Development of New Antimicrobials for Urogenital Gonorrhea Therapy: Clinical Trial Design Considerations.

Gonorrhea remains a major public health challenge, and current recommendations for gonorrhea treatment are threatened by evolving antimicrobial resistance and a diminished pipeline for new antibiotics. Evaluations of potential new treatments for gonorrhea currently make limited use of new understanding of the pharmacokinetic and pharmacodynamic contributors to effective therapy, the prevention of antimicrobial resistance, and newer designs for clinical trials. They are hampered by the requirement to utilize combination ceftriaxone/azithromycin therapy as the comparator regimen in noninferiority trials designed to seek an indication for gonorrhea therapy. Evolving gonococcal epidemiology and clinical trial design constraints hinder the enrollment of those populations at the greatest risk for gonorrhea (adolescents, women, and persons infected with antibiotic-resistant Neisseria gonorrhoeae). This article summarizes a recent meeting on the evaluation process for antimicrobials for urogenital gonorrhea treatment and encourages the consideration of new designs for the evaluation of gonorrhea therapy.

Elimination of mother-to-child transmission of HIV and syphilis: A dual approach in the African Region to improve quality of antenatal care and integrated disease control.

The World Health Organization's (WHO) Strategic Framework for the Elimination of New HIV Infections among Children in Africa by 2015 identifies important synergies for the elimination of mother-to-child transmission of HIV and syphilis in terms of prevention interventions, implementation logistics and service delivery, monitoring and evaluation systems, and need for sustained political commitment. The WHO advocates the use of an integrated, rights-based dual approach with partnerships and collaboration to make the best use of available resources. Through a consultative approach, six countries in the African Region committed to dual elimination and developed and implemented action plans for this purpose. Where interest and commitment are high, this may also be possible and effective in other African countries.

Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data.

BACKGROUND: The World Health Organization initiative to eliminate mother-to-child transmission of syphilis aims for ≥ 90% of pregnant women to be tested for syphilis and ≥ 90% to receive treatment by 2015. We calculated global and regional estimates of syphilis in pregnancy and associated adverse outcomes for 2008, as well as antenatal care (ANC) coverage for women with syphilis. METHODS AND FINDINGS: Estimates were based upon a health service delivery model. National syphilis seropositivity data from 97 of 193 countries and ANC coverage from 147 countries were obtained from World Health Organization databases. Proportions of adverse outcomes and effectiveness of screening and treatment were from published literature. Regional estimates of ANC syphilis testing and treatment were examined through sensitivity analysis. In 2008, approximately 1.36 million (range: 1.16 to 1.56 million) pregnant women globally were estimated to have probable active syphilis; of these, 80% had attended ANC. Globally, 520,905 (best case: 425,847; worst case: 615,963) adverse outcomes were estimated to be caused by maternal syphilis, including approximately 212,327 (174,938; 249,716) stillbirths (>28 wk) or early fetal deaths (22 to 28 wk), 91,764 (76,141; 107,397) neonatal deaths, 65,267 (56,929; 73,605) preterm or low birth weight infants, and 151,547 (117,848; 185,245) infected newborns. Approximately 66% of adverse outcomes occurred in ANC attendees who were not tested or were not treated for syphilis. In 2008, based on the middle case scenario, clinical services likely averted 26% of all adverse outcomes. Limitations include missing syphilis seropositivity data for many countries in Europe, the Mediterranean, and North America, and use of estimates for the proportion of syphilis that was "probable active," and for testing and treatment coverage. CONCLUSIONS: Syphilis continues to affect large numbers of pregnant women, causing substantial perinatal morbidity and mortality that could be prevented by early testing and treatment. In this analysis, most adverse outcomes occurred among women who attended ANC but were not tested or treated for syphilis, highlighting the need to improve the quality of ANC as well as ANC coverage. In addition, improved ANC data on syphilis testing coverage, positivity, and treatment are needed. Please see later in the article for the Editors' Summary.

Cholinergic modulation of visuospatial responding in central thalamus.

Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory-guided goal-directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABA(A) agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 micromol/kg) and scopolamine (0.03, 0.09, 0.26 micromol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3-s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention-demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors.