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Competing Interests: Competing interests:: Hans Rosenberg reports payment for expert testimony from the Canadian Medical Protective Association and travel support from Canadian Women in Medicine. Bryden Magee reports payment from BioSyent as an advisory board member. No other competing interests were declared.

The increasing demand for fertility treatments has led to the rise of private clinics offering complementary and alternative medicine (CAM) treatments. The most frequently offered CAM infertility treatment is acupuncture. However, there is no good evidence to support the effectiveness of acupuncture in treating infertility. This study evaluates the scope of information provided by CAM fertility clinics in the UK. A content analysis was conducted on 200 websites of CAM fertility clinics in the UK that offer acupuncture as a treatment for infertility. Of the 48 clinics that met the eligibility criteria, the majority of the websites did not provide sufficient information on the efficacy, risks and success rates of acupuncture for infertility. This has the potential to infringe on patient autonomy, provide false hope and reduce the chances of pregnancy ever being achieved as fertility declines during the time course of ineffective acupuncture treatment., (© 2023. The Author(s).)

Objective: To report a case of ovarian stimulation for the purposes of oocyte cryopreservation in a transgender man without cessation of long-term testosterone therapy., Design: Report of a unique case of fertility preservation through ovarian stimulation and oocyte cryopreservation in a transgender man who had been on testosterone therapy for 18 months before treatment. The patient elected to continue testosterone therapy throughout ovarian stimulation and oocyte retrieval. To our knowledge, there have not been any published reports of patients undergoing oocyte cryopreservation while continuing long-term testosterone therapy., Setting: Private fertility clinic with university affiliation., Patients: A 20-year-old transgender man undergoing oocyte cryopreservation before gonadectomy., Interventions: Fertility preservation through oocyte cryopreservation., Main Outcome Measures: This patient had a robust response to ovarian gonadotropin stimulation. Leuprolide acetate was used for final oocyte maturation to minimize ovarian hyperstimulation syndrome risk., Results: Cryopreservation of 22 mature oocytes., Conclusions: Cryopreservation of mature oocytes is possible for patients on continued long-term testosterone therapy. The impact of long-term testosterone therapy on markers of ovarian reserve, reproductive potential, and long-term reproductive outcomes have yet to be elucidated and further studies are needed in this area., (© 2021 The Authors.)

This article considers semi-flexible composite (SFC) pavement materials made with reclaimed asphalt planings (RAP) and geopolymer cement-based grouts. Geopolymer grouts were developed and used to fill the internal void structure of coarse RAP skeletons with varying levels of porosity. The geopolymer grouts were formulated at ambient temperature using industrial by-products to offer economic and environmental savings relative to conventional Portland cement-based grouting systems. They were characterised on flowability, setting time, and compressive strength. The effect of grout and RAP on SFC material performance was evaluated using permeable porosity, compressive strength, and ultrasonic pulse velocity. SFC performance was significantly influenced by both grout type and RAP content. Improved performance was associated with mixtures of high-flowability/high-strength grout and low RAP content. A practical limitation was identified for combination of grout with low-flowability/fast-setting time and well-compacted RAP skeletons. Solids content exceeding 49% by volume was not feasible, owing to inadequate grout penetration. A suite of SFC materials was produced offering performance levels for a range of practical pavement applications. Preliminary relationships enabling prediction of SFC elastic modulus based on strength and/or ultrasonic pulse velocity test data are given. A pavement design is given using SFC as a sub-base layer for an industrial hardstanding.

Introduction: Although sport participation is a key contributor to the physical and mental health of children and youth, exposure to subconcussive head impacts in football has raised concerns about safety for athletes., Purpose: To demonstrate the efficacy of incorporating targeted football drills into a team's practice routine with the goal of improving players' technique and reduce exposure to subconcussive head impacts., Methods: Seventy high school football players (age, 16.4 ± 1.1 yr) were tested PRE season using a sport-specific functional assessment. Results from the testing were used to inform the design of a prepractice intervention aimed at improving tackling and blocking techniques while reducing exposure to head impacts. The assessment included drills which evaluated the players' ability to safely tackle, and block while simulating game-like situations. Testing was repeated at MID season (internal control) without an intervention, and again at POST season (experimental), after introduction of the prepractice intervention between these timepoints, administered twice weekly. All testing sessions were recorded, and subsequently reviewed by trained graders based on selected criteria defined by football coaches. A subset of 19 participants wore in-helmet accelerometers to assess the effectiveness of the intervention in decreasing head impacts during practice., Results: Significant improvements in blocking and tackling techniques were observed after the introduction of the intervention (P < 0.0001). Participating athletes also showed better techniques when evaluated in new game-like situations, postseason, providing evidence for proper acquisition and generalizability of these safer habits. Finally, frequency of head impacts (>15g) per practice was significantly reduced by ~30% after 1 month of training., Conclusion: Our results suggest that data-informed methods can be used to improve coaching practices and promote safer play, which can have a positive public health impact moving forward.

