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Crude oil toxicity to early life stage fish is commonly attributed to polycyclic aromatic hydrocarbons (PAHs). However, it remains unclear how the polar unresolved complex mixture (UCM), which constitutes the bulk of the water-soluble fraction of crude oil, contributes to crude oil toxicity. Additionally, the role of photomodification-induced toxicity in relation to the polar UCM is not well understood. This study addresses these knowledge gaps by assessing the toxicity of two laboratory generated polar UCMs from Cook Inlet crude oil, representing the readily water-soluble fraction of crude oil and photoproduced hydrocarbon oxidation products (HOPs), to Pacific herring (Clupea pallasii) embryos. A small-scale semi-static exposure design was utilized with a range of polar UCM concentrations (0.5-14 mg/L) in nonvolatile dissolved organic carbon (NVDOC) units, quantifying the entire polar UCM. Compositional analyses revealed a photochemical-driven shift toward more complex aromatic compositions, naphthenic acids, and no detectable levels of PAHs (above 0.3 μg/L). Exposure to the dark polar UCM resulted in higher mortality than exposure to the light polar UCM. Both dark and light polar UCMs induced developmental abnormalities commonly attributed to the PAH fraction, including edema, reduced heart rate, body axis defects, and decreased body lengths, with these effects observed at the lowest dose group (0.5 mg/L NVDOC). These responses suggest photomodification-induced toxicity is driven by exposure to increased concentrations of dissolved HOPs rather than photochemical induced compositional changes. Gene expression analyses focusing on xenobiotic metabolism and cardiac morphogenesis yielded results consistent with previous studies examining the biological mechanisms of crude oil toxicity. In summary, these phenotypic and genotypic responses in Pacific herring embryos indicate that the polar UCM is a significant driver of crude oil toxicity. These findings emphasize the importance of considering the polar UCM in future studies, metric reporting, and risk assessments related to crude oil toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The relative apportion of above and below ground carbon sources is known to be an important factor in soil organic matter formation. Although lignin is the most abundant aromatic plant material in the terrestrial biosphere, our understanding of lignin source contributions to soil organic matter (SOM) is limited due to the complex molecular structure and analysis of lignin. In this study, we novelly apply the dual isotopic analysis (δ 13 C and δ 2 H values) of lignin methoxy groups (LMeO) with the Bayesian mixing model, MixSIAR, to apportion lignin sources in two contrasting soil types, a podzol and a stagnosol. Results of the isotopic analysis of LMeO demonstrate the ability of δ 2 H LMeO values to discriminate between above and below ground lignin sources, while δ 13 C LMeO values discriminated between photosynthesising and non-photosynthesising tissues. In the stagnosol subsurface horizons, a decreasing proportion of the leaf litter lignin was observed with increasing organic matter degradation, cumulating in the Ah horizon being dominated by lignin from roots. The podzol sites indicated a similar reduction in leaf litter lignin with an increase in organic matter degradation and depth. However, the Ah horizon was shown to accumulate lignin from the above ground woody material. Furthermore, given the significant abundance of LMeO groups in the terrestrial biosphere and the extremely depleted δ 13 C LMeO values in leaf litter, we employed a mass balance approach to determine the extent in which the 13 C bulk enrichment generally associated with isotopic fractionation during organic matter decomposition can be attributed to the shift in lignin sources. Analysis reveals that 14 % and 11 % of bulk 13 C enrichment can be attributed to the transition in LMeO sources from leaf litter to roots in the stagnosol and podzol, respectively. Thus, models relying on 13 C enrichment with depth as an indicator of carbon turnover may be partially overestimating rates., Competing Interests: Declaration of competing interest The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Several of the authors have worked over a number of years for various sponsors on PFAS issues as shown in part below. However, no outside funding was accepted to do this work by the Alliance for Risk Assessment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The transition to adulthood has become increasingly uncertain and variable. Among South Koreans, this transition has become more de-standardized since 1990, reflecting the effects of long-term economic stagnation and persistent, traditional gender norms, but little is known about the variability in pathways to adulthood among recent cohorts. This study employs sequence analysis to examine early life course trajectories between the ages of 19 and 35 and assess gender and cohort differences for South Koreans born between 1970 and 1985 (N = 8647), using the Korean Labor and Income Panel Study (KLIPS, Wave 1-23). The main results show that pathways into adulthood have become more varied in the current socioeconomic and cultural contexts in South Korea, particularly for women compared to men. At the same time, new gender-specific pathways into adulthood have appeared, while the traditional, distinctly gendered breadwinner-homemaker trajectory has declined., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Musculoskeletal pain is a common reason to seek outpatient physical therapy care. Generational differences regarding attitudes and beliefs have been found in many areas, but it has not been explored regarding pain., Objectives: This study aimed to examine generational differences in attitudes and beliefs regarding pain and the potential differences between beneficial and non-beneficial treatment options in patients receiving care in outpatient physical therapy clinics., Design: Cross-sectional descriptive survey., Method: A survey was developed to explore attitudes, beliefs, and treatment preferences. The survey was emailed out to past and current physical therapy patients as part of the customer satisfaction survey over a four-month period., Results/findings: 2260 surveys were completed during the