Search

Context: The American Diabetes Association and Surviving Sepsis Campaign recommend tight glucose control in critically ill patients based largely on 1 trial that shows decreased mortality in a surgical intensive care unit. Because similar studies report conflicting results and tight glucose control can cause dangerous hypoglycemia, the data underlying this recommendation should be critically evaluated.Objective: To evaluate benefits and risks of tight glucose control vs usual care in critically ill adult patients.Data Sources: MEDLINE (1950-2008), the Cochrane Library, clinical trial registries, reference lists, and abstracts from conferences from both the American Thoracic Society (2001-2008) and the Society of Critical Care Medicine (2004-2008).Study Selection: We searched for studies in any language in which adult intensive care patients were randomly assigned to tight vs usual glucose control. Of 1358 identified studies, 34 randomized trials (23 full publications, 9 abstracts, 2 unpublished studies) met inclusion criteria.Data Extraction and Analysis: Two reviewers independently extracted information using a prespecified protocol and evaluated methodological quality with a standardized scale. Study investigators were contacted for missing details. We used both random- and fixed-effects models to estimate relative risks (RRs).Results: Twenty-nine randomized controlled trials totaling 8432 patients contributed data for this meta-analysis. Hospital mortality did not differ between tight glucose control and usual care overall (21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85-1.03). There was also no significant difference in mortality when stratified by glucose goal ([1] very tight: < or = 110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77-1.04; or [2] moderately tight: < 150 mg/dL; 17.3% vs 18.0%; RR, 0.99; 95% CI, 0.83-1.18) or intensive care unit setting ([1] surgical: 8.8% vs 10.8%; RR, 0.88; 95% CI, 0.63-1.22; [2] medical: 26.9% vs 29.7%; RR, 0.92; 95% CI, 0.82-1.04; or [3] medical-surgical: 26.1% vs 27.0%; RR, 0.95; 95% CI, 0.80-1.13). Tight glucose control was not associated with significantly decreased risk for new need for dialysis (11.2% vs 12.1%; RR, 0.96; 95% CI, 0.76-1.20), but was associated with significantly decreased risk of septicemia (10.9% vs 13.4%; RR, 0.76; 95% CI, 0.59-0.97), and significantly increased risk of hypoglycemia (glucose < or= 40 mg/dL; 13.7% vs 2.5%; RR, 5.13; 95% CI, 4.09-6.43).Conclusion: In critically ill adult patients, tight glucose control is not associated with significantly reduced hospital mortality but is associated with an increased risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

Purpose: Human papillomavirus (HPV) causes an estimated 300,000 high grade cervical dysplasias and 36,000 preventable cancers each year in the United States alone. Despite having a safe, effective and long lasting vaccine since 2006, the rate of uptake has been suboptimal, particularly in rural areas. In 2020, Utah ranked near last in teenage HPV vaccination rates with rural areas trailing urban areas by about 18 percent. In this study, we identified factors that affect the intent of rural Utah parents to vaccinate their children against HPV., Methods: A survey was distributed electronically to Utah residents in rural areas. Recruitment was carried out through targeted advertising, community organizations, and professional survey panels. The survey was open from Nov. 15, 2022 to April 15, 2023. A total of 410 respondents were used for analysis. Survey results were analyzed using exploratory factor analysis, confirmatory factor analysis, and structural equation modeling., Findings: Distance to care was shown to negatively influence direct intent to vaccinate, while trust in government, general vaccine attitudes, and HPV knowledge positively influence intent to vaccinate. It was found that religious practice decreased vaccine hesitancy while cautious sexual attitudes, distance to care, and general negative vaccine attitudes increased vaccine hesitancy. Conservative political identity and high income were both shown to decrease vaccine hesitancy as covariates., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hispanic Immigrants (HI) have lower vaccination rates than their non-Hispanic white counterparts. Culturally appropriate interventions are more influential in evoking change among viewers; therefore, it is important to understand the cultural factors of specific ethnic groups. In this study, we identify cultural barriers to vaccination of Hispanic Immigrants. An electronic survey was administered among HI parents living in the United States. Using structural equation modeling, we found that high religious practice and positive religious beliefs towards vaccination correspond with positive vaccine attitudes (+0.20 and +0.587, respectively). Trust in institutions is strongly correlated with strong positive vaccine attitudes (+0.734). While trusting one's folk practitioner more than a medical doctor leads to negative vaccine attitudes (-0.596), the use of home remedies is associated with positive vaccine attitudes (+0.486). The cultural competence of a medical practitioner, especially regarding folk medicine, is essential to lower cultural barriers HI patients face in vaccination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Larson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Safe and effective vaccines have been developed that protect against high-risk strains of HPV, but uptake is relatively low. We previously identified factors such as sexual attitudes and HPV knowledge that impact the intent of Christian parents to vaccinate their children against HPV. We hypothesized that culturally specific interventions in the form of short videos would be effective at improving HPV vaccine intentions and attitudes. We made three short educational videos, one with a Christian focus, one informational about HPV, and one control. Videos were distributed electronically with accompanying surveys, and responses were measured before and after watching a randomly selected video. The religious-focused and educational interventions significantly (p < 0.0001, p = 0.0015) improved intentions towards HPV vaccination. The religiously-focused video also significantly diminished the belief that the HPV vaccine is unnecessary because of a family's values (p = 0.014). Parents significantly credited both interventions with improving their intent to vaccinate their children against HPV (p < 0.001 for both). These results suggest that culturally focused educational interventions are effective at influencing vaccine intentions and attitudes, even when those are based on religious or cultural feelings. Highly specific interventions are likely to be necessary for optimal improvement in vaccine hesitancy., (© 2024. The Author(s).)

