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We compared patient management during primary care visits in 3 settings (health centers, hospital outpatient departments, and physicians' offices) and investigated racial/ethnic and insurance-based disparities in the wake of the recent health center program expansion. Within health centers, there were few differences in patient management across racial/ethnic or insurance groups. In contrast, the other settings displayed more racial/ethnic and insurance disparities in patient management during visits. Health centers performed processes of care with comparable or higher occurrence, relative to physicians' offices. Health care disparities were also attenuated in health centers, compared with other primary care settings. [ABSTRACT FROM AUTHOR]

Objective: To conduct cross-country comparisons and assess the effect of foreign birth on access to primary and preventive care in Canada and the United States.Data Sources: Secondary data from the 2002 to 2003 Joint Canada-United States Survey of Health.Study Design: Descriptive and comparative analyses were conducted, and logistic regression models were used to assess the effect of immigrant status and country of residence on access to care. Outcomes included measures of health care systems and processes, utilization, and patient perceptions.Principal Findings: In adjusted analyses, immigrants in Canada fared worse than nonimmigrants regarding having timely Pap tests; in the United States, immigrants fared worse for having a regular doctor and an annual consultation with a health professional. Immigrants in Canada had better access to care than immigrants in the United States; most of these differences were explained by differences in socioeconomic status and insurance coverage across the two countries. However, U.S. immigrants were more likely to have timely Pap tests than Canadian immigrants, even after adjusting for potential confounders.Conclusions: In both countries, foreign-born populations had worse access to care than their native-born counterparts for some indicators but not others. However, few differences in access to care were found when direct cross-country comparisons were made between immigrants in Canada versus the United States, after accounting for sociodemographic differences. [ABSTRACT FROM AUTHOR]

Abstract:The overall aim was to determine whether health care delivery for vulnerable populations served by community health centers (CHCs) was comparable to care for mainstream Americans primarily seen in physicians' offices (POs). Data came from the 2006 National Ambulatory Medical Care Survey. Patient visits occurring in CHCs were largely from younger, uninsured or Medicaid-insured, minority populations, while POs catered mainly to older, Medicare- or privately-insured, White patients. Communities served by CHCs were more often in low-income, low-education, urban regions. A greater proportion of visits to CHCs were from diabetic, obese, and depressed patients; CHCs also offered more evening/weekend visits and provided more health education during visits, but spent less time per visit than POs and had more difficulty referring patients to specialists. Results affirmed the significant role of CHCs as safety-net providers for vulnerable populations, and indicated that CHCs provide adequate care compared with POs although there remains room for improvement. [ABSTRACT FROM AUTHOR]

This article presents a mechanism for tracking and reporting health disparities data that are based on a general model of vulnerability. We briefly discuss the origins of this model and describe its focus on the cumulative impact of multiple risk factors on health-related outcomes. We then demonstrate how the model can be applied to inform the collection and reporting of health disparities data by providing three examples. Since national and state datasets contain information on a wide range of risk factors, researchers and policy makers would benefit from examining the multiple risks that affect vulnerable populations simultaneously, as we have demonstrated in the three examples. These examples suggest that the determinants of health and healthcare problems are multifactorial and that they can be studied in an integrative approach using risk profiles. This research methodology can strengthen our existing knowledge of health disparities and aid in the recognition of points of intervention to successfully improve health and healthcare for vulnerable populations. [ABSTRACT FROM AUTHOR]

Predicting the behaviour of complex microbial communities is challenging. However, this is essential for complex biotechnological processes such as those in biological wastewater treatment plants (BWWTPs), which require sustainable operation. Here we summarize 14 months of longitudinal meta-omics data from a BWWTP anaerobic tank into 17 temporal signals, explaining 91.1% of the temporal variance, and link those signals to ecological events within the community. We forecast the signals over the subsequent five years and use 21 extra samples collected at defined time intervals for testing and validation. Our forecasts are correct for six signals and hint on phenomena such as predation cycles. Using all the 17 forecasts and the environmental variables, we predict gene abundance and expression, with a coefficient of determination ≥0.87 for the subsequent three years. Our study demonstrates the ability to forecast the dynamics of open microbial ecosystems using interactions between community cycles and environmental parameters., (© 2023. The Author(s).)