There is an increasing interest in hierarchical design and additive manufacturing (AM) of cement-based materials. However, the brittle behavior of these materials and the presence of interfaces from the AM process currently present a major challenge. Contrary to the commonly adopted approach in AM of cement-based materials to eliminate the interfaces in 3D-printed hardened cement paste (hcp) elements, this work focuses on harnessing the heterogeneous interfaces by employing novel architectures (based on bioinspired Bouligand structures). These architectures are found to generate unique damage mechanisms, which allow inherently brittle hcp materials to attain flaw-tolerant properties and novel performance characteristics. It is hypothesized that combining heterogeneous interfaces with carefully designed architectures promotes such damage mechanisms as, among others, interfacial microcracking and crack twisting. This, in turn, leads to damage delocalization in brittle 3D-printed architectured hcp and therefore results in quasi-brittle behavior, enhanced fracture and damage tolerance, and unique load-displacement response, all without sacrificing strength. It is further found that in addition to delocalization of the cracks, the Bouligand architectures can also enhance work of failure and inelastic deflection of the architectured hcp elements by over 50% when compared to traditionally cast elements from the same materials., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Saturn's moon Enceladus harbours a global water ocean 1 , which lies under an ice crust and above a rocky core 2 . Through warm cracks in the crust 3 a cryo-volcanic plume ejects ice grains and vapour into space 4-7 that contain materials originating from the ocean 8,9 . Hydrothermal activity is suspected to occur deep inside the porous core 10-12 , powered by tidal dissipation 13 . So far, only simple organic compounds with molecular masses mostly below 50 atomic mass units have been observed in plume material 6,14,15 . Here we report observations of emitted ice grains containing concentrated and complex macromolecular organic material with molecular masses above 200 atomic mass units. The data constrain the macromolecular structure of organics detected in the ice grains and suggest the presence of a thin organic-rich film on top of the oceanic water table, where organic nucleation cores generated by the bursting of bubbles allow the probing of Enceladus' organic inventory in enhanced concentrations.

Background: Marijuana is a commonly used substance in pregnancy in the United States. It is unknown what public health messages about perinatal marijuana use are being disseminated in the changing policy landscape., Methods: The authors systematically searched 51 state and 5 federal public health agencies' Web sites in February 2016 for information about perinatal marijuana use. Of these, 1 federal agency and 10 state agencies had published information about perinatal marijuana use. Content analysis was performed by 2 investigators, with excellent interrater reliability (mean κ = 0.87)., Results: Most content was targeted to the public, although 3 agencies had content targeted to health care providers. Common messages about health effects included adverse outcomes in infants and children exposed in utero and that marijuana can be passed via breast milk to infants. Eight sites mentioned health effects of marijuana use during breastfeeding, 5 included resources to stop using marijuana, 5 mentioned implications of marijuana use for infant safety, and 3 mentioned potential legal consequences., Conclusions: The volume of public health messages about perinatal marijuana use is low, content of messages differs across state agencies, and perinatal marijuana is seldom addressed in content published by federal agencies.

Thrombelastography (TEG) measured by the TEG5000 Hemostasis Analyzer is an established but the labor-intensive method for assessing global hemostasis. The first true point-of-care TEG, the TEG6s system, uses resonance-frequency viscoelasticity measurements and a disposable multi-channel microfluidic cartridge to assess hemostasis and response to antiplatelet therapy. TEG assays (n = 5,100) were performed on the blood of healthy volunteers (n = 157) and patients undergoing coronary revascularization at three hospitals (n = 300). The results from the TEG6s were compared with the conventional TEG5000 in accordance with Clinical and Laboratory Standards Institute (CLSI) and FDA recommendations. Precision testing was conducted using blood from healthy donors, all assays were run for 5 consecutive days in duplicate using multiple operators, lots, and instruments. Reference ranges were comparable between the TEG systems. Deming regression analysis demonstrated a strong correlation between the two systems for the standard hemostasis tests (R r = 0.932, MA r = 0.972, LY30 r = 0.938). Method comparison analysis showed an acceptable agreement between PlateletMapping (PM) assays for measuring arachidonic acid (indicator of aspirin response)- and adenosine diphosphate (indicator of P2Y 12 inhibitor response)-induced platelet aggregation (total agreement = 90%, and 72%, respectively). TEG6s precision testing yielded low variability (CV 0-13%) in all measures. The new point-of-care TEG6s is associated with greater ease of use than the TEG5000 and provides precise results. The results correlated between methods for all variables. TEG6s is a promising device for near-patient hemostasis monitoring and future trials of personalized therapy designed to reduce bleeding and thrombosis.

