P-selectin (sP-sel) in combination with the Wells score, establishes the diagnosis of LE-DVT with a specificity of 96% and a positive predictive value of 100%. In order to validate our previous results, we applied the model to a separate but similar patient cohort. Additionally, we analyzed the role of biomarkers for diagnosing upper extremity DVT (UE-DVT).
Between April 2009 and March 2012, all patients presenting for a duplex ultrasound exam with concern of DVT were screened. Demographics, clinical data, D-dimer, sP-sel, C-reactive protein, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, and von Willebrand factor levels were prospectively collected in 279 patients (234 LE-DVT, 45 UE-DVT). Continuous and categorical variables among patients with DVT were compared with patients without DVT. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were then calculated using our previously derived cut points to rule in or exclude DVT.
Among 234 patients evaluated for LE-DVT, 112 (48%) patients had a confirmed LE-DVT with significant differences in all biomarkers. When Wells score ≥2, sP-sel could rule in LE-DVT with a specificity of 97.5% and a positive predictive value of 91%, which was more accurate than Wells score ≥2 and D-dimer (specificity, 65%; positive predictive value, 69%). When Wells score was <2, D-dimer was superior to sP-sel for excluding the diagnosis of LE-DVT (sensitivity, 98%; negative predictive value, 95% vs sensitivity, 91%; negative predictive value, 79%). The use of additional biomarkers did not increase accuracy. Had imaging not been available, we could have correctly ruled in or ruled out LE-DVT in 29% (67/234) of patients. The use of sP-sel in UE-DVT was nondiagnostic.
We demonstrate that when Wells score ≥2, sP-sel is an excellent biomarker to rule in LE-DVT. Different from our previous study, D-dimer and a Wells score <2 was most sensitive at excluding a diagnosis of LE-DVT. Combined, Wells score, sP-sel, and D-dimer can both rule in and exclude LE-DVT in approximately one-third of patients.
PMCID: PMC3752921  PMID: 23998134
10.  Alcohol Peer Influence of Participating in Organized School Activities: A Network Approach 
This study compares the network influences on adolescent substance use from peers who co-participated in school-sponsored organized activities (affiliation-based peer influence) with the influence both from their “nominated” friends (i.e., the adolescent named the alter as a friend), and only “reciprocated” friends (i.e., both adolescents mutually named each other as friends). The study also attempts to parse affiliation-based peer influence into the influence of both activity members who are also friends, and those who are not, to address the potential confounding of these sources of peer influence.
The study data consisted of a nationally representative sample of 12,551 adolescents in Grades 7–12 within 106 schools from the Add Health data. Ordinal logistic regression was conducted to estimate the effects of affiliation-based and friends influence on alcohol use and drinking frequency.
Peer influence via organized activities (sports or clubs) with drinkers and the influence of friends who drink had significant effects on adolescent drinking. Peer influence through club activities with drinkers had a stronger effect on any drinking behavior than through sports activities with drinkers. After decomposing peer influence through activities by friendship status, influence through sport activities had a significant effect on drinking only when co-participant drinkers were also “reciprocated” friends (but not “nominated” friends), whereas influence through club activities had a significant effect on drinking, regardless of friendship reciprocation.
The design and implementation of school based substance use prevention and treatment programs should consider the contextual effects of school-sponsored activities.
PMCID: PMC3971990  PMID: 22924449
affiliation; peer influence; friends influence; organized school activities; alcohol use; adolescents
11.  Aflatoxin Regulations and Global Pistachio Trade: Insights from Social Network Analysis 
PLoS ONE  2014;9(3):e92149.
Aflatoxins, carcinogenic toxins produced by Aspergillus fungi, contaminate maize, peanuts, and tree nuts in many regions of the world. Pistachios are the main source of human dietary aflatoxins from tree nuts worldwide. Over 120 countries have regulations for maximum allowable aflatoxin levels in food commodities. We developed social network models to analyze the association between nations’ aflatoxin regulations and global trade patterns of pistachios from 1996–2010. The main pistachio producing countries are Iran and the United States (US), which together contribute to nearly 75% of the total global pistachio market. Over this time period, during which many nations developed or changed their aflatoxin regulations in pistachios, global pistachio trade patterns changed; with the US increasingly exporting to countries with stricter aflatoxin standards. The US pistachio crop has had consistently lower levels of aflatoxin than the Iranian crop over this same time period. As similar trading patterns have also been documented in maize, public health may be affected if countries without aflatoxin regulations, or with more relaxed regulations, continually import crops with higher aflatoxin contamination. Unlike the previous studies on maize, this analysis includes a dynamic element, examining how trade patterns change over time with introduction or adjustment of aflatoxin regulations.
