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Testing has been central to our response to the COVID-19 pandemic. However, the accuracy of testing relies on standards, including reference materials, proficiency testing schemes, and information and reporting guidelines. The use of standards is a simple, inexpensive, and effective method to ensure reliable test results that inform clinical and public health decisions. Here we describe the central role of standards during the COVID-19 pandemic, where they have enabled population-scale screening, genomic surveillance and measures of immune protection measures. Given these benefits, the Coronavirus Standards Working Group (CSWG) was formed to coordinate standards in SARS-CoV-2 testing. This network of scientists has developed best-practices, reference materials, and conducted proficiency studies to harmonize laboratory performance. We propose that this coordinated development of standards should be prioritized as a key early step in the public health response to future pandemics that is necessary for reliable, large-scale testing for infectious disease.

Relatively little has been reported characterizing cumulative risk associated with co-occurring risk factors for cigarette smoking. The purpose of the present study was to address that knowledge gap in a U.S. nationally representative sample.Data were obtained from 114,426 adults (≥18years) in the U.S. National Survey on Drug Use and Health (years 2011-13). Multiple logistic regression and classification and regression tree (CART) modeling were used to examine risk of current smoking associated with eight co-occurring risk factors (age, gender, race/ethnicity, educational attainment, poverty, drug abuse/dependence, alcohol abuse/dependence, mental illness).Each of these eight risk factors was independently associated with significant increases in the odds of smoking when concurrently present in a multiple logistic regression model. Effects of risk-factor combinations were typically summative. Exceptions to that pattern were in the direction of less-than-summative effects when one of the combined risk factors was associated with generally high or low rates of smoking (e.g., drug abuse/dependence, age ≥65). CART modeling identified subpopulation risk profiles wherein smoking prevalence varied from a low of 11% to a high of 74% depending on particular risk factor combinations. Being a college graduate was the strongest independent predictor of smoking status, classifying 30% of the adult population.These results offer strong evidence that the effects associated with common risk factors for cigarette smoking are independent, cumulative, and generally summative. The results also offer potentially useful insights into national population risk profiles around which U.S. tobacco policies can be developed or refined.

Use of technology (e.g., Internet, cell phones) to allow remote implementation of incentives interventions for health-related behavior change is growing. To our knowledge, there has yet to be a systematic review of this literature reported. The present report provides a systematic review of the controlled studies where technology was used to remotely implement financial incentive interventions targeting substance use and other health behaviors published between 2004 and 2015. For inclusion in the review, studies had to use technology to remotely accomplish one of the following two aims alone or in combination: (a) monitor the target behavior, or (b) deliver incentives for achieving the target goal. Studies also had to examine financial incentives (e.g., cash, vouchers) for health-related behavior change, be published in peer-reviewed journals, and include a research design that allowed evaluation of the efficacy of the incentive intervention relative to another condition (e.g., non-contingent incentives, treatment as usual). Of the 39 reports that met inclusion criteria, 18 targeted substance use, 10 targeted medication adherence or home-based health monitoring, and 11 targeted diet, exercise, or weight loss. All 39 (100%) studies used technology to facilitate remote monitoring of the target behavior, and 26 (66.7%) studies also incorporated technology in the remote delivery of incentives. Statistically significant intervention effects were reported in 71% of studies reviewed. Overall, the results offer substantial support for the efficacy of remotely implemented incentive interventions for health-related behavior change, which have the potential to increase the cost-effectiveness and reach of this treatment approach.

Classic examples of pharmacogenomic biomarkers for drug efficacy include genetic variation in the drug target (including its expression level) and drug metabolizing enzymes (DMEs). Recent US FDA approvals of tests for cytochrome P450 2D6/2C9 and uridine diphosphate glucuronsyltransferase (UGT)1A1 have given regulatory endorsement to biomarkers that can improve drug safety by identifying individuals at risk for drug toxicity. Markers that predict risk for disease can identify patients who will have a greater than average benefit from therapy. This creates a new opportunity to enrich clinical trials with patients who are likely to have more events and to achieve earlier drug approval. Markers that predict for risk of cardiovascular, thrombotic and liver diseases may also identify a subset of individuals at substantially elevated risk for adverse drug effects. The adaptive clinical trial design provides a mechanism for incorporating genomic information during clinical trials, while providing sufficient time for diagnostic product development and co-registration with a new drug application. Genetic biomarkers for drug efficacy and adverse