Arthropods have long been thought to respond to noxious stimuli by reflex reaction. One way of testing if this is true is to provide the animal with a way to avoid the stimulus but to vary the potential cost of avoidance. If avoidance varies with potential cost then a decision making process is evident and the behaviour is not a mere reflex. Here we examine the responses of hermit crabs to electric shock within their shell when also exposed to predator or non-predator odours or to no odour. The electric shocks start with low voltage but increase in voltage with each repetition to determine how odour affects the voltage at which the shell is abandoned. There was no treatment effect on the voltage at which hermit crabs left their shells, however, those exposed to predator odours were less likely to evacuate their shells compared with no odour or low concentrations of non-predator odour. However, highly concentrated non-predator also inhibited evacuation. The data show that these crabs trade-off avoidance of electric shock with predator avoidance. They are thus not responding purely by reflex and the data are thus consistent with predictions of pain but do not prove pain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Insights into the potential for pain may be obtained from examination of behavioural responses to noxious stimuli. In particular, prolonged responses coupled with long-term motivational change and avoidance learning cannot be explained by nociceptive reflex but are consistent with the idea of pain. Here, we placed shore crabs alternately in two halves of a test area divided by an opaque partition. Each area had a dark shelter and in one repeated small electric shocks were delivered in an experimental but not in a control group. Crabs showed no specific avoidance of the shock shelter either during these trials or in a subsequent test in which both were offered simultaneously; however they often emerged from the shock shelter during a trial and thus avoided further shock. More crabs emerged in later trials and took less time to emerge than in early trials. Thus, despite the lack of discrimination learning between the two shelters they used other tactics to markedly reduce the amount of shock received. We note that a previous experiment using simultaneous presentation of two shelters demonstrated rapid discrimination and avoidance learning but the paradigm of sequential presentation appears to prevent this. Nevertheless, the data show clearly that the shock is aversive and tactics, other than discrimination learning, are used to avoid it. Thus, the behaviour is only partially consistent with the idea of pain., (© 2016. Published by The Company of Biologists Ltd.)

Retroperitoneal hemorrhage and an associated hematoma are uncommon but potentially serious complications following ureteroscopy with laser lithotripsy. However, no reports of serious bleeding complications have been published regarding ureteroscopy without laser lithotripsy in the management of stone disease. We report of such a case here and then review the current literature in order to discuss the incidence, risk factors, and management of such events.

Background: The purpose of this study was to describe the delivery of prenatal care services to women with opioid use disorder (OUD) on opioid maintenance therapy at high risk for hepatitis C virus (HCV) infection., Methods: We conducted a retrospective cohort evaluation of 791 pregnant women with OUD from 2009 to 2012. HCV screening was defined as documentation of (a) an anti-HCV antibody test or (b) a provider discussion regarding a known HCV diagnosis during pregnancy. Multivariate logistic regression was used to identify predictors of HCV screening during pregnancy., Results: Among 791 pregnant women with OUD, 611 (77.2%) were screened for HCV infection and 369/611 (60.4%) were HCV positive. In multivariable analysis, patients who were married (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.29, 0.91), used buprenorphine (OR = 0.45; 95% CI = 0.28, 0.71), and were cared for by private practice providers (OR = 0.29; 95% CI = 0.19, 0.45) were significantly less likely to be screened. In contrast, patients who used benzodiazepines (OR = 1.72; 95% CI = 1.02, 2.92), intravenous (IV) opioids (OR = 6.15; 95% CI = 3.96, 9.56), had legal problems (OR = 2.23; 95% CI = 1.12, 4.45), had children not in their custody (OR = 1.81; 95% CI = 1.01, 3.24), and who had a partner with substance abuse history (OR = 2.38; 95% CI = 1.23, 4.59) were significantly more likely to be screened. Of 369 HCV-positive patients, a new diagnosis of HCV was made during pregnancy for 108 (29.3%) patients. Only 94 (25.5%) had HCV viral load testing, 61 (16.5%) had HCV genotype testing, and 38 (10.4%) received an immunization for hepatitis A. Although 285 (77.2%) patients were referred to hepatology, only 71 (24.9%) attended the consultation. Finally, only 6 (1.6%) patients received HCV treatment 1 year following delivery., Conclusions: Prenatal care approaches to HCV infection remain inconsistent, and the majority of patients diagnosed with HCV infection during pregnancy do not receive treatment after delivery.

Objective: Anecdotal reports suggest that application of a cool device to the back of the neck at the onset of a hot flush can afford symptomatic relief. The effects of a novel handheld mechanical cooling device in a population of perimenopausal women with moderate-to-severe vasomotor symptoms were evaluated., Methods: In this randomized, double-blind, sham-controlled pilot study, 40 perimenopausal women experiencing ≥ 7 moderate-to-severe hot flushes per day were recruited at a single university site. Women were randomized to the active (n = 20) or sham (n = 20) device, which was applied to the back of the neck with each hot flush over the 4-week treatment period. Hot flush scores were calculated based on frequency and severity of symptoms. The Carpenter Hot Flash Related Daily Interference Scale and Zung Anxiety Scale were used to evaluate impact on quality of life. At study end, participants completed an open-ended questionnaire to assess the degree of unblinding and overall subjective improvement in symptoms with use of the device., Results: No statistically significant differences were observed between the effects of the active and sham device. However, thematic analysis of the open-ended questionnaire revealed that 12/17 women (70.6%) in the active group, compared to 4/18 (22.2%) women in the sham group felt the device provided some symptomatic relief., Conclusions: Although the majority of women using the active device acknowledged that its cooling effect afforded a degree of symptomatic relief, the symptom scores chosen for this pilot study did not reflect a beneficial effect.