Background: The faecal immunochemical test (FIT) is an inexpensive and convenient modality to screen for colorectal cancer. However, its one-time sensitivity for detecting colorectal cancer and cancer precursors is limited. There is growing interest in using the non-haemoglobin contents of FIT residual buffer to enhance colonic neoplasia detection., Aim: To establish from the literature a framework to catalogue candidate biomarkers within FIT residual buffer for non-invasive colorectal cancer screening., Methods: The search strategy evaluated PubMed, Scopus, Web of Science, Embase, and Google Scholar for publications through 25 October 2023, with search terms including FIT, buffer, OC-sensor, biomarkers, microbiome, microRNA (miR), colon, rectum, screening, neoplasm, and early detection. Studies employing home-based collection samples using quantitative FIT first processed for haemoglobin were included. One author reviewed all articles; a second author completed a 20% full-text audit to ensure adherence to eligibility criteria., Results: A broad search yielded 1669 studies and application of eligibility criteria identified 18 relevant studies. Multiple protein, DNA/RNA, and microbiome biomarkers (notably haptoglobin, miR-16, miR-27a-3p, miR-92a, miR-148a-3p, miR-223, miR-421, let-7b-5p, and Tyzzerella 4) were associated with colorectal neoplasia. Furthermore, studies highlighted the short-term stability of biomarkers for clinical use and long-term stability for research purposes., Conclusions: This scoping review summarises the framework and progress of research on stability of biomarkers in FIT residual buffer and their associations with colorectal neoplasia to guide opportunities for further confirmatory studies to enhance colorectal cancer screening., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: Prior research explores whether seasonal and childhood vaccines mitigate the risk of SARS-CoV-2 infection. Although there are trials investigating COVID-19 infection in response to the effects of the oral poliovirus vaccine (OPV), there has been no prior research assessing COVID-19 outcomes in recently immunized adults with the inactivated poliovirus vaccine (IPV). Methods: SARS-CoV-2 infection and COVID-19 symptoms were analyzed across a cohort of 282 adults who received an IPV booster. Bivariate and multivariate regression models explored associations among variables related to vaccination histories and COVID-19 outcomes. Results: One year post-IPV inoculation, participants who had never received OPV were more likely to test positive for SARS-CoV-2 and experience COVID-19 symptoms, compared to those who had previously received OPV (OR = 3.92, 95%CI 2.22-7.03, p < 0.001; OR = 4.45, 95%CI 2.48-8.17, p < 0.001, respectively). Those who had never received OPV experienced COVID-19 symptoms for 6.17 days longer than participants who had previously received OPV (95%CI 3.68-8.67, p < 0.001). Multivariate regression modeling indicated COVID-19 vaccination did not impact SARS-CoV-2 infection or COVID-19 symptoms in this sample of adults who had recently received IPV. Discussion: Findings suggest IPV may boost mucosal immunity among OPV-primed individuals, and COVID-19 vaccination may not provide additional protection among those who had received IPV. Future, larger-scale studies should measure the extent of protective effects against COVID-19 to inform public health policies in resource-deficient settings.

Background: Structural and functional commonalities between poliovirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suggest that poliovirus inoculation may induce antibodies that mitigate the coronavirus disease (COVID-19). No known studies have evaluated COVID-19 risk factors in adults recently vaccinated against poliovirus., Study Objective: Among adults with no history of COVID-19 infection or vaccination, who recently received an inactivated poliovirus vaccine (IPV), we sought to determine which biological factors and social determinants of health (SDOH) may be associated with (1) testing positive for SARS-CoV-2, (2) experiencing COVID-19 symptoms, and (3) a longer duration of COVID-19 symptoms., Methods: The influence of biological factors and SDOH on SARS-CoV-2 infection and COVID-19 symptoms were evaluated among 282 adults recently inoculated with IPV. Participant-reported surveys were analyzed over 12 months post-enrollment. Bivariate and multivariate linear and logistic regression models identified associations between variables and COVID-19 outcomes., Results: Adjusting for COVID-19 vaccinations, variants, and other SDOH, secondary analyses revealed that underlying conditions, employment, vitamin D, education, and the oral poliovirus vaccination (OPV) were associated with COVID-19 outcomes. The odds of testing positive for SARS-CoV-2 and experiencing symptoms were significantly reduced among participants who took vitamin D (OR 0.12 and OR 0.09, respectively). Unemployed or part-time working participants were 72% less likely to test positive compared with full-time workers. No prior dose of OPV was one of the strongest predictors of SARS-CoV-2 infection (OR 4.36) and COVID-19 symptoms (OR 6.95)., Conclusions: Findings suggest that prophylactic measures and mucosal immunity may mitigate the risk and severity of COVID-19 outcomes. Larger-scale studies may inform future policies.

Background: As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp., Methods: A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2., Results: Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings., Conclusions: Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.

Objective: To determine the clinical effect of personal continuous glucose monitoring (CGM) in a diverse population with type 2 diabetes (T2D). Research Design and Methods: A report was created from the electronic health record identifying adults prescribed CGM at an urban family medicine clinic between January 1, 2019, and February 23, 2022. An "index date" was identified as the start of CGM. The closest hemoglobin A 1c (A1c) 6 months or more after the index date was identified as the "follow-up date." The primary outcome of this study was to compare the percentage of individuals meeting the MN Community Measure (MNCM) D5 HbA1c goal of <8% at the follow-up date versus the index date. Results: Seventy-two patients were identified after the exclusion criteria were applied. Approximately one-third of patients required utilization of an interpreter and 76% of patients were of a racial or ethnic minority. The mean HbA1c prior to CGM use was 9.8%, with 16.7% of the population meeting the MNCM D5 A1c goal of <8%. At the follow-up date, the mean A1c was 8.4% (mean difference -1.4%; p  < 0.001), with 41.7% of the population meeting goal (mean difference +25%; p  < 0.001). Subgroup analyses affirm that the results of the primary outcome were sustained despite insulin use status. Conclusion: A diverse population with T2D had a significant reduction in A1c and was more likely to meet the MNCM D5 A1c goal of <8% after an average of 6 months using personal CGM., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Requests for outpatient specialty consultations occur frequently but often are of poor quality because of incompleteness. The authors searched bibliographic databases, trial registries, and references during October 2014 for studies evaluating interventions to improve the quality of outpatient specialty referral requests compared to usual practice. Two reviewers independently extracted data and assessed quality. Findings were qualitatively summarized for completeness of information relayed in a referral request within naturally emerging intervention categories. Of 3495 articles screened, 11 were eligible. All 3 studies evaluating software-based interventions found statistically significant improvements. Among 4 studies evaluating template/pro forma interventions, completeness was uniformly improved but with variable or unreported statistical significance. Of 4 studies evaluating educational interventions, 2 favored the intervention and 2 found no difference. One study evaluating referral management was negative. Current evidence for improving referral request quality is strongest for software-based interventions and templates, although methodological quality varied and findings may be setting specific., (© The Author(s) 2015.)

Purpose: To compare treatment strategies for ocular surface squamous neoplasia (OSSN), ranging from surgical excision to empiric topical interferon alpha-2b (IFN-α2b)., Methods: A decision model was constructed to determine which of 4 treatment strategies minimized expected persistence/recurrence of disease in patients with OSSN: excision followed by repeat excision for positive surgical margins, excision followed by IFN-α2b for positive margins, incisional biopsy followed by IFN-α2b for positive biopsies, and empiric treatment with IFN-α2b. Probabilities were estimated from literature published between 1983 and 2015. Expected values for the probability of recurrence could range from 0 (no persistence/recurrence) to 1 (persistence/recurrence). Sensitivity analyses were performed for each variable., Results: Excision followed by IFN-α2b for positive margins was estimated to minimize persistence/recurrence of OSSN (expected value 0.13 versus 0.17 for empiric IFN-α2b, 0.22 for excision-only, and 0.30 for incisional biopsy-directed IFN-α2b). The optimal strategy was sensitive to 3 variables: efficacy of IFN-α2b, recurrence after negative surgical margins, and accuracy of excisional biopsy., Conclusions: In our decision analysis using studies published between 1983 and 2015, surgical excision followed by IFN-α2b for positive margins is the favored strategy for minimizing persistence/recurrence of OSSN. Future prospective studies would add to the certainty of these conclusions.

