Hypertensive disorders of pregnancy and subsequent maternal cardiovascular health

To examine associations between hypertensive pregnancy disorders and maternal cardiovascular disease (CVD) in later life. We examined the associations between blood pressure (BP) in pregnancy, gestational hypertension (GH) and preeclampsia (PE) with cardiovascular measurements 6 years after index pregnancy among 4912 women participating in the Generation R Study, the Netherlands. BP, left ventricular mass (LV mass), aortic root diameter (AOD), left atrial diameter, fractional shortening, and carotid-femoral pulse wave velocity (PWV). Early pregnancy systolic and diastolic BP were associated with more adverse maternal cardiovascular measurements and a higher incidence of chronic hypertension 6 years after pregnancy. GH was associated with a higher BP, a higher PWV, a larger AOD and an increased LV mass 6 years after index pregnancy. Compared to previous normotensive pregnancies these women had a sixfold increased risk to develop chronic hypertension after pregnancy (OR 6.6, 95% CI 4.6–9.5). Compared to women with a normotensive pregnancy, women with PE had a higher BP and a higher risk of chronic hypertension (OR 4.5, 95% CI 2.6–7.8) at follow-up. After adjustment for BMI at follow-up in all the analyses on GH, PE and cardiovascular measurements, effect estimates attenuated up to 65%, but remained significant. Both GH and PE are associated with markers of adverse maternal cardiovascular health after pregnancy with an increased risk of chronic hypertension. Women with GH and PE may be offered long-term cardiovascular follow-up incorporated in CVD risk management guidelines

Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction

A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected of USH2A-associated disease and no or mono-allelic USH2A variants using whole genome sequencing (WGS) followed by an improved pipeline for variant interpretation to provide a conclusive diagnosis. One hundred subjects were screened using WGS to identify causative variants in USH2A or other USH/arRP-associated genes. In addition to the existing variant interpretation pipeline, a particular focus was put on assessing splice-affecting properties of variants, both in silico and in vitro. Also structural variants were extensively addressed. For variants resulting in pseudoexon inclusion, we designed and evaluated antisense oligonucleotides (AONs) using minigene splice assays and patient-derived photoreceptor precursor cells. Biallelic variants were identified in 49 of 100 subjects, including novel splice-affecting variants and structural variants, in USH2A or arRP/USH-associated genes. Thirteen variants were shown to affect USH2A pre-mRNA splicing, including four deep-intronic USH2A variants resulting in pseudoexon inclusion, which could be corrected upon AON treatment. We have shown that WGS, combined with a thorough variant interpretation pipeline focused on assessing pre-mRNA splicing defects and structural variants, is a powerful method to provide subjects with a rare genetic condition, a (likely) conclusive genetic diagnosis. This is essential for the development of future personalized treatments and for patients to be eligible for such treatments.</p

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Cost-utility of repeated screening for Chlamydia trachomatis

OBJECTIVE: To estimate the cost-effectiveness of repeated screening for chlamydia trachomatis at various time intervals compared to one-off screening of Dutch young adults. METHODS: We used a dynamic model to fully take the spread of the disease over time in the population into account, with data being used gathered within the context of a recently performed pilot study in The Netherlands. The screening frequencies analyzed were: every year, every 2 years, every 5 years, and every 10 years. The strategies were compared in terms of incremental cost-effectiveness, expressed as the net costs per quality-adjusted life-year (QALY). RESULTS: For all interval strategies, with the exception of screening every year, incremental cost-effectiveness stays below the informal Dutch threshold of euro20,000 per QALY. CONCLUSION: From a health-economic point of view, for the Dutch situation, we estimated screening every 2 years as the optimal strategy among the options investigated

Using intervention mapping for the development of a targeted secure web-based outreach strategy named SafeFriend, for Chlamydia trachomatis testing in young people at risk