This report describes results from a systematic literature review examining gender differences in U.S. prevalence rates of current use of tobacco and nicotine delivery products and how they intersect with other vulnerabilities to tobacco use. We searched PubMed on gender differences in tobacco use across the years 2004-2014. For inclusion, reports had to be in English, in a peer-reviewed journal or federal government report, report prevalence rates for current use of a tobacco product in males and females, and use a U.S. nationally representative sample. Prevalence rates were generally higher in males than in females across all products. This pattern remained stable despite changes over time in overall prevalence rates. Gender differences generally were robust when intersecting with other vulnerabilities, although decreases in the magnitude of gender differences were noted among younger and older users, and among educational levels and race/ethnic groups associated with the highest or lowest prevalence rates. Overall, these results document a pervasive association of gender with vulnerability to tobacco use that acts additively with other vulnerabilities. These vulnerabilities should be considered whenever formulating tobacco control and regulatory policies.

Retrievable inferior vena cava (IVC) filter use has increased over 115% since the Food and Drug Administration (FDA) approval in 2009. Likewise, there has been a marked increase in complications related to their increased use. In 2014 the FDA, recognizing both the high rate of new complications and

Objectives We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment. Background Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology. Methods We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial. Results We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval [CI] 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial. Conclusions In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.

This report describes a systematic literature review of voucher and related monetary-based contingency management (CM) interventions for substance use disorders (SUDs) over 5.2 years (November 2009 through December 2014). Reports were identified using the search engine PubMed, expert consultations, and published bibliographies. For inclusion, reports had to (a) involve monetary-based CM; (b) appear in a peer-reviewed journal; (c) include an experimental comparison condition; (d) describe an original study; (e) assess efficacy using inferential statistics; (f) use a research design allowing treatment effects to be attributed to CM. Sixty-nine reports met inclusion criteria and were categorized into 7 research trends: (1) extending CM to special populations, (2) parametric studies, (3) extending CM to community clinics, (4) combining CM with pharmacotherapies, (5) incorporating technology into CM, (6) investigating longer-term outcomes, (7) using CM as a research tool. The vast majority (59/69, 86%) of studies reported significant (p < 0.05) during-treatment effects. Twenty-eight (28/59, 47%) of those studies included at least one follow-up visit after CM was discontinued, with eight (8/28, 29%) reporting significant (p < 0.05) effects. Average effect size (Cohen’s d) during treatment was 0.62 (95% CI: 0.54, 0.70) and post-treatment it was 0.26 (95% CI: 0.11, 0.41). Overall, the literature on voucher-based CM over the past 5 years documents sustained growth, high treatment efficacy, moderate to large effect sizes during treatment that weaken but remain evident following treatment termination, and breadth across a diverse set of SUDs, populations, and settings consistent with and extending results from prior reviews.

This paper examines how the human demand on bioproductive lands, as measured by the Ecological Footprint, is distributed across the globe using methods commonly used to measure the distribution of income. Measuring the distribution of natural resource use will be necessary to achieve an economy that is sustainable, just and efficient. Currently, different nations place different demands on the environment, i.e. the Ecological Footprint is not evenly distributed across the globe. Calculation of the Gini coefficient for total Ecological Footprint and its components explains the sources of inequality in overall resource use. Calculation of the Atkinson index shows how inequality in the Ecological Footprint is related to the inequality of income, and environmental intensity.

INTRODUCTION The present study examines whether use of machine-estimated high-nicotine/tar-yield (full-flavor) cigarettes predicts greater risk of nicotine dependence after controlling for the influence of potential confounding factors in US nationally representative samples. METHODS Data were obtained from multiple years of the National Survey on Drug Use and Health (NSDUH). Nicotine dependence was measured by (1) the Nicotine Dependence Syndrome Scale and (2) latency to first cigarette after waking. Associations between use of high-nicotine/tar-yield cigarettes and risk for nicotine dependence were examined using multiple logistic regression. RESULTS The odds of nicotine dependence were reliably greater among users of high- compared to lower-nicotine/tar-yield cigarettes even after adjusting for sociodemographic and other smoking characteristics (Ps < .0001). This relationship was (1) generally graded across differing nicotine/tar-yield cigarettes, (2) discernible across two definitions of nicotine dependence and multiple NSDUH survey years, and (3) observed among adult and adolescent smokers. CONCLUSION Use of high-nicotine/tar-yield cigarettes is associated with increased odds of nicotine dependence, a relationship that has important tobacco regulatory implications. Whether the widespread marketing and availability of high-nicotine/tar-yield cigarettes is increasing risk of nicotine dependence among US smokers warrants further research. IMPLICATIONS This study adds additional empirical evidence to the relation of machine measured high-yield cigarettes and likelihood of nicotine dependence, and draws some implications in regards to regulation.

