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Fine particulate air pollution <2.5 μm in diameter (PM 2.5 ) is a major environmental threat to global public health. Multiple national and international medical and governmental organizations have recognized PM 2.5 as a risk factor for cardiopulmonary diseases. A growing body of evidence indicates that several personal-level approaches that reduce exposures to PM 2.5 can lead to improvements in health endpoints. Novel and forward-thinking strategies including randomized clinical trials are important to validate key aspects (e.g., feasibility, efficacy, health benefits, risks, burden, costs) of the various protective interventions, in particular among real-world susceptible and vulnerable populations. This paper summarizes the discussions and conclusions from an expert workshop, Reducing the Cardiopulmonary Impact of Particulate Matter Air Pollution in High Risk Populations, held on May 29 to 30, 2019, and convened by the National Institutes of Health, the U.S. Environmental Protection Agency, and the U.S. Centers for Disease Control and Prevention., Competing Interests: Author Disclosures The views expressed in this paper are those of the authors and do not necessarily represent the views of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences, Environmental Protection Agency, Centers for Disease Control and Prevention, or the United States Department of Health and Human Services. Drs. Bhatt and Brooks served as co-chairs of this NIH/NHLBI/EPA/CDC Expert Workshop on air pollution. Dr. Newman has received grant support from the NIH (K23HL125991). Dr. Bhatt has served on the advisory board of Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado Biosciences; has served on the Board of Directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on the data monitoring committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as Deputy Editor of Clinical Cardiology; has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; served as a trustee of the American College of Cardiology; and has received unfunded research from FlowCo, Merck, Novo Nordisk, and Takeda. Dr. Balmes is the Physician Member of the California Air Resources Board. Dr. Brook has received an investigator-initiated grant from RB, Inc.; and has received support from NIH awards 2R01-ES019616 and 2R01-NR014484. Dr. Brauer has received grant support from the Health Effects Institute, the Canadian Institutes of Health Research, The Terry Fox Research Institute, and the Wellcome Trust. Dr. Hansel has received grant support from the NIH, EPA, NHLBI, National Institute of Environmental Health Sciences, COPD Foundation, and Boehringer Ingelheim; and has participated in advisory boards for GlaxoSmithKline, AstraZeneca, and Mylan. Dr. Hernandez has received research funding from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, and Verily; and has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, and Relypsa. Dr. Hochman has received grant support from the NHLBI for the ISCHEMIA Trial, for which there were in-kind donations for participating sites from Abbott Vascular, Medtronic, Inc., St. Jude Medical, Inc., Volcano Corporation, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Merck Sharp & Dohme Corp., Omron Healthcare, Inc., and Amgen Inc; has received financial donations from Arbor Pharmaceuticals and AstraZeneca Pharmaceuticals; and has served as PI for the ZEDS (Long-term Suppressive Valacyclovir Treatment for Herpes Zoster Ophthalmicus) Study, supported by NIH/National Eye Institute. Dr. Kaufman has received grant support from the National Institutes of Health and the Environmental Protection Agency. Dr. Malik is supported by the NHLBI of the NIH under Award Number T32HL110837. Dr. Peel has received research funding from the NIH (1UM1HL134590 and R01ES023688). Dr. Rajagopalan has received research funding from the NIH; and has served as a consultant to Novo Nordisk, Takeda, GlaxoSmithKline, and AstraZeneca. Dr. Zhang’s research has been partly funded by the NIH, Underwriter’s Laboratory, and Natural Science Foundation of China (via Duke Kunshan University in China). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

Background: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis., Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual., Findings: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events)., Interpretation: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab., Funding: F Hoffmann-La Roche Ltd., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Resuspension of microbes in floor dust and subsequent inhalation by human occupants is an important source of human microbial exposure. Microbes in carpet dust grow at elevated levels of relative humidity, but rates of this growth are not well established, especially under changing conditions. The goal of this study was to model fungal growth in carpet dust based on indoor diurnal variations in relative humidity utilizing the time-of-wetness framework. A chamber study was conducted on carpet and dust collected from 19 homes in Ohio, USA and exposed to varying moisture conditions of 50%, 85%, and 100% relative humidity. Fungal growth followed the two activation regime model, while bacterial growth could not be evaluated using the framework. Collection site was a stronger driver of species composition (P = 0.001, R 2  = 0.461) than moisture conditions (P = 0.001, R 2  = 0.021). Maximum moisture condition was associated with species composition within some individual sites (P = 0.001-0.02, R 2  = 0.1-0.33). Aspergillus, Penicillium, and Wallemia were common fungal genera found among samples at elevated moisture conditions. These findings can inform future studies of associations between dampness/mold in homes and health outcomes and allow for prediction of microbial growth in the indoor environment., (© 2020 The Authors. Indoor Air published by John Wiley & Sons Ltd.)

