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Context: Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date., Objective: Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined., Methods: CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed., Results: The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment., Conclusion: Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant has caused a dramatic resurgence in infections in the United Sates, raising questions regarding potential transmissibility among vaccinated individuals., Methods: Between October 2020 and July 2021, we sequenced 4439 SARS-CoV-2 full genomes, 23% of all known infections in Alachua County, Florida, including 109 vaccine breakthrough cases. Univariate and multivariate regression analyses were conducted to evaluate associations between viral RNA burden and patient characteristics. Contact tracing and phylogenetic analysis were used to investigate direct transmissions involving vaccinated individuals., Results: The majority of breakthrough sequences with lineage assignment were classified as Delta variants (74.6%) and occurred, on average, about 3 months (104 ± 57.5 days) after full vaccination, at the same time (June-July 2021) of Delta variant exponential spread within the county. Six Delta variant transmission pairs between fully vaccinated individuals were identified through contact tracing, 3 of which were confirmed by phylogenetic analysis. Delta breakthroughs exhibited broad viral RNA copy number values during acute infection (interquartile range, 1.2-8.64 Log copies/mL), on average 38% lower than matched unvaccinated patients (3.29-10.81 Log copies/mL, P < .00001). Nevertheless, 49% to 50% of all breakthroughs, and 56% to 60% of Delta-infected breakthroughs exhibited viral RNA levels above the transmissibility threshold (4 Log copies/mL) irrespective of time after vaccination., Conclusions: Delta infection transmissibility and general viral RNA quantification patterns in vaccinated individuals suggest limited levels of sterilizing immunity that need to be considered by public health policies. In particular, ongoing evaluation of vaccine boosters should specifically address whether extra vaccine doses curb breakthrough contribution to epidemic spread., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

In vitro (geno)toxicity assessment of electronic vapour products (EVPs), relative to conventional cigarette, currently uses assays, including the micronucleus and Ames tests. Whilst informative on induction of a finite endpoint and relative risk posed by test articles, such assays could benefit from mechanistic supplementation. The ToxTracker and Aneugen Clastogen Evaluation analysis can indicate the activation of reporters associated with (geno)toxicity, including DNA damage, oxidative stress, the p53-related stress response and protein damage. Here, we tested for the different effects of a selection of neat e-liquids, EVP aerosols and Kentucky reference 1R6F cigarette smoke samples in the ToxTracker assay. The assay was initially validated to assess whether a mixture of e-liquid base components, propylene glycol (PG) and vegetable glycerine (VG) had interfering effects within the system. This was achieved by spiking three positive controls into the system with neat PG/VG or phosphate-buffered saline bubbled (bPBS) PG/VG aerosol (nicotine and flavour free). PG/VG did not greatly affect responses induced by the compounds. Next, when compared to cigarette smoke samples, neat e-liquids and bPBS aerosols (tobacco flavour; 1.6% freebase nicotine, 1.6% nicotine salt or 0% nicotine) exhibited reduced and less complex responses. Tested up to a 10% concentration, EVP aerosol bPBS did not induce any ToxTracker reporters. Neat e-liquids, tested up to 1%, induced oxidative stress reporters, thought to be due to their effects on osmolarity in vitro. E-liquid nicotine content did not affect responses induced. Additionally, spiking nicotine alone only induced an oxidative stress response at a supraphysiological level. In conclusion, the ToxTracker assay is a quick, informative screen for genotoxic potential and mechanisms of a variety of (compositionally complex) samples, derived from cigarettes and EVPs. This assay has the potential for future application in the assessment battery for next-generation (smoking alternative) products, including EVPs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.)

Objective: Systematic reviews are important in health care but are expensive to produce and maintain. The authors explore the use of automated transformations of Boolean queries to improve the identification of relevant studies for updates to systematic reviews., Materials and Methods: A set of query transformations, including operator substitution, query expansion, and query reduction, were used to iteratively modify the Boolean query used for the original systematic review. The most effective transformation at each stage is identified using information about the studies included and excluded from the original review. A dataset consisting of 22 systematic reviews was used for evaluation. Updated queries were evaluated using the included and excluded studies from the updated version of the review. Recall and precision were used as evaluation measures., Results: The updated queries were more effective than the ones used for the original review, in terms of both precision and recall. The overall number of documents retrieved was reduced by more than half, while the number of relevant documents found increased by 10.3%., Conclusions: Identification of relevant studies for updates to systematic reviews can be carried out more effectively by using information about the included and excluded studies from the original review to produce improved Boolean queries. These updated queries reduce the overall number of documents retrieved while also increasing the number of relevant documents identified, thereby representing a considerable reduction in effort required by systematic reviewers., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The relative risk of lung cancer decreases with years since quitting (YSQ) smoking, but risk beyond 25 YSQ remains unclear. Current lung cancer screening guidelines, which exclude smokers with more than 15 YSQ, may not detect lung cancers in this population., Methods: We analyzed data from Framingham Heart Study Original (n = 3905) and Offspring cohort (n = 5002) participants for lifetime smoking and lung cancer incidence from 1954 to 1958 (Exam 4) and 1971 to 1975 (Exam 1), respectively, through 2013. We used multivariable-adjusted Cox proportional hazards regression models to compare current, former, and never smokers and lung cancer risk. Smoking status and covariates were time-updated every two years (Original) or four years (Offspring). Primary analyses were restricted to heavy ever smokers with more than 21.3 pack-years; additional analyses included all ever smokers., Results: On follow-up (median = 28.7 years), 284 lung cancers were detected: incidence rates/1000 person-years in current, former, and never smokers were 1.97 (95% confidence interval [CI] = 1.66 to 2.33), 1.61 (95% CI = 1.34 to 1.93), and 0.26 (95% CI = 0.17 to 0.39), respectively. Heavy former (vs never) smokers had elevated lung cancer risk at all YSQ (<5: hazard ratio [HR] = 12.12, 95% CI = 6.94 to 21.17; 5-9: HR = 11.77, 95% CI = 6.78 to 20.45; 10-14: HR = 7.81, 95% CI = 3.98 to 15.33; 15-24: HR = 5.88, 95% CI = 3.19-10.83; ≥25: HR = 3.85, 95% CI = 1.80 to 8.26). Heavy former (vs current) smokers had 39.1% lower lung cancer risk within five YSQ. Among all former smokers, 40.8% of lung cancers occurred after more than 15 YSQ., Conclusions: Among heavy former smokers, lung cancer risk drops within five YSQ relative to continuing smokers, yet it remains more than threefold higher than never smokers after 25 YSQ. Four of ten lung cancers occurred in former smokers with more 15 YSQ, beyond the screening window of the current guideline.