Introduction Individuals with lower socioeconomic status (SES) are at increased risk for cigarette smoking. Less research has been conducted characterizing the relationship between SES and risk of using of other tobacco products. The present study examined SES as a risk factor for smokeless tobacco (ST) use in a US nationally representative sample, utilizing data from the 2012 National Survey on Drug Use and Health. Methods Odds were generated for current cigarette smoking and ST use among adults (≥18 years) based on SES markers (educational attainment, income, blue-collar employment, and unemployment) after controlling for the influence of demographics and other substance dependence. Results Odds of current cigarette smoking increased as a graded, inverse function of educational attainment as well as lower income and being unemployed. Odds of current ST use also increased as a function of lower educational attainment, although not in the linear manner seen with cigarette smoking. Odds of ST use but not cigarette smoking also increased with blue-collar employment. In contrast to patterns seen with cigarette smoking, ST use did not change in relation to income or unemployment. Conclusions Markers of SES are significantly associated with odds of cigarette smoking and ST use, but which indicators are predictive and the shape of their relationship to use differs across the two tobacco products.

We examined whether impulsiveness moderates response to financial incentives for cessation among pregnant smokers. All participants were randomized to either a condition wherein financial incentives were delivered contingent on smoking abstinence or to a control condition wherein incentives were delivered independent of smoking status. The study was conducted in two steps: First, we examined associations between baseline impulsiveness scores and abstinence at late pregnancy and 24-weeks postpartum as part of a planned prospective study of this topic using data from a recently completed, randomized controlled clinical trial (N = 118). Next, to increase statistical power, we conducted a second analysis collapsing results across that recent trial and two prior trials involving the same contingent incentive and control conditions (N = 236). Impulsivity was assessed using a delay discounting (DD) of hypothetical monetary rewards task in all three trials and Barratt Impulsiveness Scale (BIS) in the most recent trial. Neither DD nor BIS predicted antepartum or postpartum smoking status in the single or combined trials. Receiving abstinence-contingent incentives, lower baseline smoking rate (cigs/day), and a history of quit attempts pre-pregnancy predicted greater odds of antepartum abstinence across the single and combined trials. No variable predicted postpartum abstinence across the single and combined trials, although a history of antepartum quit attempts and receiving abstinence-contingent incentives predicted in the single and combined trials, respectively. Overall, this study provides no evidence that impulsiveness as assessed by DD or BIS moderates response to this treatment approach while underscoring a substantial association of smoking rate and prior quit attempts with abstinence across the contingent incentives and control treatment conditions.

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), ∼ O.4; 95% confidence interval (CI), 0.2–0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2–3.8; P < 0.05). A unique risk haplotype was present in ∼7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2–2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.

While clinical trials of medications often use a double-blind procedure, the integrity of the blind and its relationship to treatment outcome is seldom examined. In this review, 73 double-blind, placebo-controlled clinical trials of the nicotine replacement therapies (NRTs) in smoking cessation were identified. Seventeen articles were found that assessed blindness integrity, demonstrating major variations in the assessment, analysis, and reporting of blindness integrity. Although 12 studies found that subjects accurately judged treatment assignment at a rate significantly above chance, the available literature does not permit definitive conclusions about blindness integrity. Recommendations for the assessment, analysis, and reporting of blindness integrity are made.

