Net benefit of smaller human populations to environmental integrity and individual health and wellbeing.

Introduction: The global human population is still growing such that our collective enterprise is driving environmental catastrophe. Despite a decline in average population growth rate, we are still experiencing the highest annual increase of global human population size in the history of our species-averaging an additional 84 million people per year since 1990. No review to date has accumulated the available evidence describing the associations between increasing population and environmental decline, nor solutions for mitigating the problems arising. Methods: We summarize the available evidence of the relationships between human population size and growth and environmental integrity, human prosperity and wellbeing, and climate change. We used PubMed, Google Scholar, and Web of Science to identify all relevant peer-reviewed and gray-literature sources examining the consequences of human population size and growth on the biosphere. We reviewed papers describing and quantifying the risks associated with population growth, especially relating to climate change. Results: These risks are global in scale, such as greenhouse-gas emissions, climate disruption, pollution, loss of biodiversity, and spread of disease-all potentially catastrophic for human standards of living, health, and general wellbeing. The trends increasing the risks of global population growth are country development, demographics, maternal education, access to family planning, and child and maternal health. Conclusion: Support for nations still going through a demographic transition is required to ensure progress occurs within planetary boundaries and promotes equity and human rights. Ensuring the wellbeing for all under this aim itself will lower population growth and further promote environmental sustainability.

How climate change degrades child health: A systematic review and meta-analysis.

BACKGROUND: Children are more vulnerable than adults to climate-related health threats, but reviews examining how climate change affects human health have been mainly descriptive and lack an assessment of the magnitude of health effects children face. This is the first systematic review and meta-analysis that identifies which climate-health relationships pose the greatest threats to children. OBJECTIVES: We reviewed epidemiologic studies to analyse various child health outcomes due to climate change and identify the relationships with the largest effect size. We identify population-specific risks and provide recommendations for future research. METHODS: We searched four large online databases for observational studies published up to 5 January 2023 following PRISMA (systematic review) guidelines. We evaluated each included study individually and aggregated relevant quantitative data. We used quantitative data in our meta-analysis, where we standardised effect sizes and compared them among different groupings of climate variables and health outcomes. RESULTS: Of 1301 articles we identified, 163 studies were eligible for analysis. We identified many relationships between climate change and child health, the strongest of which was increasing risk (60 % on average) of preterm birth from exposure to temperature extremes. Respiratory disease, mortality, and morbidity, among others, were also influenced by climate changes. The effects of different air pollutants on health outcomes were considerably smaller compared to temperature effects, but with most (16/20 = 80 %) pollutant studies indicating at least a weak effect. Most studies occurred in high-income regions, but we found no geographical clustering according to health outcome, climate variable, or magnitude of risk. The following factors were protective of climate-related child-health threats: (i) economic stability and strength, (ii) access to quality healthcare, (iii) adequate infrastructure, and (iv) food security. Threats to these services vary by local geographical, climate, and socio-economic conditions. Children will have increased prevalence of disease due to anthropogenic climate change, and our quantification of the impact of various aspects of climate change on child health can contribute to the planning of mitigation that will improve the health of current and future generations.

Gene dysregulation in acute HIV-1 infection - early transcriptomic analysis reveals the crucial biological functions affected.

Introduction: Transcriptomic analyses from early human immunodeficiency virus (HIV) infection have the potential to reveal how HIV causes widespread and lasting damage to biological functions, especially in the immune system. Previous studies have been limited by difficulties in obtaining early specimens. Methods: A hospital symptom-based screening approach was applied in a rural Mozambican setting to enrol patients with suspected acute HIV infection (Fiebig stage I-IV). Blood samples were collected from all those recruited, so that acute cases and contemporaneously recruited, uninfected controls were included. PBMC were isolated and sequenced using RNA-seq. Sample cellular composition was estimated from gene expression data. Differential gene expression analysis was completed, and correlations were determined between viral load and differential gene expression. Biological implications were examined using Cytoscape, gene set enrichment analysis, and enrichment mapping. Results: Twenty-nine HIV infected subjects one month from presentation and 46 uninfected controls were included in this study. Subjects with acute HIV infection demonstrated profound gene dysregulation, with 6131 (almost 13% of the genome mapped in this study) significantly differentially expressed. Viral load was correlated with 1.6% of dysregulated genes, in particular, highly upregulated genes involved in key cell cycle functions, were correlated with viremia. The most profoundly upregulated biological functions related to cell cycle regulation, in particular, CDCA7 may drive aberrant cell division, promoted by overexpressed E2F family proteins. Also upregulated were DNA repair and replication, microtubule and spindle organization, and immune activation and response. The interferome of acute HIV was characterized by broad activation of interferon-stimulated genes with antiviral functions, most notably IFI27 and OTOF. BCL2 downregulation alongside upregulation of several apoptotic trigger genes and downstream effectors may contribute to cycle arrest and apoptosis. Transmembrane protein 155 (TMEM155) was consistently highly overexpressed during acute infection, with roles hitherto unknown. Discussion: Our study contributes to a better understanding of the mechanisms of early HIV-induced immune damage. These findings have the potential to lead to new earlier interventions that improve outcomes.

