Exploring psychosocial vulnerability among Dutch pregnant women: a register study.

In the Netherlands adverse perinatal outcomes are also associated with non-medical factors which vary across geographical locations. This study analyses the presence of non-medical vulnerabilities in pregnant women in two regions with high numbers of psychosocial adversity using the same definition for vulnerability in both regions. A register study was performed in 2 regions. Files from women in midwife-led care were analyzed using a standardized case report form addressing non-medical vulnerability based on the Rotterdam definition for vulnerability: measurement A in Groningen (n = 500), measurement B in South-Limburg (n = 538). Only in South-Limburg a second measurement was done after implementing an identification tool for vulnerability (C (n = 375)). In both regions about 10% of pregnant women had one or more urgent vulnerabilities and almost all of these women had an accumulation of several urgent and non-urgent vulnerabilities. Another 10% of women had an accumulation of three or more non-urgent vulnerabilities. This study showed that by using the Rotterdam definition of vulnerability in both regions about 20% of pregnant women seem to live in such a vulnerable situation that they may need psychosocial support. The definition seems a good tool to determine vulnerability. However, without considering protective factors it is difficult to establish precisely women's vulnerability. Research should reveal whether relevant women receive support and whether this approach contributes to better perinatal and child outcomes.

Exploring the determinants of student midwives' wellbeing during their studies: A qualitative study.

PROBLEM: Student wellbeing is a global concern in the aftermath of the COVID pandemic. Students in healthcare often are exposed to academic, clinical, and psychosocial factors of stress, in particularly student midwives, as they are exposed to other people's intimate life experiences. The aim of this study was to identify factors which help and hinder student midwives in their studies. BACKGROUND: Midwifery students in the Netherlands must complete 35-50 % of their bachelor's degree with placements in community and hospital-based maternity care. METHODS: An exploratory qualitative study was conducted, using the Job-Demands-Resources model. Data were collected through semi-structured individual and group interviews with Bachelor student midwives from the Netherlands. FINDINGS: During coursework students found the high workload and lack of recovery time demanding. During placements, their sense of being constantly assessed, having to be available on call and being away from home were experienced as demands. The relationships with teachers as supportive. Support from their placement supervisors and peers were also resourceful if available and positive. In other cases, peer pressure and grand expectations from supervisors were demanding. Personal demands were setting ambitious standards and feeling alone during their placements, and personal resources were positive attitude towards to becoming a midwife. DISCUSSION: The academic programme for student midwives seemed highly demanding, with a stark difference between the learning environment in the faculty coursework and in the placements. Positive support from placement supervisors in a culture that values learning and development, can contribute to student midwives' socialization into midwifery.

Retinoic acid-loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro.

The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.

Corrigendum: Health problems experienced by women during the first year postpartum: A systematic review.

[This corrects the article DOI: 10.18332/ejm/173417.].

Sialic acid-modified der p 2 allergen exerts immunomodulatory effects on human PBMCs.

Background: House dust mite extract-based allergen immunotherapy (AIT) to treat house dust mite allergy is substantially effective but still presents some safety and efficacy concerns that warrant improvement. Several major allergen-based approaches to increase safety and efficacy of AIT have been proposed. One of them is the use of the group 2 allergen, Der p 2. Objective: We sought to investigate the immunomodulatory effects of sialic acid-modified major allergen recombinant Der p 2 (sia-rDer p 2) on PBMCs from healthy volunteers. Methods: We activated PBMCs with anti-CD3/CD28 antibodies and incubated them at 37°C for 6 days in the presence or absence of either native rDer p 2 or α2-3 sialic acid-modified rDer p 2 (sia-rDer p 2). We assessed the changes in CD4+ T-cell activation and proliferation by flow cytometry and changes in T-lymphocyte cytokine production in cell culture supernatant by ELISA. Results: We observed that PBMCs treated with sia-rDer p 2 presented with a markedly decreased expression of CD69 and an increased abundance of LAG-3+ lymphocytes compared with cells treated with rDer p 2. Moreover, PBMCs treated with sia-rDer p 2 showed a reduced production of IL-4, IL-13, and IL-5 and displayed a higher IL-10/IL-5 ratio compared with rDer p 2-treated PBMCs. Conclusions: We demonstrate that sia-rDer p 2 might be a safer option than native rDer p 2 for Der p 2-specific AIT. This is most relevant in the early phase of AIT that is often characterized by heightened TH2 responses, because sia-rDer p 2 does not enhance the production of TH2 cytokines.