Coccidioides posadasii sp. nov., formerly known as non-California (non-CA) Coccidioides immi- tis, is described. Phylogenetic analyses using single nucleotide polymorphisms, genes, and microsatellites show that C. posadasii represents a divergent, genet- ically recombining monophyletic clade. Coccidioides posadasii can be distinguished from C. immitis by nu- merous DNA polymorphisms, and we show how ei- ther of two microsatellite loci may be used as diag- nostic markers for this species. Growth experiments show that C. posadasii has significantly slower growth rates on high-salt media when compared with C. im- mitis, suggesting that other phenotypic characters may exist.

We investigated three potential predictors (educational attainment, prepregnancy smoking rate, and delay discounting [DD]) of spontaneous quitting among pregnant smokers. These predictors were examined alone and in combination with other potential predictors using study-intake assessments from controlled clinical trials examining the efficacy of financial incentives for smoking cessation and relapse prevention. Data from 349 pregnant women (231 continuing smokers and 118 spontaneous quitters) recruited from the greater Burlington, VT, area contributed to this secondary analysis, including psychiatric/sociodemographic characteristics, smoking characteristics, and performance on a computerized DD task. Educational attainment, smoking rate, and DD values were each significant predictors of spontaneous quitting in univariate analyses. A model examining those three predictors together retained educational attainment as a main effect and revealed a significant interaction of DD and smoking rate (i.e., DD was a significant predictor at lower but not higher smoking rates). A final model considering all potential predictors, included education, the interaction of DD and smoking rate, and five additional predictors (i.e., stress ratings, the belief that smoking during pregnancy will "greatly harm my baby," age of smoking initiation, marital status, and prior quit attempts during pregnancy). The study presented here contributes new knowledge on predictors of spontaneous quitting among pregnant smokers with substantive practical implications for reducing smoking during pregnancy.

Smoking prevalence is unevenly distributed in the U.S. population, with those with mental illness, other substance use disorders, and lower socioeconomic status being especially vulnerable. Less research has been conducted on the association between these same vulnerabilities and smokeless tobacco (ST) use. The present study examined cigarette and ST use among adolescents and adults who met diagnostic criteria for major depressive disorder in the National Survey on Drug Use and Health (NSDUH). Utilizing the most recent (2011) NSDUH, we compared odds for current cigarette smoking and ST use among adolescents and adults meeting criteria for past-year major depressive disorder to the general population, after adjusting for potential confounding influences of sociodemographic and other substance use characteristics. Analyses were conducted to examine sex as a moderator of the relation between major depressive disorder and tobacco use. Odds for current cigarette smoking among those classified with major depressive disorder were increased among adolescents (OR = 1.33, 95% CI [1.05, 1.69], p = .021) and adults (OR = 1.70, 95% CI [1.47, 1.97], p < .0005), and odds for current ST use did not differ among adolescents (OR = 0.90, 95% CI [0.54, 1.49], p = .678) and were lower among adults (OR = 0.68, 95% CI [0.51, 0.91], p = .010). Sex was not a significant moderator in adolescents or adults. Major depressive disorder is associated with increased risk for smoking but not ST use among adolescents and adults further demonstrating heterogeneity in predictors of vulnerability to use of different tobacco products.

Histoplasma capsulatum has a worldwide distribution but is particularly concentrated in the midwestern United States and throughout Central and South America. Genetic differences between isolates resident in separate parts of the world have been reported, but the relationship between the isolates and the level of migration between different endemic foci has not been clear. In this study we used multilocus genotypes based on amplified polymorphic loci and one microsatellite to quantify the level of genetic differentiation occurring between North and South American populations of H. capsulatum. Significant genetic differentiation occurred between isolates obtained from Indiana and Alabama, and a marked division was seen between the Indiana population and the Class 1 isolates from St. Louis. Strong genetic differentiation occurred between the two North American populations and the Colombian population. This study supports the separation of North and South American H. capsulatum into different species, which has been proposed under the phylogenetic species concept.

In this Round Table, the application of several methods of molecular typing were discussed in reference to four important pathogenic fungi: Coccidioides immitis , Histoplasma capsulatum , Candida albicans and Paracoccidioides brasiliensis . Among the different methods the following were discussed: restriction fragment length polymorphisms (RFLP), single nucleotide polymorphisms, random amplie ed polymorphic DNA (RAPD), polymerase chain reaction (PCR)-RFLP and microsatellites. By means of these methods, several important biological questions related to speciation, mode of reproduction and population genetics could be approached. The basic information obtained from this approach has implications in the understanding of these pathogenic fungi in relation to their behavior and the development of pathogenic features, such as resistance to antimicrobials and virulence factors used for colonization of mammalian hosts. The knowledge obtained from these studies could also be used for the development of innovative diagnostic methods, as well as for novel therapeutic approaches and production of vaccines.

