A multi-organ map of the human immune system across age, sex and ethnicity.

Understanding tissue biology's heterogeneity is crucial for advancing precision medicine. Despite the centrality of the immune system in tissue homeostasis, a detailed and comprehensive map of immune cell distribution and interactions across human tissues and demographics remains elusive. To fill this gap, we harmonised data from 12,981 single-cell RNA sequencing samples and curated 29 million cells from 45 anatomical sites to create a comprehensive compositional and transcriptional healthy map of the healthy immune system. We used this resource and a novel multilevel modelling approach to track immune ageing and test differences across sex and ethnicity. We uncovered conserved and tissue-specific immune-ageing programs, resolved sex-dependent differential ageing and identified ethnic diversity in clinically critical immune checkpoints. This study provides a quantitative baseline of the immune system, facilitating advances in precision medicine. By sharing our immune map, we hope to catalyse further breakthroughs in cancer, infectious disease, immunology and precision medicine.

Ensuring it works: a community-based approach to HIV prevention intervention development for men who have sex with men in Chennai, India.

Men who have sex with men (MSM) in India have an HIV seroprevalence 22 times greater than the country's general population and face unique challenges that may hinder the effectiveness of current HIV prevention efforts. To obtain an understanding of the logistical and sociocultural barriers MSM experience while accessing HIV prevention services, focus groups and key informant interviews were conducted with 55 MSM in Chennai, India. Qualitative data were analyzed using descriptive qualitative content analysis. Sixty-five percent of participants identified as kothi (receptive partners), 9% as panthi (insertive partners), 22% as double decker (receptive and insertive), and 4% did not disclose. Themes included: (a) fatigue with current HIV risk reduction messages; (b) increased need for non-judgmental and confidential services; and (c) inclusion of content that acknowledges individual and structural-level determinants of risk such as low self-esteem, depression, and social discrimination. MSM interventions may benefit from approaches that address multilevel psychosocial factors, including skills building and strategies to foster self-acceptance and increased social support.

Diet type and changes in food cravings following weight loss: findings from the POUNDS LOST Trial.

Few well-controlled trials have evaluated the effects that macronutrient composition has on changes in food cravings during weight loss treatment. The present study, which was part of the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, investigated whether the fat and protein content of four different diets affected changes in specific food cravings in overweight and obese adults. A sample of 811 adults were recruited across two clinical sites, and each participant was randomly assigned to one of four macronutrient prescriptions: 1) low fat (20% of energy), average protein (15% of energy); 2) moderate fat (40%), average protein (15%); 3) low fat (20%), high protein (25%); 4) moderate fat (40%), high protein (25%). With few exceptions, the type of diet that participants were assigned did not differentially affect changes in specific food cravings. Participants assigned to the high-fat diets, however, had reduced cravings for carbohydrates at month 12 (p<0.05) and fruits and vegetables at month 24. Also, participants assigned to high-protein diets had increased cravings for sweets at month 6 and month 12 (ps<0.05). Participants in all four dietary conditions reported significant reductions in food cravings for specific types of foods (i.e., high fat foods, fast food fats, sweets, and carbohydrates/starches; all ps<0.05). Cravings for fruits and vegetables, however, were increased at month 24 (p<0.05). Calorically restricted diets (regardless of their macronutrient composition) yielded significant reductions in cravings for fats, sweets, and starches whereas cravings for fruits and vegetables were increased.

Effect of diet composition on energy expenditure during weight loss: the POUNDS LOST Study.