Objectives: Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study., Methods: Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96., Results: Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period., Conclusions: Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab., Trial Registration Number: NCT01532869; Results., Competing Interests: Competing interests: DK reports personal fees from Actelion, Boehringer-Ingelheim, Covis, CSL Behring, Corbus, Cytori, EMD Serono, Genentech/Roche, GSK, Inventiva, Medac, Sanofi-Aventis and UCB; grants from BMS, Bayer and Pfizer; stocks in Eicos Sciences, Inc, during the conduct of the study; and personal fees from Astra Zeneca outside the submitted work. CPD reports personal fees from Roche, Actelion, EMD Serono, Sanofi and Boehringer Ingelheim; grants and personal fees from GSK and Inventiva; and grants from CSL Behring during the conduct of the study. CJFL is an employee of Genentech. JMvL reports grants and personal fees from MSD and Genentech and personal fees from BMS, Eli Lilly and Pfizer outside the submitted work. MEA reports funding to Hospital Trust from Roche during the conduct of the study and personal fees from Actelion Pharmaceuticals outside the submitted work. YA has received research support and grants related to the submitted work from BMS, Roche/Genentech, Inventiva, Pfizer and Sanofi; consulting honoraria and personal fees related to the current work from Actelion, Bayer, Boehringer, Roche/Genentech, Galapagos, Inventiva, Medac, Pfizer, Sanofi, Servier and UCB; and personal fees outside the submitted work from Sandoz. JEP reports funding for the current trial by Roche. GR has received lecturer’s fees from Roche and Chugai outside the submitted work. UM-L is a speaker and advisor to Roche and Chugai related to the submitted work. HS is an employee of and has non-voting shares in Roche Products Limited. LB is an employee of Roche. JS is an employee of Genentech. AJ is an employee of Genentech, owns stock and options in Roche and owns a patent for subcutaneous tocilizumab. All other authors have no conflicts of interest to disclose., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo., Methods: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR., Results: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023)., Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

In the United States, humans spend the majority of their time indoors, where they are exposed to the microbiome of the built environment (BE) they inhabit. Despite the ubiquity of microbes in BEs and their potential impacts on health and building materials, basic questions about the microbiology of these environments remain unanswered. We present a study on the impacts of geography, material type, human interaction, location in a room, seasonal variation, and indoor and microenvironmental parameters on bacterial communities in offices. Our data elucidate several important features of microbial communities in BEs. First, under normal office environmental conditions, bacterial communities do not differ on the basis of surface material (e.g., ceiling tile or carpet) but do differ on the basis of the location in a room (e.g., ceiling or floor), two features that are often conflated but that we are able to separate here. We suspect that previous work showing differences in bacterial composition with surface material was likely detecting differences based on different usage patterns. Next, we find that offices have city-specific bacterial communities, such that we can accurately predict which city an office microbiome sample is derived from, but office-specific bacterial communities are less apparent. This differs from previous work, which has suggested office-specific compositions of bacterial communities. We again suspect that the difference from prior work arises from different usage patterns. As has been previously shown, we observe that human skin contributes heavily to the composition of BE surfaces. IMPORTANCE Our study highlights several points that should impact the design of future studies of the microbiology of BEs. First, projects tracking changes in BE bacterial communities should focus sampling efforts on surveying different locations in offices and in different cities but not necessarily different materials or different offices in the same city. Next, disturbance due to repeated sampling, though detectable, is small compared to that due to other variables, opening up a range of longitudinal study designs in the BE. Next, studies requiring more samples than can be sequenced on a single sequencing run (which is increasingly common) must control for run effects by including some of the same samples in all of the sequencing runs as technical replicates. Finally, detailed tracking of indoor and material environment covariates is likely not essential for BE microbiome studies, as the normal range of indoor environmental conditions is likely not large enough to impact bacterial communities.