A sample of 30 clinical isolates of Histoplasma capsulatum was analyzed to determine (i) whether genetic exchange is important in the life cycle of this fungus and (ii) whether distinct subpopulations which correlate with disease severity or host immune status exist. Eleven biallelic molecular markers were developed, with the frequency of the least common allele at each molecular locus ranging from 10 to 50%. Every isolate had a different, unique multilocus genotype. Data analysis indicated that frequent recombination occurs within the Indianapolis, Ind., population. There were no associations between isolates from the immunocompromised population or from those with different clinical manifestations of histoplasmosis.

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient’s lifetime, can help guide therapy selection, and may be of utility in family counseling.

The striking similarity between the first two human immunodeficiency virus type 1 (HIV-1) isolates Lai/LAV (formerly LAV, isolated at the Pasteur Institute) and Lai/IIIB (formerly HTLV-IIIB, reported to be isolated from a pooled culture at the Laboratory of Tumor Cell Biology (LTCB) of the National Cancer Institute) provoked considerable controversy in light of the high level of variability found among subsequent HIV-1 isolates. In November 1990, the Office of Scientific Integrity at the National Institutes of Health commissioned our group to analyse archival samples established at the Pasteur Institute and LTCB between 1983 and 1985. Retrospective analyses have shown that contamination of a culture derived from patient BRU by one from patient LAI was responsible for the provenance of HIV-1 Lai/LAV; the contaminated culture (M2T-/B) was sent to LTCB in September 1983. Our goals were to determine which HIV-1 variants were present in the samples and the sequence diversity among HIV-1 isolates from the earliest stages of the AIDS epidemic. We examined archival specimens and report here the detection of six novel HIV-1 sequences in the cultures used to establish the pool: none is closely related to HIV-1 Lai/IIIB. A sample derived from patient LAI contained variants of both HIV-1 Lai/IIIB and HIV-1 Lai/LAV, and a sequence identical to a variant of HIV-1 Lai/IIIB was detected in the contaminated M2T-/B culture. We conclude that the pool, and probably another LTCB culture, MoV, were contaminated between October 1983 and early 1984 by variants of HIV-1 Lai from the M2T-/B culture. Therefore, the origin of the HIV-1 Lai/IIIB isolate also was patient LAI.

For over two decades, substantial National efforts have been directed toward ­reducing blood cholesterol levels of the American population with the intent of reducing the burden of cardiovascular events. This initiative was initially prompted by the successful results of the Lipid Research Clinic-Coronary Primary Prevention Trial (LRC-CPPT) that first proved reducing LDL-C resulted in a statistically ­significant reduction in cardiovascular events [2]. Since then an abundance of monotherapy cholesterol-lowering drug trials have consistently reported an approximate 25% relative risk reduction (RRR) for cardiovascular events [3].

sive analysis of gene structure from a limited number of species, primarily humans, mice, fruit flies, yeast, and the bacterium Escherichia coli. The powerful new molecular biological methods have also led to major discoveries in population biology and the study of organismal evolution. Among the many achievements are a better understanding of the evolutionary relationships among the major groups of microorganisms (Woese 1987) and the discovery that apes and humans had a common ancestor as recently as 5 million years ago (Wilson et al. 1989). Despite the profound nature of such discoveries, little data have been generated by molecular biological methods when the world's total biota is considered. Only a small number of individuals and species have been

Background and Purpose— The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial. Methods— Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes. Results— A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke ( P =0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (χ 2 8df =45.58, P Conclusions— These results suggest that Gln192Arg genotype is an important risk factor for stroke.

