The cost-effectiveness of training US primary care physicians to conduct colorectal cancer screening in family medicine residency programs.

BACKGROUND: Demand for a wide array of colorectal cancer screening strategies continues to outpace supply. One strategy to reduce this deficit is to dramatically increase the number of primary care physicians who are trained and supportive of performing office-based colonoscopies or flexible sigmoidoscopies. This study evaluates the clinical and economic implications of training primary care physicians via family medicine residency programs to offer colorectal cancer screening services as an in-office procedure. METHODS: Using previously established clinical and economic assumptions from existing literature and budget data from a local grant (2013), incremental cost-effectiveness ratios are calculated that incorporate the costs of a proposed national training program and subsequent improvements in patient compliance. Sensitivity analyses are also conducted. RESULTS: Baseline assumptions suggest that the intervention would produce 2394 newly trained residents who could perform 71,820 additional colonoscopies or 119,700 additional flexible sigmoidoscopies after ten years. Despite high costs associated with the national training program, incremental cost-effectiveness ratios remain well below standard willingness-to-pay thresholds under base case assumptions. Interestingly, the status quo hierarchy of preferred screening strategies is disrupted by the proposed intervention. CONCLUSIONS: A national overhaul of family medicine residency programs offering training for colorectal cancer screening yields satisfactory incremental cost-effectiveness ratios. However, the model places high expectations on primary care physicians to improve current compliance levels in the US.

Determinants of variations in self-reported barriers to colonoscopy among uninsured patients in a primary care setting.

Colorectal cancer (CRC) is the third most common type of cancer among both males and females in the United States and the second leading cause of cancer-related deaths. Although largely preventable through screening, early detection and removal of polyps, screening rates are considered sub-optimal. Perceived barriers to screening have been reported to influence screening rates. This paper examines variations in the extent to which uninsured patients identified barriers to CRC screening using colonoscopy based on race/ethnicity, educational attainment, age, gender, marital status and prior colonoscopy. Multivariate analyses showed that compared to Caucasians, African Americans had an increased likelihood of identifying lack of transportation as a barrier [odds ratio (OR) 2.68; 95 % confidence interval (CI) 1.35-5.32] while Hispanics were more likely to identify fear of finding cancer as a barrier (OR 2.09; 95 % CI 1.19-3.66). Compared to those with more than a high school education, there was increased likelihood of identifying lack of knowledge as a barrier among individuals with high school education (OR 3.51; 95 % CI 1.94-6.36) or less than a high school education (OR 2.16; 95 % CI 1.04-4.50). Our findings suggest that strategies aimed at increasing colonoscopy screening rates among underserved populations should take into consideration race/ethnicity, educational attainment, age, and prior colonoscopy experience when developing education and outreach plans to reduce barriers to colonoscopy.

Directional Darwinian Selection in proteins.

BACKGROUND: Molecular evolution is a very active field of research, with several complementary approaches, including dN/dS, HON90, MM01, and others. Each has documented strengths and weaknesses, and no one approach provides a clear picture of how natural selection works at the molecular level. The purpose of this work is to present a simple new method that uses quantitative amino acid properties to identify and characterize directional selection in proteins. METHODS: Inferred amino acid replacements are viewed through the prism of a single physicochemical property to determine the amount and direction of change caused by each replacement. This allows the calculation of the probability that the mean change in the single property associated with the amino acid replacements is equal to zero (H0: µ = 0; i.e., no net change) using a simple two-tailed t-test. RESULTS: Example data from calanoid and cyclopoid copepod cytochrome oxidase subunit I sequence pairs are presented to demonstrate how directional selection may be linked to major shifts in adaptive zones, and that convergent evolution at the whole organism level may be the result of convergent protein adaptations. CONCLUSIONS: Rather than replace previous methods, this new method further complements existing methods to provide a holistic glimpse of how natural selection shapes protein structure and function over evolutionary time.

Update on the evaluation and management of functional dyspepsia.