collection period. Generational differences were found between the different generational groups. Younger generations were more in line with current pain neuroscience, understanding that pain is normal and part of the survival mechanism and less likely to believe that pain meant something wrong with one's tissues. Younger generations also reported more agreeance to the ability to cope without medication. However, significant variations existed in treatment choices that were most beneficial and least beneficial between respondents., Conclusion: Generational differences do exist in some areas of pain attitudes and beliefs. Less variation was noted in treatment options between generations, but there were significant variations within all patient respondents., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant., Methods: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137., Findings: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages., Interpretation: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2., Funding: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca., Competing Interests: Declaration of interests Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the data from the study and the final manuscript before submission but the authors retained editorial control. SCG is cofounder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is chair of the UK Department of Health and Social Care Joint Committee on Vaccination and Immunisation but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts. AJP and SNF are NIHR senior investigators. AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467). MDS reports grants from Janssen, GlaxoSmithKline, Medimmune, Novavax, and MCM Vaccine, and grants and non-financial support from Pfizer outside of the submitted work. CMG reports personal fees from the Duke Human Vaccine Institute outside of the submitted work. ADD reports grants and personal fees from AstraZeneca outside of the submitted work. SNF reports grants from Janssen and Valneva outside of the submitted work. TLV and JV are employees of AstraZeneca. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Aboriginal people and Torres Strait Islanders are impacted by dementia at higher rates and at a younger age of onset than the broader Australia population. Public health strategies to support this population require a thorough understanding of how Aboriginal people perceive dementia and dementia care support needs. The aim of this study was to investigate Aboriginal community understandings of dementia and their responses to dementia care., Study Design: This study is a community participatory action research partnership., Methods: The mixed method study was undertaken in 2017 with members of a discrete Aboriginal community from rural Tasmania, Australia. Participants were older than 18 years, self-identified as an Aboriginal person and were living or had lived in the community studied. Data were derived from 50 participants who completed the 27-item Dementia Knowledge Assessment Scale (DKAS). Twelve of these participants also shared their dementia care experiences in individual interviews., Results: The DKAS results showed a low overall level of dementia knowledge, with a total mean score of 27.73 (scoring 51% on average) of a possible score of 54. The salient interview theme was the cultural obligation to care for family members living with dementia. Dementia care metaphors represented ways to protect family members living with dementia and maintain their ongoing connections to home and community. However, limited understandings of dementia affected their capacity to provide quality care., Conclusion: The findings contribute to public health scholarship involving Aboriginal community responses to dementia care. The study has resulted in important initiatives including a community-based dementia education program to ensure Aboriginal people impacted by dementia are provided with effective and culturally appropriate care., (Copyright © 2019 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Adenoma detection rate (ADR) is the most important quality indicator for screening colonoscopy, due to its association with colorectal cancer outcomes. As a result, a number of techniques and technologies have been proposed that have the potential to improve ADR. The aim of this study was to assess the potential impact of new-generation high-definition (HD) colonoscopy on ADR within the Bowel Cancer Screening Programme (BCSP)., Method: This was a retrospective single-center observational study in patients undergoing an index screening colonoscopy. The examination was performed with either standard-definition colonoscopes (Olympus Q240/Q260 series) or HD colonoscopes (Olympus HQ290 EVIS LUCERA ELITE system) with the primary outcome measures of ADR and mean adenoma per procedure (MAP) between the 2 groups., Results: A total of 395 patients (60.5% male, mean age 66.8 years) underwent screening colonoscopy with 45% performed with HD colonoscopes. The cecal intubation rate was 97.5% on an intention-to-treat basis and ADR was 68.6%. ADR with standard-definition was 63.13%, compared with 75.71% with HD (P = .007). The MAP in the HD group was 2.1 (± 2.0), whereas in the standard-definition group it was 1.6 (± 1.8) (P = .01). There was no significant difference in withdrawal time between the 2 groups. In the multivariate regression model, only HD scopes (P = .03) and male sex (P = .04) independently influenced ADR., Conclusion: Olympus H290 LUCERA ELITE HD colonoscopes improved adenoma detection within the moderate-risk population. A 12% improvement in ADR might be expected to increase significantly the protection afforded by colonoscopy against subsequent colorectal cancer mortality., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case–control sets: 1) samples from patients diagnosed with pancreatic cancer (n = 40), chronic pancreatitis (n = 20), benign jaundice due to gall stones (n = 20) and healthy subjects (n = 20); 2) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0–12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0–12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers., Biological Significance: Pancreatic cancer is usually diagnosed when at an advanced stage which greatly limits therapeutic options. Biomarkers that could facilitate earlier diagnosis are urgently sought.

