The dispersion-brightness relation for fast radio bursts from a wide-field survey.

Despite considerable efforts over the past decade, only 34 fast radio bursts-intense bursts of radio emission from beyond our Galaxy-have been reported1,2. Attempts to understand the population as a whole have been hindered by the highly heterogeneous nature of the searches, which have been conducted with telescopes of different sensitivities, at a range of radio frequencies, and in environments corrupted by different levels of radio-frequency interference from human activity. Searches have been further complicated by uncertain burst positions and brightnesses-a consequence of the transient nature of the sources and the poor angular resolution of the detecting instruments. The discovery of repeating bursts from one source3, and its subsequent localization4 to a dwarf galaxy at a distance of 3.7 billion light years, confirmed that the population of fast radio bursts is located at cosmological distances. However, the nature of the emission remains elusive. Here we report a well controlled, wide-field radio survey for these bursts. We found 20, none of which repeated during follow-up observations between 185-1,097 hours after the initial detections. The sample includes both the nearest and the most energetic bursts detected so far. The survey demonstrates that there is a relationship between burst dispersion and brightness and that the high-fluence bursts are the nearby analogues of the more distant events found in higher-sensitivity, narrower-field surveys5.

Predictors of recovery of ovarian function during aromatase inhibitor therapy.

BACKGROUND: Aromatase inhibitors (AIs) may cause a rise in estrogen levels due to ovarian function recovery in women with clinical chemotherapy-induced ovarian failure (CIOF). We carried out a prospective registry trial to identify predictors of ovarian function recovery during AI therapy. PATIENTS AND METHODS: Women with hormone receptor (HR)-positive breast cancer who remained amenorrheic and had hormonal levels consistent with ovarian failure after adjuvant chemotherapy were enrolled in a multi-institutional clinical trial of anastrozole. Subjects underwent frequent assessment using an ultrasensitive estradiol assay. Multivariable analysis was used to evaluate clinical and biochemical predictors of ovarian function recovery within 48 weeks. RESULTS: Recovery of ovarian function during AI therapy was observed in 13 of 45 (28.9%) assessable subjects after a median 2.1 months (range 0.6-11.9). Median age at chemotherapy initiation was statistically significantly different between those who regained ovarian function (43 years, range 40-51) and those who remained postmenopausal (49 years, range 44-52; P < 0.0001). CONCLUSIONS: A significant proportion of women with CIOF recover ovarian function during AI therapy, including a woman over age 50 at initiation of chemotherapy. Tamoxifen remains the standard of care for women with CIOF. If an AI is used, patients should be monitored frequently with high-quality estradiol assays. CLINICALTRIALS.GOV: NCT00555477.

Evaluation of the trade-offs encountered in planning and treating locally advanced head and neck cancer: intensity-modulated radiation therapy vs dual-arc volumetric-modulated arc therapy.

OBJECTIVE: The primary purpose of this study was to assess the practical trade-offs between intensity-modulated radiation therapy (IMRT) and dual-arc volumetric-modulated arc therapy (DA-VMAT) for locally advanced head and neck cancer (HNC). METHODS: For 15 locally advanced HNC data sets, nine-field step-and-shoot IMRT plans and two full-rotation DA-VMAT treatment plans were created in the Pinnacle(3) v. 9.0 (Philips Medical Systems, Fitchburg, WI) treatment planning environment and then delivered on a Clinac iX (Varian Medical Systems, Palo Alto, CA) to a cylindrical detector array. The treatment planning goals were organised into four groups based on their importance: (1) spinal cord, brainstem, optical structures; (2) planning target volumes; (3) parotids, mandible, larynx and brachial plexus; and (4) normal tissues. RESULTS: Compared with IMRT, DA-VMAT plans were of equal plan quality (p>0.05 for each group), able to be delivered in a shorter time (3.1 min vs 8.3 min, p<0.0001), delivered fewer monitor units (on average 28% fewer, p<0.0001) and produced similar delivery accuracy (p>0.05 at γ(2%/2mm) and γ(3%/3mm)). However, the VMAT plans took more planning time (28.9 min vs 7.7 min per cycle, p<0.0001) and required more data for a three-dimensional dose (20 times more, p<0.0001). CONCLUSIONS: Nine-field step-and-shoot IMRT and DA-VMAT are both capable of meeting the majority of planning goals for locally advanced HNC. The main trade-offs between the techniques are shorter treatment time for DA-VMAT but longer planning time and the additional resources required for implementation of a new technology. Based on this study, our clinic has incorporated DA-VMAT for locally advanced HNC. ADVANCES IN KNOWLEDGE: DA-VMAT is a suitable alternative to IMRT for locally advanced HNC.