Background: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM)., Results: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract., Conclusions: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract., (© 2022. The Author(s).)

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE-host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR-Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid-host and phage-host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant 'Candidatus Microthrix parvicella' population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes.

The development of reliable, mixed-culture biotechnological processes hinges on understanding how microbial ecosystems respond to disturbances. Here we reveal extensive phenotypic plasticity and niche complementarity in oleaginous microbial populations from a biological wastewater treatment plant. We perform meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics) on in situ samples over 14 months at weekly intervals. Based on 1,364 de novo metagenome-assembled genomes, we uncover four distinct fundamental niche types. Throughout the time-series, we observe a major, transient shift in community structure, coinciding with substrate availability changes. Functional omics data reveals extensive variation in gene expression and substrate usage amongst community members. Ex situ bioreactor experiments confirm that responses occur within five hours of a pulse disturbance, demonstrating rapid adaptation by specific populations. Our results show that community resistance and resilience are a function of phenotypic plasticity and niche complementarity, and set the foundation for future ecological engineering efforts.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Aplysina aerophoba is an emerging model marine sponge, with a well-characterized microbial community in terms of diversity and structure. However, little is known about the expressed functional capabilities of its associated microbes. Here, we present the first metaproteomics-based study of the microbiome of A. aerophoba. We found that transport and degradation of halogenated and chloroaromatic compounds are common active processes in the sponge microbiomes. Our data further reveal that the highest number of proteins were affiliated to a sponge-associated Tectomicrobium, presumably from the family Entotheonellaceae, as well as to the well-known symbiont "Candidatus Synechococcus spongiarium", suggesting a high metabolic activity of these two microorganisms in situ. Evidence for nitric oxide (NO) conversion to nitrous oxide was consistently observed for Tectomicrobia across replicates, by production of the NorQ protein. Moreover, we found a potential energy-yielding pathway through CO oxidation by putative Chloroflexi bacteria. Finally, we observed expression of enzymes that may be involved in the transformation of chitin, glycoproteins, glycolipids and glucans into smaller molecules, consistent with glycosyl hydrolases predicted from analyses of the genomes of Poribacteria sponge symbionts. Thus, this study provides crucial links between expressed proteins and specific members of the A. aerophoba microbiome.

The gastrointestinal microbiome plays a central role in health and disease. Imbalances in the microbiome, also referred to as dysbiosis, have recently been associated with a number of human idiopathic diseases ranging from metabolic to neurodegenerative. However, to causally link specific microorganisms or dysbiotic communities with tissue-specific and/or systemic disease-associated phenotypes, systematic in vivo studies are fundamental. Gnotobiotic mouse models have proven to be particularly useful for the elucidation of microbiota-associated characteristics as they provide a means to conduct targeted perturbations followed by analyses of induced localized and systemic effects. Here, we describe a methodology in the framework of systems biology which allows the comprehensive isolation of high quality biomolecular fractions (DNA, RNA, proteins and metabolites) from limited and/or heterogeneous sample material derived from murine brain, liver, and colon tissues, as well as from intestinal contents (fecal pellets and fecal masses). The obtained biomolecular fractions are compatible with current high-throughput genomic, transcriptomic, proteomic, and metabolomic analyses. The resulting data fulfills the premise of systematic measurements and allows the detailed study of tissue-specific and/or systemic effects of host-microbiota interactions in relation to health and disease.

The Gram-negative beta-proteobacterium Zoogloea sp. LCSB751 (LMG 29444) was newly isolated from foaming activated sludge of a municipal wastewater treatment plant. Here, we describe its draft genome sequence and annotation together with a general physiological and genomic analysis, as the first sequenced representative of the Zoogloea genus. Moreover, Zoogloea sp. gene expression in its environment is described using metatranscriptomic data obtained from the same treatment plant. The presented genomic and transcriptomic information demonstrate a pronounced capacity of this genus to synthesize poly-β-hydroxyalkanoate within wastewater.

