Probiotics: insights and new opportunities for Clostridioides difficile intervention.

Clostridioides difficile infection (CDI) is a life-threatening disease caused by the Gram-positive, opportunistic intestinal pathogen C. difficile. Despite the availability of antimicrobial drugs to treat CDI, such as vancomycin, metronidazole, and fidaxomicin, recurrence of infection remains a significant clinical challenge. The use of live commensal microorganisms, or probiotics, is one of the most investigated non-antibiotic therapeutic options to balance gastrointestinal (GI) microbiota and subsequently tackle dysbiosis. In this review, we will discuss major commensal probiotic strains that have the potential to prevent and/or treat CDI and its recurrence, reassess the efficacy of probiotics supplementation as a CDI intervention, delve into lessons learned from probiotic modulation of the immune system, explore avenues like genome-scale metabolic network reconstructions, genome sequencing, and multi-omics to identify novel strains and understand their functionality, and discuss the current regulatory framework, challenges, and future directions.

Phase 3 study evaluating the safety and efficacy of oteseconazole in the treatment of recurrent vulvovaginal candidiasis and acute vulvovaginal candidiasis infections.

BACKGROUND: Recurrent vulvovaginal candidiasis affects nearly 138 million women globally each year. In the United States, fluconazole is considered the standard of care for acute vulvovaginal candidiasis, but until recently there was no US Food and Drug Administration-approved drug for the treatment of recurrent vulvovaginal candidiasis. Oteseconazole is a novel oral selective inhibitor of fungal lanosterol demethylase (sterol 14α-demethylase cytochrome P450, an enzyme required for fungal growth) approved for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: This study was conducted to evaluate the efficacy and safety of oral oteseconazole (VT-1161) in the prevention of recurrent culture-verified acute vulvovaginal candidiasis episodes through 50 weeks in participants with recurrent vulvovaginal candidiasis and to compare the efficacy of oteseconazole and fluconazole in the treatment of the presenting acute vulvovaginal candidiasis episode. STUDY DESIGN: Women and postmenarcheal girls aged ≥12 years with a history of recurrent vulvovaginal candidiasis (N=219) were enrolled at 38 US sites. Eligible participants presenting with an active vulvovaginal candidiasis infection entered an induction phase in which they were randomly assigned 2:1 to receive 600 mg oral oteseconazole on day 1 and 450 mg on day 2, with matching placebo capsules, or to 3 sequential 150-mg oral doses (once every 72 hours) of fluconazole, with matching placebo capsules. Following the 2-week induction phase, the 185 participants with resolved acute vulvovaginal candidiasis infection (a clinical signs and symptoms score of <3) entered the maintenance phase and received 150 mg of oteseconazole or placebo weekly for 11 weeks. Participants were observed for an additional 37 weeks. RESULTS: In the induction phase, oteseconazole was noninferior to fluconazole in the proportion of participants in the intent-to-treat population with resolved acute vulvovaginal candidiasis infection at the week 2 (day 14) test-of-cure visit, with 93.2% of participants on oteseconazole vs 95.8% on fluconazole achieving resolution. In the maintenance phase, oteseconazole was superior to placebo in the proportion of participants in the intent-to-treat population with ≥1 culture-verified acute vulvovaginal candidiasis episode through 50 weeks, 5.1% compared with 42.2%, respectively (P<.001). Overall, treatment-emergent adverse event rates were similar in both groups: 54% for participants who received oteseconazole in the induction and maintenance phases vs 64% for participants who received fluconazole in the induction phase and placebo in the maintenance phase. Most treatment-emergent adverse events in each group were mild or moderate, with 3.4% of treatment-emergent adverse events graded as severe or higher in the OTESECONAZOLE/oteseconazole group vs 4.2% in FLUCONAZOLE/placebo group. CONCLUSION: In participants with recurrent vulvovaginal candidiasis, oteseconazole was safe and efficacious in the treatment and prevention of recurrent acute vulvovaginal candidiasis episodes and was noninferior to vulvovaginal candidiasis standard-of-care fluconazole in the treatment of the presenting acute vulvovaginal candidiasis infection.

