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IntroductionFetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to severe fetal or neonatal bleeding and/or perinatal death. Maternal alloantibodies, targeted against fetal human platelet antigens (HPAs), can result thrombocytopenia and bleeding complications. In pregnancies with known immunisation, fetal bleeding can be prevented by weekly maternal intravenous immunoglobulin infusions. Without population-based screening, immunisation is only detected after birth of an affected infant. Affected cases that might have been prevented, when timely identified through population-based screening. Implementation is hampered by the lack of knowledge on incidence, natural history and identification of pregnancies at high risk of bleeding. We designed a study aimed to obtain this missing knowledge.Methods and analysisThe HIP (HPA-screening in pregnancy) study is a nationwide, prospective and observational cohort study aimed to assess incidence and natural history of FNAIT as well as identifying pregnancies at high risk for developing bleeding complications. For logistic reasons, we invite rhesus D-negative or rhesus c-negative pregnant women, who take part in the Dutch population-based prenatal screening programme for erythrocyte immunisation, to participate in our study. Serological HPA-1a typing is performed and a luminex-based multiplex assay will be performed for the detection of anti-HPA-1a antibodies. Results will not be communicated to patients or caregivers. Clinical data of HPA-1a negative women and an HPA-1a positive control group will be collected after birth. Samples of HPA-1a immunised pregnancies with and without signs of bleeding will be compared with identify parameters for identification of pregnancies at high risk for bleeding complications.Ethics and disseminationEthical approval for this study has been obtained from the Medical Ethical Committee Leiden-The Hague-Delft (P16.002). Study enrolment began in March 2017. All pregnant women have to give informed consent for testing according to the protocol. Results of the study will be disseminated through congresses and publication in relevant peer-reviewed journals.Trial registration numberNCT04067375.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/β phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis.

Patients with the mesenchymal subtype colorectal cancer (CRC) have a poor prognosis, in particular patients with stroma-rich tumors and aberrant SMAD4 expression. We hypothesized that interactions between SMAD4-deficient CRC cells and cancer-associated fibroblasts provide a biological explanation. In transwell invasion assays, fibroblasts increased the invasive capacity of SMAD4-deficient HT29 CRC cells, but not isogenic SMAD4-proficient HT29 cells. A TGF-β/BMP-specific array showed BMP2 upregulation by fibroblasts upon stimulation with conditioned medium from SMAD4-deficient CRC cells, while also stimulating their invasion. In a mouse model for experimental liver metastasis, the co-injection of fibroblasts increased metastasis formation of SMAD4-deficient CRC cells (p = 0.02) but not that of SMAD4-proficient CRC cells. Significantly less metastases were seen in mice co-injected with BMP2 knocked-down fibroblasts. Fibroblast BMP2 expression seemed to be regulated by TRAIL, a factor overexpressed in SMAD4-deficient CRC cells. In a cohort of 146 stage III CRC patients, we showed that patients with a combination of high stromal BMP2 expression and the loss of tumor SMAD4 expression had a significantly poorer overall survival (HR 2.88, p = 0.04). Our results suggest the existence of a reciprocal loop in which TRAIL from SMAD4-deficient CRC cells induces BMP2 in fibroblasts, which enhances CRC invasiveness and metastasis.

Colon cancer is associated with an increased risk of physical and psychosocial morbidity, even after treatment. General practitioner (GP) care could be beneficial to help to reduce this morbidity. We aimed to assess quality of life (QOL) in patients who received GP-led survivorship care after treatment for colon cancer compared with those who received surgeon-led care. Furthermore, the effect of an eHealth app (Oncokompas) on QOL was assessed in both patient groups. We did a pragmatic two-by-two factorial, open-label, randomised, controlled trial at eight hospitals in the Netherlands. Eligible patients were receiving primary surgical treatment for stage I–III colon cancer or rectosigmoid carcinoma and qualified for routine follow-up according to Dutch national guidelines. Patients were randomly assigned (1:1:1:1)—via computer-generated variable block randomisation stratified by age and tumour stage—to survivorship care overseen by a surgeon, survivorship care overseen by a surgeon with access to Oncokompas, survivorship care overseen by a GP, or survivorship care overseen by a GP with access to Oncokompas. Blinding of the trial was not possible. The primary endpoint of the trial was QOL at 5 years, as measured by the change from baseline in the European Organistion for Research and Treatment of Cancer QLQ-C30 summary score. Here, we report an unplanned interim analysis of QOL at the 12-month follow-up. Grouped comparisons were done (ie, both GP-led care groups were compared with both surgeon-led groups, and both Oncokompas groups were compared with both no Oncokompas groups). Differences in change of QOL between trial groups were estimated with linear mixed-effects models. A change of ten units was considered clinically meaningful. Analysis was by intention to treat. This trial is registered with the Netherlands Trial Register, NTR4860. Between March 26, 2015, and Nov 21, 2018, 353 patients were enrolled and randomly assigned. There were 50 early withdrawals (27 patient decisions and 23 GP withdrawals). Of the remaining 303 participants, 79 were assigned to surgeon-led care, 83 to surgeon-led care with Oncokompas, 73 to GP-led care, and 68 to GP-led care with Oncokompas. Median follow-up was 12·2 months (IQR 12·0–13·0) in all groups. At baseline, QOL was high in all trial groups. At 12 months, there was no clinically meaningful difference in change from baseline in QOL between the GP-led care groups and the surgeon-led care groups (difference in summary score –2·3 [95% CI –5·0 to 0·4]) or between the Oncokompas and no Oncokompas groups (−0·1 [–2·8 to 2·6]). In terms of QOL, GP-led survivorship care can be considered as an alternative to surgeon-led care within the first year after colon cancer treatment. Other outcomes, including patient and physician preferences, will be important for decisions about the type of survivorship care. Dutch Cancer Society (KWF).

