Applicability of Outpatient Quality Indicators for Appropriate Antibiotic Use in a Primary Health Care Area: a Point Prevalence Survey.

The ability to measure the quality of antibiotic prescriptions is a critical element in all antimicrobial stewardship programs. The aims of the present study were to evaluate the clinimetric properties of 32 recently developed outpatient quality indicators (OQIs) and to identify potential room for improvement in antibiotic use in a primary health care (PHC) area. The study was performed in a PHC area in Barcelona, Spain with 260,657 inhabitants, nine PHC centers, and a 400-bed acute-care teaching hospital. We selected 9 of the 32 OQIs that were applicable to our PHC area and evaluated them for measurability, adherence, and room for improvement. Nonmeasurable OQIs, OQIs without room for improvement, and OQIs beyond the scope of the PHC antimicrobial stewardship program were excluded. Data from 260,561 registered patients were assessed. Measurability was high for all OQIs except those that required manual recording of the clinical diagnosis (OQIs on group A streptococcal diagnostic testing). Adherence to guidelines was poor for most OQIs, but particularly for the indicator on the avoidance of antibiotics for viral or self-limiting bacterial infections, where we observed more than 60% room for improvement for both acute tonsillitis and sinusitis. The QIs evaluated were applicable to clinical practice and proved useful for identifying areas with room for improvement in our setting and for guiding the design of future interventions with specific objectives.

Rifampin Resistance in Staphylococci after Rifaximin Intake for Surgical Prophylaxis in Elective Colorectal Surgery.

The aim of our study was to determine whether rifampin resistance emerges in human skin staphylococci after oral intake of rifaximin for surgical prophylaxis. Rifampin-resistant staphylococci appeared on the skin of 32 out of 74 patients (43.2%) two weeks after prophylactic treatment with rifaximin. In all cases, the resistant strains were coagulase-negative staphylococci. The resistance completely reverted after three months. This study shows the emergence of transient resistance to rifampin after rifaximin intake.

Bacteremia associated with pressure ulcers: a prospective cohort study.

The objective of this study is to evaluate the clinical and microbiological characteristics of bacteremia associated with pressure ulcers (BAPU) and factors associated with mortality. This study was a prospective observational cohort study of patients with BAPU at a teaching hospital between January 1984 and December 2015. Fifty-six episodes were included. The incidence of BAPU decreased from 2.78 cases per 10,000 hospital discharges in the period from 1984 to 1999 to 1.05 cases per 10,000 hospital discharges in the period from 2000 to 2015 (p < 0.001). In 20 cases (35.7%), the bacteremia was hospital-acquired, since it occurred more than 48 h after the hospital admission. The most frequent microorganisms isolated in blood culture were Staphylococcus aureus, Proteus spp., and Bacteroides spp. The bacteremia was polymicrobial in 14 cases (25.0%). Overall mortality was observed in 23 episodes (41.1%). The risk factors independently associated with mortality were hospital-acquired bacteremia (odds ratio [OR] 5.51, 95% confidence interval [95%CI] 1.24-24.40), polymicrobial bacteremia (OR 6.88, 95%CI 1.22-38.89), and serum albumin <23 g/L (OR 8.00, 95%CI 1.73-37.01). BAPU is an uncommon complication of pressure ulcers and is mainly caused by S. aureus, Proteus spp., and Bacteroides spp. In our hospital, the incidence of BAPU has declined in recent years, coinciding with the implementation of a multidisciplinary team aimed at preventing and treating chronic ulcers. Mortality rate is high, and hospital-acquired bacteremia, polymicrobial bacteremia, and serum albumin < 23 g/L are associated with increased mortality.

Legionella pneumophila recurrently isolated in a Spanish hospital: Two years of antimicrobial resistance surveillance.