The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra- and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease.

Linking taxonomic identity and functional potential at the population-level is important for the study of mixed microbial communities and is greatly facilitated by the availability of microbial reference genomes. While the culture-independent recovery of population-level genomes from environmental samples using the binning of metagenomic data has expanded available reference genome catalogs, several microbial lineages remain underrepresented. Here, we present two reference-independent approaches for the identification, recovery, and refinement of hitherto undescribed population-level genomes. The first approach is aimed at genome recovery of varied taxa and involves multi-sample automated binning using CANOPY CLUSTERING complemented by visualization and human-augmented binning using VIZBIN post hoc. The second approach is particularly well-suited for the study of specific taxa and employs VIZBIN de novo. Using these approaches, we reconstructed a total of six population-level genomes of distinct and divergent representatives of the Alphaproteobacteria class, the Mollicutes class, the Clostridiales order, and the Melainabacteria class from human gastrointestinal tract-derived metagenomic data. Our results demonstrate that, while automated binning approaches provide great potential for large-scale studies of mixed microbial communities, these approaches should be complemented with informative visualizations because expert-driven inspection and refinements are critical for the recovery of high-quality population-level genomes.

Microorganisms in biological wastewater treatment plants require adaptive strategies to deal with rapidly fluctuating environmental conditions. At the population level, the filamentous bacterium Candidatus Microthrix parvicella (Ca. M. parvicella) has been found to fine-tune its gene expression for optimized substrate assimilation. Here we investigated in situ substrate assimilation by single cells of Ca. M. parvicella using nano-scale secondary-ion mass spectrometry (nanoSIMS). NanoSIMS imaging highlighted phenotypic heterogeneity among Ca. M. parvicella cells of the same filament, whereby (13)C-oleic acid and (13)C-glycerol-3-phosphate assimilation occurred in ≈21-55% of cells, despite non-assimilating cells being intact and alive. In response to alternating aerobic-anoxic regimes, (13)C-oleic acid assimilation occurred among subpopulations of Ca. M. parvicella cells (≈3-28% of cells). Furthermore, Ca. M. parvicella cells exhibited two temperature optima for (13)C-oleic acid assimilation and associated growth rates. These results suggest that phenotypic heterogeneity among Ca. M. parvicella cells allows the population to adapt rapidly to fluctuating environmental conditions facilitating its widespread occurrence in biological wastewater treatment plants.

Background: Mixed microbial communities underpin important biotechnological processes such as biological wastewater treatment (BWWT). A detailed knowledge of community structure and function relationships is essential for ultimately driving these systems towards desired outcomes, e.g., the enrichment in organisms capable of accumulating valuable resources during BWWT., Methods: A comparative integrated omic analysis including metagenomics, metatranscriptomics and metaproteomics was carried out to elucidate functional differences between seasonally distinct oleaginous mixed microbial communities (OMMCs) sampled from an anoxic BWWT tank. A computational framework for the reconstruction of community-wide metabolic networks from multi-omic data was developed. These provide an overview of the functional capabilities by incorporating gene copy, transcript and protein abundances. To identify functional genes, which have a disproportionately important role in community function, we define a high relative gene expression and a high betweenness centrality relative to node degree as gene-centric and network topological features, respectively., Results: Genes exhibiting high expression relative to gene copy abundance include genes involved in glycerolipid metabolism, particularly triacylglycerol lipase, encoded by known lipid accumulating populations, e.g., Candidatus Microthrix parvicella . Genes with a high relative gene expression and topologically important positions in the network include genes involved in nitrogen metabolism and fatty acid biosynthesis, encoded by Nitrosomonas spp. and Rhodococcus spp. Such genes may be regarded as 'keystone genes' as they are likely to be encoded by keystone species., Conclusion: The linking of key functionalities to community members through integrated omics opens up exciting possibilities for devising prediction and control strategies for microbial communities in the future., Competing Interests: The authors declare no conflict of interest.