Aberrant neutrophil degranulation in hospitalized patients with COVID-19 partially remains for 6 months.

Neutrophils are important players in COVID-19, contributing to tissue damage by release of inflammatory mediators, including ROS and neutrophil elastase. Longitudinal studies on the effects of COVID-19 on neutrophil phenotype and function are scarce. Here, we longitudinally investigated the phenotype and degranulation of neutrophils in COVID-19 patients (28 nonhospitalized and 35 hospitalized patients) compared with 17 healthy donors (HDs). We assessed phenotype, degranulation, CXCL8 (IL-8) release, and ROS generation within 8 days, at one or 6 month(s) after COVID-19 diagnosis. For degranulation and ROS production, we stimulated neutrophils, either with ssRNA and TNF or granulocyte-macrophage colony-stimulating factor and N-Formylmethionyl-leucyl-phenylalanine. During active COVID-19, neutrophils from hospitalized patients were more immature than from HDs and were impaired in degranulation and ROS generation, while neutrophils from nonhospitalized patients only demonstrated reduced CD66b+ granule release and ROS production. Baseline CD63 expression, indicative of primary granule release, and CXCL8 production by neutrophils from hospitalized patients were elevated for up to 6 months. These findings show that patients hospitalized due to COVID-19, but not nonhospitalized patients, demonstrated an aberrant neutrophil phenotype, degranulation, CXCL8 release, and ROS generation that partially persists up to 6 months after infection.

Health problems experienced by women during the first year postpartum: A systematic review.

INTRODUCTION: During pregnancy and childbirth, health issues can arise that can negatively influence women's postpartum health. Although it is imperative to identify these health problems in order to tailor care to women's needs, they often remain unrecognized. A comprehensive overview of postpartum health problems does not exist in the current literature. This systematic review aimed to explore the health problems experienced by women residing in high-income countries during the first year postpartum. METHODS: Scientific databases were searched for articles on health problems experienced by women during the first year postpartum, published between January 2000 and 2 July 2021. Studies investigating the experiences of healthy women from the age of 18 years, residing in high-income countries, who gave birth to a healthy neonate, were included. Identified health issues were divided into five categories and presented in an overview. RESULTS: A total of 25 articles were eligible for inclusion. In all, 83 health problems were identified and divided into five different categories (physical health problems, mental health problems, social health problems, problems related to feeding the infant, and other challenges). Common health issues postpartum were exhaustion, urinary incontinence, painful breasts, depressive symptoms, problems related to sexuality and sleep, lack of social support, and problems with breastfeeding. CONCLUSIONS: This systematic review contributes to a wider understanding of postpartum health problems and can be used to adapt healthcare to women's needs. It distinguishes itself from previous studies by the wide variety of identified health problems and its specific focus on women's experiences in the postpartum period.

A novel peanut allergy immunotherapy: Plant-based enveloped Ara h 2 Bioparticles activate dendritic cells and polarize T cell responses to Th1.

Introduction: As the only market-authorized allergen immunotherapy (AIT) for peanut allergy is accompanied by a high risk of side effects and mainly induces robust desensitization without sustained efficacy, novel treatment options are required. Peanut-specific plant-derived eBioparticles (eBPs) surface expressing Ara h 2 at high density have been shown to be very hypoallergenic. Here, we assessed the dendritic cell (DC)-activating and T cell polarization capacity of these peanut-specific eBPs. Methods: Route and kinetics of eBP uptake were studied by (imaging) flow cytometry using monocyte-derived DCs incubated with fluorescently-labelled Ara h 2 eBPs or natural Ara h 2 (nAra h 2) in the presence or absence of inhibitors that block pathways involved in macropinocytosis, phagocytosis, and/or receptor-mediated uptake. DC activation was monitored by flow cytometry (maturation marker expression) and ELISA (cytokine production). T cell polarization was assessed by co-culturing DCs exposed to Ara h 2 eBPs or nAra h 2 with naïve CD4+ T cells, followed by flow cytometry assessment of intracellular IFNγ+ (Th1) and IL-13+ (Th2), and CD25+CD127-Foxp3+ regulatory T cells (Tregs). The suppressive activity of Tregs was tested using a suppressor assay. Results: Ara h 2 eBPs were taken up by DCs through actin-dependent pathways. They activated DCs demonstrated by an induced expression of CD83 and CD86, and production of TNFα, IL-6, and IL-10. eBP-treated DCs polarized naïve CD4+ T cells towards Th1 cells, while reducing Th2 cell development. Furthermore, eBP-treated DCs induced reduced the frequency of Foxp3+ Tregs but did not significantly affect T cell IL-10 production or T cells with suppressive capacity. In contrast, DC activation and Th1 cell polarization were not observed for nAra h 2. Conclusion: Ara h 2 eBPs activate DCs that subsequently promote Th1 cell polarization and reduce Th2 cell polarization. These characteristics mark Ara h 2 eBPs as a promising novel candidate for peanut AIT.

