Exosome-based liquid biopsies in cancer: opportunities and challenges.

Liquid biopsy in cancer has gained momentum in clinical research and is experiencing a boom for a variety of applications. There are significant efforts to utilize liquid biopsies in cancer for early detection and treatment stratification, as well as residual disease and recurrence monitoring. Although most efforts have used circulating tumor cells and circulating tumor DNA for this purpose, exosomes and other extracellular vesicles have emerged as a platform with potentially broader and complementary applications. Exosomes/extracellular vesicles are small vesicles released by cells, including cancer cells, into the surrounding biofluids. These exosomes contain tumor-derived materials such as DNA, RNA, protein, lipid, sugar structures, and metabolites. In addition, exosomes carry molecules on their surface that provides clues regarding their origin, making it possible to sort vesicle types and enrich signatures from tissue-specific origins. Exosomes are part of the intercellular communication system and cancer cells frequently use them as biological messengers to benefit their growth. Since exosomes are part of the disease process, they have become of tremendous interest in biomarker research. Exosomes are remarkably stable in biofluids, such as plasma and urine, and can be isolated for clinical evaluation even in the early stages of the disease. Exosome-based biomarkers have quickly become adopted in the clinical arena and the first exosome RNA-based prostate cancer test has already helped >50 000 patients in their decision process and is now included in the National Comprehensive Cancer Network guidelines for early prostate cancer detection. This review will discuss the advantages and challenges of exosome-based liquid biopsies for tumor biomarkers and clinical implementation in the context of circulating tumor DNA and circulating tumor cells.

Osteoarthritis year in review 2019: rehabilitation and outcomes.

OBJECTIVE: Inactivity and obesity are risk factors for osteoarthritis (OA) progression. The purpose of this review was to highlight intervention parameters of exercise and lifestyle diet interventions on clinical outcomes in OA that were published over 15 months, starting January 1, 2018. DESIGN: Systematic literature searches were performed in Medline (Pubmed, OVID), Scopus, CINAHL, CENTRAL and Embase from January 1, 2018 to April 1, 2019. Key words included osteoarthritis, exercise, physical activity, diet and nutrition. Randomized controlled designs and data synthesis papers (systematic reviews, meta-analyses, clinical guidelines) written in English, that included humans with OA of any joint were included. Trials were evaluated using the Physiotherapy Evidence Database (PEDro) critical appraisal tool and the Template for Intervention Description and Replication (TIDieR). Systematic reviews and meta-analyses were evaluated using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2). Intervention details (RCTs) and key finding from papers were summarized. RESULTS: Of 540 titles and abstracts retrieved, 147 full articles were reviewed and 53 met the inclusion criteria, comprised of 39 RCTs and 14 synthesis papers. By addressing inactivity, exercise effectively improves clinical outcomes and, based on low-moderate quality evidence, without further damage to cartilage or synovial tissue. By comparison, much less work focused on minimizing obesity. Diet must be combined with exercise to improve pain, but alone, can improve physical function. CONCLUSIONS: Future work is necessary to identify the ideal exercise frequency and intensity and lifestyle diet intervention parameters. Improved adherence to reporting guidelines in future work will greatly enhance the OA rehabilitation field.

Using epidemiology to estimate the impact and burden of exposure to air pollutants.

This paper focuses on the use of results of epidemiological studies to quantify the effects on health, particularly on mortality, of long-term exposure to air pollutants. It introduces health impact assessment methods, used to predict the benefits that can be expected from implementation of interventions to reduce emissions of pollutants. It also explains the estimation of annual mortality burdens attributable to current levels of pollution. Burden estimates are intended to meet the need to communicate the size of the effect of air pollution on public health to policy makers and others. The implications, for the interpretation of the estimates, of the assumptions and approximations underlying the methods are discussed. The paper starts with quantification based on results obtained from studies of the association of mortality risk with long-term average concentrations of particulate air pollution. It then tackles the additional methodological considerations that need to be addressed when also considering the mortality effects of other pollutants such as nitrogen dioxide (NO2). Finally, approaches that could be used to integrate morbidity and mortality endpoints in the same assessment are touched upon. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Recommended pre-analytical plasma glucose sampling methodology may distort gestational diabetes mellitus prevalence: implications for diagnostic thresholds.