Adjunctive GnRH-a treatment attenuates depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients.

BACKGROUND: We measured antimullerian hormone (AMH), a marker of ovarian reserve, in women with lupus treated with cyclophosphamide (CYC) (group I), CYC plus gonadotropin-releasing hormone agonist (GnRH-a) (group II) or neither (group III). We hypothesized that AMH would be diminished in women exposed to CYC versus women receiving adjunctive GnRH-a treatment or no CYC exposure. METHODS: Forty-eight premenopausal lupus patients were retrospectively divided into three treatment groups: CYC alone (group I, n = 11), CYC + GnRH-a (group II, n = 10) and neither (group III, n = 27). Serum AMH levels between groups were compared using a nonparametric test (Wilcoxon rank-sum). Multiple linear regression adjusting for age was performed. RESULTS: AMH (ng/mL) levels at the last collection were significantly lower in group I versus group III (mean ± SD: 0.18 ± 0.20 group I vs 1.33 ± 1.59 group III; p = 0.015), and versus group II (mean ± SD: 0.86 ± 1.06; p = 0.018). When centered on age 30 years, average AMH levels for group I, group II and group III were 0.20, 0.44 and 1.00, respectively. When adjusted for age, AMH between all groups was significantly different (p<0.0001). CONCLUSION: Posttreatment AMH levels were significantly higher among patients receiving CYC + GnRH-a compared to CYC alone, suggesting that GnRH-a coadministration mitigates CYC-induced ovarian injury.

Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging.

BACKGROUND: In this study, levels and rates of change in total testosterone (T), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were related to chronological age and to the final menstrual period (FMP) as an indicator of ovarian aging. METHODS: Data were annually acquired over a 15-year period in 629 women of the Michigan Bone Health and Metabolism Study cohort. Data were censored for hormone therapy use. Endogenous androgen patterns over time were described with stochastic processes and bootstrapping. RESULTS: With ovarian aging, T levels rose from a mean of 18 ng/dl commencing 10 years prior to the FMP to 27 ng/dl at the FMP. Over the 20-year period encompassing the FMP, modeled mean SHBG levels changed from 58 to 34 nM and the FAI ratio increased from 1.6 to 2.9 in a non-linear manner. With chronological aging, total T levels increased (P < 0.0001) from 43 to 50 years, but not thereafter. SHBG declined steadily with age with a modestly greater rate of change between 49 and 54 years. The FAI increased from 1.3 to 2.5 from 34 to 58 years. CONCLUSIONS: T increased from approximately age 40 until the FMP whereas SHBG had rate of change patterns reflecting both chronological and ovarian aging components. These data provide new insight into the endogenous androgen patterns at mid-life.

Intracranial calcification after cord blood neonatal transplantation for krabbe disease.

Infantile-onset Krabbe disease results from a deficiency of the lysosomal enzyme galactocerebrosidase and leads to death from profound central and peripheral demyelination. Neonatal hematopoietic cell transplantation may result in near-normal cognitive development and partial rescue of gross motor development. The long-term course of the disorder for treated patients seems to involve slowly progressive neurological impairment. We describe the detailed 3-year outcomes of this experimental procedure using umbilical cord blood in a prenatally-diagnosed newborn with Krabbe disease. Substantial perivascular calcifications and atrophy of the white matter developed in the first year post-transplantation. Despite persistent neuroradiological and electrophysiological evidence of leukodystrophy, at age 3 years she has had only mildly impaired non-motor development and moderately impaired motor skills. The cause of these severe white matter changes may have been due to ongoing Krabbe disease or to effects of the chemotherapy regimen or to an interaction of these factors. Extended long-term follow-up of children neonatally transplanted for Krabbe disease is needed before the full utility and limitations of neonatal transplantation can be determined.