BACKGROUND: Weight loss reduces energy expenditure, but the contribution of different macronutrients to this change is unclear. HYPOTHESIS: We tested the hypothesis that macronutrient composition of the diet might affect the partitioning of energy expenditure during weight loss. DESIGN: A substudy of 99 participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial had total energy expenditure (TEE) measured by doubly labeled water, and resting energy expenditure (REE) measured by indirect calorimetry at baseline and repeated at 6 months in 89 participants. Participants were randomly assigned to one of four diets with either 15 or 25% protein and 20 or 40% fat. RESULTS: TEE and REE were positively correlated with each other and with fat-free mass and body fat, at baseline and 6 months. The average weight loss of 8.1 ± 0.65 kg (least-square mean ± s.e.) reduced TEE by 120 ± 56 kcal per day and REE by 136 ± 18 kcal per day. A greater weight loss at 6 months was associated with a greater decrease in TEE and REE. Participants eating the high-fat diet (HF) lost significantly more fat-free mass (1.52 ± 0.55 kg) than the low-fat (LF) diet group (P<0.05). Participants eating the LF diet had significantly higher measures of physical activity than the HF group. CONCLUSION: A greater weight loss was associated with a larger decrease in both TEE and REE. The LF diet was associated with significant changes in fat-free body mass and energy expenditure from physical activity compared with the HF diet.

Barriers and facilitators to routine HIV testing: perceptions from Massachusetts Community Health Center personnel.

Since 2006, the Centers for Disease Control and Prevention (CDC) has recommended routine, voluntary HIV testing for persons aged 13-64 in all health care settings, including the elimination of separate informed consent, which remains in effect in five states including Massachusetts. Community health centers (CHCs) represent an important HIV testing site for at-risk populations. From April to December 2008 a qualitative interview was administered to one senior personnel from each of 30 CHCs in Massachusetts, to identify barriers and facilitators to implementing CDC recommendations and to elucidate strategies to improve routine HIV testing. The following themes emerged as routine HIV testing barriers: (1) provider time constraints, including time to administer counseling and separate informed consent; (2) lack of funding, staff, and space; (3) provider, patient, and community discomfort; (4) inconsistent levels of awareness regarding CDC recommendations; and (5) perceived incompatibility with Massachusetts HIV testing policy. Facilitators included designation of personnel to serve as organizational "champions" for routine testing and use of clinical reminders within electronic medical records to prompt HIV testing. Strategies identified to improve routine HIV testing rates among Massachusetts CHCs included more explicit state-level guidelines; organizational buy-in; collaborative analysis to integrate testing within existing activities; and provider, patient and community education.

Barriers to routine HIV testing among Massachusetts community health center personnel.

OBJECTIVES: We assessed the extent to which Centers for Disease Control and Prevention (CDC) recommendations have influenced routine HIV testing among Massachusetts community health center (CHC) personnel, and identified specific barriers and facilitators to routine testing. METHODS: Thirty-one CHCs were enrolled in the study. We compared those that did and did not receive funding support from the federal Ryan White HIV/AIDS Program. An anonymous survey was administered to a maximum five personnel from each CHC, including a senior administrator, the medical director, and three medical providers. Overall, 137 participants completed the survey. RESULTS: Among all CHCs, 53% of administrators reported having implemented routine HIV testing at their CHCs; however, only 33% of medical directors/providers reported having implemented routine HIV testing in their practices (p<0.05). Among administrators, 60% of those from Ryan White-supported CHCs indicated that both they and their CHCs were aware of CDC's recommendations, compared with 27% of administrators from non-Ryan White-supported CHCs. The five most frequently reported barriers to the implementation of routine HIV testing were (1) constraints on providers' time (68%), (2) time required to administer counseling (65%), (3) time required to administer informed consent (52%), (4) lack of funding (35%), and (5) need for additional training (34%). In a multivariable logistic regression model, the provision of on-site HIV testing by nonmedical staff resulted in increased odds of conducting routine HIV testing (odds ratio [OR] = 9.84, 95% confidence interval [CI] 1.77, 54.70). However, the amount of time needed to administer informed consent was associated with decreased odds of providing routine testing (OR=0.21, 95% CI 0.05, 0.92). CONCLUSIONS: Routine HIV testing is not currently being implemented uniformly among Massachusetts CHCs. Future efforts to increase implementation should address personnel concerns regarding time and staff availability.