A previous randomized clinical trial compared immobilization for 15 min with immediate mobilization subsequent to intrauterine insemination (IUI) and showed higher ongoing pregnancy rates in couples immobilizing subsequent to IUI. The current study compared the long-term effectiveness of immobilization subsequent to IUI. All couples (n = 391) included in the trial were followed for 3 years after randomization and pregnancies and treatments were recorded. After the initial trial period, couples in both groups were offered treatment according to local protocol. The primary outcome was an ongoing pregnancy during the 3 years after the initial trial. In this time period, there were 143 ongoing pregnancies in the immobilization group (n = 199 couples) and 112 ongoing pregnancies in the immediate mobilization group (n = 192). The ongoing pregnancy rates were 72% and 58%, respectively (relative risk 1.2, 95% CI 1.1-1.4). The persistent significant difference in ongoing pregnancy rates underpins the importance of immobilization after IUI. There is no valid reason to withhold women from immobilizing for 15 min after IUI., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Nitrogen (N) enrichment of tropical reefs can result in the dominance of invasive algae. The invasive alga Acanthophora spicifera and the native alga Laurencia nidifica are part of a diverse reef assemblage in 'Ewa Beach, O'ahu. Their N contents and δ(15)N values were investigated to determine if N was enriched and to evaluate potential nitrogenous sources near and removed from storm-drain outlets. δ(15)N values of algae (3.8-17.7‰) were within and above the range for algae around the island (1.9-11.9‰). Elevated algae N isotope values (δ(15)N>+7‰, [N]>1.6%) and seawater nitrate+nitrite levels (0.59-7.93 μM) indicated a mixed, high nutrient environment. The overlap in δ(15)N values with multiple nitrogenous sources precluded identification. However, spatial and temporal patterns did not support stormwater as the dominant, nitrogenous source. Patterns were congruent with algal incorporation of terrestrial derived N, subjected to a high degree of biogeochemical cycling., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Storm-water drainage systems have potential to collect and focus nutrient enriched runoff into coastal systems. Storm-drain effluent could support macroalgal production and result in altered communities. To test this hypothesis, we assessed species composition and percent cover of native and non-native benthic macroalgae at eight intertidal sites along 'Ewa Beach, Hawai'i. Three sites contain storm-drainage outlets (drain 16-52 acres) that deliver effluent into the intertidal zone whereas five sites were located ≥ 100 m away and served as comparisons to determine differences related to the presence of storm-water. Results revealed lush and diverse macroalgal assemblages, similar at all sites. Furthermore, the abundance of non-native species (Acanthophora spicifera, Hypnea musciformis) was not related to presence of storm-drains. The finding that macroalgal assemblages are not related to storm-waters is contrary to an earlier investigation in the same location and underscores the importance of sampling design and habitat variation when assessing impacts., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Endoscopic screening and surveillance of cirrhotic patients for oesophageal varices is advocated before initiation of prophylactic therapy for prevention of the first variceal haemorrhage., Aims: To compare the diagnostic yield of oesophageal capsule endoscopy (ECE) with Esophagogastroduodenoscopy (EGD) for detecting and grading oesophageal varices and to determine patient tolerance for each procedure., Patients: Twenty consecutive cirrhotic patients scheduled for EGD were enrolled in the study., Methods: Patients underwent ECE followed by EGD. Patients completed a visual analogue scale after each procedure, assessing level of anxiety, pain, overall satisfaction, and willingness to repeat each procedure., Results: On EGD, 19/20 patients had oesophageal varices. ECE detected varices in 13/19 (68% sensitivity). ECE identified nine out of ten varices rated grade II or higher on EGD. The post-study analogue scale showed a greater level of anxiety before EGD (avg. 2.75/10) versus ECE (avg. 1.5/10)., Conclusions: ECE may be used in the assessment of EV. It appears to have more discordance with EGD when evaluating smaller varices. The minimal discomfort, lack of sedation, and decreased risk make ECE a possible substitute to EGD in patients unable or unwilling to undergo EGD.

