Intra-amniotic inflammatory response in subgroups of women with preterm prelabor rupture of the membranes

Background

To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on the magnitude of intra-amniotic inflammatory response in preterm prelabor rupture of membranes (PPROM).

Methodology/Principal Finding

A prospective cohort study was performed in 107 women with PPROM between 23.0 and 36.6 weeks of gestational age. Twenty-six proteins were assayed by multiple immunoassay in amniotic fluid. The policy for PPROM in Czech Republic is active, and 90% of the women were delivered within 96 hours of membrane rupture. Histopathological placental findings were evaluated based on the Salafia classification. Data were analyzed in four subgroups of population according to the presence of MIAC and/or HCA. Results were stratified by gestational age at PPROM (< or ≥34.0 weeks). The rates of MIAC and HCA were 44% and 57%, respectively. Regardless of gestational age at PPROM, intra-amniotic inflammatory response was higher when MIAC and HCA were both present. There were no differences in the intra-amniotic inflammatory response between women with MIAC or HCA alone and women without infection.

Conclusion

A higher intra-amniotic inflammatory response was identified when both HCA and MIAC were detected.     

Maternal Serum C-Reactive Protein in Women with Preterm Prelabor Rupture of Membranes

Objective

This study evaluated maternal C-reactive protein (CRP) as a predictor of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) in women with preterm prelabor rupture of the membranes (PPROM) before and after 32 weeks of gestation.

Methods

This study was a prospective observational cohort study of 386 women. Maternal serum CRP concentrations were evaluated, and amniotic fluid samples were obtained via transabdominal amniocentesis at the time of admission. Placentas underwent histopathological examination after delivery. MIAC was defined based on a positive PCR for Ureaplasma species, Mycoplasma hominis and Chlamydia trachomatis and/or positive 16S rRNA gene amplification. HCA was defined based on the Salafia classification.

Results

Maternal CRP was significantly higher in women with MIAC and HCA (median 9.0 mg/l) than in women with HCA alone (median 6.9 mg/l), MIAC alone (median 7.4 mg/l) and without MIAC or HCA (median 4.5 mg/l) (p<0.0001). CRP was a weak predictor of the occurrence of MIAC and HCA before and after 32 weeks of gestation. Only the 95^th percentile of CRP and PPROM before 32 weeks exhibited a false-positive rate of 1%, a positive predictive value of 90% and a positive likelihood ratio of 13.2 to predict MIAC and HCA. However, the low sensitivity of 15% limits the clinical utility of this detection.

Conclusion

CRP is a poor predictor of the occurrence of MIAC and HCA, even at early gestational ages.     

Amniotic fluid cathelicidin in PPROM pregnancies: from proteomic discovery to assessing its potential in inflammatory complications diagnosis

Background

Preterm prelabor rupture of membranes (PPROM) complicated by microbial invasion of the amniotic cavity (MIAC) leading to histological chorioamnionitis (HCA) significantly impacts perinatal morbidity. Unfortunately, no well-established tool for identifying PPROM patients threatened by these disorders is available.

Methodology/Principal Findings

We performed an unbiased exploratory analysis of amniotic fluid proteome changes due to MIAC and HCA. From among the top five proteins that showed the most profound and significant change, we sought to confirm results concerning cathelicidin ({"type":"entrez-protein","attrs":{"text":"P49913","term_id":"1706745","term_text":"P49913"}}P49913, CAMP_HUMAN), since an ELISA kit was readily available for this protein. In our exploratory proteomic study, cathelicidin showed a ∼6-fold higher concentration in PPROM patients with confirmed MIAC and HCA. We verified significantly higher levels of cathelicidin in exploratory samples (women without both MIAC and HCA: median 1.4 ng/ml; women with both conditions confirmed: median 3.6 ng/ml; p = 0.0003). A prospective replication cohort was used for independent validation and for assessment of cathelicidin potential to stratify women with MIAC leading to HCA from women in whom at least one of these conditions was ruled out. We confirmed the association of higher amniotic fluid cathelicidin levels with MIAC leading to HCA (the presence of both MIAC and HCA: median 3.1 ng/ml; other women: median 1.4 ng/ml; p<0.0001). A cathelicidin concentration of 4.0 ng/ml was found to be the best cut-off point for identifying PPROM women with both MIAC and HCA. When tested on the validation cohort, a sensitivity of 48%, a specificity of 90%, a likelihood ratio of 5.0, and an area under receiver-operating characteristic curve of 71% were achieved for identification of women with MIAC leading to HCA.