Toxicology and human health risk assessment of polyethoxylated tallow amine surfactant used in glyphosate formulations.

Roundup® branded herbicides contain glyphosate, a surfactant system and water. One of the surfactants used is polyethoxylated tallow amine (POE-T). A toxicology dataset has been developed to derive the most representative points of departure for human health risk assessments. Concentrated POE-T was very irritating to skin, corrosive to eyes, and sensitizing to skin. The irritation and sensitization potential of POE-T diminishes significantly upon dilution with water. Repeated dosing of rats with POE-T produced gastrointestinal effects but no systemic effect on organ systems. POE-T was not genotoxic and had no effect on embryo-fetal development or reproduction. The occupational risk assessment of POE- T for the agricultural use of glyphosate products has demonstrated that margins of exposure (MOEs) are 2517 and 100,000 for maximum and geometric mean dermal exposures, respectively. In the food risk assessment for relevant agricultural uses, the range of MOEs for consumption of foods from plant and animal origin were 330 to 2909. MOEs ≥100 are generally considered to be of no toxicological concern. Based on the results of the occupational and food risk assessments, it is concluded that there are no significant human health issues associated with the use of POE-T as a surfactant in glyphosate products.

Scorpion Envenomation in Pregnancy.

Scorpion envenomation affects more than 1 million people every year and represents an important public health problem worldwide. The effects of envenomation range from localized pain and paresthesias to overactivation of the sympathetic nervous system, leading to neurotoxicity and even death. Of the individuals affected by scorpion envenomation, certain populations, such as young children and older adults, are at high risk for severe disease. Substantial literature exists on the management of envenomation in children; however, scant literature exists that addresses the same phenomenon in pregnant women. This review serves to identify the effects of scorpion envenomation on pregnant women and the treatment options available to them. After thorough review of the treatment modalities that are used to treat scorpion envenomation, we developed a treatment algorithm that may help guide the management of pregnant women who present with scorpion envenomation.

Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.

BACKGROUND: Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women. METHODS: In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047. FINDINGS: The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (<1%) and eight (<1%) of these events, respectively, were believed to be related to vaccination. INTERPRETATION: In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45. FUNDING: GlaxoSmithKline Biologicals SA.

Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against low-risk HPV types (PATRICIA randomized trial): an unexpected observation.

BACKGROUND: Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent. METHODS: Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations. RESULTS: In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74. CONCLUSIONS: The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.

Clinical evaluation of a new Pap test-based method for screening of Chlamydia trachomatis and Neisseria gonorrhoeae using liquid-based cytology media.

OBJECTIVES: The majority of chlamydial and gonococcal infections in women are asymptomatic and, if left untreated, may result in serious sequelae. Simple and accurate testing of men and women at risk for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) is the single most effective strategy for control of sexually transmitted infections. New tests using easy-to-acquire samples, such as the Papanicolaou (Pap) test, need to be validated in an effort to expand and improve detection. The objective of this study was to determine the performance of a new nucleic acid amplification test using two liquid-based cytology media for the detection of CT and GC. METHODS: The study was conducted in two phases at 11 geographically diverse, high- and low-prevalence sites. Three endocervical reference swabs as well as an endocervical SurePath or PreservCyt liquid cytology specimen sampled with a broom or brush/spatula were collected in a randomized order from each subject. Reference endocervical swabs were tested with three Food and Drug Administration-approved methods and compared to two new automated tests, the CT Q Amplified DNA Assay (CTQ) and the GC Q Amplified DNA Assay (GCQ). RESULTS: For the SurePath phase, 1838 subjects were enrolled. The sensitivity and specificity of the CTQ assay were 95.0% and 99.7%, respectively, and the GCQ assay was 100% for both. In the PreservCyt phase, 2164 subjects were enrolled. The sensitivity and specificity of the CTQ assay were 94.1% and 99.8%, respectively, and the GCQ assay was 95.3% and 99.95%, respectively. There was no significant difference in the results. CONCLUSIONS: In this investigation, high sensitivity and specificity of the CTQ and GCQ assays were demonstrated for samples collected in either of two liquid-based cytology media when compared with endocervical swabs. The results were similar in both collection methods (broom or brush/spatula) and in high- and low-risk populations.