This paper presents a risk assessment of exposure to metal residues in laundered shop towels by workers. The concentrations of 27 metals measured in a synthetic sweat leachate were used to estimate the releasable quantity of metals which could be transferred to workers' skin. Worker exposure was evaluated quantitatively with an exposure model that focused on towel-to-hand transfer and subsequent hand-to-food or -mouth transfers. The exposure model was based on conservative, but reasonable assumptions regarding towel use and default exposure factor values from the published literature or regulatory guidance. Transfer coefficients were derived from studies representative of the exposures to towel users. Contact frequencies were based on assumed high-end use of shop towels, but constrained by a theoretical maximum dermal loading. The risk estimates for workers developed for all metals were below applicable regulatory risk benchmarks. The risk assessment for lead utilized the Adult Lead Model and concluded that predicted lead intakes do not constitute a significant health hazard based on potential worker exposures. Uncertainties are discussed in relation to the overall confidence in the exposure estimates developed for each exposure pathway and the likelihood that the exposure model is under- or overestimating worker exposures and risk., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of histological chorioamnionitis associated with preterm prelabour rupture of membranes (PPROM) in women following spontaneous onset of labour, urgent delivery or planned delivery after 34 weeks' gestation., Methods: Charts of all women admitted to Kingston General Hospital with PPROM prior to 34 weeks' gestation over five years were collected. Obstetrical outcomes and histopathology reports were reviewed., Results: Two hundred forty-four women with PPROM were identified and reviewed. The majority of women (169; 69%) went into spontaneous labour and, of those, 24 (14%) had clinical chorioamnionitis and 79 (47%) had histological chorioamnionitis. Of the 45 women (18%) who required urgent delivery, 27 (60%) had clinical chorioamnionitis and 31 (69%) had histological chorioamnionitis. Only 26 of the original 244 women with PPROM (11%) were managed expectantly until 34 weeks' gestation and then had a planned delivery. The prevalence of histological chorioamnionitis in this group whose placentas were sent for histopathologic review was 24%. Overall, the clinical suspicion of chorioamnionitis was found to be specific (91%) but not sensitive (37%) for identifying chorioamnionitis on the basis of histopathology., Conclusion: Histological chorioamnionitis complicates almost one half of all cases of PPROM that occur prior to 34 weeks' gestation. Most women will progress to spontaneous labour or require urgent delivery for clinical chorioamnionitis or other complications related to ruptured membranes before reaching 34 weeks' gestation. Only a subset of women remain pregnant long enough to have labour induced, but among those the prevalence of histological chorioamnionitis is lower (24%).

Nociception allows for immediate reflex withdrawal whereas pain allows for longer-term protection via rapid learning. We examine here whether shore crabs placed within a brightly lit chamber learn to avoid one of two dark shelters when that shelter consistently results in shock. Crabs were randomly selected to receive shock or not prior to making their first choice and were tested again over 10 trials. Those that received shock in trial 2, irrespective of shock in trial 1, were more likely to switch shelter choice in the next trial and thus showed rapid discrimination. During trial 1, many crabs emerged from the shock shelter and an increasing proportion emerged in later trials, thus avoiding shock by entering a normally avoided light area. In a final test we switched distinctive visual stimuli positioned above each shelter and/or changed the orientation of the crab when placed in the chamber for the test. The visual stimuli had no effect on choice, but crabs with altered orientation now selected the shock shelter, indicating that they had discriminated between the two shelters on the basis of movement direction. These data, and those of other recent experiments, are consistent with key criteria for pain experience and are broadly similar to those from vertebrate studies.

Objective: To determine whether a novel web-based learning module could adequately prepare first-year undergraduate medical students to skilfully perform their first female pelvic examination., Methods: First-year Queen's University medical students without prior training or experience in female pelvic examination were recruited for this study. After viewing key segments of the learning module, students were evaluated while performing a pelvic examination on a female volunteer using a standardized assessment checklist (total score = 30 points). Descriptive and comparative statistics were generated., Results: Forty-five students participated with a mean age of 24 years (range 20 to 40). The mean score (±SD) on the assessment checklist was 23.9 ± 3.6 points, (range 17 to 30). All study participants received a passing grade of ≥ 50% (15/30 points), and 53.3% (24/45) received an honours grade of ≥ 80% (24/30 points). Of the participants, 88.9% (40/45) agreed that they were well prepared for their first female pelvic examination after viewing the training video. Mean scores were similar for male students (23.9, n = 22) and female students (23.8, n = 23) (P = 0.90, t test). Mean scores were not higher in those who watched key segments of the learning module more than once., Conclusion: This learning module viewed immediately prior to a simulated clinic session afforded first-year medical students the necessary knowledge and skills to perform a first female pelvic examination. This was accomplished with as little as one viewing, and could lead to savings in organizational costs and instruction time for medical school curricula.