Dyspepsia affects up to 40 percent of adults each year and is often diagnosed as functional (nonulcer) dyspepsia. The defining symptoms are postprandial fullness, early satiation, or epigastric pain or burning in the absence of causative structural disease. These symptoms may coexist with symptoms of functional gastrointestinal disorders, such as gastroesophageal reflux and irritable bowel syndrome, as well as anxiety and depression. The history and physical examination can help identify other possible causes of the symptoms. Warning signs of serious disease, such as cancer, are unintended weight loss, progressive dysphagia, persistent vomiting, evidence of gastrointestinal bleeding, and a family history of cancer. In these cases, more extensive laboratory investigation, imaging, and endoscopy should be considered as clinically indicated. During the initial evaluation, a test-and-treat strategy to identify and eradicate Helicobacter pylori infection is more effective than empiric treatment and more cost-effective than initial endoscopy. Eradication of H. pylori helps one out of 15 patients with functional dyspepsia diagnosed by endoscopy, but may not be cost-effective. Treatment options that may be beneficial for functional dyspepsia include histamine H2 blockers, proton pump inhibitors, and prokinetic agents. Although psychotropic medications and psychological interventions have no proven benefit in patients with functional dyspepsia, they are appropriate for treating common psychiatric comorbidities.

The evolution of foot-and-mouth disease virus: impacts of recombination and selection.

Foot-and-mouth disease virus is an economically important animal virus that exhibits extensive genetic and antigenic heterogeneity. To examine the evolutionary forces that have influenced the population dynamics of foot-and-mouth disease virus, individual genes and the coding genomes for the Eurasian (Asia1, A, C, and O) serotypes were examined for phylogenetic relationships, recombination, genetic diversity and selection. Our analyses demonstrate that paraphyletic relationships among serotypes are not as prevalent as previously proposed and suggest that convergent evolution might be obscuring phylogenetic relationships. We provide evidence that identification of recombinant sequences and recombination breakpoint patterns among and within serotypes are heavily dependent on the level of genetic diversity and convergent characters present in a particular data set as well as the methods used to detect recombination. Here, we also investigate the impact of adaptive positive selection on the capsid proteins and the non-structural genes 2B, 2C, 3A, and 3Cpro to identify genome regions involved in genetic diversity and antigenic variation. Two different categories of positive selection at the amino acid level were examined; conservative (stabilizing) selection that maintains particular phenotypic properties of an amino acid residue and radical (destabilizing), and selection that dramatically alters the phenotype and potentially the functional and/or structural features of the protein. Approximately, 29% of residues in the capsid proteins were under positive selection. Of those, 64% were under the influence of destabilizing selection, 80% were under the influence of stabilizing selection, and 44% had phenotypic properties influenced by both selection types. The majority of residues under selection (74%) were located outside of known antigenic sites; suggestive of additional uncharacterized epitopes and genomic regions involved in antigenic drift.

Determinants of HPV vaccine awareness and healthcare providers' discussion of HPV vaccine among females.

Two human papillomavirus (HPV) vaccines are available and can prevent 98% of HPV 16 and 18 infections. This study aimed to explore determinants of 1) HPV vaccine awareness among a cohort of low-income women participating in a cancer prevention program in Central Texas and compare them to United States residents; 2) determinants of healthcare providers' discussion of HPV vaccine among female residents of the United States. Bivariate and multivariable analysis of HPV vaccine awareness using survey data (n = 359) collected between 2014 and 2016 in Central Texas, and the Health Information and Nutrition Survey (HINTS) data which is a nationally representative dataset (unweighted n = 1214) collected in 2013 were conducted. Bivariate and multivariable regression analyses of healthcare providers' discussion of the HPV vaccine using the HINTS survey data were also conducted. Compared to non-Hispanic Whites, there was a decreased likelihood of HPV vaccine awareness among non-Hispanic Blacks (OR = 0.50; 95% CI = 0.28-0.90) and Hispanics (OR = 0.55; 95% CI = 0.30-0.99) in the grant funded program, as well as non-Hispanic Blacks (OR = 0.28; 95% CI = 0.14-0.58) and Hispanics (OR = 0.22; 95% CI = 0.12-0.41) in the HINTS data. There was also a decreased likelihood of healthcare providers discussing the HPV vaccine with respondents who were 35-49 years (OR = 0.50; 95% CI = 0.30-0.84), 50-64 years (OR = 0.26; 95% CI = 0.14-0.49) or ≥ 65 years compared to those who were 18-34 years among the HINTS data respondents. Interventions to increase HPV awareness among non-Hispanic Blacks and Hispanics, as well as encourage healthcare providers' discussion of the HPV vaccination during patient encounters regardless of the patient's age are needed.

