A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.

Rotary and High-Pressure Nozzle Spray Plume Droplet Analysis For Aerially Applied Mosquito Adulticides: Laser Diffraction Characterization.

The droplet spectrum of a mosquito adulticide spray plume determines its ability to drift through the target area, impinge on the mosquito, deliver a toxic dose, and the risk of environmental contamination. This paper provides data on droplet spectra produced from 6 nozzles in a high-pressure nozzle spray system and 5 rotary nozzle systems for common mosquito adulticides. Spray plume spectra were measured by laser diffraction. High-pressure nozzles were evaluated at pressures ranging from 500 psi to 6,000 psi. Rotary nozzles were evaluated at rotational speeds ranging from 500 rpm to 24,000 rpm. Measurements were made at wind speeds of 129 km/h (80 mph) to 225 km/h (140 mph). Adulticides included were Fyfanon®, Aqua-Reslin®, Dibrom®, Duet®, Permanone®, and the inert mineral oil, Orchex® 796. High-pressure nozzles produced spray plumes within the US Environmental Protection Agency (EPA) label requirements for all configurations tested except for one at a wind speed of 225 km/h, BETE® MW125. Air speed had no significant effect on the spray plume volume median diameter (Dv(0.5)) at the speeds tested with Fyfanon®. The spray plume 90% drop volume diameter (Dv(0.9)) significantly decreased, 13% at the higher wind speed of 225 km/h. Drop size was inversely related to pressure. Dilution of the product formulations increased the Dv(0.5) of the spray plume but it did not exceed the label requirements. For the PJ15 nozzle, orientation of the nozzle into the wind of up to 135° showed a significant increase in Dv(0.5) at 500 psi, 750 psi, and 1,500 psi. The Dv(0.5) varied <5 µm over the 3 angles examined for any specific pressure. Rotary nozzles produced spray plumes within the EPA label requirements for all test configurations examined. Air speed had no significant effect on Dv(0.5) or Dv(0.9) of the plume at speeds tested with Fyfanon for the ASC A20 nozzle. The rotary AU5000 nozzle using Orchex 796 produced plumes of larger drops in all configurations than any of the rotary nozzles of similar configurations using active ingredient formulations and within EPA label requirements.

Substance abuse treatment as HIV prevention: more questions than answers.

This report examines associations between the availability of human immunodeficiency virus (HIV)-related health services in substance abuse treatment programs and characteristics of the programs and the patients they serve. In a cross-sectional, descriptive design and via a validated survey, program administrators within the National Drug Abuse Treatment Clinical Trials Network provided information on program characteristics, patient characteristics (rates of risky sexual and drug behaviors and HIV infection), and the availability of 31 different HIV-related health services. Of 319 programs, 84% submitted surveys. Service availability rates ranged from: 10% (pneumococcal vaccination) to 86% (drug testing) for the 6 HIV-related services offered to all patients, 13% (Pap smear for women) to 54% (tuberculin skin testing) for the 6 services offered to new patients, 2% (sterile injection equipment) to 64% (male condoms) for the 4 risk-reduction services, 37% (Pap smear for women) to 61% (tuberculin skin testing) for the 11 biological assessments offered to HIV-positive patients, and 33% (medical treatments) to 52% (counseling) for the 4 other services offered to HIV-positive patients. The availability of these HIV-related services was associated with clinical settings, the types of addiction treatment services, the rates of risky drug and sexual behaviors, and HIV infection rates among patients. Availability of such services was below published guidelines. While the results provide another basis for the infection-related prevention benefits of substance abuse treatment, the variability in the availability of HIV-related health care deserves further study and has health policy implications in determining how to utilize substance abuse treatment in reducing drug-related HIV transmission.

States and substance abuse treatment programs: funding and guidelines for infection-related services.

Community-based substance abuse treatment programs provide HIV, hepatitis C virus, and sexually transmitted infection services. To explore how state funding and guidelines affect practice, we surveyed state agency administrators and substance abuse treatment program administrators and clinicians regarding 8 infection-related services. Although state funding for infection-related services is widely available, substance abuse treatment programs do not always access it. Substance abuse treatment program guidelines are clearer in states that have written guidelines. Improved communication between state agencies and substance abuse treatment programs may enhance service.

Longitudinal trends in antibiotic resistance in US nursing homes, 2000-2004.

We evaluated antibiotic resistance trends in US nursing homes using the Minimum Data Set. Significant increases in the number and proportion of infections caused by antibiotic-resistant bacteria were documented over the 5-year study. Further research on antibiotic resistance in nursing homes is urgently needed.

Health services for HIV/AIDS, HCV, and sexually transmitted infections in substance abuse treatment programs.

