To compare bleeding profiles of a traditional 28-day oral contraceptive pill cycle with continuous administration.
After a 28-day run-in cycle, women were randomized to either 28-day cycles (21 ...active pills and a pill-free week) or continuous use of the same 20 microg ethinyl estradiol/100 microg levonorgestrel formulation for 12 study cycles (336 days). The number of bleeding and spotting days were measured by daily diary. A subset underwent cycle 1 (n = 16), and nine (n = 14) pelvic ultrasound and endometrial histology sampling. Blood pressure, weight, hemoglobin, and adverse events were measured at revisit. The sample size with 80% power to detect a 67% reduction in bleeding days required 27 subjects in each arm.
Of the 79 subjects randomized, 28 (70%) of the 28-day cycle and 32 (82%) of the continuous-use subjects completed the entire study (P =.6). With continuous use, 49%, 68%, and 88% of women reported no bleeding during cycles 2, 6, and 12, respectively. Amenorrhea or infrequent bleeding was present in 68% of continuous users during cycles 1-3 and increased to 88% during cycles 10-12. Spotting during cycle days 1-21 increased initially with continuous use but reduced over time, and by 9 months was less than the spotting reported by cyclic users. Adverse events, blood pressure, weight, and hemoglobin findings were similar between groups.
Extension of the 28-day oral contraceptive cycle to continuous use with a low-estrogen dose combination oral birth control pill resulted in significantly fewer bleeding days.
Although acute urinary tract infections are common in young women, the associated risk factors have not been defined prospectively.
We recruited sexually active young women who were starting a new ...method of contraception at a university health center or a health maintenance organization (HMO) and monitored them for six months for symptomatic urinary tract infections. Daily diaries and serial interviews were used to collect data on potential risk factors.
Among 796 women, the incidence of urinary tract infections per person-year was 0.7 in the university cohort (mean age, 23 years; n = 348) and 0.5 in the HMO cohort (mean age, 29; n = 448). In both cohorts, there were strong dose-response relations between the risk of infection and both recent use of a diaphragm with spermicide (respective relative risks for one, three, and five days of use in the past week, 1.42, 2.83, and 5.68 in the university cohort, P<0.001; and 1.29, 2.14, and 3.54 in the HMO cohort, P=0.04) and recent sexual intercourse (respective relative risks for one, three, and five days with intercourse in the past week, 1.37, 2.56, and 4.81 in the university cohort, P<0.001; and 1.24, 1.91, and 2.96 in the HMO cohort, P=0.002). The risk of acute infection was also associated with a history of recurrent infection (relative risk, 5.58 in the university group and 2.10 in the HMO group) but not with cervical-cap use, ABO-blood-group nonsecretor phenotype, or delayed postcoital voiding.
Among sexually active young women the incidence of symptomatic urinary tract infection is high, and the risk is strongly and independently associated with recent sexual intercourse, recent use of a diaphragm with spermicide, and a history of recurrent urinary tract infections.
Understanding chronic inflammatory and neuropathic pain Hughes, Jane P.; Chessell, Iain; Malamut, Richard ...
Annals of the New York Academy of Sciences,
20/May , Letnik:
1255, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
This meeting report highlights the main topics presented at the conference “Chronic Inflammatory and Neuropathic Pain,” convened jointly by the New York Academy of Sciences, MedImmune, and Grünenthal ...GmbH, on June 2–3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.
Principles of early drug discovery Hughes, JP; Rees, S; Kalindjian, SB ...
British journal of pharmacology,
March 2011, Letnik:
162, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15 years and cost in excess of $1 billion. The idea for a target can come from a ...variety of sources including academic and clinical research and from the commercial sector. It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development.
Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with ...increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval CI, 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
We present evidence for cosmic-ray acceleration at the forward shock in Tycho's supernova remnant (SNR) from three X-ray observables: (1) the proximity of the contact discontinuity to the forward ...shock, or blast wave, (2) the morphology of the emission from the rim of Tycho, and (3) the spectral nature of the rim emission. We determine the locations of the blast wave (BW), contact discontinuity (CD), and reverse shock (RS) around the rim of Tycho's supernova remnant using a principal component analysis and other methods applied to new Chandra data. The azimuthal-angle-averaged radius of the BW is 251. For the CD and RS we find average radii of 241 and 183, respectively. Taking account of projection effects, we find ratios of 1 : 0.93 : 0.70 (BW : CD : RS). We show these values to be inconsistent with adiabatic hydrodynamic models of SNR evolution. The CD : BW ratio can be explained if cosmic-ray acceleration of ions is occurring at the forward shock. The RS : BW ratio, as well as the strong Fe Ka emission from the Tycho ejecta, imply that the RS is not accelerating cosmic rays. We also extract radial profiles from 634% of the rim of Tycho and compare them to models of surface brightness profiles behind the BW for a purely thermal plasma with an adiabatic shock. The observed morphology of the rim is much more strongly peaked than predicted by the model, indicating that such thermal emission is implausible here. Spectral analysis also implies that the rim emission is nonthermal in nature, lending further support to the idea that Tycho's forward shock is accelerating cosmic rays.