Facility- and ward-level factors associated with SARS-CoV-2 outbreaks among residents in long-term care facilities: A retrospective cohort study.

OBJECTIVES: Long-term care facilities (LTCFs) have been disproportionately impacted by COVID-19. Yet, the reasons why certain LTCFs are affected more by outbreaks are poorly understood. This study aimed to identify the facility- and ward-level factors associated with SARS-CoV-2 outbreaks among LTCF residents. METHODS: We conducted a retrospective cohort study of multiple Dutch LTCFs (N = 60; with 298 wards providing care for ∼5600 residents) from September 2020 to June 2021. A dataset was constructed linking SARS-CoV-2 cases among LTCF residents to facility- and ward-level factors. Multilevel logistic regression analyses examined the associations between these factors and the likelihood of a SARS-CoV-2 outbreak among residents. RESULTS: During periods of the Classic variant, the mechanical recirculation of air was associated with significantly increased odds of a SARS-CoV-2 outbreak. During periods of the Alpha variant, the factors associated with significantly increased odds included large ward size (≥21 beds), wards providing psychogeriatric care, fewer restrictions on staff movement between wards and facilities, and a greater number of cases among staff (>10 cases). CONCLUSION: Policy and protocols on reducing resident density, staff movement, and mechanical recirculation of air in buildings are recommended to enhance outbreak preparedness in LTCFs. The implementation of low-threshold preventive measures among psychogeriatric residents is important because they appear as a particularly vulnerable group.

Type-specific identification of anogenital herpes simplex virus infections by use of a commercially available nucleic acid amplification test.

Herpes infections are among the most common sexually transmitted infections (STI), but diagnostic methods for genital herpes have not kept pace with the movement toward molecular testing. Here, we describe an FDA-approved molecular assay that identifies and types herpes simplex virus (HSV) infections for use in routine clinical settings. Paired samples from anogenital lesions were tested using the BD ProbeTec HSV Q(x) (HSVQ(x)) system, HSV culture and, a laboratory-developed PCR assay. Family planning, obstetrics/gynecology (OB/GYN), or sexually transmitted disease (STD) clinics in the United States served as recruitment sites. Sensitivity and specificity estimates, head-to-head comparisons, measures of agreement, and latent-class analyses were performed to provide robust estimates of performance. A total of 508 participants (174 men and 334 women) with anogenital lesions were included; 260 HSV-2 and 73 HSV-1 infections were identified. No differences in test performance based on gender, clinic type, location of the lesion, or type of lesion were observed. The sensitivity of HSV-2 detection ranged from 98.4 to 100% depending on the analytical approach, while the specificity ranged from 80.6%, compared to the less sensitive culture method, to 97.0%, compared to PCR. For HSV-1, the sensitivity and specificity ranges were 96.7 to 100% and 95.1 to 99.4%, respectively. This assay may improve our ability to accurately diagnose anogenital lesions due to herpes infection.

The effects of QuikClot Combat Gauze and movement on hemorrhage control in a porcine model.

The purpose of this study was twofold: (1) to examine the effectiveness of QuikClot Combat Gauze (QCG) compared to a control group and (2) investigate the effect of movement on hemorrhage control when QCG is employed. This was a prospective, experimental design employing an established porcine model of uncontrolled hemorrhage. The minimum number of animals (n = 11 per group) was used to obtain a statistically valid result. There were no statistically significant differences between the groups (p > 0.05) indicating that the groups were equivalent on the following parameters: activating clotting time, the subject weights, core body temperatures, amount of 1 minute hemorrhage, arterial blood pressures, and the amount and percentage of total blood volume. There were significant differences in the amount of hemorrhage (p = 0.018) and the number of movements (p = 0.000) between the QCG and control. QCG is statistically and clinically superior at controlling hemorrhage compared to the standard pressure dressing control group. Furthermore, it produces a more robust clot that can withstand significant movement. In conclusion, QCG is an effective hemostatic agent for use in civilian and military trauma management.