The structure-activity relationship (SAR) of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives related to ZM241385 as antagonists of the A(2A) adenosine receptor (AR) was explored through the synthesis of analogues substituted at the 5 position. The A(2A) AR X-ray structure was used to propose a structural basis for the activity and selectivity of the analogues and to direct the synthetic design strategy to provide access to solvent-exposed regions. Thus, we have identified a point of substitution for the attachment of solubilizing groups to enhance both aqueous solubility and physicochemical properties, maintaining potent interactions with the A(2A) AR and, in some cases, receptor subtype selectivity. Among the most potent and selective novel compounds were a long-chain ether-containing amine congener 20 (K(i) 11.5 nM) and its urethane-protected derivative 14 (K(i) 17.8 nM). Compounds 20 and 31 (K(i) 11.5 and 16.9 nM, respectively) were readily water-soluble up to 10 mM. The analogues were docked in the crystallographic structure of the hA(2A) AR and in a homology model of the hA(3) AR, and the per residue electrostatic and hydrophobic contributions to the binding were assessed and stabilizing factors were proposed.

Biomarkers are important tools for identifying and stratifying diseases, predicting their progression and determining the effectiveness, safety, and doses of therapeutic interventions. This is important for common chronic diseases such as diabetic nephropathy, osteoporosis, and rheumatoid arthritis which affect large numbers of patients worldwide. This article summarizes the current knowledge of established and novel biomarkers for each of these diseases as presented at the 2008 AAPS/ACCP joint symposium "Success Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications," in Atlanta, Georgia. The advantages and disadvantages of various proteomic, metabolomic, genomic, and imaging biomarkers are discussed in relation to disease diagnosis and stratification, prognosis, drug development, and potential clinical applications. The use of biomarkers as a means to determine therapeutic interventions is also considered. In addition, we show that biomarkers may be useful for adapting therapies for individual needs by allowing the selection of patients who are most likely to respond or react adversely to a particular treatment. They may also be used to determine whether the development of a novel therapy is worth pursuing by informing crucial go/no go decisions around safety and efficacy. Indeed, regulatory bodies now suggest that effective integration of biomarkers into clinical drug development programs is likely to promote the development of novel therapeutics and more personalized medicine.

Objective: Malignancies reported in children using tumor necrosis factor alpha (TNFalpha) blockers have raised concerns of a potential increased risk. This study was undertaken to investigate postmarketing reports of malignancy in children treated with TNF blockers., Methods: The FDA's Adverse Event Reporting System was searched to identify malignancies associated with the use of infliximab, etanercept, and adalimumab in children in whom therapy was initiated between the ages of 0 and 18 years. The reporting rates for infliximab and etanercept were compared with the background rate of malignancy in the general pediatric population., Results: Forty-eight reports of malignancy in children were identified: 31 following infliximab use, 15 following etanercept use, and 2 following adalimumab use. Half of the malignancies reported were lymphomas and included both Hodgkin's and non-Hodgkin's lymphoma. The remaining reported cases involved a variety of different malignancies including leukemia, melanoma, and solid organ cancers. The majority of the reported cases (88%) involved the concomitant use of other immunosuppressants. Reporting rates for malignancy showed that infliximab had a consistently higher reporting rate when compared with background rates in the general pediatric population for lymphomas and all malignancies. The reporting rates for etanercept were elevated above background for lymphomas and were on par with background for all malignancies., Conclusion: There is evidence that treatment with TNF blockers in children may increase the risk of malignancy. However, the cases were confounded by the potential risk of malignancy associated with underlying illnesses and the use of concomitant immunosuppressants; therefore, a clear causal relationship could not be established.