AIM: Current International Association of the Diabetes and Pregnancy Study Groups/World Health Organization gestational diabetes mellitus (GDM) diagnostic thresholds are based on a landmark study in which the pre-analytical plasma glucose sampling methodology is unclear. Worldwide, plasma glucose pre-analytical sampling methodology practices are divergent. We considered the effects of pre-analytical plasma glucose sampling methodology on GDM prevalence and gestational outcomes. METHODS: This is a retrospective observational cohort study of 1178 pregnant women undergoing an oral glucose tolerance test (OGTT). Of the 1178 pregnant women, a subset of 892 non-GDM women with singleton births undergoing OGTT between 24 and 28 weeks' gestation were investigated for large for gestation age (LGA) outcomes. OGTT were determined using traditional methods (sodium fluoride tubes batched at roomed temperature). We modelled the potential effects of using a recommended pre-analytical plasma glucose methodology (lyophilized citrate tubes) on GDM prevalence. RESULTS: The GDM prevalence in our cohort was 13.5%. The incidence of LGA showed a linear association with maternal plasma glucose that was similar to the association observed in the Hyperglycemia and Adverse Pregnancy Outcome study. Frequency of LGA exceeded 10% at HAPO glucose category 4 (fasting, 4.8 to 4.9 mmol/l; 1-h, 8.7 to 9.5 mmol/l) for fasting and 1-h plasma glucose. The use of a recommended pre-analytical method is projected to increase the prevalence of GDM to 39.2%. CONCLUSION: We challenge the consensus that recommended pre-analytical plasma glucose methodologies are optimal for the accurate diagnosis of GDM. Recommended pre-analytical plasma glucose methods may profoundly over-diagnose GDM. Centres using recommended pre-analytical plasma glucose methodologies may need to reappraise their diagnostic thresholds.

An age difference of two billion years between a metal-rich and a metal-poor globular cluster.

Globular clusters trace the formation history of the spheroidal components of our Galaxy and other galaxies, which represent the bulk of star formation over the history of the Universe. The clusters exhibit a range of metallicities (abundances of elements heavier than helium), with metal-poor clusters dominating the stellar halo of the Galaxy, and higher-metallicity clusters found within the inner Galaxy, associated with the stellar bulge, or the thick disk. Age differences between these clusters can indicate the sequence in which the components of the Galaxy formed, and in particular which clusters were formed outside the Galaxy and were later engulfed along with their original host galaxies, and which were formed within it. Here we report an absolute age of 9.9 ± 0.7 billion years (at 95 per cent confidence) for the metal-rich globular cluster 47 Tucanae, determined by modelling the properties of the cluster's white-dwarf cooling sequence. This is about two billion years younger than has been inferred for the metal-poor cluster NGC 6397 from the same models, and provides quantitative evidence that metal-rich clusters like 47 Tucanae formed later than metal-poor halo clusters like NGC 6397.

Person-centred, integrated and pro-active care for multi-morbid elderly with advanced care needs: a propensity score-matched controlled trial.