Background & Aims: Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC. Methods: A total of 916 subjects with CHC was enrolled from 2 centers. A gene-centric disease association study of 24,832 putative functional, single nucleotide polymorphisms (SNPs) was performed. Of the 1609 SNPs that were significantly associated ( P ≤ .05) with advanced fibrosis in the discovery cohort (University of California San Francisco [UCSF], N=433), the first batch of 100 SNPs were selected for validation in the replication cohort (Virginia Commonwealth University [VCU], N=483). Results: A missense SNP in the DEAD box polypeptide 5 (DDX5) gene was significantly associated with an increased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 1.8 and 2.2, respectively). Two diplotype groups, carrying the haplotypes composed of the DDX5 SNP and 2 neighboring POLG2 SNPs were also significantly associated with an increased risk of advanced fibrosis and had comparable or better risk estimates. In addition, a missense SNP in the carnitine palmitoyltransferase 1A (CPT1A) gene was associated with a decreased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 0.3 and 0.6, respectively). Conclusions: Subjects with CHC carrying DDX5 minor allele or DDX5-POLG2 haplotypes are at an increased risk of developing advanced fibrosis, whereas those carrying the CPT1A minor allele are at a decreased risk.

Aims: Integration of behavioral health including substance use problems into primary care is an essential benefit that federally qualified health centers (FQHCs) will offer as part of the Affordable Care Act (ACA). This study explores FQHC primary care clinicians’ beliefs and behaviors in integrating drug use assessment and treatment into their practices with a screening, brief intervention and referral to treatment (SBIRT) protocol. Methods: We administered a 10-min questionnaire to 68 primary care clinicians of 5 FQHCs in Los Angeles. Results: Clinicians expressed limited confidence in their ability to deal with illicit drug use of their patients, scoring on average 3.31 on a five point Likert scale. Two-thirds reported assessing for drug use regularly ‘at every visit’ and/or ‘at annual visits’. Median response for how often they counsel regarding drug use (on a five point Likert Scale from ‘Never’ to ‘Always’), was 4 (‘Usually’). Regarding their perspectives on the best practical resource for addressing drug use in their clinics, 45.6% named primary care clinicians. A minority (29.4%) of clinicians had completed a clinical rotation dealing with substance use, and 27.2% reported that more than 10h of their trainingwas devoted to substance use problems. Having a substance use rotation was associated with greater confidence in SBIRT (p

Aims: Functional magnetic resonance imaging (fMRI) research has indicated the involvement of frontal network in cocaine addiction. Resting-state f MRI approaches have revealed reduced (Kelly, 2011;Munier, 2012) aswell as enhanced (Camchong, 2011) resting state functional connectivity (RSFC) in frontal network in cocaine users relative to control participants. Also, task fMRI research has identified the insula as an important region activated during cocaine craving (Bonson, 2002). We examined the relationship between resting state networks and measures of cocaine use [frequency, money spent per week; duration] in nontreatmentseeking, chronic cocaine smokers. Methods: Ten participants (39–53yrs; 6M;4F) abstinent from cocaine for 72h completed a resting state scan and an anatomical MPRAGE scan. Whole-brain Independent component analysis was performed on resting state fMRI data using FSL’sMELODIC program that identified brain networks representing RSFC of frontalparietal, dorsal-attention, and insula networks. FSL’s regression model then determined any correlations between the activity of these brain networks and cocaine use measures. Results: Activity in frontal-parietal and insula networks was positively correlated with all three outcomes: frequency of use, money spent/week and cocaine use duration. Medial frontal gyrus and inferior parietal lobule [a part of dorsal-attention network (DAN)] positively correlated with each measure. Thus, the increased activity in these brain regions was associated with increased cocaine use. Conclusions: To the best of our knowledge, this is the first study to demonstrate a relationship between RSFC in frontal and insula networks and measures of cocaine use in chronic cocaine smokers. Relationship between the DAN and cocaine use may suggest increased attentional bias to cocaine cues in the environment. As potential network level biomarkers of chronic cocaine use, these identified resting state networks may be usefully applied in treatment development. Financial support: Research supported byNIDAK01DA029047.

