Improving integrated care for (future) parents facing vulnerable circumstances in the early life course of their (future) child: An action research protocol.

INTRODUCTION: Suboptimal circumstances during the early life course, ranging from 100 days before conception to 1000 days following birth, significantly impact a child's future health and well-being. To optimize these circumstances, collaboration is needed which includes professionals working in medical, social and public domains, as well as parents. This action research protocol aims to improve care for (future) parents facing suboptimal circumstances during the early life course by enhancing inter-professional, cross-domain collaboration and (future) parents-professional collaboration. By employing iterative action research cycles, we seek to foster integrated care pathways and improve continuity of care across the medical, social and public domains. The research will be conducted in Rotterdam, the Netherlands. METHODS AND ANALYSIS: Four action research cycles incorporating descriptive qualitative and quantitative studies, including focus groups, questionnaires and observations with (future) parents facing suboptimal circumstances, professionals and policymakers. This intervention study will not only foster improved, integrated care around identification of the need of additional support, referral and care, but also foster the necessary conditions for a self-supporting neighbourhood care learning network of (future) parents, professionals and policymakers to encourage bidirectional feedback and enable reflection beyond a single organisation. These interventions will also be evaluated. DISSEMINATION: The results will be disseminated through peer-reviewed publications, layman summaries, regional and national knowledge platforms and presentations and factsheets relevant to all involved actors.

Exploring perceptions of vulnerability among women facing psychosocial adversity before, during and after pregnancy: A qualitative interview-study using thematic analysis.

OBJECTIVE: The term 'vulnerable' is often used to describe women facing psychosocial adversity during pregnancy, implying a heightened risk of experiencing suboptimal pregnancy outcomes. While this label might facilitate the pathway to appropriate care, it can be perceived as stigmatizing by the women it intends to help, which could deter their interaction with healthcare services. This study explores how women facing psychosocial adversity before, during and after pregnancy perceive the concept of vulnerability and experience being labeled as such. METHODS: We conducted a thematic analysis of semi-structured, in-depth interviews. Through purposive sampling targeting maximum variation, ten women of diverse backgrounds were included. RESULTS: Three central themes emerged: defining vulnerability, embracing vulnerability and the feeling of being stigmatized. Women perceived vulnerability as an inability to adequately care for themselves or their children, necessitating additional support alongside routine antenatal care. Acceptance of the 'vulnerable' label came when it also acknowledged their proactive efforts and strengths to improve their situation. Conversely, if discussions surrounding vulnerability failed to recognize women's agency - specifically, their personal journeys and the courage needed to seek support - the label was perceived as stigmatizing. CONCLUSIONS: Addressing vulnerability effectively in maternity care requires a nuanced, patient-centered approach, acknowledging both the challenges and strengths of women facing psychosocial adversities. Emphasizing personal narratives and their courage in seeking support can mitigate the stigmatizing effects of the 'vulnerable' label. Integrating these narratives into maternal healthcare practices can foster deeper connections with the women involved, enhancing the overall quality of care.

A prospective ecological risk assessment of high-efficiency III-V/silicon tandem solar cells.

III-V/Silicon tandem solar cells offer one of the most promising avenues for high-efficiency, high-stability photovoltaics. However, a key concern is the potential environmental release of group III-V elements, especially arsenic. To inform long-term policies on the energy transition and energy security, we develop and implement a framework that fully integrates future PV demand scenarios with dynamic stock, emission, and fate models in a probabilistic ecological risk assessment. We examine three geographical scales: local (including a floating utility-scale PV and waste treatment), regional (city-wide), and continental (Europe). Our probabilistic assessment considers a wide range of possible values for over one hundred uncertain technical, environmental, and regulatory parameters. We find that III-V/silicon PV integration in energy grids at all scales presents low-to-negligible risks to soil and freshwater organisms. Risks are further abated if recycling of III-V materials is considered at the panels' end-of-life.