Suicidality, clinical depression, and anxiety disorders are highly prevalent in men who have sex with men in Mumbai, India: findings from a community-recruited sample.

In India men who have sex with men (MSM) are a stigmatized and hidden population, vulnerable to a variety of psychosocial and societal stressors. This population is also much more likely to be HIV-infected compared to the general population. However, little research exists about how psychosocial and societal stressors result in mental health problems. A confidential, quantitative mental-health interview was conducted among 150 MSM in Mumbai, India at The Humsafar Trust, the largest non-governmental organization serving MSM in India. The interview collected information on sociodemographics and assessed self-esteem, social support and DSM-IV psychiatric disorders using the Mini International Neuropsychiatric Interview (MINI). Participants' mean age was 25.1 years (SD = 5.1); 21% were married to women. Forty-five percent reported current suicidal ideation, with 66% low risk, 19% moderate risk, and 15% high risk for suicide per MINI guidelines. Twenty-nine percent screened in for current major depression and 24% for any anxiety disorder. None of the respondents reported current treatment for any psychiatric disorder. In multivariable models controlling for age, education, income, and sexual identity, participants reporting higher levels of self-esteem and greater levels of satisfaction with the social support they receive from family and friends were at lower risk of suicidality (self-esteem AOR = 0.85, 95% CI: 0.78-0.93; social support AOR = 0.76, 95% CI: 0.62-0.93) and major depression (self-esteem AOR = 0.79, 95% CI: 0.71-0.89; social support AOR = 0.68, 95% CI: 0.54-0.85). Those who reported greater social support satisfaction were also at lower risk of a clinical diagnosis of an anxiety disorder (AOR = 0.80; 95% CI: 0.65-0.99). MSM in Mumbai have high rates of suicidal ideation, depression, and anxiety. Programs to improve self-esteem and perceived social support may improve these mental health outcomes. Because they are also a high-risk group for HIV, MSM HIV prevention and treatment services may benefit from incorporating mental health services and referrals into their programs.

What makes a respondent-driven sampling "seed" productive? Example of finding at-risk Massachusetts men who have sex with men.

Several recent studies have sought to elaborate upon the applicability and validity of respondent-driven sampling (RDS) to find hard-to-reach samples in general and men who have sex with men (MSM) in particular. Few published studies have elucidated the characteristics associated with initial RDS participants ("seeds") who successfully recruited others into a study. A total of 74 original seeds were analyzed from four Massachusetts studies conducted between 2006 and 2008 that used RDS to reach high-risk MSM. Seeds were considered "generative" if they recruited two or more subsequent participants and "non-generative" if they recruited zero or one participant. Overall, 34% of seeds were generative. In separate multivariable logistic regression models controlling for age, race, health insurance, HIV status, and the study for which the seed was enrolled, unprotected anal sex in the past 12 months [adjusted odds ratio (AOR) = 6.68; 95% confidence interval (95% CI) = 1.27-35.12; p = 0.03], cocaine use during sex at least monthly during the past 12 months (AOR = 8.81; 95% CI = 1.68-46.27; p = 0.01), and meeting sex partners at social gatherings (AOR = 7.42; 95% CI = 1.58-34.76; p = 0.01) and public cruising areas (AOR = 4.92; 95% CI = 1.27-19.01; p = 0.02) were each significantly associated with increased odds of being a generative seed. These findings have methodological and practical implications for the recruitment of MSM via RDS. Finding ways to identify RDS seeds that are consistently generative may facilitate collecting a sample that is closer to reflecting the MSM who live in all of the communities in a given location or study sample.

HIV prevention interventions in Chennai, India: are men who have sex with men being reached?

