The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial.

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Oil-based versus water-based contrast media for hysterosalpingography in infertile women of advanced age, with ovulation disorders or a high risk for tubal pathology: study protocol of a randomized controlled trial (H2Oil2 study).

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. METHODS: We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. DISCUSSION: This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as 'H2Oil2' (reference number NL7925, https://www.trialregister.nl/trial/7925 ).

Comparison of the Performance of the PanBio COVID-19 Antigen Test in SARS-CoV-2 B.1.1.7 (Alpha) Variants versus non-B.1.1.7 Variants.

This study evaluates the performance of the PanBio COVID-19 antigen (Ag) test as part of a hospital infection control policy. Hospital staff was encouraged to get tested for COVID-19 when presenting with SARS-CoV-2-related symptoms. In a period of approximately 5 months, a steady decline in the performance of the Ag test was noted, epidemiologically coinciding with the rise of the SARS-CoV-2 B.1.1.7 (alpha) variant of concern (VOC) in the Netherlands. This led to the hypothesis that the diagnostic performance of the PanBio COVID-19 Ag test was influenced by the infecting viral variant. The results show a significantly lower sensitivity of the PanBio COVID-19 Ag test in persons infected with the B.1.1.7 (alpha) variant of SARS-CoV-2 in comparison with that in persons infected with non-B.1.1.7 variants, also after adjustment for viral load. IMPORTANCE Antigen tests for COVID-19 are widely used for rapid identification of COVID-19 cases, for example, for access to schools, festivals, and travel. There are several FDA- and CE-cleared tests on the market. Their performance has been evaluated mainly on the basis of infections by the classical variant of the causing virus, SARS-CoV-2. This paper provides evidence that the performance of one of the most widely used antigen tests detects significantly fewer cases of COVID-19 by the alpha variant than by the classical variants of SARS-CoV-2. This means that the role of antigen tests needs to be reevaluated in regions where other variants of SARS-CoV-2 predominate.

Differences in prevalence of hepatitis B virus infection and genotypes between ethnic populations in Suriname, South America.

Epidemiological data on hepatitis B virus (HBV) are needed to benchmark HBV elimination goals. We recently assessed prevalence of HBV infection and determinants in participants attending the Emergency Department in Paramaribo, Suriname, South America. Overall, 24.5% (95%CI = 22.7-26.4%) of participants had anti-Hepatitis B core antibodies, which was associated with older age (per year, adjusted Odds Ratio [aOR] = 1.03, 95%CI = 1.02-1.04), Afro-Surinamese (aOR = 1.84, 95%CI = 1.52-2.19) and Javanese ethnicity (aOR = 1.63, 95%CI = 1.28-2.07, compared to the grand mean). 3.2% of participants were Hepatitis B surface Ag-positive, which was also associated with older age (per year, aOR = 1.02, 95%CI = 1.00-1.04), Javanese (aOR = 4.3, 95%CI = 2.66-6.95) and Afro-Surinamese ethnicity (aOR = 2.36, 95%CI = 1.51-3.71). Sex, nosocomial or culturally-related HBV transmission risk-factors were not associated with infection. Phylogenetic analysis revealed strong ethnic clustering: Indonesian subgenotype HBV/B3 among Javanese and African subgenotypes HBV/A1, HBV/QS-A3 and HBV/E among Afro-Surinamese. Testing for HBV during adulthood should be considered for individuals living in Suriname, specifically with Javanese and Afro-Surinamese ancestry.

From cooperative to uncorrelated clogging in cross-flow microfluidic membranes.

