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1.  Comparative promoter region analysis powered by CORG 
BMC Genomics  2005;6:24.
Promoters are key players in gene regulation. They receive signals from various sources (e.g. cell surface receptors) and control the level of transcription initiation, which largely determines gene expression. In vertebrates, transcription start sites and surrounding regulatory elements are often poorly defined. To support promoter analysis, we present CORG , a framework for studying upstream regions including untranslated exons (5' UTR).
The automated annotation of promoter regions integrates information of two kinds. First, statistically significant cross-species conservation within upstream regions of orthologous genes is detected. Pairwise as well as multiple sequence comparisons are computed. Second, binding site descriptions (position-weight matrices) are employed to predict conserved regulatory elements with a novel approach. Assembled EST sequences and verified transcription start sites are incorporated to distinguish exonic from other sequences.
As of now, we have included 5 species in our analysis pipeline (man, mouse, rat, fugu and zebrafish). We characterized promoter regions of 16,127 groups of orthologous genes. All data are presented in an intuitive way via our web site. Users are free to export data for single genes or access larger data sets via our DAS server . The benefits of our framework are exemplarily shown in the context of phylogenetic profiling of transcription factor binding sites and detection of microRNAs close to transcription start sites of our gene set.
The CORG platform is a versatile tool to support analyses of gene regulation in vertebrate promoter regions. Applications for CORG cover a broad range from studying evolution of DNA binding sites and promoter constitution to the discovery of new regulatory sequence elements (e.g. microRNAs and binding sites).
PMCID: PMC555765  PMID: 15723697
2.  Reliability of Surgeon-Specific Reporting of Complications After Colectomy 
Annals of surgery  2015;261(5):920-925.
We sought to determine the reliability of surgeon-specific postoperative complication rates after colectomy.
Conventional measures of surgeon-specific performance fail to acknowledge variation attributed to statistical noise, risking unreliable assessment of quality.
We examined all patients who underwent segmental colectomy with anastomosis from 2008 through 2010 participating in the Michigan Surgical Quality Collaborative (MSQC) Colectomy Project. Surgeon-specific complication rates were risk-adjusted according to patient characteristics with multiple logistic regression. Hierarchical modeling techniques were used to determine the reliability of surgeon-specific risk-adjusted complication rates. We then adjusted these rates for reliability. To evaluate the extent to which surgeon-level variation was reduced, surgeons were placed into quartiles based on performance and complication rates were compared before and after reliability adjustment
A total of 5,033 patients (n=345 surgeons) undergoing partial colectomy reported a risk-adjusted complication rate of 24.5%. Approximately 86% of the variability of complication rates across surgeons was explained by measurement noise, while the remaining 14% represented true signal. Risk-adjusted complication rates varied from 0% to 55.1% across quartiles prior to adjusting for reliability. Reliability adjustment greatly diminished this variation, generating a 1.2 fold difference (21.4%-25.6%). A caseload of 168 colectomies across three years was required to achieve a reliability of >0.7, which is considered a proficient level. Only one surgeon surpassed this volume threshold.
The vast majority of surgeons do not perform enough colectomies to generate a reliable surgeon-specific complication rate. Risk-adjusted complication rates should be viewed with caution when evaluating surgeons with low operative volume, as statistical noise is a large determinant in estimating their surgeon-specific complication rates.
PMCID: PMC4388106  PMID: 25844969
colectomy; outcomes; health services research; surgeon-specific reporting
3.  Factors Determining Delta-Bilirubin Levels in Biliary Atresia Infants Running head: Delta-Bilirubin in Biliary Atresia 
Delta bilirubin (Bδ) forms when bilirubin conjugates covalently bind to albumin by way of non-enzymatic transesterification in patients with cholestasis. Cholestatic infants with biliary atresia form Bδ. The aim of this study was to investigate the factors determining serum Bδ concentrations in infants with biliary atresia.
Study subjects were infants enrolled into a prospective study (PROBE: NCT00061828) of biliary atresia. We acquired data of concurrently measured serum bilirubin analytes (total bilirubin (TB), conjugated bilirubin (Bc), and unconjugated bilirubin (Bu)) and applied graphical methods and linear mixed effects model to study factors contributing to Bδ variability.
Bδ level increased with increasing levels of Bc and TB. In addition, the length of time cholestasis persisted partially determined the level of Bδ. One mg/dL increase in Bc is related to approximately 0.36 mg/dL increase in Bδ (p < 0.0001); every 100 days of cholestasis is associated with an approximately 1.0 mg/dL increase in Bδ (p < 0.0001) given the same level of Bc. Serum albumin levels are not significantly related to Bδ (p=0.89).
Bδ levels in infants with BA increase with increasing levels of Bc and longer duration of cholestasis. Understanding the relationship between Bδ, Bc, total bilirubin and direct-reacting bilirubin levels can help in interpretation of the clinical extent of cholestasis in infants and children with biliary atresia assisting in the diagnosis and management of these infants.
PMCID: PMC4409472  PMID: 25564820
delta bilirubin; conjugated bilirubin; biliary atresia
4.  The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling 
Photoreceptor genesis in the retina requires precise regulation of progenitor cell competence, cell cycle exit, and differentiation, although information around the mechanisms that govern these events currently is lacking. In zebrafish, the basic helix-loop-helix (bHLH) transcription factor NeuroD governs photoreceptor genesis, but the signaling pathways through which NeuroD functions are unknown. The purpose of this study was to identify these pathways, and during photoreceptor genesis, Notch signaling was investigated as the putative mediator of NeuroD function.
In embryos, genetic mosaic analysis was used to determine if NeuroD functions is cell- or non–cell-autonomous. Morpholino-induced NeuroD knockdown, CRISPR/Cas9 mutation, and pharmacologic and transgenic approaches were used, followed by in situ hybridization, immunocytochemistry, and quantitative RT-PCR (qRT-PCR), to identify mechanisms through which NeuroD functions. In adults, following photoreceptor ablation and NeuroD knockdown, similar methods as above were used to identify NeuroD function during photoreceptor regeneration.
In embryos, NeuroD function is non–cell-autonomous, NeuroD knockdown increases Notch pathway gene expression, Notch inhibition rescues the NeuroD knockdown-induced deficiency in cell cycle exit but not photoreceptor maturation, and Notch activation and CRISPR/Cas9 mutation of neurod recapitulate NeuroD knockdown. In adults, NeuroD knockdown prevents cell cycle exit and photoreceptor regeneration and increases Notch pathway gene expression, and Notch inhibition rescues this phenotype.
These data demonstrate that during embryonic development, NeuroD governs photoreceptor genesis via non–cell-autonomous mechanisms and that, during photoreceptor development and regeneration, Notch signaling is a mechanistic link between NeuroD and cell cycle exit. In contrast, during embryonic development, NeuroD governs photoreceptor maturation via mechanisms that are independent of Notch signaling.
PMCID: PMC4654396  PMID: 26580854
photoreceptor development; photoreceptor regeneration; rods; cones; cell cycle
5.  A contemporary risk model for predicting 30-day mortality following percutaneous coronary intervention in England and Wales 
The current risk model for percutaneous coronary intervention (PCI) in the UK is based on outcomes of patients treated in a different era of interventional cardiology. This study aimed to create a new model, based on a contemporary cohort of PCI treated patients, which would: predict 30 day mortality; provide good discrimination; and be well calibrated across a broad risk-spectrum.
Methods and results
The model was derived from a training dataset of 336,433 PCI cases carried out between 2007 and 2011 in England and Wales, with 30 day mortality provided by record linkage. Candidate variables were selected on the basis of clinical consensus and data quality. Procedures in 2012 were used to perform temporal validation of the model. The strongest predictors of 30-day mortality were: cardiogenic shock; dialysis; and the indication for PCI and the degree of urgency with which it was performed. The model had an area under the receiver operator characteristic curve of 0.85 on the training data and 0.86 on validation. Calibration plots indicated a good model fit on development which was maintained on validation.
We have created a contemporary model for PCI that encompasses a range of clinical risk, from stable elective PCI to emergency primary PCI and cardiogenic shock. The model is easy to apply and based on data reported in national registries. It has a high degree of discrimination and is well calibrated across the risk spectrum. The examination of key outcomes in PCI audit can be improved with this risk-adjusted model.
PMCID: PMC4819905  PMID: 26942330
AUC, area under the receiver operating characteristic curve; BCIS, British Cardiovascular Intervention Society; LVEF, left ventricular ejection fraction; NHS, (UK) National Health Service; MI, myocardial infarction; NICOR, National Institute for Cardiovascular Outcomes Research; NWQIP, North West Quality Improvement Programme; PCI, percutaneous coronary intervention; Angioplasty; Catheterization; Coronary disease; Prognosis; Risk factors
6.  Sports Participation in Genotype Positive Children With Long QT Syndrome 
JACC. Clinical electrophysiology  2015;1(1-2):62-70.
The study sought to examine the prevalence and outcomes of sports participation (both competitive and recreational) in our single-center LQTS genotype positive pediatric population.
The risks of sports participation in patients with long QT syndrome (LQTS) are not clearly elucidated.
A retrospective review was performed on genotype positive patients referred for the evaluation and management of LQTS between 1998 and 2013 at the Children’s Hospital of Philadelphia. Pediatric patients participating in competitive or recreational sports were included in the analysis and their charts were reviewed for documented LQTS events during follow-up.
The cohort of genotype-positive LQTS patients included 212 patients, and 103 patients (49%, female n = 53, average follow-up 7.1 ± 4.0 years, average QTc 468 ± 42 ms) participated in sports. A total of 105 LQTS disease-causing mutations were identified: KCNQ1 n = 60 (58%), KCNH2 n = 36 (35%), SCN5A n = 6 (6%), KCNE1 n = 1 (1%), and KCNE2 n = 2 (2%). All patients were treated with beta-blockade, with noncompliance in 1 patient and intolerance in 1 patient. Twenty-six patients participated in competitive sports (26%, female n = 15, average follow-up 6.9 ± 4.1 years, average QTc 461 ± 35 ms). Seventy-seven patients (75%, female n = 35, average follow-up 7.3 ± 3.9 years, average QTc 470 ± 43 ms) participated in recreational sports. No patients had LQTS symptoms during sports participation. Five appropriate implantable cardioverter-defibrillator shocks occurred in 2 patients, though none were related to sports participation.
In this series no cardiac events and no deaths were observed in treatment-compliant LQTS children while participating in sports in 755 patient-years of follow-up.
PMCID: PMC4540361  PMID: 26301263
cardiac arrest; long QT syndrome; pediatrics; sports participation
7.  Complement factor H binds malondialdehyde epitopes and protects from oxidative stress 
Nature  2011;478(7367):76-81.
Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.
PMCID: PMC4826616  PMID: 21979047
8.  Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression 
We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS).
Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care.
Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission.
HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings.
PMCID: PMC4827101  PMID: 27065108
HIV Care Continuum; Latin America; retention; cART use; viral suppression; cohort studies
9.  Quantifying Contact with the Environment: Behaviors of Young Children in Accra, Ghana 
To better understand the risks of exposure for young children to fecal contamination in their environment, we systematically characterized and quantified behaviors of 154 children, 0–5 years old, in four high-density, low-income neighborhoods in Accra, Ghana. A repertoire of six different activities and five different compartments (categories of locations within the household) was developed, and about 500 hours of ordered structured observations of activities and locations of individual children were collected. These records were analyzed using a competing hazards model, estimating (Weibull) hazard rates for each state (activity/compartment combination), dependent on the present state and the preceding state. The estimated rates were used to simulate sequences of behavior and describe days in the life of a child in low-income, urban Africa. Children younger than 1 year spent most time playing or sleeping off the ground, older children frequently played on floors. Relatively little time was spent in drains or wet trash areas. Critical combinations of activities, like handwashing after defecation or before eating were estimated to occur rarely. These quantitative behavior estimates can inform future risk assessments that examine the relative roles of various fecal–oral exposure pathways in low-income urban settings.