Conclusions

Our multi-stage study suggests cathelicidin as a candidate marker that should be considered for a panel of amniotic fluid proteins permitting identification of PPROM women with MIAC leading to HCA.     

Oligohydramnios in Women with Preterm Prelabor Rupture of Membranes and Adverse Pregnancy and Neonatal Outcomes

Objective

To determine the association between the presence of oligohydramnios, determined as an amniotic fluid index ≤ 5 cm and the intra-amniotic inflammatory response, fetal inflammatory response and neonatal outcomes in actively managed preterm prelabor rupture of membranes (PPROM).

Methods

Women with singleton pregnancies complicated by PPROM at a gestational age of between 24+0 and 36+6 weeks were included in the study. Ultrasound assessments of the amniotic fluid index and evaluation of the amniotic fluid interleukin (IL)-6 levels were performed at admission. The umbilical cord blood IL-6 levels were evaluated after delivery.

Results

In total, 74 women were included. The women with oligohydramnios did not have different amniotic fluid IL-6 levels [with oligohydramnios: median 342 pg/mL, interquartile range (IQR) 110-1809 vs. without oligohydramnios: median 256 pg/mL, IQR 122–748; p = 0.71] or umbilical cord blood IL-6 levels (with oligohydramnios: median 8.2 pg/mL, IQR 3.8–146.9 vs. without oligohydramnios: median 5.9 pg/mL, IQR 2.1–27.9; p = 0.14) than those without oligohydramnios. No association between oligohydramnios and neonatal morbidity was found. A correlation between the amniotic fluid index and the interval from rupture of membranes to amniocentesis was observed (rho = −0.34; p = 0.003).

Conclusion

The presence of oligohydramnios is not associated with an adverse outcome in actively managed PPROM in singleton pregnancies in the absence of other complications.     

Umbilical Cord Blood IL-6 as Predictor of Early-Onset Neonatal Sepsis in Women with Preterm Prelabour Rupture of Membranes

Objective

To evaluate umbilical cord interleukin (IL)-6 and funisitis as independent predictors of early-onset neonatal sepsis (EONS) in preterm prelabor rupture of membranes (PPROM).

Design

Prospective cohort study.

Setting

Evaluation of umbilical cord IL-6 and funisitis as predictors of early-onset neonatal sepsis in PPROM.

Population

176 women with PPROM between 23+0−36+6 weeks of gestation.

Methods

Umbilical cord IL-6 was assayed by ELISA. Funisitis was defined according to the Salafia classification. Data was adjusted by gestational age at delivery and prenatal administration of corticosteroids and antibiotics.

Main Outcome Measures

Binary logistic regression was performed to assess the independence of umbilical cord IL-6 and funisitis to predict EONS in women complicated with PPROM.

Results

The rate of EONS was 7%. Funisitis was present in 18% of women. Umbilical cord IL-6 was significantly higher in women complicated with EONS than without [median (range) 389.5 pg/mL (13.9–734.8) vs 5.2 (0.1–801–4), p<0.001]. Umbilical cord IL-6 was the only independent predictor of early-onset neonatal sepsis (odds ratio 13.6, p = 0.004).

Conclusion

Umbilical cord IL-6 was the only predictor of early-onset neonatal sepsis in PPROM. Contrary to what is reported, funisitis was not.     

Regional Variation in Tissue Composition and Biomechanical Properties of Postmenopausal Ovine and Human Vagina

Objective

There are increasing numbers of reports describing human vaginal tissue composition in women with and without pelvic organ prolapse with conflicting results. The aim of this study was to compare ovine and human posterior vaginal tissue in terms of histological and biochemical tissue composition and to assess passive biomechanical properties of ovine vagina to further characterise this animal model for pelvic organ prolapse research.

Study Design

Vaginal tissue was collected from ovariectomised sheep (n = 6) and from postmenopausal women (n = 7) from the proximal, middle and distal thirds. Tissue histology was analyzed using Masson''s Trichrome staining; total collagen was quantified by hydroxyproline assays, collagen III/I+III ratios by delayed reduction SDS PAGE, glycosaminoglycans by dimethylmethylene blue assay, and elastic tissue associated proteins (ETAP) by amino acid analysis. Young''s modulus, maximum stress/strain, and permanent strain following cyclic loading were determined in ovine vagina.