Clinical challenges in diagnosis and treatment of recurrent vulvovaginal candidiasis.

Vulvovaginal candidiasis is a common infection associated most often with the overgrowth of the fungal species Candida albicans. Although most women will have at least one episode of vulvovaginal candidiasis in their lifetime, some will experience recurrent infections. Recurrent vulvovaginal candidiasis can significantly impact quality of life, causing both physical and psychological symptoms, and poses a substantial financial burden for women and the health care system. Acute vulvovaginal candidiasis infections are often diagnosed symptomatically by clinicians or self-diagnosed by patients themselves; this can result in over- and underdiagnosis, as well as misdiagnosis, and has the potential to lead to ineffective treatment and incomplete infection resolution. Clinical diagnosis should include confirmatory laboratory tests, including microscopy and fungal culture, especially in women with a history of recurrent vulvovaginal candidiasis, who are more likely than women with vulvovaginal candidiasis to be infected with less-common Candida species or with azole-resistant strains. With proper diagnosis, most acute vulvovaginal candidiasis episodes can be successfully treated; however, women with recurrent vulvovaginal candidiasis may require long-term maintenance therapy. US-based guidelines recommend ⩽6 months of maintenance fluconazole treatment, but infection recurs in up to 50% of women treated. There are currently no US Food and Drug Administration-approved treatments for recurrent vulvovaginal candidiasis; however, several promising treatments for recurrent vulvovaginal candidiasis are in development.

Topical Treatment of Recurrent Vulvovaginal Candidiasis: An Expert Consensus.

Background: Recurrent vulvovaginal candidiasis (RVVC), defined as three or more confirmed infections over 1 year, occurs in up to 10% of women. In these women, the objective is often symptomatic control rather than mycologic cure. Current Centers for Disease Control and Prevention (CDC) guidelines recommend oral fluconazole as first-line maintenance, but state if this oral regimen is not feasible, intermittent topical treatments can be considered. No specific recommendations for type or frequency of topical applications are provided by the CDC. Methods: A panel of vulvovaginal experts convened to develop a consensus recommendation for topical maintenance dosing for RVVC. Results: Data suggest that clotrimazole, miconazole, terconazole, and intravaginal boric acid are suggested recommendations for recurrent vulvovaginitis caused by both Candida albicans and nonalbicans species. Nystatin ovules may not be as effective as azoles. Identification of species will influence treatment decisions. In addition, treatment may be modified based on prior response to a specific agent, especially in nonalbicans species. Fluconazole, ibrexafungerp, and intravaginal boric acid should be avoided during pregnancy. Conclusions: The expert consensus for women with RVVC is an initial full course of treatment followed by topical maintenance beginning at one to three times weekly, based on chosen agent. Twice a week dosing was the regimen most often utilized. In some women, episodic treatment may be used, but maintenance should remain an option for this population.

Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies.

OBJECTIVE: To evaluate if new imiquimod formulations using a shorter treatment duration are safe and efficacious to treat anogenital warts. METHODS: In two studies 534 women ≥12 years of age (mean 33.4) with 2-30 warts (mean 7.9) and total wart area ≥10 mm(2) (mean 166.3) were randomized (1:2:2) to placebo (106), imiquimod 2.5% (212) or 3.75% (216) creams applied once daily until complete clearance or a maximum of 8 weeks. RESULTS: For placebo, imiquimod 2.5% and 3.75%, respectively, complete clearance of all warts was achieved in 14.2%, 28.3%, and 36.6% of women (intent-to-treat, P = 0.008 imiquimod 2.5%, and P < 0.001 3.75% versus placebo). Mean changes in wart counts were -10.7%, -50.9%, and -63.5% (per-protocol, P < 0.001 each active versus placebo) and safety-related discontinuation rates 0.9%, 1.4%, and 2.3%. CONCLUSIONS: Imiquimod 3.75% applied daily for up to 8 weeks was well tolerated and superior to placebo in treating women with external anogenital warts.

Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial.

BACKGROUND: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. METHODS: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated. FINDINGS: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. INTERPRETATION: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. FUNDING: Sanofi Pasteur.