PMCID: PMC3966772  PMID: 24670581
12.  Computational Neuropsychiatry – Schizophrenia as a Cognitive Brain Network Disorder 
Computational modeling of functional brain networks in fMRI data has advanced the understanding of higher cognitive function. It is hypothesized that functional networks mediating higher cognitive processes are disrupted in people with schizophrenia. In this article, we review studies that applied measures of functional and effective connectivity to fMRI data during cognitive tasks, in particular working memory fMRI studies. We provide a conceptual summary of the main findings in fMRI data and their relationship with neurotransmitter systems, which are known to be altered in individuals with schizophrenia. We consider possible developments in computational neuropsychiatry, which are likely to further our understanding of how key functional networks are altered in schizophrenia.
PMCID: PMC3971172  PMID: 24723894
computational neuropsychiatry; schizophrenia; fMRI; dynamic causal modeling; cognition; neurotransmitter; dopamine; glutamate
13.  Differential Susceptibility of Two Field Aedes aegypti Populations to a Low Infectious Dose of Dengue Virus 
PLoS ONE  2014;9(3):e92971.
The infectious dose required to infect mosquito vectors when they take a blood meal from a viremic person is a critical parameter underlying the probability of dengue virus (DENV) transmission. Because experimental vector competence studies typically examine the proportion of mosquitoes that become infected at intermediate or high DENV infectious doses in the blood meal, the minimum blood meal titer required to infect mosquitoes is poorly documented. Understanding the factors influencing the lower infectiousness threshold is epidemiologically significant because it determines the transmission potential of humans with a low DENV viremia, possibly including inapparent infections, and during the onset and resolution of the viremic period of acutely infected individuals.
Methodology/Principal Findings
We compared the susceptibility of two field-derived Aedes aegypti populations from Kamphaeng Phet, Thailand when they were orally exposed to low titers of six DENV-2 isolates derived from the serum of naturally infected humans living in the same region. The infectious dose, time-point post-blood feeding, viral isolate and mosquito population, were significant predictors of the proportion of mosquitoes that became infected. Importantly, the dose-response profile differed significantly between the two Ae. aegypti populations. Although both mosquito populations had a similar 50% oral infectious dose (OID50), the slope of the dose-response was shallower in one population, resulting in a markedly higher susceptibility at low blood meal titers.
Our results indicate that mosquitoes in nature vary in their infectious dose-response to DENV. Thus, different mosquito populations have a differential ability to acquire DENV infection at low viremia levels. Future studies on human-to-mosquito DENV transmission should not be limited to OID50 values, but rather they should be expanded to account for the shape of the dose-response profile across a range of virus titers.
PMCID: PMC3963970  PMID: 24664142
14.  Functional MRI of mild traumatic brain injury (mTBI): progress and perspectives from the first decade of studies 
Brain imaging and behavior  2012;6(2):193-207.
Mild traumatic brain injury (mTBI) represents the great majority of traumatic brain injuries, and is a common medical problem affecting cognitive and vocational functioning as well as quality of life in some individuals. Functional MRI (fMRI) is an important research method for investigating the neuroanatomic substrates of cognitive disorders and their treatment. Surprisingly, however, relatively little research has utilized fMRI to examine alterations in brain functioning after mTBI. This article provides a critical overview of the published fMRI research on mTBI to date. These topics include examination of frontal lobe/ executive functions such as working memory, as well as episodic memory and resting state/functional connectivity. mTBI has also been investigated in military populations where studies have focused on effects of blast injury and comorbid conditions such as post-traumatic stress disorder and major depressive disorder. Finally, we address fMRI evaluations of response to behavioral or pharmacological challenges and interventions targeting cognitive and behavioral sequelae of mTBI. The review concludes with identification and discussion of gaps in current knowledge and future directions for fMRI studies of mTBI. The authors conclude that fMRI in combination with related methods can be expected to play an increasing role in research related to studies of pathophysiological mechanisms of the sequelae of mTBI as well as in diagnosis and treatment monitoring.