India has the greatest number of HIV infections in Asia and the third highest total number of infected persons globally. Men who have sex with men (MSM) are considered by the Government of India's National AIDS Control Organization (NACO) a "core risk group" for HIV in need of HIV prevention efforts. However there is a dearth of information on the frequency of participation in HIV prevention interventions and subsequent HIV risk and other correlates among MSM in India. Recruited through peer outreach workers, word of mouth and snowball sampling techniques, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about participating in any HIV prevention interventions in the past year, sexual risk taking, demographics, MSM identities, and other psychosocial variables. Bivariate and multivariable logistic regression procedures were used to examine behavioral and demographic correlates with HIV prevention intervention participation. More than a quarter (26%) of the sample reported participating in an HIV prevention intervention in the year prior to study participation. Participants who reported engaging in unprotected anal sex (UAS; odds ratio [OR] = 0.28; p = 0.01) in the 3 months prior to study enrollment were less likely to have participated in an HIV prevention program in the past year. MSM who were older (OR = 1.04; p = 0.05), kothis (feminine acting/appearing and predominantly receptive partners in anal sex) compared to panthis (masculine appearing, predominantly insertive partners; OR = 5.52, p = 0.0004), those with higher educational attainment (OR = 1.48, p = 0.01), being "out" about having sex with other men (OR = 4.03, p = 0.0001), and MSM who reported ever having been paid in exchange for sex (OR = 2.92, p = 0.001) were more likely to have reported participation in an HIV prevention intervention in the preceding year. In a multivariable model, MSM reporting UAS in the prior 3 months were less likely to have participated in an HIV prevention intervention (AOR = 0.34, p = 0.04). MSM who were older (AOR = 1.05, p = 0.05), those with higher educational attainment (AOR = 1.92, p = 0.0009), and MSM who were "out" about having sex with other men (AOR = 2.71, p = 0.04) were more likely to have reported participating in an HIV prevention program. Findings suggest that exposure to HIV prevention interventions may be protective against engaging in UAS for some MSM in India. Understanding predictors of participation in an HIV prevention intervention is helpful for identifying Indian MSM who might have had no exposure to HIV prevention information and skills building, hence allowing researchers and prevention workers to focus efforts on individuals at greatest need.

Preexposure antiretroviral prophylaxis attitudes in high-risk Boston area men who report having sex with men: limited knowledge and experience but potential for increased utilization after education.

BACKGROUND: Preexposure prophylaxis (PrEP) could protect individuals engaging in repeated high-risk behaviors from HIV infection. Understanding the demographic and behavioral predictors of intent-to-use PrEP may prove useful to identify clinical trial participants. METHODS: In 2007, 227 HIV-uninfected men who report having sex with men (MSM) recruited through modified respondent-driven sampling completed an interviewer-administered survey assessing prior PrEP use and awareness, future intent-to-use PrEP, demographics, sexual risk, psychosocial variables, and drug/alcohol use. Bivariate and multivariable logistic regression procedures examined predictors of intent-to-use PrEP. RESULTS: Mean age of participants was 41 (SD = 9.1); 54% were nonwhite. One participant reported prior off-label PrEP use (medication obtained from his HIV-infected brother). Nineteen percent had previously heard of PrEP, whereas 74% reported intent-to-use PrEP if available after being educated about its potential. In multivariable analysis controlling for age and race/ethnicity, significant predictors of intent-to-use PrEP included the following: less education [odds ratio (OR) = 7.7; P = 0.04], moderate income (OR = 13.0; P = 0.04), no perceived side effects from taking PrEP (OR = 3.5; P = 0.001), and not having to pay for PrEP (OR = 4.2; P = 0.05). DISCUSSION: Many New England MSM indicated an interest in using PrEP after learning about its potential, particularly if they could obtain PrEP at no expense and if PrEP had no side effects. Less educated MSM and those who knew less about PrEP and antiretroviral therapy before entering the study were more open to using antiretroviral therapy for prevention once they had received some information suggesting its potential value. Findings suggest that careful educational messages are necessary to ensure appropriate PrEP use if clinical trials reveal partial efficacy.

A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth.

