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1.  Optimizing Clinical Trial Enrollment Methods Through "Goal Programming" 
Applied clinical trials  2014;23(6-7):46-50.
Introduction
Clinical trials often fail to reach desired goals due to poor recruitment outcomes, including low participant turnout, high recruitment cost, or poor representation of minorities. At present, there is limited literature available to guide recruitment methodology. This study, conducted by researchers at the University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI), provides an example of how iterative analysis of recruitment data may be used to optimize recruitment outcomes during ongoing recruitment.
Study methodology
UW-CTRI’s research team provided a description of methods used to recruit smokers in two randomized trials (n = 196 and n = 175). The trials targeted low socioeconomic status (SES) smokers and involved time-intensive smoking cessation interventions. Primary recruitment goals were to meet required sample size and provide representative diversity while working with limited funds and limited time. Recruitment data was analyzed repeatedly throughout each study to optimize recruitment outcomes.
Results
Estimates of recruitment outcomes based on prior studies on smoking cessation suggested that researchers would be able to recruit 240 low SES smokers within 30 months at a cost of $72,000. With employment of methods described herein, researchers were able to recruit 374 low SES smokers over 30 months at a cost of $36,260.
Discussion
Each human subjects study presents unique recruitment challenges with time and cost of recruitment dependent on the sample population and study methodology. Nonetheless, researchers may be able to improve recruitment outcomes though iterative analysis of recruitment data and optimization of recruitment methods throughout the recruitment period.
PMCID: PMC4310466  PMID: 25642125
2.  Health worker perspectives on barriers to delivery of routine tuberculosis diagnostic evaluation services in Uganda: a qualitative study to guide clinic-based interventions 
Background
Studies of the quality of tuberculosis (TB) diagnostic evaluation of patients in high burden countries have generally shown poor adherence to international or national guidelines. Health worker perspectives on barriers to improving TB diagnostic evaluation are critical for developing clinic-level interventions to improve guideline implementation.
Methods
We conducted structured, in-depth interviews with staff at six district-level health centers in Uganda to elicit their perceptions regarding barriers to TB evaluation. Interviews were transcribed, coded with a standardized framework, and analyzed to identify emergent themes. We used thematic analysis to develop a logic model depicting health system and contextual barriers to recommended TB evaluation practices. To identify possible clinic-level interventions to improve TB evaluation, we categorized findings into predisposing, enabling, and reinforcing factors as described by the PRECEDE model, focusing on potentially modifiable behaviors at the clinic-level.
Results
We interviewed 22 health center staff between February 2010 and November 2011. Participants identified key health system barriers hindering TB evaluation, including: stock-outs of drugs/supplies, inadequate space and infrastructure, lack of training, high workload, low staff motivation, and poor coordination of health center services. Contextual barrier challenges to TB evaluation were also reported, including the time and costs borne by patients to seek and complete TB evaluation, poor health literacy, and stigma against patients with TB. These contextual barriers interacted with health system barriers to contribute to sub-standard TB evaluation. Examples of intervention strategies that could address these barriers and are related to PRECEDE model components include: assigned mentors/peer coaching for new staff (targets predisposing factor of low motivation and need for support to conduct job duties); facilitated workshops to implement same day microscopy (targets enabling factor of patient barriers to completing TB evaluation), and recognition/incentives for good TB screening practices (targets low motivation and self-efficacy).
Conclusions
Our findings suggest that health system and contextual barriers work together to impede TB diagnosis at health centers and, if not addressed, could hinder TB case detection efforts. Qualitative research that improves understanding of the barriers facing TB providers is critical to developing targeted interventions to improve TB care.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0668-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-014-0668-0
PMCID: PMC4307676  PMID: 25609495
Tuberculosis; Qualitative research; Diagnosis; Barriers; Provider behavior; PRECEDE
3.  DEVELOPMENTAL EXPOSURE OF FETAL OVARIES AND FETAL GERM CELLS TO ENDOMETRIOSIS CAUSES DIFFERENTIAL GENE EXPRESSION IN PRE-IMPLANTATION EMBRYOS OF FIRST AND SECOND GENERATION EMBRYOS OFFSPRING IN AN ENDOMETRIOSIS MODEL 
Fertility and sterility  2013;100(5):10.1016/j.fertnstert.2013.07.007.
Objective
Characterize multigenerational gene expression anomalies in 8-cell stage embryos associated with developmental exposure to endometriosis.
Design
Using an endometriosis model in rats (F0 founder generation), evaluate gene expression in F1 (fetal exposure) and F2 (fetal germ cell exposure) generation 8-cell stage embryos.
Setting
Laboratory
Animals
Endometriosis model in rats (Endo) and controls (Sham)
Interventions
F0 Endo and Sham rats were bred. Half of the pregnant rats were euthanatized on gestational day 3 (F1 8-cell stage embryos); the others gestated to term (F1 females). Adult F1 females were bred and F2 8-cell embryos collected.