BACKGROUND: Person-centred care (PCC) focusing on personalised goals and care plans derived from "What matters to you?" has an impact on single disease outcomes, but studies on multi-morbid elderly are lacking. Furthermore, the combination of PCC, Integrated Care (IC) and Pro-active care are widely recognised as desirable for multi-morbid elderly, yet previous studies focus on single components only, leaving synergies unexplored. The effect of a synergistic intervention, which implements 1) Person-centred goal-oriented care driven by "What matters to you?" with 2) IC and 3) pro-active care is unknown. METHODS: Inspired by theoretical foundations, complexity science, previous health service research and a patient-driven evaluation of care quality, we designed the Patient-Centred Team (PACT) intervention across primary and secondary care. The PACT team collaborate with the patient to make and deliver a person-centred, integrated and proactive multi-morbidity care-plan. The control group receives conventional care. The study design is a pragmatic six months prospective, controlled clinical trial based on hospital electronic health record data of 439 multi-morbid frail elderly at risk for emergency (re) admissions referred to PACT and 779 propensity score matched controls in Norway, 2014-2016. Outcomes are emergency admissions, the sum of emergency inpatient bed days, 30-day readmissions, planned and emergency outpatient visits and mortality at three and six months follow-up. RESULTS: The Rate Ratios (RR) for emergency admissions was 0,9 (95%CI: 0,82-0,99), for sum of emergency bed days 0,68 (95%CI:0,52-0,79) and for 30-days emergency readmissions 0,72 (95%CI: 0,41-1,24). RRs were 2,3 (95%CI: 2,02-2,55) and 0,9 (95%CI: 0,68-1,20) for planned and emergency outpatient visits respectively. The RR for death at 3 months was 0,39 (95% CI: 0,22-0,70) and 0,57 (95% CI: 0,34-0,94) at 6 months. CONCLUSION: Compared with propensity score matched controls, the care process of frail multi-morbid elderly who received the PACT intervention had a reduced risk of high-level emergency care, increased use of low-level planned care, and substantially reduced mortality risk. Further study of process differences between groups is warranted to understand the genesis of these results better. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT02541474 ), registered Sept 2015.

Understanding STAT3 signaling in cardiac ischemia.

Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.

Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas.

Population-based testing for BRCA1/2 mutations detects a high proportion of carriers not identified by cancer family history-based testing. We sought to determine whether population-based testing is an effective approach to genetic testing in the Bahamas, where 23% of women with breast cancer carry one of seven founder mutations in the BRCA1 or BRCA2 gene. We determined the prevalence of founder BRCA mutations in 1847 Bahamian women without a personal history of breast or ovarian cancer, unselected for age or family history. We found that 2.8% (20/705) of unaffected women with a family history of breast/ovarian cancer and 0.09% (1/1089) of unaffected women without a family history carry a BRCA mutation. A total of 38% of unaffected women with a known mutation in the family were found to carry the familial mutation. We previously suggested that all Bahamian women with breast or ovarian cancer be offered genetic testing. These current data suggest that additionally all unaffected Bahamian women with a family history of breast/ovarian cancer should be offered genetic testing for the founder BRCA mutations.

Impact of selective digestive decontamination on respiratory tract Candida among patients with suspected ventilator-associated pneumonia. A meta-analysis.

The purpose here is to establish the incidence of respiratory tract colonization with Candida (RT Candida) among ICU patients receiving mechanical ventilation within studies in the literature. Also of interest is its relationship with candidemia and the relative importance of topical antibiotic (TA) use as within studies of selective digestive decontamination (SDD) versus other candidate risk factors towards it. The incidence of RT Candida was extracted from component (control and intervention) groups decanted from studies of various TA and non-TA ICU infection prevention methods with summary estimates derived using random effects. A benchmark RT Candida incidence to provide overarching calibration was derived using (observational) groups from studies without any prevention method under study. A multi-level regression model of group level data was undertaken using generalized estimating equation (GEE) methods. RT Candida data were sourced from 113 studies. The benchmark RT Candida incidence is 1.3; 0.9-1.8 % (mean and 95 % confidence intervals). Membership of a concurrent control group of a study of SDD (p = 0.02), the group-wide presence of candidemia risk factors (p < 0.001), and proportion of trauma admissions (p = 0.004), but neither the year of study publication, nor membership of any other component group, nor the mode of respiratory sampling are predictive of the RT Candida incidence. RT Candida and candidemia incidences are correlated. RT Candida incidence can serve as a basis for benchmarking. Several relationships have been identified. The increased incidence among concurrent control groups of SDD studies cannot be appreciated in any single study examined in isolation.

Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas.

The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first-degree relatives of 58 mutation carriers. Of 159 women who were contacted by the proband or other family member, only 14 made an appointment for genetic testing (9%). In contrast, among 32 relatives who were contacted directly by the genetic counselor, 27 came for an appointment (84%). This study suggests that for recruitment of relatives in the Bahamas, direct contact by counselor is preferable to using the proband as an intermediary.

