Mechanisms of action of currently available woman-controlled, vaginally administered, non-hormonal contraceptive products.

Woman-controlled, vaginally administered contraceptives offer women discreet, self-administered, and reversible options. This brief report summarizes the mechanisms of action (MOAs) of currently available, woman-controlled, vaginally administered, non-hormonal products, excluding those that need to be fitted by a healthcare provider. MOAs of three general types of contraceptives will be reviewed, including pH modulators, spermicides, and barrier methods. The recently approved vaginal pH modulator (lactic acid, citric acid, and potassium bitartrate) has a non-hormonal MOA, acting as a buffering agent in the presence of alkaline semen and resulting in sperm immobilization. In contrast, spermicides, such as nonoxynol-9, act by lysing sperm membranes, resulting in sperm death. Barrier methods, such as the diaphragm and female condom, prevent sperm from entering the uterus. In addition to their varying MOAs, each woman-controlled, vaginally administered method has different instructions for use, efficacy, side effects, and availability/insurance coverage, thus providing a range of characteristics to fit different needs and preferences.

Ibrexafungerp Versus Placebo for Vulvovaginal Candidiasis Treatment: A Phase 3, Randomized, Controlled Superiority Trial (VANISH 303).

BACKGROUND: Current treatment of vulvovaginal candidiasis (VVC) is largely limited to azole therapy. Ibrexafungerp is a first-in-class triterpenoid antifungal with broad-spectrum anti-Candida fungicidal activity. The objective of this study was to evaluate the efficacy and safety of ibrexafungerp compared with placebo in patients with acute VVC. METHODS: Patients were randomly assigned 2:1 to receive ibrexafungerp (300 mg twice for 1 day) or placebo. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms [VSS] = 0) at test-of-cure (day 11 ± 3). Secondary endpoints included the percentage of patients with mycological eradication, overall success (clinical cure and mycological eradication), clinical improvement (VSS ≤ 1) at test-of-cure, and symptom resolution at follow-up (day 25 ± 4). RESULTS: Patients receiving ibrexafungerp had significantly higher rates of clinical cure (50.5% [95/188] vs 28.6% [28/98]; P = .001), mycological eradication (49.5% [93/188] vs 19.4% [19/98]; P < .001), and overall success (36.0% [64/178] vs 12.6% [12/95]; P < .001) compared with placebo. Symptom resolution was sustained and further increased with ibrexafungerp compared with placebo (59.6% [112/188] vs 44.9% [44/98]; P = .009) at follow-up. Post hoc analysis showed similar rates of clinical cure and clinical improvement at test-of-cure for Black patients (54.8% [40/73] and 63.4% [47/73], respectively) and patients with a body mass index >35 (54.5% [24/44] and 68.2% [30/44], respectively) compared with overall rates. Ibrexafungerp was well tolerated. Adverse events were primarily gastrointestinal and mild in severity. CONCLUSIONS: Ibrexafungerp provides a promising safe and efficacious oral treatment that mechanistically differs from current azole treatment options for acute VVC.

EVO100 prevents chlamydia and gonorrhea in women at high risk of infection.

