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1.  Systemic glucocorticoid use and early-onset basal cell carcinoma 
Annals of epidemiology  2014;24(8):625-627.
doi:10.1016/j.annepidem.2014.05.009
PMCID: PMC4119504  PMID: 24958637
basal cell carcinoma; case-control; epidemiology; glucocorticoids; immunosuppressives; keratinocyte carcinoma; non-melanoma skin cancer
2.  Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study 
Objectives
Tea and coffee are hypothesized to play a protective role in skin carcinogenesis via bioactive components, such as caffeine, yet the epidemiologic evidence is mixed. Existing data supports an inverse association with basal cell carcinoma (BCC) more so than for melanoma or squamous cell carcinoma. To understand if tea, coffee, and caffeine are related to early-onset BCC, we evaluated data from 767 non-Hispanic Whites under age 40 in a case-control study in Connecticut.
Methods
BCC cases (n=377) were identified through Yale's Dermatopathology database. Controls (n=390) were randomly sampled from individuals in the same database with benign skin diagnoses and frequency matched to cases on age, gender, and biopsy site. Subjects completed an in-person interview including assessment of caffeinated coffee and hot tea. We calculated multivariate odds ratios (OR) and 95% confidence intervals (CIs) with unconditional logistic regression for regular consumption and frequency and duration measures.
Results
Combined regular consumption of caffeinated coffee plus hot tea was inversely associated with early-onset BCC (OR=0.60, 95% CI=0.38–0.96). Those in the highest category of caffeine from these sources had a 43% reduced risk of BCC compared to non-consumers (OR=0.57, 95% CI=0.34–0.95, p-trend=0.037).
Conclusions
Our findings suggest a modest protective effect for caffeinated coffee plus tea in relation to early-onset BCC that may, in part, be due to caffeine. This study adds to the growing body of literature suggesting potential health benefits from these beverages.
doi:10.1097/CEJ.0000000000000037
PMCID: PMC4059399  PMID: 24841641
non-melanoma skin cancer; tea; coffee; caffeine; epidemiology
3.  Response Trajectories to Clozapine in a Secondary Analysis of Pivotal Trials Support Using Treatment Response to Subtype Schizophrenia 
Objective:
Groups of nonrefractory patients with schizophrenia, taking antipsychotics other than clozapine, show distinct trajectories of treatment response over time. Whether similar patterns of response occur with clozapine-treated patients remains uncertain.
Method:
We used a cluster analysis approach for longitudinal data (k-means longitudinal) to analyze individual patient data from 2 pivotal studies of clozapine, compared with chlorpromazine. Trajectories and symptom severity were examined in a younger, less chronic, mixed-sample (study 16, n = 100) and in treatment-refractory (study 30, n = 257) patients.
Results:
Early-good and delayed-partial trajectory groups were observed, with the early-good trajectory group comprised of 73/100 (73.0%) from the mixed patient study, and 147/257 (57.2%) refractory patients. In the mixed patient sample, the distribution of clozapine and chlorpromazine treatments did not differ between the early-good and delayed-partial trajectory groups; in refractory patients proportionately more clozapine treatment was present in the early-good (87/147, 59.2%), compared with the delayed-partial (35/110, 31.8%), trajectory group. In the early-good trajectory group, improvement in mean symptom severity was 63% in mixed-study patients. Clozapine resistance appeared to be present in 10/50 (20.0%) mixed-study patients, and in 35/122 (28.9%) refractory patients.
Conclusions:
Early-good and delayed-partial response trajectories are seen in clozapine studies. The advantage of clozapine over chlorpromazine is seen most clearly in previous refractory patients, within the early-good trajectory group. Good and partial or poor responders to clozapine may merit further investigation.
PMCID: PMC4418624  PMID: 25886676
antipsychotics; schizophrenia; trajectories; clinical trial; treatment response
4.  Big Five Personality Characteristics and Adherence to Clinic-Based Rehabilitation Activities after ACL Surgery: A Prospective Analysis 
Purpose
A prospective, longitudinal study was conducted to examine Big Five personality characteristics as predictors of adherence to clinic-based rehabilitation activities following anterior cruciate ligament (ACL) reconstruction surgery.