The spectrum of BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas.

We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation-dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8-9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas.

Using PM2.5 concentrations to estimate the health burden from solid fuel combustion, with application to Irish and Scottish homes.

BACKGROUND: This study estimates the potential population health burden from exposure to combustion-derived particulate air pollution in domestic settings in Ireland and Scotland. METHODS: The study focused on solid fuel combustion used for heating and the use of gas for cooking. PM2.5 (particulate matter with an aerodynamic diameter < 2.5 µm) was used as the pollutant mixture indicator. Measured PM2.5 concentrations in homes using solid fuels were adjusted for other sources of PM2.5 by subtracting PM2.5 concentrations in homes using gas for cooking but not solid fuel heating. Health burden was estimated for exposure indoors 6 pm - midnight, or all day (24-hour), by combining estimated attributable annual PM2.5 exposures with (i) selected epidemiological functions linking PM2.5 with mortality and morbidity (involving some re-scaling from PM10 to PM2.5, and adjustments 'translating' from concentrations to exposures) and (ii) on the current population exposed and background rates of morbidity and mortality. RESULTS: PM2.5 concentrations in coal and wood burning homes were similar to homes using gas for cooking, used here as a baseline (mean 24-hr PM2.5 concentrations 8.6 µg/m3) and so health impacts were not calculated. Concentrations of PM2.5 in homes using peat were higher (24-hr mean 15.6 µg/m3); however, health impacts were calculated for the exposed population in Ireland only; the proportion exposed in Scotland was very small. The assessment for winter evening exposure (estimated annual average increase of 2.11 µg/m3 over baseline) estimated 21 additional annual cases of all-cause mortality, 55 of chronic bronchitis, and 30,100 and 38,000 annual lower respiratory symptom days (including cough) and restricted activity days respectively. CONCLUSION: New methods for estimating the potential health burden of combustion-generated pollution from solid fuels in Irish and Scottish homes are provided. The methodology involves several approximations and uncertainties but is consistent with a wider movement towards quantifying risks in PM2.5 irrespective of source. Results show an effect of indoor smoke from using peat (but not wood or coal) for heating and cooking; but they do not suggest that this is a major public health issue.

Lung cancer mortality and exposure to polycyclic aromatic hydrocarbons in British coke oven workers.

BACKGROUND: Workers on coke oven plants may be exposed to potentially carcinogenic polycyclic aromatic hydrocarbons (PAHs), particularly during work on the ovens tops. Two cohorts, employees of National Smokeless Fuels (NSF) and the British Steel Corporation (BSC) totalling more than 6,600 British coke plant workers employed in 1967, had been followed up to mid-1987 for mortality. Previous analyses suggested an excess in lung cancer risk of around 25%, or less when compared with Social Class IV ('partly skilled').Analyses based on internal comparisons within the cohorts identified statistical associations with estimates of individual exposures, up to the start of follow-up, to benzene-soluble materials (BSM), widely used as a metric for mixtures of PAHs. Some associations were also found with times spent in certain coke ovens jobs with specific exposure scenarios, but results were not consistent across the two cohorts and limitations in the exposure estimates were noted. The present study was designed to reanalyse the existing data on lung cancer mortality, incorporating revised and improved exposure estimates to BSM and to benzo[a]pyrene (B[a]P), including increments during the follow-up and a lag for latency. METHODS: Mean annual average concentrations of both BSM and B[a]P were estimated by analysis of variance (ANOVA) from concentration measurements at all NSF and six BSC plants, and summarised by job and plant, with a temporal trend (for the BSM only). These were combined with subjects' work histories, to produce exposure estimates in each year of follow-up, with a 10-year lag to allow for latency. Exposures to BSM and to B[a]P were sufficiently uncorrelated to permit analysis in relation to each variable separately.Lung cancer death risks during the follow-up were analysed in relation to the estimated time-dependent exposures, both continuous and grouped, using Cox regression models, with adjustment for age. RESULTS: Changing the exposure estimates changed the estimated relative risks compared with earlier results, but the new analyses showed no significant trends with continuous measures of exposure to either BSM or B[a]P, nor with time spent on ovens tops. Analyses with grouped exposures showed mixed results. Across all BSC plants, the relative risk coefficient for working 5 or more years on ovens tops, where the exposures were highest, was 1.81, which was statistically significant. However, results for those with 0-5 years on ovens tops did not suggest a trend; the evidence for an underlying relationship was thus suggestive but not strong. CONCLUSIONS: The new results are in line with previous findings; they show some signs consistent with an effect of coke ovens work on lung cancer risk, especially on ovens tops, but the preponderant absence of significant results, and the inconsistencies between results for NSF and BSC, highlight how little evidence there is in these data of any effect.

