Effects of a combined oral contraceptive containing oestradiol valerate/dienogest on hormone withdrawal-associated symptoms: results from the multicentre, randomised, double-blind, active-controlled HARMONY II study.

The objective of this multicentre, randomised, double-blind study was to compare a combined oral contraceptive (COC) containing oestradiol valerate/dienogest (E2V/DNG) administered in a dynamic dosing regimen with a monophasic COC containing ethinyloestradiol/levonorgestrel (EE/LNG), with regard to their ability to reduce the frequency and intensity of headache and pelvic pain in women with hormone withdrawal-associated symptoms (HWAS). Women aged 18-50 years received E2V/DNG in an oestrogen step-down and progestin step-up regimen (26/2 regimen; n = 223) or EE 20 µg/LNG 100 µg (21/7 regimen; n = 218) over six cycles. Headache and pelvic pain were assessed using a visual analogue scale (VAS) during cycle days 22-28. Rescue medication use was also assessed. E2V/DNG was superior to EE/LNG with regard to reducing the frequency and intensity of headache and pelvic pain from baseline to cycle 6 (change from baseline in the average of the three highest VAS values [mean ± standard deviation]: 47.7 ± 29.4 vs 34.5 ± 25.7 mm, respectively; p < 0.0001). The use of rescue medication was also significantly reduced with E2V/DNG compared with EE/LNG (p < 0.05). E2V/DNG may be a good option for women who experience HWAS with traditional 21/7-day regimen COCs.

Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial.

BACKGROUND: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E(2)V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology. METHODS: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E(2)V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90-day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. RESULTS: The intention-to-treat population comprised 231 women. The E(2)V/DNG response rate was much higher than with placebo (P < 0.0001). The mean reduction in MBL volume in E(2)V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E(2)V/DNG (95% confidence interval 490, 255 ml; P < 0.0001). Significant improvements in iron metabolism parameters were observed with E(2)V/DNG but not placebo. Overall, 14 women (9.7%) treated with E(2)V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E(2)V/DNG and placebo groups (each n = 2). CONCLUSIONS: E(2)V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E(2)V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801.

Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957-2006: incidence, treatment and outcome.

Malignant bone tumours in the paediatric age group (0-14 years) are uncommon; various aetiological theories exist and few reports of incidence, age and sex distributions have been published. We examined the incidence of childhood malignant bone tumours in one large single region of the UK over an extended period of 50 years. The West Midlands specialist regional children's tumour registry holds data on all malignancies and benign brain tumours in children under 15 years in the West Midlands region, which has a population of around 1 million children. Demographic and clinical data have been abstracted and diagnoses reviewed by a panel of expert pathologists. During the period 1957-2006, 259 cases of malignant paediatric bone tumours were diagnosed. There were 153 osteosarcomas, 78 Ewing sarcomas and 28 other primary bone tumours. The overall age standardised rate was 4.66, with no increase over time, although there was a significant increase in the incidence of Ewing sarcomas in the period 1965-92. Sixty-eight per cent of tumours were in patients over 10 years, whereas the incidence in patients under 10 years showed a non-significant increase. Survival rates increased dramatically post-chemotherapy introduction, with Ewing sarcoma demonstrating better survival overall. This is a large study giving an overview of malignant bone tumours in the childhood population of a single region over an extended period, showing results consistent with national reports. It also examines late effects, which were mostly mobility/orthopaedic, although almost one-fifth of patients had cardiac problems and five went on to develop second malignancies.

Solving inequities in provider distribution: loan repayment.

The distribution of primary health care professionals in England and Wales is inequitable, with relatively lower concentrations of professionals in deprived areas. The objective of the present study was to determine whether graduate health professionals would be willing to work in under-served areas in return for educational loan repayment. The study group consisted of a convenience sample of 50 newly qualified and trainee general practitioners, and 50 newly qualified community nurses and health visitors in mid- and west Wales. At interview, the subjects were presented with descriptions of general practices and asked to indicate their preferred practice. Practice descriptions varied systematically in terms of location (i.e. urban, suburban and rural), population deprivation (i.e. deprived or mixed affluent/deprived) and availability of loan repayment (i.e. none or loans paid off over a period of between one and 4 years). The main outcome was the probability that a practice with loan repayment was chosen. Compared with a suburban practice, a one-year loan repayment option made the rural and urban deprived practices 1.6 times and 1.2 times more likely to be chosen, respectively. Nurses were generally more willing than doctors to work in a deprived area in return for loan repayment. The findings suggest that loan repayment may offset health professionals' aversion to working in deprived areas. Such a scheme needs to be piloted to see whether it does offer value for money in recruiting health professionals to under-served areas.

pp(macro)-->tt(macro)H: a discovery mode for the Higgs boson at the Fermilab Tevatron.

The production of a standard model Higgs boson in association with a top quark pair at the upcoming high luminosity run ( 15 fb(-1) integrated luminosity) of the Fermilab Tevatron ( square root of s = 2.0 TeV) is revisited. For Higgs masses below 140 GeV we demonstrate that the production cross section times branching ratio for H-->bb macro decays yields a significant number of events and that this mode is competitive with and complementary to the searches using pp(macro) -->WH,ZH associated production. For higher mass Higgs bosons the H-->W(+)W(-) decays are more difficult but have the potential to provide a few spectacular events.