End-stage liver disease is a common cause of non-AIDS-related mortality in HIV + patients, despite effective anti-retroviral therapies (ARTs). HIV-1 infection causes gut CD4 depletion and is thought to contribute to increased gut permeability, bacterial translocation, and immune activation. Microbial products drain from the gut into the liver via the portal vein where Kupffer cells (KCs), the resident liver macrophage, clear translocated microbial products. As bacterial translocation is implicated in fibrogenesis in HIV patients through unclear mechanisms, we tested the hypothesis that HIV infection of KCs alters their response to LPS in a TLR4-dependent manner. We showed that HIV-1 productively infected KCs, enhanced cell-surface TLR4 and CD14 expression, and increased IL-6 and TNF-α expression, which was blocked by a small molecule TLR4 inhibitor. Our study demonstrated that HIV infection sensitizes KCs to the proinflammatory effects of LPS in a TLR4-dependent manner. These findings suggest that HIV-1-infected KCs and their dysregulated innate immune response to LPS may play a role in hepatic inflammation and fibrosis and represent a novel target for therapy., (© Society for Leukocyte Biology.)

Background: Occupational health nurses (OHNs) play a pivotal role in the delivery of occupational health (OH) services. Specific competency guidance has been developed in a number of countries, including the UK. While it is acknowledged that UK OHN practice has evolved in recent years, there has been no formal research to capture these developments to ensure that training and curricula remain up-to-date and reflect current practice., Aims: To identify current priorities among UK OHNs of the competencies required for OH practice., Methods: A modified Delphi study undertaken among representative OHN networks in the UK. This formed part of a larger study including UK and international occupational physicians. The study was conducted in two rounds using a questionnaire based on available guidance on training competencies for OH practice, the published literature, expert panel reviews and conference discussions., Results: Consensus among OHNs was high with 7 out of the 12 domains scoring 100% in rating. 'Good clinical care' was the principal domain ranked most important, followed by 'general principles of assessment & management of occupational hazards to health'. 'Research methods' and 'teaching & educational supervision' were considered least important., Conclusions: This study has established UK OHNs' current priorities on the competencies required for OH practice. The timing of this paper is opportune with the formal launch of the Faculty of Occupational Health Nursing planned in 2018 and should inform the development of competency requirements as part of the Faculty's goals for standard setting in OHN education and training., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine.)

Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/-) mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/-) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/-) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.

Objective: Literature-based discovery (LBD) aims to identify "hidden knowledge" in the medical literature by: (1) analyzing documents to identify pairs of explicitly related concepts (terms), then (2) hypothesizing novel relations between pairs of unrelated concepts that are implicitly related via a shared concept to which both are explicitly related. Many LBD approaches use simple techniques to identify semantically weak relations between concepts, for example, document co-occurrence. These generate huge numbers of hypotheses, difficult for humans to assess. More complex techniques rely on linguistic analysis, for example, shallow parsing, to identify semantically stronger relations. Such approaches generate fewer hypotheses, but may miss hidden knowledge. The authors investigate this trade-off in detail, comparing techniques for identifying related concepts to discover which are most suitable for LBD., Materials and Methods: A generic LBD system that can utilize a range of relation types was developed. Experiments were carried out comparing a number of techniques for identifying relations. Two approaches were used for evaluation: replication of existing discoveries and the "time slicing" approach.(1) RESULTS: Previous LBD discoveries could be replicated using relations based either on document co-occurrence or linguistic analysis. Using relations based on linguistic analysis generated many fewer hypotheses, but a significantly greater proportion of them were candidates for hidden knowledge., Discussion and Conclusion: The use of linguistic analysis-based relations improves accuracy of LBD without overly damaging coverage. LBD systems often generate huge numbers of hypotheses, which are infeasible to manually review. Improving their accuracy has the potential to make these systems significantly more usable., (© The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Aims: To determine the symptomatic and prognostic differences resulting from a novel diagnostic pathway based on cardiac computerized tomography (CT) compared with the traditional exercise stress electrocardiography test (EST) in stable chest pain patients., Methods and Results: A prospective randomized controlled trial compared selected patient outcomes in EST and cardiac CT coronary angiography groups. Five hundred patients with troponin-negative stable chest pain and without known coronary artery disease were recruited. Patients completed the Seattle Angina Questionnaires (SAQ) at baseline, 3, and 12 months to assess angina symptoms. Patients were also followed for management strategies and clinical events. Over the year 12 patients withdrew, resulting in 245 in the EST cohort and 243 in the CT cohort. There was no significant difference in baseline demographics. The CT arm had a statistical difference in angina stability and quality-of-life domains of the SAQ at 3 and12 months, suggesting less angina compared with the EST arm. In the CT arm, there was more significant disease identified and more revascularizations. Significantly, more inconclusive results were seen in the EST arm with a higher number of additional investigations ordered. There was also a longer mean time to management. There were no differences in major adverse cardiac events between the cohorts. At 1 year in the EST arm, there were more Accident and Emergency (A&E) attendances and cardiac admission., Conclusion: Cardiac CT as an index investigation for stable chest pain improved angina symptoms and resulted in fewer investigations and re-hospitalizations compared with EST., Clinical Trial Registration: http://www.controlled-trials.com/ISRCTN52480460., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence., Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL., Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples., Setting: The study was conducted at university hospitals., Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study., Outcome: Outcomes included genetic screening and clinical characteristics., Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context., Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Context: Cell division cycle 73 (CDC73), encoding the protein parafibromin, is the most prevalent mutated gene in familial and sporadic parathyroid carcinoma (PC)., Objective: To identify additional genetic abnormalities in PCs., Design: Whole-exome sequencing was performed using DNA from seven pairs of matched PCs and one triplet containing double primary tumor and normal leukocyte. Somatic variants were confirmed using Sanger sequencing and recurrently mutated genes were assessed in 13 additional PCs as well as 40 parathyroid adenomas (PA)., Results: PC had an average of 51 somatic variants/tumor (range 3-176) with approximately 58% of variants occurring as nonsynonymous single nucleotide variants. The importance of CDC73 in PC is reinforced with a remarkable preferential amplification of the mutant CDC73 allele. Furthermore, recurrent germ line and somatic mutations in prune homolog 2 [Drosophila] (PRUNE2) were found in PC and computationally predicted to be deleterious; in addition, recurrent mutations in kinase genes related to cell migration and invasion were found. PRUNE2 showed recurrent mutations in 18% (4/22) of PCs with additional screening in 40 PAs revealing only one rare missense polymorphism (Asp1677Asn). For the first time, the mutational signature associated with apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-catalyzed cytosine-to-uracil deamination is found in a subset of PC., Conclusion: This study outlines the genetic landscape of PC and attempts to characterize the mutational processes shaping the PC genome.