A randomised controlled trial to evaluate the effect of self-administered analgesia on women's experience of outpatient treatment at colposcopy.

OBJECTIVE: To evaluate the effect of self-administered isoflurane and desflurane on women's experience of outpatient treatment at colposcopy. DESIGN: A prospective double-blinded randomised controlled trial. SETTING: A colposcopy clinic serving a regional population. POPULATION: Three hundred and ninety-six women scheduled for treatment of cervical intraepithelial neoplasia (CIN) by large loop excision of the transformation zone (LLETZ). METHODS: Self-administration of trial gas during a LLETZ procedure. One hundred and ninety-eight women were randomised to use isoflurane and desflurane and 198 to use placebo. MAIN OUTCOME MEASURES: Patient satisfaction, pain and anxiety. RESULTS: The mean pain score for cervical surgery was significantly lower for women using isoflurane and desflurane (22.4) than the placebo arm (29.6) (P= 0.003). There was no significant difference between arms in anxiety levels before or after treatment. More women using isoflurane and desflurane (78%) reported 'total helpfulness' of the trial gas than those using placebo (67%) (P= 0.012). A subgroup analysis of trial participants classified as anxious by Hospital Anxiety and Depression Scale (HADS) score at recruitment showed that using isoflurane and desflurane significantly increased total treatment acceptability, helpfulness of the gas and willingness to undergo a similar procedure at six-month follow up. CONCLUSION: Satisfaction with outpatient treatment at colposcopy is generally high. The main effect of isoflurane and desflurane evaluated in this trial was to reduce pain. It appeared to be effective for women with clinically significant anxiety and could be offered as an alternative to general anaesthesia.

Occult cancer of the fallopian tube in a BRCA2 germline mutation carrier at prophylactic salpingo-oophorectomy.

BACKGROUND: Women with a germline BRCA1 or BRCA2 mutation have a significantly increased risk of developing ovarian cancer compared with women in the general population and may consider bilateral prophylactic oophorectomy as a risk-reducing option. CASE: We report a case of occult fallopian tube cancer diagnosed at prophylactic surgery in a patient with a BRCA2 mutation. CONCLUSIONS: This report acts as a reminder of the importance of removing as much of the fallopian tube as possible during prophylactic surgery in BRCA1 and BRCA2 carriers and of the need for careful pathological examination of surgical specimens after surgery.

Malignant mixed Müllerian tumour of the cervix treated with concurrent chemoradiation.

Malignant mixed Müllerian tumours of the cervix are very uncommon. Of the 26 cases reported in the literature only 8 consist of homologous sarcoma with squamous cell carcinoma. Historically, treatment has been with radiation or surgery or a combination of both. We describe a locally advanced case treated with concurrent chemoradiation.

Human papillomavirus and vulval intra-epithelial neoplasia.

The association between human papillomavirus vulval skin infection and vulval intra-epithelial neoplasia is strong. Vulval skin carcinogenesis is, however, multifactorial. Both human papillomavirus oncogenic subtype infection and p53 mutations are likely to contribute to the risk of malignant transformation of normal epithelium. The long-term cumulative risk of developing vulval squamous carcinoma following the diagnosis of high-grade vulval intra-epithelial neoplasia is thought to be approximately 6% per decade, but observational data supporting this are mostly non-population based and retrospective. Surgical treatment may reduce this risk, but the rates of recurrence and treatment-related morbidity are high. Surveillance should therefore be discussed as an alternative. New treatments being researched include photodynamic therapy, human papillomavirus vaccines, immunotherapy, immune modulators and gene therapy. The advantages of these new modalities over surgery is the potential to preserve body image and sexual functioning while targeting more generalized epithelial molecular dysfunction.

Testosterone concentrations in women aged 25-50 years: associations with lifestyle, body composition, and ovarian status.