Objectives: To determine the enamel abrasivity of three whitening toothpastes and a silica toothpaste and to measure the brushing forces used., Methods: Polished human enamel blocks were indented with a Knoop diamond and attached to dentures of adult volunteers. The blocks were brushed ex vivo, twice per day with either a whitening toothpaste containing Perlite (White System), a commercial whitening toothpaste (A and B) or a silica toothpaste. After four and twelve-weeks, one block per subject was removed and the Knoop indent remeasured. From the changes in the indent length, the amount of enamel wear was calculated., Results: The mean enamel wear (sd) for White System, silica toothpaste, whitening toothpaste A and B after four-weeks was 0.14 (0.15), 0.09 (0.16), 0.14 (0.12) and 0.89 (0.93) and after twelve-weeks was 0.24 (0.21), 0.37 (0.73), 0.36 (0.52) and 1.04 (0.98) microm respectively. After four-weeks, the differences in enamel wear between whitening toothpaste B and all other toothpastes were of statistical significance (p < 0.003), but not after twelve-weeks. The mean ex vivo normal brushing force (sd) was 2.67 (1.33) N., Conclusions: All three whitening toothpastes did not give significantly more enamel wear than a silica toothpaste after twelve-weeks in situ with ex vivo brushing.

Objectives: To determine the rates of enamel and dentine wear in situ during tooth brushing with a range of five toothpastes of differing RDA and REA values., Methods: Enamel/dentine inserts were placed in the buccal aspects of full upper dentures of human volunteers. Enamel wear was determined by change in Knoop indent length and dentine wear was determined from the enamel-dentine step height, measured using optical profilometry., Results: Significant differences between the test products were found for both enamel and dentine (p < 0.05). However for the conventional toothpastes the rate of wear was similar and differences between the products were not generally statistically significant for either enamel or dentine, despite the fact that their RDA values differed by more than a factor of two. The rate of wear was found to decrease throughout the duration of the study., Conclusions: The study demonstrated that the methodology used is capable of assessing enamel and dentine wear in situ within a relatively short period of time. The data suggest that whilst in vitro tests have value in understanding differences in abrasivity between products, they cannot be used to predict in vivo effects.

Objectives: To determine the enamel and dentine wear of two whitening toothpastes using an in situ model with ex vivo brushing., Methods: Human enamel/dentine (approximately 50:50) blocks (approximately 4 x 4mm) were placed in the upper buccal aspects of full or partial dentures of a group of 25 subjects. Subjects brushed the specimens ex vivo with either a calcium carbonate/perlite or silica containing whitening toothpaste under exaggerated conditions as compared to normal for 30 s, twice per day. Specimens were removed after 4, 8 and 12 weeks and the wear to the enamel and dentine was determined. Enamel wear was determined by change in Knoop indent length and dentine wear was determined from the enamel-dentine step height, measured using optical profilometry., Results: The mean wear after 12 weeks was for enamel 0.27 and 0.19 microns, and for dentine 34.3 and 61.1 microns, for the calcium carbonate/perlite and silica toothpastes respectively. There were no significant differences between products after 12 weeks. The rate of wear was found to decrease throughout the duration of the study., Conclusion: There were no significant differences between the two whitening toothpastes in terms of enamel and dentine wear after 12 weeks brushing.

Objective: The current study was designed to determine the effect of natural calcium carbonate toothpaste containing Perlite and microgranules (Whitening toothpaste) on extrinsic tooth stain compared to a standard commercial toothpaste formulation with precipitated calcium carbonate (PCC) as abrasive and a commercial toothpaste with dicalcium phosphate dihydrate (DCPD) as abrasive., Methods: The toothpastes were evaluated in a double blind, three-cell, stratified (tobacco use; baseline tooth stain level), parallel group design study involving 600 subjects with extrinsic tooth stain. Subjects brushed twice daily with their allocated toothpaste for four weeks. Extrinsic tooth stain was measured using the Macpherson modification of the Lobene stain index., Results: ANCOVA showed significant differences between toothpastes (p=0.037). Subsequent multiple comparisons using pairwise t-tests, showed the Whitening toothpaste to be superior to the DCPD toothpaste (p=0.014) and the PCC toothpaste (p=0.067). When a Box-Cox transformation was made to the data (y0.6) to improve normality, these two differences were more accurately estimated at p=0.004 and p=0.03 respectively., Conclusion: The Whitening toothpaste has been shown to be significantly more effective in tooth stain removal than the two standard commercial toothpaste formulations.

Objectives: A) To assess plaque lactate production following consumption of three foods (cake, chocolate/caramel bar, sweetened coffee), and B) To measure the effect of a fluoride dentifrice containing 2% zinc citrate and 0.3% Triclosan on plaque lactate and pH drop following consumption of cake., Methods: A) 10 subjects completed the first study. Plaque samples taken before and at 8,15 and 30 minutes after eating. Samples were analysed for lactate via Capillary Electrophoresis. B) 30 subjects completed the second study. Plaque samples were taken before and after cake and use of test dentifrice or no treatment control. Plaque pH and lactate content were assessed., Results: A) Plaque lactate levels increased after all three foods; peak lactate levels occurred 8 minutes after eating. B) Plaque lactate concentrations after eating cake were 39.2mM for the control treatment and a significantly lower value, 23.6mM, for the test 2% zinc citrate, 0.3% Triclosan dentifrice. After food challenge, pH values were 5.53 for the no treatment group and a significantly higher value of 5.79 for the test dentifrice group., Conclusions: A toothpaste containing 2% zinc citrate, 0.3% Triclosan can significantly reduce plaque lactate generation and pH drop induced by cake, compared to no treatment control.