Objective: We aim to identify duplicate pairs of Medline citations, particularly when the documents are not identical but contain similar information., Materials and Methods: Duplicate pairs of citations are identified by comparing word n-grams in pairs of documents. N-grams are modified using two approaches which take account of the fact that the document may have been altered. These are: (1) deletion, an item in the n-gram is removed; and (2) substitution, an item in the n-gram is substituted with a similar term obtained from the Unified Medical Language System Metathesaurus. N-grams are also weighted using a score derived from a language model. Evaluation is carried out using a set of 520 Medline citation pairs, including a set of 260 manually verified duplicate pairs obtained from the Deja Vu database., Results: The approach accurately detects duplicate Medline document pairs with an F1 measure score of 0.99. Allowing for word deletions and substitution improves performance. The best results are obtained by combining scores for n-grams of length 1-5 words., Discussion: Results show that the detection of duplicate Medline citations can be improved by modifying n-grams and that high performance can also be obtained using only unigrams (F1=0.959), particularly when allowing for substitutions of alternative phrases.

Objectives: To determine whether the daily use of 5% tea tree oil (TTO) body wash (Novabac 5% Skin Wash) compared with standard care [Johnson's Baby Softwash (JBS)] had a lower incidence of methicillin-resistant Staphylococcus aureus (MRSA) colonization., Patients: The study setting was two intensive care units (ICUs; mixed medical, surgical and trauma) in Northern Ireland between October 2007 and July 2009. The study population comprised 391 patients who were randomized to JBS or TTO body wash., Methods: This was a Phase 2/3, prospective, open-label, randomized, controlled trial., Trial Registration: ISRCTN65190967. The primary outcome was new MRSA colonization during ICU stay. Secondary outcomes included the incidence of MRSA bacteraemia and maximum increase in sequential organ failure assessment score., Results: A total of 445 patients were randomized to the study. After randomization, 54 patients were withdrawn; 30 because of a positive MRSA screen at study entry, 11 due to lack of consent, 11 were inappropriately randomized and 2 had adverse reactions. Thirty-nine (10%) patients developed new MRSA colonization (JBS n = 22, 11.2%; TTO body wash n = 17, 8.7%). The difference in percentage colonized (2.5%, 95% CI - 8.95 to 3.94; P = 0.50) was not significant. The mean maximum increase in sequential organ failure assessment score was not significant (JBS 1.44, SD 1.92; TTO body wash 1.28, SD 1.79; P = 0.85) and no study patients developed MRSA bacteraemia., Conclusions: Compared with JBS, TTO body wash cannot be recommended as an effective means of reducing MRSA colonization.

Background: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients., Methods and Results: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative., Conclusion: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Study Objectives: As obstructive sleep apnea (OSA) is associated with a higher risk of motor vehicle crashes, there is increasing regulatory interest in the identification of commercial motor vehicle (CMV) drivers with this condition. This study aimed to determine the relationship between subjective versus objective assessment of OSA in CMV drivers., Design: Cross-sectional survey., Settings: Heavy vehicle truck stops located across the road network of 2 large Australian states., Participants: A random sample of long distance commercial vehicle drivers (n = 517)., Interventions: None., Measurements and Results: Drivers were interviewed regarding their driving experience, personal health, shift schedules, payments, and various questions on sleep and tiredness in order to describe their sleep health across a range of variables. In addition, home recordings using a flow monitor were used during one night of sleep. Only 4.4% of drivers reported a previous diagnosis of sleep apnea, while our at home diagnostic test found a further 41% of long-distance heavy vehicle drivers likely to have sleep apnea. The multivariable apnea prediction index, based on self-report measures, showed poor agreement with the home-monitor detected sleep apnea (AUC 0.58, 95%CI = 0.49-0.62), and only 12% of drivers reported daytime sleepiness (Epworth Sleepiness Scale score > 10). Thirty-six percent of drivers were overweight and a further 50% obese; 49% of drivers were cigarette smokers., Conclusions: Sleep apnea remains a significant and unrecognized problem in CMV drivers, who we found to have multiple health risks. Objective testing for this sleep disorder needs to be considered, as symptom reports and self-identification appear insufficient to accurately identify those at risk.

Objective: Current techniques for knowledge-based Word Sense Disambiguation (WSD) of ambiguous biomedical terms rely on relations in the Unified Medical Language System Metathesaurus but do not take into account the domain of the target documents. The authors' goal is to improve these methods by using information about the topic of the document in which the ambiguous term appears., Design: The authors proposed and implemented several methods to extract lists of key terms associated with Medical Subject Heading terms. These key terms are used to represent the document topic in a knowledge-based WSD system. They are applied both alone and in combination with local context., Measurements: A standard measure of accuracy was calculated over the set of target words in the widely used National Library of Medicine WSD dataset., Results and Discussion: The authors report a significant improvement when combining those key terms with local context, showing that domain information improves the results of a WSD system based on the Unified Medical Language System Metathesaurus alone. The best results were obtained using key terms obtained by relevance feedback and weighted by inverse document frequency.

Motivation: Word Sense Disambiguation (WSD), automatically identifying the meaning of ambiguous words in context, is an important stage of text processing. This article presents a graph-based approach to WSD in the biomedical domain. The method is unsupervised and does not require any labeled training data. It makes use of knowledge from the Unified Medical Language System (UMLS) Metathesaurus which is represented as a graph. A state-of-the-art algorithm, Personalized PageRank, is used to perform WSD., Results: When evaluated on the NLM-WSD dataset, the algorithm outperforms other methods that rely on the UMLS Metathesaurus alone., Availability: The WSD system is open source licensed and available from http://ixa2.si.ehu.es/ukb/. The UMLS, MetaMap program and NLM-WSD corpus are available from the National Library of Medicine https://www.nlm.nih.gov/research/umls/, http://mmtx.nlm.nih.gov and http://wsd.nlm.nih.gov. Software to convert the NLM-WSD corpus into a format that can be used by our WSD system is available from http://www.dcs.shef.ac.uk/∼marks/biomedical&#95;wsd under open source license.