Shaping the risk for late-life neurodegenerative disease: A systematic review on prenatal risk factors for Alzheimer's disease-related volumetric brain biomarkers.

Environmental exposures including toxins and nutrition may hamper the developing brain in utero, limiting the brain's reserve capacity and increasing the risk for Alzheimer's disease (AD). The purpose of this systematic review is to summarize all currently available evidence for the association between prenatal exposures and AD-related volumetric brain biomarkers. We systematically searched MEDLINE and Embase for studies in humans reporting on associations between prenatal exposure(s) and AD-related volumetric brain biomarkers, including whole brain volume (WBV), hippocampal volume (HV) and/or temporal lobe volume (TLV) measured with structural magnetic resonance imaging (PROSPERO; CRD42020169317). Risk of bias was assessed using the Newcastle Ottawa Scale. We identified 79 eligible studies (search date: August 30th, 2020; Ntotal=24,784; median age 10.7 years) reporting on WBV (N = 38), HV (N = 63) and/or TLV (N = 5) in exposure categories alcohol (N = 30), smoking (N = 7), illicit drugs (N = 14), mental health problems (N = 7), diet (N = 8), disease, treatment and physiology (N = 10), infections (N = 6) and environmental exposures (N = 3). Overall risk of bias was low. Prenatal exposure to alcohol, opioids, cocaine, nutrient shortage, placental dysfunction and maternal anemia was associated with smaller brain volumes. We conclude that the prenatal environment is important in shaping the risk for late-life neurodegenerative disease.

Sexual Development in Perinatally HIV-Infected Young People: A Systematic Review and Explorative Study.

BACKGROUND: Similar to other young people with a chronic health condition, perinatally HIV-infected (PHIV) adolescents may have an impacted sexual development. OBJECTIVES: This paper aims to compare sexual milestones of PHIV to HIV uninfected peers, through a systematic review (SR) and explorative study. METHODS: We performed a systematic search in 4 electronic databases (Medline, Embase, Web of Science, and Scopus), according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Last search in all databases was performed in May 2021. We included studies that reported on quantitative data of any of the main outcomes and compared PHIV to HIV uninfected control groups. Main outcomes were defined as the occurrence and/or debut age of sexual milestones (falling in love, having been in a romantic relationship, masturbation, kissing, non-genital caressing (feeling or petting, touching), genital caressing (fingering, handjob), giving or receiving oral sex, and penetrative sex (vaginal or anal). We excluded case reports, audits, guidelines, editorials, abstracts, studies that reported on behaviorally infected HIV patients, studies that did not include an HIV uninfected control group and studies that could not be translated to English or Dutch. We used the Agency for Health Care Research and Quality (AHRQ) Checklist for quality assessment. We performed qualitative synthesis of the data. In the explorative study, we compared sexual milestones of PHIV and HIV uninfected controls matched for age, sex, ethnicity and educational level, using a subset of questions of a validated questionnaire. RESULTS: We included eighteen studies in the SR, describing outcomes of an estimated 1,963 participants. Seventeen studies compared the occurrence and/or debut age of intercourse in PHIV and HIV uninfected controls and 4 studies reported on any of the other sexual milestones. The majority of studies found no difference in occurrence (12 of 16 studies) or debut age (6 of 8 studies) of intercourse in PHIV compared to controls. Two of 4 studies reporting on any of the other milestones found no significant differences between PHIV and HIV uninfected controls. In the explorative study, we included ten PHIV participants and 16 HIV uninfected, matched controls. PHIV tended to report a later debut age of sexual milestones than controls (not significant). STRENGTHS AND LIMITATIONS: The SR includes only a small number of studies and few studies report on non-penetrative milestones. The explorative study adds to this review by including non-penetrative milestones and comparing PHIV to HIV-uninfected, well-matched controls. However, the sample size was small. CONCLUSION: PHIV seem to engage in sexual activities and achieve sexual milestones at a similar rate as their HIV uninfected peers, with a tendency of a later start in well treated PHIV. The review was registered in the PROSPERO database (CRD42021252103) and funded by AIDSfonds. AIDSfonds had no role in the study design or interpretations of this study. ter Haar AM, Fieten A, Van den Hof M, et al. Sexual Development in Perinatally HIV-Infected Young People: A Systematic Review and Explorative Study. Sex Med 2022;10:100578.

