Gonorrhoea

The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea, which has an estimated global annual incidence of 86.9 million adults. Gonorrhoea can present as urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva and, rarely, systemically) in both sexes. Confirmation of diagnosis requires microscopy of Gram-stained samples, bacterial culture or nucleic acid amplification tests. As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing transmission. Single-dose systemic therapy (usually injectable ceftriaxone plus oral azithromycin) is the recommended first-line treatment. However, a major public health concern globally is that N. gonorrhoeae is evolving high levels of antimicrobial resistance (AMR), which threatens the effectiveness of the available gonorrhoea treatments. Improved global surveillance of the emergence, evolution, fitness, and geographical and temporal spread of AMR in N. gonorrhoeae, and improved understanding of the pharmacokinetics and pharmacodynamics for current and future antimicrobials in the treatment of urogenital and extragenital gonorrhoea, are essential to inform treatment guidelines. Key priorities for gonorrhoea control include strengthening prevention, early diagnosis, and treatment of patients and their partners; decreasing stigma; expanding surveillance of AMR and treatment failures; and promoting responsible antimicrobial use and stewardship. To achieve these goals, the development of rapid and affordable point-of-care diagnostic tests that can simultaneously detect AMR, novel therapeutic antimicrobials and gonococcal vaccine(s) in particular is crucial

How to Identify Exposed Women Who Are Infected with Neisseria gonorrhoeae.

Treatment trials of antibiotics for Neisseria gonorrhoeae infections frequently enroll primarily men with urethritis, as the diagnosis of acute gonococcal infection in men with urethritis is easily made by Gram stain of the urethral exudate, followed by confirmatory culture or nucleic acid amplification tests (NAATs). Enrolling women in treatment trials is of great importance, but N. gonorrhoeae cervical infections cause nonspecific symptoms. This makes it difficult to conduct interventional trials, as large numbers of women with nonspecific symptoms need to be screened for infection. Gram stain of cervical secretions has a strikingly low sensitivity, and culture and/or NAAT results are not available at the time of screening. This necessitates recall and delayed treatment of infected women who may not return and who may spread the infection during the interval. In this chapter we present an algorithm, derived from a comparison of women who did, or did not, become infected during exposure, which identifies those women who are highly likely to be infected before culture and/or NAAT results are available. The algorithm provides an efficient way to conduct interventional trials in women without the problem of recall and delayed treatment

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

Patterns of sexually transmitted infections in adolescents and youth in Dar es Salaam, Tanzania

BACKGROUND: Syndromic management of STIs has been advocated as simplified and cheap approach. Youth have been reported to be at increased risk of acquiring STIs which can facilitate HIV transmission. We have investigated the relationship between the syndromic management and specific aetiology diagnosis and its relationship with HIV infection and health seeking behaviour among youth attending a reproductive health clinic in Dar es Salaam, Tanzania. METHODS: Between September 1998 and February 1999 among 1895 adolescents and youth below 25 years seen in the clinic 199 (10.5%) were randomly selected and consented to participate in the study. A standard questionnaire was administered. Blood and vaginal or urethral specimens were taken and investigated for STI causative agents. RESULTS: Among a total of 199 studied adolescents and youth 22.6 % were teenagers, with fewer females 17.8% than males; 27.5% (p < 0.018). 20.8% of the females compared to 11.5% in males were HIV infected. Genital discharge was the most common complaint which was reported in 54.1% of male and 63.4 % of female patients. All males with gonorrhoea and four out of five with Chlamydia were given appropriate treatment with syndromic management, while 28% women with gonorrhoea or Chlamydia received appropriate treatment by syndromic management. All patients found with active syphilis by serology had not complained of genital ulcers and would not have been assigned to syndromic treatment for syphilis at the initial visit. CONCLUSION: The burden of STIs in this youth population is large indicating that youth are at increased risk of STIs and will certainly require youth friendly clinics. There is a need to refine the current syndromic management guidelines

Sexual behavior and awareness of Chinese university students in transition with implied risk of sexually transmitted diseases and HIV infection: A cross-sectional study

BACKGROUND: The vulnerability of young people to HIV and the recent emergence of the HIV epidemic in China have made it urgent to assess and update the HIV/STD risk profile of Chinese young people. METHODS: A self-administered questionnaire survey with cross-sectional design was conducted among 22,493 undergraduate students in two universities in Ningbo, China. Bivariate trend analysis and multiple logistic regression analysis were used to compare sexual behaviors and awareness between grades. RESULTS: Of respondents, 17.6% of males and 8.6% of females reported being sexually active. Condom was reported never/rarely used by 35% of sexually active students in both genders in the previous year. Pregnancy and induced abortion had each been experienced by about 10% of sexually active female students and the female partners of male students, and about 1.5% of sexually active students of both genders reported being diagnosed with an STD. Multivariate analysis revealed that students in lower grades, compared to those in higher grades, were more likely to have become sexually active before university, to have become aware of sex before high school, and to have been exposed to pornographic media before the age of 17 years, and for sexually active respondents of both genders, to have engaged in sex without using a condom. CONCLUSION: Sexual behaviors of Chinese university students are poorly protected and sexual behaviors and awareness may have been undergoing rapid change, becoming active earlier and more risky. If this trend continues, vulnerable sexual network will grow among them that allow more expansion of sexually transmitted diseases and HIV

Serotype-specific mortality from invasive Streptococcus pneumoniae disease revisited

BACKGROUND: Invasive infection with Streptococcus pneumoniae (pneumococci) causes significant morbidity and mortality. Case series and experimental data have shown that the capsular serotype is involved in the pathogenesis and a determinant of disease outcome. METHODS: Retrospective review of 464 cases of invasive disease among adults diagnosed between 1990 and 2001. Multivariate Cox proportional hazard analysis. RESULTS: After adjustment for other markers of disease severity, we found that infection with serotype 3 was associated with an increased relative risk (RR) of death of 2.54 (95% confidence interval (CI): 1.22–5.27), whereas infection with serotype 1 was associated with a decreased risk of death (RR 0.23 (95% CI, 0.06–0.97)). Additionally, older age, relative leucopenia and relative hypothermia were independent predictors of mortality. CONCLUSION: Our study shows that capsular serotypes independently influenced the outcome from invasive pneumococcal disease. The limitations of the current polysaccharide pneumococcal vaccine warrant the development of alternative vaccines. We suggest that the virulence of pneumococcal serotypes should be considered in the design of novel vaccines

Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes—modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5′-AGAAA-3′. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between “differentiated” cell types

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families