PMCID: PMC4824240  PMID: 26880773
10.  Renal Transplant Recipients Treated with Calcineurin-Inhibitors Lack Circulating Immature Transitional CD19+CD24hiCD38hi Regulatory B-Lymphocytes 
PLoS ONE  2016;11(4):e0153170.
CD19+CD24hiCD38hi transitional immature B-lymphocytes have been demonstrated to play an important role in regulating the alloimmune response in transplant recipients. Here, we analyzed the effect of calcineurin inhibition on these peripherally circulating regulatory B-cells (Breg) in renal transplant recipients receiving cyclosporine A (CsA) or tacrolimus.
PBMCs from healthy subjects (HS) (n = 16) and renal transplant recipients (n = 46) were isolated. Flow cytometry was performed for CD19, CD24, CD38 and IL-10 either after isolation or after 72 hours of co-culture in presence of PMA/Ionomycin and TLR9-ligand in presence or absence of increasing concentrations of tacrolimus or CsA.
The amount of CD19+ B-cells among lymphocytes was ∼9.1% in HS, ∼3.6% in CsA (n = 11, p<0.05) and ∼6.4% in TAC (n = 35, p<0.05) treated patients. Among B-cells, a distinct subset of Breg was found to be 4.7% in HS, 1.4% in tacrolimus treated patients and almost blunted in patients receiving CsA. Similarily, ∼4% of B-cells in HS and even fewer in CsA or tacrolimus treated patients produced IL-10 (0.5% and 1.5%, p<0.05) and this was confirmed both in non-transplanted CsA-treated healthy subjects and in in vitro co-culture experiments. Among 29 patients with <1% of Breg, 9 cases (31%) displayed an allograft rejection in contrast to only one case of rejection (6%) among 17 patients with >1%.
Calcineurin inhibitors reduce number and IL-10 production of Bregs in the peripheral circulation of both renal transplant recipients and non-transplanted healthy subjects. CNI induced Breg reduction is not restricted to a solid organ transplant setting and is not mediated by co-medication with steroids or MPA. A low proportion of Breg cells is associated with an elevated frequency of allograft rejection events.
PMCID: PMC4821620  PMID: 27045291
11.  Getting Physical With the Aortic Valve 
PMCID: PMC4820062  PMID: 21325667
aortic valve disease; extracellular matrix stiffness; TGFβ signaling; mechanosignaling in fibrosis; myofibroblast differentiation
12.  A picture is worth a thousand words: maps of HIV indicators to inform research, programs, and policy from NA-ACCORD and CCASAnet clinical cohorts 
Maps are powerful tools for visualization of differences in health indicators by geographical region, but multi-country maps of HIV indicators do not exist, perhaps due to lack of consistent data across countries. Our objective was to create maps of four HIV indicators in North, Central, and South American countries.
Using data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet), we mapped median CD4 at presentation for HIV clinical care, proportion retained in HIV primary care, proportion prescribed antiretroviral therapy (ART), and the proportion with suppressed plasma HIV viral load (VL) from 2010 to 2012 for North, Central, and South America. The 15 Canadian and US clinical cohorts and 7 clinical cohorts in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru represented approximately 2–7% of persons known to be living with HIV in these countries.
Study populations were selected for each indicator: median CD4 at presentation for care was estimated among 14,811 adults; retention was estimated among 87,979 adults; ART use was estimated among 84,757 adults; and suppressed VL was estimated among 51,118 adults. Only three US states and the District of Columbia had a median CD4 at presentation >350 cells/mm3. Haiti, Mexico, and several states had >85% retention in care; lower (50–74%) retention in care was observed in the US West, South, and Mid-Atlantic, and in Argentina, Brazil, and Peru. ART use was highest (90%) in Mexico. The percentages of patients with suppressed VL in the US South and Northeast were lower than in most of Central and South America.
These maps provide visualization of gaps in the quality of HIV care and allow for comparison between and within countries as well as monitoring policy and programme goals within geographical boundaries.