Method
Participants (72 men, 36 women) completed a questionnaire assessing Big Five personality dimensions prior to surgery. For the first 7 weeks after surgery, participants' rehabilitation session attendance was recorded and rehabilitation professionals rated participants' adherence during rehabilitation sessions..
Results
Results of multiple regression analyses indicated that the 5 personality factors explained 11 percent of the variance in attendance and 17 percent of the variance in adherence ratings, that agreeableness was a significant positive predictor of attendance, and that conscientiousness and openness to experience were significant positive predictors of adherence ratings.
Conclusion
As a potential contributor to adherence, personality warrants consideration when implementing rehabilitation programs after ACL surgery.
PMCID: PMC4316726  PMID: 25663952
attendance; Big Five; compliance; knee; physical therapy; psychology
5.  Functional connectivity in the developing brain: A longitudinal study from 4 to 9 months of age 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.08.038.
We characterize the development of intrinsic connectivity networks (ICNs) from 4 to 9 months of age with resting state magnetic resonance imaging performed on sleeping infants without sedative medication. Data is analyzed with independent component analysis (ICA). Using both low (30 components) and high (100 components) ICA model order decompositions, we find that the functional network connectivity (FNC) map is largely similar at both 4 and 9 months. However at 9 months the connectivity strength decreases within local networks and increases between more distant networks. The connectivity within the default-mode network, which contains both local and more distant nodes, also increases in strength with age. The low frequency power spectrum increases with age only in the posterior cingulate cortex and posterior default mode network. These findings are consistent with a general developmental pattern of increasing longer distance functional connectivity over the first year of life and raise questions regarding the developmental importance of the posterior cingulate at this age.
doi:10.1016/j.neuroimage.2013.08.038
PMCID: PMC3881974  PMID: 23994454
Longitudinal study in infants; Intrinsic connectivity networks; Independent component analysis; Functional network connectivity; High model order analysis
6.  A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2 
Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P < 10−4 and 12 imputed SNPs with P < 10−4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P = 1.30 × 10−5) on chromosome 2 in the independent otitis media population (P = 4.7 × 10−5; meta-analysis P = 1.52 × 10−8). Three additional SNPs had replication P values < 0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P = 3.4 ×10−7) in KIF7 intron 7 (P = 0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P = 0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P = 0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.
doi:10.1007/s10162-013-0411-2
PMCID: PMC3825021  PMID: 23974705
otitis media; genetics; genome; susceptibility; locus
7.  48 echo T2 myelin imaging of white matter in first-episode schizophrenia: Evidence for aberrant myelination 
NeuroImage : Clinical  2014;6:408-414.
Myelin water imaging provides a novel strategy to assess myelin integrity and corresponding clinical relationships in psychosis, of particular relevance in frontal white matter regions. In the current study, T2 myelin water imaging was used to assess the myelin water fraction (MWF) signal from frontal areas in a sample of 58 individuals experiencing first-episode psychosis (FEP) and 44 healthy volunteers. No differences in frontal MWF were observed between FEP subjects and healthy volunteers; however, differences in normal patterns of associations between frontal MWF and age, education and IQ were seen. Significant positive relationships between frontal MWF and age, North American Adult Reading Test (NAART) IQ, and years of completed education were observed in healthy volunteers. In contrast, only the relationship between frontal MWF and NAART IQ was significant after Bonferroni correction in the FEP group. Additionally, significant positive relationships between age and MWF in the anterior and posterior internal capsules, the genu, and the splenium were observed in healthy volunteers. In FEP subjects, only the relationship between age and MWF in the splenium was statistically significant. Frontal MWF was not associated with local white matter volume. Altered patterns of association between age, years of education, and MWF in FEP suggest that subtle disturbances in myelination may be present early in the course of psychosis.