Main outcome measures
Maintenance of differential gene expression in F1 and F2 generation 8-cell embryos in endometriosis.
Results
Developmental exposure to endometriosis altered gene signaling pathways including apoptosis, cell cycle process, response to oxidative stress, negative regulation of molecular function and RNA processing. Apoptotic genes Diablo, Casp3, Parp1, Cad and Dnaja3 were increased, Nfkbia transcripts decreased in F1 Endo versus F1 Sham embryos. In F2 Endo versus Sham embryos, Casp3 and Cad were significantly increased plus Parp1 and Nfkbia tended to be elevated.
Conclusions
Fetal and germ cell exposure to endometriosis alters apoptotic gene expression in first and second generation 8-cell stage embryos, supporting the hypothesis of multigenerational inheritance from exposure to endometriosis in utero.
doi:10.1016/j.fertnstert.2013.07.007
PMCID: PMC3847911  PMID: 23954358
endometriosis; embryo; genome analysis; apoptosis; multigenerational
4.  A Mechanistic Systems Pharmacology Model for Prediction of LDL Cholesterol Lowering by PCSK9 Antagonism in Human Dyslipidemic Populations 
PCSK9 is a promising target for the treatment of hyperlipidemia and cardiovascular disease. A Quantitative Systems Pharmacology model of the mechanisms of action of statin and anti-PCSK9 therapies was developed to predict low density lipoprotein (LDL) changes in response to anti-PCSK9 mAb for different treatment protocols and patient subpopulations. Mechanistic interactions and cross-regulation of LDL, LDL receptor, and PCSK9 were modeled, and numerous virtual subjects were developed and validated against clinical data. Simulations predict a slightly greater maximum percent reduction in LDL cholesterol (LDLc) when anti-PCSK9 is administered on statin background therapy compared to as a monotherapy. The difference results primarily from higher PCSK9 levels in patients on statin background. However, higher PCSK9 levels are also predicted to increase clearance of anti-PCSK9, resulting in a faster rebound of LDLc. Simulations of subjects with impaired LDL receptor (LDLR) function predict compromised anti-PCSK9 responses in patients such as homozygous familial hypercholesterolemics, whose functional LDLR is below 10% of normal.
doi:10.1038/psp.2014.47
PMCID: PMC4260002  PMID: 25426564
5.  DNA-Methylation Gene Network Dysregulation in Peripheral Blood Lymphocytes of Schizophrenia Patients 
Schizophrenia research  2013;150(1):312-318.
The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways -- DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients.
The finding that the expression of DNMT1and TET1are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients
doi:10.1016/j.schres.2013.07.030
PMCID: PMC4121849  PMID: 23938174
Brain derived neurotrophic factor (BDNF); DNA demethylation; DNA methyltransferase (DNMT); Epigenetic; Glucocorticoid receptor (GCortR); Ten-eleven-translocation hydroxylase (TET)
6.  Shame, guilt, and communication in lung cancer patients and their partners 
Current Oncology  2014;21(5):e718-e722.
Lung cancer patients report the highest distress levels of all cancer groups. In addition to poor prognosis, the self-blame and stigma associated with smoking might partially account for that distress and prevent patients from requesting help and communicating with their partners. The present study used innovative methods to investigate potential links of shame and guilt in lung cancer recovery with distress and marital adjustment. A specific emphasis was an examination of the impact of shame on partner communication. Lung cancer patients (n = 8) and their partners (n = 8) completed questionnaires and interviews that were videotaped. We report descriptive statistics and Spearman correlations between shame and guilt, relationship talk, marital satisfaction, distress, and smoking status. We coded the interviews for nonverbal expressions of shame.
Greater self-reported shame was associated with decreased relationship-talk frequency and marital satisfaction, and with increased depression and smoking behaviour. Nonverbal shame behaviour also correlated with higher depression and increased smoking behaviour. Guilt results were more mixed. More recent smoking behaviour also correlated with higher depression. At a time when lung cancer patients often do not request help for distress, possibly because of shame, our preliminary study suggests that shame can also disrupt important partner relationships and might prevent patients from disclosing to physicians their need for psychosocial intervention and might increase their social isolation. Even if patients cannot verbally disclose their distress, nonverbal cues could potentially give clinicians an opportunity to intervene.
doi:10.3747/co.21.2034
PMCID: PMC4189577  PMID: 25302043
Lung cancer; shame; guilt; communication; relationships; smoking
7.  Assessing the Quality of Tuberculosis Evaluation for Children with Prolonged Cough Presenting to Routine Community Health Care Settings in Rural Uganda 
PLoS ONE  2014;9(8):e105935.
