We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was ...hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18–45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 µg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women. Trial Registration ClinicalTrials.gov NCT00637962
ABSTRACT—
Scholars are giving increased attention to the need to incorporate research on more basic developmental processes into new paradigms for understanding and treating mental illness in ...children and adolescents. The study of emotion regulation, rooted in neurodevelopment, has proven a fruitful model for understanding and characterizing problems of behavior and risk in children and adolescents. This article summarizes NIMH initiatives designed to encourage transformational research on the neurodevelopment origins of mental illness. It highlights the NIMH Strategic Plan and the Report on Transformative Neurodevelopment Research as part of an introduction to a collection of articles that grew out of a previously organized NIMH workshop on developmental and translational models of emotion regulation and dysregulation.
The modifications to the vaginal habitat accompanying a change to vaginal flora in bacterial vaginosis (BV) are poorly understood. In this study enzymes involved in mucin degradation were measured, ...including a novel glycosulfatase assay. Women attending an emergency walk-in sexually transmitted disease clinic were studied. One high vaginal swab (HVS) was used to prepare a gram-stained smear to determine BV status, using Ison and Hay's criteria, and a separate swab was used for the purposes of the assays. The median glycosulfatase activity was 8.5 (range, -1.2 to 31.9) nmol h⁻¹ 1.5 ml⁻¹ of HVS suspension in patients with BV compared to 0.5 (range, -0.7 to 9.4) nmol h⁻¹ 1.5 ml⁻¹ of HVS suspension in patients without BV (P = <0.001). The median glycoprotein sialidase activity was 29.2 (range, -17 to 190) nmol h⁻¹ 1.5 ml⁻¹ of HVS suspension in patients with BV compared to -1.1 (range, -41 to 48) nmol h⁻¹ 1.5 ml⁻¹ of HVS suspension in patients without BV (P < 0.001). A rapid spot test for sialidase was positive in 22/24 patients with BV (sensitivity, 91.7%; 95% confidence interval CI, 73 to 99%) and negative in 32/35 patients without BV (specificity, 91.4%; 95% CI, 76.9 to 98.2%) (P < 0.001). Glycosulfatase activity significantly correlated with both glycoprotein sialidase activity and the sialidase spot test (P = 0.006 and P < 0.001, respectively). The results are consistent with the hypothesis that the consortium of bacteria present in BV requires the ability to break down mucins in order to colonize the vagina and replace the normal lactobacilli.
The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main ...objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.
•An overview of the MRI processing pipeline for the ABCD Study.•A discussion on the challenges of large, multisite population studies.•A methodological reference for users of publicly shared data from the ABCD Study.•Preliminary results from technical survey of baseline dataset.
We quantitatively investigated inflammatory cells in the male urethra. Leukocytes in the first catch urine (FCU) from 87 men with and without urethritis were quantitated using haemocytometer counts ...and stained with an anti-CD45 pan-leukocyte antibody. An increased number of leukocytes in FCU specimens was associated with urethritis (P > 0.002), the presence of discharge and/or dysuria (P < 0.001), and detection of Chlamydia trachomatis (P < 0.001) and Neisseria gonorrhoeae (P < 0.001). In men with urethritis, higher leukocyte counts were also observed in the above groups (P = 0.07, 0.03 and P < 0.0001, respectively). As leukocyte number increased, the likelihood of detecting either pathogen increased. This study suggests that symptoms and signs are a surrogate marker for the degree of inflammation present, and that as urethral inflammation increases, the likelihood of detecting a sexually transmitted pathogen also increases. This would explain why men with asymptomatic urethritis are less likely to have a sexually transmitted infection detected than those with discharge and/or dysuria.
Infant and toddler mental health is a growing area of interest for psychiatrists, child psychologists, pediatricians, and educators. Expanding research in this area highlights the need for early ...identification and assessment of mental health problems and risk factors in infants and toddlers. In addition, public policy and recent legislation have offered new opportunities to provide services to infants and toddlers who are at risk or are already exhibiting delays or deviance in social and emotional functioning. This handbook is the first of its kind to bring together the several new diagnostic and assessment approaches for working with infant and toddler mental health.
Epithelial cells in first catch urine (FCU) specimens from 87 men with and without urethritis were quantified. Epithelial cells were broadly categorised into transitional and squamous populations ...using morphological characteristics and immunostaining with anti-pan leukocyte and anti-cytokeratin monoclonal antibodies.
The majority (77/87 = 89%) of samples contained both transitional (76/87 = 87%; range 1 x 10(4) - 6 x 10(5), median 6 x 10(4)) and squamous (57/87 = 66%; range 1 x 10(4) - 8 x 10(5), median 2 x 10(4)) epithelial cells. The number of transitional cells correlated with the number of squamous cells (Spearman's rho = 0.697 p < 0.001). Squamous, but not transitional, cell numbers correlated with leukocyte numbers (Spearman's rho = 0.216 p = 0.045 and rho = 0.171 and p = 0.113, respectively). However there was no significant difference in epithelial cell numbers between men with and without urethritis. Nevertheless, some men with urethritis had relatively high numbers of transitional cells in their FCU. Transitional cells were morphologically heterogeneous and appeared to display complex cytokeratin phenotypes.
Further studies are required to explore the complexity of epithelial cell populations in urine. These would provide novel opportunities for studying cellular interactions of C. trachomatis in male urethral infections, about which little is currently known.
Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new ...treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6–180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42–120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.
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Post-kala-azar dermal leishmaniasis (PKDL) is a chronic parasitic disease with limited treatment options. Here, Musa and colleagues report on a phase IIa therapeutic trial of the adenoviral-vectored leishmaniasis vaccine ChAd63-KH. Single-dose vaccination with ChAd63-KH was safe and induced innate and T cell responses in Sudanese patients with PKDL.
is the world's most prevalent bacterial sexually transmitted infection and leading infectious cause of blindness, yet it is one of the least understood human pathogens, in part due to the ...difficulties of in vitro culturing and the lack of available tools for genetic manipulation. Genome sequencing has reinvigorated this field, shedding light on the contemporary history of this pathogen. Here, we analyze 563 full genomes, 455 of which are novel, to show that the history of the species comprises two phases, and conclude that the currently circulating lineages are the result of evolution in different genomic ecotypes. Temporal analysis indicates these lineages have recently expanded in the space of thousands of years, rather than the millions of years as previously thought, a finding that dramatically changes our understanding of this pathogen's history. Finally, at a time when almost every pathogen is becoming increasingly resistant to antimicrobials, we show that there is no evidence of circulating genomic resistance in
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