Phylogenomics and molecular evolution of polyomaviruses.

We provide in this chapter an overview of the basic steps to reconstruct evolutionary relationships through standard phylogeny estimation approaches as well as network approaches for sequences more closely related. We discuss the importance of sequence alignment, selecting models of evolution, and confidence assessment in phylogenetic inference. We also introduce the reader to a variety of software packages used for such studies. Finally, we demonstrate these approaches throughout using a data set of 33 whole genomes of polyomaviruses. A robust phylogeny of these genomes is estimated and phylogenetic relationships among the polyomaviruses determined using Bayesian and maximum likelihood approaches. Furthermore, population samples of SV40 are used to demonstrate the utility of network approaches for closely related sequences. The phylogenetic analysis suggested a close relationship among the BK viruses, JC viruses, and SV40 with a more distant association with mouse polyomavirus, monkey polymavirus (LPV) and then avian polyomavirus (BFDV).

Expanding Access to Colorectal Cancer Screening: Benchmarking Quality Indicators in a Primary Care Colonoscopy Program.

BACKGROUND: An inadequate supply of physicians who perform colonoscopies contributes to suboptimal screening rates, especially among the underserved. This shortage could be reduced if primary care physicians perform colonoscopies. This purpose of this article is to report quality indicators from colonoscopy procedures performed by family medicine physicians as part of a colorectal cancer prevention program targeting uninsured, low-income individuals. METHODS: A grant-funded colorectal cancer screening program was implemented to increase access to affordable colonoscopies for underinsured or uninsured residents of target counties while providing colonoscopy training to family medicine resident physicians. Colonoscopies were performed or supervised by 4 board-certified family physicians. Data were collected between 2011 and 2014. RESULTS: A total of 1155 colonoscopies were performed on 1101 individuals over a 3-year period. Cecal intubation rate was 96.25%. Adenoma detection rates among men and women >50 years old were 38.15% and 25.96%, respectively. There was 1 perforation, which was referred to a hospital, and 1 instance of postprocedural bleeding, which spontaneously resolved. CONCLUSIONS: Primary care physicians performing colonoscopies met the recommended quality indicators set forth by the American Society for Gastrointestinal Endoscopy.

The role of health literacy and communication habits on previous colorectal cancer screening among low-income and uninsured patients.

OBJECTIVE: To determine the association between health literacy, communication habits and colorectal cancer (CRC) screening among low-income patients. METHODS: Survey responses of patients who received financial assistance for colonoscopy between 2011 and 2014 at a family medicine residency clinic were analyzed using multivariate logistic regression (n = 456). There were two dependent variables: (1) previous CRC screening and (2) CRC screening adherence. Our independent variables of interest were health literacy and communication habits. RESULTS: Over two-thirds (67.13%) of respondents had not been previously screened for CRC. Multivariate analysis showed a decreased likelihood of previous CRC screening among those who had marginal (OR = 0.52; 95% CI = 0.29-0.92) or inadequate health literacy (OR = 0.49; 95% CI = 0.27-0.87) compared to those with adequate health literacy. Controlling for health literacy, the significant association between educational attainment and previous CRC screening was eliminated. Thus, health literacy mediated the relationship between educational attainment and previous CRC screening. There was no significant association between communication habits and previous CRC screening. There was no significant association between screening guideline adherence, and health literacy or communication. CONCLUSION: Limited health literacy is a potential barrier to CRC screening. Suboptimal CRC screening rates reported among those with lower educational attainment may be mediated by limited health literacy.

Detecting molecular selection on single amino acid replacements.

Amino acid property methods have repeatedly proven more sensitive than nucleotide-based methods, especially to the subtle influences of selection on Single Nucleotide Polymorphisms (SNPs). The purpose of this study is to evaluate the effects of population sampling and sliding window size on the sensitivity of one amino acid based method by assessing drug resistant SNPs from the HIV-1 gag-pol gene. The analysis of most of the SNPs produced positive results. There was not a trend in terms of properties affected most often, but sliding window size affected results more than population sampling.

Tired of seeing your patients in the ED? Let's give parent education another look!

This study was conducted to determine if a parent-oriented educational intervention reduces the use of emergency department (ED) services for the care of infants. Infants aged 7 days to 1 year and older children aged 2 to 10 years were tracked for 3 years in two separate primary care (PC) practices in Washington County, Texas, with the last year being the interventional study period. Also, infants aged 7 days to 1 year and older children aged 7 days to 5 years were tracked in a third PC practice in Burleson County, Texas. The study group consisted of all parents of patients aged 7 days to 1 year seen by the pediatric group in Washington County during the 1-year interventional period. Only parents of infants in the study group received a specific educational intervention booklet. Five separate control groups were followed in this study. The control groups received usual care with standardized patient information, but they did not receive the educational intervention booklet. Each group was evaluated by calculating its monthly ED utilization rate, which is the quotient derived from dividing the number of children from that particular group seen in the ED per month by the number of children from the same group seen in the PC clinic per month. A difference of proportions test was applied to test for statistical significance regarding ED utilization. Compared with parents in the control group, parents receiving the intervention booklet (the study group) showed significantly (P < .05) lower use of ED services for care of their infants. We found no change in ED utilization for children of parents receiving other standard educational information.

A reduction in emergency department use by children from a parent educational intervention.

BACKGROUND AND OBJECTIVES: A substantial proportion of emergency department (ED) visits by children are for non-urgent care. The objective of this research is to determine whether a parent-focused educational intervention can reduce non-urgent ED visits. METHODS: A regional hospital system (which includes a central hospital, four satellite hospitals, and two primary care clinics) provided monthly data retrospectively from January 2006 to October 2007 on ED visits by children. The same information was provided prospectively from November 2007 to April 2009. Starting in November 2007, a family medicine residency program affiliated with the same hospital network distributed a 6.7 grade reading level booklet on non-urgent care of children to the parents who brought their children to the outpatient clinic. The number of ED visits as a proportion of outpatient clinic visits at the residency program was calculated for each month and compared to historical and geographic trends. RESULTS: Long-term changes were observed only among the intervention group. There was a substantial and statistically significant reduction in ED use for non-urgent care of children. There was also a proportional reduction in ED charges for this group. CONCLUSION: An educational intervention among parents can substantially reduce non-urgent ED visits for their children.

Assessing and improving the accuracy of detecting protein adaptation with the TreeSAAP analytical software.

TreeSAAP has been used in a variety of protein studies for detecting adaptation in terms of the physicochemical properties involved in amino acid replacement. The accuracy of TreeSAAP was here tested using simulated protein-coding DNA data. A sampling of 1402 simulated amino acid replacements resulted in a default accuracy of 81.1%, with most properties exhibiting >90% accuracy. More than half of the false-positive results were traced to just 11 of the 180 possible single-step amino acid exchanges. Overall accuracy increased as the number of magnitude partitions used in the analysis decreased. Sliding window size did not significantly affect accuracy.

Evolutionary pressure on mitochondrial cytochrome b is consistent with a role of CytbI7T affecting longevity during caloric restriction.

