Objective
Characterise the vaginal metabolome of cervical HPV‐infected and uninfected women.
Design
Cross‐sectional.
Setting
The Center for Health Behavior Research at the University of Maryland ...School of Public Health.
Sample
Thirty‐nine participants, 13 categorised as HPV‐negative and 26 as HPV‐positive (any genotype; HPV+), 14 of whom were positive with at least one high‐risk HPV strain (hrHPV).
Method
Self‐collected mid‐vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing, metabolites by both gas and liquid chromatography mass spectrometry, and 37 types of HPV DNA.
Main outcome measures
Metabolite abundances.
Results
Vaginal microbiota clustered into Community State Type (CST) I (Lactobacillus crispatus‐dominated), CST III (Lactobacillus iners‐dominated), and CST IV (low‐Lactobacillus, ‘molecular‐BV’). HPV+ women had higher biogenic amine and phospholipid concentrations compared with HPV– women after adjustment for CST and cigarette smoking. Metabolomic profiles of HPV+ and HPV− women differed in strata of CST. In CST III, there were higher concentrations of biogenic amines and glycogen‐related metabolites in HPV+ women than in HPV– women. In CST IV, there were lower concentrations of glutathione, glycogen, and phospholipid‐related metabolites in HPV+ participants than in HPV– participants. Across all CSTs, women with hrHPV strains had lower concentrations of amino acids, lipids, and peptides compared with women who had only low‐risk HPV (lrHPV).
Conclusions
The vaginal metabolome of HPV+ women differed from HPV− women in terms of several metabolites, including biogenic amines, glutathione, and lipid‐related metabolites. If the temporal relation between increased levels of reduced glutathione and oxidised glutathione and HPV incidence/persistence is confirmed in future studies, anti‐oxidant therapies may be considered as a non‐surgical HPV control intervention.
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Metabolomics study: Vaginal microenvironment of HPV+ women may be informative for non‐surgical interventions.
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Metabolomics study: Vaginal microenvironment of HPV+ women may be informative for non‐surgical interventions.
Background. We sought to describe the temporal relationship between vaginal microbiota and human papillomavirus (HPV) detection. Methods. Thirty-two reproductive-age women self-collected midvaginal ...swabs twice weekly for 16 weeks (937 samples). Vaginal bacterial communities were characterized by pyrosequencing of barcoded 16S rRNA genes and clustered into 6 community state types (CSTs). Each swab was tested for 37 HPV types. The effects of CSTs on the rate of transition between HPV-negative and HPV-positive states were assessed using continuous-time Markov models. Results. Participants had an average of 29 samples, with HPV point prevalence between 58%-77%. CST was associated with changes in HPV status (P<.001). Lactobacillus gassen-dominated CSTs had the fastest HPV remission rate, and a low Lactobacillus community with high proportions of the genera Atopobium (CST IV-B) had the slowest rate compared to L. crispat ws-dominated CSTs (adjusted transition rate ratio aTRR, 4.43, 95% confidence interval CI, 1.11-17.7; aTRR, 0.33, 95% CI, .12-1.19, respectively). The rate ratio of incident HPV for low Lactobacillus CST IV-Awas 1.86 (95% CI, .52-6.74). Conclusions. Vaginal microbiota dominated by L. gasseri was associated with increased clearance of detectable HPV. Frequent longitudinal sampling is necessary for evaluation of the association between HPV detection and dynamic microbiota.
Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without ...recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
The vaginal microbiota may modulate susceptibility to human papillomavirus (HPV), Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections. Persistent infection with a ...carcinogenic HPV is a prerequisite for cervical cancer, and C. trachomatis, N. gonorrheae and M. genitalium genital infections are all associated with pelvic inflammatory disease and subsequent infertility issues.
To evaluate the association between these infections and the vaginal microbiota.
The search was conducted on Medline and the Web of Science for articles published between 2000 and 2016.
Inclusion criteria included a measure of association for vaginal microbiota and one of the considered STIs, female population, cohort, cross-sectional and interventional designs, and the use of PCR methods for pathogen detection.
The vaginal microbiota was dichotomized into high-Lactobacillus vaginal microbiota (HL-VMB) and low-Lactobacillus vaginal microbiota (LL-VMB), using either Nugent score, Amsel's criteria, presence of clue cells or gene sequencing. A random effects model assuming heterogeneity among the studies was used for each STI considered.
The search yielded 1054 articles, of which 39 met the inclusion criteria. Measures of association with LL-VMB ranged from 0.6 (95% CI 0.3–1.2) to 2.8 (95% CI 0.3–28.0), 0.7 (95% CI 0.4–1.2) to 5.2 (95% CI 1.9–14.8), 0.8 (95% CI 0.5–1.4) to 3.8 (95% CI 0.4–36.2) and 0.4 (95% CI 0.1–1.5) to 6.1 (95% CI 2.0–18.5) for HPV, C. trachomatis, N. gonorrhoeae and M. genitalium infections, respectively.
Although no clear trend for N. gonorrhoeae and M. genitalium infections could be detected, our results support a protective role of HL-VMB for HPV and C. trachomatis. Overall, these findings advocate for the use of high-resolution characterization methods for the vaginal microbiota and the need for longitudinal studies to lay the foundation for its integration in prevention and treatment strategies.
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been ...associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide‐gated ion channel in cone photoreceptors and is one of the major disease‐associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease‐causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease‐causing” according to ACMG/AMP criteria. We report 48 novel “likely disease‐causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
Comprehensive overview of the CNGA3 variant spectrum extending it to 316 variants.