A thyroid hormone receptor that is required for the development of green cone photoreceptors.

Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina. The mechanisms that control which opsin is expressed in a particular cone are poorly understood, but previous in vitro studies implicated thyroid hormone in cone differentiation. Thyroid hormone receptor beta 2 (TR beta 2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Tr beta 2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders.

Length of intensive care unit stay and the apparent efficacy of antimicrobial-based versus non-antimicrobial-based ventilator pneumonia prevention interventions within the Cochrane review database.

BACKGROUND: The risk of acquiring ventilator-associated pneumonia (VAP) increases with intensive care unit (ICU) length of stay (LOS). The objectives here are to estimate, using data derived from randomized concurrent control trials (RCCTs) of non-antimicrobial versus antimicrobial interventions, the relation of LOS with firstly, apparent VAP prevention effect, and secondly, with VAP incidence in control and intervention groups. METHODS: Control and intervention group data derived from 13 Cochrane reviews of 78 RCCTs of antimicrobial-based interventions versus 111 RCCTs of various non-antimicrobial-based VAP prevention interventions. RESULTS: In meta-regression models of VAP prevention effect versus group mean LOS, the effect size of non-antimicrobial-based interventions regress towards the null (+0.028; +0.002 to +0.054) whereas antimicrobial-based interventions regress away from the null (-0.043; -0.08 to -0.004). The day 9-10 VAP incidence increase is 1.28 (0.97-1.6) percentage points among the control groups of antimicrobial interventions per day. By contrast, these increases among antimicrobial- (0.45; 0.19-0.71) and non-antimicrobial- (0.58; 0.29-0.87) intervention groups and in control groups of non-antimicrobial- (0.76; 0.46-1.05) interventions are all similar. CONCLUSIONS: Antimicrobial-based versus non-antimicrobial-based interventions show overall greater apparent VAP prevention which is most apparent with longer group mean LOS. The basis for this surprising relationship with LOS resides, paradoxically, within the control rather than the intervention groups. This discrepancy implicates indirect (spill-over) effects, inapparent within individual antimicrobial-based RCCTs, which could spuriously conflate the appearance of VAP prevention.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Contribution of solid fuel, gas combustion, or tobacco smoke to indoor air pollutant concentrations in Irish and Scottish homes.

UNLABELLED: There are limited data describing pollutant levels inside homes that burn solid fuel within developed country settings with most studies describing test conditions or the effect of interventions. This study recruited homes in Ireland and Scotland where open combustion processes take place. Open combustion was classified as coal, peat, or wood fuel burning, use of a gas cooker or stove, or where there is at least one resident smoker. Twenty-four-hour data on airborne concentrations of particulate matter<2.5 µm in size (PM2.5), carbon monoxide (CO), endotoxin in inhalable dust and carbon dioxide (CO2), together with 2-3 week averaged concentrations of nitrogen dioxide (NO2) were collected in 100 houses during the winter and spring of 2009-2010. The geometric mean of the 24-h time-weighted-average (TWA) PM2.5 concentration was highest in homes with resident smokers (99 µg/m3--much higher than the WHO 24-h guidance value of 25 µg/m3). Lower geometric mean 24-h TWA levels were found in homes that burned coal (7 µg/m3) or wood (6 µg/m3) and in homes with gas cookers (7 µg/m3). In peat-burning homes, the average 24-h PM2.5 level recorded was 11 µg/m3. Airborne endotoxin, CO, CO2, and NO2 concentrations were generally within indoor air quality guidance levels. PRACTICAL IMPLICATIONS: Little is known about indoor air quality (IAQ) in homes that burn solid or fossil-derived fuels in economically developed countries. Recent legislative changes have moved to improve IAQ at work and in enclosed public places, but there remains a real need to begin the process of quantifying the health burden that arises from indoor air pollution within domestic environments. This study demonstrates that homes in Scotland and Ireland that burn solid fuels or gas for heating and cooking have concentrations of air pollutants generally within guideline levels. Homes where combustion of cigarettes takes place have much poorer air quality.