Solution properties and sweetness response of selected bulk and intense sweeteners.

Two bulk sweeteners (sucrose and maltitol) and four intense sweeteners (acesulfame K, aspartame, sodium cyclamate, and sodium saccharin) are used in this study. Densities and sound velocity values of the sweeteners in solution are measured at 20 degrees C, and their apparent molar and specific volumes, their isentropic apparent molar and specific compressibilities, as well as their compressibility hydration numbers are calculated and reported. The introduction of solute molecules in water results in a volume change of the solvent as a result of attractive forces exerted by the solute molecules; such forces are in the form of electrostrictive or hydrogen-bonding forces, or charge-dipole attraction. Changes of molar volumes with increasing concentration give an indication of the extent of solute-solute interaction, whereas isentropic compressibilities give a direct measurement of the state of hydration of the solute molecules. The compressibility hydration numbers reported give an indication of the number of water molecules disturbed by the presence of each solute molecule in solution. Isentropic compressibilities seem to be a more sensitive parameter for distinguishing the bulk sweeteners from the artificial sweeteners. The sweetness response of the sweeteners is then explained in terms of their solution behaviors.

Some taste molecules and their solution properties.

The solution properties of a variety of different sapid substances from all four basic taste modalities, namely, sweet (n = 24), salty (n = 7), sour (n = 11) and bitter (n = 2), have been investigated. Some multisapophoric molecules, i.e. molecules exhibiting more than one taste, have also been included in the study in an attempt to define their properties in relation to the tastes they exhibit; eight sweet-bitter and three salty-bitter molecules were used. The density and sound velocity of their solutions in water have been measured and their apparent volumes, apparent compressibilities and compressibility hydration numbers calculated and compared. Apparent molar volumes (phi(v)) and apparent specific volumes (ASV) reflect the state of hydration of the molecules, and thus their extent of interaction with water structure. The range of ASVs reported are 0.13-0.49 cm3/g for salty molecules, 0.55-0.68 cm3/g for sweet molecules, 0.53-0.88 cm3/g for sweet-bitter molecules and a much wider range (0.16-0.85 cm3/g) for sour molecules. Isentropic apparent specific compressibilities range from -2.33 x 10(-5) to -8.06 x 10(-5) cm3/g x bar for salty molecules, -3.38 x 10(-7) to -2.34 x 10(-5) cm3/g x bar for sweet molecules, +6.35 x 10(-6) to -2.22 x 10(-5) cm3/g x bar for sweet-bitter molecules and +6.131 x 10(-6) to -2.99 x 10(-5) cm3/g x bar for sour molecules. Compressibility hydration numbers are also determinable from the measurements of isentropic compressibilities and these reflect the number of water molecules that are disturbed by the presence of the solutes in solution. This study also shows that it is possible to group isentropic apparent molar compressibility values by the taste quality exhibited by the molecules in the same order as for ASV.

[111Indium-DTPA-D-phe] octreotide scintigraphy in the diagnostic assessment of palpable breast lumps.

It has been suggested that [111Indium-DTPA-D-Phe] octreotide scintigraphy may be useful in the staging of breast cancer. We evaluated its role in the diagnostic assessment of 40 female patients with palpable breast lumps. All were clinically assessed and imaged by ultrasound or mammography. Thirty patients had adequate FNA cytology performed. Histological examination following core or excision biopsy showed 31 lumps to be benign and 9 to be malignant. All patients with invasive cancer proceeded to wide local excision or mastectomy with an axillary clearance. The mean diameter of malignant lesions was 2.4 cm (SEM 0.3 cm). The sensitivity (22%), specificity (81%) and positive predictive value (25%) of octreotide scintigraphy in the detection of breast cancer was inferior to that of clinical assessment (56%, 90% and 71%), radiological imaging(77%, 96% and 100%) and FNA cytology (88%, 95% and 88%). No axillary uptake of isotope was seen in 4 patients with nodal metastases. Four scans showed uptake of isotope at one or more sites remote from the clinically or radiologically significant lesion. [111Indium-DTPA-D-Phe] octreotide scintigraphy provided no additional diagnostic information to that given by triple assessment and does not appear to have a role in the evaluation of breast lumps.

Tastes, structure and solution properties of D-glucono-1,5-lactone.

D-glucono-1,5-lactone differs from D-glucopyranose only in that it has a C = O group instead of CHOH group at carbon atom number one. The molecule therefore possesses an intact 3,4 alpha-glycol group and is sweet. However, it autohydrolyses in water solution at room temperature, forming D-gluconic acid and D-glucono-1,4-lactone. As the solution pH falls it becomes sweet-sour and eventually almost completely sour as the generated hydronium ions dominate both the solution properties and the taste perceptions elicited. It is shown that the ratio of generated hydronium ions to unchanged lactone accords with anticipated taste quality during the first 28 min of autohydrolysis. Changes in both apparent specific volume and apparent isentropic compressibility illustrate increasing solute-solvent interaction and increasing disturbance of water structure during the course of autohydrolysis. These changes are consistent with the concurrent sweet to sour change, but do not explain the weak bitterness which also accompanies them.