The National Drug Abuse Treatment Clinical Trials Network conducted this study to determine the availability of and factors associated with infection-related health services in substance abuse treatment settings. In a cross-sectional descriptive design, state policies, reimbursement for providers, state level of priority, and treatment program characteristics were studied via written surveys of administrators of substance abuse treatment programs and of state health and substance abuse departments. Data from health departments and substance abuse agencies of 48 states and from 269 substance abuse treatment programs revealed that human immunodeficiency virus/acquired immunodeficiency syndrome-related services are more frequent than hepatitis C virus or sexually transmitted infection-related services, and that nonmedical services are more frequent than medical services. While the availability of infection-related health services is associated with medical staffing patterns, addiction pharmacotherapy services, and state priorities, reimbursement was the most significant determining factor. These findings suggest that greater funding of these health services in substance abuse treatment settings, facilitated by supportive state policies, represents an effective response to the excess morbidity and mortality of these substance use-related infections.

Characteristics of substance abuse treatment programs providing services for HIV/AIDS, hepatitis C virus infection, and sexually transmitted infections: the National Drug Abuse Treatment Clinical Trials Network.

Illicit drug users sustain the epidemics of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), hepatitis C (HCV), and sexually transmitted infections (STIs). Substance abuse treatment programs present a major intervention point in stemming these epidemics. As a part of the "Infections and Substance Abuse" study, established by the National Drug Abuse Treatment Clinical Trials Network, sponsored by National Institute on Drug Abuse, three surveys were developed; for treatment program administrators, for clinicians, and for state and District of Columbia health and substance abuse department administrators, capturing service availability, government mandates, funding, and other key elements related to the three infection groups. Treatment programs varied in corporate structure, source of revenue, patient census, and medical and non-medical staffing; medical services, counseling services, and staff education targeted HIV/AIDS more often than HCV or STIs. The results from this study have the potential to generate hypotheses for further health services research to inform public policy.

Laser-diffraction characterization of flat-fan nozzles used to develop aerosol clouds of aerially applied mosquito adulticides.

The importance of appropriate drop size and density for successful mosquito adulticide applications mandates the necessity for accurate determination of drop spectra of a particular nozzle. There is considerable disparity between mass median diameter (MMD) determinations for flat-fan nozzles relative to the horizontal or vertical orientation of the microscope slide used to collect the drops. To remove this ambiguity, the definitive MMDs of flat-fan nozzles used in aerially applied mosquito control adulticides were determined by laser-diffraction-based characterization and analysis. These data were compared with previous data, and the impact of these data on aerial adult mosquito control was discussed. At The Florida Wind Tunnel for Mosquito Control, the Malvern Spraytec Spray Particle Analysis System was used to characterize the entire aerosol plume of the nozzles. Nozzle characterizations were carried out at aircraft operational wind speeds and pressures with nozzles mounted at 135 degrees relative to the direction of air flow. The mean drop-diameter volumes (Dv) Dv(0.1), Dv(0.5), and Dv(0.9) with 95% confidence intervals for each scenario were determined. Characterizations of flat-fan nozzles of 80005 to 8005 for Orchex 796, Dibrom and a Permanone:Orchex 796 mix (1:1) resulted in no Dv(0.5) less than 50 microm and a maximum of 133 microm. The Dv(0.1) was greater than 25 min for 52% of the nozzles and ranged from 14 to 42 microm. The Dv(0.9) ranged from 130 to 296 microm. There was a decrease in drop-diameter values (Dv(0.1), Dv(0.5), Dv(0.9)) relative to increased wind speed and/or pressure for any particular nozzle. Relative to characterizations with Orchex 796, drop-diameter values for Dibrom varied from the same to slightly larger, whereas the Permanone:Orchex 796 mix values were larger except for 2. Relative to the goal of creating an aerosol cloud efficient in controlling adult mosquitoes, none of the nozzles were capable of producing a Dv(0.5) of less than 50 microm. Fifty percent of the spray was capable of causing visible damage to a car's finish. The concept that droplets larger than 25 microm are wasteful because they contain more malathion than required for kill suggests that for 52% of the nozzle configurations, those with Dv(0.1) greater than 25 microm, 90% of the spray is of little use in controlling mosquitoes. None of the flat-fan nozzle regimes tested will satisfy new label requirements of a Dv(0.5) and Dv(0.9) of around 50 and 100 microm, respectively, because of their high Dv(0.9).

Hepatitis B virus and hepatitis C virus services offered by substance abuse treatment programs in the United States.