PMCID: PMC4821890  PMID: 27049052
Map; HIV indicators; CD4 T-lymphocyte count; retention in care; antiretroviral therapy; HIV RNA suppression; North America; Central America; South America; implementation science
13.  The profound effects of patient arm positioning on organ doses from CT procedures calculated using Monte Carlo simulations and deformable phantoms 
Radiation Protection Dosimetry  2014;164(3):368-375.
The purpose of this study was to evaluate the organ dose differences caused by the arms-raised and arms-lowered postures for multidetector computed tomography procedures. Organ doses were calculated using computational phantoms and Monte Carlo simulations. The arm position in two previously developed adult male and female human phantoms was adjusted to represent ‘raised’ and ‘lowered’ postures using advanced BREP-based mesh surface geometries. Organ doses from routine computed tomography (CT) scan protocols, including the chest, abdomen–pelvis, and chest–abdomen–pelvis scans, were simulated at various tube voltages and reported in the unit of mGy per 100 mAs. The CT scanner model was based on previously tested work. The differences in organ dose per unit tube current between raised and lowered arm postures were studied. Furthermore, the differences due to the tube current modulation (TCM) for these two different postures and their impact on organ doses were also investigated. For a given scan parameter, a patient having lowered arms received smaller doses to organs located within the chest, abdomen or pelvis when compared with the patient having raised arms. As expected, this is caused by the attenuation of the primary X rays by the arms. However, the skin doses and bone surface doses in the patient having lowered arms were found to be 3.97–32.12 % larger than those in a patient having raised arms due to the fact that more skin and spongiosa were covered in the scan range when the arms are lowered. This study also found that dose differences become smaller with the increase in tube voltage for most of organs or tissues except the skin. For example, the liver dose differences decreased from −15.01 to −11.33 % whereas the skin dose differences increased from 21.53 to 25.24 % with tube voltage increased from 80 to 140 kVp. With TCM applied, the organ doses of all the listed organs in patient having lowered arms are larger due to the additional tube current necessary to overcome the presence of the arms while maintaining sufficient image quality Arm position affects the dose to internal organs from CT scans by as much as 25.3 %. The presence of arms in the scan range results in a dose increase for the skin and bone surface, but a dose decrease for organs located in the torso. Considering the use of TCM, which is common in many clinics, the patient having lowered arms may receive 50 % higher radiation dose to most of the organs because of the increased tube current. The use of higher tube voltage might narrow such dose differences between patients of these two postures due to the greater penetration of higher-energy X rays. Therefore, when calculating or reporting patient doses from CT scans, it is prudent to select an appropriate phantom that accurately represents the patient posture.
PMCID: PMC4405194  PMID: 25227436
14.  Design criteria for synthetic riboswitches acting on transcription 
RNA Biology  2015;12(2):221-231.
Riboswitches are RNA-based regulators of gene expression composed of a ligand-sensing aptamer domain followed by an overlapping expression platform. The regulation occurs at either the level of transcription (by formation of terminator or antiterminator structures) or translation (by presentation or sequestering of the ribosomal binding site). Due to a modular composition, these elements can be manipulated by combining different aptamers and expression platforms and therefore represent useful tools to regulate gene expression in synthetic biology. Using computationally designed theophylline-dependent riboswitches we show that 2 parameters, terminator hairpin stability and folding traps, have a major impact on the functionality of the designed constructs. These have to be considered very carefully during design phase. Furthermore, a combination of several copies of individual riboswitches leads to a much improved activation ratio between induced and uninduced gene activity and to a linear dose-dependent increase in reporter gene expression. Such serial arrangements of synthetic riboswitches closely resemble their natural counterparts and may form the basis for simple quantitative read out systems for the detection of specific target molecules in the cell.