PMCID: PMC3962305  PMID: 22618832
Episodic memory; Frontal lobes; Functional connectivity; Functional MRI; Mild traumatic brain injury; Working memory
15.  Next Generation MUT-MAP, a High-Sensitivity High-Throughput Microfluidics Chip-Based Mutation Analysis Panel 
PLoS ONE  2014;9(3):e90761.
Molecular profiling of tumor tissue to detect alterations, such as oncogenic mutations, plays a vital role in determining treatment options in oncology. Hence, there is an increasing need for a robust and high-throughput technology to detect oncogenic hotspot mutations. Although commercial assays are available to detect genetic alterations in single genes, only a limited amount of tissue is often available from patients, requiring multiplexing to allow for simultaneous detection of mutations in many genes using low DNA input. Even though next-generation sequencing (NGS) platforms provide powerful tools for this purpose, they face challenges such as high cost, large DNA input requirement, complex data analysis, and long turnaround times, limiting their use in clinical settings. We report the development of the next generation mutation multi-analyte panel (MUT-MAP), a high-throughput microfluidic, panel for detecting 120 somatic mutations across eleven genes of therapeutic interest (AKT1, BRAF, EGFR, FGFR3, FLT3, HRAS, KIT, KRAS, MET, NRAS, and PIK3CA) using allele-specific PCR (AS-PCR) and Taqman technology. This mutation panel requires as little as 2 ng of high quality DNA from fresh frozen or 100 ng of DNA from formalin-fixed paraffin-embedded (FFPE) tissues. Mutation calls, including an automated data analysis process, have been implemented to run 88 samples per day. Validation of this platform using plasmids showed robust signal and low cross-reactivity in all of the newly added assays and mutation calls in cell line samples were found to be consistent with the Catalogue of Somatic Mutations in Cancer (COSMIC) database allowing for direct comparison of our platform to Sanger sequencing. High correlation with NGS when compared to the SuraSeq500 panel run on the Ion Torrent platform in a FFPE dilution experiment showed assay sensitivity down to 0.45%. This multiplexed mutation panel is a valuable tool for high-throughput biomarker discovery in personalized medicine and cancer drug development.
PMCID: PMC3962342  PMID: 24658394
16.  Dissemination and implementation of comparative effectiveness evidence: key informant interviews with Clinical and Translational Science Award institutions 
To identify ongoing practices and opportunities for improving national comparative effectiveness research (CER) translation through dissemination and implementation (D&I) via NIH-funded Clinical and Translational Science Award (CTSA) institutions.
Materials & methods
Key informant interviews were conducted with 18 CTSA grantees sampled to represent a range of D&I efforts.
Results & conclusions
The institutional representatives endorsed fostering CER translation nationally via the CTSA Consortium. However, five themes emerged from the interviews as barriers to CER D&I: lack of institutional awareness, insufficient capacity, lack of established D&I methods, confusion among stakeholders about what CER actually is and limited funding opportunities. Interviewees offered two key recommendations to improve CER translation: development of a centralized clearing house to facilitate the diffusion of CER D&I resources and methods across CTSA institutions; and formalization of the national CTSA network to leverage existing community engagement relationships and resources for the purpose of adapting and disseminating robust CER evidence locally with providers, patients and healthcare systems.
PMCID: PMC3961460  PMID: 24236560
comparative effectiveness research; dissemination; implementation; NIH
17.  The Cognitive Characteristics of PTEN Hamartoma Tumor Syndromes 
To characterize cognition in individuals with germline PTEN mutations (N=23) as well as in PTEN mutation-negative individuals with classic Cowden Syndrome or Bannayan-Riley-Ruvalcaba Syndrome (N=2).
Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. Chi-square analyses compared these classifications to expected proportions in normal control samples.
The mean IQ was in the average range, and there was a wide range of intellectual functioning (extremely low to very superior). However, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall suggesting a pattern of frontal lobe dysfunction in a large subset of participants.