Mortality following elective abdominal aortic aneurysm repair in women.

BACKGROUND: Previous studies have focused on patient-related risk factors to explain the higher mortality risk in women undergoing elective abdominal aortic aneurysm (AAA) repair. The aim of this study was to evaluate whether hospital-related factors influence outcomes following AAA repair in women. METHODS: Patients undergoing elective AAA repair in 61 hospitals in the Netherlands were identified from the Dutch Surgical Aneurysm Audit registry (2013-2018). A mixed-effects logistic regression analysis was conducted to assess the effect of sex on in-hospital and/or 30-day mortality. This analysis accounted for possible correlation of outcomes among patients who were treated in the same hospital, by adding a hospital-specific random effect to the statistical model. The analysis adjusted for patient-related risk factors and hospital volume of open surgical repair (OSR) and endovascular aneurysm repair (EVAR). RESULTS: Some 12 034 patients were included in the analysis. The mortality rate was higher in women than among men: 53 of 1780 (3.0 per cent) versus 152 of 10 254 (1.5 per cent) respectively. Female sex was significantly associated with mortality after correction for patient- and hospital-related factors (odds ratio 1.68, 95 per cent c.i. 1.20 to 2.37). OSR volume was associated with lower mortality (OR 0.91 (0.85 to 0.95) per 10-procedure increase) whereas no such relationship was identified with EVAR volume (OR 1.03 (1.01 to 1.05) per 10-procedure increase). CONCLUSION: Women are at higher risk of death after abdominal aortic aneurysm repair irrespective of patient- and hospital-related factors.

Initial experience, feasibility and safety of permanent left bundle branch pacing: results from a prospective single-centre study.

BACKGROUND: Left bundle branch (LBB) pacing is a novel pacing technique which may serve as an alternative to both right ventricular pacing for symptomatic bradycardia and cardiac resynchronisation therapy (CRT). A substantial amount of data is reported by relatively few, highly experienced centres. This study describes the first experience of LBB pacing in a high-volume device centre. METHODS: Success rates (i.e. the ability to achieve LBB pacing), electrophysiological parameters and complications at implant and up to 6 months of follow-up were prospectively assessed in 100 consecutive patients referred for various pacing indications. RESULTS: The mean age was 71 ± 11 years and 65% were male. Primary pacing indication was atrioventricular (AV) block in 40%, CRT in 42%, and sinus node dysfunction or refractory atrial fibrillation prior to AV node ablation in 9% each. Baseline left ventricular ejection fraction was < 50% in 57% of patients, mean baseline QRS duration 145 ± 34 ms. Overall LBB pacing was successful in 83 of 100 (83%) patients but tended to be lower in patients with CRT pacing indication (69%, p = ns). Mean left ventricular activation time (LVAT) during LBB pacing was 81 ms and paced QRS duration was 120 ± 19 ms. LBB capture threshold and R­wave sense at implant was 0.74 ± 0.4 mV at 0.4 ms and 11.9 ± 5.9 V and remained stable at 6­month follow-up. No complications occurred during implant or follow-up. CONCLUSION: LBB pacing for bradycardia pacing and resynchronisation therapy can be easily adopted by experienced implanters, with favourable success rates and safety profile.

Health-related quality of life of perinatally HIV-infected young people: a longitudinal study.

