ICP: A midwifery perspective.

Background: ICP is a liver condition specific to pregnancy affecting 0.5-0.6% of pregnancies in Australia. Aims: to review the SOMANZ guidelines and extrapolate information relevant to midwives proving care for women with ICP. Findings: Multidisciplinary input is essential in caring for women with ICP and their families. Non-fasting TSBA samples ≥19 µmol/L are diagnostic in the presence of pruritus. Peak TSBA denotes the severity of the disease. Increased risk of stillbirth is small when peak TSBA ≥100 µmol/L. Conclusion: Midwives play an essential role in supporting women with ICP helping them navigate complex appointments and manage the pruritus and concomitant issues.

MicroRNA-146a deficiency enhances host protection against murine cytomegalovirus.

Natural killer (NK) cells are innate lymphoid cells that protect a host from viral infections and malignancies. MicroRNA-146a (miR-146a) is an important regulator of immune function that is highly expressed in NK cells and is further upregulated during murine cytomegalovirus (MCMV) infection. Here we utilized mice with a global targeted deletion of miR-146a to understand its impact on the innate immune responses to MCMV infection. MiR-146a-/- mice were protected from lethal MCMV infection, which was intrinsic to the hematopoietic compartment based on bone marrow chimera experiments. NK cell depletion abrogated this protection, implicating NK cells as critical for the miR-146a-/- protection from MCMV. Surprisingly, NK cells from miR-146a-deficient mice were largely similar to control NK cells with respect to development, maturation, trafficking, and effector functions. However, miR-146a-/- mice had increased NK cell numbers and frequency of the most mature Stage IV (CD27-CD11b+) NK cells in the liver at baseline, enhanced STAT1 phosphorylation, and increased selective expansion of Ly49H+ NK cells and T cells during MCMV infection. This study demonstrates a critical role for miR-146a in the host response to MCMV, arising from mechanisms that include increased NK cell numbers and early T-cell expansion.

Case report: Deep sequencing and long-read genome sequencing refine prior genetic analyses in families with apparent gonadal mosaicism in PIK3CD-related activated PI3K delta syndrome.

Gonadal and gonosomal mosaicism describe phenomena in which a seemingly healthy individual carries a genetic variant in a subset of their gonadal tissue or gonadal and somatic tissue(s), respectively, with risk of transmitting the variant to their offspring. In families with one or more affected offspring, occurrence of the same apparently de novo variants can be an indicator of mosaicism in either parent. Panel-based deep sequencing has the capacity to detect low-level mosaic variants with coverage exceeding the typical limit of detection provided by current, readily available sequencing techniques. In this study, we report three families with more than one affected offspring with either confirmed or apparent parental gonosomal or gonadal mosaicism for PIK3CD pathogenic variants. Data from targeted deep sequencing was suggestive of low-level maternal gonosomal mosaicism in Family 1. Through this approach we did not detect pathogenic variants in PIK3CD from parental samples in Family 2 and Family 3. We conclude that mosaicism was likely confined to the maternal gonads in Family 2. Subsequent long-read genome sequencing in Family 3 showed that the paternal chromosome harbored the pathogenic variant in PIK3CD in both affected children, consistent with paternal gonadal mosaicism. Detection of parental mosaic variants enables accurate risk assessment, informs reproductive decision-making, and provides helpful context to inform clinical management in families with PIK3CD pathogenic variants.

Immunology of Cytokine Storm Syndromes: Natural Killer Cells.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.

Screening and early intervention for substance use during pregnancy: A retrospective case note review of antenatal care records.

INTRODUCTION: Screening for substance use during pregnancy is critical for enhancing maternal health and perinatal outcomes. However, disparities persist in screening and intervention rates within maternity services. This retrospective case note review explored contemporaneous practices around screening and interventions for substance use among pregnant women during routine antenatal care. METHODS: A random sample of 100 sets of maternity records were reviewed. Eligible cases included any woman attending initial pregnancy assessments at one of two South Australian metropolitan Hospital-based antenatal clinics, from July 2019-September 2020. Screening rates for past and current alcohol, tobacco and other substance use were identified and compared with data from a subset of a nationally representative survey. Intervention details and referral pathways were also assessed. RESULTS: The final sample of eligible cases (n = 93) demonstrated prioritisation of screening for current use, over past use, across all substances (p < 0.001). Screening was most likely for tobacco and least likely for e-cigarettes (p < 0.001). Significant underreporting of past use compared with the benchmark was identified for all substances (except tobacco, p = 0.224). Interventions typically involved written resources, which were usually declined by clients. DISCUSSION AND CONCLUSIONS: Despite longstanding recommendations, screening and intervention practices for substance use appear inconsistent. With the recent emergence of vaping, no evidence of updated approaches to identifying e-cigarette consumption in pregnant women was found. Several opportunities for enhancing routine screening and intervention practices within antenatal clinics were identified, and will inform the development of policy directives, targeted training modules, and other resources for health professionals working in these services.