Results

Both sheep and human vaginal tissue showed comparable tissue composition. Ovine vaginal tissue showed significantly higher total collagen and glycosaminoglycan values (p<0.05) nearest the cervix. No significant differences were found along the length of the human vagina for collagen, GAG or ETAP content. The proximal region was the stiffest (Young''s modulus, p<0.05), strongest (maximum stress, p<0.05) compared to distal region, and most elastic (permanent strain).

Conclusion

Sheep tissue composition and mechanical properties showed regional differences along the postmenopausal vaginal wall not apparent in human vagina, although the absolute content of proteins were similar. Knowledge of this baseline variation in the composition and mechanical properties of the vaginal wall will assist future studies using sheep as a model for vaginal surgery.     

Limited Relationship between Cervico-Vaginal Fluid Cytokine Profiles and Cervical Shortening in Women at High Risk of Spontaneous Preterm Birth

Objective

To determine the relationship between high vaginal pro-inflammatory cytokines and cervical shortening in women at high risk of spontaneous preterm labor and to assess the influence of cervical cerclage and vaginal progesterone on this relationship.

Methods

This prospective longitudinal observational study assessed 112 women with at least one previous preterm delivery between 16 and 34 weeks’ gestation. Transvaginal cervical length was measured and cervico-vaginal fluid sampled every two weeks until 28 weeks. If the cervix shortened (<25 mm) before 24 weeks’ gestation, women (cases) were randomly assigned to cerclage or progesterone and sampled weekly. Cytokine concentrations were measured in a subset of cervico-vaginal fluid samples (n = 477 from 78 women) by 11-plex fluid-phase immunoassay.

Results

All 11 inflammatory cytokines investigated were detected in cervico-vaginal fluid from women at high risk of preterm birth, irrespective of later cervical shortening. At less than 24 weeks’ gestation and prior to intervention, women destined to develop a short cervix (n = 36) exhibited higher cervico-vaginal concentrations than controls (n = 42) of granulocyte-macrophage colony-stimulating factor [(GM-CSF) 16.2 fold increase, confidence interval (CI) 1.8–147; p = 0.01] and monocyte chemotactic protein-1 [(MCP-1) 4.8, CI 1.0–23.0; p = 0.05]. Other cytokines were similar between cases and controls. Progesterone treatment did not suppress cytokine concentrations. Interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ and tumour necrosis factor (TNF)-α concentrations were higher following randomization to cerclage versus progesterone (p<0.05). Cerclage, but not progesterone treatment, was followed by a significant increase in cervical length [mean 11.4 mm, CI 5.0–17.7; p<0.001].

Conclusions

Although GM-CSF and MCP-1 cervico-vaginal fluid concentrations were raised, the majority of cervico-vaginal cytokines did not increase in association with cervical shortening. Progesterone treatment showed no significant anti-inflammation action on cytokine concentrations. Cerclage insertion was associated with an increase in the majority of inflammatory markers and cervical length.     

Cervical Mucus Properties Stratify Risk for Preterm Birth

Background

Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth.

Methods and Findings

To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus.

Conclusions

Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.     

Circulating alpha1-antitrypsin in the general population: Determinants and association with lung function

Background

Severe alpha1-antitrypsin (AAT) deficiency associated with low AAT blood concentrations is an established genetic COPD risk factor. Less is known about the respiratory health impact of variation in AAT serum concentrations in the general population. We cross-sectionally investigated correlates of circulating AAT concentrations and its association with FEV1.

Methods

In 5187 adults (2669 females) with high-sensitive c-reactive protein (CRP) levels ≤ 10 mg/l from the population-based Swiss SAPALDIA cohort, blood was collected at the time of follow-up examination for measuring serum AAT and CRP.

Results

Female gender, hormone intake, systolic blood pressure, age in men and in postmenopausal women, as well as active and passive smoking were positively, whereas alcohol intake and BMI inversely correlated with serum AAT levels, independent of CRP adjustment. We observed an inverse association of AAT with FEV1 in the total study population (p < 0.001), that disappeared after adjustment for CRP (p = 0.28). In addition, the AAT and FEV1 association was modified by gender, menopausal status in women, and smoking.

Conclusion

The results of this population-based study reflect a complex interrelationship between tobacco exposure, gender related factors, circulating AAT, systemic inflammatory status and lung function.     

