Assessing the effects of population-level political, economic and social exposures, interventions and policies on inclusive economy outcomes for health equity in high-income countries: a systematic review of reviews.

BACKGROUND: A fairer economy is increasingly recognised as crucial for tackling widening social, economic and health inequalities within society. However, which actions have been evaluated for their impact on inclusive economy outcomes is yet unknown. OBJECTIVE: Identify the effects of political, economic and social exposures, interventions and policies on inclusive economy (IE) outcomes in high-income countries, by systematically reviewing the review-level evidence. METHODS: We conducted a review of reviews; searching databases (May 2020) EconLit, Web of Science, Sociological Abstracts, ASSIA, International Bibliography of the Social Sciences, Public Health Database, Embase and MEDLINE; and registries PROSPERO, Campbell Collaboration and EPPI Centre (February 2021) and grey literature (August/September 2020). We aimed to identify reviews which examined social, political and/or economic exposures, interventions and policies in relation to two IE outcome domains: (i) equitable distribution of the benefits of the economy and (ii) equitable access to the resources needed to participate in the economy. Reviews had to include primary studies which compared IE outcomes within or between groups. Quality was assessed using a modified version of AMSTAR-2 and data synthesised informed by SWiM principles. RESULTS: We identified 19 reviews for inclusion, most of which were low quality, as was the underlying primary evidence. Most reviews (n = 14) had outcomes relating to the benefits of the economy (rather than access to resources) and examined a limited set of interventions, primarily active labour market programmes and social security. There was limited high-quality review evidence to draw upon to identify effects on IE outcomes. Most reviews focused on disadvantaged groups and did not consider equity impacts. CONCLUSIONS: Review-level evidence is sparse and focuses on 'corrective' approaches. Future reviews should examine a diverse set of 'upstream' actions intended to be inclusive 'by design' and consider a wider range of outcomes, with particular attention to socioeconomic inequalities.

What is the potential for plural ownership to support a more inclusive economy? A systematic review protocol.

BACKGROUND: The world is facing an unprecedented systemic shock to population health, the economy and society due to the devastating impact of the COVID-19 pandemic. As with most economic shocks, this is expected to disproportionately impact vulnerable groups in society such as those in poverty and those in precarious employment as well as marginalised groups such as women, the elderly, Black, Asian and Minority Ethnic (BAME) groups and those with health conditions. The current literature is rich in normative recommendations on plural ownership as a key building block of an inclusive economy rooted in communities and their needs. There is, however, a need for a rigorous synthesis of the available evidence on what impact (if any) plural ownership may potentially have on the inclusivity of the economy. This review seeks to synthesise and compare the available evidence across the three economic sectors (private, public and third). METHODS: We will search eight bibliographic databases (Sociological abstracts, EBSCO Econlit, OVID Embase, OVID Medline, Applied Social Sciences Index and Abstracts (ASSIA), ProQuest Public Health, Web of Science, Research Papers in Economics (Repec) - EconPapers) from the earliest data available in each database until January 2021. Grey literature will be identified from Google (advanced), Google Scholar and 37 organisational websites identified as relevant to the research question. We will include comparative studies of plural ownership from high-income countries that report outcomes on access to opportunities, distribution of benefits, poverty, and discrimination. A bespoke search strategy will be used for each website to account for the heterogeneity in content and search capabilities and will be fully documented. A standardised data extraction template based on the Population-Intervention-Context-Outcome (PICO) template will be developed. We will assess the strength of evidence for different forms of economic ownership identified in relation to the impact of each on the four economic outcomes of interest, paying particular attention to the role of wider contextual factors as they emerge through the evidence. DISCUSSION: The findings of this review are intended to inform policymaking at local, national and international level that prioritises and supports the development of different economic and business models. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework registration DOI: https://doi.org/10.17605/OSF.IO/BYH5A.

Knowing the goal: an inclusive economy that can address the public health challenges of our time.