Background
Improving childhood tuberculosis (TB) evaluation and care is a global priority, but data on performance at community health centers in TB endemic regions are sparse.
Objective
To describe the current practices and quality of TB evaluation for children with cough ≥2 weeks' duration presenting to community health centers in Uganda.
Methods
Cross-sectional analysis of children (<15 years) receiving care at five Level IV community health centers in rural Uganda for any reason between 2009–2012. Quality of TB care was assessed using indicators derived from the International Standards of Tuberculosis Care (ISTC).
Results
From 2009–2012, 1713 of 187,601 (0.9%, 95% CI: 0.4–1.4%) children presenting to community health centers had cough ≥ 2 weeks' duration. Of those children, only 299 (17.5%, 95% CI: 15.7–19.3%) were referred for sputum microscopy, but 251 (84%, 95% CI: 79.8–88.1%) completed sputum examination if referred. The yield of sputum microscopy was only 3.6% (95% CI: 1.3–5.9%), and only 55.6% (95% CI: 21.2–86.3%) of children with acid-fast bacilli positive sputum were started on treatment. Children under age 5 were less likely to be referred for sputum examination and to receive care in accordance with ISTC. The proportion of children evaluated in accordance with ISTC increased over time (4.6% in 2009 to 27.9% in 2012, p = 0.03), though this did not result in increased case-detection.
Conclusion
The quality of TB evaluation was poor for children with cough ≥2 weeks' duration presenting for health care. Referrals for sputum smear microscopy and linkage to TB treatment were key gaps in the TB evaluation process, especially for children under the age of five.
doi:10.1371/journal.pone.0105935
PMCID: PMC4149493  PMID: 25170875
8.  Epigenetic GABAergic Targets in Schizophrenia and Bipolar Disorder 
Neuropharmacology  2010;60(0):1007-1016.
It is becoming increasingly clear that a dysfunction of the GABAergic/glutamatergic network in telencephalic brain structures may be the pathogenetic mechanism underlying psychotic symptoms in schizophrenia (SZ) and bipolar (BP) disorder patients. Data obtained in Costa’s laboratory (1996–2009) suggest that this dysfunction may be mediated primarily by a downregulation in the expression of GABAergic genes (e.g., glutamic acid decarboxylase67 [GAD67] and reelin) associated with DNA-methyltransferase (DNMT)-dependent hypermethylation of their promoters.
A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that induce DNA-demethylation when administered at doses that facilitate chromatin remodeling. The benefits elicited by combining VPA with antipsychotics in the treatment of BP disorder suggest that an investigation of the epigenetic interaction of these drugs is warranted.
Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA’s action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors.
By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising treatment strategy for normalizing GABAergic promoter hypermethylation and the GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP disorder patients.
doi:10.1016/j.neuropharm.2010.10.021
PMCID: PMC4144274  PMID: 21074545
9.  Blunted Heart Rate Recovery Is Improved Following Exercise Training in Overweight Adults with Obstructive Sleep Apnea 
International journal of cardiology  2012;167(4):1610-1615.
Background
Obstructive sleep apnea (OSA) predisposes individuals to cardiovascular morbidity, and cardiopulmonary exercise test (CPET) markers prognostic for cardiovascular disease have been found to be abnormal in adults with OSA. Due to the persistence of OSA and its cardiovascular consequences, whether the cardiovascular adaptations normally conferred by exercise are blunted in adults not utilizing established OSA treatment is unknown. The aims of this study were to document whether OSA participants have abnormal CPET responses and determine whether exercise modifies these CPET markers in individuals with OSA.
Methods
The CPET responses of 43 sedentary, overweight adults (body mass index [BMI]>25) with untreated OSA (apnea-hypopnea index [AHI]≥15) were compared against matched non-OSA controls (n=9). OSA participants were then randomized to a 12-week exercise training (n=27) or stretching control treatment (n=16), followed by a post-intervention CPET. Measures of resting, exercise, and post-exercise recovery heart rate (HRR), blood pressure, and ventilation, as well as peak oxygen consumption (VO2peak), were obtained.
Results
OSA participants had blunted HRR compared to non-OSA controls at 1 (P=.03), 3 (P=.02), and 5 min post-exercise (P=.03). For OSA participants, exercise training improved VO2peak (P=.04) and HRR at 1 (P=.03), 3 (P<.01), and 5 min post-exercise (P<.001) compared to control. AHI change was associated with change in HRR at 5-min post-exercise (r=−.30, P<.05), but no other CPET markers.
Conclusions
These results suggest that individuals with OSA have autonomic dysfunction, and that exercise training, by increasing HRR and VO2peak, may attenuate autonomic imbalance and improve functional capacity independent of OSA severity reduction.
doi:10.1016/j.ijcard.2012.04.108
PMCID: PMC3417075  PMID: 22572632
obstructive sleep apnea; exercise testing; exercise training; heart rate recovery; peak oxygen consumption
10.  Influence of Chronic Moderate Sleep Restriction and Exercise Training on Anxiety, Spatial Memory, and Associated Neurobiological Measures in Mice 
Behavioural brain research  2013;250:74-80.
Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training on anxiety-related behavior, spatial memory, and neurobiological correlates in mice. Male mice were randomized to one of four 11-week treatments in a 2 [sleep restriction (~4 h loss/day) vs. ad libitum sleep] × 2 [exercise (1 h/day/6 d/wk) vs. sedentary activity] experimental design. Anxiety-related behavior was assessed with the elevated-plus maze, and spatial learning and memory were assessed with the Morris water maze. Chronic moderate sleep restriction did not alter anxiety-related behavior, but exercise training significantly attenuated anxiety-related behavior. Spatial learning and recall, hippocampal cell activity (i.e., number of c-Fos positive cells), and brain derived neurotrophic factor were significantly lower after chronic moderate sleep restriction, but higher after exercise training. Further, the benefit of exercise training for some memory variables was evident under normal sleep, but not chronic moderate sleep restriction conditions. These data indicate clear detrimental effects of chronic moderate sleep restriction on spatial memory and that the benefits of exercise training were impaired after chronic moderate sleep restriction.
doi:10.1016/j.bbr.2013.04.038
PMCID: PMC3801204  PMID: 23644185
sleep restriction; moderate; anxiety; memory; BDNF; exercise training
11.  Detection of Mycobacterium tuberculosis Peptides in the Exosomes of Patients with Active and Latent M. tuberculosis Infection Using MRM-MS 
PLoS ONE  2014;9(7):e103811.
The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states.
doi:10.1371/journal.pone.0103811
PMCID: PMC4117584  PMID: 25080351
12.  Reducing Methylmercury Accumulation in the Food Webs of San Francisco Bay and Its Local Watersheds 
Environmental research  2012;119:3-26.
San Francisco Bay (California, USA) and its local watersheds present an interesting case study in estuarine mercury (Hg) contamination. This review focuses on the most promising avenues for attempting to reduce methylmercury (MeHg) contamination in Bay Area aquatic food webs and identifying the scientific information that is most urgently needed to support these efforts. Concern for human exposure to MeHg in the region has led to advisories for consumption of sport fish. Striped bass from the Bay have the highest average Hg concentration measured for this species in USA estuaries, and this degree of contamination has been constant for the past 40 years. Similarly, largemouth bass in some Bay Area reservoirs have some of the highest Hg concentrations observed in the entire US. Bay Area wildlife, particularly birds, face potential impacts to reproduction based on Hg concentrations in the tissues of several Bay species. Source control of Hg is one of the primary possible approaches for reducing MeHg accumulation in Bay Area aquatic food webs. Recent findings (particularly Hg isotope measurements) indicate that the decades-long residence time of particle-associated Hg in the Bay is sufficient to allow significant conversion of even the insoluble forms of Hg into MeHg. Past inputs have been thoroughly mixed throughout this shallow and dynamic estuary. The large pool of Hg already present in the ecosystem dominates the fraction converted to MeHg and accumulating in the food web. Consequently, decreasing external Hg inputs can be expected to reduce MeHg in the food web, but it will likely take many decades to centuries before those reductions are achieved. Extensive efforts to reduce loads from the largest Hg mining source (the historic New Almaden mining district) are underway. Hg is spread widely across the urban landscape, but there are a number of key sources, source areas, and pathways that provide opportunities to capture larger quantities of Hg and reduce loads from urban runoff. Atmospheric deposition is a lower priority for source control in the Bay Area due to a combination of a lack of major local sources and Hg isotope data indicating it is a secondary contributor to food web MeHg. Internal net production of MeHg is the dominant source of MeHg that enters the food web. Controlling internal net production is the second primary management approach, and has the potential to reduce food web MeHg more effectively and within a much shorter time-frame. MeHg cycling and control opportunities vary by habitat. Controlling net MeHg production and accumulation in the food web of upstream reservoirs and ponds is very promising due to the many features of these ecosystems that can be manipulated. The most feasible control options in tidal marshes relate to the design of flow patterns and subhabitats in restoration projects. Options for controlling MeHg production in open Bay habitat are limited due primarily to the highly dispersed distribution of Hg throughout the ecosystem. Other changes in these habitats may also have a large influence on food web MeHg, including temperature changes due to global warming, sea level rise, food web alterations due to introduced species and other causes, and changes in sediment supply. Other options for reducing or mitigating exposure and risk include controlling bioaccumulation, cleanup of contaminated sites, and reducing other factors (e.g., habitat availability) that limit at risk wildlife populations.
doi:10.1016/j.envres.2012.10.002
PMCID: PMC4062181  PMID: 23122771
methylmercury; mercury; San Francisco Bay; management; bioaccumulation
13.  Prevalence and Outcomes of Cryptococcal Antigenemia in HIV-seropositive Patients Hospitalized for Suspected Tuberculosis in Uganda 
Background
Cryptococcal infection occurs in HIV-seropositive patients and is associated with high mortality. However, limited information is available on the prevalence and outcomes of cryptococcal antigenemia among hospitalized HIV-seropositive patients in sub-Saharan Africa.