Background: Hispanics are the fastest growing minority group in the United States; however, minimal information is available on their cancer risks from exposures to hazardous air pollutants (HAPs) and how these risks compare to risks to non-Hispanic whites., Methods: We estimated the personal exposure and cancer risk of Hispanic and white adults who participated in the Relationships of Indoor, Outdoor, and Personal Air (RIOPA) study. We evaluated 12 of the sampled volatile organic compounds and carbonyls and identified the HAPs of most concern and their possible sources. Furthermore, we examined sociodemographic factors and building characteristics., Results: Cumulative cancer risks (CCRs) estimated for Hispanics (median = 519 x 10(-6), 90th percentile = 3,968 x 10(-6)) and for whites (median = 443 x 10(-6), 90th percentile = 751 x 10(-6)) were much greater than the U.S. Environmental Protection Agency (EPA) benchmark of 10(-6). Cumulative risks were dominated by formaldehyde and p-dichlorobenzene (p-DCB) and, to a lesser extent, by acetaldehyde, chloroform, and benzene. Exposure to all of these compounds except benzene was primarily due to indoor residential sources. Hispanics had statistically higher CCRs than did whites (p

The role of rhodopsin as a structural prototype for the study of the whole superfamily of G protein-coupled receptors (GPCRs) is reviewed in an historical perspective. Discovered at the end of the nineteenth century, fully sequenced since the early 1980s, and with direct three-dimensional information available since the 1990s, rhodopsin has served as a platform to gather indirect information on the structure of the other superfamily members. Recent breakthroughs have elicited the solution of the structures of additional receptors, namely the beta(1)- and beta(2)-adrenergic receptors and the A(2A) adenosine receptor, now providing an opportunity to gauge the accuracy of homology modeling and molecular docking techniques and to perfect the computational protocol. Notably, in coordination with the solution of the structure of the A(2A) adenosine receptor, the first "critical assessment of GPCR structural modeling and docking" has been organized, the results of which highlighted that the construction of accurate models, although challenging, is certainly achievable. The docking of the ligands and the scoring of the poses clearly emerged as the most difficult components. A further goal in the field is certainly to derive the structure of receptors in their signaling state, possibly in complex with agonists. These advances, coupled with the introduction of more sophisticated modeling algorithms and the increase in computer power, raise the expectation for a substantial boost of the robustness and accuracy of computer-aided drug discovery techniques in the coming years.

A review of the issues involved in placement of Tunneled Dialysis Catheter with a suggested scheme for maximizing good catheter placement and function.

Vacuuming is generally considered to be an important activity with respect to the cleanliness of indoor environments but may lead to short-term resuspension of particulate matter and elevated particle mass in indoor air. Because resuspended particles often contain toxicants, such as lead and pesticides, or consist of biological agents that can trigger allergic reactions, it is important to understand the role of vacuuming on short-term variations in indoor particulate matter concentrations. The inhalation of particles during vacuuming events may affect adversely those whose occupation requires them to clean a wide range of indoor environments, from homes to schools and offices, as well as those who occupy those environments. In response, a series of 46 experiments was completed to determine time-variant concentrations of both PM(10) and PM(2.5) during various vacuuming activities in 12 separate apartments. Experiments involved the use of two different non-HEPA vacuum cleaners and were completed with a vacuum cleaner activated (switched on) as well as deactivated (switched off). The latter was intended to provide insight on the potential for resuspension of particles by the mechanical agitation of vacuum cleaner movement across carpet. Separate experiments were completed also using "mock" vacuuming simulations, that is, walking on the carpet in a manner consistent with using a vacuum cleaner. Results are presented as incremental particulate matter concentration increases, relative to background (prevacuum) concentrations, and peak-to-background particle concentration ratios. Results indicate significant resuspension of PM(10) mass during vacuum cleaning, with a mean time-averaged PM(10) increase of greater than 17 mu g/m(3) above background. Resuspension of PM(2.5) mass was determined to be small, that is, PM(10) mass was dominated by particles greater than 2.5 mu m. The frequency of vacuuming (between a 10-day standard frequency and several experiments at > 24 days between vacuuming) had little influence on resuspended particle mass. Resuspension by mechanical agitation (rolling of vacuum cleaner across carpet) with the vacuum cleaner switched off was determined to be substantial, with a mean time-averaged (during vacuuming) PM(10) increase of 35 mu g/m(3) relative to background. Peak-to-background PM(10) concentrations exceeded 6 for some experiments and averaged between approximately 3 and 4 for experiments when the vacuum cleaner was switched on.