Midwives' work-related fear and anxiety and its impact on their wellbeing and performance. A qualitative study of perceived anxiety in community midwives.

INTRODUCTION: Working with acute situations is usually part of midwifery practice. In the Netherlands the community midwives work in a context where they are mostly the sole decision-makers and policymakers and often do not have the support of a multidisciplinary team during a birth. How Dutch community midwives maintain their emotional hygiene is not known. This study aims to explore how Dutch midwives perceive fear and its influence on their performance. METHODS: This is a qualitative study with semi-structured interviews of 19 Dutch community midwives between October 2018 and January 2019. RESULTS: Four themes were identified: 1) midwives' perceptions of fear and anxiety, 2) how years of experience affect fear and anxiety, 3) influence of the work content; and 4) implications for performance. Midwives perceived fear in acute situations where maternal and/or fetal complications were imminent. Participants perceived anxiety either as helpful or a hindrance. Awareness of these feelings helps them to regulate whether or not to give in to these feelings. CONCLUSIONS: Our findings suggest similar perspectives on fear in Dutch community midwives compared to previous outcomes. In the Netherlands, midwives seem reluctant to talk about fear and anxiety in the profession. The awareness of these emotions occurring while working is essential for the wellbeing of midwives, as well as the importance of knowing how to act on fear and anxiety.

How to improve newly qualified midwives' transition-into-practice. A Delphi study.

BACKGROUND: In the Netherlands, newly qualified midwives start work as registered midwives without any formal transition support. Research shows that newly qualified midwives do not feel sufficiently confident and competent in their work during the period following graduation. This could impact the quality of care provided by newly registered midwives. The aim of this study is to seek consensus with stakeholders concerning viable components of support for newly qualified midwives working in midwifery care in the Netherlands. METHODS: A Delphi study was conducted among maternity care stakeholders in the Netherlands. During two rounds, sixteen statements derived from a theoretical framework of organizational socialization theory and previous studies were assessed (round 1, n = 56; round 2, n = 52). Stakeholders (N = 61) were invited and completed an online questionnaire that included spaces for opinions and remarks. RESULTS: Stakeholders agreed about an introductory support period for newly qualified midwives, involving performance feedback and regional-level backup from fellow midwives during shifts. They further agreed on the responsibilities of established professionals that they should support newcomers in practice and provide mentoring or group coaching, although they face organizational barriers for supporting newcomers. CONCLUSIONS: Stakeholders found consensus upon several components of support at the workplace. In addition, a stable work environment seemed less important in their opinion while previous research suggests otherwise. Practice organisations need to improve the employment conditions and support for newly qualified midwives to ensure the quality of midwifery care is guaranteed.

Midwives' occupational wellbeing and its determinants. A cross-sectional study among newly qualified and experienced Dutch midwives.

OBJECTIVE: Internationally, about 40 percent of midwives report symptoms of burnout, with young and inexperienced midwives being most vulnerable. There is a lack of recent research on burnout among Dutch midwives. The aim of this study was to examine the occupational wellbeing and its determinants of newly qualified and inexperienced midwives in the Netherlands. The majority of practicing Dutch midwives are aged under 40, which could lead to premature turnover. DESIGN: A cross-sectional study was conducted using an online questionnaire that consisted of validated scales measuring job demands, job and personal resources, burnout symptoms and work engagement. The Job Demands-Resources model was used as a theoretical model. SETTING AND PARTICIPANTS: We recruited Dutch midwives who were actually working in midwifery practice. A total of N=896 midwives participated in this study, representing 28 percent of practicing Dutch midwives. MEASUREMENTS AND FINDINGS: Data were analysed using regression analysis. Seven percent of Dutch midwives reported burnout symptoms and 19 percent scored high on exhaustion. Determinants of burnout were all measured job demands, except for experience level. Almost 40 percent of midwives showed high work engagement; newly qualified midwives had the highest odds of high work engagement. Master's or PhD-level qualifications and employment status were associated with high work engagement. All measured resources were associated with high work engagement. KEY CONCLUSIONS: A relatively small percentage of Dutch midwives reported burnout symptoms, the work engagement of Dutch midwives was very high. However, a relatively large number reported symptoms of exhaustion, which is concerning because of the risk of increasing cynicism levels leading to burnout. In contrast to previous international research findings, being young and having less working experience was not related to burnout symptoms of Dutch newly qualified midwives. IMPLICATIONS FOR PRACTICE: The recognition of job and personal resources for midwives' occupational wellbeing must be considered for a sustainable midwifery workforce. Midwifery Academies need to develop personal resources of their students that will help them in future practice.