Objectives: Young people are sleeping less. Short sleep duration has a range of negative consequences including a hypothesized link with psychological distress, which has yet to be studied, Design: Prospective cohort study, Setting: Community-based sample from Australia, Participants: Twenty thousand (20,822) young adults (aged 17-24) identified through the state vehicle licensing authority. A random sample (n = 5000) was approached for follow-up 12-18 months later, with 2837 providing full data., Main Outcome Measure: Psychological distress, determined by a Kessler 10 score > 21, at baseline; and as both onset and persistence of distress at follow-up., Results: Shorter sleep duration was linearly associated with prevalent psychological distress: relative risk (RR) 1.14 (95% CI 1.12 to 1.15). Only the very short (< 5 h) sleepers among those not distressed at baseline had an increased risk for onset of psychological distress (RR 3.25 [95% CI 1.84, 5.75]). Of 945 cohort participants reporting psychological distress at baseline, 419 (44%) were distressed at follow-up. Each hour less of sleep increased the risk of psychological distress persisting after adjustment for potential confounding variables: RR 1.05 (95% CI 1.01 to 1.10). Long sleep duration showed no association with distress at any time point., Conclusions: Self-reported shorter sleep duration is linearly associated with prevalent and persistent psychological distress in young adults. In contrast, only the very short sleepers had a raised risk of new onset of distress. Different approaches to sleep duration measurement yield different results and should guide any interventions to improve subjective sleep duration in young adults.

Background: Sperm DNA damage shows great promise as a biomarker of infertility. The study aim is to determine the usefulness of DNA fragmentation (DF), including modified bases (MB), to predict assisted reproduction treatment (ART) outcomes., Methods: DF in 360 couples (230 IVF and 130 ICSI) was measured by the alkaline Comet assay in semen and in sperm following density gradient centrifugation (DGC) and compared with fertilization rate (FR), embryo cumulative scores (ECS(1)) for the total number of embryos/treatment, embryos transferred (ECS(2)), clinical pregnancy (CP) and spontaneous pregnancy loss. MB were also measured using formamidopyrimidine DNA glycosylase to convert them into strand breaks., Results: In IVF, FR and ECS decreased as DF increased in both semen and DGC sperm, and couples who failed to achieve a CP had higher DF than successful couples (+12.2% semen, P = 0.004; +9.9% DGC sperm, P = 0.010). When MB were added to existing strand breaks, total DF was markedly higher (+17.1% semen, P = 0.009 and +13.8% DGC sperm, P = 0.045). DF was not associated with FR, ECS or CP in either semen or DGC sperm following ISCI. In contrast, by including MB, there was significantly more DNA damage (+16.8% semen, P = 0.008 and +15.5% DGC sperm, P = 0.024) in the group who did not achieve CP., Conclusions: DF can predict ART outcome for IVF. Converting MB into further DNA strand breaks increased the test sensitivity, giving negative correlations between DF and CP for ICSI as well as IVF.

Background: Antimicrobial silver dressings are used beneath graduated compression in the treatment of venous ulceration. There is little information on whether their use is effective. This was a prospective randomized trial and cost-effectiveness analysis of silver-donating versus non-silver low-adherence dressings in the treatment of venous leg ulcers., Methods: Patients were randomized between the two types of dressing. The primary outcome measure was complete ulcer healing at 12 weeks. Secondary outcomes included time to healing, quality of life and cost-effectiveness., Results: A total of 213 patients were recruited. There was no difference between the dressings in the proportion of ulcers healed at 12 weeks (59.6 per cent for silver and 56.7 per cent for control dressings). Mean utility scores for the EuroQol 5D and Short Form 6D were similar in both groups at 1, 3, 6 and 12 months. Compared with the control group the antimicrobial group had an incremental cost of pounds sterling 97.85 and an incremental quality-adjusted life year gain of 0.0002, giving an incremental cost-effectiveness ratio of pounds sterling 489 250 for the antimicrobial dressings., Conclusion: No significant differences were found in either primary or secondary endpoints. There was no evidence to support the routine use of silver-donating dressings beneath compression for venous ulceration., Registration Number: ISRCTN 72485131 (http://www.controlled-trials.com).

We have developed a PCR-based short interfering RNA (siRNA) quantification method based on competition between siRNA and a homologous DNA primer for annealing to template DNA, avoiding the requirement for prior conversion of RNA to cDNA. Primers and probe were designed to amplify regions of the human papillomavirus E6 or enhanced green fluorescent protein genes. Having confirmed siRNA could not act as primer for amplicon generation, the lowest competing primer concentration yielding a linear relationship between template DNA amount (0.1-50 ng) and cycle of threshold (Ct) was determined (6.25 nM). Under these conditions addition of sequence-specific siRNA to the competitive quantitative PCR (cqPCR), resulted in a dose-dependent linear increase in Ct value. 2'-O-methyl ribose-modified siRNA retained an ability to inhibit template amplification in serum, unlike unmodified siRNAs that were susceptible to endonucleases. Mismatch-bearing or truncated siRNAs failed to inhibit template amplification confirming sequence specificity and an ability to discriminate between degraded and non-degraded siRNA sequences. Following delivery of E6 siRNA to C33-A cells using oligofectamine or His6 reducible polymers, siRNA uptake was quantified by cqPCR, revealing dose-dependent uptake. We anticipate that cqPCR will allow accurate determination of siRNA pharmacokinetics following in vivo delivery, greatly facilitating development of therapeutic siRNA delivery strategies.

The continued quest to intervene in HIV-1 infection by halting transmission, suppressing replication, or eradicating disease in infected subjects stresses the significance of dendritic cell and macrophage biology as early and persistent players in the relationship between infection and disease. As highlighted by new data and presentations at the Sixth International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs, a greater emphasis is currently underway in studying the potential of targeting these cell types by intervention early in infection, better defining viral phenotypes and entry mechanisms with a more precise nomenclature system, identifying new, intrinsic cellular factors that may restrict infection within these cell types, and pursuing novel roles for macrophage activation and trafficking. Other key areas include examination of these cells as sources of viral persistence in patients, their roles in coinfection, and their metabolic function in HIV pathogenesis and drug toxicity. This issue of JLB contains reviews and original research reports from the workshop, which highlight new findings, current research questions, and key areas in need of future investigation as a result of their significance to HIV prevention and pathogenesis.