Advances in antiretroviral medications have resulted in precipitous declines in HIV-associated morbidity and mortality; however, high levels of adherence are crucial to the success of HIV therapies. This article reviews published studies in the United States on HIV-infected youth (ages 13 to 24 years), focusing on adherence to antiretroviral regimens and interventions designed to enhance adherence. A systematic search yielded 21 articles published between 1999 and 2008 that reported data on medication adherence in HIV-infected youth, of which 7 described unique interventions to enhance medication adherence. Five thematic areas were identified to classify factors associated with adherence. Findings suggest psychosocial factors, in particular depression and anxiety, were consistently associated with poorer adherence across studies. Three types of adherence interventions with HIV-infected youth were found. Results suggest that examining adherence within the broader contextual issues present in the lives of youth, including HIV stigma and disclosure, caregiver stress, peer relations, mental health and substance use, and length of time on medications, may be most important to understanding how best to intervene with adherence among this population. Secondary HIV prevention interventions for youth represent a possible mode through which to deliver individually tailored adherence skill building and counseling to improve medication adherence.

Health care access and sexually transmitted infection screening frequency among at-risk Massachusetts men who have sex with men.

OBJECTIVES: We sought to assess risk exposures, health care access, and screening rates for HIV and sexually transmitted infections (STIs) among men who have sex with men (MSM) in Massachusetts. METHODS: We used a modified respondent-driven sampling method to collect data between March 2006 and May 2007. Overall, 126 MSM completed a survey. RESULTS: Seventy percent of participants reported unprotected receptive anal intercourse with at least 1 nonmonogamous male partner; 50% reported having had a previous STI. Although 98% had visited a health care provider in the previous year, 39% had not been screened for STIs during the previous 2 years. Bisexual respondents were less likely to have told their health care providers that they engage in male-to-male sexual contact (OR = 4.66; P < .001), less likely to have been tested for STIs during in the previous 2 years (OR = 6.91; P < .001), and more likely to engage in insertive anal intercourse without a condom with an HIV-infected partner (OR = 5.04; P < .005) than were non-bisexual respondents. CONCLUSIONS: Clinicians need to assess sexual risk-taking behaviors and more routinely screen for STIs among sexually active men regardless of disclosure of a history of having sex with men.

Interpreting genetics of gene expression: integrative architecture in Bioconductor.

Several influential studies of genotypic determinants of gene expression in humans have now been published based on various populations including HapMap cohorts. The magnitude of the analytic task (transcriptome vs. SNP-genome) is a hindrance to dissemination of efficient, thorough, and auditable inference methods for this project. We describe the structure and use of Bioconductor facilities for inference in genetics of gene expression, with simultaneous application to multiple HapMap cohorts. Tools distributed for this purpose are readily adapted for the structure and analysis of privately-generated data in expression genetics.

Predictors of identifying as a barebacker among high-risk New England HIV seronegative men who have sex with men.

Studies have found that between 14% and 46% of US men who have sex with men (MSM) consistently report "barebacking" behavior (i.e., intentional unprotected anal intercourse) with other men. This is of public health significance because MSM continue to constitute more than 50% of new HIV infections in the USA. Men who self-identify as barebackers may represent a different and unique subset of MSM with distinct HIV prevention needs. In 2007, 227 HIV seronegative MSM recruited through modified respondent-driven sampling completed an interviewer-administered survey which assessed barebacker identity (i.e., personally identifying with the barebacker scene), demographics, sexual risk behaviors, psychosocial variables, and drug/alcohol use. Bivariate and multivariable logistic regression procedures were used to examine predictors of barebacker identity in relation to HIV risk behavior. Overall, 31% of participants identified as a barebacker. In bivariate analyses, lower education (OR = 1.76; 95% CI = 0.99-3.13; p < 0.05), a current drinking problem (OR = 2.34, 95% CI = 1.29-4.23; p < 0.01), higher levels of HIV treatment optimism (OR = 1.06; 95% CI = 1.01-1.12; p < 0.05), meeting sexual partners at private sex parties (OR = 2.47; 95% CI = 1.28-4.74; p < 0.01) or at bars/cubs (OR = 1.97; 95% CI = 1.10-3.52; p < 0.05), and engaging in serodiscordant unprotected insertive anal sex (OR = 3.42; 95% CI = 1.27-9.21; p < 0.01) significantly predicted barebacker identification compared to those with no barebacker identification. In a multivariable model, barebackers were more likely to screen in for alcohol abuse (adjusted OR = 2.16; 95% CI = 1.09-4.27; p < 0.05) and engage in serodiscordant unprotected insertive anal sex (adjusted OR = 3.17; 95% CI = 1.09-9.20; p < 0.05) compared to their non-barebacker counterparts. No significant differences were found in serodiscordant unprotected receptive anal sex between barebackers and non-barebackers. These findings suggest that barebacker identity is related to intentional HIV sexual risk taking and alcohol abuse. Furthermore, strategic positioning (i.e., engaging in insertive rather than receptive sex) might be associated with barebacker identification and may indicate a harm-reduction strategy being used among some HIV-uninfected MSM to reduce their risk of becoming infected. Additional research is warranted to understand the social identity of barebacking among MSM in order to develop more nuanced prevention strategies.