Toll-like receptor 4 and Syk kinase shape dendritic cell-induced immune activation to major house dust mite allergens.

Background: House dust mite (HDM) is a major cause of respiratory allergic diseases. Dendritic cells (DCs) play a central role in orchestrating adaptive allergic immune responses. However, it remains unclear how DCs become activated by HDM. Biochemical functions of the major HDM allergens Der p 1 (cysteine protease) and Der p 2 (MD2-mimick) have been implicated to contribute to DC activation. Methods: We investigated the immune activating potential of HDM extract and its major allergens Der p 1 and Der p 2 using monocyte-derived DCs (moDCs). Maturation and activation markers were monitored by flow cytometry and cytokine production by ELISA. Allergen depletion and proteinase K digestion were used to investigate the involvement of proteins, and in particular of the major allergens. Inhibitors of spleen tyrosine kinase (Syk), Toll-like receptor 4 (TLR4) and of C-type lectin receptors (CLRs) were used to identify the involved receptors. The contribution of endotoxins in moDC activation was assessed by their removal from HDM extract. Results: HDM extract induced DC maturation and cytokine responses in contrast to the natural purified major allergens Der p 1 and Der p 2. Proteinase K digestion and removal of Der p 1 or Der p 2 did not alter the immune stimulatory capacity of HDM extract. Antibodies against the CLRs Dectin-1, Dectin-2, and DC-SIGN did not affect cytokine responses. In contrast, Syk inhibition partially reduced IL-6, IL-12 and completely blocked IL-10. Blocking TLR4 signaling reduced the HDM-induced IL-10 and IL-12p70 induction, but not IL-6, while endotoxin removal potently abolished the induced cytokine response. Conclusion: Our data strongly suggest that HDM-induced DC activation is neither dependent on Der p 1 nor Der p 2, but depend on Syk and TLR4 activation, which might suggest a crosstalk between Syk and TLR4 pathways. Our data highlight that endotoxins play a potent role in immune responses targeting HDM.

Glycan dependent phenotype differences of HIV-1 generated from macrophage versus CD4+ T helper cell populations.

Human immunodeficiency virus type 1 (HIV-1) is able to infect a variety of cell types with differences in entry efficiency and replication kinetics determined by the host cell type or the viral phenotype. The phenotype of the virus produced from these various cell types, including infectivity, co-receptor usage and neutralisation sensitivity, may also be affected by the characteristics of the producing cell. This can be due to incorporation of variant cell-specific molecules or differences in post-translational modifications of the gp41/120 envelope. In this study we produced genetically identical virus strains from macrophages, CD4-enriched lymphocytes as well as Th1 and Th2 CD4+ cell lines and compared each different virus stock for their infectivity in various cell types and sensitivity to neutralisation. In order to study the effect of the producer host cell on the virus phenotype, virus stocks were normalised on infectivity and were sequenced to confirm env gene homogeneity. Virus production by Th1 or Th2 cells did not compromise infectivity of the variant cell types tested. We observed no difference in sensitivity to co-receptor blocking agents upon viral passage through Th1 and Th2 CD4+ cell lineages nor did this affect DC-SIGN-mediated viral capture as measured in a transfer assay to CD4+ lymphocytes. Virus produced by macrophages was comparably sensitive to CC-chemokine inhibition as was virus generated from the array of CD4+ lymphocytes. We identified that virus produced from macrophages was fourteen times more resistant to 2G12 neutralisation than virus produced from CD4+ lymphocytes. Macrophage-produced dual-tropic (R5/X4) virus was six times more efficiently transmitted to CD4+ cells than lymphocyte-derived HIV-1 (p<0.0001) after DCSIGN capture. These results provide further insights to what extent the host cell influences viral phenotype and thereby various aspects of HIV-1 pathogenesis but suggest that viruses generated from Th1 versus Th2 cells are consistent in phenotype.

Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge.