Microbial communities are complex and dynamic systems that are primarily structured according to their members' ecological niches. To investigate how niche breadth (generalist versus specialist lifestyle strategies) relates to ecological success, we develop and apply an integrative workflow for the multi-omic analysis of oleaginous mixed microbial communities from a biological wastewater treatment plant. Time- and space-resolved coupled metabolomic and taxonomic analyses demonstrate that the community-wide lipid accumulation phenotype is associated with the dominance of the generalist bacterium Candidatus Microthrix spp. By integrating population-level genomic reconstructions (reflecting fundamental niches) with transcriptomic and proteomic data (realised niches), we identify finely tuned gene expression governing resource usage by Candidatus Microthrix parvicella over time. Moreover, our results indicate that the fluctuating environmental conditions constrain the accumulation of genetic variation in Candidatus Microthrix parvicella likely due to fitness trade-offs. Based on our observations, niche breadth has to be considered as an important factor for understanding the evolutionary processes governing (microbial) population sizes and structures in situ.

High-throughput sequencing of ribosomal RNA gene (rDNA) amplicons has opened up the door to large-scale comparative studies of microbial community structures. The short reads currently produced by massively parallel sequencing technologies make the choice of sequencing region crucial for accurate phylogenetic assignments. While for 16S rDNA, relevant regions have been well described, no truly systematic design of 18S rDNA primers aimed at resolving eukaryotic diversity has yet been reported. Here we used 31,862 18S rDNA sequences to design a set of broad-taxonomic range degenerate PCR primers. We simulated the phylogenetic information that each candidate primer pair would retrieve using paired- or single-end reads of various lengths, representing different sequencing technologies. Primer pairs targeting the V4 region performed best, allowing discrimination with paired-end reads as short as 150 bp (with 75% accuracy at genus level). The conditions for PCR amplification were optimised for one of these primer pairs and this was used to amplify 18S rDNA sequences from isolates as well as from a range of environmental samples which were then Illumina sequenced and analysed, revealing good concordance between expected and observed results. In summary, the reported primer sets will allow minimally biased assessment of eukaryotic diversity in different microbial ecosystems.

Background: We obtained the prevalence of overweight/obesity, weight-loss attempts, and weight-related counseling and treatment among U.S. adults who sought care in federally funded community health centers. We investigated whether racial/ethnic and gender disparities existed for these measures., Methods: Data came from the 2009 Health Center Patient Survey. Measures included body mass index (BMI), self-perceived weight, weight-loss attempts, being told of a weight problem, receipt of weight-related counseling, nutritionist referrals, weight-loss prescriptions, and cholesterol checks. We conducted bivariate analyses to determine distributions by race/ethnicity and gender, then ran logistic regressions to examine the effects of several sociodemographic factors on weight-loss attempts and on being told of a weight problem., Results: Overall, 76% of adult patients seen in health centers were overweight or obese (BMI ≥ 25.0 kg/m(2)); 55% of overweight patients, and 87% of obese patients correctly perceived themselves as overweight. There were no racial/ethnic differences in BMI categories or self-perceptions of weight. Females were more likely than males to be obese and also more likely to perceive themselves as overweight. About 60% of overweight/obese patients reported trying to lose weight in the past year. There were no racial/ethnic disparities favoring non-Hispanic White patients in weight-related treatment. Women were more likely than men to receive referrals to a nutritionist or weight-loss prescriptions. Overweight/obese patients had higher adjusted odds of a past-year weight-loss attempt if they perceived themselves as overweight (OR = 3.30, p < 0.0001), were female (OR = 1.95, p < 0.05), African American (OR = 3.34, p < 0.05), or Hispanic/Latino (OR = 2.14, p < 0.05). Overweight/obese patients had higher odds of being told they had a weight problem if they were Hispanic/Latino (OR = 2.56, p < 0.05) or if they had two or more chronic conditions (OR = 2.77, p < 0.01)., Conclusions: Patients seen in community health centers have high rates of overweight and obesity, even higher than the general U.S. population. Efforts to address weight problems during primary care visits are needed to reduce the burden of obesity and its sequellae among health center patients., (© Published by Elsevier Ltd on behalf of Asia Oceania Assoc. for the Study of Obesity.)