Importance: Protamine sulfate can be administered at the conclusion of carotid endarterectomy (CEA) to reverse the anticoagulant effects of heparin and to limit the risk for postoperative bleeding. Protamine use remains controversial owing to concern for increased thrombotic complications with its use., Objective: To review the evidence for and against protamine use, both in its association with increased thrombotic complications and with decreased bleeding., Data Sources: We searched Medline (1946-2014), EMBASE (1966-2014), Cochrane Library (1972-2014), clinical trial registries (World Health Organization International Clinical Trials Registry and clinicaltrials.gov), and abstracts from conferences of the Society of Vascular Surgery (2002-2014) and American Heart Association Scientific Sessions (1980-2014) in November 2014. No language restrictions were applied., Study Selection: We included clinical trials and observational studies comparing reversal of heparin with protamine sulfate vs no reversal in patients undergoing carotid revascularization and reporting stroke during hospitalization. Of 360 records screened, 12 studies (3%) of CEA were eligible for data pooling., Data Extraction and Synthesis: Two reviewers extracted data and assessed quality. Random-effects models were used to summarize relative risks (RRs)., Main Outcome and Measure: Stroke after CEA., Results: We included 12 observational studies involving 10,621 patients in the meta-analysis. Event rates did not differ significantly between patients who received protamine vs those who did not for the following outcomes: stroke (RR, 0.84; 95% CI, 0.55-1.29; I(2) = 15%; 9 studies), myocardial infarction (RR, 0.89; 95% CI, 0.53-1.51; I(2) = 0%; 3 studies), or mortality (RR, 0.9, 95% CI, 0.62-1.29; I(2) = 0%; 7 studies). The use of protamine was associated with a significant decrease in major bleeding complications requiring reoperation (RR, 0.57; 95% CI, 0.39-0.84; I(2) = 32%; 10 studies)., Conclusions and Relevance: Based on available evidence, the use of protamine following CEA is associated with a reduction in bleeding complications, without increasing major thrombotic outcomes, including stroke, myocardial infarction, or death.

Background: Providing simulation training directly before an actual clinical procedure-or 'just-in-time' (JiT)-is resource intensive, but could improve both provider performance and patient outcomes., Objectives: To assess the effects of JiT simulation training versus no JiT training on provider performance and patient complications following clinical procedures on patients., Study Selection: We searched MEDLINE, Cochrane Library, CINAHL, PsycINFO, ERIC, ClinicalTrials.gov, simulation journals indexes and references of included studies during October 2014 for randomised trials, non-randomised trials and before-after studies comparing JiT simulation training versus no JiT training among providers performing clinical procedures. Findings were synthesised qualitatively., Findings: Of 1805 records screened, 8 studies comprising 3540 procedures and 1969 providers were eligible. 5 involved surgical procedures; the other 3 included paediatric endotracheal intubations, central venous catheter dressing changes, or infant lumbar puncture. Methodological quality was high. Of the 8 studies evaluating provider performance, 5 favoured JiT simulation training with 18-48% relative improvement on validated clinical performance scales, 16-20% relative reduction in surgical time and 12% absolute reduction in corrective prompts during central venous catheter dressing changes; 3 studies were equivocal with no improvement in intubation success, lumbar puncture success or urological surgery clinical performance scores. 3 studies evaluated patient complications; 1 favoured JiT simulation training with 45% relative reduction in central line-associated blood stream infections; 2 studies found no differences following intubation or laparoscopic nephrectomy., Conclusions: JiT simulation training improves provider performance, but currently available literature does not demonstrate a reduction in patient complications., Competing Interests: Competing interests: AN discloses funded research from the Agency for Healthcare Research and Quality (AHRQ). AN and MA are authors on manuscripts included in this systematic review., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Hip fracture surgery and lower extremity arthroplasty are associated with increased risk of both venous thromboembolism and bleeding. The best pharmacologic strategy for reducing these opposing risks is uncertain., Purpose: To compare venous thromboembolism (VTE) and bleeding rates in adult patients receiving aspirin versus anticoagulants after major lower extremity orthopedic surgery., Data Sources: Medline, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library through June 2013; reference lists, ClinicalTrials.gov, and scientific meeting abstracts., Study Selection: Randomized trials comparing aspirin to anticoagulants for prevention of VTE following major lower extremity orthopedic surgery., Data Extraction: Two reviewers independently extracted data on rates of VTE, bleeding, and mortality., Data Synthesis: Of 298 studies screened, 8 trials including 1408 participants met inclusion criteria; all trials screened participants for deep venous thrombosis (DVT). Overall rates of DVT did not differ statistically between aspirin and anticoagulants (relative risk [RR]: 1.15 [95% confidence interval {CI}: 0.68-1.96]). Subgrouped by type of surgery, there was a nonsignificant trend favoring anticoagulation following hip fracture repair but not knee or hip arthroplasty (hip fracture RR: 1.60 [95% CI: 0.80-3.20], 2 trials; arthroplasty RR: 1.00 [95% CI: 0.49-2.05], 5 trials). The risk of bleeding was lower with aspirin than anticoagulants following hip fracture repair (RR: 0.32 [95% CI: 0.13-0.77], 2 trials), with a nonsignificant trend favoring aspirin after arthroplasty (RR: 0.63 [95% CI: 0.33-1.21], 5 trials). Rates of pulmonary embolism were too low to provide reliable estimates., Conclusion: Compared with anticoagulation, aspirin may be associated with higher risk of DVT following hip fracture repair, although bleeding rates were substantially lower. Aspirin was similarly effective after lower extremity arthroplasty and may be associated with lower bleeding risk. Journal of Hospital Medicine 2014;9:579-585. © 2014 Society of Hospital Medicine., (© 2014 Society of Hospital Medicine.)