Objectives
To determine the prevalence of and risk factors for cryptococcal antigenemia among HIV-seropositive patients presenting to Mulago Hospital (Kampala, Uganda) with unexplained cough ≥2 weeks and suspected TB, and also to determine if antigenemia is associated with an increased mortality.
Methods
Between September 2009 and September 2010, we enrolled consecutive HIV-seropositive adults hospitalized at Mulago Hospital with cough ≥2 weeks and suspected TB. Banked serum was tested for cryptococcal antigen. We compared demographic, clinical characteristics and 2-month mortality in patients with and without cryptococcal antigenemia.
Results
Of 563 HIV-seropositive patients, 32 (5.7%) were CrAg-positive. None had Cryptococcus neoformans detected on fungal culture of BAL fluid (n=116). CrAg-positive patients had a lower median CD4-count compared to CrAg-negative patients (25 vs. 55 cells/uL, p=0.02) and a substantial proportion of CrAg-positive patients also had concurrent TB (31%). A positive CrAg test was not associated with increased mortality during the 2-month follow-up period (HR: 0.99, 95% CI: 0.63–1.54, p=0.95) after adjusting for CD4 count and ART use at enrollment and/or follow-up.
Conclusions
Occult cryptococcal antigenemia occurs commonly among hospitalized HIV-seropositive patients with suspected TB. CrAg testing should be considered in hospitalized, HIV-seropositive patients with CD4 count <50 cells/uL, coupled with longer follow-up to evaluate the diagnostic value of CrAg and therapeutic interventions in patients with asymptomatic cryptococcal antigenemia.
doi:10.1097/QAI.0b013e3182926f95
PMCID: PMC3779784  PMID: 23542636
Cryptococcus neoformans; antigenemia; tuberculosis; HIV; AIDS
14.  Influence of Urbanicity and County Characteristics on the Association between Ozone and Asthma Emergency Department Visits in North Carolina 
Environmental Health Perspectives  2014;122(5):506-512.
Background: Air pollution epidemiologic studies, often conducted in large metropolitan areas because of proximity to regulatory monitors, are limited in their ability to examine potential associations between air pollution exposures and health effects in rural locations.
Methods: Using a time-stratified case-crossover framework, we examined associations between asthma emergency department (ED) visits in North Carolina (2006–2008), collected by a surveillance system, and short-term ozone (O3) exposures using predicted concentrations from the Community Multiscale Air Quality (CMAQ) model. We estimated associations by county groupings based on four urbanicity classifications (representative of county size and urban proximity) and county health.
Results: O3 was associated with asthma ED visits in all-year and warm season (April–October) analyses [odds ratio (OR) = 1.019; 95% CI: 0.998, 1.040; OR = 1.020; 95% CI: 0.997, 1.044, respectively, for a 20-ppb increase in lag 0–2 days O3]. The association was strongest in Less Urbanized counties, with no evidence of a positive association in Rural counties. Associations were similar when adjusted for fine particulate matter in copollutant models. Associations were stronger for children (5–17 years of age) compared with other age groups, and for individuals living in counties identified with poorer health status compared with counties that had the highest health rankings, although estimated associations for these subgroups had larger uncertainty.
Conclusions: Associations between short-term O3 exposures and asthma ED visits differed by overall county health and urbanicity, with stronger associations in Less Urbanized counties, and no positive association in Rural counties. Results also suggest that children are at increased risk of O3-related respiratory effects.