Several naphthalene Unit Risk Factors (URFs) were proposed by the US Environmental Protection Agency in 2004 using data on the development of olfactory epithelial neuroblastomas and nasal respiratory epithelial adenomas in rats, but these URFs may be inappropriate and unnecessarily conservative for estimating human cancer risks. The purpose of the present exercise was to perform a screening-level population risk assessment of the US population to compare the observed number of naphthalene-induced nasal tumors in the US to the number that would be predicted if the URFs for naphthalene were as proposed. Nine scenarios were evaluated to represent the range of exposures individuals have typically experienced. Results indicate that the total predicted burden of naphthalene-induced nasal tumors per year in the US (65,905 rare nasal tumors, of which 29,121 are olfactory epithelial neuroblastomas) is much greater than the number of these tumors actually observed per year (910 total nasal tumors, of which 66 are olfactory neuroblastomas) over the period 1973-2006. This suggests that using rat nasal tumor data to derive a naphthalene URF for humans should be re-evaluated., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To evaluate the current patient care practices that address the predisposing and precipitating factors contributing to the prevention of hospital-acquired delirium in the elderly., Design: Prospective cohort (observational) study., Participants: Patients 65 years of age and older who were admitted to medical teaching units at the University of Alberta Hospital in Edmonton over a period of 7 months and who were at risk of delirium., Setting: Medical teaching units at the University of Alberta., Main Outcome Measures: Demographic data and information on predisposing factors for hospital-acquired delirium were obtained for all patients. Documented clinical practices that likely prevent common precipitants of delirium were also recorded., Results: Of the 132 patients enrolled, 20 (15.2%) developed hospital-acquired delirium. At the time of admission several predisposing factors were not documented (eg, possible cognitive impairment 16 [12%], visual impairment 52 [39.4%], and functional status of activities of daily living 99 [75.0%]). Recorded precipitating factors included catheter use, screening for dehydration, and medications. Catheters were used in 35 (26.5%) patients, and fluid intake-and-output charting assessed dehydration in 57 (43.2%) patients. At the time of admission there was no documentation of hearing status in 69 (52.3%) patients and aspiration risk in 104 (78.8%) patients. After admission, reorientation measures were documented in only 16 (12.1%) patients. Although all patients had brief mental status evaluations performed once daily, this was not noted to occur twice daily (which would provide important information about fluctuation of mental status) and there was no formal attention span testing. In this study, hospital-acquired delirium was also associated with increased mortality (P < .004), increased length of stay (P < .007), and increased institutionalization (P < .027)., Conclusion: Gaps were noted in patient care practices that might contribute to hospital-acquired delirium and also in measures to identify the development of delirium at an earlier stage. Effort should be made to educate health professionals to identify the predisposing and precipitating factors, and to screen for delirium. This might improve the prevention of delirium.

Background and Purpose: Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity., Materials and Methods: Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose., Results: Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9)mm laterally, 2.8 (3.5)mm vertically and 2.3 (3.2)mm longitudinally. Rotations >2 degrees in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity., Conclusions: CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.

Candida albicans is a diploid organism that exhibits high levels of heterozygosity. Although the precise manner by which this heterozygosity provides advantage for the commensal/pathogenic life styles of C. albicans is not known, heterozygous markers are themselves useful for studying genomic rearrangements, which occur frequently in C. albicans. Treatment of CAI-4 with UV light yielded histidine auxotrophs which could be complemented by HIS4, suggesting that strain CAI-4 is heterozygous for HIS4. These auxotrophs appeared to have undergone mitotic recombination and/or chromosome loss. As expected from a heterozygote, disruption of the functional allele of HIS4 resulted in a his4::hisG-URA3-hisG strain that is auxotrophic for histidine. Sequencing of random clones of the HIS4 ORF from CAI-4 and its precursor SC5314 revealed the presence of 11 SNPs, seven synonymous and four non-synonymous. Site-directed mutagenesis indicates that only one of those SNPs, T929G (Gly310Val), is responsible for the non-functionality of the encoded enzyme. HIS4 analysis of five commonly used laboratory strains is reported. This study provides a new, easily measured nutritional marker that can be used in future genetic studies in C. albicans.

Titan's lower atmosphere has long been known to harbor organic aerosols (tholins) presumed to have been formed from simple molecules, such as methane and nitrogen (CH4 and N2). Up to now, it has been assumed that tholins were formed at altitudes of several hundred kilometers by processes as yet unobserved. Using measurements from a combination of mass/charge and energy/charge spectrometers on the Cassini spacecraft, we have obtained evidence for tholin formation at high altitudes (approximately 1000 kilometers) in Titan's atmosphere. The observed chemical mix strongly implies a series of chemical reactions and physical processes that lead from simple molecules (CH4 and N2) to larger, more complex molecules (80 to 350 daltons) to negatively charged massive molecules (approximately 8000 daltons), which we identify as tholins. That the process involves massive negatively charged molecules and aerosols is completely unexpected.