Lower infant mortality, higher household size, and more access to contraception reduce fertility in low- and middle-income nations.

Although average contraceptive use has increased globally in recent decades, an estimated 222 million (26%) of women of child-bearing age worldwide face an unmet need for family planning-defined as a discrepancy between fertility preferences and contraception practice, or failing to translate desires to avoid pregnancy into preventative behaviours and practices. While many studies have reported relationships between availability/quality of contraception and family planning, infant mortality, and fertility, these relationships have not been evaluated quantitatively across a broad range of low- and middle-income countries. Using publicly available data from 64 low- and middle-income countries, we collated test and control variables in six themes: (i) availability of family planning, (ii) quality of family planning, (iii) female education, (iv) religion, (v) mortality, and (vi) socio-economic conditions. We predicted that higher nation-level availability/quality of family-planning services and female education reduce average fertility, whereas higher infant mortality, greater household size (a proxy for population density), and religious adherence increase it. Given the sample size, we first constructed general linear models to test for relationships between fertility and the variables from each theme, from which we retained those with the highest explanatory power within a final general linear model set to determine the partial correlation of dominant test variables. We also applied boosted regression trees, generalised least-squares models, and generalised linear mixed-effects models to account for non-linearity and spatial autocorrelation. On average among all countries, we found the strongest associations between fertility and infant mortality, household size, and access to any form of contraception. Higher infant mortality and household size increased fertility, whereas greater access to any form of contraception decreased fertility. Female education, home visitations by health workers, quality of family planning, and religious adherence all had weak, if any, explanatory power. Our models suggest that decreasing infant mortality, ensuring sufficient housing to reduce household size, and increasing access to contraception will have the greatest effect on decreasing global fertility. We thus provide new evidence that progressing the United Nation's Sustainable Development Goals for reducing infant mortality can be accelerated by increasing access to family planning.

HIV infection in Eastern and Southern Africa: Highest burden, largest challenges, greatest potential.

BACKGROUND: The burden of HIV is especially concerning for Eastern and Southern Africa (ESA), as despite expansion of test-and-treat programmes, this region continues to experience significant challenges resulting from high rates of morbidity, mortality and new infections. Hard-won lessons from programmes on the ground in ESA should be shared. OBJECTIVES: This report summarises relevant evidence and regional experts' recommendations regarding challenges specific to ESA. METHOD: This commentary includes an in-depth review of relevant literature, progress against global goals and consensus opinion from experts. RESULTS: Recommendations include priorities for essential research (surveillance data collection, key and vulnerable population education and testing, in-country testing trials and evidence-based support services to improve retention in care) as well as research that can accelerate progress towards the prevention of new infections and achieving ambitious global goals in ESA. CONCLUSION: The elimination of HIV in ESA will require continued investment, commitment to evidence-based programmes and persistence. Local research is critical to ensuring that responses in ESA are targeted, efficient and evaluated.

Vitamin D(3) deficiency enhances allergen-induced lymphocyte responses in a mouse model of allergic airway disease.

There is debate as to whether vitamin D deficiency contributes towards the extent of the asthma epidemic. In this study, using a mouse model, we determined whether vitamin D deficiency in utero and during early life modulated the severity of asthma. Using dietary restriction, vitamin D(3) -replete and vitamin D(3) -deficient colonies of BALB/c mice were established. Utilizing the allergic airway disease model of asthma with the experimental allergen ovalbumin (OVA), we examined asthma-like responses 24 h after airway challenge with OVA in adult offspring born to vitamin D(3) -replete and vitamin D(3) -deficient mothers. The ability of airway-draining lymph node cells to proliferate and secrete cytokines in response to OVA ex vivo was significantly enhanced by vitamin D(3) deficiency. However, other aspects of allergic disease, including the numbers and proportions of inflammatory cells and cytokines in the lungs and the quantity of OVA-specific IgE in serum, were not modified. These results suggest that vitamin D(3) deficiency modulates the capacity of lymphocytes to respond to allergens.