OBJECTIVES: The aim of this study was to monitor the spread, persistence and antibiotic resistance patterns of Legionella spp. strains found in a hospital water distribution system. These environmental studies are intended to help detect the presence of antibiotic resistant strains before they infect patients. METHODS: Antimicrobial surveillance tests were performed at 27 different sampling points of the water network of a large Spanish hospital over two years. Water samples were screened for Legionella according to ISO 11731:2007. Legionella spp. isolates were identified by serotyping and by mass spectrometry (MALDI-ToF). Epidemiological molecular typing was done by Pulse-Field Gel Electrophoresis (PFGE) and by Sequence-Based Typing (SBT). Antibiotic susceptibility tests were performed using disk diffusion and ETEST®. RESULTS: Legionella spp. were recurrently isolated for 2 years. All isolates belonged the same group, L. pneumophila serogroups 2-14. Isolates were all attributed by SBT to sequence type (ST) ST328, although PFGE revealed 5 different patterns. No significant change in antibiotic susceptibility could be observed for this study period, irrespectively of the method used. CONCLUSION: Colonization of water systems by Legionella spp. is still occurring, although all the prevention rules were strictly followed. Antibiotic resistance monitoring may help us to find resistance in bacteria with environmental reservoirs but difficult to isolate from patients. The knowledge of the antibiotic susceptibility in environmental strains may help us to predict changes in clinical strains. This study might also help reconsidering Legionnaires' disease (LD) diagnostic methods. L. pneumophila serogroups 2-14 present all along the time of the investigation in the water distribution system can cause LD. However, they may not be detected by routine urine tests run on patients, thereby missing an ongoing LD infection.

Incidence of pediatric invasive pneumococcal disease in the Island of Majorca (2008-2010), an area with non-universal vaccination, and estimations of serotype & children population coverage by available conjugate vaccines.

BACKGROUND: The World Health Organization reported in 2007 that inclusion of PCV7 in national immunization programs should be seen as a priority, also encouraging countries to conduct appropriate surveillances for monitoring the impact of vaccination. These analyses should be conducted in specific geographical areas and should be aimed to evolution of invasive pneumococcal disease (IPD), by age groups, clinical presentation, and vaccine serotypes (and non-vaccine serotypes to detect possible replacement). This study aimed to monitor the evolution of IPD incidence in children <15 years requiring hospitalization in the Island of Majorca. METHODS: A prospective clinical surveillance of all culture and/or PCR-confirmed IPD in children <15 years was performed in all hospitals in the Island of Majorca (approximately 900,000 inhabitants) from January 2008 to December 2010. Incidence rate (IR) was calculated as cases/100,000 inhabitants using children population data. RESULTS: 66 IPDs were identified: 39 (59.1%) parapneumonic pneumococcal empyema (PPE), 16 (24.2%) bacteremic pneumonia (BP), 7 (10.6%) primary bacteremia, 3 (4.5%) meningitis, and 1 (1.5%) osteomyelitis. IRs in the three-year study period were: 64.22 for children 12- < 24 months, 37.21 for those 24-59 months, 22.62 for those <12 months, and 3.98 for children >59 months. By study year, IRs were 21.25 in 2008, 19.89 in 2009 and 9.80 in 2010. The reduction found in 2010 was significant and due to significant reductions in IRs of IPDs caused by serotypes included in PCV10 and PCV13. Overall, estimated serotype coverage by conjugate vaccines was 12.1% for PCV7, 37.9% for PCV10 and 65.2% for PCV13. Of the 66 hospitalized children with IPD, 20 had received at least one dose of PCV7 (13 cases with identified serotype). None of these 13 cases was caused by PCV7 serotypes, all were caused by PCV13 serotypes and only 53.8% by PCV10 serotypes. CONCLUSIONS: The results of the present study evidence the importance of expanding the number of serotypes covered by PCV, and the added value of PCV13 with respect to PCV10 and PCV7, even in an area of low prevalence of 19A as the Island of Majorca.

Evaluation of Plasma Lipocalin-2 as a Predictor of Etiology and Severity in Adult Patients with Community-Acquired Pneumonia.

The aim of this study was to evaluate the diagnostic performance of plasma Lipocalin-2 (LCN2) concentration in adult patients with community-acquired pneumonia (CAP) to determine its etiology, severity and prognosis. A prospective observational study involving adults with CAP from November 2015 to May 2017 was conducted. Plasma LCN2 concentration was measured upon admission by a modified enzyme immunoassay coupled with chemiluminescence (Architect, Abbott Laboratories). The diagnostic performance of LCN2, C-reactive protein (CRP) and white blood cell to predict bacterial CAP was assessed. A total of 130 patients with CAP were included: 71 (54.6%) bacterial CAP, 42 (32.3%) unknown origin CAP and 17 (13.1%) viral CAP. LCN2 was higher in bacterial CAP than in non-bacterial CAP (122.0 vs. 89.7 ng/mL, respectively) (p = 0.03) with a limited ability to distinguish bacterial and non-bacterial CAP (AUROC: 0.62 [95% CI 0.52-0.72]). The LCN2 cutoff ≥ 204 ng/mL predicted the presence of pneumococcal bacteremia with an AUROC of 0.74 (sensitivity 70%, specificity 79.1%). Regarding severity, as defined by CURB-65 and PSI scores, there was a significant linear trend in the mean concentration of LCN2, exhibiting a shift from the low-risk to the intermediate-risk and high-risk group (p < 0.001 and 0.001, respectively). LCN2 concentration was associated with severity in adult patients with CAP. However, its utility as a biomarker to discriminate viral and bacterial etiology in CAP is limited.

Serological response to COVID-19 pneumonia and increasing severity over 18 months in a prospective cohort of hospitalized patients.

In this study, we present an 18-month serological follow-up of 294 patients with COVID-19 pneumonia. The aim was to assess the dynamics of serological response and its correlation with clinical worsening, as well as to describe clinical worsening determinants. Results of the study showed an early immunoglobulin M response, which clearly diminished starting at 4 months, but nonetheless, a small group of patients remained positive. As for immunoglobulin G, levels were higher up to 6 months in patients who presented clinical worsening during hospitalization. High titers of the immunoglobulin were maintained in all patients during follow-up, which would indicate that humoral immunity due to infection is long-lasting. Male sex, presence of myalgias and extensive radiological affectation were significantly correlated with clinical worsening.

Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence.

Respiratory infections caused by Klebsiella pneumoniae are characterized by high rates of mortality and morbidity. Management of these infections is often difficult, due to the high frequency of strains that are resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. In the present study, we investigated the role of the K. pneumoniae AcrRAB operon in antimicrobial resistance and virulence by using isogenic knockouts deficient in the AcrB component and the AcrR repressor, both derived from the virulent strain 52145R. We demonstrated that the AcrB knockout was more susceptible, not only to quinolones, but also to other antimicrobial agents, including beta-lactams, than the wild-type strain and the AcrR knockout. We further showed that the AcrB knockout was more susceptible to antimicrobial agents present in human bronchoalveolar lavage fluid and to human antimicrobial peptides than the wild-type strain and the AcrR knockout. Finally, the AcrB knockout exhibited a reduced capacity to cause pneumonia in a murine model, in contrast to the wild-type strain. The results of this study suggest that, in addition to contributing to the multidrug resistance phenotype, the AcrAB efflux pump may represent a novel virulence factor required for K. pneumoniae to resist innate immune defense mechanisms of the lung, thus facilitating the onset of pneumonia.

High clonal diversity of ESBL-producing Klebsiella pneumoniae isolates from clinical samples in a non-outbreak situation. A cohort study.