Objective: To compare the antimicrobial efficacy and effect on plaque growth of a new silica-based fluoride toothpaste containing 2% zinc citrate/ 0.3% Triclosan with a silica-based fluoride toothpaste containing 0.3% Triclosan/2% copolymer., Methods: In Study 1, plaque was collected after one week's use of each toothpaste and assessed for bacterial viability, live/ dead ratio and microbial membrane integrity. In study 2, plaque was measured immediately and 18 hours after a single brushing with the specified toothpastes., Results: The 2% zinc citrate/0.3% Triclosan formulation significantly reduced the total number of viable aerobic and anaerobic bacteria (p = 0.0223 and p = 0.0443 respectively) compared to the 0.3% Triclosan/2% copolymer formulation. Both toothpastes increased the bacterial membrane permeability significantly. However, the proportion of live bacteria for the 2% zinc citrate/0.3% Triclosan product was significantly reduced (p < 0.05). Study 2 showed significantly less plaque growth 18 hours after using the 2% zinc citrate/0.3% Triclosan toothpaste compared to the 0.3% Triclosan/2% copolymer toothpaste (p < 0.01)., Conclusion: Regular use of a fluoride toothpaste containing 2% zinc citrate and 0.3% Triclosan, significantly reduced the viability of plaque bacteria compared to a fluoride toothpaste containing 0.3% Triclosan/ 2% copolymer 12 hours after brushing. In addition, a clinical plaque growth study confirmed that this anti-microbial efficacy leads to a significant reduction in plaque growth.

Objective: This document describes the technique of intracameral anesthesia and examines the available evidence to address questions about its effectiveness, possible corneal endothelial and retinal toxicity, and the optimal and maximal dose., Methods: A literature search conducted for the years 1968 to 2000 retrieved over 180 citations that matched the search criteria. Panel members and a methodologist reviewed this information, and it was evaluated for the quality of the evidence presented., Results: Some studies report effectiveness of intracameral anesthesia while others report no effect. In those studies showing an effect, levels of pain in the groups that were compared were low. Short-term studies seem to indicate that preservative (methylparaben)-free lidocaine 1% is well tolerated by the corneal endothelium but that higher concentrations of lidocaine are toxic. There is some evidence of electroretinogram changes after exposure to lidocaine or bupivacaine., Conclusions: The ideal timing and placement of intracameral anesthesia has not been determined. Because topical anesthesia alone is effective, surgeons may elect to use intracameral anesthesia for incremental pain control in patients who cannot be adequately managed with topical alone. Appropriate patient selection is important when using this method of anesthesia. While short-term studies seem to indicate safety, long-term effects are unknown. Patient preferences for anesthesia are not well studied.

Deficiency of lysosomal acid beta-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, alpha-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 +/- 35, 97 +/- 39, and 91 +/- 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 +/- 4, 10.5 +/- 2, and 4.0 +/- 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P <.001), but compared with control plasma samples, neither cathepsin B nor K activities were significantly elevated in 8 patients with nonglycosphingolipid lysosomal storage diseases or in 9 patients with other glycosphingolipidoses, which suggests disease specificity. All 3 cathepsin activities were increased 2-fold to 3-fold in Gaucher sera compared with control sera. In all 6 patients treated by enzyme replacement for 16-22 months, serum cathepsin activities decreased significantly (P <.01). Longitudinal studies confirmed the progressive reduction of proteinase activities during imiglucerase therapy but in 3 Gaucher patients with mild disease not so treated, serum cathepsin activities remained constant or increased during follow-up. Enhanced expression of cysteine proteinases may promote tissue destruction. Moreover, the first identification of aberrant cathepsin K expression in hematopoietic tissue other than osteoclasts implicates this protease in the breakdown of the matrix that characterizes lytic bone lesions in Gaucher disease. (Blood. 2000;96:1969-1978)

Background: Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease., Methods: We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity). Patients were started on 100 mg oral OGT 918 three times daily., Findings: Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment., Interpretation: Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.