Topical 1,25-dihydroxyvitamin D3 subverts the priming ability of draining lymph node dendritic cells.

The active form of vitamin D, 1,25-hydroxyvitamin D(3) [1,25(OH)(2)D(3)] is produced in skin following exposure to sunlight. It is also used topically to control inflammatory skin diseases by stimulating keratinocyte differentiation and suppressing immune responses. Administration of 1,25(OH)(2)D(3) to the skin of mice increases the capacity of CD4(+) CD25(+) (Foxp3(+) ) regulatory T cells residing in the skin-draining lymph nodes (SDLN) to suppress immune responses. We hypothesized that dendritic cells (DC) may migrate from the skin to the lymph nodes to regulate T-cell function. Increased proportions of skin-derived DC (CD11c(+) ClassII(+) DEC-205(hi) CD8(lo)) cells were detected in the SDLN 18 hr after topical 1,25(OH(2) D(3) treatment of mouse skin. The capacity of DC from the SDLN to take up, process and present antigen to co-cultured T cells was not modified following topical 1,25(OH)(2)D(3). However, CD11c(+) cells from the SDLN of 1,25(OH)(2)D(3)-treated mice induced a significantly smaller ear-swelling response in a T helper type 1/17-mediated model of contact hypersensitivity. CD4(+) CD25(+) cells isolated from the ear-draining lymph nodes (EDLN) of mice that received ear injections of CD11c(+) cells from donor mice topically treated with 1,25(OH)(2)D(3) more potently suppressed effector cell proliferation. In addition, EDLN cells from recipients of CD11c(+) cells from 1,25(OH)(2)D(3)-treated mice produced increased interleukin-4 levels. The CD11c(+) cells from the SDLN of mice treated with topical 1,25(OH)(2)D(3) expressed increased levels of indoleamine 2,3-dioxygenase messenger RNA, a molecule by which topical 1,25(OH)(2)D(3) may enhance the ability of DC to control the suppressive function of CD4(+) CD25(+) cells.

Gene regulation by 1,25-dihydroxyvitamin D3 in CD4+CD25+ cells is enabled by IL-2.

Vitamin D may be responsible for reducing the development and severity of autoimmune and allergic diseases. Topically applied 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) enhances the immunoregulatory ability of CD4+CD25+ T cells residing in the skin-draining lymph nodes (SDLNs) of mice. The mechanisms responsible were investigated by examining the expression of 84 cytokine and cytokine-related genes in a 96-well gene array. CD4+CD25+ cells isolated from the SDLNs of BALB/c mice, 24 and 96 hours after topical treatment with 1,25(OH)(2)D(3), consistently expressed increased IL-2 mRNA levels and also secreted enhanced quantities of IL-2 after ex vivo stimulation with phorbol 12-myristate 13-acetate and ionomycin. CD4+CD25+ cells from the lymph nodes of naive mice constitutively express the vitamin D receptor, allowing direct modulation by 1,25(OH)(2)D(3). However, in vitro treatment with 1,25(OH)(2)D(3) did not modify the expression of 84 tested cytokine and cytokine-related mRNAs. It was only in the presence of IL-2 that 1,25(OH)(2)D(3) increased the expression of genes including IL-2 and TLR4. Further, 1,25(OH)(2)D(3) enhanced the ability of IL-2 to stimulate CD4+CD25+ cells to proliferate in vitro and also regulate contact hypersensitivity responses on adoptive transfer into naive mice. Therefore, 1,25(OH)(2)D(3) enabled by IL-2 can directly enhance the regulatory potential of CD4+CD25+ T cells to control immune disease.

Immune-modifying properties of topical vitamin D: Focus on dendritic cells and T cells.