Background: Klebsiella pneumoniae has been responsible for a large number of clonal hospital outbreaks. However, some epidemiological changes have been observed since the emergence of CTX-M enzymes in K. pneumoniae. Aim: To analyse the transmission dynamics of Extended Spectrum ß-Lactamase-producing Klebsiella pneumoniae (ESBL-Kp) in an acute care hospital. Methods: In 2015 a prospective cohort study was conducted. All new consecutive adult patients with ESBL-Kp isolates in all clinical samples were included. Patients with a previous known infection/colonization by ESBL-Kp and patients in high risk areas (e.g., intensive care units) were excluded. Cross-transmission was defined as the carriage of a clonally-related ESBL-Kp between newly diagnosed patients who shared the same ward for ≥48 h with another case, within a maximum time window of 4 weeks. ESBL-production was confirmed using the double-disk diffusion method and PCR. Clonal relationships were investigated by rep-PCR and multilocus sequence typing (MLST). Results: Sixty ESBL-Kp isolates from 60 patients were included and analysed. Infections and colonizations were classified as hospital-acquired (52%), healthcare-related (40%) or community-acquired (8%).High genetic diversity was detected. When epidemiological clinical data were combined with the rep-PCR, the patterns identified did not show any cases of cross-transmission. ESBL-Kp were detected in 12.5% of environmental samples. No clonal relationship could be established between environmental reservoirs and patients. The genetic mechanism detected in all strains was associated with blaCTX-M genes, and 97% were CTX-M-15. Conclusions: The dynamics of ESBL-K. pneumoniae isolated in our setting could not be explained by clonal transmission from an index patient. A polyclonal spread of ESBL-Kp was identified.

Impact of a Multifaceted Antimicrobial Stewardship Intervention in a Primary Health Care Area: A Quasi-Experimental Study.

The aim of the study was to evaluate the impact of a multifaceted antimicrobial stewardship intervention on antibiotic consumption in a primary health care (PHC) area in Spain. Quasi-experimental study conducted in a PHC area with nine PHC centers, a 400-bed acute care teaching hospital, and 18 nursing homes serving a population of 260,561. The intervention was based on the 2016 CDC Core Elements of Outpatient Antibiotic Stewardship publication and targeted 130 PHC physicians, 41 PHC pediatricians, 19 emergency physicians, and 18 nursing home physicians. The components were commitment, actions for improving antibiotic prescribing, tracking and feedback, and education and experience. The primary outcome was overall antibiotic consumption. Secondary outcomes were consumption of antibiotics to treat pharyngotonsillitis, acute otitis media, acute sinusitis, acute bronchitis, and urinary tract infection (UTI), percentage of patients treated with specific antibiotics, and dispensing costs. Consumption was measured in defined daily doses per 1,000 inhabitants per day (DID) and compared pre- and postintervention (2016 vs. 2018). Overall antibiotic consumption decreased from 16.01 to 13.31 DID (-16.85%). Consumption of amoxicillin/clavulanic acid and quinolones decreased from 6.04 to 4.72 DID (-21.88%) and 1.64 to 1.23 DID (-25.06%), respectively. The percentage of patients treated with antibiotics decreased from 26.99 to 22.41%. The intervention resulted in cost savings of €72,673. Use of antibiotics to treat pharyngotonsillitis, UTI, and acute otitis media, sinusitis, and bronchitis decreased significantly. Our antimicrobial stewardship program led to a decrease in antibiotic consumption and significantly improved the use of antibiotics for the most prevalent PHC infections.

Tuberculosis infection in children visiting friends and relatives in countries with high incidence of tuberculosis: A study protocol.

INTRODUCTION: Tuberculosis (TB) is a global infectious disease. In low-incidence countries, paediatric TB affects mostly immigrant children and children of immigrants. We hypothesize that these children are at risk of exposure to Mycobacterium tuberculosis when they travel to the country of origin of their parents to visit friends and relatives (VFR). In this study, we aim to estimate the incidence rate and risk factors associated to latent tuberculosis infection (LTBI) and TB in VFR children. METHODS AND ANALYSIS: A prospective study will be carried out in collaboration with 21 primary health care centres (PCC) and 5 hospitals in Catalonia, Spain. The study participants are children under 15 years of age, either immigrant themselves or born to immigrant parents, who travel to countries with high incidence of TB (≥ 40 cases/100,000 inhabitants). A sample size of 492 children was calculated. Participants will be recruited before traveling, either during a visit to a travel clinic or to their PCC, where a questionnaire including sociodemographic, epidemiological and clinical data will be completed, and a tuberculin skin test (TST) will be performed and read after 48 to 72 hours; patients with a positive TST at baseline will be excluded. A visit will be scheduled eight to twelve-weeks after their return to perform a TST and a QuantiFERON-TB Gold Plus test. The incidence rate of LTBI will be estimated per individual/month and person/year per country visited, and also by age-group. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Ethics Committee of the Hospital Universitari Mútua Terrassa (code 02/16) and the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (code P16/094). Articles will be published in indexed scientific journals. TRIAL REGISTRATION: Clinical-Trials.gov: NCT04236765.

HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer.

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P<0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR]=1.90, 95% confidence interval [CI]=1.15-3.12; P<0.0001; and protein: HR=2.09, 95% CI=1.31-3.33; P=0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome.

Paromomycin is superior to metronidazole in Dientamoeba fragilis treatment.

Dientamoeba fragilis is a trichomonad parasite of the human intestine that is found worldwide. However, the biological cycle and transmission of this parasite have yet to be elucidated. Although its pathogenic capacity has been questioned, there is increasing evidence that clinical manifestations vary greatly. Different therapeutic options with antiparasitic drugs are currently available; however, very few studies have compared the effectiveness of these drugs. In the present longitudinal study, we evaluate 13,983 copro-parasitological studies using light microscopy of stools, during 2013-2015, in Terrassa, Barcelona (Spain). A total of 1150 (8.2%) presented D. fragilis. Of these, 739 episodes were finally analyzed: those that involved a follow-up parasitology test up to 3 months later, corresponding to 586 patients with gastrointestinal symptoms (53% under 15 years of age). Coinfection by Blastocystis hominis was present in 33.6% of the subjects. Our aim was to compare therapeutic responses to different antiparasitic drugs and the factors associated with the persistence of D. fragilis post-treatment. Gender, age, and other intestinal parasitic coinfections were not associated with parasite persistence following treatment. Metronidazole was the therapeutic option in most cases, followed by paromomycin: 65.4% and 17.5% respectively. Paromomycin was found to be more effective at eradicating parasitic infection than metronidazole (81.8% vs. 65.4%; p = 0.007), except in children under six years of age (p = 0.538). Although Dientamoeba fragilis mainly produces mild clinical manifestations, the high burden of infection means we require better understanding of its epidemiological cycle and pathogenicity, as well as adequate therapeutic guidelines in order to adapt medical care and policies to respond to this health problem.

No association between common chemokine and chemokine receptor gene variants and prostate cancer risk.

There is growing evidence that inflammation and infection play important roles in the etiology of prostate cancer. As the chemokine network is directly involved in inflammation and infectious diseases, we tested for an association between six common putative functional variants and prostate cancer risk using an Australian case-control study. We measured CCL5 -403G>A, CXCL12 +801G>A, CCR2V64I (G>A), CCR5Delta32, CX3CR1V249I (G>A), and CX3CR1T280M (C>T) for 815 cases and 738 controls. Of these, only CXCL12 +801G>A has previously been tested and found to be associated with prostate cancer risk. We found no significant associations with prostate cancer risk (all P > 0.4). All per allele odds ratios ranged from 0.96 (95% confidence intervals, 0.80-1.16) to 1.06 (95% confidence intervals, 0.90-1.23). This suggests that these common chemokine and chemokine receptor variants do not play a major, if any, role in susceptibility to prostate cancer.

The rs743572 common variant in the promoter of CYP17A1 is not associated with prostate cancer risk or circulating hormonal levels.

OBJECTIVE: To use a large population-based case-control study to test the association between the common genetic variant rs743572 (-34 T to C), prostate cancer risk and circulating levels of several hormones. SUBJECTS AND METHODS: A previous meta-analysis concluded that reported associations between rs743572 in the promoter of CYP17A1 and prostate cancer risk might reflect publication bias, but a few recent studies reported associations with prostate cancer risk and data suggesting that rs743572 is functional. We genotyped 824 prostate cancer cases and 737 population-based controls, and applied unconditional logistic regression to estimate the association between rs743572 and prostate cancer risk. We also used linear regression of transformed testosterone, androstanediol glucuronide, dehydroepiandrosterone sulphate, androstenedione, sex hormone-binding globulin and oestradiol (circulating levels) measured for controls, to estimate the association between these levels and rs743572. The linear models were adjusted for age and laboratory batch. RESULTS: Men with different genotypes had similar circulating levels of all the hormones measured (all P < 0.05). In the case-control comparison using unconditional unadjusted logistic regression, the odds ratios (95% confidence interval) for prostate cancer were 1.07 (0.87-1.32) and 0.94 (0.71-1.25) for the dominant and recessive models, respectively, and for the co-dominant model, 1.10 (0.88-1.36) and 0.99 (0.73-1.35) for carriers of one or two copies of the C allele, respectively. There was no evidence of heterogeneity in the odds ratios by tumour stage (all P > 0.3) and grade (all P > 0.3). CONCLUSION: The results of the present study are consistent with the conclusions of the previous meta-analysis, and suggest that rs743572 has no role in the risk of prostate cancer for men of Caucasian origin.

The common variant rs1447295 on chromosome 8q24 and prostate cancer risk: results from an Australian population-based case-control study.

A recent study from deCode reported an association between common variants in the region 8q24 and prostate cancer risk. The strongest association was found with the single nucleotide polymorphism rs1447295. We genotyped 821 prostate cancer cases and 732 population controls for rs1447295 to test the association between this common variant and prostate cancer risk, and examine whether this association depends on Gleason score. Our case-control study confirmed the association between rs1447295 and prostate cancer risk (P = 0.0005). The odds ratio (OR) for prostate cancer was 1.52 [95% confidence interval (CI), 1.20-1.93] for carriers of any A allele compared with noncarriers. The OR for Gleason score 5 to 6 prostate cancer (1.48; 95% CI, 1.13-1.95) was similar to the OR for Gleason score 7 to 10 prostate cancer (1.58; 95% CI, 1.18-2.11, P for heterogeneity = 0.7). We conclude that the A allele of rs1447295 is associated with a higher risk of prostate cancer regardless of tumor aggressiveness, suggesting that such a variant, or a variant in linkage disequilibrium with it, plays a role early in prostate carcinogenesis.

Mammographic density and candidate gene variants: a twins and sisters study.

BACKGROUND: Mammographic density, the light/white radiographic appearance on a mammogram that represents connective and epithelial tissue, is a strong risk factor for breast cancer which seems to be highly heritable. Little is known about its genetic determinants. METHODS: We studied 457 women from 207 sisterhoods (104 monozygotic twins, 182 dizygotic twins, and 171 singletons). Percentage mammographic density (PMD) as well as dense area and nondense area were calculated using a computer-assisted method. We measured six single nucleotide polymorphisms from six candidate genes (COMT, HSD3B1, IGFBP3, HER2, XPD, and XRCC3). Associations between genotypes and mammographic measures were tested (a) cross-sectionally using a multivariate normal model fitted using FISHER that allowed separate correlations for monozygotic, dizygotic, and nontwin pairs and (b) within sister pairs using paired t tests. RESULTS: Cross-sectionally, each additional copy of the HSD3B1 Asn(367)Thr variant allele was associated with lower PMD (-3.47% per allele; SE = 1.65; P = 0.035). Within-pair regression estimates confirmed this association. There was no evidence for an association between the mammographic density measures and any of the other variants studied. CONCLUSION: We have replicated an association between a variant in the HSD3B1 gene and PMD, which suggests that HSD3B1 may be genetic determinant of mammographic density.

Macrophage inhibitory cytokine-1 H6D polymorphism, prostate cancer risk, and survival.

Macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-beta superfamily, is important in regulating inflammation. Inflammation of the prostate has been suggested to favor tumor development. A recent study (JNCI 2004, 96:1248-1254) found marginal evidence of an association between the presence of the mature MIC-1 protein nonsynonymous polymorphism H6D C-to-G (rs1058587) with reduced prostate cancer risk [odds ratio, 0.83; 95% confidence interval (95% CI), 0.69-0.99]. We tested this in a population-based study of 819 cases and 731 controls from Australia and found a similar, yet not significant, odds ratio of 0.85 (95% CI, 0.7-1.04; P = 0.11). We also tested the potential association between the H6D variant and disease-specific survival in 640 cases followed-up for an average of 8.2 years. We found that cases carrying the H6D G allele had an increased risk of death from prostate cancer than cases carrying two copies of the C allele (hazard ratio, 1.72; 95% CI, 1.06-2.78; P = 0.03). Our data suggest that the H6D variant in MIC-1 might play a role in prostate cancer, but it is difficult to explain how a variant can be associated with lower risk of developing prostate cancer but more aggressive growth if cancer develops.

Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA.

An A to G substitution, rs925013, in the promoter of the prostate-specific antigen gene (PSA) was recently found to be associated with promoter activity and circulating PSA levels. The objective of this study was to test the associations between rs925013 and another A to G substitution, rs266882, in the PSA gene with prostate cancer risk using a population-based case-control study of 821 prostate cancer cases and 734 controls carried out in Perth and Melbourne, Australia. The study focused on young (i.e., < 70 years) and aggressive cases (i.e., well-differentiated tumors were excluded). Cases in the Melbourne arm of the study (N = 638) were followed up prospectively for an average period of 8.2 years and deaths from prostate cancer ascertained through record linkage to study the possible association between genetic variants and disease-specific survival. PSA-circulating levels were measured in controls to test the association with the genetic variants using a cross-sectional design. Linear regression of log PSA levels, unconditional logistic regression, Cox regression, and haplotype analyses were undertaken. For rs925013, the G allele was associated with an increased risk of prostate cancer [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-1.7; P = 0.001], and the hazard ratio for survival for cases homozygous for the G allele compared with cases homozygous for the A allele was increased but not statistically significant (hazard ratio, 2.3; 95% CI, 1-5.6; P = 0.06). For rs266882, there was no association with overall prostate cancer risk and survival (all P > 0.1). Men homozygous or heterozygous for the G/G (rs925013/rs266882) haplotype were at higher risk of prostate cancer than men homozygous for the A/A haplotype (odds ratio, 1.3; 95% CI, 1.1-1.7; P = 0.009). Adjusted geometric means of circulating PSA levels in controls were similar in men with zero, one, and two copies of the G allele in rs266882 (1.2, 1.1, and 1.3 ng/mL, respectively; all P > or = 0.2) and rs925013 (1.1, 1.2, and 1.5 ng/mL, respectively; all P > 0.1). For rs925013, our study provides good evidence of association with prostate cancer risk, marginal evidence of association with survival, and little evidence of detectable association with circulating PSA levels in controls. We found no evidence of an independent association between rs266882 and any of the outcomes. The genotypes and haplotypes studied might be associated with the PSA gene function or be in linkage disequilibrium with other unmeasured and functional variants in the PSA or other genes.

The E211 G>A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia.

The androgen receptor (AR) gene encodes a transcription factor, which mediates androgen action in target tissues, including the prostate. Prostate cancer is androgen dependent, implicating AR in susceptibility to this male condition. Male pattern balding, androgenetic alopecia, has recently been associated with prostate cancer, suggesting shared androgen pathways. The CAG and GGC repeats in the AR have been studied extensively as markers of prostate cancer susceptibility, with inconclusive findings, whereas the AR-E211 G>A polymorphism has been associated with androgenetic alopecia. We assessed the repeat linked single nucleotide polymorphism as a marker of risk association in prostate cancer, including androgenetic alopecia, in an Australian population-based case-control study. In 815 prostate cancer cases and 719 controls, the proportion of A-allele carriers was the same in each group. Overall, there was no evidence for an association between the A allele and risk of prostate cancer, however, the proportion of A-allele carriers in metastatic prostate cancer (5%) was lower than in less advanced disease (16%, P = 0.03). The proportion of A-allele carriers was 24% in nonbald men but it was lower in men with vertex alopecia alone (13%, P = 0.001) or in combination with frontal alopecia (7%, P < 0.0001). This inverse association between the A allele and baldness was independent of prostate cancer status (P for interaction = 0.2). These results suggest that the AR-E211 A allele, in linkage with the functional repeat sequences, is associated with a lower risk of metastatic prostate cancer and a lower risk of alopecia.