PTPN2 deficiency: Amping up JAK/STAT.

Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.

Lost in transition: Perspectives from women and their families living in rural Australia on relocation for specialist maternal and neonatal care.

PROBLEM: Families living in rural communities need to relocate, be transferred or travel long distances to access specialist maternal and neonatal care, leading to isolation from their support networks. BACKGROUND: High-risk maternal and neonatal complexities in rural maternity units results in more transfers and retrievals to metropolitan services. There is limited understanding of the physical and psychological impacts for women and their families when they are transferred or displaced from their rural communities during pregnancy. AIM: To investigate the lived experience of relocation for specialist pregnancy, birthing, postnatal and neonatal care on women and families. METHODS: Women (n=5) and partners (n=4) from rural South Australia, participated in semi-structured interviews on their experiences of transfer from local maternity providers. Couples interviewed together, interactions were recorded, transcribed verbatim and thematically analysed to identify overarching and sub-themes. FINDINGS: The overarching theme was 'mismatched expectations', with three identified sub-themes: 'communication', 'compassion' and 'safety'. Discrepancies between expectations and realities during relocation left participants feeling isolated, alone and needing to self-advocate during this vulnerable period. Despite receiving specialist care, women and partners encountered unique hardships when separated from their rural community. Their social needs were poorly understood and seldom addressed in specialist units, resulting in poor experiences. DISCUSSION: Consideration regarding the impact of attending specialist maternity services for women and partners from rural areas is required. The 'one size fits all' approach for maternity care is unrealistic and research is needed to improve the experiences for those uprooted from rural communities for higher levels of care.

A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice.

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.

Interprofessional Education in Child Protection for Preservice Health and Allied Health Professionals: A Scoping Review.

Health and allied health professionals are uniquely positioned to collaborate in prevention, early intervention and responses to child maltreatment. Effective collaboration requires comprehensive interprofessional education (IPE), and inadequate collaboration across sectors and professions continually contributes to poor outcomes for children. Little is known about what interprofessional preparation health and allied health professionals receive before initial qualification (preservice) that equips them for interprofessional collaboration and provision of culturally safe care in child protection. This scoping review aimed to identify what is known internationally about IPE in child protection for preservice health and allied health professionals. Thirteen manuscripts reporting 12 studies met the inclusion criteria and were included in the synthesis. Key characteristics of the educational interventions are presented, including target disciplines, core content and their learning objectives and activities. Findings demonstrated primarily low-quality methodologies and educational interventions that had not been replicated beyond their initial context. Many educational interventions did not provide comprehensive content covering the spectrum of prevention, early intervention and responses for all types of child maltreatment, and/or did not clearly indicate how IPE was achieved. Key challenges to delivering comprehensive interprofessional child protection include lack of institutional support and competing priorities across disciplines who must meet requirements of separate regulatory bodies. Consequently, there is a need for further development and robust evaluation of educational interventions to explore how interprofessional collaborative skills for child protection can be developed and delivered in preservice health and allied health professional education.

Improving the quality of antenatal screening and early intervention for alcohol and other drug use: protocol for a multi-stage approach to systems reform.

BACKGROUND: Alcohol, tobacco and illicit drug use during pregnancy can cause significant harm to women and their developing fetuses. Despite recommendations for abstinence during pregnancy, some women continue to use, making screening for substance use during antenatal clinic attendances an important strategy for reducing risk. This study aims to improve the rates of screening and intervention for substance use among pregnant women, including appropriate referral for those who may be substance-dependent. The protocol outlined here focuses on a multi-stage implementation study. METHODS: This study will occur in four phases. Phase 1 will identify a baseline rate of screening and subsequent care at the antenatal clinics of two, South Australian hospital-based maternity services, through a retrospective case note audit. Rates of self-reported substance use identified in the case notes will also be compared against representative data from Adelaide Primary Health Network to establish rates of over or underreporting. Phase 2 will involve an online Training Needs Analysis of midwifery staff working at those services, to assess their knowledge, attitudes, beliefs, and commitment to the care of women who use substances during pregnancy. Phase 3 will involve a training package for all midwifery staff at those services, focused on routine screening for substance use, and how to provide appropriate care. Outcome measures from phase 2 will be reassessed during phase 3 and any changes since training will be evaluated. Phase 4 will then repeat phase 1 to compare the changes in rates of both screening and any associated intervention before and after training. DISCUSSION: From a public health perspective, this project has the potential to make a significant impact on reducing risk of harm from substance use disorders among pregnant women, and contribute to better health outcomes for their children. TRIAL REGISTRATION: This trial has been pre-registered under the Open Science Framework. REGISTRATION: https://doi.org/10.17605/OSF.IO/73FDZ .

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency.

BACKGROUND: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK-cell and B-cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date. OBJECTIVES: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2. METHODS: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency. RESULTS: The investigators identified novel heterozygous variants in PLCG2 in 2 families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss of function due to haploinsufficiency with impaired NK-cell calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B-cell function remained intact. Plcg2+/- mice also displayed impaired NK-cell function with preserved B-cell function, phenocopying human disease. CONCLUSIONS: PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK-cell immunodeficiency with herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease.

MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.

BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.

Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations.

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

Understanding the barriers and facilitators related to birthing pool use from organisational and multi-professional perspectives: a mixed-methods systematic review.

AIMS: To identify and synthesize the evidence regarding the facilitators and barriers relating to birthing pool use from organizational and multi-professional perspectives. DESIGN: A systematic integrated mixed methods review was conducted. DATA SOURCES: MEDLINE, CINAHL, PsychINFO, EMCARE, PROQUEST and Web of Science databases were searched in April 2021, March 2022 and April 2024. We cross-referenced with Google Scholar and undertook reference list searches. REVIEW METHODS: Data were extracted from studies meeting the inclusion criteria. Barriers and facilitators to birthing pool use were mapped and integrated into descriptive statements further synthesized to develop overarching themes. RESULTS: Thirty seven articles (29 studies) were included-quantitative (12), qualitative (8), mixed methods (7), and audits (2), from 12 countries. These included the views of 9,082 multi-professionals (midwives, nurses, obstetricians, neonatologists, students, physicians, maternity support workers, doulas and childbirth educators). Additionally, 285 institutional policies or guidelines were included over 9 papers and 1 economic evaluation. Five themes were generated: The paradox of prescriptiveness, The experienced but elusive practitioner, Advocacy and tensions, Trust or Trepidation and It's your choice, but only if it is a choice. These revealed when personal, contextual, and infrastructural factors were aligned and directed towards the support of birth pool use, birthing pool use was a genuine option. Conversely, the more barriers that women and midwives experienced, the less likely it was a viable option, reducing choice and access to safe analgesia. CONCLUSION: The findings demonstrated a paradoxical reality of water immersion with each of the five themes detailing how the "swing" within these factors directly affected whether birthing pool use was facilitated or inhibited.

Sense of coherence as facilitated by water immersion during labour and birth: A concept analysis and synthesis.

OBJECTIVE: To explore the concept of sense of coherence as facilitated by water immersion during labour and/or birth. DESIGN: A concept analysis and synthesis. A literature search of CINAHL, Medline, PubMed, PsycINFO and Emcare was undertaken in February 2022. Results were cross-checked with Google Scholar. No timeframe was specified, and results were restricted to research papers written in English. Overall, 2768 papers were retrieved and after removal of duplicates and unrelated papers, abstracts were screened to ensure the paper met the inclusion criteria i.e. women's experiences of water immersion for labour and/or birth. This process yielded a total of 37 articles and two theses, these were used for the concept analysis. Attributes were described and an exemplar case developed after mapping and charting of the data set. FINDINGS: Three attributes were identified; agency, holistic and complete and more than pain relief which align with the three sense of coherence components: comprehensible, meaningfulness and manageability. KEY CONCLUSION: There is a growing evidence base regarding the use of intrapartum water immersion. The literature exploring women's experiences and views of water immersion, appears to consistently report that women experience physiological, physical and psychological benefits and that these benefits complement each other to facilitate greater self-efficacy and a more holistic experience. This combination of benefits afforded by water immersion facilitates a sense of coherence and subsequently, increases the likelihood of the woman experiencing labour and birth as both positive and satisfying. IMPLICATIONS FOR PRACTICE: A greater understanding of women's experiences of water immersion will provide rationale and reason for making the option a real choice while revealing the positive impacts that it can have on all outcomes beyond just the physical.

IL-15 Priming Alters IFN-γ Regulation in Murine NK Cells.

NK effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. NK cell production of IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine NK cells exhibit activation-specific metabolic requirements for IFN-γ production, which are reversed for activating receptor-mediated stimulation following IL-15 priming. Although both cytokine and activating receptor stimulation leads to similar IFN-γ protein production, only cytokine stimulation upregulates Ifng transcript, suggesting that protein production is translationally regulated after receptor stimulation. Based on these differences in IFN-γ regulation, we hypothesized that ex vivo IL-15 priming of murine NK cells allows a switch to IFN-γ transcription upon activating receptor engagement. Transcriptional analysis of primed NK cells compared with naive cells or cells cultured with low-dose IL-15 demonstrated that primed cells strongly upregulated Ifng transcript following activating receptor stimulation. This was not due to chromatin accessibility changes in the Ifng locus or changes in ITAM signaling, but was associated with a distinct transcriptional signature induced by ITAM stimulation of primed compared with naive NK cells. Transcriptional analyses identified a common signature of c-Myc (Myc) targets associated with Ifng transcription. Although Myc marked NK cells capable of Ifng transcription, Myc itself was not required for Ifng transcription using a genetic model of Myc deletion. This work highlights altered regulatory networks in IL-15-primed cells, resulting in distinct gene expression patterns and IFN-γ regulation in response to activating receptor stimulation.