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Modeling the extension of ovarian function after therapeutic targeting of the primordial follicle reserve
Get PDFBACKGROUNDWomen are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or ‘boost’, the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan.OBJECTIVE AND RATIONALEIn this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated.SEARCH METHODSCurrent methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified.OUTCOMESWe review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause.WIDER IMPLICATIONSExtending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal
Characteristics of people with severe mental illness excluded from incentivised physical health checks in the UK:An electronic healthcare record study
Get PDFBackgroundIn the UK, financial incentivisation for physical health checks in primary care for people with severe mental illness (SMI; schizophrenia; bipolar disorder; non-organic psychosis) aims to reduce physical health inequalities. Patients who decline (explicitly or through repeated non-response to invites) or who are deemed unsuitable for screening are removed from the denominator that is used to calculate incentivisation, a process termed exception reporting. AimsWe aimed to describe the prevalence of exception reporting in patients with SMI and to identify patient characteristics associated with being exception reported.MethodsWe identified adult patients with SMI from the UK Clinical Practice Research Datalink (CPRD) registered with a GP between 2004 and 2018. We calculated the annual prevalence of exception reporting overall and stratified by reason for being exception reported. We investigated the patient characteristics associated with exception reporting using logistic regression. ResultsOf 193,850 patients with SMI, 27.7% were exception reported from physical health checks at least once. Of these, 50.8% were deemed unsuitable and 56.4% did not respond or declined screening (informed dissent) at least once. The proportion of exception reporting due to informed dissent increased over the study period. Patients of Asian or Black ethnicity (compared to White: OR:0.72; 95%CI: 0.65-0.80 and 0.86; 95%CI:0.76-0.97) and females (OR:0.90; 95%CI:0.88-0.92) had a reduced odds of being exception reported; while patients diagnosed with ‘other psychoses’ (compared to bipolar disorder: OR:1.19, 95%CI:1.15-1.23) had increased odds of being exception reported. Associations differed by reason for exception reporting, with younger patients and those with a diagnosis of schizophrenia more likely to be exception reported due to informed dissent.ConclusionsException reporting from physical health checks was common in people with SMI. Interventions are required to improve accessibility and uptake of physical health checks in order to improve physical health in people with SMI.<br/
Consensus recommendations for measuring the impact of contraception on the menstrual cycle in contraceptive clinical trials
No full textObjective: We sought to develop consensus recommendations for measurement and analysis of data on contraceptive-induced menstrual changes (CIMCs) in contraceptive clinical trials. We built upon previous standardization efforts over the last 50 years and prioritized input from a variety of global experts and current regulatory authority guidance on patient-reported outcomes. Study design: We completed a formal consensus-building process with an interdisciplinary group of 57 experts from 30 organizations and 14 countries in five global regions who work across academia, nonprofit research organizations, the pharmaceutical industry, and funding agencies. Smaller topical working groups drafted and revised recommendations. Results: We developed 44 consensus recommendations, including research approaches to establish the evidence for future improvement in the measurement and analysis of CIMC data and guidance for investigators to implement presently. Priority recommendations call for simplification of terminology to make measurement accessible and patient-centered, accounting for intrinsic and extrinsic factors that may impact outcomes during study design and recruitment, standardized data collection of primary CIMC and acceptability outcomes, and harmonized approaches for analysis of these data, including addressing missing data. Conclusion: By virtually convening a large group of global experts working across disciplines and sectors via a formal methodology, we developed consensus recommendations that will improve the current and future measurement and analysis of CIMC data in contraceptive clinical trials. Using these standardized approaches will permit valid and reliable contraceptive product labeling on CIMC outcomes that matter to users and greater comparability across trials that can inform clinical guidance and contraceptive counseling. Implications: Consensus recommendations on measuring bleeding changes and related outcomes in contraceptive clinical trials can improve reporting of standardized, patient-centered outcomes in future product labeling. These improvements can enable healthcare providers to offer more relevant guidance on contraceptives and users to make more informed decisions about their choice of method.</p
Nanopore sequencing reveals that DNA replication compartmentalisation dictates genome stability and instability in Trypanosoma brucei
No full textThe Trypanosoma brucei genome is structurally complex. Eleven megabase-sized chromosomes each comprise a transcribed core flanked by silent subtelomeres, housing thousands of Variant Surface Glycoprotein (VSG) genes. Additionally, hundreds of sub-megabase chromosomes contain 177 bp repeats of unknown function, and VSG transcription sites localise to many telomeres. DNA replication dynamics have only been described in the megabase chromosome cores, and in the single active VSG transcription site. Using a Nanopore genome assembly, we show that megabase chromosome subtelomeres display a paucity of replication initiation events relative to the core, correlating with increased instability. In addition, replication of the active VSG transcription site is shown to originate from the telomere, likely causing targeted VSG recombination. Lastly, we provide evidence that the 177 bp repeats act as conserved DNA replication origins, explaining submegabase chromosome stability. Compartmentalized DNA replication therefore explains how T. brucei balances stable genome transmission with localised instability driving immune evasion
Digital healing:Metadata and documentation for health web archives