This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous association with intellectual disability, mean IQ was average, and there was a broad range of intellectual abilities. Specific evidence of frontal lobe dysfunction may have implications for treatment compliance and cancer surveillance and warrants further investigation.
PMCID: PMC3956109  PMID: 23470840
PTEN; PTEN Hamartoma Tumor Syndromes; Cowden Syndrome; Bannayan-Riley-Ruvalcaba Syndrome; Cognition; Neuropsychology
18.  Social Media and Physicians’ Online Identity Crisis 
Physicians are increasingly counted among Face-book’s 1 billion users and Twitter’s 500 million members. Beyond these social media platforms, other innovative social media tools are being used in medical practice, including for online consultation,1 in the conduct of clinical research,2 and in medical school curricula.3 Social media content is brief, characterized as “many-to-many” communication, and able to spread rapidly across the Internet beyond a person’s control. These and other features of social media create new dimensions to traditional ethical issues, particularly around maintaining appropriate boundaries between physicians and patients.
PMCID: PMC3954788  PMID: 23942675
20.  Considerations in reporting palliative care clinical trials: Standardizing information reported and authorship practices 
Purpose of Review
The nature of palliative care practice, especially the reliance on referrals and differing models of service delivery, poses unique challenges for the creation and interpretation of an evidence base, frequently limiting the applicability of data to patient care. Here we discuss two core aspects of clinical trials reporting in palliative medicine: 1) proposed standards governing the collection and reporting of data, and 2) rules governing authorship and publication.
Recent Findings
Existing literature often inadequately describes the characteristics of patients, caregivers, clinicians, systems, and interventions included in studies, thereby limiting the utility of results.
A generalizability framework is needed to ensure a robust evidence base that advances practice. Lessons learned through the development of research cooperative groups in palliative care reinforce the importance of an authorship protocol for large trials and working groups.
PMCID: PMC3950540  PMID: 23080306
palliative care; authorship; clinical trial; randomized controlled trials; generalizability
21.  The efficacy of the Cook-Swartz implantable Doppler in the detection of free-flap compromise: a systematic review protocol 
BMJ Open  2014;4(3):e004253.
The Cook-Swartz implantable Doppler monitors venous or arterial blood flow from free flaps and can detect free-flap compromise. Previous studies have shown that the use of this Doppler can improve detection and salvage rates as it provides an earlier warning than the current method of clinical assessment. Such studies assert that the implantable Doppler is of great value in monitoring free flaps in current microsurgical units. This systematic review aims to compare the efficacy of the Cook-Swartz implantable Doppler in monitoring free-flap compromise against conventional clinical free-flap monitoring techniques.
Methods and analysis
Various electronic databases will be systematically searched for studies that compare the use of Cook-Swartz implantable Doppler with clinical assessment. The selected studies will then have their titles and abstracts screened by two authors. Articles selected after title and abstract screen will have full text downloaded and the complete article will be assessed for suitability. Once the articles have been selected for inclusion, data extraction will take place. For data analysis, the outcomes of the studies will be tabulated, with descriptive statistics performed as appropriate and the detection rate of the Doppler and clinical assessment will be compared and synthesised where possible.
Ethics and dissemination
The authors hope to disseminate the findings as widely as possible. This systematic review will be published in a peer-reviewed journal and include a number of recommendations as its conclusion based on the evidence contained within. Given the wide range of specialties now utilising flaps, it will be presented at a wide range of national and international conferences.
Protocol Registration in PROSPERO
The literature search and data extraction went on until 28 January 2014. These steps were revised in line with peer review comments.
PMCID: PMC3963127  PMID: 24622948
23.  Evaluation of Osteoconductive Scaffolds in the Canine Femoral Multi-Defect Model 
Tissue Engineering. Part A  2013;19(5-6):634-648.