The Cassini spacecraft passed within 168.2 kilometers of the surface above the southern hemisphere at 19:55:22 universal time coordinated on 14 July 2005 during its closest approach to Enceladus. Before and after this time, a substantial atmospheric plume and coma were observed, detectable in the Ion and Neutral Mass Spectrometer (INMS) data set out to a distance of over 4000 kilometers from Enceladus. INMS data indicate that the atmospheric plume and coma are dominated by water, with significant amounts of carbon dioxide, an unidentified species with a mass-to-charge ratio of 28 daltons (either carbon monoxide or molecular nitrogen), and methane. Trace quantities (<1%) of acetylene and propane also appear to be present. Ammonia is present at a level that does not exceed 0.5%. The radial and angular distributions of the gas density near the closest approach, as well as other independent evidence, suggest a significant contribution to the plume from a source centered near the south polar cap, as distinct from a separately measured more uniform and possibly global source observed on the outbound leg of the flyby.

In an effort to replace the complement-dependent cytotoxicity test (CDC) with a more sensitive single technique we looked at flow cytometry as a possible replacement. The Flow PRA Bead technique (One Lambda) performed well in our laboratory. Although as expected this technique was more sensitive and specific than CDC, there remained 11 samples from eight patients which were flow negative, CDC positive. The results of various antibody identification tests on these samples prompted us to alter the positive selection criteria which we had been using on our routine screening with the Flow PRA Beads and persuaded us that the initial CDC result was correctly positive in nine of the 11 samples.

Background and Purpose: Evaluation of effect of timing of external beam radiation therapy (EBRT) following surgery for craniopharyngioma., Materials and Methods: Between 1976 and 2002, 87 patients (28 children) received EBRT in a regional referral centre. Forty-four patients received EBRT adjuvantly and 43 on relapse. The median total dose was 42.5Gy (range 34.7-52.5Gy) in 2.25-2.83Gy fractions over a median of 20 days (range 17-32). Effect of EBRT timing, type of original surgery, age on survival, progression-free survival (PFS) and quality of life (QOL) was studied., Results: Survival from diagnosis was 86 and 76% and PFS was 78 and 66% at 10 and 20 years, respectively, with no significant difference seen between those treated adjuvantly or at relapse or according to age. QOL deteriorated significantly from diagnosis to last follow-up. Excluding patients who relapsed following EBRT, QOL did not deteriorate significantly overall (P=0.35). Children had worse QOL and greater morbidity at all timepoints compared to adults., Conclusions: EBRT is effective both adjuvantly and at relapse. QOL deteriorates over time-relapse following EBRT was the only significant factor. Children have greater morbidity compared to adults, but no evidence for greater EBRT-induced toxicity was seen.

Aims: To investigate intensity-modulated radiotherapy (IMRT) plans for women with carcinoma of the breast, using a small number of Sim-CT slices, thus avoiding changing the patient's position and potential problems with CT capacity., Materials and Methods: Ten CT scans of women with breast cancer were obtained for use in the study. IMRT plans based on an open tangent pair and additional top-up segment fields were created using the full CT scan, and represented the gold standard treatment plan for comparison purposes. Five-slice CT simulator scans were artificially created by omitting intermediate slices from the full CT scans. Additionally, the intermediate CT slices were recreated via interpolation of the five slices using a standard interpolation algorithm. IMRT plans were created in the same way as for the full CT scans. To allow a suitable plan comparison to be made, the beam segments and monitor units were transferred to the full CT scans, and the dose distribution calculated., Results: The interpolated five-slice plans showed no significant difference in the volume of tissue receiving dose outside the range 95-105%, compared with the IMRT plans created using the full CT data set (1.3 +/- 2.2%, P = 0.092). In contrast, the discrete slice CT simulator plans increased by 6.3 +/- 5.4%, P = 0.0054, showing a statistically significant difference in the dose distribution produced and a clinically inferior plan., Conclusions: Plans created using five discrete slice CT scans were inferior to full CT-derived IMRT treatment plans, and are therefore not acceptable for IMRT. However, interpolating five CT simulator slices provides adequate anatomical information to produce comparable IMRT plans to those created by full CT scans of the patient. This allows the introduction of IMRT for this patient group without the need to change treatment position to accommodate CT scanning.

The Cassini Ion Neutral Mass Spectrometer (INMS) has obtained the first in situ composition measurements of the neutral densities of molecular nitrogen, methane, molecular hydrogen, argon, and a host of stable carbon-nitrile compounds in Titan's upper atmosphere. INMS in situ mass spectrometry has also provided evidence for atmospheric waves in the upper atmosphere and the first direct measurements of isotopes of nitrogen, carbon, and argon, which reveal interesting clues about the evolution of the atmosphere. The bulk composition and thermal structure of the moon's upper atmosphere do not appear to have changed considerably since the Voyager 1 flyby.

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.

