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1.  Novel Methodologic Approaches to Phase I, II, and III Trials 
Stroke; a journal of cerebral circulation  2013;44(6 0 1):S116-S118.
PMCID: PMC3684044  PMID: 23709704
clinical trial design; continual reassessment method; futility design; selection design; adaptive design
2.  Optimal Design for the Precise Estimation of an Interaction Threshold: The Impact of Exposure to a Mixture of 18 Polyhalogenated Aromatic Hydrocarbons 
Traditional additivity models provide little flexibility in modeling the dose–response relationships of the single agents in a mixture. While the flexible single chemical required (FSCR) methods allow greater flexibility, its implicit nature is an obstacle in the formation of the parameter covariance matrix, which forms the basis for many statistical optimality design criteria. The goal of this effort is to develop a method for constructing the parameter covariance matrix for the FSCR models, so that (local) alphabetic optimality criteria can be applied. Data from Crofton et al. are provided as motivation; in an experiment designed to determine the effect of 18 polyhalogenated aromatic hydrocarbons on serum total thyroxine (T4), the interaction among the chemicals was statistically significant. Gennings et al. fit the FSCR interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, providing evidence of a dose-dependent interaction. However, the corresponding likelihood-ratio-based confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, supplemental data are required. Using the available data as the first stage, the Ds-optimal second-stage design criterion was applied to minimize the variance of the hypothesized interaction threshold. Practical concerns associated with the resulting design are discussed and addressed using the penalized optimality criterion. Results demonstrate that the penalized Ds-optimal second-stage design can be used to more precisely define the interaction threshold while maintaining the characteristics deemed important in practice.
PMCID: PMC4035215  PMID: 22640366
Dose-dependent interaction; implicit differentiation; implicit models; optimal design; synergy
3.  The Association of Trauma and PTSD with the Substance Use Profiles of Alcohol and Cocaine Dependent Out-of-Treatment Women 
The association of trauma and PTSD with alcohol and cocaine use is explored to determine if there is additive risk associated with dual dependence. Data were collected from out-of-treatment women enrolled in an HIV-prevention study. Women who experienced a DSM-IV qualifying event (N=791) were stratified into four substance use groups based on lifetime alcohol and cocaine use. Women with lifetime co-morbid alcohol and cocaine dependence experienced significantly more traumatic events, had a higher prevalence of violent events and lifetime diagnosis of PTSD and PTSD-related impairment. There is added risk for associated trauma and subsequent PTSD among women who have dual substance dependence.
PMCID: PMC3992920  PMID: 20958843
4.  A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans 
Psychopharmacology  2013;226(4):721-737.
This study examined the effects of propranolol vs. placebo, administered immediately after a 'retrieval' session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 hr. later during a subsequent 'test' session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up.
CD participants received either 40 mg propranolol or placebo immediately following a 'retrieval' CCE session. The next day, participants received a 'test' session of CCE that was identical to the 'retrieval' session except no medication was administered. Participants underwent a ‘follow-up’ CCE session 1-week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions.
Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use.
This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered and implications of the results for treatment were noted.
PMCID: PMC3637960  PMID: 23460266
Reconsolidation; Retrieval; Craving; Cocaine Dependence; Cue Exposure; Human Subjects
5.  Macrophages and CSF-1 
Organogenesis  2013;9(4):249-260.
Recent focus on the diversity of macrophage phenotype and function signifies that these trophic cells are no longer of exclusive interest to the field of immunology. As key orchestrators of organogenesis, the contribution of macrophages to fetal development is worthy of greater attention. This review summarizes the key functions of macrophages and their primary regulator, colony-stimulating factor (CSF)-1, during development; highlighting trophic mechanisms beyond phagocytosis and outlining their roles in a range of developing organ systems. Advances in the understanding of macrophage polarization and functional heterogeneity are discussed from a developmental perspective. In addition, this review highlights the relevance of CSF-1 as a pleiotropic developmental growth factor and summarizes recent experimental evidence and clinical advancements in the area of CSF-1 and macrophage manipulation in reproduction and organogenic settings. Interrogation of embryonic macrophages also has implications beyond development, with recent attention focused on yolk sac macrophage ontogeny and their role in homeostasis and mediating tissue regeneration.