Treatment of large segmental bone defects remains an unsolved clinical challenge, despite a wide array of existing bone graft materials. This project was designed to rapidly assess and compare promising biodegradable osteoconductive scaffolds for use in the systematic development of new bone regeneration methodologies that combine scaffolds, sources of osteogenic cells, and bioactive scaffold modifications. Promising biomaterials and scaffold fabrication methods were identified in laboratories at Rutgers, MIT, Integra Life Sciences, and Mayo Clinic. Scaffolds were fabricated from various materials, including poly(L-lactide-co-glycolide) (PLGA), poly(L-lactide-co-ɛ-caprolactone) (PLCL), tyrosine-derived polycarbonate (TyrPC), and poly(propylene fumarate) (PPF). Highly porous three-dimensional (3D) scaffolds were fabricated by 3D printing, laser stereolithography, or solvent casting followed by porogen leaching. The canine femoral multi-defect model was used to systematically compare scaffold performance and enable selection of the most promising substrate(s) on which to add cell sourcing options and bioactive surface modifications. Mineralized cancellous allograft (MCA) was used to provide a comparative reference to the current clinical standard for osteoconductive scaffolds. Percent bone volume within the defect was assessed 4 weeks after implantation using both MicroCT and limited histomorphometry. Bone formed at the periphery of all scaffolds with varying levels of radial ingrowth. MCA produced a rapid and advanced stage of bone formation and remodeling throughout the defect in 4 weeks, greatly exceeding the performance of all polymer scaffolds. Two scaffold constructs, TyrPCPL/TCP and PPF4SLA/HAPLGA Dip, proved to be significantly better than alternative PLGA and PLCL scaffolds, justifying further development. MCA remains the current standard for osteoconductive scaffolds.
PMCID: PMC3568967  PMID: 23215980
24.  A Comparison of Peer Influence Measures as Predictors of Smoking among Predominately Hispanic/Latino High School Adolescents 
Consistent evidence has shown that one of the most significant influences on adolescent smoking is peer influence. There is considerable variation, however, in how peer influence is measured. This study constructs social network influence and selection variables from egocentric and sociometric data to compare their associations with smoking with considerations of perceived smoking norms and adolescent popularity.
Longitudinal data were collected in 9th and 10th grades in October 2006 and 2007 from predominantly Hispanic/Latino adolescents in seven southern California schools among which 1,950 adolescents completed surveys at both waves. Both cross-sectional (separately for 9th and 10th graders) and longitudinal models were estimated.
An ego-centric measure of perceived friend smoking was strongly and consistently associated with individual smoking (AOR 1.80, p<0.001) whereas its sociometric counterpart of friend self-report smoking was only associated with smoking in 9th grade cross-sectional models (e.g., AOR=1.56, p<0.001) and rarely in longitudinal models. Popularity, measured by proportion of nominations received by class size, was associated with smoking and becoming a smoker (AOR=1.67, p<0.001) whereas perceived norms was not in longitudinal models. Friend selection was also associated with becoming a smoker (AOR=1.32, p=0.05).
This study illustrates the utility of ego-centric data for understanding peer influence and underscores the importance of perceptions and popularity as mechanisms that influence adolescent smoking.
PMCID: PMC3580024  PMID: 23299016
social network analysis; peer influence; smoking; perceived smoking; smoking norms; friends
25.  Toward Exercise as Personalized Medicine 
Sports medicine (Auckland, N.Z.)  2013;43(3):157-165.
The early 21st century has witnessed a steady push by scientists, industry leaders, and government officials to make medicine more personalized. To date, the concept of personalized medicine has referred largely to the field of pharmacogenomics. In contrast, relatively few data exist regarding the application of preventive strategies such as physical exercise in the context of personalized medicine. Within this review, we highlight the extant literature and propose five strategies for scientists that may propel the exercise and sports science fields toward this global goal. Notably, these approaches are in addition to methods to maintain adherence to training – a well-known factor in determining exercise responsiveness. Briefly, these strategies include (1) evaluating participant responses to training at the individual as well as group level; (2) identifying sources of variability in responsiveness to training; (3) optimizing exercise dosing strategies to maximize benefits while minimizing barriers to participation; (4) evaluating the efficacy of multimodal interventions for relevant population subgroups; and (5) increasing the clinical relevance of study populations and outcomes in exercise trials. We look forward to seeing these strategies considered in trials of preventive health interventions such as exercise. Extensive future research in this area is needed for the vision of exercise as a personalized form of medicine to become a reality.
PMCID: PMC3595541  PMID: 23382011

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