Although substance abuse treatment programs are important contact points for providing health services for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, availability of services in these programs has not been well characterized. This study evaluated the spectrum of HBV and HCV services offered by substance abuse treatment programs within the National Drug Abuse Treatment Clinical Trials Network. Our survey of substance abuse treatment program administrators covered availability of testing for HBV and HCV; hepatitis A virus (HAV) and HBV immunization; and HCV medical and nonmedical services. There were also questions covering clarity of guidelines for HBV and HCV testing and HAV and HBV immunization. Differences between methadone and nonmethadone programs were examined. Despite the importance of substance abuse in sustaining the hepatitis epidemics, few programs offer comprehensive HBV and HCV testing or HCV health care services. Interventions to improve access to hepatitis services for substance-abusing patients are needed.

Diffusion of biologically relevant molecules through gel-like tissue scaffolds.

Encapsulation of living cells into gel-like matrices that are capable of maintaining their viability over an extended time period is starting to play a major role in medicine in applications such as, cell-based sensors, cellular therapy, and tissue engineering. The permeability of nutrients and waste products through these matrices is critical to their performance. In this article, we report a methodology for selecting scaffolds with different permeabilities and surface area/volume ratios that can be used to house a 3D cell aggregate. Such a system can be modeled if the consumption or production rates for metabolites and waste products, respectively and the diffusion coefficients of these solutes in culture medium and the encapsulating gel matrix are known. A transient finite volume mass diffusion model, based on Fick's law, is derived where the consumption of a solute by the cells is modeled through a source term. The results show that the "performance" of cell-doped gel is critically dependent on the rate at which cells consume key molecules e.g., glucose. Pragmatically, the model also provides insight as to how many cells a given gel geometry and structure can support. The approach used applies to any porous structure where mass transport occurs through diffusion.

Barriers to providing health services for HIV/AIDS, hepatitis C virus infection and sexually transmitted infections in substance abuse treatment programs in the United States.

We sought to identify barriers to offering services for HIV/AIDS, hepatitis C virus, and sexually transmitted infections in substance abuse treatment programs. We surveyed treatment program administrators and clinicians within the National Drug Abuse Treatment Clinical Trials Network to evaluate the availability of medical and non-medical services for patients with or at risk for acquiring these infections. A substantial proportion of programs do not offer services (particularly medical services) for these infections. The most commonly cited barriers were funding, health insurance benefits, patient acceptance, and staff training. The findings highlight a missed opportunity to positively impact these infectious disease epidemics.

Disparities in Health Services for HIV/AIDS, Hepatitis C Virus, and Sexually Transmitted Infections: Role of Substance Abuse Treatment Programs.

OBJECTIVES: This report focused upon the availability of infection-related health services in substance abuse treatment programs with and without addiction services tailored for special populations (women and non-white populations). METHODS: In a cross-sectional, descriptive design, treatment program administrators across the United States within the National Drug Abuse Treatment Clinical Trials Network provided information on program characteristics, the availability of infection-related services (four medical services and three non-medical services for HIV, HCV, and STI), and barriers to providing infection-related services. RESULTS: Of 319 programs, 269 submitted surveys (84% response rate). Of these, 80% provided addiction services for special populations. Programs providing addiction services designed for at least one special population, were more likely to provide infection-related health services, especially HIV-related education (94% versus 85%, p = 0.05) and patient counseling (76% versus 60%, p = 0.03) and were more likely to include outpatient addiction services (86% versus 57%, p<0.001) and outreach and support services (92% versus 70%, p=0.01). Barriers to providing infection-related services included funding (cited by 48.3% to 74.7% of programs), health insurance (cited by 28.9% to 60.8% of programs), and patient acceptance (cited by 23.2% to 54.3% of programs). CONCLUSIONS: Despite many barriers, infection-related healthcare is available in programs with addiction treatment services tailored for special populations, especially for African Americans and Latino Americans. Tailoring substance abuse treatment along with reducing barriers to infection-related care represent public health interventions with potential to reduce the burdens and disparities associated with these infections.

Substance abuse treatment clinician opinions and infectious disease service delivery.

Substance abuse treatment programs are an important platform for delivery of services for infectious diseases associated with drug and alcohol use. However, important components of infectious disease care are not universally provided. Clinician training often focuses on information about infectious diseases and less attention is paid to provider opinions and attitudes that may be barriers to providing infectious diseases services. In a national multi-site trial conducted by the National Drug Abuse Treatment Clinical Trials Network (CTN), we investigated the relationship between clinician opinions and the delivery of services for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections in substance abuse treatment settings. Survey data were collected from 1,723 clinicians at 269 CTN treatment programs. Clinician opinion was found to be significantly related to infectious disease service delivery. Implications for training are discussed.

Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis.

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.

Analysis of Fcgamma receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B.

The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.