Young people perinatally infected with HIV (pHIV) are at risk of a lowered health-related quality of life (HRQOL). Previous evaluation of the NeurOlogical, VIsual and Cognitive performance in HIV-infected Children (NOVICE)-cohort showed no difference in HRQOL between pHIV and matched HIV-uninfected controls (HIV-), yet a higher percentage of pHIV had impaired HRQOL. The aim of this study is to compare the change over time in HRQOL of pHIV to HIV- over a 5-year period. We used the Pediatric Quality of Life Inventory (PedsQL)™ 4.0 to repeat HRQOL assessment. High PedsQL scores indicate good HRQOL. Fifteen/33 (45.5%) pHIV and 17/37 (45.9%) HIV- completed both assessments. At the first assessment, the mean age was 13.1 years (range 8.0-18.4). PHIV scored higher than HIV- on Emotional functioning and on Total scale score. After five years, the mean age was 17.6 years (range 12.1-22.8). PHIV scored higher than HIV- on all scales, except Social functioning. PHIV did not differ significantly from the Dutch norm on either time-point. LMEM showed no difference in change over time for any of the PedsQL scales. In this study, young people with pHIV receiving high-quality health care, including monitoring of HRQOL, remain to experience a good HRQOL.

Fatigue in children and adolescents perinatally infected with human immunodeficiency virus: an observational study.

BACKGROUND: Fatigue is common among adults living with human immunodeficiency virus (HIV) as well as children with a chronic disease (CCD). Fatigue can have disastrous effects on health status, including health related quality of life (HRQOL). Even so, fatigue is underexplored in children and adolescents perinatally infected with HIV (PHIV+) in the Netherlands. The objective of this observational study is to explore fatigue in PHIV+ and its association with their HRQOL. METHODS: We measured HRQOL and fatigue using the Pediatric Quality of Life Inventory™ (PedsQL 4.0) and the PedsQL Multidimensional Fatigue Scale (MFS). The PedsQL MFS encompasses three subscales: general fatigue, sleep/rest fatigue and cognitive fatigue, and a total fatigue score. We compared outcomes of PHIV+ children and adolescents in the Amsterdam University Medical Centre with three groups: 1) HIV-uninfected controls (HIV-) matched for age, sex, region of birth, socioeconomic status and adoption status, 2) CCD, and 3) the general Dutch population. Within the PHIV+ group we explored associations between fatigue and HRQOL. RESULTS: We enrolled 14 PHIV+ (median age 10.2 years [IQR 9.2-11.4]) and 14 HIV-. Compared to CCD, PHIV+ significantly reported less general fatigue (mean difference 13.0, 95% CI 1.3 to 24.8). PHIV+ did not score significantly different on any of the other PedsQL MFS scales compared to HIV-, CCD or the general Dutch population. PHIV children scored relatively low on the cognitive fatigue scale in comparison to HIV-uninfected matched controls, CCD and the general population, although these differences did not reach significance. Among PHIV+, a lower score on total fatigue, general fatigue and cognitive fatigue was associated with a lower HRQOL score. CONCLUSIONS: The results of this study suggest that PHIV children and adolescents do not experience more symptoms of fatigue than their healthy peers. However, PHIV children and adolescents may be more likely to experience cognitive fatigue. Fatigue in PHIV also appears to be associated with children's HRQOL. Further research should confirm these exploratory findings.

Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTION: Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER: Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY: Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS: Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE: The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228-338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84-117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with 'male factor' as treatment indication (compared to 'tubal factor'). LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS: Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.

[Prioritization of intensive medical treatment places - Concept proposal]. / Priorisierung intensivmedizinischer Behandlungsplätze ­ Konzeptvorschlag.

In the situation of a shortage of ventilation beds, ethically justifiable, transparent and comprehensible decisions must be made. This concept proposes that all patients are first intubated depending on necessity and then assessed by a triage team afterwards. In this situation newly admitted COVID patients compete with newly admitted Non-COVID patients as well as patients already treated in intensive care units for a ventilator. The combination of short-term and long-term prognoses should enable the interprofessional triage team to make comprehensible decisions. The aim of the prioritization concept is to save as many human lives as possible and to relieve the treatment team of the difficult decision on prioritization.