Health care issues among lesbian, gay, bisexual, transgender and intersex (LGBTI) populations in the United States: Introduction.

This supplemental issue of the Journal of Homosexuality presents research that explores a variety of health care issues encountered by lesbian, gay, bisexual, transgender and intersex (LGBTI) population groups in the United States over the 10-year period from 1993 to 2002. Topics include access to health care, utilization of care, training of medical and mental health providers, and the appropriate preparation of clinical offices and waiting areas. Authors used a variety of community-based public health research methods, including participant and provider surveys and retrospective chart reviews of patients, to develop this body of research, providing a recent-historical perspective on the complex health care and health-related needs of sexual and gender minorities. Particularly for transgender and intersex populations, the state of research describing their health care needs is in its infancy, and much remains to be done to design effective medical and mental health programs and interventions.

Polymorphic variation in surfactant protein B is associated with COPD exacerbations.

Exacerbations of chronic obstructive pulmonary disease (COPD) reduce quality of life and increase mortality. Genetic variation might explain the substantial variability seen in exacerbation frequency among COPD subjects with similar lung function. Polymorphisms in five candidate genes, previously associated with COPD susceptibility, were analysed in order to determine whether they demonstrated association with COPD exacerbations. A total of 88 single nucleotide polymorphisms (SNPs) in the genes microsomal epoxide hydrolase (EPHX1), transforming growth factor, beta-1 (TGFB1), serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2), glutathione S-transferase pi (GSTP1) and surfactant protein B (SFTPB) were genotyped in 389 non-Hispanic white participants in the National Emphysema Treatment Trial. Exacerbations were defined as COPD-related emergency room visits or hospitalisations using the Centers for Medicare and Medicaid Services claims data. One or more exacerbations were experienced by 216 (56%) subjects during the study period. An SFTPB promoter polymorphism, rs3024791, was associated with COPD exacerbations. Logistic regression models, analysing a binary outcome of presence or absence of exacerbations, confirmed the association of rs3024791 with COPD exacerbations. Negative binomial regression models demonstrated association of multiple SFTPB SNPs (rs2118177, rs2304566, rs1130866 and rs3024791) with exacerbation rates. Polymorphisms in EPHX1, GSTP1, TGFB1 and SERPINE2 did not demonstrate association with COPD exacerbations. In conclusion, genetic variation in surfactant protein B is associated with chronic obstructive pulmonary disease susceptibility and exacerbation frequency.

SGDI: system for genomic data integration.

This paper describes a framework for collecting, annotating, and archiving high-throughput assays from multiple experiments conducted on one or more series of samples. Specific applications include support for large-scale surveys of related transcriptional profiling studies, for investigations of the genetics of gene expression and for joint analysis of copy number variation and mRNA abundance. Our approach consists of data capture and modeling processes rooted in R/Bioconductor, sample annotation and sequence constituent ontology management based in R, secure data archiving in PostgreSQL, and browser-based workspace creation and management rooted in Zope. This effort has generated a completely transparent, extensible, and customizable interface to large archives of high-throughput assays. Sources and prototype interfaces are accessible at www.sgdi.org/software.

Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression.

Lipoprotein lipase (LPL) is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL) related to immunoglobulin V(H) gene (IgV(H))mutational status. We determined gene expression profiles using Affymetrix U133A GeneChips in two groups of B-CLLs selected for either high ('LPL+', n=10) or low ('LPL-', n=10) LPL mRNA expression. Selected genes were verified by real-time PCR in an extended patient cohort (n=42). A total of 111 genes discriminated LPL+ from LPL- B-CLLs. Of these, the top three genes associated with time to first treatment were Septin10, DMD and Gravin (P

Distribution of four capsular serotypes of Enterococcus faecalis among clinical isolates from different geographical origins and infection sites.

BACKGROUND: Enterococci possess capsular polysaccharide antigens that are the targets of opsonic antibodies. These antibodies are potential candidates for development as immunotherapy. MATERIAL AND METHODS: The present study analyzes the distribution of four capsular serotypes within a collection of 157 isolates of Enterococcus faecalis from four countries with different sites of clinical infection. RESULTS: By using a capsular polysaccharide-specific ELISA, 42% of the isolates were grouped into one of four serogroups, and another 9% showed cross-reactivity between two serotype-specific sera. Heterogeneity of serotype distribution by both geographical origin and infection site was observed. CONCLUSION: Half of the strain collection could be typed with four serotype-specific sera. No serotype from a given country or infection site clearly predominated.

Familial aggregation of FEF(25-75) and FEF(25-75)/FVC in families with severe, early onset COPD.

BACKGROUND: The Boston Early-Onset COPD study showed that current or ex-smoking first degree relatives of severe early onset COPD probands have significantly lower forced expiratory volume in 1 second (FEV(1)) and FEV(1)/forced vital capacity (FVC) values than current or ex-smoking control subjects, which suggests the existence of genetic risk factors for the development of COPD in response to cigarette smoking. We hypothesised that first degree relatives of early onset COPD probands may also have lower values of spirometric parameters such as forced expiratory flow at the mid-portion of forced vital capacity (FEF(25-75)) and FEF(25-75)/FVC. METHODS: Using generalised estimating equations, FEF(25-75) and FEF(25-75)/FVC were analysed in 333 first degree relatives of probands with severe early onset COPD and 83 population based controls; analyses were also performed on data stratified by smoking status. Narrow sense heritability estimates were calculated using a variance component approach. RESULTS: Significantly lower FEF(25-75) and FEF(25-75)/FVC were observed in smoking (FEF(25-75): beta -0.788 l/s (95% CI -1.118 to -0.457), FEF(25-75)/FVC: beta -20.4% (95% CI -29.3 to -11.6, p<0.0001 for both phenotypes) and non-smoking (FEF(25-75): beta -0.357 l/s (95% CI -0.673 to -0.041, p = 0.0271), FEF(25-75)/FVC: beta -9.5% (95% CI -17.1 to -1.9, p = 0.0145)) first degree relatives of early onset COPD probands. Narrow sense heritability estimates for FEF(25-75) (h(2) = 0.38) and FEF(25-75)/FVC (h(2) = 0.45) were similar to those for FEV(1) and FEV(1)/FVC. CONCLUSION: Lower values of FEF(25-75) and FEF(25-75)/FVC in non-smoking first degree relatives of early onset COPD probands than in controls suggest a genetic susceptibility to develop obstructive lung disease, independent of smoking, which is magnified by exposure to deleterious environments as suggested by the further decrements in FEF(25-75) and FEF(25-75)/FVC seen in smoking first degree relatives. FEF(25-75) and FEF(25-75)/FVC have high heritability and are important intermediate phenotypes for inclusion in genetic epidemiological studies of COPD.