OBJECTIVE: Inequality is deeply embedded in our economic structures-it is necessary to address these economic inequalities if we are to reduce health inequalities. An inclusive economic approach was conceptualised as a way to reduce these economic inequalities, although the attributes of this approach are unclear. Public health practitioners are increasingly asked to provide a health perspective on the economic recovery plans in the light of the COVID-19 pandemic. This paper aims to identify the attributes of an inclusive economy to enable the public health profession to influence an inclusive economic recovery. APPROACH: We conducted a rapid review of grey and peer-reviewed literature to identify the attributes of an inclusive economy as currently defined in the literature. ATTRIBUTES OF AN INCLUSIVE ECONOMY: Twenty-two concepts were identified from 56 reports and articles. These were collapsed into four distinct attributes of an inclusive economy: (1) an economy that is designed to deliver inclusion and equity, (2) equitable distribution of the benefits from the economy (eg, assets, power, value), (3) equitable access to the resources needed to participate in the economy (eg, health, education), and (4) the economy operates within planetary boundaries. CONCLUSION: As economies are (re)built following the COVID-19 pandemic, these attributes of an inclusive economy-based on the current literature-can be used to develop, and then monitor progress of, economic policy that will reduce health inequalities, improve health and mitigate against climate change.

Cloning of oestrogen receptor beta from Old and New World primates: identification of splice variants and functional analysis.

Oestrogens have a major impact on reproductive function in both males and females. Two oestrogen receptor genes known as ERalpha (ESR1NR3A1) and ERbeta (ESR2NR3A2) have been cloned. Splice variant isoforms of the ERbeta gene have been identified in human, bovine and rodents and it has been suggested that the existence of these forms can influence oestrogen responsiveness. In the human, splicing of an alternative eighth exon results in the formation of a C-terminal variant called hERbetacx, or hERbeta2, but this isoform has not been identified in other species. The aim of the present study was to clone ERbeta cDNAs from primates so as to determine how closely they resembled the ERbeta isoforms found in the human. The two species studied were the stump-tailed macaque (Macaca arctoides), an Old World primate, and the common marmoset (Callithrix jacchus jacchus), a New World primate. Full length ERbeta (wild type, ERbeta1) cDNAs were cloned from macaque and marmoset; they encoded proteins of similar size to those found in human (59 and 54 kDa, long and short forms respectively) and shared significant sequence homology (97.5% in macaque and 93.8% in marmoset) with the human peptide sequence. Full length cDNAs homologous to the hERbeta2 variant were identified in both primates. Marmoset ERbeta2 was slightly shorter than that of human ERbeta2 (54 kDa compared with 55 kDa) and did not contain the peptide sequence used to raise an anti-hERbeta2 antibody. All the macaque ERbeta2 cDNAs contained 56 bp of intronic sequence which included an in-frame stop codon resulting in translation of a truncated protein ( approximately 35 kDa). In all three species, truncated, alternatively spliced mRNAs lacking exon 5 were isolated on multiple occasions from all tissue extracts. In transient transfection assays, ERbeta2-containing constructs were unable to induce transcription of an oestrogen response element (ERE) reporter plasmid in the presence of oestradiol. ERbeta1 from human, macaque and marmoset exhibited minor differences in their ability to induce transcription of the ERE reporter when incubated with different ligands (oestradiol, PPT, DPN, 5-alpha-androstane-3-beta, 17beta-diol (3betaAdiol), genistein) and this may be due to amino acid substitutions within their ligand binding domains. In conclusion, we have identified and cloned wild type ERbeta (ERbeta1) from macaque and marmoset and demonstrated that splice variant mRNAs homologous to hERbeta2 are formed in both species. The marmoset monkey, therefore, provides a suitable animal model in which to investigate the impact of ERbeta variant expression on tissue responsiveness to oestrogens.

Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation.

Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC. One mutation, Y399X, resulted in a premature stop codon and was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin. The second, L297P, was a missense mutation, and human chorionic gonadotropin responsiveness was maintained. Kindred analysis established that the mutations had been inherited from the proband's mothers. The L297P has not been described previously and occurs within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity. Immunohistochemical analysis of testicular tissue obtained from an affected sibling of the subject with the Y399X mutation, who had died with adrenal failure as a neonate, showed normal testicular morphology and expression of DAX-1, steroidogenic factor-1, and anti-Mullerian hormone protein. These data extend the clinical and molecular information on DAX-1 mutations, confirm normal testicular development at the neonatal stage, and illustrate variability in Leydig cell function.

Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle.

Estrogen action is mediated via two subtypes of the estrogen receptor (ER), usually referred to as ERalpha and ERbeta. We have previously compared the spatial and temporal expressions of ERalpha and ERbeta proteins in human endometrium and reported that endothelial cells exclusively express ERbeta. In the present study we have extended our investigations to compare the pattern of expression of wild-type (ERbeta1) and a newly identified ERbeta variant isoform (ERbetacx/beta2) that lacks the ability to bind steroids. mRNAs encoding both ERbeta1 and ERbetacx/beta2 receptors were identified in human endometrial extracts by RT-PCR. Quantitative TaqMan R-TPCR demonstrated that levels of total mRNAs were increased significantly premenstrually as circulating progesterone levels declined. ERbeta1 and ERbetacx/beta2 proteins were identified within multiple cell types within the endometrium using isotype-specific monoclonal antibodies; immunoexpression of ERbetacx/beta2 appeared less intense than that of ERbeta1 in endometrial glandular epithelium and endothelial cells. Immunoexpression of ERbeta1 appeared unchanged throughout the menstrual cycle. In contrast, levels of ERbetacx/beta2-specific immunoreactivity were specifically reduced in gland cells within the functional layer, but not in those of the basal layer, in the midsecretory phase. It is possible that coexpression of ERbetacx/beta2 in cells containing ERbeta1 and/or ERalpha may modulate the effects of estrogens on the endometrium.

Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants.

Two structurally related subtypes of oestrogen receptor (ER), known as alpha (ER alpha, NR3A1) and beta (ER beta, NR3A2) have been identified. ER beta mRNA and protein have been detected in a wide range of tissues including the vasculature, bone, and gonads in both males and females, as well as in cancers of the breast and prostate. In many tissues the pattern of expression of ER beta is distinct from that of ER alpha. A number of variant isoforms of the wild type beta receptor (ER beta 1), have been identified. In the human these include: (1). use of alternative start sites within the mRNA leading to translation of either a long (530 amino acids, hER beta 1L) or a truncated form (487aa hER beta 1s); (2). deletion of exons by alternative splicing; (3). formation of several isoforms (ER beta 2-beta 5) due to alternative splicing of exons encoding the carboxy terminus (F domain). We have raised monoclonal antibodies specific for hER beta1 as well as to three of the C terminal isoforms (beta2, beta 4 and beta 5). Using these antibodies we have found that ER beta 2, beta 4 and beta 5 proteins are expressed in nuclei of human tissues including the ovary, placenta, testis and vas deferens. In conclusion, in addition to the differential expression of full length ER alpha and ER beta a number of ER variant isoforms have been identified. The impact of the expression of these isoforms on cell responsiveness to oestrogens may add additional complexity to the ways in which oestrogenic ligands influence cell function.

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis.

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has been identified in testicular cDNA libraries by two laboratories. The present study examined the expression of wild-type (ERbeta1) and variant (ERbeta2) beta receptors in human testes by 1) RT-PCR with isoform specific primers, and 2) single and double immunohistochemistry using monoclonal antibodies raised against peptides unique to the C termini of hERbeta1 and hERbeta2. PCR products specific for ERbeta1 and ERbeta2 were amplified from cDNA pools prepared from human testes and granulosa cells. On Western blots, the anti-ERbeta1 monoclonal antibody bound to recombinant ERbeta1 and the anti-ERbeta2 monoclonal to recombinant hERbeta2. Neither bound to the other ERbeta isoform nor to recombinant ERalpha. ERbeta1 and ERbeta2 proteins were both detected in human testis. Immunoexpression of ERbeta1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ERbeta2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ERbeta2 than ERbeta1. It is speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ERbeta1 are high. In contrast, expression of ERbeta2, an isoform that may act as a dominant negative inhibitor of ER action, in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.