Objective: Although cilostazol is commonly used as an adjunct after peripheral vascular interventions, its efficacy remains uncertain. We assessed the effect of cilostazol on outcomes after peripheral vascular interventions using meta-analytic techniques., Methods: We searched MEDLINE (1946-2012), Cochrane CENTRAL (1996-2012), and trial registries for studies comparing cilostazol in combination with antiplatelet therapy to antiplatelet therapy alone after peripheral vascular interventions. Treatment effects were reported as pooled risk/hazard ratio (HR) with random-effects models., Results: Two randomized trials and four retrospective cohorts involving 1522 patients met inclusion criteria. Across studies, mean age ranged from 65 to 76 years, and the majority of patients were male (64%-83%); mean follow-up ranged from 18 to 37 months. Most interventions were in the femoropopliteal segment, and overall, 68% of patients had stents placed. Pooled estimates demonstrated that the addition of cilostazol was associated with decreased restenosis (relative risk [RR], 0.71; 95% confidence interval [CI], 0.60-0.84; P < .001), improved amputation-free survival (HR, 0.63; 95% CI, 0.47-0.85; P = .002), improved limb salvage (HR, 0.42; 95% CI, 0.27-0.66; P < .001), and improved freedom from target lesion revascularization (RR, 1.36; 95% CI, 1.14-1.61; P < .001). There was no significant reduction in mortality among those receiving cilostazol (RR, 0.73; 95% CI, 0.45-1.19; P = .21)., Conclusions: The addition of cilostazol to antiplatelet therapy after peripheral vascular interventions is associated with a reduced risk of restenosis, amputation, and target lesion revascularization in our meta-analysis of six studies. Consideration of cilostazol as a medical adjunct after peripheral vascular interventions is warranted, presuming these findings are broadly generalizable., (Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: While patients' hypertensive problems are usually actively and effectively managed by their primary physician, the dermatologic surgeon can still be affected by hypertension where the condition is unrecognized or uncontrolled. Hypertension is an important contributor to both bleeding and hematoma formation during and after surgery, ultimately affecting functional and cosmetic outcomes., Objective: To extensively review the literature on perioperative management of the hypertensive patient as relates to the dermatologic surgeon., Materials and Methods: An updated and comprehensive literature review, focusing on current diagnostic guidelines, practice by specific dermatologic surgery groups and management recommendations, was conducted., Results: Review of the literature does support generalized guidelines for the management of hypertensive patients in the Mohs Micrographic Surgery (MMS) setting; however data on implementation and outcomes by specific dermatologic surgery groups is variable and lacking., Conclusions: The treatment of nonmelanoma skin cancers with MMS is now routine, and fortunately can be performed quite safely. There are still improvements to be made however, in managing perioperative hypertension-both in making patients aware of their condition and in treating it effectively. Practicing these measures can promote patients' overall health and the efficiency of the dermatologic surgeon's practice.

Background: Many oncologists reduce chemotherapy doses in obese patients due to fear of excess toxic effect from very large weight-based calculations. While recent guidelines advise against this practice, quantitative summarization of the supporting evidence is not available., Materials and Methods: We systematically identified studies that compared toxic effect or survival outcomes between obese and normal-weight adults receiving chemotherapy dosed by actual body weight (ABW). We pooled odds ratios (OR) and 95% confidence intervals (CI) using random-effects models., Results: Of 5490 records screened, 12 studies representing 9314 relevant patients met inclusion criteria. The large majority of reported toxic effect and survival outcomes did not statistically differ between obese and normal-weight subjects. Exceptions included five studies in which one or more toxic effect or survival outcomes statistically favored obese patients, and one study that statistically favored normal-weight patients. Pooling usable data, rates of toxic effects were similar or lower in obese patients (grade 3/4 hematologic toxic effect: OR 0.73, CI 0.55-0.98, 4 studies; grade 3/4 nonhematologic toxic effect: OR 0.98, CI 0.76-1.26, 3 subgroups; any grade 3/4 toxic effect: OR 0.75, CI 0.65-0.87, three studies)., Conclusions: Obese patients receiving chemotherapy based on ABW experience similar or lower rates of toxic effects compared with normal-weight patients, and survival outcomes do not differ.

Objective: Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack., Methods: A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30., Results: On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point., Conclusions: Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers., (Published by Elsevier Inc.)

Background: The use of computers to deliver education and support strategies has been shown to be effective in a variety of conditions. We conducted a systematic review and meta-analysis to evaluate the impact of computer-based technology on interventions for reducing weight., Methods: We searched MEDLINE, CENTRAL, CINAHL, PsycINFO, Google Scholar and ClinicalTrials.gov (all updated through June 2010) for randomized controlled trials evaluating the effect of computer-based technology on education or support interventions aimed at reducing weight in overweight or obese adults. We calculated weighted mean differences (WMD) and 95% confidence intervals (CI) using random effects models., Results: Eleven trials with 13 comparisons met inclusion criteria. Based on six comparisons, subjects who received a computer-based intervention as an addition to the standard intervention given to both groups lost significantly more weight (WMD -1.48 kg, 95% CI -2.52, -0.43). Conversely, based on six comparisons, subjects for whom computer-based technology was substituted to deliver an identical or highly comparable intervention to that of the control group lost significantly less weight (WMD 1.47 kg, 95% CI 0.13, 2.81). Significantly different weight loss seen in "addition" comparisons with less than six months of follow-up (WMD -1.95 kg, 95% CI -3.50, -0.40, two comparisons) was not seen in comparisons with longer follow-up (-1.08 kg, 95% CI -2.50, 0.34, four comparisons). Analyses based on quality and publication date did not substantially differ., Conclusions: While the addition of computer-based technology to weight loss interventions led to statistically greater weight loss, the magnitude (<1.5 kg) was small and unsustained.

Background: HIV-associated lipodystrophy syndrome (HALS) is characterized by insulin resistance, abnormal lipid metabolism and redistribution of body fat. To date, there has been no quantitative summary of the effects of insulin sensitizing-agents for the treatment of this challenging problem., Methods: We searched MEDLINE, the Cochrane Library, clinical trial registries, conference proceedings and references for randomized trials evaluating rosiglitazone, pioglitazone or metformin in patients with evidence of HALS (last update December 2009). Two reviewers independently abstracted data and assessed quality using a standard form. We contacted authors for missing data and calculated weighted mean differences (WMD) and 95% confidence intervals (CI) for each outcome., Results: Sixteen trials involving 920 patients met inclusion criteria. Rosiglitazone modestly improved fasting insulin (WMD -3.67 mU/L; CI -7.03, -0.31) but worsened triglycerides (WMD 32.5 mg/dL; CI 1.93, 63.1), LDL (WMD 11.33 mg/dL; CI 1.85, 20.82) and HDL (WMD -2.91 mg/dL; CI -4.56, -1.26) when compared to placebo or no treatment in seven trials. Conversely, pioglitazone had no impact on fasting insulin, triglycerides or LDL but improved HDL (WMD 7.60 mg/dL; CI 0.20, 15.0) when compared to placebo in two trials. Neither drug favorably impacted measures of fat redistribution. Based on six trials with placebo or no treatment controls, metformin reduced fasting insulin (WMD -8.94 mU/L; CI -13.0, -4.90), triglycerides (WMD -42.87 mg/dL; CI -73.3, -12.5), body mass index (WMD -0.70 kg/m2; CI -1.09, -0.31) and waist-to-hip ratio (WMD -0.02; CI -0.03, 0.00). Three trials directly compared metformin to rosiglitazone. While effects on insulin were comparable, lipid levels and measures of fat redistribution all favored metformin. Severe adverse events were uncommon in all 16 trials., Conclusion: Based on our meta-analysis, rosiglitazone should not be used in HALS. While pioglitazone may be safer, any benefits appear small. Metformin was the only insulin-sensitizer to demonstrate beneficial effects on all three components of HALS.