Objective: The aim of this study was to translate and adapt the Primary Care Assessment Tool to assess the perceptions of the quality of primary care among patients in China and to examine the psychometric properties of the adapted Primary Care Assessment Tool Chinese version (PCAT-C)., Design: A cross-sectional survey to assess the validity and reliability of PCAT-C using standard psychometric techniques., Setting: Outpatient departments of five state-level and provincial-level hospitals and four municipal-level hospitals as well as nine community health centers in Changsha, China., Participants: A total of 2532 patients visiting primary care providers., Results: The PCAT-C was acceptable to patients, as evidenced by low proportions of missing data and a full range of possible scores for all items. Two items were eliminated following principal component analysis and reliability testing. The principal component analysis extracted eight multiple-item scales and one single-item scale. Multiple-item scales had reasonable internal consistency and high item-scale correlations., Conclusions: This study represents the first attempt to construct an instrument for assessing patient reports on the quality of primary care, which is applicable to the Chinese context. Psychometric assessments indicated that the PCAT-C is a useful instrument for assessing the core attributes of primary care in China.

More than 1100 federally funded health centers provide primary and preventive care to about 20 million underserved patients in the United States. Since 2008, the Health Resources and Services Administration has implemented a clinical quality improvement initiative to measure and evaluate the quality of care across all health centers. We assessed racial/ethnic disparities in clinical quality among US health centers, and examined whether performance on quality measures varied across 3 health center characteristics. National data came from the 2009 Uniform Data System. We examined performance across 3 indicators of clinical quality: poorly controlled hypertension among adult patients, poorly controlled diabetes among adult patients, and low birth weight among newborns. We compared results for each measure across racial/ethnic groups, as well as across 3 health center characteristics: health center patient volume, duration of health center funding, and extent of managed care penetration. Non-Hispanic Asian patients had the best results among racial/ethnic groups for 2 of the 3 measures examined: lowest rates of poorly controlled diabetes (26%) and hypertension (34%). Hispanics/Latinos had similar rates of poor hypertension control compared with non-Hispanic whites (38% for both), and lower rates of low birth weight (8% vs 10%). Poor diabetes control was more prevalent among Hispanic/Latino patients than non-Hispanic white patients, but the absolute difference was small (5 percentage points). Non-Hispanic black/African American patients had statistically worse outcomes than non-Hispanic white patients, but the absolute differences were also small (2-6 percentage points, depending on outcome). Health centers with larger patient volume fared better than their counterparts with smaller volume for all racial/ethnic groups. For Hispanic/Latino patients, more established health centers compared favorably to new health centers for all 3 outcomes. Health centers with some managed care penetration did better for diabetes and hypertension control relative to health centers without managed care penetration. Compared with national rates, health centers report minimal racial/ethnic disparities in clinical outcomes. Health center characteristics are also associated with clinical outcomes. More research is needed to determine the nature of disparities after accounting for health center patient, provider, and institutional characteristics.