Aims: To investigate the feasibility and efficacy of novel low-tilt biphasic waveforms in transvenous cardioversion of atrial fibrillation (AF), delivered by a radiofrequency-powered defibrillator., Methods and Results: The investigation was performed in three phases in an animal model of AF: a feasibility and efficacy study (in 10 adult Large White Landrace swine), comparison with low-tilt monophasic and standard capacitor-based waveforms, and an assessment of sequential shocks delivered over several pathways (in 15 adult Suffolk sheep). Defibrillation electrodes were positioned transvenously under fluoroscopic control in the high lateral right atrium and distal coronary sinus. When multiple defibrillation pathways were tested, a third electrode was also attached to the lower interatrial septum. The electrodes were then connected to a radiofrequency (RF)-powered defibrillator or a standard defibrillator. After confirmation of successful induction of sustained AF, defibrillation was attempted. Percentage success was calculated from the effects of all shocks delivered to all the animals within each set of experiments. Of the low-tilt (RF) biphasic waveforms delivered during internal atrial cardioversion, 100% success was achieved with a 6/6 ms 100/-50 V waveform (1.45+/-0.01 J). This waveform was similar in efficacy to low-tilt (RF) monophasic waveforms (88 vs. 92% success, 1.58+/-0.01 vs. 2.67+/-0.03 J; P=NS; delivered energy 41% lower) and superior to equivalent voltage standard monophasic (50% success, 0.67+/-0.00 J; P<0.001) and biphasic waveforms (72% success, 0.69+/-0.00 J; P=0.03). Sequential shocks delivered over dual pathways did not improve the efficacy of low-tilt biphasic waveforms., Conclusion: A low-tilt biphasic waveform from a RF-powered defibrillator (6/6 ms 100/-50 V) is more efficacious than standard monophasic or biphasic waveforms (equivalent voltage) and is similar in efficacy to low-tilt monophasic waveforms.

Non-viral vectors are promising vehicles for gene therapy but delivery of plasmid DNA to post-mitotic cells is challenging as nuclear entry is particularly inefficient. We have developed and evaluated a hybrid mRNA/DNA system designed to bypass the nuclear barrier to transfection and facilitate cytoplasmic gene expression. This system, based on co-delivery of mRNA(A64) encoding for T7 RNA polymerase (T7 RNAP) with a T7-driven plasmid, produced between 10- and 2200-fold higher gene expression in primary dorsal root ganglion neuronal (DRGN) cultures isolated from Sprague-Dawley rats compared to a cytomegalovirus (CMV)-driven plasmid, and 30-fold greater expression than the enhanced T7-based autogene plasmid pR011. Cell-free assays and in vitro transfections highlighted the versatility of this system with small quantities of T7 RNAP mRNA required to mediate expression at levels that were significantly greater than with the T7-driven plasmid alone or supplemented with T7 RNAP protein. We have also characterized a number of parameters, such as mRNA structure, intracellular stability and persistence of each nucleic acid component that represent important factors in determining the transfection efficiency of this hybrid expression system. The results from this study demonstrate that co-delivery of mRNA is a promising strategy to yield increased expression with plasmid DNA, and represents an important step towards improving the capability of non-viral vectors to mediate efficient gene transfer in cell types, such as in DRGN, where the nuclear membrane is a significant barrier to transfection.

This study investigated the influence of changing lower face vertical proportion on the attractiveness ratings scored by lay people.Ninety-two social science students rated the attractiveness of a series of silhouettes with normal, reduced or increased lower face proportions. The random sequences of 10 images included an image with the Eastman normal lower face height relative to total face height [lower anterior face height/total anterior face height (LAFH/TAFH) of 55 per cent], and images with LAFH/TAFH increased or decreased by up to four standard deviations (SD) from the Eastman norm. All the images had a skeletal Class I antero-posterior (AP) relationship. A duplicate image in each sequence assessed repeatability. The participants scored each image using a 10 point numerical scale and also indicated whether they would seek treatment if the image was their own profile. The profile image with normal vertical facial proportions was rated by the lay people as the most attractive. Attractiveness scores reduced as the vertical facial proportions diverged from the normal value. Images with a reduced lower face proportion were rated as significantly more attractive than the corresponding images with an increased lower face proportion. Images with a reduced lower face proportion were also significantly less likely to be judged as needing treatment than the corresponding images with an increased lower face proportion.

Aims: To compare the success rate for transthoracic direct current cardioversion (DCC) of atrial fibrillation (AF) with antero-posterior (AP) and antero-apical (AA) electrode positions using an impedance compensated biphasic (ICB) waveform., Methods and Results: Three-hundred and seven patients [mean age 66 (SD+/-13), 195 male] with AF were recruited in three centres. Patients were randomized to an AA (n=150) or AP (n=144) pad position. Thirteen patients with implanted pacemakers were defaulted to the AP pad position. Cardioversion was performed using an ICB waveform with a 70, 100, 150, and 200 J energy selection protocol. If the fourth shock was unsuccessful, the pads were crossed over to the alternative position for a final 200 J shock. Shock 1 was successful in 54/150 (36%) AA and 45/144 (31%) AP patients, whereas success was achieved by shock 2 in 99/150 (66%) AA and 74/144 (51%) AP, by shock 3 in 123/150 (82%) AA and 109/144 (76%) AP, and by shock 4 in 143/150 (95%) AA and 127/144 (88%) AP and after cross-over in 144/150 (96%) AA and 135/144 (94%) AP. Overall success rate was higher than expected at 95%. Pad position was not associated significantly with success. There was a trend towards an improved outcome with the AA configuration (P=0.05)., Conclusion: The influence of pad position for DCC of AF may be less pertinent with ICB waveforms than with monophasic waveforms.

Synthetic vectors based on reducible polycations consisting of histidine and polylysine residues (HIS RPCs) were evaluated for their ability to deliver nucleic acids. Initial experiments showed that RPC-based vectors with at least 70% histidine content mediated efficient levels of gene transfer without requirement for the endosomolytic agent chloroquine. Significant gene transfer was observed in a range of cell types achieving up to a 5-fold increase in the percentage of transfected cells compared to 25 kDa PEI, a gold standard synthetic vector. In contrast to 25 kDa PEI, HIS RPCs also mediated efficient transfer of other nucleic acids, including mRNA encoding green fluorescent protein in PC-3 cells and siRNA directed against the neurotrophin receptor p75(NTR) in post-mitotic cultures of rat dorsal root ganglion cell neurons. Experiments to elevate intracellular glutathione and linear profiling of cell images captured by multiphoton fluorescent microscopy highlighted that parameters such as the molecular weight and rate of cleavage of HIS RPCs were important factors in determining transfection activity. Altogether, these results demonstrate that HIS RPCs represent a novel and versatile type of vector that can be used for efficient cytoplasmic delivery of a broad range of nucleic acids. This should enable different or a combination of therapeutic strategies to be evaluated using a single type of polycation-based vector.