PMCID: PMC4615730  PMID: 25826571
riboswitch design; synthetic biology; synthetic riboswitch; tandem riboswitch; theophylline aptamer; transcription regulation
15.  Insights into 6‐Methylsalicylic Acid Bio‐assembly by Using Chemical Probes 
Chemical probes capable of reacting with KS (ketosynthase)‐bound biosynthetic intermediates were utilized for the investigation of the model type I iterative polyketide synthase 6‐methylsalicylic acid synthase (6‐MSAS) in vivo and in vitro. From the fermentation of fungal and bacterial 6‐MSAS hosts in the presence of chain termination probes, a full range of biosynthetic intermediates was isolated and characterized for the first time. Meanwhile, in vitro studies of recombinant 6‐MSA synthases with both nonhydrolyzable and hydrolyzable substrate mimics have provided additional insights into substrate recognition, providing the basis for further exploration of the enzyme catalytic activities.
PMCID: PMC4797705  PMID: 26833898
chemical probes; dehydratase; iterative polyketide catalysis
17.  Intramedullary nailing has sufficient durability for metastatic femoral fractures 
Surgical treatment options of femoral metastases include intramedullary nailing (IMN) and endoprosthetic reconstruction (EPR). Previous studies have demonstrated functional and oncological advantages of EPR over IMN. The purpose of this study was to (1) report the durability of IMN and (2) establish the indication of IMN for femoral metastases.
In 2003–2013, among 186 surgically treated femoral metastasis cases, we retrospectively reviewed 80 consecutive IMN cases in 75 patients, including 14 pathological and 66 impending fractures. For the decision of surgical procedure (IMN, EPR, or plating), the following factors are considered: (1) fracture pattern (impending or pathological fracture), (2) Mirels’ score (≥8 or <8), (3) fracture site (femoral head, neck, intertrochanter, subtrochanter, diaphysis, or distal), (4) number of metastases (solitary or multiple), and (5) patient’s estimated prognosis. Patient demographics, postoperative survival, implant survival, and early postoperative mortality were reviewed.
The patients were 37 males and 38 females, with a mean age of 60.1 (20–84) years. Average follow-up period was 11.4 (1–77) months. The most common fracture site was the subtrochanter (46/80), followed by the diaphysis (26/80) and the intertrochanter (8/80). The most common primary tumor was lung cancer (24/80, 32 %), followed by breast cancer (24 %) and melanoma (15 %). With the exception of six cases, all patients underwent postoperative radiotherapy to the affected whole femur. The postoperative patient survival was 14.2 and 8.4 % at 2 and 3 years from surgery, respectively, while the implant survival rate remained 94.0 % at both 2 and 3 years. Three out of 46 subtrochanteric cases required revision surgeries because of proximal breakage of implant 4–50 months after initial surgery for femoral metastases, but all were replaced by mega-prosthesis and did not need further operation until their death. Early postoperative fatal complications were observed in three patients, all of which were pulmonary dysfunction.
The performance of IMN in this study was satisfactory although a large portion of sub- and intertrochanter metastases were included. Broader indication including these parts should be considered, for IMN has advantages such as lower cost and less invasiveness and even an implant failure can be revised by mega-prosthetic reconstruction.
PMCID: PMC4785732  PMID: 26966046
Metastatic femoral fracture; Intramedullary nailing; Postoperative survival; Implant survival
18.  Interactive Data Visualization for HIV Cohorts: Leveraging Data Exchange Standards to Share and Reuse Research Tools 
PLoS ONE  2016;11(3):e0151201.
To develop and disseminate tools for interactive visualization of HIV cohort data.
Design and Methods
If a picture is worth a thousand words, then an interactive video, composed of a long string of pictures, can produce an even richer presentation of HIV population dynamics. We developed an HIV cohort data visualization tool using open-source software (R statistical language). The tool requires that the data structure conform to the HIV Cohort Data Exchange Protocol (HICDEP), and our implementation utilized Caribbean, Central and South America network (CCASAnet) data.
This tool currently presents patient-level data in three classes of plots: (1) Longitudinal plots showing changes in measurements viewed alongside event probability curves allowing for simultaneous inspection of outcomes by relevant patient classes. (2) Bubble plots showing changes in indicators over time allowing for observation of group level dynamics. (3) Heat maps of levels of indicators changing over time allowing for observation of spatial-temporal dynamics. Examples of each class of plot are given using CCASAnet data investigating trends in CD4 count and AIDS at antiretroviral therapy (ART) initiation, CD4 trajectories after ART initiation, and mortality.