The regulatory networks that govern development involve a complex range of growth factors, signaling pathways and transcriptional regulators arising from epithelial, mesenchymal and stromal origins. A component of the organogenic milieu common to the majority of developing organs is the tissue macrophage. These hemopoietic cells are part of the mononuclear phagocyte system regulated primarily by colony-stimulating factor (CSF)-1 1, 2.
There is a resurgence in the field of CSF-1 and macrophage biology; where greater understanding of the heterogeneity of these cells is revealing contributions to tissue repair and regeneration beyond the phagocytic and inflammatory functions for which they were traditionally ascribed 3–6. The accumulation of macrophages during tissue injury is no longer viewed as simply a surrogate for disease severity, with macrophages now known to be vital in governing tissue regeneration in many settings 7–11. In particular it is the influence of CSF-1 in regulating an alternative macrophage activation state that is increasingly linked to organ repair in a range of disease models 12–17. With many similarities drawn between organogenesis and regeneration, it is pertinent to re-examine the role of CSF-1 and macrophages in organ development.
PMCID: PMC3903694  PMID: 23974218
macrophages; colony-stimulating factor-1; CSF-1; M-CSF; development; organogenesis; M2
6.  A Prospective Study: Current Problems in Radiotherapy for Nasopharyngeal Carcinoma in Yogyakarta, Indonesia 
PLoS ONE  2014;9(1):e85959.
Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged.
All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT.
Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98−170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57–65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient’s poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient’s insurance type was correlated to DTI in disadvantage for poor people.
Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3–4 months, besides the OTT is extended by 10–12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries.
PMCID: PMC3900459  PMID: 24465811
Pediatric pulmonology  2011;10.1002/ppul.21402.
Examination of ciliary ultrastructure remains the cornerstone diagnostic test for primary ciliary dyskinesia (PCD), a disease of abnormal ciliary structure and/or function. Obtaining a biopsy with sufficient interpretable cilia and producing quality transmission electron micrographs (TEM) is challenging. Methods for processing tissues for optimal preservation of axonemal structures are not standardized. This study describes our experience using a standard operating procedure (SOP) for collecting nasal scrape biopsies and processing TEMs in a centralized laboratory. We enrolled patients with suspected PCD at research sites of the Genetic Disorders of Mucociliary Clearance Consortium. Biopsies were performed according to a SOP whereby curettes were used to scrape the inferior surface of the inferior turbinate, with samples placed in fixative. Specimens were shipped to a central laboratory where TEMs were prepared and blindly reviewed. 448 specimens were obtained from 107 young children (0–5 years), 189 older children (5–18 years), and 152 adults (> 18 years), and 88% were adequate for formal interpretation. The proportion of adequate specimens was higher in adults than in children. 50% of the adequate TEMs showed normal ciliary ultrastructure, 39% showed hallmark ultrastructural changes of PCD, and 11% had indeterminate findings. Among specimens without clearly normal ultrastructure, 72% had defects of the outer and/or inner dynein arms, while 7% had central apparatus defects with or without inner dynein arm defects. In summary, nasal scrape biopsies can be performed in the outpatient setting and yield interpretable samples, when performed by individuals with adequate training and experience according to an SOP.
PMCID: PMC3875629  PMID: 21284095
cilia; nasal biopsy; primary ciliary dyskinesia
8.  Is Rural School-aged Children's Quality of Life Affected by Their Responses to Asthma? 
Journal of pediatric nursing  2011;27(5):491-499.