While there is substantial evidence of the importance of endogenous and exogenous estrogen in reproductive health and chronic disease, there is little consideration of androgens in women's health. In the Michigan Bone Health Study (1992-1995), the authors examined the correlates of testosterone concentrations in pre- and perimenopausal women (i.e., age, menopausal status, body composition, and lifestyle behaviors) in a population-based longitudinal study including three annual examinations among 611 women aged 25-50 years identified through a census in a midwestern community. Current smokers had the highest testosterone concentrations with decreasing values in former and nonsmokers (p = 0.0001). Body composition measures (body mass index, body fat (%), weight (kg), lean body mass (kg), and fat mass (kg)) were significantly and positively associated with total testosterone concentrations in a dose-response manner. Hysterectomy with oophorectomy was associated with significantly lower testosterone concentrations. Alcohol consumption, physical activity, and dietary macronutrient intake were not associated with testosterone concentrations. This is one of the first studies to examine correlates of serum testosterone concentrations in anticipation of the growing interest in the role of androgens in women's health. The greater circulating levels of testosterone in obese women and smokers suggest that testosterone concentrations should be considered in the natural history of disease conditions where obesity and smoking are risk factors, including cardiovascular disease.

Extrathoracic arterial grafts performed for carotid artery occlusive disease not amenable to endarterectomy.

HYPOTHESIS: Extrathoracic cervical grafts are safe and provide long-lasting stroke prevention in patients with disease not amenable to standard carotid bifurcation endarterectomy. DESIGN: Review of a prospectively maintained vascular surgical registry. SETTING: Combined university and Department of Veterans Affairs vascular surgical service. PARTICIPANTS: Patients requiring surgery for carotid atherosclerotic occlusive disease not amenable to endarterectomy from January 1988 to March 1998. INTERVENTIONS: Carotid interposition grafting, subclavian-carotid bypass, or carotid-carotid bypass. MAIN OUTCOME MEASURES: Perioperative stroke and death, and life-table determination of freedom from stroke, stroke-free survival, and graft patency. RESULTS: Sixty patients (mean age, 65.8 years; range, 36-83) underwent cervically based carotid grafting. All had greater than 70% stenosis or occlusion of the innominate, common carotid, or internal carotid arteries, and 30 (50%) had undergone at least 1 previous ipsilateral carotid endarterectomy. Indication for operation was stroke or transient ischemic attack in 46 (77%) and asymptomatic high-grade stenosis in 14 (23%). Operative procedures included 31 (52%) carotid interposition grafts, 18 (30%) subclavian-carotid grafts, and 11 (18%) carotid-carotid grafts. Mean follow-up was 29 months (range, 1-117 months). Perioperative stroke rate was 5% (3/60) all in symptomatic patients, and there were no perioperative deaths. By life-table analysis, freedom from stroke was 92% at 1 and 5 years. Stroke-free survival was 90% at 1 year and 61% at 5 years. Primary graft patency was 94% at 1 year and 84% at 5 years, with assisted primary patency of 90% at 5 years. CONCLUSION: Cervical carotid artery grafts for complicated or recurrent carotid atherosclerosis not amenable to endarterectomy are durable and provide excellent freedom from stroke with low perioperative morbidity and mortality.

Improving the letters we write: an exploration of doctor-doctor communication in cancer care.

Referral and reply letters are common means by which doctors exchange information pertinent to patient care. Twenty-eight semi-structured interviews were conducted exploring the views of oncologists, referring surgeons and general practitioners. Twenty-seven categories of information in referral letters and 32 in reply letters after a consultation were defined. The letters to and from six medical oncologists relating to 20 consecutive new patients were copied, and their content analysed. Oncologists, surgeons and general practitioners Australia wide were surveyed using questionnaires developed on data obtained above. Only four of 27 categories of referral information appear regularly (in > 50%) in referral letters. Oncologists want most to receive information regarding the patient's medical status, the involvement of other doctors, and any special considerations. Referring surgeons and family doctors identified delay in receiving the consultant's reply letter as of greatest concern, and insufficient detail as relatively common problems. Reply letters include more information regarding patient history/background than the recipients would like. Referring surgeons and family doctors want information regarding the proposed treatment, expected outcomes, and any psychosocial concerns, yet these items are often omitted. Consultants and referring doctors need to review, and modify their letter writing practices.