BACKGROUND: Many young people at high risk for Chlamydia trachomatis (Ct) are not reached by current sexual health care systems, such as general practitioners and public sexual health care centres (sexually transmitted infection clinics).Ct is the most frequently diagnosed bacterial sexually transmitted infection (STI) among sexually active people and in particular young heterosexuals. Innovative screening strategies are needed to interrupt the transmission of Ct among young people and connect the hidden cases to care. METHODS: Intervention Mapping (IM), a systematic approach to develop theory- and evidence-based interventions, was used to develop a strategy to target Ct testing towards young people who are currently hidden to care in The Netherlands. Both clinical users (i.e. sexual health care nurses) and public users (i.e., young people at risk for Ct) were closely involved in the IM process. A needs assessment study was carried out using semi-structured interviews among users (N = 21), a literature search and by taking lessons learned from existing screening programmes. Theoretical methods and practical applications to reach high risk young people and influence testing were selected and translated into specific programme components. RESULTS: The IM approach resulted in the development of a secure and web-based outreach Ct screening strategy, named SafeFriend. It is developed to target groups of high-risk young people who are currently hidden to care. Key methods include web-based Respondent Driven Sampling, starting from young Ct positive sexual health care centre clients, to reach and motivate peers (i.e., sex partners and friends) to get tested for Ct. Testing and the motivation of peers were proposed as the desired behavioural outcomes and the Precaution Adoption Process Model was chosen as theoretical framework. End users, i.e., young people and sexual health care nurses were interviewed and included in the development process to increase the success of implementation. CONCLUSIONS: IM proved useful to develop an intervention for targeted Ct testing among young people. We believe this to be the first web-based outreach screening strategy which combines chain referral sampling with the delivery of targeted Ct testing to high risk young people within their sexual and social networks

Human Lymphoid Tissues Harbor a Distinct CD69(+)CXCR6(+) NK Cell Population

Transplantation and autoimmunit

Chlamydia screening is not cost-effective at low participation rates: Evidence from a repeated register-based implementation study in the Netherlands.

OBJECTIVE: In three pilot regions of the Netherlands, all 16-29 year olds were invited to participate in three annual rounds of Chlamydia screening. The aim of the present study is to evaluate the cost-effectiveness of repeated Chlamydia screening, based on empirical data. METHODS: A mathematical model was employed to estimate the influence of repeated screening on prevalence and incidence of Chlamydial infection. A model simulating the natural history of Chlamydia was combined with cost and utility data to estimate the number of major outcomes and quality-adjusted life-years (QALYs) associated with Chlamydia. Six screening scenarios (16-29 years annually; 16-24 years annually; women only; biennial screening; biennial screening women only; screening every five years) were compared with no screening in two sexual networks, representing both lower (&#39;national network&#39;) and higher (&#39;urban network&#39;) baseline prevalence. Incremental cost-effectiveness ratios (ICERs) for the different screening scenarios were estimated. Uncertainty and sensitivity analyses were performed. RESULTS: In all scenarios and networks, cost per major outcome averted are above &euro;5000. Cost per QALY are at least &euro;50 000. The default scenario as piloted in the Netherlands was least cost-effective, with ICERs of &euro;232 000 in the national and &euro;145 000 in the urban sexual network. Results were robust in sensitivity analyses. CONCLUSIONS: It is unlikely that repeated rounds of Chlamydia screening will be cost-effective. Only at high levels of willingness to pay for a QALY (&gt;&euro;50 000) screening may be more cost-effective than no screening

Missed opportunities to offer HIV tests to high-risk groups during general practitioners' STI-related consultations: an observational study

OBJECTIVES: Prior research has shown that Dutch general practitioners (GPs) do not always offer HIV testing and the number of undiagnosed HIV patients remains high. We aimed to further investigate the frequency and reasons for (not) testing for HIV and the contribution of GPs to the diagnosis of HIV infections in the Netherlands. DESIGN: Observational study. SETTING: (1) Dutch primary care network of 42-45 sentinel practices where report forms during sexually transmitted infection (STI)-related consultations were routinely collected, 2008-2013. (2) Dutch observational cohort with medical data of HIV-positive patients in HIV care, 2008-2013. OUTCOME MEASURES: The proportion of STI-related consultations in patients from high-risk groups tested for HIV, with additional information requested from GPs on HIV testing preconsultation or postconsultation for whom HIV testing was indicated, but not performed. Next, information was collected on the profile of HIV-positive patients entering specialised HIV care following diagnosis by GPs. RESULTS: Initially, an HIV test was reported (360/907) in 40% of STI-related consultations in high-risk groups. Additionally, in 26% of consultations an HIV test had been performed in previous or follow-up consultations or at different STI-care facilities. The main reasons for not testing were perceived insignificant risk; 'too' recent risk according to GPs or the reluctance of patients. The initiative of the patient was a strong determinant for HIV testing. GPs diagnosed about one third of all newly found cases of HIV. Compared with STI clinics, HIV-positive patients diagnosed in general practice were more likely to be older, female, heterosexual male or sub-Saharan African. CONCLUSIONS: In one-third of the STI-related consultations of persons from high-risk groups, no HIV test was performed in primary care, which is lower than previously reported. Risk-based testing has intrinsic limitations and implementation of new additional strategies in primary care is warranted