Lower IQ and poorer cognitive profiles in treated perinatally HIV-infected children is irrespective of having a background of international adoption.

BACKGROUND: HIV-associated cognitive deficiency in perinatally HIV-infected (PHIV) children has been studied in Western countries in a population of which an increasing proportion has been internationally adopted. Studies often lack an appropriate internationally adopted HIV-uninfected control group, potentially confounding the relationship between HIV and cognitive functioning. This study aims to further elucidate the association between treated HIV infection and cognitive development by addressing the background of international adoption. METHODS: We cross-sectionally studied the impact of HIV on cognition by comparing PHIV children and HIV- uninfected controls, matched for age-, sex-, ethnicity-, socioeconomic status (SES)- and adoption status. We used a standardized neuropsychological test battery to measure intelligence (IQ), and the cognitive domains of processing speed, working memory, executive function, learning ability and visual-motor function and compared outcomes using lineair regression models, adjusted for IQ. We determined cognitive profiles and cognitive impairment by using multivariate normative comparison (MNC) and explored associations with HIV disease- and treatment-related factors. RESULTS: We enrolled fourteen PHIV children (mean age 10.45 years [1.73 SD], 93% adopted from sub-Saharan Africa at a median age of 3.3 years [IQR 2.1-4.2]) and fifteen HIV- uninfected controls. Groups did not clinically nor statistically differ in age, sex, ethnicity, SES, region of birth, adoption status and age at adoption. PHIV scored consistently lower on all cognitive domains and MNC outcomes. Compared to controls, PHIV children had a significant lower IQ (mean 81 [SD 11] versus mean 97 [SD 15], p = 0.005), and a poorer cognitive profile by MNC (Hotelling's T2 mean -4.36 [SD 5.6] versus mean 0.16 [SD 4.5], p = 0.021), not associated with HIV disease- and treatment-related factors. Two PHIV (14%) and one control (7%) were classified as cognitively impaired (p = 0.598). CONCLUSIONS: Findings indicate treated HIV-infection to be independently associated with lower IQ and poorer cognitive profiles in PHIV children, irrespective of a background of international adoption.

TREatment of ATopic eczema (TREAT) Registry Taskforce: an international Delphi exercise to identify a core set of domains and domain items for national atopic eczema photo- and systemic therapy registries.

BACKGROUND: Evidence of immunomodulatory therapies to guide clinical management of atopic eczema (AE) is scarce, despite frequent and often off-label use. Patient registries provide valuable evidence for the effects of treatments under real-world conditions that can inform treatment guidelines, give the opportunity for health economic evaluation and the evaluation of quality of care, as well as pharmacogenetic and dynamic research, which cannot be adequately addressed in clinical trials. OBJECTIVES: The TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek international consensus on a core set of domains and items ('what to measure') for AE research registries, using a Delphi approach. METHODS: Participants from six stakeholder groups were included: doctors, nurses, nonclinical researchers, patients, industry and regulatory body representatives. The eDelphi comprised three sequential online rounds, requesting participants to rate the importance of each proposed domain item. Participants could add domain items to the proposed list in round 1. A final consensus meeting was held to ratify the core set. RESULTS: Participants (n = 479) from 36 countries accessed the eDelphi platform, of whom 86%, 79% and 74% completed rounds 1, 2 and 3, respectively. At the face-to-face consensus meeting attended by 42 participants the final core set was established containing 19 domains with 69 domain items (49 baseline and 20 follow-up items). CONCLUSIONS: This core set of domains and items to be captured by national AE systemic therapy registries will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries. Ultimately, it will provide greater insight into the effectiveness, safety and cost-effectiveness of photo- and systemic immunomodulatory therapies.

Pediatric lipid reference values in the general population: The Dutch lifelines cohort study.

BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite. OBJECTIVE: To provide health care professionals with contemporary age- and gender-based pediatric reference values for lipid and lipoprotein levels to help the identification of children with dyslipidemia, especially FH. METHODS: Lifelines is a large prospective population-based Dutch cohort study. Children from 8 till 18 years of age were included and fasting lipid levels were measured. Smoothed reference curves and percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) were generated using the Generalized Additive Models for Location, Scale and Shape package in the statistical software R. RESULTS: A total of 8071 children (3823 boys and 4248 girls) were included. In the total cohort we noted marked dynamic changes in lipid and lipoprotein levels over age, which were in part gender specific. Our data highlight a high and unexpected prevalence of severely elevated LDL-c (>190 mg/dL) in both boys and girls. CONCLUSION: Our cross-sectional data provide contemporary reference ranges for plasma lipids that can assist physicians in identifying children at increased risk of premature atherosclerosis, especially FH.

Severe laryngeal stenosis in newly born twins with 22q11.2 deletion syndrome: A case report.

Chromosome 22q11.2 deletion syndrome is common and presents with a range of clinical features from cardiac malformations to hypocalcemia. Laryngeal anomalies are not a common feature of this syndrome. We describe newly born twins who presented with unexpected severe birth depression secondary to severe type IV glottic webs requiring extensive resuscitation and emergency tracheostomy. They were diagnosed postnatally to have deletion of 22q11.2. The successful resuscitation of these infants at birth was only possible because they were born in a tertiary care hospital. This report shows the critical nature of prenatal diagnosis of 22q11.2 deletion syndrome.

Role of protein kinase C δ in apoptotic signaling of oxidized phospholipids in RAW 264.7 macrophages.

The oxidized phospholipids (oxPl) 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) are cytotoxic components of oxidized LDL (oxLDL). Sustained exposure to oxLDL or isolated oxPl induces apoptotic signaling in vascular cells, which is a hallmark of the late phase of atherosclerosis. Activation of sphingomyelinase, the coordinate formation of ceramide and activation of caspase 3/7 as well as the activation of stress-associated kinases are causally involved in this process. Here, we provide evidence for a role of PKCδ in oxPl cytotoxicity. Silencing of the enzyme by siRNA significantly reduced caspase 3/7 activation in RAW 264.7 macrophages under the influence of oxPl. Concomitantly, PKCδ was phosphorylated as a consequence of cell exposure to PGPC or POVPC. Single molecule fluorescence microscopy provided direct evidence for oxPl-protein interaction. Both oxPl recruited an RFP-tagged PKCδ to the plasma membrane in a concentration-dependent manner. In addition, two color cross-correlation number and brightness (ccN&B) analysis of the molecular motions revealed that fluorescently labeled PGPC or POVPC analogs co-diffuse and are associated with the fluorescent protein kinase in live cells. The underlying lipid-protein interactions may be due to chemical bonding (imine formation between the phospholipid aldehyde POVPC with protein amino groups) and physical association (with POVPC or PGPC). In summary, our data supports the assumption that PKCδ acts as a proapototic kinase in oxPl-included apoptosis of RAW 264.7 macrophages. The direct association of the bioactive lipids with this enzyme seems to be an important step in the early phase of apoptotic signaling.

A mixture model for the analysis of data derived from record linkage.

Combining information from two data sources depends on finding records that belong to the same individual (matches). Sometimes, unique identifiers per individual are not available, and we have to rely on partially identifying variables that are registered in both data sources. A risk of relying on these variables is that some records from both datasets are wrongly linked to each other, which introduces bias in further regression analyses. In this paper, we propose a mixture model where we treat the indicator whether records belong to the same individual as missing. Each pair of records from both datasets contributes independently to a pairwise pseudo-likelihood, which we maximize with an expectation-maximization algorithm. Each part of the pseudo-likelihood is parameterized by the appropriate (parametric) density function. Moreover, some structures of the data allow for simplifying assumptions, which makes the pseudo-likelihood considerably easier to parameterize. Because the optimization requires a product over all combinations of records from both datasets, we suggest a procedure that summarizes information from highly unlikely matches. With simulations, we showed that the new approach produces accurate estimates in different linkage scenarios. Moreover, the estimator remained accurate in scenarios where previously proposed analysis approaches give biased results. We applied the method to estimation of the association between pregnancy duration of the first and second born children from the same mother from a register without mother identifier.