Costs of occupational asthma in the UK.

OBJECTIVES: To estimate the social costs of occupational asthma in the UK. METHODS: A desk-top approach using cost-of-illness methodology was employed, defining direct and indirect lifetime costs for six scenarios: a male and a female worker each exposed to isocyanates, latex and biocides (eg, glutaraldehyde) or flour. The numbers of new cases annually in each industry were estimated from Survey of Work-related and Occupational Respiratory Disease (SWORD) data. The main outcome measure was the current value total working lifetime costs of new cases annually for each scenario. RESULTS: Assuming 209 new cases of occupational asthma in the six scenarios in the year 2003, the present value total lifetime costs were estimated to be £25.3-27.3 million (2004 prices). Grossing up for all estimated cases of occupational asthma in the UK in 2003, this came to £70-100 million. About 49% of these costs were borne by the individual, 48% by the state and 3% by the employer. CONCLUSIONS: The cost to society of occupational asthma in the UK is high. Given that the number of newly diagnosed cases is likely to be underestimated by at least one-third, these costs may be as large as £95-135 million. Each year a new stream of lifetime costs will be added as a newly diagnosed cohort is identified. Approaches to reduce the burden of occupational asthma have a strong economic justification. However, the economic burden falls on the state and the individual, not on the employer. The incentive for employers to act is thus weak.

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation.

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.

Studies to further investigate the inhibition of human liver microsomal CYP2C8 by the acyl-ß-glucuronide of gemfibrozil.

In previous studies, gemfibrozil acyl-ß-glucuronide, but not gemfibrozil, was found to be a mechanism-based inhibitor of cytochrome P450 2C8. To better understand whether this inhibition is specific for gemfibrozil acyl-ß-glucuronide or whether other glucuronide conjugates are potential substrates for inhibition of this enzyme, we evaluated several pharmaceutical compounds (as their acyl glucuronides) as direct-acting and metabolism-dependent inhibitors of CYP2C8 in human liver microsomes. Of 11 compounds that were evaluated as their acyl glucuronide conjugates, only gemfibrozil acyl-ß-glucuronide exhibited mechanism-based inhibition, indicating that CYP2C8 mechanism-based inhibition is very specific to certain glucuronide conjugates. Structural analogs of gemfibrozil were synthesized, and their glucuronide conjugates were prepared to further examine the mechanism of inhibition. When the aromatic methyl groups on the gemfibrozil moiety were substituted with trifluoromethyls, the resulting glucuronide conjugate was a weaker inhibitor of CYP2C8 and mechanism-based inhibition was abolished. However, the glucuronide conjugates of monomethyl gemfibrozil analogs were mechanism-based inhibitors of CYP2C8, although not as potent as gemfibrozil acyl-ß-glucuronide itself. The ortho-monomethyl analog was a more potent inhibitor than the meta-monomethyl analog, indicating that CYP2C8 favors the ortho position for oxidation and potential inhibition. Molecular modeling of gemfibrozil acyl-ß-glucuronide in the CYP2C8 active site is consistent with the ortho-methyl position being the favored site of covalent attachment to the heme. Moreover, hydrogen bonding to four residues (Ser100, Ser103, Gln214, and Asn217) is implicated.