Highlights
•Myelin Water Fraction (MWF) Imaging is a new technique for white matter assessment•MWF imaging revealed abnormal myelination patterns in first-episode psychosis (FEP)•Abnormal frontal MWF associations to age, education and IQ were most apparent in FEP•These findings suggest aberrant frontal myelination occur early in the illness
doi:10.1016/j.nicl.2014.10.006
PMCID: PMC4218939  PMID: 25379454
Myelin water fraction; First-episode psychosis; Schizophrenia; Frontal white matter; ALIC, anterior limb internal capsule; FEP, first episode psychosis; MWF, myelin water fraction; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, version IV; NAART, North American Adult Reading Test
9.  Bacteria in the nose of young adults during wellness and rhinovirus colds - detection by culture and microarray methods in 100 nasal lavage specimens 
International forum of allergy & rhinology  2013;3(9):10.1002/alr.21191.
Background
Patients with viral respiratory infections/viral rhinitis/common colds are often treated with antibiotic although there is little information on whether or how bacterial microbiota in the nose and nasopharynx might influence the course of viral illnesses.
Methods
To initiate investigation of possible interaction between viral respiratory illness and microbiota of the nose/nasopharynx, we utilized microarray technology to examine 100 nasal lavage fluid samples (NLF) for bacterial species and recorded the bacterial titer of culturable bacteria. Rhinovirus illnesses were induced by self-inoculation using the “finger to nose or eye natural transmission route” in ten otherwise healthy young adults. NLF samples were collected during wellness and at specific time points following experimental rhinovirus inoculation.
Results
The rhinovirus infection rate was 70%. There were no consistent changes in the prevalence of different bacterial species determined by microarray and bacterial titer by culture methods during rhinovirus infection. The bacterial profile in NLF samples showed high variability between volunteers but low variability in multiple NLF’s obtained before and following infection from the same volunteer. S. epidermidis/coagulase negative staphylococcus (CNS) were identified in all ten subjects. One or more bacterial sinus/otitis pathogens were identified by microarray in six of the ten volunteers. The microarray identified a few bacteria not included in traditional bacterial cultures.
Conclusion
Our pilot study showed that each of ten volunteers had a unique bacterial profile in the nose by microarray analysis and that bacterial load did not change during experimental rhinovirus colds. Larger scale studies are warranted.
doi:10.1002/alr.21191
PMCID: PMC3859469  PMID: 23801660
Bacteria; rhinovirus; nasopharynx; nasal lavage fluid; microarray
10.  Evaluation of Replication of Variants Associated with Genetic Risk of Otitis Media 
PLoS ONE  2014;9(8):e104212.
The first Genome Wide Association Study (GWAS) of otitis media (OM) found evidence of association in the Western Australian Pregnancy Cohort (Raine) study, but lacked replication in an independent OM population. The aim of this study was to investigate association at these loci in our family-based sample of chronic otitis media with effusion and recurrent otitis media (COME/ROM). Autosomal SNPs were selected from the Raine OM GWAS results. SNPs from the Raine cohort GWAS genotyped in our GWAS of COME/ROM had P-values ranging from P = 0.06–0.80. After removal of SNPs previously genotyped in our GWAS of COME/ROM (N = 21) and those that failed Fluidigm assay design (N = 1), 26 SNPs were successfully genotyped in 716 individuals from our COME/ROM family population. None of the SNP associations replicated in our family-based population (unadjusted P = 0.03–0.93). Replication in an independent sample would confirm that these represent novel OM loci, and that further investigation is warranted.
doi:10.1371/journal.pone.0104212
PMCID: PMC4121324  PMID: 25089819
11.  Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia 
NeuroImage : Clinical  2014;5:298-308.
Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences.
Highlights
•Studied both static and dynamic connectivity changes in schizophrenia during rest•Small but significant connectivity differences might be obscured in static analysis.•Patients show significant differences in dwell times in multiple states.•Disrupted thalamo-cortical connectivity in schizophrenia in a state-specific manner
doi:10.1016/j.nicl.2014.07.003
PMCID: PMC4141977  PMID: 25161896
12.  Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge 
Microbiome  2014;2:22.
Background
The bacterial communities of the nasopharynx play an important role in upper respiratory tract infections (URTIs). Our study represents the first survey of the nasopharynx during a known, controlled viral challenge. We aimed to gain a better understanding of the composition and dynamics of the nasopharyngeal microbiome during viral infection.