BACKGROUND: According to the Centers for Disease Control and Prevention, rates of infection for Chlamydia trachomatis and Neisseria gonorrhoeae are increasing in the United States. EVO100 is an investigational antimicrobial, pH-modulating, vaginal gel with active ingredients L-lactic acid, citric acid, and potassium bitartrate that is being evaluated for the prevention of sexually transmitted infections. OBJECTIVE: The objective of this phase 2B/3 study was to assess the efficacy and safety of EVO100 for the prevention of chlamydia and gonorrhea. STUDY DESIGN: AMPREVENCE was a double-blinded, placebo-controlled, multicenter study based in the United States conducted over approximately 16 weeks in women at the age of 18 to 45 years who were at risk of urogenital chlamydia and gonorrhea infection. Enrolled women had been diagnosed as having and treated for chlamydia or gonorrhea ≤16 weeks before enrollment. Women received either EVO100 or placebo vaginal gel and were instructed to apply the study drug immediately before or up to 1 hour before each act of vaginal sexual intercourse. The primary and secondary endpoints were the prevention of urogenital chlamydia and gonorrhea, respectively. Exploratory outcomes include women's overall satisfaction with EVO100. RESULTS: In total, 860 women were randomized 1:1 to receive EVO100 (n=426) or placebo (n=434), and 764 women (EVO100, n=376; placebo, n=388) were documented as using the study drug at least once. Baseline characteristics were similar between treatment arms. Overall, women had a mean age of 27.7 years (standard deviation, 6.9) and body mass index of 28.9 kg/m2 (standard deviation, 8.0). Most women were of White (54.3% [467 of 860]) or African American (41.6% [358 of 860]) race and of non-Hispanic/Latina ethnicity (67.1% [577 of 860]). The chlamydia infection rate in EVO100 users was 4.8% (14 of 289) compared with 9.7% (28 of 290) among placebo users (P=.0256), representing a relative risk reduction of 50%. For gonorrhea, the infection rate was 0.7% (2 of 280) in the EVO100 arm compared with 3.2% (9 of 277) in the placebo arm (P=.0316), representing a relative risk reduction of 78%. Increased efficacy was observed with increased adherence, and chlamydia infection rates were significantly reduced with increased adherence in the EVO100 group compared with placebo. Across both arms, there were similar rates of all-cause adverse events (EVO100, 21.3% [80 of 376]; placebo, 20.4% [79 of 388]) and treatment-related adverse events (EVO100, 7.2% [27 of 376]; placebo, 7.5% [29 of 388]). The most common adverse events in the EVO100 arm were vulvovaginal candidiasis (5.1% [19 of 376]), vaginal discharge (3.2% [12 of 376]), and urinary tract infection (3.2% [12 of 376]) and, in the placebo arm, bacterial vaginosis (4.6% [18 of 388]), urinary tract infection (2.6% [10 of 388]), and vaginal discharge (2.6% [10 of 388]). Few women discontinued owing to adverse events in either arm (EVO100, 1.1% [4 of 376]; placebo, 1.5% [6 of 388]). No treatment-related serious adverse events were reported. Most EVO100 users (88%) were satisfied or very satisfied with EVO100 after 16 weeks of use. CONCLUSION: EVO100 significantly reduced the risk of chlamydia and gonorrhea infections in women at high risk of Chlamydia trachomatis and Neisseria gonorrhoeae infection and was well tolerated, with observed adverse events consistent with its known safety profile.

A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial.

OBJECTIVE: The objective was to evaluate the contraceptive effectiveness, safety, and acceptability of a novel vaginal pH regulator over seven cycles of use. STUDY DESIGN: A single-arm, open-label, phase 3 study was conducted across 112 sites in the United States in sexually active 18-35-year-old women at risk of pregnancy. Women administered the study treatment ≤ 1 h before each episode of intercourse. Women recorded use of study drug, coital information, and any symptoms experienced in electronic diaries. The primary outcome was the seven-cycle cumulative pregnancy rate as calculated using the Kaplan-Meier methodology; secondary outcomes included safety. Overall satisfaction was assessed via written questionnaires. RESULTS: A total of 1384 women were enrolled in the study from July 2017 to November 2018. Mean age was 27.7 ±â€¯4.4 years; most women were white (69.0%). The seven-cycle cumulative pregnancy percentage was 13.7% [95% confidence interval (CI): 10.0%-17.5%], meeting the prespecified primary endpoint of having the upper bound 95% CI ≤ 21%. Most common adverse events (AEs) occurring in ≥ 2% of women were vulvovaginal burning sensation, vulvovaginal pruritus, urinary tract infection, vulvovaginal pain, mycotic infection, bacterial vaginosis, and nasopharyngitis. Of 1330 women who used the study drug at least once, fewer than 2% of women discontinued due to any AEs, and < 1% of women discontinued due to genitourinary symptoms. Overall, > 80% of women reported being "very satisfied" or "satisfied" with study treatment. CONCLUSIONS: In this phase 3 study, the novel vaginal pH regulator demonstrated 86.3% contraceptive effectiveness, was safe and well tolerated, and was highly acceptable. IMPLICATIONS: This novel vaginal pH regulator is a safe, nonhormonal, woman-controlled method of contraception that expands women's options.

The visualisation of fingermarks on Pangolin scales using gelatine lifters.

Recent media reports document the plight of the Pangolin and its current position as "the most trafficked mammal in the world". They are described by some as scaly anteaters as all species are covered in hard keratinous tissue in the form of overlapping scales acting as a "flexible dermal armour". It is estimated that between 2011 and 2013, 117,000-234,000 pangolins were slaughtered, but the seizures may only represent as little as 10% of the true volume of pangolins being illegally traded. In this paper, methods to visualise fingermarks on Pangolin scales using gelatine lifters is presented. The gelatine lifters provide an easy to use, inexpensive but effective method to help wildlife crime rangers across Africa and Asia to disrupt the trafficking. The gelatine lifting process visualised marks producing clear ridge detail on 52% of the Pangolin scales examined, with a further 30% showing the impression of a finger with limited ridge detail. The paper builds on an initial sociotechnical approach to establishing requirement, then it focuses on the methods and outcomes relating to lifting fingermarks off Pangolin scales using gelatine lifters, providing an evaluation of its use in practice.