Using vaginal Group B Streptococcus colonisation in women with preterm premature rupture of membranes to guide the decision for immediate delivery: a secondary analysis of the PPROMEXIL trials.

OBJECTIVE: To investigate whether vaginal Group B Streptococcus (GBS) colonisation or other baseline characteristics of women with preterm premature rupture of membranes (PPROM) can help in identifying subgroups of women who would benefit from immediate delivery. DESIGN: Secondary analysis of the PPROMEXIL trials. SETTING: Sixty hospitals in the Netherlands. POPULATION: Women with PPROM between 34 and 37 weeks of gestation. METHODS: Random assignment of 723 women to immediate delivery or expectant management. MAIN OUTCOME MEASURES: Early onset neonatal sepsis. RESULTS: Vaginal GBS colonisation status was the only marker which was significantly associated with the benefit of immediate delivery (P for interaction: 0.04). GBS colonisation was observed in 14% of women. The risk of early onset neonatal sepsis in GBS-positive women was high (15.2%) when they were managed expectantly but this risk was reduced to 1.8% with immediate delivery. The early onset neonatal sepsis risk was much lower in neonates of GBS-negative women: 2.6% after expectant management and 2.9% with immediate delivery. We estimated that by inducing labour only in GBS-positive women, there would be a 10.4% increase in term delivery rate, while keeping neonatal sepsis and caesarean delivery rates comparable to a strategy of labour induction for all. CONCLUSIONS: Our post hoc findings suggest that women with PROM between 34 and 37 weeks might benefit from immediate delivery if they have GBS vaginal colonisation, while in GBS-negative women labour induction could be delayed until 37 weeks.

Time to conception and time to live birth in women with unexplained recurrent miscarriage.

STUDY QUESTION: What is the time to conception in a cohort of women with unexplained recurrent miscarriage (RM). SUMMARY ANSWER: Median time to conception in women diagnosed with unexplained RM was 21 weeks (interquartile range (IQR) 8-55 weeks), with a cumulative incidence of conception of 74% after 12 months of trying to conceive. WHAT IS KNOWN ALREADY: There is no effective treatment in couples with unexplained RM. Adequate counselling about their prognosis, for example time to conception and time to a live birth, is therefore very important. So far, there are no studies that give insight on these issues. STUDY DESIGN, SIZE, DURATION: A nested prospective cohort study was performed from February 2004 through July 2009 within a multicentre randomized placebo-controlled trial (ALIFE trial) on anticoagulant treatment in 364 women with unexplained RM. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 251 women who were not pregnant at the time of diagnosis of unexplained RM were included in this study. Of these, 13% became pregnant with ART, and all other women conceived naturally. The primary outcome was time to conception in weeks, calculated from the moment of diagnosis until conception measured by a urinary HCG. Secondary outcome was time to a live birth in the subsequent pregnancy. The relative prognostic significance of female age, the number of preceding miscarriages, interventions within the trial and the presence or absence of a preceding late miscarriage, a previous live birth and factor V Leiden mutation, was evaluated by Cox regression for time to conception and by competing risk modelling for time to live birth, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative incidence of conception was 56% after 6 months, 74% after 12 months and 86% after 24 months of which 65% resulted in a live birth. The median time to conception was 21 weeks (IQR 8-55 weeks). Of potential prognostic factors, the presence of the factor V Leiden mutation resulted in a significantly shorter median time to conception of 11 weeks for carriers versus 23 weeks for non-carriers (hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.03-3.65). The cumulative incidence of a live birth of the subsequent pregnancy was 0% after 6 months, 23% after 12 months and 50% after 24 months. The median time to a live birth of the subsequent pregnancy was 102 weeks (IQR 82-115 weeks). The number of previous miscarriages was the only prognostic factor (HR 0.83, 95% CI 0.74-0.94) significantly associated with time to a live birth of the subsequent pregnancy. LIMITATIONS, REASONS FOR CAUTION: In our study only the subsequent pregnancy after diagnosing unexplained RM was included. A future collection of cumulative follow-up data of all the women included in this cohort may provide outcomes of all pregnancies following the diagnosis of unexplained RM. WIDER IMPLICATIONS OF THE FINDINGS: Time to conception in women diagnosed with unexplained RM appears to be comparable with time to conception in healthy fertile women, as reported in the literature. The interesting finding that women with Factor V Leiden mutation have a significant shorter time to conception may suggest a favourable embryo implantation process. Future research is needed to confirm these findings and unravel the biology of early implantation. STUDY FUNDING/COMPETING INTEREST(S): The RCT used for this nested cohort study was funded by a grant (945-27-003) from the Netherlands Organization for Health Research and Development and a grant from GlaxoSmithKline. Study drugs (aspirin and placebo) were packaged and donated by Meda Pharma. This analysis was supported by a VIDI innovative research grant from the Netherlands Organisation for Scientific Research (NWO) 016.126.364. There are no potential conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This cohort study was nested in the randomized controlled trial; ALIFE study (Current Controlled Trials number, ISRCTN 58496168).