Methods
Rhinovirus illnesses were induced by self-inoculation using the finger to nose or eye natural transmission route in ten otherwise healthy young adults. Nasal lavage fluid samples (NLF) samples were collected at specific time points before, during, and following experimental rhinovirus inoculation. Bacterial DNA from each sample (N = 97 from 10 subjects) was subjected to 16S rRNA sequencing by amplifying the V1-V2 hypervariable region followed by sequencing using the 454-FLX platform.
Results
This survey of the nasopharyngeal microbiota revealed a highly complex microbial ecosystem. Taxonomic composition varied widely between subjects and between time points of the same subject. We also observed significantly higher diversity in not infected individuals compared to infected individuals. Two genera – Neisseria and Propionibacterium – differed significantly between infected and not infected individuals. Certain phyla, including Firmicutes, Actinobacteria, and Proteobacteria, were detected in all samples.
Conclusions
Our results reveal the complex and diverse nature of the nasopharyngeal microbiota in both healthy and viral-challenged adults. Although some phyla were common to all samples, differences in levels of diversity and selected phyla were detected between infected and uninfected participants. Deeper, species-level metagenomic sequencing in a larger sample is warranted.
doi:10.1186/2049-2618-2-22
PMCID: PMC4098959  PMID: 25028608
Microbiota; nasopharynx; longitudinal; sequencing; rhinovirus illness
13.  Predictors of Adherence to Home Rehabilitation Exercises Following Anterior Cruciate Ligament Reconstruction 
Rehabilitation psychology  2013;58(1):64-72.
Purpose/Objective
Although home exercises are commonly prescribed following anterior cruciate ligament (ACL) reconstruction and are considered important in obtaining successful rehabilitation outcomes, little is known about factors associated with the completion of such exercises. Consequently, this study was designed to identify predictors of adherence to home rehabilitation exercises after ACL surgery.
Research Method/Design
Participants (33 women, 58 men) completed indices of athletic identity, neuroticism, optimism, and pessimism before ACL surgery and measures of daily pain, negative mood, stress, and home exercise completion for 42 days postoperatively.
Results
Participants reported a high level of adherence to the prescribed regimen. Home exercise completion increased significantly over time as the number of sets of prescribed home exercises declined. Personal factors were not predictive of home exercise completion. Participants completed fewer home exercises on days when they experienced more stress or negative mood.
Conclusions/Implications
Day-to-day variations in negative mood and stress may contribute to adherence to prescribed home exercises.
doi:10.1037/a0031297
PMCID: PMC4045843  PMID: 23438001
compliance; knee; surgery; psychology
14.  Nomenclature for alleles of the thiopurine methyltransferase gene 
Pharmacogenetics and genomics  2013;23(4):242-248.
The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.
doi:10.1097/FPC.0b013e32835f1cc0
PMCID: PMC3727893  PMID: 23407052
allele; nomenclature; pharmacogenetics; thiopurine methyltransferase
15.  Select Neurocognitive Impairment in HIV-Infected Women: Associations with HIV Viral Load, Hepatitis C Virus, and Depression, but Not Leukocyte Telomere Length 
PLoS ONE  2014;9(3):e89556.
Background
Through implementation of combination antiretroviral therapy (cART) remarkable gains have been achieved in the management of HIV infection; nonetheless, the neurocognitive consequences of infection remain a pivotal concern in the cART era. Research has often employed norm-referenced neuropsychological scores, derived from healthy populations (excluding many seronegative individuals at high risk for HIV infection), to characterize impairments in predominately male HIV-infected populations.
Methods
Using matched-group methodology, we assessed 81 HIV-seropositive (HIV+) women with established neuropsychological measures validated for detection of HIV-related impairments, as well as additional detailed tests of executive function and decision-making from the Cambridge Neuropsychological Test Automated Battery (CANTAB).
Results
On validated tests, the HIV+ women exhibited impairments that were limited to significantly slower information processing speed when compared with 45 HIV-seronegative (HIV−) women with very similar demographic backgrounds and illness comorbidities. Additionally, select executive impairments in shifting attention (i.e., reversal learning) and in decision-making quality were revealed in HIV+ participants. Modifiers of neurocognition in HIV-infected women included detectable HIV plasma viral load, active hepatitis C virus co-infection, and self-reported depression symptoms. In contrast, leukocyte telomere length (LTL), a marker of cellular aging, did not significantly differ between HIV+ and HIV− women, nor was LTL associated with overall neurocognition in the HIV+ group.