Objective: To describe the pressure ulcer prevalence, stage and body location, and demographic characteristics of patients with pressure ulcers at a tertiary care adult hospital and a tertiary care pediatric hospital., Design: Prevalence survey., Setting and Subjects: A total of 513 inpatients, including 416 adults admitted to a tertiary care hospital and 97 children admitted to a tertiary care pediatric hospital. Only inpatients with mental health-related diagnoses were excluded., Instruments: The Kinetics Concepts International's Prevalence and Incidence Study Collection Form was used to assess variables, including demographic information; presence, location, and stage of pressure ulcers; and presence of special support surfaces., Methods: All patients had head-to-toe skin assessments performed during an 8-hour period by teams of 3 multidisciplinary staff members. Kinetics Concepts International's Prevalence and Incidence Program software and Microsoft Excel were used for data entry and analysis., Results: Combined pressure ulcer prevalence was 26.3%, with 29.2% in adult patients and 13.1% in pediatric patients. The most common body locations for pressure ulcers were the sacrum (22.1%), heels (14.8%), ears (12.9%), elbows (10.6%), and the buttocks (6.8%). Forty-eight percent of the ulcers were stage I, 36% Stage II, 6% Stage III-IV, and 10% unable to stage., Conclusions: Overall combined pressure ulcer prevalence and common body locations were consistent with findings from comparable hospitals. Patients at the extreme ends of the age spectrum had an increased risk of pressure ulcers. Stage I and II ulcers occurred most frequently. Potential prevention and early management strategies may be effective in decreasing the prevalence of these ulcers.

Purpose: To investigate whether transforming growth factor beta-1 (TGFbeta1) single nucleotide polymorphisms were associated with the susceptibility of breast cancer patients to severe radiation-induced normal tissue damage., Materials and Methods: PCR-RFLP assays were performed for TGFbeta1 gene polymorphisms on DNA obtained from 103 breast cancer patients who received radiotherapy. The G-800A, C-509T, T+869C and G+915C polymorphic sites were examined, and genotype and allele frequencies of two subgroups of patients were calculated and compared., Results: The less prevalent -509T and +869C alleles were significantly associated with a subgroup of patients who developed severe radiation-induced normal tissue fibrosis (n=15) when compared with those who did not (n=88) (odds ratio=3.4, p=0.0036, and 2.37, p=0.035, respectively). Furthermore, patients with the -509TT or +869CC genotypes were between seven and 15 times more likely to develop severe fibrosis., Conclusions: These findings imply a role for the -509T and +869C alleles in the pathobiological mechanisms underlying susceptibility to radiation-induced fibrosis. Their predictive value would be limited to patients who are -509TT or +869CC, but if "fibrosis-associated" polymorphic sites in other genes could be identified, it may be possible to detect fibrosis prone individuals before radiotherapy with greater certainty.

Local recurrence of cancer in the treated breast following breast-conserving surgery and radiotherapy occurs in a minority of patients, but can represent a significant clinical problem. The impact of local relapse on the subsequent course of the disease is disputed. The aim of this retrospective review was to identify the rate and prognostic factors for breast recurrence and to determine the subsequent outcome. The case notes of 2159 patients treated between 1989 and 1992 were reviewed. Actuarial local relapse rate was 6.3% at 5 years. Factors predictive for recurrence on multivariate analysis were age (P<0.001), status of excision margins (P=0.019), and pathological UICC stage (P=0.01). One hundred and sixty-one patients developed local recurrence in the treated breast of whom 101 were treated with further surgery. The 5-year cancer-specific survival of this group was comparable with that of the patients who remained free of breast relapse (82 vs. 88%) but subsequently fell to 61 vs. 80% at 8 years (P<0.001). Sixty patients were unable to have salvage surgery; their cancer-specific survival was much worse than that of patients with operable recurrences at 33% at 5 years and 13% at 8 years. Eighty-three patients (4% of the original 2159 patients) had uncontrolled local disease at time of death or last follow-up. The prognosis of patients who developed recurrence within 2 years of their initial treatment was inferior to those who developed recurrences after 4 years (cancer-specific survival 5 years post-recurrence 23 vs. 57% P=0.008). Systemic therapy should be considered for patients with early breast recurrence in view of their inferior survival.

Curative radiotherapy for cancer patients requires the use of radiation doses that are limited by the tolerance of the surrounding normal tissues. Unfortunately, these tolerance doses vary not only between tissues but also between individuals. In a small proportion of sensitive patients, exposure to radiation can lead to severe irreversible morbidity and even death several months to years after treatment. At present these radiosensitive patients can be identified only retrospectively. Here we describe a cytokine microarray technique that was used to identify differentially expressed gene transcripts in fibroblasts obtained from a small group of patients who suffered either negligible or severe normal damage to tissues after radiotherapy. If our preliminary findings can be confirmed, the availability of such markers may eventually allow the prediction of outcome prior to commencement of radiotherapy, and thus allow modification of radiotherapy protocols to minimize adverse late effects, without compromising tumor control.