Citation: Sacks JD, Rappold AG, Davis JA Jr, Richardson DB, Waller AE, Luben TJ. 2014. Influence of urbanicity and county characteristics on the association between ozone and asthma emergency department visits in North Carolina. Environ Health Perspect 122:506–512; http://dx.doi.org/10.1289/ehp.1306940
doi:10.1289/ehp.1306940
PMCID: PMC4014762  PMID: 24569869
15.  Phaeochromocytoma and Acromegaly: a unifying diagnosis 
Summary
A 52-year-old lady was referred after a 5 cm left adrenal mass was detected on computed tomography (CT) scanning. She was asymptomatic although was noted to have acromegalic facies. Blood pressure (BP) was normal but plasma normetanephrines were raised to 2.81 mmol/l (<1.09) and urinary normetadrenaline excretion 5.3 μmol/24 h (0–4.3). Adrenal biochemistry screen was otherwise normal. Metaiodobenzylguanidine (MIBG) scan demonstrated uptake in the adrenal lesion. Growth hormone (GH) nadir on oral glucose tolerance test (OGTT) was 2.2 ng/ml with an elevated IGF1 level of 435 ng/ml (72–215), confirming acromegaly biochemically. The remainder of the pituitary screen was normal. A magnetic resonance imaging (MRI) scan of the pituitary revealed an enlarged pituitary gland with a microadenoma/cyst of 2–3 mm in diameter. Alpha blockade was achieved with a titrated dose of phenoxybenzamine before a successful laparoscopic hand-assisted left adrenalectomy. Postoperative biochemical testing revealed a normal plasma normetanephrine level of 0.6 nmol/l (<1.09) and a metanephrine level of 0.35 nmol/l (<0.46 nmol/l). Nadir on OGTT was normal at 0.07 ng/ml with an IGF1 level within the reference range at 111 ng/ml (75–215). Histology demonstrated a well-circumscribed and encapsulated oval mass with microscopic features typical for a phaeochromocytoma. The sections stained strongly positive for GHRH in 20% of cells on immunocytochemistry. Genetic analysis showed no pathogenic mutation. This is a report of the rare condition of a phaeochromocytoma co-secreting GHRH resulting in clinical and biochemical acromegaly. Neuroendocrine tumours can stain positive for GHRH without coexisting acromegaly, but the resolution of patient symptoms and normalisation of serum GH and IGF1 levels following surgery imply that this was functional secretion. Pituitary surgery should be avoided in such cases.
Learning points
Incidental findings on imaging require thorough investigation to determine the presence of serious pathology.Acromegaly and phaeochromocytoma are rarely coincident in the same patient. If this occurs, co-secretion of GHRH from the phaeochromocytoma or the presence of underlying genetic abnormalities must be considered.Acromegaly is due to ectopic GHRH-secreting neuroendocrine tumours in <1% of cases, most commonly pancreatic or bronchial lesions.Co-secretion of GHRH from a phaeochromocytoma is extremely rare.In such cases, the pituitary gland may appear enlarged but pituitary surgery should be avoided and surgical treatment of the neuroendocrine tumour attempted.
doi:10.1530/EDM-14-0036
PMCID: PMC4038022  PMID: 24897038
17.  The Lung Microbiome of Ugandan HIV-Infected Pneumonia Patients Is Compositionally and Functionally Distinct from That of San Franciscan Patients 
PLoS ONE  2014;9(4):e95726.
Sub-Saharan Africa represents 69% of the total number of individuals living with HIV infection worldwide and 72% of AIDS deaths globally. Pulmonary infection is a common and frequently fatal complication, though little is known regarding the lower airway microbiome composition of this population. Our objectives were to characterize the lower airway microbiome of Ugandan HIV-infected patients with pneumonia, to determine relationships with demographic, clinical, immunological, and microbiological variables and to compare the composition and predicted metagenome of these communities to a comparable cohort of patients in the US (San Francisco). Bronchoalveolar lavage samples from a cohort of 60 Ugandan HIV-infected patients with acute pneumonia were collected. Amplified 16S ribosomal RNA was profiled and aforementioned relationships examined. Ugandan airway microbiome composition and predicted metagenomic function were compared to US HIV-infected pneumonia patients. Among the most common bacterial pulmonary pathogens, Pseudomonas aeruginosa was most prevalent in the Ugandan cohort. Patients with a richer and more diverse airway microbiome exhibited lower bacterial burden, enrichment of members of the Lachnospiraceae and sulfur-reducing bacteria and reduced expression of TNF-alpha and matrix metalloproteinase-9. Compared to San Franciscan patients, Ugandan airway microbiome was significantly richer, and compositionally distinct with predicted metagenomes that encoded a multitude of distinct pathogenic pathways e.g secretion systems. Ugandan pneumonia-associated airway microbiome is compositionally and functionally distinct from those detected in comparable patients in developed countries, a feature which may contribute to adverse outcomes in this population.
doi:10.1371/journal.pone.0095726
PMCID: PMC3994144  PMID: 24752365
18.  The Role of Estrogen Signaling in a Mouse Model of Inflammatory Bowel Disease: A Helicobacter Hepaticus Model 
PLoS ONE  2014;9(4):e94209.
The pathogenesis of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, is due in part to interactions between the immune system, genetics, the environment, and endogenous microbiota. Gonadal sex hormones (GSH), such as estrogen, are thought to be involved in the development of IBD as variations in disease severity occur during pregnancy, menopause, or oral contraceptives use. In certain strains of mice, infection with Helicobacter hepaticus triggers IBD-like mucosal inflammation that is more severe in female mice than in males, suggesting a role for GSH in this model. To determine the role of estrogen signaling in microbiota-induced intestinal inflammation, estrogen receptor (ER) α and β knock-out (KO) mice, ER agonists, and adoptive transfers were utilized. We demonstrate that, when signaling is limited to ERβ on a non-CD4+ cell subset, disease is less severe and this correlates with decreased expression of pro-inflammatory mediators.
doi:10.1371/journal.pone.0094209
PMCID: PMC3978010  PMID: 24709804
19.  Choice of transcripts and software has a large effect on variant annotation 
Genome Medicine  2014;6(3):26.