This study assessed differences in the indoor air quality and occupancy levels in seventeen bars due to a city-wide smoking ban that took effect on September 1, 2005 in Austin, Texas, USA. We measured the following in each venue before and after the smoking ban: mean number of occupants, mean number of lit cigarettes, temperature, relative humidity, room volume, and PM(2.5), CO, and CO(2) concentrations. Additionally, VOC measurements were conducted at three of the venues. There was not a statistically significant change in occupancy, but the best estimate PM(2.5) concentrations in the venues decreased 71-99%, a significant reduction in all venues, relative to the pre-ban levels; CO concentrations decreased significantly in all but one venue; and concentrations of VOCs known to be emitted from cigarettes decreased to below the detection limit for all but two common compounds. These results suggest that the smoking ban has effectively improved indoor air quality in Austin bars without an associated decrease in occupancy.

Objective: Diverse neurologic syndromes have been described in association with tumor necrosis factor alpha (TNFalpha) antagonist therapy for inflammatory arthritides and Crohn's disease. The objective of this study was to review the occurrence and clinical features of Guillain-Barré syndrome and its variant, the Miller Fisher syndrome, during TNFalpha antagonist therapy., Methods: The postmarketing database of the US Food and Drug Administration (FDA) was searched, following our experience with a patient with rheumatoid arthritis in whom the Miller Fisher syndrome variant of the Guillain-Barré syndrome developed while he was receiving infliximab therapy., Results: Our index patient had a neurologic illness defined initially by ataxia and dysarthria, which fluctuated in relation to each subsequent infliximab infusion and, after 6 months, culminated in areflexic flaccid quadriplegia. In addition, 15 patients in whom Guillain-Barré syndrome developed following TNFalpha antagonist therapy were identified from the FDA database. Guillain-Barré syndrome developed following infliximab therapy in 9 patients, following etanercept therapy in 5 patients, and following adalimumab therapy in 1 patient. Among the 13 patients for whom followup data were available, 1 patient experienced no resolution, 9 patients had partial resolution, and 3 patients had complete resolution of Guillain-Barré syndrome following therapy., Conclusion: An association of Guillain-Barré syndrome with TNFalpha antagonist therapy is supported by the worsening of neurologic symptoms that occurred in our index patient following each infusion of infliximab, and by the temporal association of this syndrome with TNFalpha antagonist therapy in 15 other patients. An acute or subacute demyelinating polyneuropathy should be considered a potential adverse effect of TNFalpha antagonist therapy.

Purpose: To compare the effectiveness and safety of use of the peripheral cutting balloon (PCB) versus standard percutaneous transluminal angioplasty (PTA) for the treatment of hemodialysis-related stenoses., Materials and Methods: This prospective, randomized multicenter clinical trial included 340 patients with stenotic or thrombosed hemodialysis grafts who were randomized to receive treatment with the PCB or PTA for venous outflow stenosis. One hundred seventy-three patients underwent treatment with the PCB, 101 with stenotic grafts and 72 with thrombosed grafts. PTA was used to treat 167 patients, 94 patients with stenotic grafts and 73 with thrombosed grafts. The follow-up period extended for 6 months., Results: The procedural success rates were 80.8% and 75.4% for the PCB and PTA groups, respectively (P = .24). With use of the PCB, the primary patency rates of the target lesions were 84.3%, 65.8%, and 47.9% at 1 month, 3 months, and 6 months, respectively. With PTA, the primary patency rates of the target lesions were 77.7%, 63.4%, and 40.5% at 1 month, 3 months, and 6 months, respectively. The primary patency rates of the entire vascular access circuit were 82.6%, 61.0%, and 43.3% at 1 month, 3 months, and 6 months, respectively, with use of the PCB. For patients who were treated with PTA, the primary patency rates of the vascular access circuit were 75.9%, 61.0%, and 36.3% at 1 month, 3 months, and 6 months, respectively. When comparing the PCB and PTA, there was no difference in the 6-month primary patency rates in the target lesion (P = .373) or the entire vascular access circuit (P = .531). There were nine device-related complications in the PCB group (5.2%): five venous ruptures (2.9%), three venous dissections (1.7%), and one case of thrombosis (0.6%). There were no device-related complications in the PTA group., Conclusion: This prospective, randomized trial comparing use of the PCB versus standard PTA for treatment of hemodialysis-related venous stenoses demonstrated that the PCB provides equivalent 6-month patency to PTA for stenotic and thrombosed grafts.