Background & Aims: Although anti-tumor necrosis factor (TNF) therapy can effectively treat Crohn's disease (CD), there is concern that it might increase the risk of non-Hodgkin's lymphoma (NHL). A meta-analysis was performed to determine the rate of NHL in adult CD patients who have received anti-TNF therapy and to compare this rate with that of a population-based registry and a population of CD patients treated with immunomodulators., Methods: MEDLINE, EMBASE, Cochrane Collaboration, and Web of Science were searched. Inclusion criteria included randomized controlled trials, cohort studies, or case series reporting on anti-TNF therapy in adult CD patients. Standardized incidence ratios (SIR) were calculated by comparing the pooled rate of NHL with the expected rate of NHL derived from the Surveillance Epidemiology & End Results (SEER) database and a meta-analysis of CD patients treated with immunomodulators., Results: Twenty-six studies involving 8905 patients and 21,178 patient-years of follow-up were included. Among anti-TNF treated subjects, 13 cases of NHL were reported (6.1 per 10,000 patient-years). The majority of these patients had previous immunomodulator exposure. Compared with the expected rate of NHL in the SEER database (1.9 per 10,000 patient-years), anti-TNF treated subjects had a significantly elevated risk (SIR, 3.23; 95% confidence interval, 1.5-6.9). When compared with the NHL rate in CD patients treated with immunomodulators alone (4 per 10,000 patient-years), the SIR was 1.7 (95% confidence interval, 0.5-7.1)., Conclusions: The use of anti-TNF agents with immunomodulators is associated with an increased risk of NHL in adult CD patients, but the absolute rate of these events remains low and should be weighed against the substantial benefits associated with treatment.

Background: The news media are often criticized for exaggerated coverage of weak science. Press releases, a source of information for many journalists, might be a source of those exaggerations., Objective: To characterize research press releases from academic medical centers., Design: Content analysis., Setting: Press releases from 10 medical centers at each extreme of U.S. News & World Report's rankings for medical research., Measurements: Press release quality., Results: Academic medical centers issued a mean of 49 press releases annually. Among 200 randomly selected releases analyzed in detail, 87 (44%) promoted animal or laboratory research, of which 64 (74%) explicitly claimed relevance to human health. Among 95 releases about primary human research, 22 (23%) omitted study size and 32 (34%) failed to quantify results. Among all 113 releases about human research, few (17%) promoted studies with the strongest designs (randomized trials or meta-analyses). Forty percent reported on the most limited human studies--those with uncontrolled interventions, small samples (<30 participants), surrogate primary outcomes, or unpublished data--yet 58% lacked the relevant cautions., Limitation: The effects of press release quality on media coverage were not directly assessed., Conclusion: Press releases from academic medical centers often promote research that has uncertain relevance to human health and do not provide key facts or acknowledge important limitations., Primary Funding Source: National Cancer Institute.

Objective: To compare intravitreal triamcinolone acetonide (IVTA) injection versus no treatment or sub-Tenon triamcinolone acetonide (STTA) injection in improving visual acuity (VA) of patients with refractory diabetic macular edema (DME; unresponsive to focal laser therapy)., Clinical Relevance: Diabetic macular edema is the leading cause of visual loss in diabetic retinopathy. Laser therapy has been the standard of care for patients with persistent or progressive disease. More recently, it has been suggested that IVTA injection may improve VA. METHODS AND LITERATURE REVIEWED: The following databases were searched: Medline (1950-September Week 2 2008), The Cochrane Library (Issue 3, 2008), and the TRIP Database (up to September 1, 2008), using no language or other limits. Randomized controlled trials were included that consisted of patients with refractory DME, those comparing IVTA injection with no treatment or STTA injection, those reporting VA outcomes, and those having a minimum follow-up of 3 months., Results: In the 4 randomized clinical trials comparing IVTA injection with placebo or no treatment, IVTA injection demonstrated greater improvement in VA at 3 months, but the benefit was no longer significant at 6 months. Those who received IVTA injection had significantly higher IOP at 3 months and at 6 months. In the 2 randomized clinical trials comparing IVTA injection with STTA injection, IVTA injection demonstrated greater improvement in VA at 3 months, but not at 6 months. Intravitreal triamcinolone acetonide injection demonstrated no difference in IOP at 3 months or at 6 months., Conclusions: Intravitreal triamcinolone acetonide injection is effective in improving VA in patients with refractory DME in the short-term, but the benefits do not seem to persist in the long-term., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Using data from a nationally representative survey, we evaluated the prevalence of multiple risk factors known to predict increased health care utilization and adverse health outcomes, comparing U.S. men who rely solely on the Veterans Affairs Health Administration (VA) for health care to men in the general population. Adjusting for age and race, men who only use the VA were significantly more likely to have multiple socioeconomic and lifestyle risk factors including current smoking. Their self-reported health status was more often fair or poor and they were more likely to report the presence of multiple chronic diseases ranging from arthritis to previous heart attack to poor mental health. Although the finding that VA-only users are at elevated health risk was anticipated, our study now provides nationally representative estimates of the magnitude of these differences and reinforces the importance of accounting for them when making VA to non-VA comparisons.

Pelagic dispersal of marine organisms provides abundant opportunity for gene flow and presumably inhibits population genetic divergence. However, ephemeral, fine-scale, temporal and spatial genetic heterogeneity is frequently observed in settled propagules of marine species that otherwise exhibit broad-scale genetic homogeneity. A large variance in reproductive success is one explanation for this phenomenon. Here, genetic analyses of 16 microsatellite loci are used to examine temporal patterns of variation in young-of-year kelp rockfish (Sebastes atrovirens) recruiting to nearshore habitat in Monterey Bay, California, USA. Population structure of adults from central California is also evaluated to determine if spatial structure exists and might potentially contribute to recruitment patterns. Genetic homogeneity was found among 414 young-of-year sampled throughout the entire 1998 recruitment season. No substantial adult population structure was found among seven populations spanning 800 km of coastline that includes the Point Conception marine biogeographic boundary. Comparison of young-of-year and adult samples revealed no genetic differentiation and no measurable reduction in genetic variation of offspring, indicating little variance in reproductive success and no reduction in effective population size for this year class. Simulation analyses determined that the data set was sufficiently powerful to detect both slight population structure among adults and a small reduction in effective number of breeders contributing to this year class. The findings of high gene flow and low genetic drift have important implications for fisheries management and conservation efforts.