BackgroundTo determine the potential value of human papillomavirus (HPV) vaccines, information concerning the incidence and duration of clinically important lesions is needed MethodsA total of 603 ...female university students were followed for a mean duration of 38.8 months. Triannual gynecologic examinations included cervical and vulvovaginal specimen collection for Pap and HPV DNA testing. Women with cytologic evidence of a high-grade squamous intraepithelial lesion (SIL) were referred for colposcopically directed biopsy ResultsAmong women with incident HPV infection, the 36-month cumulative incidence of cervical SILs found by cytologic testing (47.2%; 95% confidence interval CI, 38.9%–56.4%) was higher than that of vaginal SILs (28.8%; 95% CI, 21.3%–38.2%). The median time to clearance of cervical and vaginal SILs was 5.5 and 4.7 months, respectively. Among women with incident HPV-16 or HPV-18 infection, the 36-month cumulative incidence of cervical intraepithelial neoplasia (CIN) grade 2 was 20.0% (95% CI, 10.8%–35.1%), and that of CIN grade 3 was 6.7% (95% CI, 2.5%–17.0%). The 36-month cumulative incidence of clinically ascertained genital warts among women with incident HPV-6 or HPV-11 infection was 64.2% (95% CI, 50.7%–77.4%) ConclusionsIntraepithelial lesions are common early events among women with incident HPV infection, and the interval between incident HPV-16 or HPV-18 infection and biopsy-confirmed CIN grade 2–3 appears to be relatively short
Many sex partners of persons with gonorrhea or chlamydial infections are not treated, which leads to frequent reinfections and further transmission.
We randomly assigned women and heterosexual men ...with gonorrhea or chlamydial infection to have their partners receive expedited treatment or standard referral. Patients in the expedited-treatment group were offered medication to give to their sex partners, or if they preferred, study staff members contacted partners and provided them with medication without a clinical examination. Patients assigned to standard partner referral were advised to refer their partners for treatment and were offered assistance notifying partners. The primary outcome was persistent or recurrent gonorrhea or chlamydial infection in patients 3 to 19 weeks after treatment.
Persistent or recurrent gonorrhea or chlamydial infection occurred in 121 of 931 patients (13 percent) assigned to standard partner referral and 92 of 929 (10 percent) assigned to expedited treatment of sexual partners (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98). Expedited treatment was more effective than standard referral of partners in reducing persistent or recurrent infection among patients with gonorrhea (3 percent vs. 11 percent, P=0.01) than in those with chlamydial infection (11 percent vs. 13 percent, P=0.17) (P=0.05 for the comparison of treatment effects) and remained independently associated with a reduced risk of persistent or recurrent infection after adjustment for other predictors of infection at follow-up (relative risk, 0.75; 95 percent confidence interval, 0.57 to 0.97). Patients assigned to expedited treatment of sexual partners were significantly more likely than those assigned to standard referral of partners to report that all of their partners were treated and significantly less likely to report having sex with an untreated partner.
Expedited treatment of sex partners reduces the rates of persistent or recurrent gonorrhea or chlamydial infection.
Chronic medical conditions often necessitate regular testing for proper treatment. Regular testing of all afflicted individuals may not be feasible due to limited resources, as is true with HIV ...monitoring in resource‐limited settings. Pooled testing methods have been developed in order to allow regular testing for all while reducing resource burden. However, the most commonly used methods do not make use of covariate information predictive of treatment failure, which could improve performance. We propose and evaluate four prediction‐driven pooled testing methods that incorporate covariate information to improve pooled testing performance. We then compare these methods in the HIV treatment management setting to current methods with respect to testing efficiency, sensitivity, and number of testing rounds using simulated data and data collected in Rakai, Uganda. Results show that the prediction‐driven methods increase efficiency by up to 20% compared with current methods while maintaining equivalent sensitivity and reducing number of testing rounds by up to 70%. When predictions were incorrect, the performance of prediction‐based matrix methods remained robust. The best performing method using our motivating data from Rakai was a prediction‐driven hybrid method, maintaining sensitivity over 96% and efficiency over 75% in likely scenarios. If these methods perform similarly in the field, they may contribute to improving mortality and reducing transmission in resource‐limited settings. Although we evaluate our proposed pooling methods in the HIV treatment setting, they can be applied to any setting that necessitates testing of a quantitative biomarker for a threshold‐based decision.
Incidence data on human papillomavirus (HPV) infection are limited, and risk factors for transmission are largely unknown. The authors followed 603 female university students in Washington State at ...4-month intervals between 1990 and 2000. At each visit, a sexual and health questionnaire was completed and cervical and vulvovaginal samples were collected to detect HPV DNA. At 24 months, the cumulative incidence of first-time infection was 32.3% (95% confidence interval: 28.0, 37.1). Incidences calculated from time of new-partner acquisition were comparable for enrolled virgins and nonvirgins. Smoking, oral contraceptive use, and report of a new male sex partner—in particular, one known for less than 8 months before sex occurred or one reporting other partners—were predictive of incident infection. Always using male condoms with a new partner was not protective. Infection in virgins was rare, but any type of nonpenetrative sexual contact was associated with an increased risk. Detection of oral HPV was rare and was not associated with oral-penile contact. The data show that the incidence of HPV associated with acquisition of a new sex partner is high and that nonpenetrative sexual contact is a plausible route of transmission in virgins.
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