The unpredictable nature of asthma makes it stressful for children and can affect their quality of life. An exploratory analysis of 183 rural school-aged children's data was conducted to determine relationships among demographic factors, children's responses to asthma (coping, asthma self-management), and their quality of life (QOL). Coping frequency, asthma severity, and race/ethnicity significantly predicted children's asthma-related QOL. Children reported more frequent coping as asthma-related QOL worsened (higher scores). Children with more asthma severity had worse asthma-related QOL. Post-hoc analyses showed that racial/ethnic minorities reported worse asthma-related QOL scores than did non-Hispanic Whites.
PMCID: PMC3428597  PMID: 22920660
9.  History of Sexual Trauma and Recent HIV-Risk Behaviors of Community-Recruited Substance Using Women 
AIDS and behavior  2011;15(1):172-178.
This study examines whether substance using women exposed to a lifetime sexual trauma (n = 457) are distinguishable from substance using women exposed to non-sexual trauma (n = 275) in terms of demographics, psychopathology and high-risk sexual behaviors. Baseline data were collected from out-of-treatment substance using women enrolled in an HIV prevention study. Logistic regression analyses revealed that when demographics, psychopathology and lifetime indicators of sexual risk were assessed simultaneously, poor health, depression, antisocial personality disorder and lifetime sex-trading were associated with sexual trauma exposure. When these significant factors were controlled, the experience of sexual trauma predicted recent (past 4 month) high risk sexual behaviors such as higher than average sexual partners. Treatment efforts with women who have experienced a sexual trauma may be enhanced by the inclusion of assessments of physical and mental health needs as well as sexual risk awareness training.
PMCID: PMC3785001  PMID: 20625927
Sexual trauma exposure; HIV-risk; Substance dependence
10.  Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke 
The New England journal of medicine  2013;368(10):893-903.
Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain.
We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability).
The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], −6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8–19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, −4.4 to 18.1) and those with a score of 19 or lower (−1.0 percentage point; 95% CI, −10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 0.83).
The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; number, NCT00359424.)
PMCID: PMC3651875  PMID: 23390923
11.  Does a Nephron Deficit Exacerbate the Renal and Cardiovascular Effects of Obesity? 
PLoS ONE  2013;8(9):e73095.
It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance and albumin excretion were measured, and kidneys collected (histopathology, collagen content). Bodyweights of HFF WT (50.6±1.2 g) and HET (48.8±1.4 g) mice were ∼14 g greater than control mice (37.3±1.3 g, 36.4±1.1 g respectively; Pdiet<0.001). Obesity led to significantly greater 24 hr MAP (Pdiet<0.001), heart rate (Pdiet<0.01) and lower locomotor activity (Pdiet<0.01) in HET and WT mice. Whilst there was no significant impact of genotype on 24 hr MAP response to obesity, night-time MAP of obese HET mice was significantly greater than obese WT mice (122.3±1.6 vs 116.9±1.3 mmHg; P<0.05). 24 hr creatinine clearance was 50%, and albumin excretion 180% greater in obese WT and HET mice compared to controls (Pdiet<0.05) but this response did not differ between genotypes. Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001). Obese GDNF HET mice had exacerbated total renal collagen (P<0.01), and greater levels of the collagen I subtype compared to kidneys of obese WT mice. In summary, obese nephron-deficient GDNF HET mice were able to maintain the high creatinine clearances of obese WT mice but at the expense of higher MAP and greater renal fibrosis. Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.
PMCID: PMC3760915  PMID: 24019901
12.  Blood-Based Gene Expression Signatures of Autistic Infants and Toddlers 
Autism spectrum disorders (ASDs) are highly heritable neurodevelopmental disorders that onset clinically during the first years of life. ASD-risk biomarkers expressed early in life could significantly impact diagnosis and treatment, but no transcriptome-wide biomarker classifiers derived from fresh blood samples from children with autism have yet emerged.
Using a community-based, prospective, longitudinal method, we identified 60 infants and toddlers at-risk for ASDs (autistic disorder and pervasive developmental disorder), 34 at-risk for language delay (LD), 17 at-risk for global developmental delay (DD), and 68 typically developing (TD) comparison children. Diagnoses were confirmed via longitudinal follow-up. Each child's mRNA expression profile in peripheral blood mononuclear cells (PBMCs) was determined by microarray.