Background
Variant annotation is a crucial step in the analysis of genome sequencing data. Functional annotation results can have a strong influence on the ultimate conclusions of disease studies. Incorrect or incomplete annotations can cause researchers both to overlook potentially disease-relevant DNA variants and to dilute interesting variants in a pool of false positives. Researchers are aware of these issues in general, but the extent of the dependency of final results on the choice of transcripts and software used for annotation has not been quantified in detail.
Methods
This paper quantifies the extent of differences in annotation of 80 million variants from a whole-genome sequencing study. We compare results using the RefSeq and Ensembl transcript sets as the basis for variant annotation with the software Annovar, and also compare the results from two annotation software packages, Annovar and VEP (Ensembl’s Variant Effect Predictor), when using Ensembl transcripts.
Results
We found only 44% agreement in annotations for putative loss-of-function variants when using the RefSeq and Ensembl transcript sets as the basis for annotation with Annovar. The rate of matching annotations for loss-of-function and nonsynonymous variants combined was 79% and for all exonic variants it was 83%. When comparing results from Annovar and VEP using Ensembl transcripts, matching annotations were seen for only 65% of loss-of-function variants and 87% of all exonic variants, with splicing variants revealed as the category with the greatest discrepancy. Using these comparisons, we characterised the types of apparent errors made by Annovar and VEP and discuss their impact on the analysis of DNA variants in genome sequencing studies.
Conclusions
Variant annotation is not yet a solved problem. Choice of transcript set can have a large effect on the ultimate variant annotations obtained in a whole-genome sequencing study. Choice of annotation software can also have a substantial effect. The annotation step in the analysis of a genome sequencing study must therefore be considered carefully, and a conscious choice made as to which transcript set and software are used for annotation.
doi:10.1186/gm543
PMCID: PMC4062061  PMID: 24944579
21.  Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in zebrafish 
Nature protocols  2013;8(6):1114-1124.
Mycobacterium marinum infected zebrafish are used to study tuberculosis pathogenesis, as well as for antitubercular drug discovery. The small size of zebrafish larvae coupled with their optical transparency allows for rapid analysis of bacterial burdens and host survival in response to genetic and pharmacological manipulations of both mycobacteria and host. Automated fluorescence microscopy and automated plate fluorimetry (APF) are coupled with facile husbandry to facilitate large-scale, repeated analysis of individual infected fish. Both methods allow for in vivo screening of chemical libraries, requiring only 0.1 μmol of drug per fish to assess efficacy; they also permit a more detailed evaluation of the individual stages of tuberculosis pathogenesis. Here we describe a 16-h protocol spanning 22 d, in which zebrafish larvae are infected via the two primary injection sites, the hindbrain ventricle and caudal vein; this is followed by the high-throughput evaluation of pathogenesis and antimicrobial efficacy.
doi:10.1038/nprot.2013.068
PMCID: PMC3919459  PMID: 23680983
22.  Intraocular lymphoma: a clinical perspective 
Eye  2012;27(2):153-162.
Primary vitreoretinal lymphoma (PVRL) is a rare malignancy that is speculated to arise extraocularly, and preferentially invade and flourish in the ocular and CNS microenvironments. The eye is involved in about 20% of primary central nervous system lymphomas, but the brain is eventually involved in about 80% of PVRL. Most are B-cell lymphomas with small numbers of T-cell lymphomas metastatic to the vitreous and retina. Metastatic systemic B-cell lymphoma usually involves choroid. Primary choroidal lymphoma is rare. Intraocular lymphoma can usually be distinguished from uveitis clinically, although there are overlaps, which may be pronounced in eyes with a large component of reactive inflammation related to tumor surveillance and control. There are controversies in diagnosis and treatment. Diagnosis through examination of ocular fluid is technically difficult and can utilize cytology, immunohistochemistry, flow cytometry, molecular detection of gene rearrangements, and cytokine profiling. Treatment of intraocular lymphoma without detectable CNS disease could consist of a full course of systemic chemotherapy with ocular adjunctive treatment, or ocular treatment alone depending on the preference of the clinical center. In ocular only cases where the vitreous has been debulked to improve vision and there is no sight-threatening involvement of the RPE, orbital irradiation or intravitreal chemotherapy stabilizes the intraocular process but does not seem to modify the CNS component, which can present symptomatically in an advanced state. This is a highly malignant disease with a poor prognosis. Close collaboration with a pathologist and oncologist, and good communication with patients is essential.
doi:10.1038/eye.2012.250
PMCID: PMC3574250  PMID: 23196650
intraocular lymphoma; masquerade syndromes; primary vitreoretinal lymphoma; primary central nervous system lymphoma
23.  Diagnostic accuracy of same-day microscopy versus standard microscopy for pulmonary tuberculosis: a systematic review and meta-analysis 
The Lancet infectious diseases  2012;13(2):10.1016/S1473-3099(12)70232-3.