Objective: To review the evidence evaluating perioperative intranasal mupirocin for the prevention of surgical-site infections according to type of surgical procedure., Design: Systematic review and meta-analysis of published clinical trials., Setting: Studies included were either randomized clinical trial or prospective trials at a single institution that measured outcomes both before and after an institution-wide intervention (before-after trial). In all studies, intervention and control groups differed only by the use of perioperative intranasal mupirocin in the intervention group., Patients: Patients undergoing general or nongeneral surgery (eg, cardiothoracic surgery, orthopedic surgery, and neurosurgery)., Main Outcome Measure: Risk of surgical-site infection following perioperative intranasal mupirocin versus usual care., Results: Three randomized and four before-after trials met the inclusion criteria. No reduction in surgical-site infection rate was seen in randomized general surgery trials (summary estimates: 8.4% in the mupirocin group and 8.1% in the control group; relative risk [RR], 1.04; 95% confidence interval [CI95], 0.81 to 1.33). In nongeneral surgery, the use of mupirocin was associated with a reduction in surgical-site infection in randomized trials (summary estimates: 6.0% in the mupirocin group and 7.6% in the control group; RR, 0.80; CI95, 0.58 to 1.10) and in before-after trials (summary estimates: 1.7% in the mupirocin group and 4.1% in the control group; RR, 0.40; CI95, 0.29 to 0.56)., Conclusions: Perioperative intranasal mupirocin appears to decrease the incidence of surgical-site infection when used as prophylaxis in nongeneral surgery. Given its low risk and low cost, use of perioperative intranasal mupirocin should be considered in these settings.

Celebrities often promote cancer screening by relating personal anecdotes about their own diagnosis or that of a loved one. We used data obtained from a random-digit dialing survey conducted in the United States from December 2001 through July 2002 to examine the extent to which adults of screening age without a history of cancer had seen or heard or been influenced by celebrity endorsements of screening mammography, prostate-specific antigen (PSA) testing, or sigmoidoscopy or colonoscopy. The survey response rate was 72% among those known to be eligible and 51% among potentially eligible people accounting for those who could not be contacted. A total of 360 women aged 40 years or older and 140 men aged 50 years or older participated in the survey. Most respondents reported they "had seen or heard a celebrity talk about" mammography (73% of women aged 40 years or older), PSA testing (63% of men aged 50 years or older), or sigmoidoscopy or colonoscopy (52% of adults aged 50 years or older). At least one-fourth of respondents who had seen or heard a celebrity endorsement said that the endorsement made them more likely to undergo mammography (25%), PSA testing (31%), or sigmoidoscopy or colonoscopy (37%).

Background: Many academic medical centers have increased their use of advertising to attract patients. While the content of direct-to-consumer pharmaceutical advertisements (ads) has been studied, to our knowledge, advertising by academic medical centers has not. We aimed to characterize advertising by the nation's top academic medical centers., Methods: We contacted all 17 medical centers named to the US News & World Report 2002 honor roll of "America's Best Hospitals" for a semistructured interview regarding their advertising practices. In addition, we obtained and systematically analyzed all non-research-related print ads placed by these institutions in their 5 most widely circulating local newspapers during 2002., Results: Of the 17 institutions, 16 reported advertising to attract patients; 1 stated, "We're just word of mouth." While all 17 centers confirmed the presence of an institutional review board process for approving advertising to attract research subjects, none reported a comparable process for advertising to attract patients. We identified 127 unique non-research-related print ads for the 17 institutions during 2002 (mean, 7.5; range, 0-39). Three ads promoted community events with institution sponsorship, 2 announced genuine public services, and 122 were aimed at attracting patients. Of the latter group, 36 ads (29.5%) promoted the medical center as a whole, while 65 (53.3%) promoted specific clinical departments and 21 (17.2%) promoted single therapeutic interventions or diagnostic tests. The most commonly used marketing strategies included appealing to emotions (61.5%), highlighting institution prestige (60.7%), mentioning a symptom or disease (53.3%), and promoting introductory lectures or special offers likely to lead to further business (47.5%). Of the 21 ads for single interventions, most were for unproved (38.1%) or cosmetic (28.6%) procedures. While more than half of these ads presented benefits, none quantified their positive claims and just 1 mentioned potential harms., Conclusions: Advertising to attract patients is common among top academic medical centers but is not subjected to the oversight standard for clinical research. Many of the ads seemed to place the interests of the medical center before the interests of the patients.

Background and Objective: Clinicians frequently face the decision of whether to continue aspirin when starting patients on warfarin. We performed a meta-analysis to characterize the tradeoffs involved in this common clinical dilemma., Data Sources: Multiple computerized databases (1966 to 2003), reference lists of relevant articles, conference proceedings, and queries of primary authors., Study Selection: Randomized trials comparing warfarin plus aspirin versus warfarin alone. Studies with target international normalized ratios (INRs) <2 were excluded., Data Extraction: Two reviewers independently extracted baseline data and major outcomes: rates of thromboembolism, hemorrhage, and all-cause mortality., Data Synthesis: Nine studies met the inclusion criteria. Of the five that enrolled patients with mechanical heart valves, four used the same target INR in both groups, while one used a reduced target INR for the warfarin plus aspirin group. Pooling the results of the first four studies demonstrated that combination of warfarin plus aspirin significantly decreased thromboembolic events (relative risk [RR], 0.33; 95% confidence interval [CI], 0.19 to 0.58), increased major bleeding (RR, 1.58; 95% CI, 1.02 to 2.44), and decreased all-cause mortality (RR, 0.43; 95% CI, 0.23 to 0.81) compared to warfarin alone. The one valve trial using a reduced INR in the warfarin plus aspirin group reported no difference in thromboembolic outcomes but found decreased major bleeding and a significant mortality benefit with combination therapy. Of the remaining trials, three evaluated a warfarin indication not routinely used in the United States (post-myocardial infarction), and the only trial that considered atrial fibrillation was terminated early due to inadequate enrollment., Conclusions: For mechanical heart valve patients, the benefits of continuing aspirin when starting warfarin therapy are clear. For other routine warfarin indications, there are not adequate data to guide this common clinical decision.