Conclusions
The findings suggest that well-managed HIV infection may entail a more circumscribed neurocognitive deficit pattern than that reported in many norm-referenced studies, and that common comorbidities make a secondary contribution to HIV-related neurocognitive impairments.
doi:10.1371/journal.pone.0089556
PMCID: PMC3942358  PMID: 24595021
16.  Impaired musical ability in people with schizophrenia 
Background
Assessment of the musical ability of people with schizophrenia has attracted little interest despite the diverse and substantive findings of impairments in sound perception and processing and the therapeutic effect of music in people with the illness. The present study investigated the musical ability of people with schizophrenia and the association with psychiatric symptoms and cognition.
Methods
We recruited patients with chronic schizophrenia and healthy controls for participation in our study. To measure musical ability and cognitive function, we used the Montreal Battery of Evaluation of Amusia (MBEA) and the Brief Assessment of Cognition in Schizophrenia (BACS). We carried out a mediation analysis to investigate a possible pathway to a deficit in musical ability.
Results
We enrolled 50 patients and 58 controls in the study. The MBEA global score in patients with schizophrenia was significantly lower than that in controls (p < 0.001), and was strongly associated with both the composite cognitive function score (r = 0.645, p < 0.001) and the negative symptom score (r = −0.504, p < 0.001). Further analyses revealed direct and indirect effects of negative symptoms on musical ability. The indirect effects were mediated through cognitive impairment.
Limitations
The relatively small sample size did not permit full evaluation of the possible effects of age, sex, education, medication and cultural influences on the results.
Conclusion
Examining the associations between musical deficits, negative symptoms and cognitive imapirment in patients with schizophrenia may identify shared biological mechanisms.
doi:10.1503/jpn.120207
PMCID: PMC3937280  PMID: 24119791
17.  Identification of Cinnabarinic Acid as a Novel Endogenous Aryl Hydrocarbon Receptor Ligand That Drives IL-22 Production 
PLoS ONE  2014;9(2):e87877.
The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.
doi:10.1371/journal.pone.0087877
PMCID: PMC3912126  PMID: 24498387
18.  Personalized Risk Assessment of Drug-Related Harm Is Associated with Health Outcomes 
PLoS ONE  2013;8(11):e79754.
Background
The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users.
Methods
A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes.
Results
Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 0–12). The median CHS was 2845 (interquartile range 1865–3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07–2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02–1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13–1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40–1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46–2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26–1.63, p < 0.001).
Conclusions
Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.
doi:10.1371/journal.pone.0079754
PMCID: PMC3819243  PMID: 24223192
19.  Indoor tanning and risk of early-onset basal cell carcinoma 
Background
Despite a rise in incidence of basal cell carcinoma (BCC) among young people and the ubiquity of indoor tanning in this population, few epidemiologic studies have investigated this exposure-disease relationship.
Objective
Evaluate the association between indoor tanning and early-onset BCC.
Methods
BCC cases (n=376) and controls with minor benign skin conditions (n=390) under age 40 were identified through Yale Dermatopathology. Participants provided information on ever indoor tanning, age of initiation, frequency, duration, burns while tanning, and type of tanning device during an in-person interview. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariate logistic regression with never indoor tanners as the referent group.
Results
Ever indoor tanning was associated with a 69% increased risk of early-onset BCC (95% CI=1.15-2.48). This association was stronger among women (OR=2.14, 95% CI=1.31-3.47), for multiple BCCs (OR=2.16, 95% CI=1.26-3.70), and for BCCs on the trunk and extremities (OR=2.81, 95% CI=1.57-5.02). Risk increased dose-dependently with years used regular indoor tanning devices (p-trend=0.003), number of overall burns (p-trend=<0.001) and burns to biopsy site (p-trend=<0.001) from indoor tanning. Approximately one-quarter (27%) of early-onset BCCs (or 43% among women) could be prevented if individuals never tanned indoors.
Limitations
Potential recall bias of indoor tanning by cases and generalizability of the control population suggest replication in other studies is warranted.