Potential ASD biomarkers were discovered in one half of the sample and used to build a classifier with high diagnostic accuracy in the remaining half of the sample.
The mRNA expression abnormalities reliably observed in PBMCs, which are safely and easily assayed in babies, offer the first potential peripheral blood-based early biomarker panel of risk for autism in infants and toddlers. Future work should verify these biomarkers and evaluate if they may also serve as indirect indices of deviant molecular neural mechanisms in autism.
PMCID: PMC3756503  PMID: 22917206
autism; biomarker; classifier; microarray; support vector machine
13.  Mutations of DNAH11 in Primary Ciliary Dyskinesia Patients with Normal Ciliary Ultrastructure 
Thorax  2011;67(5):433-441.
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterized by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognized to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in DNAH11.
In order to test further for mutant DNAH11 as a cause of PCD, we sequenced DNAH11 in patients with a PCD clinical phenotype, but no known genetic etiology.
We sequenced 82 exons and intron/exon junctions in DNAH11 in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer ± inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, we sequenced DNAH11 in 13 patients with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Of the 58 unrelated PCD patients with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; plus, 2 PCD patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or Ioss-of-function splice-site mutations.
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
PMCID: PMC3739700  PMID: 22184204
Cilia; Dynein; Kartagener syndrome; Dextrocardia; Heterotaxy
14.  Clinical and Genetic Aspects of Primary Ciliary Dyskinesia / Kartagener Syndrome 
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (DNAH5) or intermediate (DNAI1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for PCD is available for the most common mutations. The respiratory manifestations of PCD (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis and chronic otitis media) reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of PCD patients have laterality defects (including situs inversus totalis and, less commonly, heterotaxy and congenital heart disease), reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most PCD patients have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with PCD.
PMCID: PMC3739704  PMID: 19606528
Primary ciliary dyskinesia; PCD; Kartagener syndrome; situs inversus; dynein
15.  Understanding prognostic benefits of exercise and antidepressant therapy for persons with depression and heart disease: the UPBEAT study – rationale, design, and methodological issues 
Depression is relatively common in patients with coronary heart disease (CHD) and is associated with worse prognosis. Recently there has been interest in evaluating the impact of treating depression on clinical outcomes. Anti-depressant medications have been shown to be safe and efficacious for many patients; exercise also may be effective for treating depression and may also improve cardiopulmonary functioning. However, methodological limitations of previous studies have raised questions about the value of exercise, and no study has compared the effects of exercise with standard anti-depressant medication in depressed cardiac patients.
UPBEAT is a randomized clinical trial (RCT) funded by NHLBI to evaluate the effects of sertraline or exercise compared to placebo on depression and biomarkers of cardiovascular risk in patients with CHD and elevated depressive symptoms.
The UPBEAT study includes 200 stable CHD patients with scores on the Beck Depression Inventory (BDI) ≥ 9 randomized to 4 months of treatment with aerobic exercise, sertraline, or placebo. The primary outcomes include depressive symptoms determined by clinical ratings on the Hamilton Rating Scale for Depression (HAM-D) and measures of heart rate variability (HRV), baroreflex control (BRC), vascular function (i.e., flow-mediated dilation (FMD)), and measures of inflammation and platelet aggregation.
This article reviews the rationale and design of UPBEAT and addresses several key methodologic issues that were carefully considered in the development of this protocol: the use of a placebo control condition in depressed cardiac patients, study design, and selection of intermediate endpoints or biomarkers of cardiovascular risk.
This study is not powered to assess treatment group differences in CHD morbidity and mortality. Intermediate endpoints are not equivalent to ‘hard’ clinical events and further studies are needed to determine the clinical significance of these biomarkers.