Phasic Contractions of the Mouse Vagina and Cervix at Different Phases of the Estrus Cycle and during Late Pregnancy

Background/Aims

The pacemaker mechanisms activating phasic contractions of vaginal and cervical smooth muscle remain poorly understood. Here, we investigate properties of pacemaking in vaginal and cervical tissues by determining whether: 1) functional pacemaking is dependent on the phase of the estrus cycle or pregnancy; 2) pacemaking involves Ca²⁺ release from sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) -dependent intracellular Ca²⁺ stores; and 3) c-Kit and/or vimentin immunoreactive ICs have a role in pacemaking.

Methodology/Principal Findings

Vaginal and cervical contractions were measured in vitro, as was the distribution of c-Kit and vimentin positive interstitial cells (ICs). Cervical smooth muscle was spontaneously active in estrus and metestrus but quiescent during proestrus and diestrus. Vaginal smooth muscle was normally quiescent but exhibited phasic contractions in the presence of oxytocin or the K⁺ channel blocker tetraethylammonium (TEA) chloride. Spontaneous contractions in the cervix and TEA-induced phasic contractions in the vagina persisted in the presence of cyclopiazonic acid (CPA), a blocker of the SERCA that refills intracellular SR Ca²⁺ stores, but were inhibited in low Ca²⁺ solution or in the presence of nifedipine, an inhibitor of L-type Ca²⁺channels. ICs were found in small numbers in the mouse cervix but not in the vagina.

Conclusions/Significance

Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips were normally quiescent but could be induced to exhibit phasic contractions independent on phase of the estrus cycle or late pregnancy. Spontaneous cervical or TEA-induced vaginal phasic contractions were not mediated by ICs or intracellular Ca²⁺ stores. Given that vaginal smooth muscle is normally quiescent then it is likely that increases in hormones such as oxytocin, as might occur through sexual stimulation, enhance the effectiveness of such pacemaking until phasic contractile activity emerges.     

How Accurate Is Preoperative Evaluation of Pelvic Organ Prolapse in Women Undergoing Vaginal Reconstruction Surgery?

Objective

To evaluate the differences between the in-office and intraoperative techniques used to evaluate pelvic organ prolapse.

Materials and Methods

A prospective study included 25 women undergoing vaginal reconstruction surgery including vaginal hysterectomy for pelvic organ prolapse. The outpatient pelvic and site-specific vaginal examination was performed in the lithotomy position with the Valsalva maneuver. Repeated intraoperative examination was performed under general anesthesia with standard mild cervical traction. The Pelvic Organ Prolapse Quantification system (POPQ) was used for both measurements and staging. The values found under the two conditions were compared.

Results

The intraoperative POPQ-measurements values were significantly higher than the outpatient values for apical wall prolapse in 17/25 (68%) women and for anterior wall prolapse in 8/25 (32%) women. There was not a significant difference in the posterior wall where increase in staging was shown in 3/25 (12%) patients.

Conclusions

Clinicians and patients should be alert to the possibility that pelvic organ measurements performed under general anesthesia with mild traction may be different from preoperative evaluation.     

The Association between Intrauterine Inflammation and Spontaneous Vaginal Delivery at Term: A Cross-Sectional Study

Background

Different factors contribute to the onset of labor at term. In animal models onset of labor is characterized by an inflammatory response. The role of intrauterine inflammation, although implicated in preterm birth, is not yet established in human term labor. We hypothesized that intrauterine inflammation at term is associated with spontaneous onset of labor.

Methods/Results

In two large urban hospitals in the Netherlands, a cross-sectional study of spontaneous onset term vaginal deliveries and elective caesarean sections (CS), without signs of labor, was carried out. Placentas and amniotic fluid samples were collected during labor and/or at delivery. Histological signs of placenta inflammation were determined. Amniotic fluid proinflammatory cytokine concentrations were measured using ELISA. A total of 375 women were included. In term vaginal deliveries, more signs of intrauterine inflammation were found than in elective CS: the prevalence of chorioamnionitis was higher (18 vs 4%, p = 0.02) and amniotic fluid concentration of IL-6 was higher (3.1 vs 0.37 ng/mL, p<0.001). Similar results were obtained for IL-8 (10.93 vs 0.96 ng/mL, p<0.001) and percentage of detectable TNF-α (50 vs 4%, p<0.001).

Conclusions

This large cross-sectional study shows that spontaneous term delivery is characterized by histopathological signs of placenta inflammation and increased amniotic fluid proinflammatory cytokines.     