BACKGROUND: Metabolism of energy nutrients by the mitochondrial electron transport chain (ETC) is implicated in the aging process. Polymorphisms in core ETC proteins may have an effect on longevity. Here we investigate the cytochrome b (cytb) polymorphism at amino acid 7 (cytbI7T) that distinguishes human mitochondrial haplogroup H from haplogroup U. PRINCIPAL FINDINGS: We compared longevity of individuals in these two haplogroups during historical extremes of caloric intake. Haplogroup H exhibits significantly increased longevity during historical caloric restriction compared to haplogroup U (p = 0.02) while during caloric abundance they are not different. The historical effects of natural selection on the cytb protein were estimated with the software TreeSAAP using a phylogenetic reconstruction for 107 mammal taxa from all major mammalian lineages using 13 complete protein-coding mitochondrial gene sequences. With this framework, we compared the biochemical shifts produced by cytbI7T with historical evolutionary pressure on and near this polymorphic site throughout mammalian evolution to characterize the role cytbI7T had on the ETC during times of restricted caloric intake. SIGNIFICANCE: Our results suggest the relationship between caloric restriction and increased longevity in human mitochondrial haplogroup H is determined by cytbI7T which likely enhances the ability of water to replenish the Q(i) binding site and decreases the time ubisemiquinone is at the Q(o) site, resulting in a decrease in the average production rate of radical oxygen species (ROS).

Molecular coevolution of the vertebrate cytochrome c(1) and Rieske iron sulphur protein in the cytochrome bc(1) complex.

Cytochrome c(1) (cyt-c(1)) and the Rieske Iron Sulphur Protein (ISP) are subunits of the cytochrome bc(1) complex located in the mitochondria functioning both as a proton pump and an electron transporter. Vertebrate model organism phylogenies were used in conjunction with existing 3D protein structures to evaluate the biochemical evolution of cyt-c(1) and ISP in terms of selection on amino acid properties. We found selection acting on the exterior surfaces of both proteins and specifically the core region of cyt-c(1). There is evidence supporting coevolution of these proteins relative to alpha helical tendencies, compressibility and equilibrium constant.

Molecular characterization of crustacean visual pigments and the evolution of pancrustacean opsins.

Investigations of opsin evolution outside of vertebrate systems have long been focused on insect visual pigments, whereas other groups have received little attention. Furthermore, few studies have explicitly investigated the selective influences across all the currently characterized arthropod opsins. In this study, we contribute to the knowledge of crustacean opsins by sequencing 1 opsin gene each from 6 previously uncharacterized crustacean species (Euphausia superba, Homarus gammarus, Archaeomysis grebnitzkii, Holmesimysis costata, Mysis diluviana, and Neomysis americana). Visual pigment spectral absorbances were measured using microspectrophotometry for species not previously characterized (A. grebnitzkii=496 nm, H. costata=512 nm, M. diluviana=501 nm, and N. americana=520 nm). These novel crustacean opsin sequences were included in a phylogenetic analysis with previously characterized arthropod opsin sequences to determine the evolutionary placement relative to the well-established insect spectral clades (long-/middle-/short-wavelength sensitive). Phylogenetic analyses indicate these novel crustacean opsins form a monophyletic clade with previously characterized crayfish opsin sequences and form a sister group to insect middle-/long-wavelength-sensitive opsins. The reconstructed opsin phylogeny and the corresponding spectral data for each sequence were used to investigate selective influences within arthropod, and mainly "pancrustacean," opsin evolution using standard dN/dS ratio methods and more sensitive techniques investigating the amino acid property changes resulting from nonsynonymous replacements in a historical (i.e., phylogenetic) context. Although the conservative dN/dS methods did not detect any selection, 4 amino acid properties (coil tendencies, compressibility, power to be at the middle of an alpha-helix, and refractive index) were found to be influenced by destabilizing positive selection. Ten amino acid sites relating to these properties were found to face the binding pocket, within 4 A of the chromophore and thus have the potential to affect spectral tuning.

Pharmacogenomics: analysing SNPs in the CYP2D6 gene using amino acid properties.