Objective: To describe current clinical quality among the nation's community health centers and to examine health center characteristics associated with performance excellence., Data Sources: National data from the 2009 Uniform Data System., Data Collection/extraction Methods: Health centers reviewed patient records and reported aggregate data to the Uniform Data System., Study Design: Six measures were examined: first-trimester prenatal care, childhood immunization completion, Pap tests, low birth weight, controlled hypertension, and controlled diabetes. The top 25 percent performing centers were compared with lower performing (bottom 75 percent) centers on these measures. Logistic regressions were utilized to assess the impact of patient, provider, and institutional characteristics on health center performance., Principal Findings: Clinical care and outcomes among health centers were generally comparable to national averages. For instance, 67 percent of pregnant patients received timely prenatal care (national = 68 percent), 69 percent of children achieved immunization completion (national = 67 percent), and 63 percent of hypertensive patients had blood pressure under control (national = 48 percent). Depending on the measure, centers with more uninsured patients were less likely to do well, while centers with more physicians and enabling service providers were more likely to do well., Conclusions: Health centers provide quality care at rates comparable to national averages. Performance may be improved by increasing insurance coverage among patients and increasing the ratios of physicians and enabling service providers to patients., (© Health Research and Educational Trust.)

Objectives: We examined primary care and public health activities among federally funded health centers, to better understand their successes, the barriers encountered, and the lessons learned., Methods: We used qualitative and quantitative methods to collect data from 9 health centers, stratified by administrative division, urban-rural location, and race/ethnicity of patients served. Descriptive data on patient and institutional characteristics came from the Uniform Data System, which collects data from all health centers annually. We administered questionnaires and conducted phone interviews with key informants., Results: Health centers performed well on primary care coordination and community orientation scales and reported conducting many essential public health activities. We identified specific needs for integrating primary care and public health: (1) more funding for collaborations and for addressing the social determinants of health, (2) strong leadership to champion collaborations, (3) trust building among partners, with shared missions and clear expectations of responsibilities, and (4) alignment and standardization of data collection, analysis, and exchange., Conclusions: Lessons learned from health centers should inform strategies to better integrate public health with primary care.

This study sought to examine the influence of length of stay and language proficiency on immigrants' access to and utilization of care in Canada and the United States (U.S,). Data came from the 2007-2008 Canadian Community Health Survey and the National Health Interview Survey. Analyses were limited to foreign-born, non-elderly adults in each country (n = 12,870 in Canada and n = 7440 in the U.S.). Health care indicators included having a usual source of care; annual consultation with a health professional, dentist, and eye doctor; flu shot in the past year; and Pap test in the past 3 years. Logistic regression models were employed to estimate the relative odds of access or use of care, adjusting for need, demographic factors, socioeconomic status, and insurance coverage. In general, rates of health care access and utilization were higher in Canada than the U.S. among all immigrant groups. In both countries, adjusted analyses indicated that immigrants with shorter length of stay (less than 10 years) and limited language proficiency generally had lower rates of access/use compared with those with longer length of stay (10 years or more) and proficiency in each country's official language(s), respectively. There was one exception to this pattern in the U.S.: immigrants with limited English had higher odds of having a recent Pap test relative to English-proficient immigrants. The persistence of disparities in health care experiences based on length of stay and language proficiency in Canada suggests that universal health insurance coverage may not be sufficient for ensuring access to and utilization of primary and preventive care for this population., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The literature on health disparities in the United States typically focuses on race/ethnicity or on socioeconomic status (SES) separately, but not often together. The purpose of the study was to assess the separate effects of race/ethnicity and SES on health status, health behaviors, and health care utilization. Cross-sectional analyses were conducted using the 2008 National Health Interview Survey (n = 17,337 non-elderly adults). SES disparities within specific racial groups were examined, as were race disparities within high and low SES groups. Within each racial/ethnic group, a greater proportion of low versus high SES individuals were in poor health, a lower proportion had healthy behaviors, and a lower proportion had access to care. In both SES groups, blacks and Hispanics had poorer health outcomes than whites. While whites were more likely to exercise than blacks and Hispanics, they are more likely to be smokers and less likely to have no or moderate alcohol consumption. Blacks had similar or better health care use than whites, especially for cancer screening; Hispanics had lower use within each SES group. Race/ethnicity disparities among adults of similar incomes, while important, were dwarfed by the disparities identified between high- and low-income populations within each racial/ethnic group.