The UPBEAT study is designed to assess the efficacy of exercise in treating depression in cardiac patients and evaluates the impact of treating depression on important biomarkers of cardiovascular risk.
PMCID: PMC3677197  PMID: 17942470
16.  Clinical Research and Development of Tuberculosis Diagnostics: Moving From Silos to Synergy 
The Journal of Infectious Diseases  2012;205(Suppl 2):S159-S168.
The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations.
PMCID: PMC3334509  PMID: 22476718
17.  The effect of covariate adjustment for baseline severity in acute stroke clinical trials with responder analysis outcomes 
Trials  2013;14:98.
Traditionally in acute stroke clinical trials, the primary clinical outcome employed is a dichotomized modified Rankin Scale (mRS). New statistical methods, such as responder analysis, are being used in stroke studies to address the concern that baseline prognostic variables, such as stroke severity, impact the likelihood of a successful outcome. Responder analysis allows the definition of success to vary according to baseline prognostic variables, producing a more clinically relevant insight into the actual effect of investigational treatments. It is unclear whether or not statistical analyses should adjust for prognostic variables when responder analysis is used, as the outcome already takes these prognostic variables into account. This research aims to investigate the effect of covariate adjustment in the responder analysis framework in order to determine the appropriate analytic method.
Using a current stroke clinical trial and its pilot studies to guide simulation parameters, 1,000 clinical trials were simulated at varying sample sizes under several treatment effects to assess power and type I error. Covariate-adjusted and unadjusted logistic regressions were used to estimate the treatment effect under each scenario. In the case of covariate-adjusted logistic regression, the trichotomized National Institute of Health Stroke Scale (NIHSS) was used in adjustment.
Under various treatment effect settings, the operating characteristics of the unadjusted and adjusted analyses do not substantially differ. Power and type I error are preserved for both the unadjusted and adjusted analyses.
Our results suggest that, under the given treatment effect scenarios, the decision whether or not to adjust for baseline severity when using a responder analysis outcome should be guided by the needs of the study, as type I error rates and power do not appear to vary largely between the methods. These findings are applicable to stroke trials which use the mRS for the primary outcome, but also provide a broader insight into the analysis of binary outcomes that are defined based on baseline prognostic variables.
Trial registration
This research is part of the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial, Identification Number NCT01369069.
PMCID: PMC3821551  PMID: 24499406
Responder analysis; Sliding dichotomy; Clinical trials; Acute stroke; Modified rankin scale; Baseline severity
18.  M2 macrophage polarisation is associated with alveolar formation during postnatal lung development 
Respiratory Research  2013;14(1):41.
Macrophages are traditionally associated with inflammation and host defence, however a greater understanding of macrophage heterogeneity is revealing their essential roles in non-immune functions such as development, homeostasis and regeneration. In organs including the brain, kidney, mammary gland and pancreas, macrophages reside in large numbers and provide essential regulatory functions that shape organ development and maturation. However, the role of macrophages in lung development and the potential implications of macrophage modulation in the promotion of lung maturation have not yet been ascertained.
Embryonic day (E)12.5 mouse lungs were cultured as explants and macrophages associated with branching morphogenesis were visualised by wholemount immunofluorescence microscopy. Postnatal lung development and the correlation with macrophage number and phenotype were examined using Colony-stimulating factor-1 receptor-enhanced green fluorescent protein (Csf1r-EGFP) reporter mice. Structural histological examination was complemented with whole-body plethysmography assessment of postnatal lung functional maturation over time.
Flow cytometry, real-time (q)PCR and immunofluorescence microscopy were performed to characterise macrophage number, phenotype and localisation in the lung during postnatal development. To assess the impact of developmental macrophage modulation, CSF-1 was administered to neonatal mice at postnatal day (P)1, 2 and 3, and lung macrophage number and phenotype were assessed at P5. EGFP transgene expression and in situ hybridisation was performed to assess CSF-1R location in the developing lung.