The Relationship between Zinc Status and Inflammatory Marker Levels in Rural Korean Adults Aged 40 and Older

Background

Serum cytokines and C-reactive protein (CRP) are known as one of the major risk factors in atherosclerosis. The antioxidant and anti-inflammatory properties of zinc have been suggested, but few data are available on the relationship between zinc status and inflammatory markers in epidemiological studies.

Objective

The present study aims to investigate the cross-sectional relationships of serum cytokines and CRP with dietary zinc intake and serum zinc levels in healthy men and women aged 40 and older in rural areas of South Korea.

Materials and Methods

A group of 1,055 subjects (404 men, 651 women) was included in dietary zinc analysis while another group of 695 subjects (263 men, 432 women) was included in serum zinc analysis. Serum IL-6, TNF-α, and CRP were measured as inflammatory markers.

Results

There was no significant inverse relationship between dietary zinc intake and inflammatory markers. We found a significant inverse relationship between serum zinc levels and all three inflammatory markers in women (P for trend = 0.0236 for IL-6; P for trend = 0.0017 for TNF-α; P for trend = 0.0301 for CRP) and between serum zinc levels and a single inflammatory marker (IL-6) in men (P for trend = 0.0191), although all R2 values by regression were less than 10%.

Conclusion

In conclusion, serum zinc levels may be inversely related to inflammatory markers (IL-6, TNF-α, and CRP), particularly in women.     

Tolerance of the vaginal vault to high-dose rate brachytherapy and concomitant chemo-pelvic irradiation: Long-term perspective

Aim/background

We sought to determine the tolerance level and complication rates of the vaginal vault to combined high-dose-rate intra-cavitary brachytherapy with concomitant chemo-radiotherapy.

Patients and methods

A retrospective review of medical records of all the patients who received definitive chemo-radiotherapy for cervical cancer between 1998 and 2002 was undertaken. The records were reviewed for doses and for radiation-associated early and late sequelae of the vagina, rectum and bladder. Cumulative biological effective dose was calculated for two reference vaginal surface points.

Results

Fifty patients were included. Average age at diagnosis was 54 years. Median follow-up was 59 months. There were no recorded instances of acute grade IV toxicity. Maximal high-dose-rate vaginal surface dose (upper central point) was 103 Gy, and maximal brachytherapy lateral surface dose was 70 Gy. Maximal cumulative biological effective dose for the lateral surface reference point was 465.5 Gy₃, and the maximal cumulative biological effective dose for the superior reference point was 878.6 Gy₃. There were no cases of vaginal necrosis or fistulas, and no cases of grade IV late vaginal, rectal or bladder toxicity. No correlation was found between the maximal vaginal surface dose and vaginal, rectal or bladder toxicity.

Conclusions

The maximal surface HDR brachytherapy dose of 103 Gy and the maximal cBED of 878.6 Gy₃ were not associated with fistula or necrosis or other grade 3–4 vaginal complications. Concomitant chemo-radiotherapy, including pelvic radiotherapy and high-dose-rate intracavitary brachytherapy, is relatively safe for cervical cancer patients.     

Association of Trichomonas vaginalis and Cytological Abnormalities of the Cervix in Low Risk Women

Objective

Is Trichomonas vaginalis (TV) an inducing factor for the development of (pre-)cancerous lesions of the cervix?

Design

Cross sectional study.

Setting

Screening healthy Belgian women with low infection risk.

Sample

63,251 consecutive liquid based cervical samples.

Methods

Real time quantitative PCR for presence of TV, 18 HPV types and Pap smear analysis of cytologic abnormalities.

Main Outcome Measures

Association of TV and HPV with cervix dysplasia

Results

The overall prevalence of TV DNA was 0.37%, of low risk HPV 2%, of high risk HPV 13.2%, and 8.8 % had cytological abnormalities. Both LR-HPV and HR-HPV were significantly associated with all cytological abnormalities. Presence of TV was associated with LR- and HR-HPV, ASC-US and HSIL, but not with other abnormalities. All women with TV and HSIL also had HR-HPV, while the latter was present in only 59% of women with TV and ASC-US. Amongst HPV negative women, TV was found in 1.3% of women with ASC-US, but only in 0.03% of women with normal cytology (OR 4.2, CL95% 2.1-8.6). In HR-HPV positive women, presence of TV increased the likelihood of cytological abnormalities somewhat (P=0.05), mainly due to an increase in ASC-US and LSIL, but not HSIL.