The CYP2D6 gene is responsible for metabolising a large portion of the commonly prescribed drugs. Because of its importance, various approaches have been taken to analyse CYP2D6 and Single Nucleotide Polymorphisms (SNPs) throughout its sequence. This study introduces a novel method to analyse the effects of SNPs on encoded protein complexes by focusing on the biochemical properties of each non-synonymous substitution using the program TreeSAAP. Our results show four SNPs in CYP2D6 that exhibit radical changes in amino acid properties which may cause a lack of functionality in the CYP2D6 gene and contribute to a person's inability to metabolise specific drugs.

Evolutionary selective pressure on three mitochondrial SNPs is consistent with their influence on metabolic efficiency in Pima Indians.

We investigated whether the effect of evolutionary selection on three recent Single Nucleotide Polymorphisms (SNPs) in the mitochondrial sub-haplogroups of Pima Indians is consistent with their effects on metabolic efficiency. The mitochondrial SNPs impact metabolic rate and respiratory quotient, and may be adaptations to caloric restriction in a desert habitat. Using TreeSAAP software, we examined evolutionary selection in 107 mammalian species at these SNPs, characterising the biochemical shifts produced by the amino acid substitutions. Our results suggest that two SNPs were affected by selection during mammalian evolution in a manner consistent with their effects on metabolic efficiency in Pima Indians.

Comparing phylogenetic codivergence between polyomaviruses and their hosts.

Seventy-two full genomes corresponding to nine mammalian (67 strains) and two avian (5 strains) polyomavirus species were analyzed using maximum likelihood and Bayesian methods of phylogenetic inference. Our fully resolved and well-supported (bootstrap proportions > 90%; posterior probabilities = 1.0) trees separate the bird polyomaviruses (avian polyomavirus and goose hemorrhagic polyomavirus) from the mammalian polyomaviruses, which supports the idea of spitting the genus into two subgenera. Such a split is also consistent with the different viral life strategies of each group. Simian (simian virus 40, simian agent 12 [Sa12], and lymphotropic polyomavirus) and rodent (hamster polyomavirus, mouse polyomavirus, and murine pneumotropic polyomavirus [MPtV]) polyomaviruses did not form monophyletic groups. Using our best hypothesis of polyomavirus evolutionary relationships and established host phylogenies, we performed a cophylogenetic reconciliation analysis of codivergence. Our analyses generated six optimal cophylogenetic scenarios of coevolution, including 12 codivergence events (P < 0.01), suggesting that Polyomaviridae coevolved with their avian and mammal hosts. As individual lineages, our analyses showed evidence of host switching in four terminal branches leading to MPtV, bovine polyomavirus, Sa12, and BK virus, suggesting a combination of vertical and horizontal transfer in the evolutionary history of the polyomaviruses.

Characterization of a mitochondrially targeted single-stranded DNA-binding protein in Arabidopsis thaliana.

A gene encoding a predicted mitochondrially targeted single-stranded DNA binding protein (mtSSB) was identified in the Arabidopsis thaliana genome sequence. This gene (At4g11060) codes for a protein of 201 amino acids, including a 28-residue putative mitochondrial targeting transit peptide. Protein sequence alignment shows high similarity between the mtSSB protein and single-stranded DNA binding proteins (SSB) from bacteria, including residues conserved for SSB function. Phylogenetic analysis indicates a close relationship between this protein and other mitochondrially targeted SSB proteins. The predicted targeting sequence was fused with the GFP coding region, and the organellar localization of the expressed fusion protein was determined. Specific targeting to mitochondria was observed in in-vitro import experiments and by transient expression of a GFP fusion construct in Arabidopsis leaves after microprojectile bombardment. The mature mtSSB coding region was overexpressed in Escherichia coli and the protein was purified for biochemical characterization. The purified protein binds single-stranded, but not double-stranded, DNA. MtSSB stimulates the homologous strand-exchange activity of E. coli RecA. These results indicate that mtSSB is a functional homologue of the E. coli SSB, and that it may play a role in mitochondrial DNA recombination.