Summary
Background
Sputum smear microscopy is the most widely available diagnostic test for pulmonary tuberculosis in countries with a high burden of the disease. Improving its accuracy is crucial to achievement of case-detection targets established by the Millennium Development Goals. Unfortunately, many patients are unable to submit all of the specimens needed for examination or to return for treatment because standard sputum collection and reporting requires several clinic visits. To inform policy recommendations by a WHO-convened Expert Group, we aimed to assess the accuracy of sputum smear examination with strategies for obtaining sputum on 1 day compared with strategies for obtaining sputum over 2 days.
Methods
We did a systematic review and meta-analysis of research articles comparing the accuracy of front-loaded or same-day microscopy and standard sputum smear microscopy for diagnosis of culture-confirmed pulmonary tuberculosis. We searched Medline, Embase, Biosis, and Web of Science for articles published between Jan 1, 2005, and Feb 14, 2012. Two investigators identified eligible articles and extracted data for individual study sites. We generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random-effects meta-analysis when four or more studies were available.
Findings
We identified eight relevant studies from five articles enrolling 7771 patients with suspected tuberculosis in low-income countries. Compared with the standard approach of examination of two smears with Ziehl-Neelsen light microscopy over 2 days, examination of two smears taken on the same day had much the same sensitivity (64% [95% CI 60 to 69] for standard microscopy vs 63% [58 to 68] for same-day microscopy) and specificity (98% [97 to 99] vs 98% [97 to 99]). We noted similar results for studies employing light-emitting diode fluorescence microscopy and for studies examining three smears, whether they were compared with two-smear strategies or with one another.
Interpretation
Same-day sputum smear microscopy is as accurate as standard smear microscopy. Data from tuberculosis programmes are needed to document the changes required in the health system to successfully implement the strategy and understand its effects.
doi:10.1016/S1473-3099(12)70232-3
PMCID: PMC3836432  PMID: 23099183
24.  Qualitative evaluation of care plans for Canadian breast and head-and-neck cancer survivors 
Current Oncology  2014;21(1):e18-e28.
Background
Survivorship care plans (scps) have been recommended as a way to ease the transition from active cancer treatment to follow-up care, to reduce uncertainty for survivors in the management of their ongoing health, and to improve continuity of care. The objective of the demonstration project reported here was to assess the value of scps for cancer survivors in western Canada.
Methods
The Alberta CancerBridges team developed, implemented, and evaluated scps for 36 breast and 21 head-and-neck cancer survivors. For the evaluation, we interviewed 12 of the survivors, 9 nurses who delivered the scps, and 3 family physicians who received the scps (n = 24 in total). We asked about satisfaction, usefulness, emotional impact, and communication value. We collected written feedback from the three groups about positive aspects of the scps and possible improvements (n = 85). We analyzed the combined data using qualitative thematic analysis.
Results
Survivors, nurses, and family physicians agreed that scps could ease the transition to survivorship partly by enhancing communication between survivors and care providers. Survivors appreciated the individualized attention and the comprehensiveness of the plans. They described positive emotional impacts, but wanted a way to ensure that their physicians received the scps. Nurses and physicians responded positively, but expressed concern about the time required to implement the plans. Suggestions for streamlining the process included providing survivors with scp templates in advance, auto-populating the templates for the nurses, and creating summary pages for physicians.
Conclusions
The results suggest ways in which scps could help to improve the transition to cancer survivorship and provide starting points for larger feasibility studies.
doi:10.3747/co.21.1698
PMCID: PMC3921045  PMID: 24523618
Care plans; survivorship; communication; breast cancer; head-and-neck cancer; qualitative analysis
25.  Effects of 5-fluorouracil chemotherapy on fatigue: Role of MCP-1 
Brain, behavior, and immunity  2012;27(1):155-161.
Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1–5) as well as during the recovery period (day 6–14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1−/− mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p < 0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p = 0.10) and 14 (p < 0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p < 0.05). Both C57BL/6 and MCP-1−/− mice saw similar decrements in PA through the duration of the treatment period (days 1–5), however the MCP-1−/− mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.
doi:10.1016/j.bbi.2012.10.012
PMCID: PMC3711245  PMID: 23085145
Cancer; Inflammation; MCP-1; Fatigue; Chemotherapy

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