Conclusions
Indoor tanning was a strong risk factor for early-onset BCC, particularly among women. Indoor tanning should continue to be targeted by both policy-based and behavioral interventions, as the impact on BCC-associated morbidity may be substantial.
doi:10.1016/j.jaad.2011.11.940
PMCID: PMC3307842  PMID: 22153793
basal cell carcinoma; epidemiology; indoor tanning; case-control; skin cancer; risk factors
20.  Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy 
PLoS ONE  2013;8(9):e75697.
Tendon injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition.
BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (p<0.05) although no significant difference in calculated modulus of elasticity, lower (improved) histological scoring of organisation (p<0.003) and crimp pattern (p<0.05), lower cellularity (p<0.007), DNA content (p<0.05), vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05), and MMP-13 activity (p<0.02).
Treatment with autologous MSCs in marrow supernatant therefore provides significant benefits compared to untreated tendon repair in enhancing normalisation of biomechanical, morphological, and compositional parameters. These data in natural disease, with no adverse findings, support the use of this treatment for human tendon injuries.
doi:10.1371/journal.pone.0075697
PMCID: PMC3783421  PMID: 24086616
21.  Integration-specific In Vitro Evaluation of Lentivirally Transduced Rhesus CD34+ Cells Correlates With In Vivo Vector Copy Number 
Hematopoietic stem cell (HSC) gene therapy using integrating vectors has a potential leukemogenic risk due to insertional mutagenesis. To reduce this risk, a limitation of ≤2 average vector copy number (VCN) per cell is generally accepted. We developed an assay for VCN among transduced CD34+ cells that reliably predicts in vivo VCN in 16 rhesus recipients of CD34+ cells transduced with a green fluorescent protein (GFP) (or yellow fluorescent protein (YFP))-encoding lentiviral vector. Using GFP (or YFP)-specific probe/primers by real-time PCR, VCN among transduced CD34+ cells had no correlation with VCN among granulocytes or lymphocytes in vivo assayed 6 months post-transplantation. This was a likely result of residual plasmids present in the vector preparation. We then designed self-inactivating long terminal repeat (SIN-LTR)-specific probe/primers, which detect only integrated provirus. Evaluation with SIN-LTR probe/primers resulted in a positive correlation of VCN among transduced CD34+ cells with granulocytes and lymphocytes in vivo. The transduced CD34+ cells had higher VCN (25.1 ± 5.6) as compared with granulocytes (2.8 ± 1) and lymphocytes (2.4 ± 0.7). In summary, an integrated provirus-specific real-time PCR system demonstrated nine- to tenfold higher VCN in transduced CD34+ cells in vitro, as compared with VCN in vivo. Therefore, the restriction of ≤2 VCN before infusion might unnecessarily limit gene transfer efficacy.
doi:10.1038/mtna.2013.49
PMCID: PMC4098567  PMID: 24045711
CD34+ cells; hematopoietic stem cell transplantation; large animal model; lentiviral vector
22.  Increased Immune Gene Expression and Immune Cell Infiltration in High Grade Astrocytoma Distinguish Long from Short-Term Survivors 
Survival in the majority of high grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and survival prediction. Factors associated with long-term survival have not been extensively studied using unbiased genome-wide expression analyses. In the present study, gene expression microarray profiles of HGA from long-term survivors were interrogated for discovery of survival-associated biological factors. Ontology analyses revealed that increased expression of immune function-related genes was the predominant biological factor that positively correlated with longer survival. A notable T-cell signature was present within this prognostic immune gene-set. Using immune cell-specific gene classifiers, both T-cell and myeloid linage-associated genes were shown to be enriched in HGA from long versus short-term survivors. Association of immune function and cell-specific genes with survival was confirmed independently in a larger publicly available glioblastoma gene expression microarray dataset. Histology was used to validate the results of microarray analyses in a larger cohort of long-term survivors of HGA. Multivariate analyses demonstrated that increased immune cell infiltration was a significant independent variable contributing to longer survival, as was Karnofsky/Lansky performance score. These data provide evidence of a prognostic anti-tumor adaptive immune response and rationale for future development of immunotherapy in HGA.
doi:10.4049/jimmunol.1103373
PMCID: PMC3411857  PMID: 22802421
23.  Relationship of Tc-99m Tetrofosmin Gated Rest SPECT Myocardial Perfusion Imaging to Death and Hospitalization in Heart Failure Patients: Results from the Nuclear Ancillary Study of the HF-ACTION Trial 
American heart journal  2011;161(6):1038-1045.