The operational lifetime of filtration membranes is reduced by the clogging of pores and subsequent build-up of a fouling or cake layer. Designing membrane operations in which clogging is delayed or even mitigated completely, requires in-depth insight into its origins. Due to the complexity of the clogging process, simplified model membranes fabricated in microfluidic chips have emerged as a powerful tool to study how clogs emerge and deteriorate membrane efficiency. However, to date, these have focussed solely on dead-end filtration, while cross-flow filtration is of greater practical relevance at the industrial scale. As such, the microscopic mechanisms of clogging in crossflow geometries have remained relatively ill-explored. Here we use a microfluidic filtration model to probe the kinetics and mechanisms of clogging in crossflow. Our study exposes two findings: (i) the primary clogging rate of individual pores depends only on the trans-membrane flux, whose strong effects are explained quantitatively by extending existing models with a term for flux-controlled flow-enhanced barrier crossing, (ii) cross-membrane flow affects the pore-pore communication, leading to a transition from correlated to uncorrelated clogging of the membrane, which we explain qualitatively by deriving a dimensionless number which captures two essential regimes of clogging at the microscale.

Deswelling and deformation of microgels in concentrated packings.

Increasing the particle density of a suspension of microgel colloids above the point of random-close packing, must involve deformations of the particle to accommodate the increase in volume fraction. By contrast to the isotropic osmotic deswelling of soft particles, the particle-particle contacts give rise to a non-homogeneous pressure, raising the question if these deformations occur through homogeneous deswelling or by the formation of facets. Here we aim to answer this question through a combination of imaging of individual microgels in dense packings and a simple model to describe the balance between shape versus volume changes. We find a transition from shape changes at low pressures to volume changes at high pressures, which can be explained qualitatively with our model. Whereas contact mechanics govern at low pressures giving rise to facets, osmotic effects govern at higher pressures, which leads to a more homogeneous deswelling. Our results show that both types of deformation play a large role in highly concentrated microgel suspensions and thus must be taken into account to arrive at an accurate description of the structure, dynamics and mechanics of concentrated suspensions of soft spheres.

Travel to Asia and traveller's diarrhoea with antibiotic treatment are independent risk factors for acquiring ciprofloxacin-resistant and extended spectrum ß-lactamase-producing Enterobacteriaceae-a prospective cohort study.

Travel to (sub)tropical countries is a well-known risk factor for acquiring resistant bacterial strains, which is especially of significance for travellers from countries with low resistance rates. In this study we investigated the rate of and risk factors for travel-related acquisition of extended spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E), ciprofloxacin-resistant Enterobacteriaceae (CIPR-E) and carbapenem-resistant Enterobacteriaceae. Data before and after travel were collected from 445 participants. Swabs were cultured with an enrichment broth and sub-cultured on selective agar plates for ESBL detection, and on plates with a ciprofloxacin disc. ESBL production was confirmed with the double-disc synergy test. Species identification and susceptibility testing were performed with the Vitek-2 system. All isolates were subjected to ertapenem Etest. ESBL and carbapenemase genes were characterized by PCR and sequencing. Twenty-seven out of 445 travellers (6.1%) already had ESBL-producing strains and 45 of 445 (10.1%) travellers had strains resistant to ciprofloxacin before travel. Ninety-eight out of 418 (23.4%) travellers acquired ESBL-E and 130 of 400 (32.5%) travellers acquired a ciprofloxacin-resistant strain. Of the 98 ESBL-E, predominantly Escherichia coli and predominantly blaCTX-M-15, 56% (55/98) were resistant to gentamicin, ciprofloxacin and co-trimoxazole. Multivariate analysis showed that Asia was a high-risk area for ESBL-E as well as CIPR-E acquisition. Travellers with diarrhoea combined with antimicrobial use were significantly at higher risk for acquisition of resistant strains. Only one carbapenemase-producing isolate was acquired, isolated from a participant after visiting Egypt. In conclusion, travelling to Asia and diarrhoea combined with antimicrobial use are important risk factors for acquiring ESBL-E and CIPR-E.

Discontinuous nature of the repulsive-to-attractive colloidal glass transition.