A prospective randomised trial of extended core prostate biopsy protocols utilizing 12 versus 15 cores.

OBJECTIVE: To prospectively evaluate the diagnostic yield of 12 versus 15 core ultrasound-guided needle prostate biopsy protocol for detection of prostate cancer. PATIENTS AND METHODS: 244 patients were prospectively randomized to undergo 12 (group A), or 15 (group B) biopsies. The cancer detection rate was compared between these groups and within group B. RESULTS: There were no differences in the age, PSA, prostate volume or Gleason score of diagnosed cancers between groups. 113 (46%) of all patients were found to have carcinoma. The number of cancers diagnosed in each group was: 63 (51.6%) in group A, and 50 (41.0%) in group B. In both groups, performing 12 biopsies increased the number of cancer cases identified by around 10% compared to 6. The frequency of cancer cases increased when 15 biopsies were performed, but not significantly (1.7%). The probability of finding a cancer after 12 biopsies was the same as after 15 biopsies (p = 0.125, McNemar's test). CONCLUSIONS: There was no advantage in increasing the number of biopsy cores from 12 to 15 for the diagnosis of prostate cancer in men with an elevated PSA but normal digital rectal examination.

Priapism as the presenting symptom of an aortocaval fistula.

The case of an elderly man with priapism as his only symptom is presented. The importance of clinical signs and simple investigations to make a diagnosis of aortocaval fistula associated with abdominal aortic aneurysm are discussed.

Is preputioplasty effective and acceptable?

Foreskin complaints in childhood, if not manageable conservatively, are usually treated by circumcision. A less radical surgical option, when balanitis xerotica obliterans is absent, is preputioplasty. We sent questionnaires to the parents of 23 boys who had had this procedure and 22 replied. Mean interval since operation was 20 months (range 3-36). The main indications for surgery had been irretractable foreskin in 9, recurrent balanoposthitis in 10 and ballooning on voiding in 3 and the operation had dealt successfully with these in 7, 7, and 3, respectively. In all but one case the parents were satisfied with the cosmetic result. However, in 8 cases (36%) the parents said they would have preferred circumcision and 3 of the boys had been listed for further surgery. Preputioplasty is a satisfactory alternative to circumcision in selected cases.

Developmental practicum experiences of preservice teachers in deaf education: implications for practicum placement and faculty-student collaborative research.

The study examined the developmental practicum experiences of second-year graduate students in deaf education. Participants in the study consisted of a convenient sample of five practicum students. Triangulated data for the study came from the researcher's observational notes, e-mail correspondence with participants, and participants' journals. Inductive analysis was used to analyze the data. Results of the study evinced developmental experiences that are different from those reported in previous studies. The results of the study have significant implications for (a) practicum placement of graduate students in deaf education in terms of site-based orientation, use of the clinical model of supervision, opportunities for self-reflection, and periodic practicum seminars; and (b) faculty-student collaborative research in terms of planning, ethical issues, students' time needs, and training.

Meeting the educational needs of general practitioners for epilepsy.

Epilepsy care in general practice has been criticized, but what do GPs feel they deal with most and complete satisfactorily? If criticism is justified, education should be useful in improving epilepsy care, but what do general practitioners want to learn and how do they want to learn it? Questionnaires about these issues were sent to randomly chosen general practitioners throughout the United Kingdom. One hundred and twenty-four out of 200 (62%) responded. They were not biased by age, sex, type of practice or previous interest in epilepsy. Drug treatment and regular review were the two areas of care GPs said they dealt with most, but only half felt they dealt with them well. Sixty-six percent wanted to learn more about drug treatment, 46% about lifestyle advice, 45% about non-drug treatment, 44% about diagnosis and only 16% did not want to learn more about any aspect of care. Weekdays and evenings were the preferred times for study. Courses up to one full day away from practices were popular, distance learning and personal education plans were not, except for a group of younger GPs. When attending courses multi-disciplinary lectures rated highly and nearly three-quarters preferred to attend courses where epilepsy was covered in conjunction with other conditions. Future epilepsy education for GPs should recognize these findings if attendance and positive outcomes are to be maximized.