Using the National Health Interview Survey, we examined associations among race/ ethnicity, insurance coverage, and cancer screening, and assessed changes in the magnitude of disparities over the past decade. Outcomes included recent cervical, breast, and colorectal cancer screening. Rates of colorectal screening increased for all racial/ethnic groups and some insurance groups from 2000 to 2008. However, rates of Pap tests and mammograms remained stagnant, and even decreased for certain groups. Some Hispanic-White and Asian-White disparities in cancer screening were reduced or eliminated over this time period. However, in 2008 Asians continued to have lower odds of Pap tests and Hispanics lower odds of colorectal cancer screening, even after accounting for potential confounders. There were no significant changes in Black-White disparities. The uninsured continued to be at a disadvantage for all three types of cancer screening, relative to the privately insured, as were publicly insured individuals with respect to colorectal cancer screening.

We conducted cross-country comparisons of Canada and the U.S., and assessed the extent to which access to care varies by nativity status overall, as well as in conjunction with race/ethnicity and socioeconomic status. Data came from the Joint Canada-U.S. Survey of Health (n=6,620 non-elderly adults). Access measures included having a regular medical doctor, consultation with a health professional in the past year, dentist visit in the past year, Pap test in the past three years, and any unmet health care needs in the past year. Logistic regression was employed to estimate the relative odds of access to care, adjusting for potential confounders. Disparities in access to care based on nativity status overall, as well as nativity-by-race joint effects, were found in both countries. There was also a dose-response effect of education on access to care among the native-born but not among the foreign-born; there were few nativity-by-income joint effects.

Background: After accounting for socioeconomic factors and other demographic characteristics, racial/ethnic disparities in access to care were examined., Methods: Using nationally representative data on 34,403 individuals from the 2004 Medical Expenditure Panel Survey (MEPS), multiple logistic regression analyses for five outcome measures were conducted: self-reports of being unable to get medical care, dental care, or prescriptions in the past year; and having no doctor or dentist visits in the past year. The main independent variables were race/ethnicity, income, and insurance status., Results: Blacks and Hispanics were less likely to report difficulties in accessing medical care, dental care, and prescriptions as compared to whites. These disparities occurred primarily among the uninsured and Medicaid insured. More objective measures of utilization (ie, no doctor visit or dental visit during the past year) showed that minorities experienced less access than whites., Conclusions: Racial/ethnic disparities in access to care persist, and cannot be entirely explained by socioeconomic differences. In addition, the nature of these disparities depends on the socioeconomic position of racial/ethnic groups as well as the access measure used.

Objectives: Based on a recent patient survey from Taiwan, where there is universal health insurance coverage and unrestricted physician choice, this study examined the relationship between physician specialty and the quality of primary medical care experiences., Methods: We assessed ambulatory patients' experiences with medical care using the Primary Care Assessment Tool, representing 7 primary care domains: first contact (ie, accessibility and utilization); longitudinality (ie, ongoing care); coordination (ie, referrals and information systems); comprehensiveness (ie, services available and provided); family centeredness; community orientation; and cultural competence., Results: Having a primary care physician was significantly associated with patients reporting higher quality of primary care experiences. Specifically, relative to specialty care physicians, primary care physicians enhanced accessibility, achieved better community orientation and cultural competence, and provided more comprehensive services., Conclusions: In an area with universal health insurance and unrestricted physician choice, ambulatory patients of primary care physicians rated their medical care experiences as superior to those of patients of specialists. In addition to providing health insurance coverage, promoting primary care should be included as a health policy to improve patients' quality of ambulatory medical care experiences.

Objectives: In 2001, the Health Center Growth Initiative was launched to increase access to primary health-care services through the expansion of the health center program. We examined the impact this initiative had on the number and types of patients seen by health centers, as well as the health center characteristics significantly associated with service expansions., Methods: We conducted secondary and time-trend analyses of the Uniform Data System, an annual dataset submitted to the Bureau of Primary Health Care by all federally qualified health centers. We performed trend and multivariable analyses to examine the impact of the initiative on health center performance., Results: Health centers that received both new access points and expanded medical capacity funding saw the most rapid growth in patients. These centers experienced a 58% increase in total number of patients and a 60% increase in total number of encounters, compared with 10% and 8%, respectively, for centers receiving no funding at all., Conclusions: were unchanged even after controlling for other health center characteristics., Conclusions: Public funding is critical to sustaining and expanding health center services to the nation's vulnerable populations.