We invite researchers interested in this data visualization effort to use these tools and to suggest new classes of data visualization. We aim to contribute additional shareable tools in the spirit of open scientific collaboration and hope that these tools further the participation in open data standards like HICDEP by the HIV research community.
PMCID: PMC4786152  PMID: 26963255
19.  A Psychometric Evaluation of the Danish Version of the Theory of Mind Storybook for 8–14 Year-Old Children 
Background: Theory-of-Mind (ToM) keeps on developing in late childhood and early adolescence, and the study of ToM development later in childhood had to await the development of sufficiently sensitive tests challenging more mature children. The current study aimed to investigate the psychometric properties of the Danish version of the Theory-of-Mind Storybook Frederik (ToM-Frederik).
Methods: We assessed whether ToM-Frederik scores differed between a group of 41 typically developing (TD) children and a group of 33 children with High Functioning Autism Spectrum Disorder (HFASD). A lower mean ToM-Frederik score was expected in the HFASD group. To determine the convergent validity of ToM-Frederik, potential associations with Strange Stories and Animated Triangles (AT) were analyzed. Furthermore, potential associations between ToM-Frederik and the Social Responsiveness Scale (SRS) and between ToM-Frederik and the Social Emotional Evaluation (SEE) Total score were analyzed.
Results: A significantly higher ToM-Frederik score was observed in the TD group compared to the HFASD group. Furthermore, the convergent validity of ToM-Frederik as a measure of ToM was supported by significant and positive associations with the Strange Stories and the AT scores in the HFASD group, whereas ToM-Frederik was significantly correlated with Strange Stories, but not with AT in the TD group. ToM-Frederik was not significantly associated with SRS in neither the HFASD nor the TD group.
Conclusion: The findings are supportive of ToM-Frederik as a valid indicator of deficits at the group level in children with HFASD between 7 and 14 years of age. Furthermore, the convergent validity is supported.
PMCID: PMC4781859  PMID: 27014139
Theory-of-Mind; validation; autism spectrum disorders
20.  Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers under Chloroquine Prophylaxis: A Randomized Controlled Trial 
Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)–infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 104 PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization. Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later. Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events. After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR). After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR. Vaccinees showed weak antibody and no detectable cellular immune responses. Intradermal immunization with up to 3 × 105 PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI.
PMCID: PMC4775905  PMID: 26711509
21.  Noninvasive In Vivo Characterization of Human Carotid Plaques with Acoustic Radiation Force Impulse (ARFI) Ultrasound: Comparison with Histology Following Endarterectomy 
Ultrasound in medicine & biology  2015;41(3):685-697.
Ischemic stroke from thromboembolic sources is linked to carotid artery atherosclerotic disease with a trend toward medical management in asymptomatic patients. Extent of disease is currently diagnosed by noninvasive imaging techniques that measure luminal stenosis, but it has been suggested that a better biomarker for determining risk of future thromboembolic events is plaque morphology and composition. Specifically, plaques that are composed of mechanically-soft lipid/necrotic regions covered by thin fibrous caps are the most vulnerable to rupture. An ultrasound technique that noninvasively interrogates the mechanical properties of soft tissue, called acoustic radiation force impulse (ARFI) imaging, has been developed as a new modality for atherosclerotic plaque characterization using phantoms and atherosclerotic pigs, but the technique has yet to be validated in vivo in humans. In this preliminary study, in vivo ARFI imaging is presented in a case-study format from four patients undergoing clinically-indicated carotid endarterectomy and compared to histology. In two type Va plaques, characterized by lipid/necrotic cores covered by fibrous caps, mean ARFI displacements in focal regions were high relative to the surrounding plaque material, suggesting soft features covered by stiffer layers within the plaques. In two type Vb plaques, characterized by heavy calcification, mean ARFI peak displacements were low relative to the surrounding plaque and arterial wall, suggesting stiff tissue. This pilot study demonstrates the feasibility and challenges of transcutaneous ARFI for characterizing the material and structural composition of carotid atherosclerotic plaques via mechanical properties, in humans, in vivo.