Clinical validation of the Cervista HPV HR and 16/18 genotyping tests for use in women with ASC-US cytology.

OBJECTIVE: High-risk (HR) human papillomavirus (HPV) testing is important in cervical cancer screening for triage to colposcopy. This study evaluated the clinical performance of the Cervista HPV HR and 16/18 genotyping tests for detection of HPV in cervical cytology specimens. METHODS: The tests were prospectively evaluated in a multicenter clinical study. DNA was extracted from approximately 4000 residual liquid-based cytology specimens collected during routine liquid-based Papanicolaou tests at standard of care visits and was assessed for the presence of HR HPV and/or HPV types 16 and 18. All women with cytology results of atypical squamous cells of undetermined significance (ASC-US) or greater underwent colposcopic examination and biopsies were collected. Test results were compared with local colposcopy and histology results from a central pathology review panel. RESULTS: There were 1347 subjects with complete data sets of cytology, HR HPV, colposcopy, and histology included in the analysis of the HPV HR test. Sensitivity of the HPV HR test for detection of cervical intraepithelial neoplasia (CIN) 2+ among women with ASC-US cytology was 92.8% (95% confidence interval [CI]: 84.1-96.9) and the negative predictive value (NPV) was 99.1% (95% CI: 98.1-99.6). Sensitivity for detection of > or =CIN 3 in women with ASC-US was 100% (95% CI: 85.1-100) and the NPV was 100% (95% CI: 99.4-100). The specificity of the test for detection of > or =CIN 2 and > or =CIN 3 was 44.2% (95% CI: 41.5-46.9) and 43% (95% CI: 40.3-45.7), respectively. The HPV 16/18 genotyping test also performed as expected in women with ASC-US cytology who were positive for HR HPV. CONCLUSION: The Cervista HPV HR test can be clinically used for detecting HR HPV types in conjunction with cervical cytology for use in triage of women with ASC-US cytology during routine cervical cancer screening.

Once daily valacyclovir for reducing viral shedding in subjects newly diagnosed with genital herpes.

OBJECTIVE: Genital herpes (GH) recurrences and viral shedding are more frequent in the first year after initial HSV-2 infection. The objective of this study was to provide the first evaluation of valacyclovir 1 g once daily compared to placebo in reducing viral shedding in subjects newly diagnosed with GH. METHODS: 70 subjects were randomized to receive valacyclovir 1 g daily or placebo in a crossover design for 60 days with a 7-day washout period. A daily swab of the genital/anal-rectal area was self-collected for HSV-2 detection by PCR. Subjects attended the clinic for routine study visits and GH recurrence visits. Treatment differences were assessed using a nonparametric crossover analysis. RESULTS: 52 subjects had at least one PCR measurement in both treatment periods and comprised the primary efficacy population. Valacyclovir significantly reduced HSV-2 shedding during all days compared to placebo (mean 2.9% versus 13.5% of all days (P < .01), a 78% reduction). Valacyclovir significantly reduced subclinical HSV-2 shedding during all days compared to placebo (mean 2.4% versus 11.0% of all days (P < .01), a 78% reduction). However, 79% of subjects had no GH recurrences while receiving valacyclovir compared to 52% of subjects receiving placebo (P < .01). CONCLUSION: In this study, the frequency of total and subclinical HSV-2 shedding was greater than reported in earlier studies involving subjects with a history of symptomatic genital recurrences. Our study is the first to demonstrate a significant reduction in viral shedding with valacyclovir 1 g daily compared to placebo in a population of subjects newly diagnosed with HSV-2 infection.

Improved GI tolerability with monthly ibandronate in women previously using weekly bisphosphonates.