The phylogeny of 46 geographically diverse Histoplasma capsulatum isolates representing the three varieties capsulatum , duboisii , and farciminosum was evaluated using partial DNA sequences of four protein coding genes. Parsimony and distance analysis of the separate genes were generally congruent and analysis of the combined data identified six clades: (i) class 1 North American H. capsulatum var. capsulatum , (ii) class 2 North American H. capsulatum var. capsulatum , (iii) Central American H. capsulatum var. capsulatum , (iv) South American H. capsulatum var. capsulatum group A, (v) South American H. capsulatum var. capsulatum group B, and (vi) H. capsulatum var. duboisii . Although the clades were generally well supported, the relationships among them were not resolved and the nearest outgroups ( Blastomyces and Paracoccidioides ) were too distant to unequivocally root the H. capsulatum tree. H. capsulatum var. farciminosum was found within the South American H. capsulatum var. capsulatum group A clade. With the exception of the South American H. capsulatum var. capsulatum group A clade, genetic distances within clades were an order of magnitude lower than those between clades, and each clade was supported by a number of shared derived nucleotide substitutions, leading to the conclusion that each clade was genetically isolated from the others. Under a phylogenetic species concept based on possession of multiple shared derived characters, as well as concordance of four gene genealogies, H. capsulatum could be considered to harbor six species instead of three varieties.

The morphological, ecological, and clinical diversity among ascomycete fungi that are pathogenic to humans suggest that the potential for pathogenicity may have arisen multiple times within these higher fungi. We have obtained 18S ribosomal DNA sequences from a diverse group of human pathogenic fungi in order to determine their evolutionary origins. The fungi studied include a skin pathogen that is confined to humans (Trichophyton rubrum) and three systemic, facultative parasites that cause histoplasmosis (Histoplasma capsulatum), blastomycosis (Blastomyces dermatitidis) and coccidioidomycosis (Coccidioides immitis) in humans and other higher animals. Also included in our analysis are representatives of non-pathogenic fungi, as well as two opportunistic pathogens, Pneumocystis carinii and Candida albicans, that cause severe disease in immunocompromised individuals, especially those with AIDS. Two of the fungi we sequenced, T. rubrum and C. immitis, are limited to asexual modes of reproduction and therefore lack the sexual structures that are most useful for evolutionary comparison as well as being essential for classification among the higher fungi. Coccidioides immitis is particularly problematic owing to its contradictory and confusing asexual morphologies, which have caused it to be placed in three fungal classes and the protista. Our analysis shows that the specialized, superficial parasite and the systemic, facultative parasites, including C. immitis, are closely related ascomycetes, which clearly demonstrates the power of molecular characters to compensate for missing or confusing reproductive morphology. Analysis also shows that the opportunistic pathogens are more distantly related, with the likely explanation that pathogenicity has arisen more than once within the Ascomycetes.

Establishing the phylogeny of fungi and protists often has proved difficult owing to the simple morphologies and convergent characters in these organisms. We used DNA sequences of nuclear small-subunit ribosomal RNA genes to determine phylogenetic relationships among three major classes of organisms considered to be fungi--Basidiomycetes, Ascomycetes and Chytridiomycetes--and to assess the taxonomic position of Neocallimastix, an economically important anaerobic rumen microorganism whose classification is controversial. The Basidiomycetes and Ascomycetes, two classes of nonflagellated fungi, are the most closely related taxa. Chytridiomycetes, though bearing flagella, group with these higher fungi rather than with the protists. Neocallimastix, a eukaryote lacking mitochondria and variously classified as a protist or as a fungus, shows closest molecular affinities with the Chytridiomycete fungi in the order Spizellomycetales.

In order to investigate the potential for Borrelia burgdorferi infection before the recognition of Lyme disease as a clinical entity, the polymerase chain reaction (PCR) was used to examine museum specimens of Ixodes dammini (deer ticks) for the presence of spirochete-specific DNA sequences. One hundred and thirty-six archival tick specimens were obtained representing various continental U.S. locations; DNA sequences characteristic of modern day isolates of B. burgdorferi were detected in 13 1940s specimens from Montauk Point and Hither Hills, Long Island, New York. Five archival specimens of Dermacentor variabilis (dog tick) from the same collection and 118 Ixodes specimens from other endemic and nonendemic sites were negative. These data suggest that the appearance of the Lyme disease spirochete in suitable arthropod vectors preceded, by at least a generation, the formal recognition of this disease as a clinical entity in the United States.