Background
We hypothesized that the severity of resting perfusion abnormalities assessed by the summed rest score (SRS) would be associated with a higher rate of adverse outcomesin patients with heart failure (HF) and reduced left ventricular (LV) ejection fraction (EF).
Methods
A subset of 240 subjects from HF-ACTION underwent resting Tc99m tetrofosmin gated single photon emission computed tomography (SPECT) myocardial perfusion imaging(MPI). Images were evaluated using a 17-segment model to derive the SRS and additional nuclear variables.
Results
After adjusting for pre-specified covariates, SRS was significantly associated with the primary endpoint (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.97–1.00, P=0.04), with a higher SRS corresponding to lower risk of an event. This association was not present in the unadjusted analysis. The relationship between SRS and the primary outcome was likely due to a higher event ratein patients with ischemic HF and a low SRS. The LV phase standard deviation (SD) was not predictive of the primary outcome (HR 1.00; 95% CI 0.99–1.01, P=0.49). In a post hoc analysis, nuclear variables provided incremental prognostic information when added to clinical information (P=0.006).
Conclusions
Gated SPECT MPI provides important information in patients with HF and reduced LVEF. In the adjusted analysis, SRS has an unexpected relationship with the primary endpoint. Phase SD was not associated with the primary endpoint. Rest gated SPECT MPI provides incrementally greater prognostic information than clinical information alone.
doi:10.1016/j.ahj.2011.02.007
PMCID: PMC3739977  PMID: 21641348
heart failure; SPECT; outcomes; coronary artery disease; cardiomyopathy
24.  Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery 
Journal of medical genetics  2008;45(5):290-297.
Background
Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) in its molecular aetiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy.
Aim
To investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrument to identify preclinical symptoms of FXTAS.
Methods
Both premutation carriers with 70–199 repeats (62 men) and their low-repeat allele carrier siblings (27 men), identified through families with an individual affected with FXS, were tested.
Results
As expected, because of its sensitivity, use of the instrument allowed identification of tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not self-reported ataxia. Among subjects with self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and the self-report.
Conclusion
Rates of these traits among premutation carriers and low-repeat allele carrier siblings could be identified, and are presented in this paper, along with the minimum estimates of age-related prevalence.
doi:10.1136/jmg.2007.054676
PMCID: PMC3696494  PMID: 18234731
25.  Droplet-Based Pyrosequencing Using Digital Microfluidics 
Analytical chemistry  2011;83(22):8439-8447.
The feasibility of implementing pyrosequencing chemistry within droplets using electrowetting-based digital microfluidics is reported. An array of electrodes patterned on a printed-circuit board was used to control the formation, transportation, merging, mixing, and splitting of submicroliter-sized droplets contained within an oil-filled chamber. A three-enzyme pyrosequencing protocol was implemented in which individual droplets contained enzymes, deoxyribonucleotide triphosphates (dNTPs), and DNA templates. The DNA templates were anchored to magnetic beads which enabled them to be thoroughly washed between nucleotide additions. Reagents and protocols were optimized to maximize signal over background, linearity of response, cycle efficiency, and wash efficiency. As an initial demonstration of feasibility, a portion of a 229 bp Candida parapsilosis template was sequenced using both a de novo protocol and a resequencing protocol. The resequencing protocol generated over 60 bp of sequence with 100% sequence accuracy based on raw pyrogram levels. Excellent linearity was observed for all of the homopolymers (two, three, or four nucleotides) contained in the C. parapsilosis sequence. With improvements in microfluidic design it is expected that longer reads, higher throughput, and improved process integration (i.e., “sample-to-sequence” capability) could eventually be achieved using this low-cost platform.
doi:10.1021/ac201416j
PMCID: PMC3690483  PMID: 21932784

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