OBJECTIVE: This subanalysis of CURRENT, an open-label, 6-month, multicenter study, assesses changes in gastrointestinal (GI) tolerability with once-monthly oral ibandronate in women who switched from once-weekly bisphosphonates and had reported GI symptoms with their previous weekly bisphosphonate regimen. METHODS: Postmenopausal women currently taking a weekly bisphosphonate switched to 150 mg monthly ibandronate. At the start of the treatment phase and after 6 months of therapy, all participants completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q), a validated instrument consisting of four domains: convenience, satisfaction, quality of life, and side effects. This subanalysis assessed GI tolerability in those women who reported GI symptoms at baseline in the side effects domain of OPSAT-Q and change in satisfaction in those who had reported stomach upset within 48 hours of taking their previous bisphosphonate at screening. RESULTS: Of women who reported GI symptoms at baseline, >60% reported an improvement in heartburn or acid reflux after switching to monthly ibandronate. Further, >70% reported improvements in stomach upset (excluding heartburn or acid reflux). Of those women who reported stomach upset within 48 hours of taking their previous weekly bisphosphonate at screening (n = 89), >80% reported improved overall satisfaction compared with baseline. Monthly ibandronate was generally well tolerated. CONCLUSION: A majority of women who experienced GI tolerability issues with weekly bisphosphonates reported improvements in GI symptoms after transitioning from a weekly bisphosphonate to monthly ibandronate for 6 months.

Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies.

BACKGROUND: Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti-HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm. METHODS: Serum anti-HPV-16/18 antibodies were determined at baseline and every 12 months in baseline DNA-negative women (N = 2687 for HPV-16 and 2705 for HPV-18) by enzyme-linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6-months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7-year period. The association between the risk of type-specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models. RESULTS: Risk of newly detected HPV-16-associated 6-month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC-US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV-16-associated incident infections (HR = 0.81 [0.56; 1.16]) and 12-month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV-18-seropositive vs -seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6-month PIs, HR = 0.31 [0.07; 1.36] for 12-month PIs, and HR = 0.61 [0.23; 1.61] for ASC-US+). CONCLUSIONS: Naturally acquired anti-HPV-16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15- to 25-year-old women.

Bone turnover marker profile in relation to the menstrual cycle of premenopausal healthy women.

OBJECTIVE: To explore the bone turnover marker profile during the menstrual cycle of premenopausal women. DESIGN: This was a noninterventional study. Levels of bone turnover markers, including serum C-terminal telopeptide of type I collagen (sCTX), bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 N propeptide, and urinary N-terminal telopeptide of type I collagen, were measured in blood and urine samples during one menstrual cycle. Levels were expressed as raw test results and percent change from serum luteinizing hormone peak. Differences in mean levels of bone turnover markers between menstrual phases and subphases were examined. RESULTS: Fifty-five women comprised the per-protocol population. Mean sCTX values were 0.48 ng/mL during the follicular phase (FP), 0.47 ng/mL at serum luteinizing hormone peak, and 0.43 ng/mL during the luteal phase (LP). Additionally, the mean percent change from luteinizing hormone peak varied from +4.35% during the FP to -5.11% during the LP (P = 0.0014). Mean sCTX levels during the early and through mid FP were significantly higher than levels during the mid and late LP. The pattern for urinary N-terminal telopeptide of type I collagen was similar to that of sCTX but not statistically significant. There was a statistically significant tendency for procollagen type I N propeptide levels to be lower during the FP relative to the LP. Levels of osteocalcin and bone-specific alkaline phosphatase did not vary significantly during the menstrual cycle. CONCLUSIONS: Levels of some bone turnover markers varied during the menstrual cycle. A statistically significant change in sCTX (9.46%) occurred between the FP and LP of the menstrual cycle.

Genotoxic potential of glyphosate formulations: mode-of-action investigations.

A broad array of in vitro and in vivo assays has consistently demonstrated that glyphosate and glyphosate-containing herbicide formulations (GCHF) are not genotoxic. Occasionally, however, related and contradictory data are reported, including findings of mouse liver and kidney DNA adducts and damage following intraperitoneal (ip) injection. Mode-of-action investigations were therefore undertaken to determine the significance of these contradictory data while concurrently comparing results from ip and oral exposures. Exposure by ip injection indeed produced marked hepatic and renal toxicity, but oral administration did not. The results suggest that ip injection of GCHF may induce secondary effects mediated by local toxicity rather than genotoxicity. Furthermore, these results continue to support the conclusion that glyphosate and GCHF are not genotoxic under exposure conditions that are relevant to animals and humans.