Targeted health and social care interventions for women and infants who are disproportionately impacted by health inequalities in high-income countries: a systematic review.

BACKGROUND: Disadvantaged populations (such as women from minority ethnic groups and those with social complexity) are at an increased risk of poor outcomes and experiences. Inequalities in health outcomes include preterm birth, maternal and perinatal morbidity and mortality, and poor-quality care. The impact of interventions is unclear for this population, in high-income countries (HIC). The review aimed to identify and evaluate the current evidence related to targeted health and social care service interventions in HICs which can improve health inequalities experienced by childbearing women and infants at disproportionate risk of poor outcomes and experiences. METHODS: Twelve databases searched for studies across all HICs, from any methodological design. The search concluded on 8/11/22. The inclusion criteria included interventions that targeted disadvantaged populations which provided a component of clinical care that differed from standard maternity care. RESULTS: Forty six index studies were included. Countries included Australia, Canada, Chile, Hong Kong, UK and USA. A narrative synthesis was undertaken, and results showed three intervention types: midwifery models of care, interdisciplinary care, and community-centred services. These intervention types have been delivered singularly but also in combination of each other demonstrating overlapping features. Overall, results show interventions had positive associations with primary (maternal, perinatal, and infant mortality) and secondary outcomes (experiences and satisfaction, antenatal care coverage, access to care, quality of care, mode of delivery, analgesia use in labour, preterm birth, low birth weight, breastfeeding, family planning, immunisations) however significance and impact vary. Midwifery models of care took an interpersonal and holistic approach as they focused on continuity of carer, home visiting, culturally and linguistically appropriate care and accessibility. Interdisciplinary care took a structural approach, to coordinate care for women requiring multi-agency health and social services. Community-centred services took a place-based approach with interventions that suited the need of its community and their norms. CONCLUSION: Targeted interventions exist in HICs, but these vary according to the context and infrastructure of standard maternity care. Multi-interventional approaches could enhance a targeted approach for at risk populations, in particular combining midwifery models of care with community-centred approaches, to enhance accessibility, earlier engagement, and increased attendance. TRIAL REGISTRATION: PROSPERO Registration number: CRD42020218357.

Accurate prediction of serum antibody levels from noninvasive saliva/nasal samples.

The importance of easily accessible, noninvasive samples, such as saliva, to effectively monitor serum antibody levels has been underscored by the SARS-CoV-2 (COVID-19) pandemic. Although a correlation between saliva and serum antibody titers has been observed, the ability to predict serum antibody levels from measurements in saliva is not well established. Herein, the authors demonstrate that measurements of SARS-CoV-2 antibody levels in both saliva and nasal specimens can be used to accurately determine serum levels by utilizing endogenous total IgG as an internal calibrator. They postulate that this method can be extended to the measurement of many different antibody analytes, making it of high interest for antibody therapeutic drug monitoring applications.

Peptide Mimotope-Enabled Quantification of Natalizumab Arm Exchange During Multiple Sclerosis Treatment.

BACKGROUND: Natalizumab, a therapeutic antibody used to treat multiple sclerosis, undergoes in vivo Fab arm exchange to form a monovalent bispecific antibody. Although highly efficacious, the immunosuppressive activity of natalizumab has been associated with JC polyomavirus-driven progressive multifocal leukoencephalopathy (PML). Development of assays that can distinguish between and quantify bivalent (unexchanged) and monovalent (exchanged) forms of natalizumab in clinical samples may be useful for optimizing extended interval dosing and reducing the risk of PML. METHODS: In vitro natalizumab arm exchange was conducted, along with peptide mimotope and anti-idiotype surface capture chemistry, to enable the development of enzyme-linked immunosorbent assays. RESULTS: An assay using a unique peptide Veritope TM was developed, which can exclusively bind to bivalent natalizumab. In combination with enzyme-linked immunosorbent assays that quantifies total natalizumab, the assay system allows quantification of both natalizumab forms. CONCLUSIONS: In this article, a novel assay for the quantification of unexchanged and exchanged natalizumab variants in clinical samples was developed. This assay will enable investigations into the clinical significance of the relationship of PK/PD with the monovalent-to-bivalent ratio, as it relates to the efficacy of the drug and risk of PML.

Reflections on an educational intervention to encourage midwives to work in a continuity of care model - exploration and potential solutions.

OBJECTIVE: To explore barriers and facilitators for midwives working in a midwifery continuity of carer model, and to assess if an educational intervention could help address some of these barriers, designed to help achieve NHS England's target of majority of women receiving midwifery continuity of carer by March 2021. DESIGN: Two-day workshops were co-designed by experienced continuity midwives, service managers and midwifery educators using implementation theory delivered to maternity staff, with barriers assessed prior to training and re-assessed at the end. SETTING AND PARTICIPANTS: 1407 maternity healthcare professionals from 62 different National Health Service trusts across England attended 56 different workshops. FINDINGS: Perceived barriers to working in this model were reported more frequently than facilitators. Reported facilitators prior to training included perceived benefits to the midwife and to women. Reported barriers included personal and professional concerns, fear, issues with the national agenda and institutional and/or organisational issues. The educational intervention was able to address the majority of barriers raised. The training was well evaluated, with an average rating of 4.2 on a five-point Likert scale. KEY CONCLUSIONS: While this specific educational intervention appears to have been useful in addressing concerns with working in a continuity model, further work is needed to identify barriers to change. This will aid more local designed interventions. IMPLICATIONS FOR PRACTICE: If policy targets related to continuity of carer are to be achieved then working in this way needs to be sustainable and appeal to the current midwifery workforce.