Background and Purpose: Using pulsed field gel electrophoresis (PFGE) a significant correlation was demonstrated between residual DNA double-strand breaks (dsbs) and the development of late radiation fibrosis in a group of 39 breast cancer patients studied retrospectively. This group formed a training cohort generating a hypothesis that there is a relationship between residual radiation-induced DNA dsbs in cultured fibroblasts and late radiotherapy reactions in breast cancer patients. The aim of this study was to retest and validate the hypothesis., Materials and Methods: The study was retrospective. Skin biopsies were taken from a validation cohort of 50 breast cancer patients and PFGE was used to examine residual radiation-induced dsbs in cultured fibroblasts. Late morbidity was measured clinically as fibrosis and using the late effects on normal tissues scales that incorporate subjective, objective management and analytic data (LENT SOMA)., Results: PFGE data were obtained for 49 biopsies. In the 49 patients there was no correlation between residual DNA damage and either fibrosis (r=-0.027, P=0.85) or LENT SOMA (r=-0.10, P=0.48) scores. There was no significant relationship between residual damage and fibrosis for the combined training and validation cohorts of 88 patients (r=0.20, P=0.063)., Conclusions: This study did not validate the hypothesis that there is a relationship between fibroblast residual DNA damage and late morbidity in breast cancer patients. The PFGE assay on fibroblasts is not a suitable test of the degree of late radiation-induced fibrosis in the breast.

Medulloblastoma is an uncommon tumour in the adult population. Maximum surgical resection followed by craniospinal irradiation with a posterior fossa boost is the standard treatment. We report the case history of an adult with medulloblastoma and severe kyphoscoliosis. The unusual anatomy of the patient posed a technical challenge to the oncologist and the physicist in planning the craniospinal radiotherapy. A shaped spinal field matched to a parallel opposed pair of shaped head fields was used. The technique used in treating this patient was made possible with the use of a multileaf collimation and verification with an electronic portal imaging device. The patient remains well with no sign of relapse 4 years after treatment.

Aim: To evaluate the sensitivity and specificity of axillary magnetic resonance imaging (MRI) in symptomatic patients, who had previously been treated for breast cancer, compared with clinical outcome after a minimum of 1 year., Methods: One hundred and five patients underwent axillary MRI examinations and were diagnosed as axillary tumour, metastatic tumour, treatment effect or normal., Results: At MRI, 48 patients had axillary tumour, 51 had metastatic tumour (37 had both), 27 had treatment effect and 22 were normal. At outcome (median follow-up, 484 days), 54 patients were positive for axillary tumour, 59 for metastatic disease (40 had both), 21 had treatment effect alone and 18 were clear. Magnetic resonance imaging showed 89% sensitivity, 100% specificity and 94% accuracy for recurrent axillary tumour, and 85% sensitivity, 98% specificity and 90% accuracy for metastatic tumour. Soft tissue plaques were the commonest axillary disease pattern seen (37). Small volume soft tissue plaques gave the most diagnostic difficulty. Non-dynamic enhancement with intravenous Gadopentetate dimeglumine (Gd-DTPA) in a subset of 34 patients improved sensitivity for axillary tumour from 40 to 74%, and improved diagnostic confidence in 11 patients (32%). Magnetic resonance imaging had a positive management impact leading to treatment alteration in 45 patients, 43 of whom had recurrent axillary and/or metastatic tumour., Conclusions: Tumour plaques were the commonest pattern of recurrent axillary disease. Forty-eight percent of the patients had metastatic deposits identified by MRI. Magnetic resonance imaging had excellent specificity (100%) and good sensitivity (89%) for recurrent axillary tumour compared with outcome at 1 year, which was improved by non-dynamic administration of Gd-DTPA in 32% of the subset who received it.

At the institute, since the late 1980s, there has been a uniform treatment protocol for the management of the regional lymph nodes in patients referred for radiotherapy following breast-conserving surgery. An analysis of 2,277 consecutive patients referred for radiotherapy between 1989 and 1992, with particular reference to regional lymph node management, has been undertaken. Axillary surgery alone was used in 517 patients (23%); 1,191 (52%) patients had no axillary surgery but had radiotherapy to the axilla, and infraclavicular and supraclavicular fossae by a single anterior field, delivering 40 Gy in 15 daily fractions over 3 weeks; and 474 patients (21%) had axillary surgery followed by radiotherapy. Ninety-five patients (4%) underwent no axillary treatment. There was a total of 155 axillary recurrences with a median follow-up of 5.9 years, giving an actuarial nodal control rate of 94% at 5 years (95% confidence interval (CI) 93.1-95.1). The overall survival at 5 years was 86% (95% CI 84.6-87.5). There was a trend towards improved axillary control with surgery alone compared with radiotherapy alone (4.5% versus 5.9% actuarial axillary failure rate at 5 years). An extremely low incidence of brachial plexus neuropathy secondary to radiotherapy was reported. The multidisciplinary treatment protocol used gave a high rate of regional node control, with minimal recorded morbidity.