Topical creams containing the active form of vitamin D (1,25-dihydroxyvitamin D3; 1,25(OH)2D3) or analogues of this compound are currently used with some success to treat skin conditions including psoriasis and vitiligo. As well as targeting inflammatory processes in the skin, topical application of 1,25(OH)2D3 also affects the function of immune cells in the skin and draining lymph nodes. Topically applied 1,25(OH)2D3 reduces the number of dendritic cells in the skin, resulting in suppressed immunity and in particular reduced contact hypersensitivity (CHS) responses. Topical 1,25(OH)2D3 may also promote the migration of dendritic cells from the skin to the draining lymph nodes. Skin application of 1,25(OH)2D3 prevented the inflammatory effects of UVB irradiation on lymph node hypertrophy, when cell numbers were examined 4 days after skin treatment. In contrast, when 1,25(OH)2D3 was applied to UVB irradiated skin, there was no reversal in the suppression of CHS responses caused by UVB irradiation. Instead, 1,25(OH)2D3 had an additive effect with UVB to suppress CHS responses to a greater degree than UVB alone. In these studies, 1,25(OH)2D3 was applied to the treated skin of BALB/c mice immediately following UVB irradiation. Finally, topical 1,25(OH)2D3 also enhanced the number and suppressive activity of CD4+CD25+ regulatory T cells in the lymphatic tissue draining skin.

1,25-dihydroxyvitamin D3 enhances the ability of transferred CD4+ CD25+ cells to modulate T helper type 2-driven asthmatic responses.

The severity of allergic diseases may be modified by vitamin D. However, the immune pathways modulated by the active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], are yet to be fully elucidated. In this study, naturally occurring CD4(+) CD25(+) cells from the skin-draining lymph nodes (SDLN) of mice treated with topical 1,25(OH)(2)D(3) had an increased ability to suppress T helper type 2 (Th2) -skewed immune responses. CD4(+) CD25(+) cells transferred from mice treated with topical 1,25(OH)(2)D(3) into ovalbumin (OVA) -sensitized mice challenged intranasally with OVA 18 hr later, significantly suppressed the capacity of airway-draining lymph node (ADLN) cells to proliferate and secrete cytokines in response to further OVA stimulation ex vivo. The CD4(+) CD25(+) cells from 1,25(OH)(2)D(3)-treated mice also reduced airway hyperresponsiveness and the proportions of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF). To test the effect of 1,25(OH)(2)D(3) on cells able to respond to a specific antigen, CD4(+) CD25(+) cells were purified from the SDLN of OVA-T-cell receptor (TCR) transgenic mice treated 4 days earlier with topical 1,25(OH)(2)D(3). CD4(+) CD25(+) cells from OVA-TCR mice treated with 1,25(OH)(2)D(3) were able to alter BALF cell content and suppress ADLN responses to a similar degree to those cells from non-transgenic mice, suggesting that the effect of 1,25(OH)(2)D(3) was not related to TCR signalling. In summary, topical 1,25(OH)(2)D(3) increased the regulatory capacity of CD4(+) CD25(+) cells from the SDLN to suppress Th2-mediated allergic airway disease. This work highlights how local 1,25(OH)(2)D(3) production by lung epithelial cells may modulate the suppressive activity of local regulatory T cells.

Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes.

The immunomodulatory effects of vitamin D have been described following chronic oral administration to mice or supplementation of cell cultures with 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D. In this study, topically applied 1,25(OH)(2)D(3), enhanced the suppressive capacity of CD4(+)CD25(+) cells from the draining lymph nodes. The effects of topical 1,25(OH)(2)D(3) were compared with those of UVB irradiation, which is the environmental factor required for 1,25(OH)(2)D(3) production in skin. CD4(+) cells from the skin-draining lymph nodes (SDLN) of either 1,25(OH)(2)D(3)-treated or UVB-irradiated mice had reduced capacity to proliferate to Ags presented in vitro, and could suppress Ag-specific immune responses upon adoptive transfer into naive mice. This regulation was lost upon removal of CD4(+)CD25(+) cells. Furthermore, purified CD4(+)CD25(+) cells from the SDLN of 1,25(OH)(2)D(3)-treated or UVB-irradiated mice compared with equal numbers of CD4(+)CD25(+) cells from control mice had increased capacity to suppress immune responses in both in vitro and in vivo assay systems. Following the sensitization of recipient mice with OVA, the proportion of CD4(+)Foxp3(+) cells of donor origin significantly increased in recipients of CD4(+)CD25(+) cells from the SDLN of 1,25(OH)(2)D(3)-treated mice, indicating that these regulatory T cells can expand in vivo with antigenic stimulation. These studies suggest that 1,25(OH)(2)D(3) may be an important mediator by which UVB-irradiation exerts some of its immunomodulatory effects.