Interobserver variability in the measurement of internal carotid stenosis.

OBJECTIVE: To assess interobserver variability in the measurement of carotid stenoses from digital subtraction angiograms displayed in different ways (nonmagnified or magnified, white or black arteries); and to compare human readers with computer-generated densitometric measurements of vessel stenosis. METHODS: Digital subtraction angiograms of 20 proximal internal carotid artery stenoses were laser printed in the following ways: (1) Nonmagnified white artery on a black background; (2) Magnified white artery on a black background; (3) Nonmagnified black artery on a white background; (4) Magnified black artery on a white background. This resulted in 80 images of internal carotid artery stenoses. These stenoses were independently measured by 4 radiologists using the North American Symptomatic Carotid Endarterectomy Trial method. A computer-generated densitometric measurement of the black nonmagnified images was also obtained. RESULTS: The most reliable stenosis measurements were obtained from the nonmagnified black and white artery images. The interobserver variability in the measurement of internal carotid stenoses using these images was quite small. Variability increased with the use of magnification. The computer-generated stenosis measurements were consistently much higher than those of the radiologists. CONCLUSION: There was significant variability in measurements made from magnified images and between human readers and computer-generated measurements. This has great clinical significance. Readers of digital angiographic images must determine the most reliable, reproducible images generated by their equipment, as these measurements significantly affect treatment of patients with symptomatic internal carotid artery stenosis.

Patient views on primary care services for epilepsy and areas where additional professional knowledge would be welcome.

In the past decade there has been increasing interest in the part that general practice can play in the care of people with epilepsy. Primary care services for epilepsy vary from practice to practice. Some studies have suggested that people with epilepsy prefer secondary care services and are not keen for their epilepsy to be managed in general practice, but much of the data were collected in secondary care. This study collected data from various sources about present provision of services, patient satisfaction with services, views about service development, areas where GP knowledge may be improved and whether the site of data collection influenced the results. A questionnaire was piloted, then distributed and collected through branches of the British Epilepsy Association, general practice and secondary care clinics. Data collected were both quantitative and qualitative. One hundred and seventy-eight questionnaires were collected from three sources. The responders were a severe seizure group. Structured care in general practice was uncommon with 54% being seen only when needed. Dose and type of antiepileptic medication was rarely altered in general practice. Information about their condition was given to 44% of the responders by their GP. Sixty-one percent would prefer their epilepsy care to be 'shared' between primary and secondary services. The majority of patients were satisfied with GP services, felt they could easily discuss their epilepsy, but 58% felt they 'rarely' or 'never' received enough information about their condition in general practice. Satisfaction with GP care varied, dependent on where the data were collected. Patients would value more information and more time to discuss the effects of their epilepsy. In conclusion general practice care for epilepsy is still reactive. Patients value more information and more time to discuss implications. The data collection point affects the results; any conclusions about the organisation of epilepsy care should draw data from community patient samples.

Managing epilepsy in general practice: the dissemination and uptake of a free audit package, and collated results from 12 practices in England and Wales.

This study aimed to assess the uptake and use by general practitioners of a free epilepsy audit protocol, and describe the care provided by practices which returned completed audits. A protocol for epilepsy audit in general practice was designed and described in the medical press. Practices were invited to reply. Responders were provided with the protocol. A total of 215 practices responded to the articles in the press. Questionnaires asking how they had used the audit protocol were sent to them 18 months later. One hundred and seventy (79%) of the 215 responding practices returned the questionnaires. Forty-seven (28%) had collected some or all of the data. Twenty-two (13%) submitted data of which 12 (7%) matched the original protocol. Aggregated list sizes for these 12 practices was 75689 and 502 (0.66%) patients were being treated. Of these, 60% were seizure free and 11% were having more than one seizure per month. Seventy-one were receiving monotherapy and only two patients were taking more than three drugs. Eighty-eight per cent of patients still having seizures had been seen by their GP for their epilepsy in the last 12 months. In 18% of cases, information on epilepsy lifestyle issues had been given and noted. Offering a free epilepsy audit package can stimulate interest amongst practices in the topic and resulted in 13% collecting and submitting their data for analysis. Practices reported a higher prevalence for epilepsy (0.66%) than in previous studies. The majority of patients with active epilepsy (88%) had been seen by a general practitioner in the last 12 months. Most (71%) were receiving monotherapy, but recording of seizure frequency and provision of information about epilepsy was low.

Generic prescribing for epilepsy. Is it safe?