PMCID: PMC4331250  PMID: 25619778
atherosclerosis; stroke; plaque characterization; carotid endarterectomy; CEA; acoustic radiation force; ARFI; ultrasound
22.  Comparison of SGA Oral Medications and a Long-Acting Injectable SGA: The PROACTIVE Study 
Schizophrenia Bulletin  2014;41(2):449-459.
Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician’s choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.
PMCID: PMC4332934  PMID: 24870446
relapse prevention; schizophrenia; psychotic symptoms; negative symptoms; clinical trial design
23.  Bayesian Nonparametric Estimation of Targeted Agent Effects on Biomarker Change to Predict Clinical Outcome 
Biometrics  2014;71(1):188-197.
The effect of a targeted agent on a cancer patient's clinical outcome putatively is mediated through the agent's effect on one or more early biological events. This is motivated by pre-clinical experiments with cells or animals that identify such events, represented by binary or quantitative biomarkers. When evaluating targeted agents in humans, central questions are whether the distribution of a targeted biomarker changes following treatment, the nature and magnitude of this change, and whether it is associated with clinical outcome. Major difficulties in estimating these effects are that a biomarker's distribution may be complex, vary substantially between patients, and have complicated relationships with clinical outcomes. We present a probabilistically coherent framework for modeling and estimation in this setting, including a hierarchical Bayesian nonparametric mixture model for biomarkers that we use to define a functional profile of pre-versus-post treatment biomarker distribution change. The functional is similar to the receiver operating characteristic used in diagnostic testing. The hierarchical model yields clusters of individual patient biomarker profile functionals, and we use the profile as a covariate in a regression model for clinical outcome. The methodology is illustrated by analysis of a dataset from a clinical trial in prostate cancer using imatinib to target platelet-derived growth factor, with the clinical aim to improve progression-free survival time.
PMCID: PMC4383707  PMID: 25319212
Bayesian nonparametrics; Nested Dirichlet Process; Receiving Operating Curve; Biomarker profiles; Survival analysis
24.  Bile Acid Pool Dynamics in Progressive Familial Intrahepatic Cholestasis with Partial External Bile Diversion 
Partial external bile diversion (PEBD) is an established therapy for low-GGT Progressive Familial Intrahepatic Cholestasis (PFIC). This study sought to determine if the dynamics of the cholic acid (CA) and chenodeoxycholic acid (CDCA) pools in low-GGT-PFIC subjects with successful PEBD were equivalent to those achieved with successful liver transplantation (LTX).
The kinetics of CA and CDCA metabolism were measured by stable isotope dilution in plasma samples in 5 PEBD subjects all with intact canalicular BSEP expression and compared to low-GGT-PFIC subjects with successful LTX. Stomal loss of bile acids was measured in PEBD subjects.
The fractional turnover rate for CA in the PEBD group ranged from 0.5 to 4.2 d−1 (LTX group, range 0.2 – 0.9 d−1, p = 0.076) and for CDCA from 0.7 to 4.5 d−1 (LTX group 0.3 – 0.4 d−1, p = 0.009). The CA and CDCA pool sizes were equivalent between groups; however pool composition in PEBD was somewhat more hydrophilic. The CA/CDCA ratio in PEBD ranged from 0.9 to 19.5, whereas in LTX it ranged from 0.5 to 2.6. Synthesis rates computed from isotope dilution correlated well with timed output for both CA: r2 = 0.760, p = 0.024 and CDCA: r2 = 0.690, p = 0.021.
PEBD results in bile acid fractional turnover rates greater than LTX, pool sizes equivalent to LTX and pool composition that is at least as hydrophilic as produced by LTX.
PMCID: PMC4418648  PMID: 25383786
familial cholestasis; surgical treatment of familial cholestasis; bile acid kinetics; liver transplantation
25.  Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats 
Alcohol (Fayetteville, N.Y.)  2015;49(2):127-138.
The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule.
PMCID: PMC4514518  PMID: 25620274
ethanol; multiple schedules; DHEA; pregnanolone; naltrexone; acamprosate; rat

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