Value based maternal and newborn care requires alignment of adequate resources with high value activities.

BACKGROUND: Evidence based practice has been associated with better quality of care in many situations, but it has not been able to address increasing need and demand in healthcare globally and stagnant or decreasing healthcare resources. Implementation of value-based healthcare could address many important challenges in health care systems worldwide. Scaling up exemplary high value care practices offers the potential to ensure values-driven maternal and newborn care for all women and babies. DISCUSSION: Increased use of healthcare interventions over the last century have been associated with reductions in maternal and newborn mortality and morbidity. However, over an optimum threshold, these are associated with increases in adverse effects and inappropriate use of scarce resources. The Quality Maternal and Newborn Care framework provides an example of what value based maternity care might look like. To deliver value based maternal and newborn care, a system-level shift is needed, 'from fragmented care focused on identification and treatment of pathology for the minority to skilled care for all'. Ideally, resources would be allocated at population and individual level to ensure care is woman-centred instead of institution/ profession centred but oftentimes, the drivers for spending resources are 'the demands and beliefs of the acute sector'. We argue that decisions to allocate resources to high value activities, such as continuity of carer, need to be made at the macro level in the knowledge that these investments will relieve pressure on acute services while also ensuring the delivery of appropriate and high value care in the long run. To ensure that high value preventive and supportive care can be delivered, it is important that separate staff and money are allocated to, for example, models of continuity of carer to prevent shortages of resources due to rising demands of the acute services. To achieve value based maternal and newborn care, mechanisms are needed to ensure adequate resource allocation to high value maternity care activities that should be separate from the resource demands of acute maternity services. Funding arrangements should support, where wanted and needed, seamless movement of women and neonates between systems of care.

Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis.

Sporadic inclusion body myositis has a significant impact on the life of the elderly. Despite some similarities to other myopathies with established genetic defects, little is known about mechanisms of its development and no effective treatment is available. Therefore, there is a need for animal models that can faithfully reconstitute important aspects of this human disease. The authors recently expressed a mutant form of human gelsolin in mice under the control of a muscle-specific promoter. This induced myopathic changes reminiscent of human inclusion body myositis. In this study, immunogold labeling is used to further characterize this model. The study demonstrates a presence of gelsolin amyloid deposits within the rough endoplasmic reticulum. It further compares this mouse model to human sporadic inclusion body myositis.

FOXO4 is necessary for neural differentiation of human embryonic stem cells.

Proteostasis is critical for maintaining cell function and proteome stability may play an important role in human embryonic stem cell (hESC) immortality. Notably, hESC populations exhibit a high assembly of active proteasomes, a key node of the proteostasis network. FOXO4, an insulin/IGF-1 responsive transcription factor, regulates proteasome activity in hESCs. We find that loss of FOXO4 reduces the potential of hESCs to differentiate into neural lineages. Therefore, FOXO4 crosses evolutionary boundaries and links hESC function to invertebrate longevity modulation.

Increased proteasome activity in human embryonic stem cells is regulated by PSMD11.

Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention.

Protein misassembly into aggregate structures, including cross-ß-sheet amyloid fibrils, is linked to diseases characterized by the degeneration of post-mitotic tissue. While amyloid fibril deposition in the extracellular space certainly disrupts cellular and tissue architecture late in the course of amyloid diseases, strong genetic, pathological and pharmacologic evidence suggests that the process of amyloid fibril formation itself, known as amyloidogenesis, likely causes these maladies. It seems that the formation of oligomeric aggregates during the amyloidogenesis process causes the proteotoxicity and cytotoxicity characteristic of these disorders. Herein, we review what is known about the genetics, biochemistry and pathology of familial amyloidosis of Finnish type (FAF) or gelsolin amyloidosis. Briefly, autosomal dominant D187N or D187Y mutations compromise Ca(2+) binding in domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations. When domain 2 is unfolded, gelsolin is subject to aberrant furin endoproteolysis as it passes through the Golgi on its way to the extracellular space. The resulting C-terminal 68 kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin. These amyloidogenic fragments deposit systemically, causing a variety of symptoms including corneal lattice dystrophy and neurodegeneration. The first murine model of the disease recapitulates the aberrant processing of mutant plasma gelsolin, amyloid deposition, and the degenerative phenotype. We use what we have learned from our biochemical studies, as well as insight from mouse and human pathology to propose therapeutic strategies that may halt the progression of FAF.