Apple (Malus×domesticaBorkh) is among the main sources of phenolic compounds in the human diet. The genetic basis of the quantitative variations of these potentially beneficial phenolic compounds was investigated. A segregating F₁ population was used to map metabolite quantitative trait loci (mQTLs). Untargeted metabolic profiling of peel and flesh tissues of ripe fruits was performed using liquid chromatography–mass spectrometry (LC-MS), resulting in the detection of 418 metabolites in peel and 254 in flesh. In mQTL mapping using MetaNetwork, 669 significant mQTLs were detected: 488 in the peel and 181 in the flesh. Four linkage groups (LGs), LG1, LG8, LG13, and LG16, were found to contain mQTL hotspots, mainly regulating metabolites that belong to the phenylpropanoid pathway. The genetics of annotated metabolites was studied in more detail using MapQTL®. A number of quercetin conjugates had mQTLs on LG1 or LG13. The most important mQTL hotspot with the largest number of metabolites was detected on LG16: mQTLs for 33 peel-related and 17 flesh-related phenolic compounds. Structural genes involved in the phenylpropanoid biosynthetic pathway were located, using the apple genome sequence. The structural geneleucoanthocyanidin reductase(LAR1) was in the mQTL hotspot on LG16, as were seven transcription factor genes. The authors believe that this is the first time that a QTL analysis was performed on such a high number of metabolites in an outbreeding plant species.

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.

ObjectivesThe I CARE study (Improving Care After colon canceR treatment in the Netherlands) aims to compare surgeon-led to general practitioner (GP)-led colon cancer survivorship care. Recruitment to the trial took longer than expected. In this descriptive study, recruitment is critically reviewed.SettingPatients were recruited from eight Dutch medical centres.ParticipantsPatients treated with curative intent for stages I–III colon cancer. Target patient sample size was calculated at 300.InterventionsPatients were randomised to surgeon-led (usual) versus GP-led care, with or without access to an eHealth application (Oncokompas).Outcome measuresBaseline characteristics of (non-)participants, reasons for non-participation and strategies to improve recruitment were reviewed.ResultsOut of 1238 eligible patients, 353 patients were included. Of these, 50 patients dropped out shortly after randomisation and before start of the intervention, resulting in a participation rate of 25%. Participants were on average slightly younger (68.1 years vs 69.3 years) and more often male (67% vs 50%) in comparison to non-participants. A total of 806 patients declined participation for reasons most often relating to research (57%), including the wish to remain in specialist care (31%) and too much effort to participate (12%). Some patients mentioned health (9%) and confrontation with the disease (5%) as a reason. In 43 cases, GPs declined participation, often related to the study objective, need for financial compensation and time restraints. The generally low participation rate led to concerns about reaching the target sample size. Methods to overcome recruitment challenges included changes to the original recruitment procedure and the addition of new study centres.ConclusionsChallenges were faced in the recruitment to a randomised trial on GP-led colon cancer survivorship care. Research on the transition of care requires sufficient time, funding and support base among patients and healthcare professionals. These findings will help inform researchers and policy-makers on the development of future practices.Trial registration numberNTR4860.

Purpose The aim of this study is to assess cost-effectiveness of general practitioner (GP) versus surgeon-led colon cancer survivorship care from a societal perspective. Methods We performed an economic evaluation alongside the I CARE study, which included 303 cancer patients (stages I–III) who were randomised to survivorship care by a GP or surgeon. Questionnaires were administered at baseline, 3-, 6-, 12-, 24- and 36-months. Costs included healthcare costs (measured by iMTA MCQ) and lost productivity costs (SF-HLQ). Disease-specific quality of life (QoL) was measured using EORTC QLQ-C30 summary score and general QoL using EQ-5D-3L quality-adjusted life years (QALYs). Missing data were imputed. Incremental cost-effectiveness ratios (ICERs) were calculated to relate costs to effects on QoL. Statistical uncertainty was estimated using bootstrapping. Results Total societal costs of GP-led care were significantly lower compared to surgeon-led care (mean difference of − €3895; 95% CI − €6113; − €1712). Lost productivity was the main contributor to the difference in societal costs (− €3305; 95% CI − €5028; − €1739). The difference in QLQ-C30 summary score over time between groups was 1.33 (95% CI − 0.049; 3.15). The ICER for QLQ-C30 was − 2073, indicating that GP-led care is dominant over surgeon-led care. The difference in QALYs was − 0.021 (95% CI − 0.083; 0.040) resulting in an ICER of 129,164. Conclusions GP-led care is likely to be cost-effective for disease-specific QoL, but not for general QoL. Implications for cancer survivors With a growing number of cancer survivors, GP-led survivorship care could help to alleviate some of the burden on more expensive secondary healthcare services.