Objective: To describe the clinical features of leukocytoclastic vasculitis (LCV) associated with the use of tumor necrosis factor-alpha (TNF-alpha) blockers., Methods: The Adverse Events Reporting System (AERS) of the US Food and Drug Administration (FDA) was queried for reports of patients who developed LCV during or after starting etanercept or infliximab from date of approval of each agent through September 6, 2002., Results: Thirty-five cases of LCV were identified, 20 following etanercept administration and 15 following infliximab administration. Seventeen of the 35 (48.5%) were biopsy-proven cases and the others had skin lesions that were clinically typical for LCV. Twenty-two of 35 (62.8%) patients had complete or marked improvement of skin lesions upon stopping the TNF-alpha blocker. Three patients who had received etanercept had continuing lesions despite discontinuation of the drug; one of these patients improved when switched to infliximab. One patient who received infliximab was reported to have continuing lesions despite discontinuation of the drug and treatment with prednisone and antihistamines. Six patients experienced a positive rechallenge (recurrence of LCV on restarting therapy with a TNF-alpha blocker) and 3 patients a negative rechallenge phenomenon. LCV lesions improved in patients despite continuing use of concomitant medications reportedly associated with LCV., Conclusion: Therapy with TNF-alpha blocking agents may be associated with the development of LCV. Skin lesions improved on discontinuation of anti-TNF-alpha therapy in most patients. Other causes of LCV should be excluded, and evaluation for systemic involvement with appropriate investigations is recommended.

Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the "reporting rate") among patients with rheumatoid arthritis (RA) was ~10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.

Agents that block the action of tumor necrosis factor-alpha and recombinant interleukin-1 have been shown to be effective biologic treatment modalities in patients with rheumatoid arthritis. Given the immunosuppressive effects of tumor necrosis factor-alpha and interleukin-1 blockers, infections have emerged as possible complications of using these agents, an observation foreshadowed in prelicensure animal studies. At this time, hundreds of thousands of patients have received these drugs, and a wide variety of infectious complications has been reported, among which reactivation tuberculosis is most notable. Case reports alone, however, do not necessarily reflect a causal association between a therapeutic product and an adverse event. The authors review the infectious complications of the use of these agents as reported in the medical literature from November 2001 through October 2002.

Objective: Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. Infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). Etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products., Methods: The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept., Results: Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in HC-endemic regions., Conclusion: Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.

Antiphosphotyrosine blotting is a technique for detecting tyrosine-phosphorylated substrates by the use of antibodies that recognize these residues on a wide variety of proteins. This unit describes conditions for cell lysis and immunoprecipitation of proteins with an antiphosphotyrosine antibody, followed by electrophoretic separation, immunoblotting, and color detection of the blotted proteins. This combination of steps provides particularly sensitive conditions for the detection of tyrosine-phosphorylated substrates, but also gives good results for any protein transferred to nitrocellulose, including whole-cell lysates or proteins immunoprecipitated with another antibody. Although the alkaline phosphatase color-detection system has the advantage of providing superior resolution and higher sensitivity without the use of any radioactivity, the (125)I-labeled Staphylococcus protein A detection system is described for use in conjunction with the blotting protocol.

The function of cells of the immune system is regulated in part by engagement of specific receptors on the cell surface by soluble ligands or ligands presented on the surface of other cells. One of the major mechanisms by which cell-surface receptor engagement influences cellular function is by activating protein kinases and increasing the phosphorylation of critical cellular proteins. There are two major categories of protein kinases: serine/threonine kinases which phosphorylate both serine and threonine residues; and tyrosine kinases which phosphorylate tyrosine residues exclusively. By metabolically labeling cells with (32)P, as described in this unit, the phosphorylation state of cellular proteins can be analyzed and changes occurring with receptor stimulation can be examined. Phosphoamino acid analysis is also described to determine whether serine, threonine, or tyrosine residues are phosphorylated, thereby indicating which category of protein kinase is responsible. A protocol for phosphopeptide mapping is provided to allow the investigator to produce a "fingerprint" of the peptides that are phosphorylated, providing information regarding the sites of phosphorylation.