This study examined the attractiveness of facial profiles. One hundred and two social science students (28 males and 74 females) rated the attractiveness of a series of silhouettes with normal, Class II or Class III profiles. A random sequence of 10 images included an image with the Eastman normal SNB value of 78 degrees, and images with SNB values of 2.5, 5, 7.5 and 10 degrees above and below normal. A duplicate image in each sequence was used to assess reproducibility. The participants scored the attractiveness of each image and also indicated whether they would seek treatment if each image was their own profile. The profile with the normal SNB angle of 78 degrees was rated as the most attractive. Attractiveness scores reduced as the mandibular profile diverged from the normal SNB value. The +5 degree profile (SNB = 83 degrees) was rated as significantly more attractive than the -5 degree profile (SNB = 73 degrees; P = 0.004). No other significant differences between the scores for Class II and Class III profile pairs of equal severity were found. At 10 degrees below the normal SNB (Class II), 74 per cent of the sample would elect to have treatment, while 78 per cent would elect to have treatment at 10 degrees above the normal SNB (Class III).

Aims: To assess the predictors of 1 year mortality in patients treated with fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) and to determine whether a strategy of early percutaneous coronary intervention (PCI) improves outcome., Methods and Results: Consecutive patients (n = 474) admitted to our unit (1998-2001) with STEMI were treated with fibrinolytic therapy. For each patient, age, gender, admission via mobile coronary care unit (MCCU), infarct location, initial systolic blood pressure and Killip class, prior history of ischaemic heart disease, hypertension, diabetes mellitus, smoking status, family history, hyperlipidaemia, and in-hospital PCI (n = 154) were recorded. Mortality at 1 year was obtained from medical records (n = 473). Binary logistic regression analysis was performed to determine independent predictors of 1 year mortality. Mortality in the non-PCI group was 21 vs. 7% in the PCI group. Independent predictors of 1 year mortality were age (risk ratio 1.12, 95% CI 1.08-1.15, P < 0.0001), initial SBP < or = 80 mmHg (risk ratio 4.34, 95% CI 1.68-11.2, P = 0.002), initial Killip class > or = 3 (risk ratio 2.97, 95% CI 1.42-6.2, P = 0.004), and lack of in-hospital PCI (risk ratio 0.39, 95% CI 0.19-0.81, P = 0.012). Although the PCI group were younger (P = 0.007), more likely to be admitted via the MCCU (P = 0.008), with a shorter pain to needle time (P = 0.04), multivariable analysis adjusted for these differences., Conclusion: In-hospital PCI in patients treated with fibrinolytic therapy for STEMI is associated with a substantial reduction in 1 year mortality.

This study investigated the prevalence of bacteraemia on removal of fixed appliances. Venous blood samples were taken before and after debonding and debanding for 30 patients (mean age 17 years 8 months) who had worn fixed appliances for an average of 19 months. Before removal of the fixed appliances, bacteraemia was detected in one of the 30 subjects (3%) and in four subjects (13%) following removal of their fixed appliances. The 95 per cent confidence intervals for the prevalence of post-debanding bacteraemia were 3.8 and 30.7 per cent. No significant relationship was detected between the mean plaque scores (t = -0.65, P = 0.52) or the mean gingival scores (t = 0.75, P = 0.46) and the occurrence of bacteraemia. The prevalence of bacteraemia detected following debanding in this study is considerably lower than reported for dental procedures traditionally covered by antibiotic prophylaxis guidelines.

Background: Male fertility potential cannot be measured by conventional parameters for the assisted reproduction technique; ICSI. This study determines the relationship between testicular and ejaculated sperm mitochondrial (mt) DNA deletions, nuclear (n) DNA fragmentation, and fertilization and pregnancy rates in ICSI., Methods: Ejaculated sperm were obtained from 77 men and testicular sperm from 28 men with obstructive azoospermia undergoing ICSI. Testicular sperm were retrieved using a Trucut needle. mtDNA was analysed using a long PCR. The alkaline Comet assay determined nDNA fragmentation., Results: Of subjects who achieved a pregnancy (50%) using testicular sperm, only 26% had partners' sperm with wild-type (WT) mtDNA. Of pregnant subjects (38%) using ejaculated sperm, only 8% had partner sperm with WT mtDNA. In each, the successful group had less mtDNA deletions and less nDNA fragmentation. There were inverse relationships between pregnancy and mtDNA deletion numbers, size and nDNA fragmentation for both testicular and ejaculated sperm. No relationships were observed with fertilization rates. An algorithm for the prediction of pregnancy is presented based on the quality of sperm nDNA and mtDNA., Conclusion: In both testicular and ejaculated sperm, mtDNA deletions and nDNA fragmentation are closely associated with pregnancy in ICSI.

Background: Fifteen percent of GP consultations are for dermatological conditions; 4% of these are referred to a dermatologist. There are long waiting lists for dermatology appointments. This study examines the value of instant photography in managing dermatology referrals., Objective: The purpose of our study was to compare outcomes of referral for dermatology appointments between patients whose referral letters do or do not include instant photograph(s)., Methods: Patients (136), referred to a dermatologist by GPs in two urban health centres, were randomly allocated to study and control groups. Instant photographs, taken by the GP, were included in the referral letters. Control group patients were given out-patient appointments in the usual way. The numbers of study group patients needing an appointment for diagnosis or management and with a changed diagnosis after face-to-face consultation were recorded. Waiting time from referral to appointment or management plan was recorded for both groups., Results: For 63% of the study group (45/71), a diagnosis and a management plan were made without the patient requiring an appointment. This included 38% (27/71) who, after diagnosis and initial management, needed an appointment and 25% (18/71) who did not. The remainder of the study group (37%; 26/71) required a face-to-face consultation. The mean time for formulation of a management plan for patients without an appointment was 17 days (SD = 11); waiting times for appointments in study and control groups were similar (mean 55 days; SD = 40)., Conclusions: Instant photography is helpful in managing dermatology referrals and offers the potential to reduce numbers requiring an out-patient appointment by 25%.

This study compared the use of horizontal parallax (HP) and vertical parallax (VP) radiography for localizing ectopic maxillary canines (EMCs). The true positions of 43 EMCs were determined using the operative notes and subsequent study models following exposure and eruption. Thirty-four palatal and nine buccal EMCs were included in the study. Six experienced orthodontists examined the radiographs of the EMCs and were asked to localize each EMC using VP and HP on separate occasions. The examiners recorded a diagnosis of 'unsure' in 12 per cent of cases using VP and in 5 per cent of cases using HP. The level of agreement of the diagnoses with the true position of the EMCs was significantly greater for HP. Eighty-three per cent of EMCs were correctly located with HP while only 68 per cent were correctly located with VP (P < 0.05). The diagnostic sensitivity for palatally placed canines was significantly greater for HP (88 per cent) than for VP (69 per cent). Both techniques performed poorly when used to localize buccal EMCs, with HP and VP each having a sensitivity of only 63 per cent. It is concluded that HP is superior to VP in diagnostic accuracy, and that two peri-apical radiographs or one peri-apical and one anterior occlusal radiograph are the radiographs of choice for localizing EMCs.