Innate mononuclear phagocytic system (MPS) cells preserve mucosal immune homeostasis. We investigated their role at nasal mucosa following allergen challenge with house dust mite. We combined single-cell proteome and transcriptome profiling on nasal immune cells from nasal biopsies cells from 30 allergic rhinitis and 27 non-allergic subjects before and after repeated nasal allergen challenge. Biopsies of patients showed infiltrating inflammatory HLA-DRhi/CD14+ and CD16+ monocytes and proallergic transcriptional changes in resident CD1C+/CD1A+ conventional dendritic cells (cDC)2 following challenge. In contrast, non-allergic individuals displayed distinct innate MPS responses to allergen challenge: predominant infiltration of myeloid-derived suppressor cells (MDSC: HLA-DRlow/CD14+ monocytes) and cDC2 expressing inhibitory/tolerogenic transcripts. These divergent patterns were confirmed in ex vivo stimulated MPS nasal biopsy cells. Thus, we identified not only MPS cell clusters involved in airway allergic inflammation but also highlight novel roles for non-inflammatory innate MPS responses by MDSC to allergens in non-allergic individuals. Future therapies should address MDSC activity as treatment for inflammatory airway diseases.

Liposomes loaded with vitamin D3 induce regulatory circuits in human dendritic cells.

Introduction: Nanomedicine provides a promising platform for manipulating dendritic cells (DCs) and the ensuing adaptive immune response. For the induction of regulatory responses, DCs can be targeted in vivo with nanoparticles incorporating tolerogenic adjuvants and auto-antigens or allergens. Methods: Here, we investigated the tolerogenic effect of different liposome formulations loaded with vitamin D3 (VD3). We extensively phenotyped monocyte-derived DCs (moDCs) and skin DCs and assessed DC-induced regulatory CD4+ T cells in coculture. Results: Liposomal VD3 primed-moDCs induced the development of regulatory CD4+ T cells (Tregs) that inhibited bystander memory T cell proliferation. Induced Tregs were of the FoxP3+ CD127low phenotype, also expressing TIGIT. Additionally, liposome-VD3 primed moDCs inhibited the development of T helper 1 (Th1) and T helper 17 (Th17) cells. Skin injection of VD3 liposomes selectively stimulated the migration of CD14+ skin DCs. Discussion: These results suggest that nanoparticulate VD3 is a tolerogenic tool for DC-mediated induction of regulatory T cell responses.

VSTM1-v2 does not drive human Th17 cell differentiation: A replication study.

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an immune inhibitory receptor expressed on human myeloid cells. We previously showed that dendritic cell (DC)-driven Th17 cell differentiation of human naive CD4+ T cells requires presence of neutrophils, which is inhibited by SIRL-1 ligation. VSTM1-v2 is a soluble isoform of SIRL-1, which was previously proposed to function as a Th17 polarizing cytokine. Here, we investigated the effect of VSTM1-v2 on DC-driven Th17 cell development. Neutrophils induced DC-driven Th17 cell differentiation, which was not enhanced by VSTM1-v2. Similarly, we found no effect of VSTM1-v2 on cytokine-driven Th17 cell development. Thus, our results do not support a role for VSTM1-v2 in Th17 cell differentiation.

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis.

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways.

Adverse Maternal and Infant Outcomes of Women Who Differ in Smoking Status: E-Cigarette and Tobacco Cigarette Users.

The electronic cigarette (e-cigarette) became commercially available around 2004, yet the characteristics of pregnant women who use these devices and their effects on maternal and infant health remain largely unknown. This study aimed to investigate maternal characteristics and pregnancy outcomes according to maternal smoking status. We conducted a cross-sectional study of Dutch women with reported pregnancies between February 2019 and May 2022, using an online questionnaire to collect data on smoking status and demographic, lifestyle, pregnancy, and infant characteristics. Smoking status is compared among non-smokers, tobacco cigarette users, e-cigarette users, and dual users (tobacco and e-cigarette). We report descriptive statistics and calculate differences in smoking status between women with the chi-square or Fisher (Freeman-Halton) test. Of the 1937 included women, 88.1% were non-smokers, 10.8% were tobacco cigarette users, 0.5% were e-cigarette users, and 0.6% were dual users. Compared with tobacco users, e-cigarette users more often reported higher education, having a partner, primiparity, and miscarriages. Notably, women who used e-cigarettes more often had small infants for gestational age. Despite including few women in the e-cigarette subgroup, these exploratory results indicate the need for more research to examine the impact of e-cigarettes on pregnancy outcomes.