Generic prescribing for epilepsy remains controversial. This study aimed to ascertain if a change occurred in the incidence of seizures or side-effects when a different pharmaceutical manufacturer's version of the same antiepileptic drug was taken (a 'switch'). Forty general practices with a list size of 350 168 were recruited. They identified 2285 people being treated for epilepsy with either carbamazepine, phenytoin or sodium valproate. A questionnaire was sent to the people with epilepsy. Those who recalled taking a different pharmaceutical manufacturer's supply of the same antiepileptic drug over the last 2 years were interviewed by their practice if they reported a problem with the control of their epilepsy after a 'switch'. One thousand, three hundred and thirty-three (58.8%) people with epilepsy responded: 251 (18.7%) had experienced a 'switch', 27 (10.8%) reported 'validated' problems; 25 (9.9%) reported unproven problems; 22 (8.8%) reported problems, but follow-up was incomplete; 177 (70.5%) reported no problems. This study suggests that money saved by generic prescribing is outweighed by negative health gain for the person with epilepsy, increased work in general practice, and increased social costs.

Correlates of employment history and employability in a British epilepsy sample.

This study examined the inter-relationships between employment status, employment experiences, background, educational and epilepsy-related variables in a community sample of 1709 people with epilepsy in England and Wales. A postal questionnaire yielded information which included attitudes to careers advice, experiences with fellow employees and management when in work, experiences of being questioned about epilepsy, and the perceived effect of having epilepsy on employment prospects. In a principal components analysis, a factor of 'employability' was identified that had high loadings for educational qualifications, socioeconomic status and employment history. Good employability was found to be related to perceptions that epilepsy had little or no effect on job prospects, good experiences with work colleagues and management, low seizure severity and good seizure control. Further data analyses which focused on people's actual employment histories confirmed the importance of past experiences in employment, educational qualifications, seizure severity and seizure frequency for distinguishing between groups. The study findings are discussed and, taken together, they imply that quality of medical care, employability and good employment history are interconnected in important ways.

Plasma epinephrine appearance and clearance rates in fetal and newborn sheep.

Newborn plasma catecholamine levels are elevated compared to fetal life. Whether this reflects increased catecholamine secretion after birth or decreased clearance is not known. To determine the plasma appearance and clearance rates for catecholamines during the transition to postnatal life, we compared plasma epinephrine appearance and clearance rates in fetal sheep before birth and in newborns after delivery. Plasma epinephrine appearance and clearance rates were measured by radiotracer analysis in eight fetuses at 127 +/- 1 days of gestation and, after cesarean delivery, at 130 +/- 1 days of gestation. There was no difference in plasma epinephrine appearance rate during the fetal (26 +/- 4 ng.kg-1 x min-1) or newborn studies (31 +/- 5 ng.kg-1 x min-1). The fetal plasma epinephrine clearance rate (131 +/- 13 ml.kg-1 x min-1) was significantly higher than newborn plasma epinephrine clearance rate (40 +/- 3 ml.kg-1 x min-1). Thus fetal plasma epinephrine appearance rate is not different from appearance rate in the immediate newborn period when catecholamine levels are higher than during most other physiological circumstances. The increase in circulating catecholamine levels at birth is due in part to a significant decrease in clearance rate. It is likely that removal of the placental contribution to whole body clearance accounts for much of the difference observed in fetal and newborn clearance rates.

Effects of corticosteroids in preterm sheep on adaptation and sympathoadrenal mechanisms at birth.

This study investigates the effects of prenatal corticosteroid administration on newborn sympathoadrenal mechanisms involved in postnatal adaptation. Randomly assigned preterm (122-125 days) fetal sheep were treated with hydrocortisone or saline for 60 h and delivered by cesarean section. We examined postnatal physiological adaptation, sympathoadrenal responses, cardiac beta-receptor density, and the receptor-cyclase system. We observed increased ventilatory, cardiovascular, and metabolic responses function in the corticosteroid-treated animals despite a marked attenuation in the anticipated surge of plasma catecholamine concentrations and a decrease in epinephrine secretion rate, which is normally seen at birth. Myocardial beta-adrenergic receptor density and affinity states were comparable in both groups. Basal and agonist-mediated adenylyl cyclase activity in myocardial tissue was increased in the corticosteroid-treated animals. We speculate that the increase in myocardial adenylyl cyclase activity may be accompanied by similar changes in other organ systems and that this could account for the augmentation in respiratory, cardiovascular, and metabolic responses in the corticosteroid-treated animals.