Macrophages in embryonic lungs were abundant and densely located within branch points during branching morphogenesis. During postnatal development, structural and functional maturation of the lung was associated with an increase in lung macrophage number. In particular, the period of alveolarisation from P14-21 was associated with increased number of Csf1r-EGFP+ macrophages and upregulated expression of Arginase 1 (Arg1), Mannose receptor 1 (Mrc1) and Chemokine C-C motif ligand 17 (Ccl17), indicative of an M2 or tissue remodelling macrophage phenotype. Administration of CSF-1 to neonatal mice increased trophic macrophages during development and was associated with increased expression of the M2-associated gene Found in inflammatory zone (Fizz)1 and the growth regulator Insulin-like growth factor (Igf)1. The effects of CSF-1 were identified as macrophage-mediated, as the CSF-1R was found to be exclusively expressed on interstitial myeloid cells.
This study identifies the presence of CSF-1R+ M2-polarised macrophages localising to sites of branching morphogenesis and increasing in number during the alveolarisation stage of normal lung development. Improved understanding of the role of macrophages in lung developmental regulation has clinical relevance for addressing neonatal inflammatory perturbation of development and highlights macrophage modulation as a potential intervention to promote lung development.
PMCID: PMC3626876  PMID: 23560845
Macrophage; CSF-1; Lung development; M2; Alveolarisation
19.  Best Practices for Improving Intervention Fidelity That Every Nurse Should Know 
PMCID: PMC3324280  PMID: 22463478
Fidelity; intervention fidelity; treatment fidelity
20.  Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults 
In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines.
Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta2-agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations.
The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified.
The present clinical practice guideline is the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee’s new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence.
PMCID: PMC3373283  PMID: 22536582
Asthma; Clinical practice guideline; Management
21.  Negative Symptoms of Psychosis Correlate with Gene Expression of the Wnt/β-Catenin Signaling Pathway in Peripheral Blood 
Psychiatry Journal  2013;2013:852930.
Genes in the Wnt (wingless)/β-catenin signaling pathway have been implicated in schizophrenia pathogenesis. No study has examined this pathway in the broader context of psychosis symptom severity. We investigated the association between symptom severity scores and expression of 25 Wnt pathway genes in blood from 19 psychotic patients. Significant correlations between negative symptom scores and deshivelled 2 (DVL2) (radj = −0.70; P = 0.0008) and glycogen synthase kinase 3 beta (GSK3B) (radj = 0.48; P = 0.039) were observed. No gene expression levels were associated with positive symptoms. Our findings suggest that the Wnt signaling pathway may harbor biomarkers for severity of negative but not positive symptoms.
PMCID: PMC3820119  PMID: 24236287
22.  The Directed Differentiation of Human iPS Cells into Kidney Podocytes 
PLoS ONE  2012;7(9):e46453.
The loss of glomerular podocytes is a key event in the progression of chronic kidney disease resulting in proteinuria and declining function. Podocytes are slow cycling cells that are considered terminally differentiated. Here we provide the first report of the directed differentiation of induced pluripotent stem (iPS) cells to generate kidney cells with podocyte features. The iPS-derived podocytes share a morphological phenotype analogous with cultured human podocytes. Following 10 days of directed differentiation, iPS podocytes had an up-regulated expression of mRNA and protein localization for podocyte markers including synaptopodin, nephrin and Wilm’s tumour protein (WT1), combined with a down-regulation of the stem cell marker OCT3/4. In contrast to human podocytes that become quiescent in culture, iPS-derived cells maintain a proliferative capacity suggestive of a more immature phenotype. The transduction of iPS podocytes with fluorescent labeled-talin that were immunostained with podocin showed a cytoplasmic contractile response to angiotensin II (AII). A permeability assay provided functional evidence of albumin uptake in the cytoplasm of iPS podocytes comparable to human podocytes. Moreover, labeled iPS-derived podocytes were found to integrate into reaggregated metanephric kidney explants where they incorporated into developing glomeruli and co-expressed WT1. This study establishes the differentiation of iPS cells to kidney podocytes that will be useful for screening new treatments, understanding podocyte pathogenesis, and offering possibilities for regenerative medicine.