Objective: To test the hypothesis that pretreatment fluorescein angiography (FA) is not necessary for effective laser treatment of patients with clinically significant diabetic macular edema (CSME)., Design: Prospective, randomized, controlled treatment simulation., Participants: Six fellowship trained retina specialists., Intervention: The authors compared the ability of four retina specialists (observers) to plan laser treatment with and without the use of FA. One hundred consecutive cases of CSME were selected, each case consisting of a stereo pair of color photographs and a corresponding fluorescein angiogram. These cases were first read by two retina specialists who reached consensus on a treatment plan for each case (standard map). Each of the 4 observers reviewed 50 of these cases on 2 occasions and plotted 2 sets of treatment maps, 1 set created with and 1 without the aid of FA. Each observer's 100 treatment maps were graded for accuracy by comparing them to the corresponding standard maps. The role of FA in improving the accuracy of treatment maps was evaluated using logistic regression analysis to control for different observers, different cases, and different posterior pole characteristics., Main Outcome Measures: Accuracy was defined as the proportion of standard treatment correctly treated by the observer., Results: For the observers as a group, the use of FA improved treatment planning accuracy from 49% to 54.5% (P = 0.02); however, there was significant interobserver variation in performance (P < 0.001). Treatment planning accuracy without and with FA was as follows: observer 1, 40.8% and 40.2%; observer 2, 49.8% and 72%; observer 3, 56.1% and 59.5%; and observer 4, 49.2% and 46.4%., Conclusion: The use of FA improves the accuracy of treatment planning for CSME. The authors' study supports the use of FA in laser treatment of patients with CSME.

Background: The effect of thyroid orbitopathy on intraocular pressure (IOP) remains controversial. We carried out a study to determine the effect of orbital decompression surgery on the IOP in patients with advanced thyroid orbitopathy., Methods: The records of 12 consecutive patients (22 eyes) who underwent decompression surgery for severe thyroid orbitopathy between 1985 and 1996 were reviewed. All patients were maintained on essentially the same medications before and after surgery. The IOP readings, obtained by means of applanation tonometry in primary gaze, from the pre- and postoperative visits were recorded, and the net change was calculated., Results: The mean preoperative and postoperative IOP values were 19.8 mm Hg and 16.8 mm Hg respectively, a significant difference (p = 0.008). Seven of eight eyes with an IOP of 21 mm Hg or greater preoperatively had a postoperative IOP less than 21 mm Hg; these eyes showed a mean decrease in IOP of 5.6 mm Hg. The degree of preoperative IOP elevation was found to be a strong predictor of the amount of IOP lowering after surgery (p = 0.014)., Interpretation: Our results support the concept that orbital congestion associated with thyroid orbitopathy produces an increase in IOP by elevation of episcleral venous pressure (EVP) and that orbital decompression may reduce the IOP by decreasing EVP. Decompression surgery may obviate the need for more aggressive management of glaucoma in patients with severe thyroid orbitopathy.

A newly-identified major histocompatibility Class I-like gene, HFE (originally HLA-H) located approximately 3.5 Mb telomeric to the Class I cluster on chromosome 6p 21.3 harbours mutations in haemochromatosis. Two of these, Cys282Tyr (C282Y) and His63Asp (H63D, a minor determinant) have diagnostic utility as approximately 90% of adults are homozygous or compound heterozygotes for these alleles. The pathophysiological role of HFE is unclear: it is expressed as a surface molecule on many cells and the C282Y mutation disrupts interactions with beta 2-microglobulin, thus preventing surface expression. Lately, there has been experimental evidence that HFE protein interacts with the transferrin-receptor, affecting receptor turnover or its affinity for ligand.

Objective: The authors compared two methods, the Marcus Gunn test and the alternating light test, for detecting a relative afferent pupillary defect., Design: A randomized, prospective clinical trial., Participants: Fourteen patients with unilateral optic neuropathy., Intervention: The Marcus Gunn and alternating light tests were performed on each patient., Main Outcome Measures: The results of the Marcus Gunn and altemating light tests for detecting a relative afferent pupillary defect on the affected side., Results: The Marcus Gunn test was able to identify the affected eye in only 8 of 14 patients, whereas the alternating light test correctly identified the affected eye in 13 of 14 patients. Results of the Marcus Gunn test were indeterminate in 4 of 14 patients and were incorrect in 2 of 14 patients. Results of the alternating light test were indeterminate in one patient and never incorrectly identified the affected eye., Conclusion: The alternating light test is superior to the Marcus Gunn test for detecting relative afferent pupillary defects.

The study sought to determine the effectiveness of a model program of psychiatric care for human immunodeficiency virus (HIV)-infected patients. This was a cohort study of 126 HIV-positive outpatients referred for psychiatric evaluation and treatment (average follow up of 14 months) in a HIV-dedicated primary-care outpatient clinic in the inner city. A global outcome measure (encompassing symptom relief, functioning, and HIV-risk behaviors), and a measure of abstinence from alcohol and illicit substances were used. Fifty percent of patients improved, with 19% "nearly well" at follow-up. Abstinence was achieved 48% of the time. Good compliance with treatment and the absence of injection drug use were the primary predictors of good outcomes. Of the compliant patients, 94% improved, with 45.7% being nearly well. Psychiatric treatment of HIV-infected patients is effective when located in the HIV primary-care setting and administered by a multidisciplinary team under the direction of a psychiatrist, using evidence-based interventions.