No full textThe Archive of Tomorrow project (2022–2023), funded by Wellcome, focused on archiving health-related discourse on the internet. This collaborative effort across multiple institutions contributed to the UK Web Archive and explored ways to make the collection more accessible to both digital researchers and the wider public. The project also focused on the concept of treating web archives collections as data. This paper examines the documentation required to enable such collections to be utilised as data, particularly through the creation of the Datasheet for Datasets and the Data Foundry project, aiming to help make web archives machine-readable.The paper discusses the type of data and support archivists provided to researchers while navigating legal restrictions. It also highlights challenges in processing the data to ensure it is accessible to a non-technical audience, addressing the difficulties in scaling and handling sensitive health-related content.Finally, the paper outlines work on the processing pipeline required to make the material accessible to a broader audience, emphasising that providing datasets and documentation alone is insufficient. It also raises concerns about the paradox of turning initially unstructured web content into structured datasets for both archival and user interaction purposes. This project contributes to understanding how web archives can be transformed for greater accessibility and research usability
International intellectual property law as applicable law in investment disputes
No full textSeveral aspects of the interface between international intellectual property law and international investment law have been examined in the existing literature. Nevertheless, an underexplored issue that is yet to receive the attention it deserves concerns the role of international intellectual property law as applicable law in investment disputes involving intellectual property rights. This note therefore seeks to fill this lacuna in the existing literature. In this regard, the focus of this note is exclusively on the role of international intellectual property law as applicable law in investment disputes especially in investment disputes that involve intellectual property rights. Thus, the role of international intellectual property law as a relevant rule of international law for the purposes of the interpretation of an investment treaty is not addressed in this note as that is quite distinct from the role of international intellectual property law as applicable law in investment disputes. Section II of the note examines the role of general international law as applicable law in investment disputes. Section III focuses on the specific issue of the role of international intellectual property law as applicable law in investment disputes. Section IV critically explores the implications of including international intellectual property law as part of the applicable law for the relationship between international intellectual property law and international investment law. Section V concludes the note
Forelimb reduction and digit loss were evolutionarily decoupled in oviraptorosaurian theropod dinosaurs
No full textTheropod forelimbs exhibit wide morphological disparity, from the elongated wings of birds to the diminutive arms of T. rex. A wealth of work has sought to understand the evolution of bird flight via arm elongation, but despite widespread occurrences of forelimb reduction and digit loss throughout theropod dinosaurs, the evolutionary drivers behind these patterns are poorly understood. Previous studies demonstrate broad allometric trends that can account for some instances of forelimb reduction, but the repeated loss of digits, and their hypothesized link to forelimb shortening, has received less attention. Here, we evaluate evolutionary associations between digit loss and forelimb reduction in an iconic and data-rich theropod clade, Oviraptorosauria. Unexpectedly, we find that the evolution of digit III and the rest of the forelimb are decoupled. Support for different evolutionary models and a lower phylogenetic signal in digit III than the rest of the forelimb suggests these segments were subject to different evolutionary processes leading to independent morphological change. Oviraptorosaurs exhibit four distinct forelimb morphotypes, but these do not exactly correspond to patterns of dietary niche partitioning. Overall, forelimb evolution in oviraptorosaurs is more complex than anticipated, potentially as a result of an evolutionary radiation they underwent in the Late Cretaceous
Global Carbon Budget 2024
No full textAccurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize datasets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC) are based on land-use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The global net uptake of CO2 by the ocean (SOCEAN, called the ocean sink) is estimated with global ocean biogeochemistry models and observation-based fCO2 products (fCO2 is the fugacity of CO2). The global net uptake of CO2 by the land (SLAND, called the land sink) is estimated with dynamic global vegetation models. Additional lines of evidence on land and ocean sinks are provided by atmospheric inversions, atmospheric oxygen measurements, and Earth system models. The sum of all sources and sinks results in the carbon budget imbalance (BIM), a measure of imperfect data and incomplete understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ
A Developmental Gene Expression Atlas Reveals Novel Biological Basis of Complex Phenotypes in Sheep
No full textSheep (Ovis aries) represent one of the most important livestock species for global animal protein and wool production. However, little is known about the genetic and biological basis of ovine phenotypes, particularly those with high economic value and environmental impact. Here, by integrating 1413 RNA sequencing (RNA-seq) samples from 51 distinct tissues across 14 developmental time points, representing early-prenatal, late-prenatal, neonatal, lamb, juvenile, adult, and elderly stages, we constructed a high-resolution Developmental Gene Expression Atlas (dGEA) in sheep. We observed dynamic patterns of gene expression and regulatory networks across tissues and developmental stages. Leveraging this resource to interpret genetic associations for 48 monogenic and 12 complex traits in sheep, we found that genes upregulated at prenatal developmental stages played more important roles in shaping these phenotypes than those upregulated at postnatal stages. For instance, genetic associations of crimp number, mean staple length (MSL), and individual birthweight were significantly enriched in the prenatal rather than postnatal skin and immune tissues. By comprehensively integrating genome-wide association study (GWAS) fine-mapping results with the sheep dGEA, we identified several candidate genes for complex traits in sheep, such as SOX9 for MSL, GNRHR for litter size at birth, and PRKDC for live weight. These results provide novel insights into the developmental and molecular architecture of ovine phenotypes. The dGEA (https://sheepdgea.njau.edu.cn/) will serve as an invaluable resource for sheep developmental biology, genetics, genomics, and selective breeding.</p
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