PMCID: PMC3460883  PMID: 23029522
23.  Update of Respiratory Tract Disease in Children with Primary Ciliary Dyskinesia 
Primary ciliary dyskinesia (PCD) is a rare genetic disease characterized by abnormal ciliary structure and function leading to impaired mucociliary clearance and chronic progressive sinopulmonary disease. Upper and lower respiratory tract manifestations are cardinal features of PCD. This review summarizes the current state of knowledge of respiratory tract disease in individuals with PCD and highlights the challenges in identifying and quantifying lung disease in very young children with PCD. No specific therapies are available to correct ciliary dysfunction in PCD. Treatment is not evidence based, and recommendations are largely extrapolated from cystic fibrosis and other conditions with impaired mucociliary clearance. There is a pressing need to develop and validate outcome measures, including patient-reported outcomes, that could be used to evaluate potential therapies in PCD. This review concludes with recommendations for clinical endpoints and outcome measures and a prioritized list of treatments to study in PCD clinical trials.
PMCID: PMC3209579  PMID: 21926396
primary ciliary dyskinesia; lung disease; outcome measure; patient-reported outcome; clinical trial
24.  Toxicity of medicinal plants used in traditional medicine in Northern Peru 
Journal of ethnopharmacology  2011;137(1):121-140.
The plant species reported here are traditionally used in Northern Peru for a wide range of illnesses. Most remedies are prepared as ethanol or aqueous extracts and then ingested. The aim of this study was to evaluate the potential toxicity of these extracts.
Materials and methods
The toxicity of ethanolic and water extracts of 341 plant species was determined using a Brine-Shrimp assay.
Overall 24% of the species in water extract and 76% of the species in alcoholic extract showed elevated toxicity levels to brine-shrimp. Although in most cases multiple extracts of the same species showed very similar toxicity values, in some cases the toxicity of different extracts of the same species varied from non-toxic to highly toxic.
Traditional preparation methods take different toxicity levels in aqueous and ethanol extracts into account when choosing the appropriate solvent for the preparation of a remedy.
PMCID: PMC3159793  PMID: 21575699
Medicinal Plants; Ethnobotany; Brine Shrimp; Artemia salina; Toxicity; Northern Peru
25.  The fate of bone marrow-derived cells carrying a polycystic kidney disease mutation in the genetically normal kidney 
BMC Nephrology  2012;13:91.
Polycystic Kidney Disease (PKD) is a genetic condition in which dedifferentiated and highly proliferative epithelial cells form renal cysts and is frequently treated by renal transplantation. Studies have reported that bone marrow-derived cells give rise to renal epithelial cells, particularly following renal injury as often occurs during transplantation. This raises the possibility that bone marrow-derived cells from a PKD-afflicted recipient could populate a transplanted kidney and express a disease phenotype. However, for reasons that are not clear the reoccurrence of PKD has not been reported in a genetically normal renal graft. We used a mouse model to examine whether PKD mutant bone marrow-derived cells are capable of expressing a disease phenotype in the kidney.
Wild type female mice were transplanted with bone marrow from male mice homozygous for a PKD-causing mutation and subjected to renal injury. Y chromosome positive, bone marrow-derived cells in the kidney were assessed for epithelial markers.
Mutant bone marrow-derived cells were present in the kidney. Some mutant cells were within the bounds of the tubule or duct, but none demonstrated convincing evidence of an epithelial phenotype.
Bone marrow-derived cells appear incapable of giving rise to genuine epithelial cells and this is the most likely reason cysts do not reoccur in kidneys transplanted into PKD patients.
PMCID: PMC3502565  PMID: 22931547
Bone marrow-derived epithelial cells; Cyst; Hematopoietic stem cells; Polycystic kidney disease; Proliferation; Renal injury

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