Opioid-receptor (OR) signaling cascades in rat cerebral cortex and model cell lines: the role of plasma membrane structure.

Large number of extracellular signals is received by plasma membrane receptors which, upon activation, transduce information into the target cell interior via trimeric G-proteins (GPCRs) and induce activation or inhibition of adenylyl cyclase enzyme activity (AC). Receptors for opioid drugs such as morphine (micro-OR, delta-OR and kappa-OR) belong to rhodopsin family of GPCRs. Our recent results indicated a specific up-regulation of AC I (8-fold) and AC II (2.5-fold) in plasma membranes (PM) isolated from rat brain cortex exposed to increasing doses of morphine (10-50 mg/kg) for 10 days. Increase of ACI and ACII represented the specific effect as the amount of ACIII-ACIX, prototypical PM marker Na, K-ATPase and trimeric G-protein alpha and beta subunits was unchanged. The up-regulation of ACI and ACII faded away after 20 days since the last dose of morphine. Proteomic analysis of these PM indicated that the brain cortex of morphine-treated animals cannot be regarded as being adapted to this drug because significant up-regulation of proteins functionally related to oxidative stress and alteration of brain energy metabolism occurred. The number of delta-OR was increased 2-fold and their sensitivity to monovalent cations was altered. Characterization of delta-OR-G-protein coupling in model HEK293 cell line indicated high ability of lithium to support affinity of delta-OR response to agonist stimulation. Our studies of PM structure and function in context with desensitization of GPCRs action were extended by data indicating participation of cholesterol-enriched membrane domains in agonist-specific internalization of delta-OR. In HEK293 cells stably expressing delta-OR-G(i)1alpha fusion protein, depletion of PM cholesterol was associated with the decrease in affinity of G-protein response to agonist stimulation, whereas maximum response was unchanged. Hydrophobic interior of isolated PM became more "fluid", chaotically organized and accessible to water molecules. Validity of this conclusion was supported by the analysis of an immediate PM environment of cholesterol molecules in living delta-OR-G(i)1alpha-HEK293 cells by fluorescent probes 22- and 25-NBD-cholesterol. The alteration of plasma membrane structure by cholesterol depletion made the membrane more hydrated. Understanding of the positive and negative feedback regulatory loops among different OR-initiated signaling cascades (micro-, delta-, and kappa-OR) is crucial for understanding of the long-term mechanisms of drug addiction as the decrease in functional activity of micro-OR may be compensated by increase of delta-OR and/or kappa-OR signaling.