Defining how human immunodeficiency virus (HIV) interacts with macrophages, dendritic cells (DC), and other non-T cell reservoirs remains a critical area of research despite widespread use in the developed world of highly active antiretroviral therapy. In fact, as highlighted at the Fifth International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs, as viral suppression in T cells becomes increasingly effective, these alternative reservoirs may take on even greater relative importance as sites for viral persistence and as a target for purging. These cells may be especially important reservoirs in several critical settings of clinical relevance, and there are major differences in the molecular mechanisms that regulate HIV replication in these cells compared with T cells. Dysfunction of these cells may also play a major role in particular aspects of pathogenesis. Three broad themes emerged from the workshop regarding areas of recent progress, which also serve to identify current research challenges of (i). determining the role played by macrophages, DC, and other non-T cell viral targets in transmission and dissemination and as viral reservoirs at various stages of disease and in different compartments in vivo; (ii). identifying the molecular mechanisms by which virus-cell interactions affect the inflammatory, immune, and other functions of these cells; and (iii). defining the unique pathways that regulate infection and replication in these cellular compartments. This issue of JLB contains several reviews and original reports resulting from the workshop that address recent progress and highlight the current research questions regarding these cell types.

Objectives: To determine whether diagnostic triage by general practitioners (GPs) or rheumatology nurses (RNs) can improve the positive predictive value of referrals to early arthritis clinics (EACs)., Methods: Four GPs and two RNs were trained in the assessment of early inflammatory arthritis (IA) by four visits to an EAC supervised by hospital rheumatologists. Patients referred to one of three EACs were recruited for study and assessed independently by a GP, an RN and one of six rheumatologists. Each assessor was asked to record their clinical findings and whether they considered the patient to have IA. Each was then asked to judge the appropriateness of the referral according to predetermined guidelines. The rheumatologists had been shown previously to have a satisfactory level of agreement in the assessment of IA., Results: Ninety-six patients were approached and all consented to take part in the study. In 49 cases (51%), the rheumatologist judged that the patient had IA and that the referral was appropriate. The assessments of GPs and RNs were compared with those of the rheumatologists. Levels of agreement were measured using the kappa value, where 1.0 represents total unanimity. The kappa value was 0.77 for the GPs when compared with the rheumatologists and 0.79 for the RNs. Significant stiffness in the morning or after rest and objective joint swelling were the most important clinical features enabling the GPs and RNs to discriminate between IA and non-IA conditions., Conclusion: Diagnostic triage by GPs or RNs improved the positive predictive value of referrals to an EAC with a degree of accuracy approaching that of a group of experienced rheumatologists.

A systematic review of studies that investigated the association of antibiotics with hospital-acquired Clostridium difficile-associated diarrhoea (CDAD) was undertaken to summarize the strength of the evidence for this relationship. The results from the studies identified were considered after critically reviewing the design and conduct of each study. Although the majority of studies found an association with various antibiotics, antibiotic classes or components of antibiotic administration, most were limited in their ability to establish a causal relationship by the use of incorrect control groups, the presence of bias, inadequate control of confounding and small sample sizes. The limitations identified in this review prevented the pooling of results in a meta-analysis. Two studies of reasonable quality suggested an association between clindamycin, cephalosporins, penicillins and CDAD. Well-designed studies grounded in epidemiological principles are needed to identify true risk factors for CDAD and to provide reliable estimates of the strength of association.

Photo-elastic models replicating a lower arch with a moderate degree of lower incisor crowding and a palatally displaced maxillary canine were used to evaluate the stresses transmitted to the roots of the teeth by initial alignment archwires. Six initial alignment archwires were compared, two multi-strand stainless steel wires, two non-super-elastic (stabilized martensitic form) nickel titanium wires, and two stress-induced super-elastic (austenitic active) nickel titanium wires. Three specimens of each archwire type were tested. Analysis of the photo-elastic fringe patterns, in the medium supporting the teeth, revealed that the non-super-elastic nickel titanium archwires produced the highest shear stresses (P = 0.001). However, the shear stresses generated by the super-elastic alignment archwires and the multi-strand stainless steel archwires were very similar (P = 1.00). These results show that even in situations where large deflections of initial alignment archwires are required, super-elastic archwires do not appear to have any marked advantage over multi-strand stainless steel alignment archwires in terms of the stresses transferred to the roots of the teeth.

The incidence of Clostridium difficile-associated diarrhea (CDAD) has increased dramatically in hospitals worldwide during the past 2 decades. In Western Australia, this increase was most obvious during the 1980s, when there was also an increase in the use of third-generation cephalosporin antibiotics. A study of the epidemiology of CDAD and the use of third-generation cephalosporins during 1993-2000 was undertaken. From 1993 through 1998, the incidence of CDAD remained relatively stable (2-3 cases per 1000 discharges annually). Then, a significant decrease in the incidence occurred, from 2.09 cases per 1000 discharges (95% confidence interval [CI], 1.71-2.47) in 1998 to 0.87 cases per 1000 discharges (95% CI, 0.63-1.11) in 1999 (P<.0001); this decrease persisted into 2000. A decrease in third-generation cephalosporin use occurred during the period of the study because of changes in the prescribing policy. These findings suggest that a reduction in the use of third-generation cephalosporins can reduce the occurrence of CDAD.

Background: Influenza is a common respiratory disease that may affect a large proportion of the population annually. Vaccination is recommended for those most at risk of complications; namely everyone aged 65 and over and those under 65 who are immunosuppressed or who have chronic disease., Objective: To explore the variations in influenza vaccination rates for the winter of 2000, with special reference to uptake amongst older patients., Design: An audit of vaccination rates amongst 12 practices that participate in the Northern Ireland Data Retrieval in Primary Care Project., Methods: Data were extracted from the practice computers; Read codes were used to determine if the patient was immunosuppressed or suffered from chronic heart, lung or renal disease or had diabetes mellitus. The postcode of residence was used as a proxy for residence in a nursing or residential home as this could not be determined directly from the data. Multiple regression analysis was used to determine which factors were significantly related to vaccination uptake., Results: We vaccinated 10,427 patients in these practices against influenza with a vaccination rate of 65.2% for the over-65 population. Uptake rates peaked at age 85 and declined thereafter so that only half of those aged over 90 had been vaccinated. This age related decline in vaccination rates was evident in ten of the twelve practices. The presence of chronic disease increased the likelihood of vaccination even amongst older patients. Logistic regression confirmed the decline in uptake rates at older ages and suggested that patients who shared the address of a nursing or residential home were less likely to have been vaccinated., Conclusions: We feel that the current monitoring of influenza vaccination rates needs to be extended so that uptake amongst those most at risk, namely the very oldest and those in nursing and residential homes, can be adequately assessed.