Improved results with conventional management of infrarenal aortic infection.

PURPOSE: Interest in alternative methods, such as autogenous vein grafts and aortic allografts, for the management of infrarenal aortic infection (IRAI) has been stimulated by the historically disappointing results with conventional surgical management. Recently, there have been dramatic improvements in the results of axillofemoral bypass grafting (AXFB) followed by excision of the IRAI that have gone relatively unrecognized. The purpose of this report is the presentation of modern-day results in the treatment of IRAI with conventional surgical methods. METHODS: From January 1, 1983, through June 30, 1998, patients with IRAI underwent treatment with AXFB and complete excision of the IRAI. The patients were followed for survival, limb salvage, and AXFB graft patency. The results were tabulated with life-table methods. RESULTS: During the 15-year study period, 60 patients (51 men, nine women; mean age, 68 years) underwent treatment for IRAI (50 graft infections, including 16 graft-enteric fistulae, and 10 primary aortic infections). The mean follow-up period was 41 months. The perioperative mortality rate was 13% (12% for graft infection, and 20% for primary infection). The overall 2-year and 5-year survival rates were 67% and 47%, respectively. The limb salvage rates at 2 and 5 years were 93% and 82%, respectively. The 5-year primary AXFB graft patency rate was 73%. CONCLUSION: These results show an improvement with the conventional management of IRAI equal or superior to those results reported with alternative methods, including femoral vein grafts or aortic allografts. These results should be regarded as the modern standard with which alternative therapies can be compared.

Audiotapes and letters to patients: the practice and views of oncologists, surgeons and general practitioners.

A range of measures have been proposed to enhance the provision of information to cancer patients and randomized controlled trials have demonstrated their impact on patient satisfaction and recall. The current study explored the practice and views of oncologists, surgeons and general practitioners (GPs) with regards to providing patients with consultation audiotapes and summary letters. In stage 1, 28 semi-structured interviews with doctors were conducted to provide qualitative data on which to base a questionnaire. In stage 2, 113 medical oncologists, 43 radiation oncologists, 55 surgeons and 108 GPs completed questionnaires. Only one-third of doctors had ever provided patients with a copy of the letter written to the oncologist or referring doctor, and one-quarter had provided a summary letter or tape. The majority of doctors were opposed to such measures; however, a substantial minority were in favour of providing a letter or tape under certain conditions. More surgeons and GPs (> two-thirds) were opposed to specialists providing a consultation audiotape than oncologists (one-third). Gender, years of experience and attitude to patient involvement in decision-making were predictive of doctors' attitudes. The majority of doctors remain opposed to offering patients personalized information aids. However, practice and perspectives appear to be changing.

Evidence that MRas1 and MRas3 proteins are associated with distinct cellular functions during growth and morphogenesis in the fungus Mucor racemosus.

The filamentous fungus Mucor racemosus provides a simple and unique model system for defining the function of individual ras genes in a gene family which is closely related to mammalian ras genes. The current study was designed to investigate the role of Mras1 and Mras3 in different stages of fungal morphogenesis, including sporangiospore germination, sporulation, and dimorphic transitions. The overall patterns of Mras1 and Mras3 transcript and protein accumulation were markedly different but, in general, transcripts and proteins were present at low levels during spherical growth and their accumulated level increased severalfold during polar growth (germ tube emergence and elongation). In contrast to Mras1, relatively high levels of Mras3 transcript accumulated during sporulation and MRas3 protein accumulated in sporangiospores. Transformation of M. racemosus with an activated allele of Mras3 reduced growth rate during aerobic sporangiospore germination, while a dominant-negative allele of Mras3 caused a 40% decrease in viable asexual spores. An activated allele of Mras1 increased growth rate during sporangiospore germination but neither activated nor dominant-negative alleles of Mras1 affected total number of asexual spores. Expression of MRas3 and MRas1 proteins appear to be subject to different regulatory mechanisms: exogenous dibutyryl-cAMP and fusidienol caused a strong repression of the level of MRas3 protein (but not MRas1) concurrent with the inhibition of polar growth. Differential posttranslational modification and intracellular localization of MRas1 and MRas3 proteins were also observed. The data strongly suggest that Mras3 and Mras1 play different roles in regulation of cell growth and morphogenesis in Mucor.