To the Editor.— I have the following comments on the radiological evaluation of adults with hematuria, the subject of the excellent review by Sutton.1 The radiology department should take responsibility for evaluation of the urinary tract above the bladder. To that end, two studies are preferred. First, for kidney parenchyma, computed tomography is the present gold standard for renal imaging, allowing diagnosis, staging, or confident exclusion of renal cell carcinoma. Second, the excretory urogram can usually diagnose urothelial neoplasm above the bladder, particularly if the entire collecting system and ureter are well distended by opaque contrast material. I propose that combining the two examinations is the most effective way to evaluate the urinary tract above the bladder. Combining the two examinations would probably modify the diagnostic algorithm. Such a combined study would begin with a recent plain roentgenogram as a preliminary to an excretory urogram, followed by a

A new assay for chloramphenicol in biological fluids has been developed that offers sensitivity, specificity, precision, accuracy, economy, and ease of performance. The assay is based on the enzymological acetylation of chloramphenicol catalyzed by an R factor-mediated enzyme. [ 14 C]acetyl coenzyme A serves as the donor of the labeled acetyl group, and the product, [ 14 C]acetoxychloramphenicol, is separated from the labeled precursor by utilizing its preferential extraction into benzene. The product is then quantified by liquid scintillation counting. This assay measures chloramphenicol concentrations in both plasma and other biological specimens and in the presence of other antibiotics, hemolysis, or jaundice. Its rapidity and ease of performance are useful for clinical laboratories, and its sensitivity allows determinations on 10 μl of plasma.

The level of expression of a β-lactamase human preproinsulin fusion protein1 in Escherichia coli was increased by plasmid and host manipulations. The initial expression level (0.01% of total protein) was increased two- to three-fold by replacing the p-lactamase promoter with two strong promoters: trp from Serratia marcescens and lacUV5 from E. coli. Replacement of the β-lactamase ribosome binding site (RBS) with a trp RBS enhanced the yield to a total of 0.16% of the total cell protein. Proinsulin was unstable, with a half-life of 14 minutes at 37°C. Proinsulin expression was increased three-fold (to about 0.5% of the total cell protein) by incubating the host at 30°C rather than 37°C.

Neuronal activity of 58 cells in the lateral nucleus of the amygdala of freely moving cats was studied across stages of sleep-wakefulness. In general, these units were very slow firing in all states (mean discharge rate less than 1 spike/sec) with the highest rates typically observed during slow wave sleep and paradoxical sleep. Most units tended to show some bursting activity during all states. The bursting during paradoxical sleep was not temporally correlated with the phasic activity characteristic of that state. These results corroborate and extend previous studies of the basal amygdaloid nuclei.

To study in detail the effects of percutaneous nephrolitholapaxy on renal function, a consecutive series of 11 patients were investigated preoperatively by excretory urography, gamma camera renography for determination of individual renal function and computerized tomography of the kidneys. Postoperatively, gamma camera examination, computerized tomography, antegrade nephrostography, renal angiography and excretory urography were performed. With 2 exceptions, percutaneous nephrostomy, dilation of the tract and stone removal were done in 1 stage with the patient under continuous epidural anesthesia. Nephrostomy tract dilation was done with an Olbert type balloon catheter or Alken metallic dilators. Thickening of Gerota's fascia was demonstrated by computerized tomography in most cases, and small to moderate perirenal hematomas were found in several. At gamma camera examination decrease of renal function was noted regularly on postoperative day 1 and returned to near initial levels 2 weeks postoperatively in most cases. Angiography in 10 patients showed discrete parenchymal scarring in some and a peripheral arteriovenous fistula in 1. We conclude that percutaneous renal stone surgery usually is tolerated well by the kidney.

Needle biopsies of the liver were performed on 30 patients with heart failure and correlated with clinical features and biochemical liver function studies. Hepatic biopsy served as a useful adjunct to other methods in deciding the status of the liver in this group. Type of heart disease, degree of heart failure and length of heart failure could not be correlated with the observed histology. Neither history, physical examination, nor biochemical functional studies provided sufficient information to predict anatomy with certainty. A histologic diagnosis improved both therapeutic and prognostic perspective.

Hepatic abnormalities constitute common and important secondary effects of congestive heart failure. Considerable information has been accumulated on the liver in heart failure, including anatomic changes, 1–10 biochemical alterations, 11–18 and physiologic disturbances. 19 The present report is based on histologic studies of the liver correlated with clinical and biochemical findings in seventy-five patients with congestive heart failure. The investigation was undertaken to further the evaluation of the mechanism and significance of hepatic abnormalities in chronic circulatory congestion.