| 1. |
- Micah, Angela E., et al.
(författare)
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Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
- 2021
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
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Forskningsöversikt (refereegranskat)abstract
- Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 2. |
- Adhikari, Deepak, et al.
(författare)
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Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:11, s. 2476-2484
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.
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| 3. |
- Adhikari, Deepak, et al.
(författare)
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Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles
- 2009
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Ingår i: Molecular human reproduction. - : Oxford University Press. - 1360-9947 .- 1460-2407. ; 15:12, s. 765-770
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Tidskriftsartikel (refereegranskat)abstract
- To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.
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| 4. |
- Adhikari, Deepak
(författare)
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In Vitro Activation of Dormant Follicles for Fertility Preservation
- 2013
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Ingår i: Advances in Experimental Medicine and Biology. - New York : Springer. - 0065-2598. ; 761:Oocyte Biology in Fertility Preservation, s. 29-42
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in radiotherapy and chemotherapy have led to higher cure rates for female children and adolescents with cancer. However, these treatments adversely affect germ cell survival, and ovarian failure is thus a probable side effect of these anticancer therapies. Moreover, an increasing number of women are choosing to postpone childbearing until later in life, but their primordial follicle reserves degenerate with advancing age. Thus there is a pressing need for the development of fertility preservation methods for these individuals. Ovarian tissue cryopreservation prior to loss of the primordial follicle population either due to cancer treatments or normal aging is a promising option for safeguarding fertility. A complete in vitro maturation (IVM) system could help generate mature eggs for later use without the patient having to undergo the cumbersome process involved in current assisted reproduction methods to generate mature eggs. Cryopreserved ovarian cortical tissues have attracted the attention of reproductive biologists and clinicians because of the large number of safely frozen primordial follicles in them, and it is theoretically possible to use these follicles for in vitro activation (IVA) and subsequent IVM. Ovarian tissue collection is independent of patient age and social or personal conditions. Despite being widely accepted potential techniques for fertility preservation, IVA and IVM of human primordial follicles to obtain fertilizable eggs remains far from reality. This chapter highlights the current achievements and obstacles in obtaining growing follicles through activation of dormant follicles.
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| 5. |
- Adhikari, Deepak, et al.
(författare)
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Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan
- 2016
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Ingår i: Cell Research. - : Springer Science and Business Media LLC. - 1001-0602 .- 1748-7838. ; 26, s. 1212-1225
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Tidskriftsartikel (refereegranskat)abstract
- © 2016 IBCB, SIBS, CAS. A unique feature of female germ cell development in mammals is their remarkably long arrest at the prophase of meiosis I, which lasts up to 50 years in humans. Both dormant and growing oocytes are arrested at prophase I and completely lack the ability to resume meiosis. Here, we show that the prolonged meiotic arrest of female germ cells is largely achieved via the inhibitory phosphorylation of Cdk1 (cyclin-dependent kinase 1). In two mouse models where we have introduced mutant Cdk1 T14AY15F which cannot be inhibited by phosphorylation (Cdk1AF) in small meiotically incompetent oocytes, the prophase I arrest is interrupted, leading to a premature loss of female germ cells. We show that in growing oocytes, Cdk1AF leads to premature resumption of meiosis with condensed chromosomes and germinal vesicle breakdown followed by oocyte death, whereas in dormant oocytes, Cdk1AF leads to oocyte death directly, and both situations damage the ovarian reserve that maintains the female reproductive lifespan, which should be around 1 year in mice. Furthermore, interruption of the inhibitory phosphorylation of Cdk1 results in DNA damage, which is accompanied by induction of the Chk2 (checkpoint kinase 2)-p53/p63-dependent cell death pathway, which eventually causes global oocyte death. Together, our data demonstrate that the phosphorylation-mediated suppression of Cdk1 activity is one of the crucial factors that maintain the lengthy prophase arrest in mammalian female germ cells, which is essential for preserving the germ cell pool and reproductive lifespan in female mammals.
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| 6. |
- Adhikari, Deepak, et al.
(författare)
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Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II.
- 2014
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 206:7, s. 843-853
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Tidskriftsartikel (refereegranskat)abstract
- In mitosis, the Greatwall kinase (called microtubule-associated serine/threonine kinase like [Mastl] in mammals) is essential for prometaphase entry or progression by suppressing protein phosphatase 2A (PP2A) activity. PP2A suppression in turn leads to high levels of Cdk1 substrate phosphorylation. We have used a mouse model with an oocyte-specific deletion of Mastl to show that Mastl-null oocytes resume meiosis I and reach metaphase I normally but that the onset and completion of anaphase I are delayed. Moreover, after the completion of meiosis I, Mastl-null oocytes failed to enter meiosis II (MII) because they reassembled a nuclear structure containing decondensed chromatin. Our results show that Mastl is required for the timely activation of anaphase-promoting complex/cyclosome to allow meiosis I exit and for the rapid rise of Cdk1 activity that is needed for the entry into MII in mouse oocytes.
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| 7. |
- Adhikari, Deepak, et al.
(författare)
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Molecular mechanisms underlying the activation of mammalian primordial follicles
- 2009
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 30:5, s. 438-464
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Tidskriftsartikel (refereegranskat)abstract
- In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.
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| 8. |
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| 9. |
- Adhikari, Deepak, et al.
(författare)
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Pharmacological Inhibition of mTORC1 Prevents Over-Activation of the Primordial Follicle Pool in Response to Elevated PI3K Signaling
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The majority of ovarian primordial follicles must be preserved in a quiescent state to allow for the regular production of gametes over the female reproductive lifespan. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Under certain pathological conditions, the entire pool of primordial follicles matures simultaneously leading to an accelerated loss of primordial follicles and to premature ovarian failure (POF). We have previously shown that loss of Pten (phosphatase and tensin homolog deleted on chromosome ten) in mouse oocytes leads to premature activation of the entire pool of primordial follicles, subsequent follicular depletion in early adulthood, and the onset of POF. Lack of PTEN leads to increased phosphatidylinositol 3-kinase (PI3K)-Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling in the oocytes. To study the functional and pathological roles of elevated mTORC1 signaling in the oocytes, we treated the Pten-mutant mice with the specific mTORC1 inhibitor rapamycin. When administered to Pten-deficient mice prior to the activation of the primordial follicles, rapamycin effectively prevented global follicular activation and preserved the ovarian reserve. These results provide a rationale for exploring the possible use of rapamycin as a drug for the preservation of the primordial follicle pool, and the possible prevention of POF.
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| 10. |
- Adhikari, Deepak, et al.
(författare)
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Regulation of quiescence and activation of oocyte growth in primordial follicles
- 2013
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Ingår i: Oogenesis. - London : Springer. - 9780857298263 - 9780857298256 ; , s. 49-62
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Bokkapitel (refereegranskat)abstract
- Once formed, the pool of dormant primordial follicles serves as the source of developing follicles and fertilizable ova for the duration of a female’s reproductive life. Depending upon the species, primordial follicles can remain quiescent for months, years, or even decades, and the highly regulated process of primordial follicle activation ensures the availability of growing follicles throughout the reproductive period. We have recently begun to elucidate the molecular mechanisms underlying the maintenance of follicular quiescence and the activation of primordial follicles, mainly through the use of genetically modified mouse models. Both overactivation as well as the failure of activation of primordial follicles can lead to pathological conditions such as premature ovarian failure (POF) in the experimental models. A thorough understanding of the underlying mechanisms that regulate quiescence and activation of oocyte growth in primordial follicles will have important biological and clinical implications. © Springer-Verlag London 2013.
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