This study examined the influence of maxillary gingival display on the attractiveness ratings awarded by lay people. One hundred and twenty university students (94 females, 26 males) were shown seven photographs of a male and seven photographs of a female subject, each with varying levels of gingival display ranging from -2 to +4 mm. Attractiveness ratings were recorded on a 10-point numerical scale for each of the photographs. The photographs where the full height of the incisors were revealed and no gingival tissue was visible (0 mm of gingiva) were rated as the most attractive. Gingival display of more than 2 mm was rated as progressively less attractive. Linear regression analysis revealed that those students who had received orthodontic treatment rated the photographs representing the female student as more attractive than those representing the male (P < 0.05).

This study aimed to determine the threshold of aesthetic impairment where orthodontic treatment would be sought by a sample of lay people. Using the 10-grade Aesthetic Component (AC) scale of the Index of Orthodontic Treatment Need (IOTN), 215 university students selected the level of aesthetic impairment that represented the point at which they would seek orthodontic treatment. Only nine (4.3 per cent) of the respondents recorded a threshold grade beyond grade 5 in the AC. The AC photograph grade 4 was found to be the most commonly selected threshold photograph. Subjects who visited the dentist every 6 months were more likely to choose a threshold photograph closer to the attractive end of the scale than those who visited their dentist less frequently (P < 0.01). This study, using lay people rather than dental health professionals, suggests that as currently used the AC does not reflect society's aesthetic expectations. The results indicate that when using the AC of the IOTN the 'no need for treatment' category should be grades 1-3 of the AC, rather than grades 1-4.

The aim of this study was to assess general dental practitioners' and orthodontists' perceptions of the benefits of orthodontic treatment. A specially designed questionnaire was sent to a random sample of 150 general dental practitioners (GDPs) and all orthodontists in Northern Ireland (excluding hospital practitioners) with a postgraduate qualification (n = 29). There was a 93 per cent response rate by the general dental practitioners and all but one specialist practitioner returned the questionnaire. The questionnaire comprised 14 visual analogue scales (VAS) whereby participants were asked to rate the importance of various possible dental health and psychosocial benefits of orthodontic treatment. In addition to the VAS, the influence of dentist variables such as number of years since qualification, orthodontic cases completed, referral rates and attendance at postgraduate lectures were examined. When ratings on the 14 dental health and psychosocial scales were examined overall, GDPs rated an improvement in self-esteem while orthodontists considered an improvement in physical attractiveness as the most important benefit of orthodontic treatment. Even though psychosocial variables received the highest ratings, examination of the mean ratings (and 95 per cent confidence intervals) revealed that some dental health factors were also rated highly by both groups. While the results do indicate an encouraging awareness of the psychosocial benefits of orthodontic treatment, they also suggest that both GDPs and orthodontists have an unrealistic expectation of the dental health gain likely to result from orthodontic treatment.

Background: The aim of this study was to examine differences in socio-economic standing and ill health between the two communities in Northern Ireland., Methods: This was a descriptive epidemiological study. Deaths from 1991 to 1995 inclusive were used to calculate standardized mortality rates (SMR, under 75 years) at small level using the 1991 Census population estimates. The standardized limiting long-term illness ratios (SIR) were based on the appropriate Census question. Regression models were tested with SMR and SIR as dependent variables and a wide range of socio-economic indicators, including income support and family credit uptake, as independent predictors., Results: Northern Ireland is a very polarized society. More than 60 per cent of the population live in areas which have more than 80 per cent of one religion. Areas with a preponderance of Catholics tend to be more deprived. Unemployment rates, percentage renting, car availability, and education attainment are all worse in Catholic areas. However, there is considerable heterogeneity between areas with similar levels of religious affiliation and the overall pattern varies with the indicator chosen. SMRs rise stepwise with increasing percentage of Catholics. SIRs increase with increasing polarization of areas, but this is much more marked in those with a predominantly Catholic affiliation. Altogether 46.8 per cent of the variance in SMR and 77.9 per cent of that of SIRs could be explained by socio-economic variables alone. Denomination did not have any residual predictive value., Conclusions: Policy-makers should continue to periodically monitor for differences between the two communities including any differences in service accessibility and uptake. Efforts should be directed towards reducing the inequalities in health for all sections of the community.

Primary factors that influence virus burden during human immunodeficiency virus type 1 (HIV-1) disease progression remain a fundamental issue in pathogenesis. Because pneumococcal vaccine is routinely given to HIV-1-infected patients and replication of HIV-1 within CD4 T cells is dependent on the activation state of the cell, it was investigated whether the T cell activation that enhances the immune response to vaccines may also enhance HIV-1 replication. Vaccination of asymptomatic HIV-1-infected patients led to rapid and significant increases in virus burden in some patients. The magnitude of these increases correlated significantly with the extent of the antibody response to the vaccination. Thus, antigenic stimulation by vaccines designed to prevent secondary infections may promote HIV-1 replication in certain patients. These findings provide a window for examining HIV-1 pathogenesis and for determining the appropriate preventive measures against other diseases in HIV-1-infected persons.

Background: Large geographic variations in hysterectomy rates are well known; however, very little is known about geographic variations in the route of the procedure, i.e. whether it is performed abdominally or vaginally. We compared utilization rates for abdominal and vaginal hysterectomies for the 14 Regional Health Authorities of England, and Northern Ireland over a three-year period., Methods: Data were collected in the form of hospital episode statistics and small area analysis techniques were used to document regional variations., Results: Large regional differences in the utilization of vaginal hysterectomies were recorded. Three areas in particular (Northern Ireland, Yorkshire and NW Thames) displayed high vaginal to abdominal ratios. Northern Ireland recorded the highest ratio (0.366), Mersey Regional Health Authority the lowest (0.139). The use of the vaginal route was found to increase with age, and was the most common route for the > 65 years age group., Conclusion: Despite an increasing volume of evidence advocating the use of the vaginal route, there appears to be a resistance to its use, except in older women. The role of physician practice style, and in particular group clinical judgement, is highlighted as being significantly involved in explaining the observed geographic variations.