Dodecylbenzene sulfonate (DBS) is a component of linear alkylbenzene sulfonate (LAS), an anionic surfactant, mainly used in household detergents. Due to the large quantity of DBS in use, there is concern over adverse environmental effects. This work examined the toxicokinetics and toxicity of the 2-phenyl isomer of dodecylbenzene sulfonate in 4-d, 10-d, and partial life-cycle tests on the midge, Chironomus riparius, exposed to aqueous solutions. Toxicokinetics were determined in 10-d uptake and 5-d elimination tests. The toxicokinetics were based on parent compound concentration in water and yielded an uptake coefficient (ku) of 17.5 (14.87-20.20) ml/g/h, an elimination rate constant (ke) of 0.073 (0.062-0.085) per h, a bioconcentration factor (BCF) of 56 to 240, and a half-life (t 1/2) of 9.5 (8.0-11.0) h. Biotransformation measurements did not reveal evidence for DBS metabolism. Thus, body residues, determined in the toxicity study, represent parent compound. In toxicity tests, 4- and 10-d LR50s (the body residue required to cause 50% mortality) in live midges were 0.72 (0.65-0.79) and 0.18 (0.08-0.42) mmol/kg, respectively. Thirty-day LR50s were 0.18 (0.09-1.64) and 0.21 (0.15-0.39) mmol/kg in duplicate studies. Of the sublethal endpoints, only developmental time increase was significant, with the lowest-observed-effect residues of 0.085 (0.067-0.105) and 0.100 (0.087-0.114) mmol/kg for male and female midges, respectively. Deformities in surviving larvae were also observed as chronic responses for body residues exceeding the 30-d LR50. The body residues required for mortality suggest that DBS acts like a polar narcotic in the midge.

The location and activity of esterase enzymes in activated sludge from three municipal wastewater treatment plants were characterized using model substrates and denaturing and non-denaturing polyacrylamide gel electrophoresis (PAGE) of particulate, freeze-thaw (primarily periplasmic enzymes and those associated with outer cell surfaces) and extracellular fractions of activated sludge bacteria. Particulate and freeze-thaw fractions had a similar spectrum of substrate specificity and contained significant levels of protein and esterase activity against model substrates, C2-C18 monoesters of p-nitrophenol and C2-C8 diesters of fluorescein. Esterase activity was highest with substrates that had short alkyl chains (C4) and decreased as the chain lengths increased beyond C8. Extracellular fractions contained very low levels of protein (<0.1 mg/l) and showed no esterase activity against any of the model substrates tested. Multiple bands were observed upon analysis of particulate and freeze-thaw fractions by non-denaturing PAGE in combination with activity staining using various alpha-naphthol ester substrates (C2-C8). Our results indicate that esterase enzymes in activated sludge are fairly diverse from a structural standpoint but exhibit a high level of functional redundancy, with different enzymes catalyzing the same reactions in different sludges. Extracellular esterase activity was totally absent for the substrates we tested and the esterase activity that we observed was closely linked to a particulate floc or cellular material.

Various methods used to assess the biodegradability of chemicals often employ activated sludge as an inoculum since chemicals that ultimately enter the environment are often discharged through wastewater. Differences in the structure and function of activated sludge microbial communities that may complicate interpretation of biodegradation tests could arise from differences in wastewater composition, wastewater treatment plant (WWTP) operation, or manipulations done after collection of the activated sludge. In this study, various methods were used to characterize the structure of microbial communities found in freshly collected activated sludge from WWTPs in Japan, Europe, and the United States, as well as sludge that had been continuously fed either sewage or a glucose-peptone mixture for several weeks after collection. Comparisons of biomass levels, whole-community substrate utilization (determined using Biolog GN and GP plates), and phospholipid fatty acid (PLFA) profiles indicated there were both geographical and temporal differences among freshly collected activated sludge samples. Moreover, marked shifts in the structure of activated sludge microbial communities occurred upon continuous cultivation in the laboratory for 5 weeks using a glucose-peptone feed. These shifts were evident from whole-community substrate utilization and PLFA profiles as well as differences in the profiles of 16S rDNA genes from numerically dominant populations obtained by denaturing gradient gel electrophoresis and terminal restriction fragment analyses. Further studies are needed to better define the variability within and between activated sludge from wastewater treatment plants and laboratory reactors and to assess the impact of such differences on the outcome of biodegradability tests., (Copyright 2001 Academic Press.)

A batch method was developed and validated for determining the sorption coefficient (Kd) of biodegradable organic compounds to activated sludge solids using a nonspecific analytical technique, total organic carbon (TOC) analysis. In this method, activated sludge solids were first inactivated by lyophilization and dry heat (103 degrees C) and then washed to remove any dissolved organic carbon released during the inactivation procedure. The inactivated sludge solids were exposed to a range of concentrations of different test compounds in synthetic wastewater until equilibrium was achieved (< 2 h). The amount of test compound sorbed to the solids was then determined by measuring TOC levels in centrifuged supernatants. Results revealed that the sorption coefficients (Kd values) for four detergent chemicals in inactivated sludge solids using TOC analysis were in good agreement with values determined in fresh activated sludge using radiolabeled materials. These Kd values are suitable for use in estimating environmental exposure concentrations and for developing screening-level models to assess the removal of organic compounds by sorption and settling during activated sludge wastewater treatment.

The cerebellar Purkinje cell-specific PCP-2 gene is transcriptionally activated by thyroid hormone during the 2nd and 3rd weeks of postnatal life in the rat. In contrast, thyroid hormone has no detectable effects on PCP-2 expression in the fetal rat. We now present data that suggest that the orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) represses triiodothyronine (T3)-dependent transcriptional activation of PCP-2 in the immature Purkinje cell. Gel shift assays show that the PCP-2 A1TRE and adjoining sequences (-295/-199 region) bind to rat and mouse brain nucleoproteins in a developmentally regulated fashion and that one of these nucleoproteins could be the orphan nucleoprotein COUP-TF. In support of this hypothesis, in vitro translated COUP-TF binds to the -295/-199 region and COUP-TF represses T3-dependent activation of the PCP-2 promoter in transient transfection analyses. Finally, immunohistochemical studies reveal that COUP-TF is specifically expressed in the immature fetal and early neonatal Purkinje cell and that this expression diminishes coincident with thyroid hormone induction of PCP-2 expression. Our findings are consistent with the hypothesis that the presence or absence of inhibitory proteins bound to the thyroid hormone response element of T3-responsive genes governs the responsivity of these genes to thyroid hormone during brain development.

Various mathematical relationships have been used to assess exposure concentrations of organic chemicals when emissions occur via wastewater treatment. These relationships range from a simple removal factor calculation to more sophisticated approaches using kinetic based mathematical models. While these existing approaches have been used by decision makers to screen new chemicals for exposure assessments, they all have limitations in the predictive capabilities. Thus, a simplified modeling approach grounded in sound scientific fundamentals that utilizes relatively easy to obtain input parameters is needed. In this paper a simplified modeling approach that utilizes microbial growth kinetics was developed for predicting effluent concentrations in secondary biological wastewater treatment systems. Receiving water predicted exposure concentrations (PEC) are assessed by using a dilution factor. One advantage of this approach is that it allows for wastewater treatment plant effluent concentrations, and therefore receiving water exposure levels, to be predicted with a minimum amount of experimental data. It also provides quantitative data that can be used to assess the relative biodegradability of different chemicals for use in regulatory and risk assessment activities.