Objective: The number of individuals with limited English proficiency in the USA is large and rapidly growing. Consequently, addressing language barriers in access to medical care is becoming increasingly important. Previous studies have reported that individuals with limited English proficiency have more difficulty gaining access to care, compared to English-proficient individuals. We assessed the impact of English language proficiency on access to medical care, accounting for health and socioeconomic status, using nationally representative data., Design: Cross-sectional data from the 2006 National Health Interview Survey (n=29,868). The main outcome measures of interest were self-reported delayed medical care, forgone needed care, and visits to a health care professional., Results: In unadjusted analyses, individuals with limited English proficiency were more likely to forgo needed medical care and less likely to have a health care visit, compared to individuals who were proficient in English. There was no significant association between language proficiency and reports of delayed care. After accounting for individuals' health and socioeconomic status, only the relationship between limited English proficiency and health care visits remained statistically significant. Most associations between language proficiency and access to care did not differ across various racial/ethnic groups., Conclusion: Results indicate that the choice of access measure may influence conclusions about language barriers in health care. Given the growing proportion of US residents with limited English proficiency, health care settings need to better address potential language barriers.

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.

Low-income urban whites in the United States have largely gone unexamined in health disparities research. In this study, we explored cancer prevention behaviors in this population. We compared data on whites with low socioeconomic status (SES) from the 2003 Exploring Health Disparities in Integrated Communities Study in Southwest Baltimore, Maryland (EHDIC-SWB) with nationally representative data for low SES white respondents from the 2003 National Health Interview Survey (NHIS). Rates for health behaviors and health indicators for whites from the EHDIC-SWB study as compared to NHIS prevalence estimates were as follows: current cigarette smoking, 59% (31% nationally); current regular drinking, 5% (5% nationally); overweight, 26% (32% nationally); obesity, 30% (22% nationally); mammography in the past 2 years, 50% (57% nationally); Pap smear in the past 2 years, 64% (68% nationally); screening for colon cancer in the past 2 years, 41% (30% nationally); and fair or poor self-reported health, 37% (22% nationally). Several cancer prevention behaviors and health indicators for white EHDIC-SWB respondents were far from the Healthy People 2010 objectives. This study provides rare estimates of cancer-related health and health care measures in an understudied population in the United States. Findings illustrate the need for further examination of health behaviors in low SES white urban populations who may share health risks with their poor minority urban counterparts.

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).

4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.

Abstract: A general affinity-based screening assay for discovery of lead compounds binding to potential protein drug targets that is based upon protein thermal unfolding and aggregation is described. ATLAS (Any Target Ligand Affinity Screen) (Anadys Pharmaceuticals, Inc., San Diego, CA) is a simple, homogeneous, and high-throughput affinity-based screening technology that can identify compounds that bind and protect the target protein from thermal unfolding, denaturation, and subsequent aggregation. ATLAS detection of thermally unfolded and aggregated hexahistidine [(His)6]-tagged proteins uses time-resolved fluorescence resonance energy transfer between two anti-(His)6 antibodies, labeled with either a donor or acceptor fluorophore, that are simultaneously bound to the aggregated protein. The ATLAS assay is simple to perform and easily automated for screening large compound libraries. The technology is applicable to lead discovery for soluble proteins of known and unknown functions, and particularly for proteins that are difficult to assay functionally. The ATLAS technology has been evaluated using p38 mitogen-activated protein (MAP) kinase as the target protein. Known inhibitors of p38 MAP kinase were examined by ATLAS and a functional assay; the results showed good correlation between the two methods.