In purely repulsive colloidal systems a glass transition can be reached by increasing the particle volume fraction beyond a certain threshold. The resulting glassy state is governed by configurational cages which confine particles and restrict their motion. A colloidal glass may also be formed by inducing attractive interactions between the particles. When attraction is turned on in a repulsive colloidal glass a re-entrant solidification ensues. Initially, the repulsive glass melts as free volume in the system increases. As the attraction strength is increased further, this weakened configurational glass gives way to an attractive glass in which motion is hindered by the formation of physical bonds between neighboring particles. In this paper, we study the transition from repulsive-to-attractive glasses using three-dimensional imaging at the single-particle level. We show how the onset of cage weakening and bond formation is signalled by subtle changes in local structure. We then demonstrate the discontinuous nature of the solid-solid transition, which is marked by a critical onset at a threshold bonding energy. Finally, we highlight how the interplay between bonding and caging leads to complex and heterogeneous dynamics at the microscale.

Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study.

Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0-52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63-15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04-12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02-6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27-192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39-8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19-2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60-14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM.

Cooperativity and segregation in confined flows of soft binary glasses.

When a suspension containing particles of different sizes flows through a confined geometry a size gradient can be established, with large particles accumulating in the channel center. Such size separation driven by hydrodynamic interactions is expected to facilitate membrane filtration and may lead to the design of novel and innovative separation techniques. For this, a wide range of particle concentrations has to be investigated, in order to clarify whether shear-induced migration can be utilized at concentrations close to or above the colloidal glass transition, where particle motion is severely hindered and hydrodynamic interactions are screened. We explore this scenario by studying the flow of binary mixtures of soft colloidal microgels, well above their liquid-solid transition, through narrow microchannels. We find that, even though the flow becomes strongly heterogeneous, in both space and time, characterized by a large cooperativity length, size segregation still occurs. This suggests that even above the glass transition shear-induced diffusion could still be used as a fractionation mechanism, which is of great relevance for process intensification purposes.

Viral hepatitis among men who have sex with men, epidemiology and public health consequences.

Viral hepatitis causes major disease burden worldwide, due to the chronic hepatitis sequelae: cirrhosis and primary liver cancer. Transmission of viral hepatitis is a problem not only in low-income countries, but also in high-income ones where viral hepatitis is a frequently occurring infection among men who have sex with men (MSM). Although the transmission routes of the three main hepatitis viruses, A, B and C, differ, MSM mainly acquire viral hepatitis during sexual contact. Vaccination programmes (only available for hepatitis A and B), raising awareness, and screening can be used to prevent transmission. However, despite the introduction of such methods in many high-income countries, the spread of viral hepatitis among MSM is still ongoing. This paper provides an overview of sexually acquired hepatitis A, B, and C among MSM in high-income countries, using recent insights obtained through molecular epidemiology, with the aim to raise awareness, improve vaccination coverage, and stimulate prevention programs.

Never injected, but hepatitis C virus-infected: a study among self-declared never-injecting drug users from the Amsterdam Cohort Studies.

The aim of this study was to gain insight in transmission routes of hepatitis C virus (HCV) infection among never-injecting drug users (DU) by studying, incidence, prevalence, determinants and molecular epidemiology of HCV infection. From the Amsterdam Cohort Studies among DU, 352 never-injecting DU were longitudinally tested for HCV antibodies. Logistic regression was used to identify factors associated with antibody prevalence. Part of HCV NS5B was sequenced to determine HCV genotype and for phylogenetic analyses, in which sequences were compared with those from injecting DU. HCV antibody prevalence was 6.3% and HCV incidence was 0.49/1000 PY. HIV-positive status, female sex and starting injection drug use during follow-up (a putative marker of past injection drug use), were independently associated with HCV prevalence. The main genotypes found were genotype 3a (50%) and 1a (30%). Phylogenetic analysis revealed that HCV strains in never-injecting DU did not cluster together and did not differ from HCV strains circulating in injecting DU. We found a higher HCV prevalence in never-injecting DU than in the general population. Phylogenetic analysis shows a strong link with the injecting DU population. The increased risk could be related to underreporting of injecting drug use or to household or sexual transmission from injectors to noninjectors. Our findings stress the need for HCV testing of DU who report never injecting, especially given the potential to treat HCV infection effectively.

HCV-specific T-cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance.

In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-gamma Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-T-cell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.