Previous studies in our laboratory show that triiodothyronine upregulates expression of the cerebellar Purkinje cell-specific gene Pcp-2 during the first 2 weeks of rat neonatal life. A specific thyroid hormone response element, the A1 TRE, mediates this regulation. The finding that the contiguous 68 bases (-267/ -199) of the Pcp-2 promoter 3' to the A1 TRE repressed T3 response in transactivation studies suggested that this sequence could play a role in preventing premature T3-dependent activation of Pcp-2 in the fetus. We now show that deletion of this region resulted in enhanced T3-dependent activation of the native Pcp-2 promoter. The sequence is not a generalized silencer since it does not alter basal activity of mouse mammary tumor virus (MMTV) or thymidine kinase (TK) promoters. Deletion and linker scanning studies indicate that the 5' 30 bases of the -267/ -199 region mediate most of the response silencing activity. The -267/ -199 region also attenuates T3-induced transactivation mediated by other TREs. Gel shift analysis reveals that nuclear proteins from fetal but not adult brains complex with the -267/ -199 region, supporting the hypothesis that this region binds proteins that suppress Pcp-2 expression early in brain development.

An in-depth biodegradation test program was executed on the hexadentate ligand Ethylene Diamine Di Succinate (EDDS). The EDDS structure contains two chiral carbon atoms, and has three stereoisomers ([R,R], [R,S]/[S,R], [S,S]). Our research has focused on the isomer mixture (i.e. 25%[S,S]; 25%[R,R]; 50%[S,R]/[R,S], as produced from the reaction of ethylene diamine with maleic anhydride) and on the single [S,S]- and [R,R]-isomers. Biodegradation screening of the 14C-labelled EDDS isomer mixture in a Batch Activated Sludge (BAS) test with various inocula revealed incomplete mineralization, up to ca. 65% after 28 days. N-(2-aminoethyl) aspartic acid (AEAA), probably the d-isomer, was identified as the major portion of the 14C-material remaining in solution. Further testing revealed that the [S,S]-isomer is rapidly and completely mineralized in all test systems. By contrast, [R,R]-EDDS remained undegraded in a Sturm (OECD 301B) test, but was very slowly biotransformed into the recalcitrant metabolite AEAA in a BAS test. The [S,R]/[R,S] form undergoes biotransformation to AEAA in both high and low biomass systems. In a sewage treatment simulation test (OECD 303) the steady state DOC removal of mixture-EDDS in a CAS test was limited to 25-35%, even after extensive pre-acclimation, while the [S,S]-isomer achieved nearly complete removal (96%). This study illustrates the importance stereospecificity may have on the biodegradation and metabolite formation of a chemical. A biodegradation scheme for the different EDDS stereoisomers is proposed.

Two thyroid hormone response elements (TREs), designated A1 TRE (-295/-268) and B1 TRE (+207/+227), have been identified within the Purkinje cell-expressed Pcp-2 gene. Previous studies have characterized the A1 TRE (Zou et al., 1994). This article analyzes the structural and functional characteristics of the intronic B1 TRE. The B1 sequence contains four overlapping TRE half-sites. The 3' DR4 motif, consisting of the second and forth half-sites, is responsible for the T3 induction observed with the B1 sequence. Gel-shift analysis reveals developmentally regulated complexes that are abundant in the fetus and at birth and then fall precipitously in the neonate bind to B1. The observed time-course of these complexes varies inversely with the rise in Pcp-2 expression, thus raising the possibility that the complexes may represent inhibitory factors. Supershift analysis indicates that endogenous TR alpha 1 is present in the fetal nuclear protein complexes that bind to B1. Competition analysis also indicates the second B1 TRE half-site is important in binding the TR alpha 1-TRAP complexes. These studies suggest that the B1 sequence may bind potential TR alpha 1-TRAP repressor complexes in the fetus, whereas in the neonate, these TRE sites may be involved in the activation of Pcp-2 by binding other TR-TRAP-activating complexes.

The kinetics and efficiency of carbon dioxide recovery in modern versions of the Sturm Ready Biodegradation Test were examined to determine the ability of CO2 evolution measurements to accurately estimate the rate and extent of ultimate biodegradation (mineralization). Kinetic data were analyzed by nonlinear regression techniques using an automated curve-fitting package available from commercial sources. The kinetics of CO2 recovery in standard 3.8 L glass carboys containing 2 L of medium were rapid when headspace aeration (approximately 6 ml/min) and moderate agitation (140 rev/min) on a rotary platform shaker were used to ensure adequate aeration and mixing. The time (half-life) for 50% CO2 recovery in external base traps was 4-5 hours, and stoichiometric recoveries of CO2 equivalents added as bicarbonate were obtained within 24 hours. The kinetics of CO2 evolution during biodegradation of several test compounds were significantly slower than the kinetics of CO2 recovery, with half-lives between 65 and 191 hours. Our results indicate that mass transfer limitations do not impact CO2 recoveries or biodegradation kinetic measurements in modern versions of the Sturm Test, even in test vessels with relatively low surface area to volume ratios (1:1). The use of headspace aeration and mixing generates reliable kinetic data, which can be analyzed by commercially-available nonlinear regression packages to provide rate information for the classification of chemicals with different biodegradation profiles.

A two-step procedure is described to characterize the removal and biodegradation potential of nonvolatile 14C-labeled organic compounds in activated sludge. In the first step, trace concentrations of radiolabeled test materials are dosed in influent wastewater to continuous-flow activated sludge (CAS) systems which have been previously exposed or acclimated to unlabeled test material. Radiolabel is quantified in influent, effluent, and activated sludge mixed liquor to determine total 14C removal and partitioning of radiolabel in solid and liquid compartments. The 14C data are used to calculate the amount of removal due to sorption and biodegradation and to estimate the apparent sorption coefficients for 14C activity to activated sludge solids. The 14C-labeled CAS studies are followed by biodegradation studies in batch-activated sludge (BAS) systems using sludge derived from the CAS system. The kinetics of biodegradation (defined as mineralization to 14CO2) are measured in the BAS system to confirm the CAS biodegradation results and generate mineralization rate constants for kinetic modeling. The two-step procedure was applied to radiolabeled anionic (linear alkylbenzene sulfonate) and cationic (dodecyltrimethylammonium chloride, distearyldimethylammonium chloride) surfactants which differed greatly in their biodegradation and sorption profiles. Laboratory removal figures for these materials were comparable to values measured in full-scale wastewater treatment systems, although the amount of removal due to sorption and biodegradation varied significantly for the different surfactants. In general, the 14C method has several advantages over standard methods used in the United States and Europe which employ unlabeled materials. These advantages include the use of realistic concentrations and test conditions for acclimating and dosing activated sludge microorganisms and the ability to generate partitioning and kinetic constants that can be used more broadly in environmental fate and exposure models.