Cervical human papillomavirus (HPV) infection may increase HIV risk. Since other genital infections enhance HIV susceptibility by inducing inflammation, we assessed the impact of HPV infection and ...clearance on genital immunology and the cervico-vaginal microbiome. Genital samples were collected from 65 women for HPV testing, immune studies and microbiota assessment; repeat HPV testing was performed after 6 months. All participants were HIV-uninfected and free of bacterial STIs. Cytobrush-derived T cell and dendritic cell subsets were assessed by multiparameter flow cytometry. Undiluted cervico-vaginal secretions were used to determine cytokine levels by multiplex ELISA, and to assess bacterial community composition and structure by 16S rRNA gene sequence analysis. Neither HPV infection nor clearance were associated with broad differences in cervical T cell subsets or cytokines, although HPV clearance was associated with increased Langerhans cells and HPV infection with elevated IP-10 and MIG. Individuals with HPV more frequently had a high diversity cervico-vaginal microbiome (community state type IV) and were less likely to have an L. gasseri predominant microbiome. In summary, HPV infection and/or subsequent clearance was not associated with inflammation or altered cervical T cell subsets, but associations with increased Langerhans cells and the composition of the vaginal microbiome warrant further exploration.
Cigarette smoking has been associated with both the diagnosis of bacterial vaginosis (BV) and a vaginal microbiota lacking protective Lactobacillus spp. As the mechanism linking smoking with vaginal ...microbiota and BV is unclear, we sought to compare the vaginal metabolomes of smokers and non-smokers (17 smokers/19 non-smokers). Metabolomic profiles were determined by gas and liquid chromatography mass spectrometry in a cross-sectional study. Analysis of the 16S rRNA gene populations revealed samples clustered into three community state types (CSTs) --- CST-I (L. crispatus-dominated), CST-III (L. iners-dominated) or CST-IV (low-Lactobacillus). We identified 607 metabolites, including 12 that differed significantly (q-value < 0.05) between smokers and non-smokers. Nicotine, and the breakdown metabolites cotinine and hydroxycotinine were substantially higher in smokers, as expected. Among women categorized to CST-IV, biogenic amines, including agmatine, cadaverine, putrescine, tryptamine and tyramine were substantially higher in smokers, while dipeptides were lower in smokers. These biogenic amines are known to affect the virulence of infective pathogens and contribute to vaginal malodor. Our data suggest that cigarette smoking is associated with differences in important vaginal metabolites, and women who smoke, and particularly women who are also depauperate for Lactobacillus spp., may have increased susceptibilities to urogenital infections and increased malodor.
Background. Genital inflammation is a key determinant of human immunodeficiency virus (HIV) transmission, and may increase HIV-susceptible target cells and alter epithelial integrity. Several genital ...conditions that increase HIV risk are more prevalent in African, Caribbean, and other black (ACB) women, including bacterial vaginosis and herpes simplex virus type-2 (HSV-2) infection. Therefore, we assessed the impact of the genital microbiota on mucosal immunology in ACB women and microbiome-HSV-2 interactions. Methods. Cervicovaginal secretions and endocervical cells were collected by cytobrush and Instead Softcup, respectively. T cells and dendritic cells were assessed by flow cytometry, cytokines by multiplex enzyme-linked immunosorbent assay (ELISA), and the microbiota by 16S ribosomal ribonucleic acid gene sequencing. Results. The cervicovaginal microbiota of 51 participants were composed of community state types (CSTs) showing diversity (20/51; 39%) or predominated by Lactobacillus iners (22/51; 42%), L. crispatus (7/51; 14%), or L. gasseri (2/51; 4%). High-diversity CSTs and specific bacterial phyla (Gardnerella vaginalis and Prevotella bivia) were strongly associated with cervicovaginal inflammatory cytokines, but not with altered endocervical immune cells. However, cervical CD4+ T-cell number was associated with HSV-2 infection and a distinct cytokine profile. Conclusions. This suggests that the genital microbiota and HSV-2 infection may influence HIV susceptibility through independent biological mechanisms.
Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The ...disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ∼70% of affected families. We have combined single-nucleotide–polymorphism array homozygosity mapping with
in silico analysis to identify a new BBS gene,
BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27.
FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that
BBS12 accounts for ∼5% of all BBS cases.
BBS12 is vertebrate specific and, together with
BBS6 and
BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.
Background Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM), but this can be prevented by an implantable cardioverter-defibrillator (ICD). The aim ...of this study is to evaluate HCM patients with ICDs for primary or secondary prevention of SCD. Methods The study population consisted of all HCM patients with an ICD in 2 tertiary referral clinics. End points during follow-up were total and cardiac mortality, appropriate and inappropriate ICD intervention, and device-related complications. Cox-regression analysis was performed to identify predictors of outcome. Results ICDs were implanted in 134 patients with HCM (mean age 44 ± 17 years, 34% women, 4.2 ± 4.8 years follow-up). Annualized cardiac mortality rate was 3.4% per year and associated with New York Heart Association class III or IV (HR 5.2 2.0-14, P = .002) and cardiac resynchronization therapy (HR 6.3 2.1-20, P = .02). Appropriate ICD interventions occurred in 38 patients (6.8%/year) and was associated with implantation for secondary prevention of SCD (HR 4.0 1.8-9.1, P = .001) and male gender (HR 3.3 1.2-9.0, P = .02). Inappropriate ICD intervention occurred in 21 patients (3.7%/year) and in 20 patients device related complications were documented (3.6%/year). Conclusion ICDs successfully abort life-threatening arrhythmias in HCM patients at increased risk of SCD with an annualized intervention rate of 6.8% per year. End-stage heart failure is the main cause of mortality in these patients. The annualized rate of inappropriate ICD intervention was 3.7% per year, whereas device-related complications occurred 3.6% per year.
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