Objectives: To compare the subjective (eyeballed) method for measuring internal carotid artery (ICA) stenosis by non-selective intra-arterial digital subtraction angiography (IA-DSA) with objective and duplex methods., Design: Retrospective study., Materials and Methods: Fifty-three consecutive patients underwent IA-DSA prior to carotid endarterectomy providing 103 carotid angiograms. Objective assessment of ICA stenosis was by the North American Symptomatic Carotid Endarteectomy Trial (NASCET) criterion and the Carotid Stenosis Index (CSI). Duplex estimation of stenosis was derived from peak systolic and diastolic velocities in the ICA and common carotid artery (CCA)., Results: The coefficient of repeatability was poorest for NASCET stenosis estimates (40%), whilst the improved values for CSI (20%) were consistent with the lower variability recorded for measuring the CCA diameter. Correlation and agreement levels between subjective (r = 0.80, -41% to +33%) or objective assessments and duplex (NASCET: r = 0.76; -52 to +28%; CSI: r = 0.72; -27 to +39%) showed similar values., Conclusions: We conclude that the inter-observer variability for assessing angiograms obtained by arch injection is considerable and precludes high agreement when IA-DSA is compared with other methods. As the agreement of duplex ultrasound with IA-DSA is similar to the agreement between DSA methods, duplex can be offered as the first stage assessment of ICA stenosis, with the proviso that the duplex assessment is performed consistently by an experienced operator.

Background: The primary defect in Gaucher's disease, a lysosomal disorder affecting macrophages, is in the activity of glucocerebrosidase. Treatment with exogenous enzyme (modified to increase its affinity for macrophage glycoprotein receptors) aims to restore this activity. However, the fate of the exogenous enzyme in vivo is unknown. We used radiolabelled enzyme to assess macrophage receptor activity for mannosylated ligands in vivo., Methods: We examined the uptake and tissue distribution of radiolabelled enzyme molecules by gamma scintigraphy after bolus injection of iodine-123-labelled recombinant or placental enzyme (imiglucerase and alglucerase, respectively) in eight patients with type 1 Gaucher's disease, and in one healthy individual. The metabolism of the tracer enzyme was followed by scintigraphy and by analysis of blood, urine, and faeces., Results: The tracer enzyme was rapidly cleared from blood (half-life 4.7 min [SD 1.0]). Concomitantly, there was avid uptake by the liver (about 30% of the injected dose), the spleen (about 15%), and the bone marrow. 40-55% of the tracer was cleared rapidly from the viscera (half-life 1-2 h) and 45-60% was cleared slowly (half-life 34-42 h). The half-life in the bone marrow was 14.1 h. Infusion of alglucerase at dose of 5 U/kg bodyweight normalised acid beta-glucosidase activity of splenic Gaucher's cells in vivo. When the enzyme was administered at a seven-fold higher dose (35 U/kg over 1 h), the receptor-mediated uptake in vivo was saturated, as shown by the increase in blood-clearance half-life of tracer enzyme from 4.5 min to 12 min., Interpretation: Avid and saturable uptake of modified glucocerebrosidase was found, which indicates high-affinity targeting to the macrophage system in vivo. The rate of enzyme turnover suggests a rational basis for use of this therapy in treatment of Gaucher's disease.

Purpose: Condensation occurs rapidly on silicone intraocular lenses (IOLs) after vitrectomy and fluid-air exchange in the presence of a posterior capsulotomy, severely limiting the retinal view. Foldable IOLs made of an acrylic polymer are now available. The authors compare the condensation and subsequent retinal view degradation after vitrectomy and fluid-air exchange in rabbit eyes implanted with polymethylmethacrylate (PMMA), soft acrylic polymer (ACRYSOF), and silicone IOLs., Methods: Thirty rabbits underwent bilateral lens removal. Twenty PMMA, 20 acrylic polymer, and 20 silicone IOLs were implanted into the capsular bag. After three-port vitrectomy, eyes were randomly assigned to undergo a posterior capsulotomy or to an intact posterior capsule. Fluid-air exchange was performed, and the amount of condensation on the IOL surface and resultant retinal view was graded. Surgical maneuvers then were performed to decrease the condensation. These maneuvers included wiping the IOL surface with a soft-tipped cannula and coating it with viscoelastic., Results: No condensation occurred on IOLs in eyes with an intact posterior capsule. Significantly more condensation occurred on IOLs in eyes with a capsulotomy, regardless of IOL type (P < 0.014). Wiping the condensation resulted in significantly less condensation and improved retinal view on the PMMA and acrylic IOLs when compared with the silicone IOLs (P < 0.024). Condensation was eliminated on all three IOL types after viscoelastic was applied. However, increased distortion of the retinal view was induced by the viscoelastic on the silicone IOL as compared with the other IOLs., Conclusions: Condensation and subsequent retinal image degradation occurs uniformly after vitrectomy, posterior capsulotomy, and fluid-air exchange in eyes with PMMA, acrylic, and silicone IOLs. Because the condensation can be eliminated most easily on acrylic IOLs compared with silicone IOLs, when foldable IOL techniques are used it is likely that an acrylic polymer IOL would be advantageous for those patients at risk for future vitreous procedures requiring fluid-air exchange.

Interleukin-15 is a new cytokine that stimulates the proliferation of T cells and other cells of the immune system. Some of the biological properties of interleukin-15 overlap that of interleukin-2. Using murine models, the present studies have shown that interleukin-15, in vivo, is three to four times more potent than interleukin-2 in generating cytolytic effector splenocytes that lyse YAC target cells. It is approximately one-third as potent as interleukin-2 in inducing specific cytolytic cells that lyse allogeneic target cells. Interleukin-15 is approximately half as potent as interleukin-2 in suppressing pulmonary metastasis induced by MCA-205 tumor cells. The dose of interleukin-15 required to induce pulmonary vascular leak in mice is six times higher than that required for interleukin-2. These results support the view that interleukin-15 exhibits a therapeutic index that is superior to interleukin-2.

We determined the prevalence and anatomical location of areas of white matter hyperintensity visualized by magnetic resonance imaging in the brains of 38 late paraphrenic patients with an onset of psychotic illness after the age of 60 and 31 healthy aged community volunteers. All degrees of white matter signal hyperintensity were very common in both groups, and there was no excess of such changes in the brain of patients. Periventricular white matter and subcortical grey matter hyperintensities were significantly associated with both measured diastolic and systolic blood pressure in patients and control subjects. Periventricular and deep white matter, together with subcortical grey matter hyperintensities, were significantly associated with increased age. The excess of such presumed brain-imaging abnormalities previously reported in patients with an onset of psychosis late in life may be a consequence of earlier authors' failure to include examination of appropriate community control populations and to carefully exclude patients with evidence of stroke.

Erythropoietic protoporphyria is an inherited disorder caused by deficient activity of the enzyme ferrochelatase. We have examined the ferrochelatase gene in an 11-year-old female with protoporphyria and have found that she is heterozygous for a mutation at a conserved residue in the exon 3 donor splice site consensus sequence (T(+2)-->G). This is inherited from her father, who also has deficient ferrochelatase activity. As a consequence of the mutation, ferrochelatase transcripts are aberrantly spliced and give rise to mRNA molecules in which sequences corresponding to exon 3 are absent. This leads to the expression of a ferrochelatase protein lacking a central region of 40 amino acids.

Background: A pigment epitheliopathy that resembles ophthalmomyiasis interna occurs in approximately 10% of a large sample of the Chamorro population of Guam age 39 years or older; the rate is approximately 50% among those who have amyotrophic lateral sclerosis or Parkinsonism-dementia complex (lytico bodig)., Methods: Since publication of an earlier clinical report of affected patients, several of them have died of their neurologic disease, and their eyes were obtained for pathologic study. This is the first pathologic report of the retinal pigment epitheliopathy seen in the setting of amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam and is based on examination of 13 eyes from 7 patients., Results/conclusion: Focal areas of attenuation of the retinal pigment epithelium in association with a reduced amount of intracellular pigment correlated with the funduscopic and gross appearance. No larvae were seen, and there was no evidence of inflammation. The pathogenesis of this pigment epitheliopathy remains undetermined.

The inherited disorder Gaucher's disease can be caused by various mutations in the glucocerebrosidase gene. Some mutations may be associated with greater severity, and there is a need for methods of gene analysis that would facilitate screening and diagnosis. We have studied the molecular basis of Gaucher's disease in twelve unrelated patients of diverse ethnic origin by means of the amplification refractory mutation system (ARMS). Primers for the polymerase chain reaction were designed to discriminate between mutant and wild-type alleles of glucocerebrosidase and to allow separation from products of the related pseudogene. The nucleotide 1226 mutation (asparagine 370----serine) and 84GG (an insertional frameshift mutation) were found exclusively in five patients of Ashkenazi Jewish descent (7 and 2 of the 10 disease alleles, respectively). Two point mutations, at nucleotides 1448 (leucine 444----proline) and 1504 (arginine 463----cysteine), were found in 4 and 3 alleles, respectively; they were associated with rapidly progressive disease and neurological involvement in non-Jewish patients. The ARMS procedure for direct detection of common mutations in glucocerebrosidase will facilitate genetic counselling and screening programmes for individuals at risk of Gaucher's disease.