Information booklets about cancer: factors influencing patient satisfaction and utilization.

Providing patients with adequate information is an important component of care. This exploratory study investigated factors influencing patient satisfaction with and utilization of information booklets. The research was conducted in two stages. In stage 1, five commonly used cancer information booklets were reviewed by 36 Australian patients who were either receiving chemotherapy or had just completed treatment. Data were collected on patient satisfaction with, preference for and utilization of information booklets. In addition data were collected on variables identified in the literature as potentially influencing patient satisfaction, including patient characteristics, presentation and readability of booklets, and the timing of provision. A high level of satisfaction was found for all five information booklets, although a clear preference for one particular booklet emerged. The most notable feature of this booklet was its readability level (grade 8); in contrast the other booklets were written at levels equivalent to grades 11-12. Stage 2 focused on the side effects of patient information preference style on their satisfaction and recall of information presented in two booklets in the course of their treatment. No differences were found between patients who seek information and those who avoid it. The findings of this study suggest that patients' information needs may be better met if information booklets are written in plain English, and presented to patients prior to treatment. Future studies incorporating a larger sample of patients and greater selection and variety of information booklets are required to further determine if patient characteristics and features of booklet presentation influence patient satisfaction and preference.

Predictors of outcome of forefoot surgery for ulceration and gangrene.

BACKGROUND: Surprisingly little is known about the long-term outcome of forefoot surgery for limb salvage. METHODS: From January 1, 1992 through December 31, 1996, patients requiring toe amputation or forefoot surgery were prospectively entered into a computerized database and followed up for healing, need for repeat foot surgery, or major amputation (below or above knee). RESULTS: A total of 162 patients (mean age 65 years), 72% diabetic, 10% with end-stage renal disease (ESRD), and 73% without palpable pulses, were entered into the study. Mean follow-up was 25 months. Of patients without palpable pulses (n = 98), 83% underwent concomitant or subsequent limb revascularization. Eleven of 98 revascularization procedures (11%) were hemodynamically unsuccessful. Nonhealing of the initial forefoot procedure occurred in 14%, and late repeat foot surgery (following initial healing) was required in an additional 14%. Major amputation was eventually required in 30 (18.5%) patients. Multivariate analysis indicated that unsuccessful revascularization, but not diabetes or ESRD, predicted nonhealing and major amputation (P <0.0001). Patients presenting with palpable pulses and neuropathic ulcers were at risk for late, repeat foot surgery, but not major amputation (P = 0.0015). CONCLUSIONS: In patients requiring toe or partial forefoot amputation, success of revascularization is the primary predictor of initial healing and freedom from major amputation. Neuropathic ulceration predicts need for repeat foot surgery following healing.

Surgical treatment of infected aortic aneurysm.

BACKGROUND: We report results of infected aortic aneurysms treated by a single group over 20 years. METHODS: Retrospective review. RESULTS: Seventeen patients were treated, 10 with infrarenal and 7 suprarenal infections. All had abdominal/back pain, 88% were febrile, 71% had leukocytosis, and 24% were hemodynamically unstable. The most common responsible organism was Staphylococcus aureus (29%) followed by Salmonella organisms (24%). All suprarenal infections were gram-positive organisms. Infrarenal infections were treated with preliminary axillofemoral bypass followed by aortic resection. Suprarenal infections were treated with either in situ prosthetic graft or patch repairs. Operative survival was 90% for infrarenal and 57% for suprarenal infections. Operative deaths occurred in the setting of overwhelming sepsis and/or severe preoperative hemodynamic instability. There was no limb loss, renal failure, or intestinal ischemia. Late deaths occurred in 4 patients at 1.3 to 6.3 years postoperatively and were unrelated to their aortic repairs. Nine patients remain alive with a median follow-up of 2 years. There have been no late aortic or graft infections. CONCLUSIONS: In the absence of hemodynamic instability and uncontrolled sepsis, infected aortic aneurysms can be successfully repaired with durable results.