Conclusions

We conclude that TV infection is associated with both LR and HR-HPV infection of the cervix, as well as with ASC-US and HSIL. TV is a concomitant STI, but is not thought to be a co-factor in the causation of HSIL and cervical cancer. However, TV may cause false positive diagnoses of ASC-US.     

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background

Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.

Objective

MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.

Methods and Findings

We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).

Conclusions

Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir’s antiviral effect substantially influence PrEP efficacy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00592124","term_id":"NCT00592124"}}NCT00592124     

HPV Testing by cobas HPV Test in a Population from Catalonia

Background

HPV testing in cervical cancer screening has been proposed as an alternative or complementary to cytology in women older than 30 years. However, adequate clinical sensitivity and specificity are crucial for a new test to be implemented. Hybrid Capture 2 (HC2) has proved good clinical performance in selecting women at risk for high-grade intraepithelial lesions with a high sensitivity and specificity. cobas HPV Test has been recently launched and its performance in different clinical settings needs to be determined.

Objectives

The aim of this study was to evaluate the cobas HPV Test for the detection of cervical HPV infection in a population of women in Catalonia (Spain) using HC2 as a reference.

Materials and Methods

Cervical liquid cytology samples from 958 women have been studied. Sensitivity was analyzed in 60 samples from patients with a high-grade intraepithelial lesion (≥CIN2) on histology and specificity was determined in 898 samples from women with no ≥CIN2. All cases had HC2 and cobas HPV Test performed. Statistical analyses of sensitivity, specificity and comparison between HC2 and cobas HPV Test by a non-inferiority test were applied.

Results

Sensitivity of HC2 and cobas HPV Test for detecting ≥CIN2 proved identical (98.3%) while specificity was 85.3% and 86.2% respectively. The non-inferiority test demonstrated that cobas HPV Test surpassed 90% sensitivity and 98% specificity of HC2.

Conclusion

The cobas HPV Test results fulfilled sensitivity and specificity requirements for HPV based cervical cancer screening and for the triage of minor cytological abnormalities, allowing its introduction in clinical settings.     

Correlates of HIV-1 genital shedding in Tanzanian women

Background

Understanding the correlates of HIV shedding is important to inform strategies to reduce HIV infectiousness. We examined correlates of genital HIV-1 RNA in women who were seropositive for both herpes simplex virus (HSV)-2 and HIV-1 and who were enrolled in a randomised controlled trial of HSV suppressive therapy (aciclovir 400 mg b.i.d vs. placebo) in Tanzania.

Methodology

Samples, including a cervico-vaginal lavage, were collected and tested for genital HIV-1 and HSV and reproductive tract infections (RTIs) at randomisation and 6, 12 and 24 months follow-up. Data from all women at randomisation and women in the placebo arm during follow-up were analysed using generalised estimating equations to determine the correlates of cervico-vaginal HIV-1 RNA detection and load.

Principal Findings

Cervico-vaginal HIV-1 RNA was detected at 52.0% of 971 visits among 482 women, and was independently associated with plasma viral load, presence of genital ulcers, pregnancy, bloody cervical or vaginal discharge, abnormal vaginal discharge, cervical ectopy, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, an intermediate bacterial vaginosis score and HSV DNA detection. Similar factors were associated with genital HIV-1 RNA load.

Conclusions

RTIs were associated with increased presence and quantity of genital HIV-1 RNA in this population. These results highlight the importance of integrating effective RTI treatment into HIV care services.     

FEV1 inversely correlates with metalloproteinases 1, 7, 9 and CRP in COPD by biomass smoke exposure

Background

Matrix metalloproteinases (MMPs) and C-reactive protein (CRP) are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. The aim of the present work was to determine plasma concentrations of MMPs and CRP in COPD associated to biomass combustion exposure (BE) and tobacco smoking (TS).

Methods

Pulmonary function tests, plasma levels of MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP were measured in COPD associated to BE (n = 40) and TS (n =40) patients, and healthy non-smoking (NS) healthy women (controls, n = 40).

Results

Plasma levels of MMP-1, MMP-7, MMP-9, and MMP-9/TIMP-1 and CRP were higher in BE and TS than in the NS healthy women (p <0.01). An inverse correlation between MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP plasma concentrations and FEV₁ was observed.

Conclusions

Increase of MMPs and CRP plasma concentrations in BE suggests a systemic inflammatory phenomenon similar to that observed in COPD associated to tobacco smoking, which may also play a role in COPD pathogenesis.