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Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO is among the most expensive media components. To address this challenge, we develop highly optimized small molecule-inducible synthetic EPO receptors (synEPORs) using design-build-test cycles and genome editing. By integrating synEPOR at the endogenous EPOR locus in O-negative induced pluripotent stem cells, we achieve equivalent erythroid differentiation, transcriptomic changes, and hemoglobin production using small molecules compared to EPO-supplemented cultures. This approach dramatically reduces culture media costs. Our strategy not only addresses RBC production challenges but also demonstrates how protein and genome engineering can introduce precisely regulated cellular behaviors, potentially improving scalable manufacturing of a wide range of clinically relevant cell types.

Some gene polymorphisms can lead to monogenic diseases, whereas other polymorphisms may confer beneficial traits. A well-characterized example is congenital erythrocytosis-the non-pathogenic hyper-production of red blood cells-that is caused by a truncated erythropoietin receptor. Here we show that Cas9-mediated genome editing in CD34+ human haematopoietic stem and progenitor cells (HSPCs) can recreate the truncated form of the erythropoietin receptor, leading to substantial increases in erythropoietic output. We also show that combining the expression of the cDNA of a truncated erythropoietin receptor with a previously reported genome-editing strategy to fully replace the HBA1 gene with an HBB transgene in HSPCs (to restore normal haemoglobin production in cells with a β-thalassaemia phenotype) gives the edited HSPCs and the healthy red blood cell phenotype a proliferative advantage. Combining knowledge of human genetics with precise genome editing to insert natural human variants into therapeutic cells may facilitate safer and more effective genome-editing therapies for patients with genetic diseases.

Abstract Background Atrial fibrillation is a common cardiac arrhythmia, associated with debilitating symptoms and a decrease in health-related quality of life. Current treatments for atrial fibrillation may not provide symptomatic relief and are associated with risks and adverse responses. Large-scale trials are justified to investigate whether complementary therapies may improve symptoms and/or health-related quality of life in atrial fibrillation. To reduce the uncertainty of a future trial, a feasibility study was carried out. Design and methods A three-arm, parallel-group, pragmatic randomised controlled feasibility study recruited 30 participants with paroxysmal AF aged 45–70 from NHS primary care, randomising to Group A (acupuncture + usual care), Group B (nutritional therapy + usual care) or Group C (usual care alone) using a 2:2:1 allocation ratio in favour of the interventions. Interventions were delivered by private practitioners. Seven feasibility objectives were investigated, including participants’ willingness to take part, appropriateness of eligibility criteria, participant retention and acceptability of interventions and study assessments. Additional exploratory feasibility objectives were investigated, including the effect of the COVID-19 pandemic and the safety of interventions. Data was analysed using descriptive statistics and reflexive thematic analysis, and the study used a sequential convergent mixed methods design to understand whether, and why, objectives were feasible and to make recommendations for a future trial. Results Five feasibility objectives’ progression criteria were met, one did not meet its progression threshold and one was abandoned as infeasible to analyse but did not affect feasibility. Recommendations for a future trial include changes in eligibility criteria to reflect real-world populations and changes to assessment methods to reduce participant burden. Uncertainty remains around the effect on the feasibility of reversion to pre-COVID therapy and study assessment delivery, including a recommended longer follow-up. Conclusion A future large-scale trial was found to be feasible with adjustments, but some uncertainty remains. Trial registration ISRCTN13671984. Registered on June 04, 2020.

Abstract Background The flea beetle Omophoita octoguttata (Coleoptera, Chrysomelidae) is a member of a group in which the males completely lack meiotic recombination (male-specific achiasmy) and that have extraordinarily large X and Y chromosomes. We combined genome sequencing, including microdissected Y and X chromosomes, and cytogenetic in situ hybridization studies, to evaluate the potential role of satellite DNAs (satDNAs) in the differentiation of those gigantic sex chromosomes. Results We report flow cytometry results showing that this species has a very large genome size (estimated to be 4.61 and 5.47 pg, or roughly 4.6 and 5.5 gigabases, for males and females, respectively), higher than the estimates from two other Alticinae species without giant sex chromosomes, suggesting that these sequences have greatly expanded on both the sex chromosomes, and that the Y has not greatly shrunk like the ones of other insects such as Drosophila with male achiasmy. About 68% of this large genome is made up of repetitive DNAs. Satellite DNAs (OocSatDNAs) form ~ 8–9% of their genomes, and we estimate how much of the sex chromosome expansions occurred due to differential amplification of different satellite classes. Analysis of divergence between sequences in the X and Y chromosomes suggests that, during the past roughly 20 mya, different OocSatDNAs amplified independently, leading to different representations. Some are specific to the Y or X chromosome, as expected when males are achiasmate, completely preventing genetic exchanges between the Y and X.

A recent paper found that the sex chromosomes of the crested ibis have more gametolog pairs than many other birds. This Comment discusses that this finding suggets that WZ recombination stopped independently in the sex chromosomes in different bird lineages.

Abstract Background An ongoing challenge with rare diseases is limited data and, consequently, limited knowledge about the collective prevalence and impact of these conditions on individuals, families, and the health system, particularly in rural and regional areas. Using existing datasets, this project aimed to examine the epidemiology of and hospital activity for Tasmanians with rare diseases. Methods Rare diseases were defined as non-infectious diseases with a prevalence of less than 1 in 2000. An initial resource set of 1028 ICD-10-AM diagnostic codes was used to identify a cohort of Tasmanians with rare diseases in Tasmanian Health datasets (1 January 2007 until 31 December 2020). Validating the resource set using a small group with known rare diseases revealed limitations in ascertainment, and so an expanded set of 1940 ICD-10-AM diagnostic codes was developed by cross-referencing ICD-10-AM codes with Orphanet data. Cohort hospital activity and admission costs were compared to statewide data for the final year of the study, 01 January 2020 to 31 December 2020. Results Using the resource set of 1028 ICD-10-AM diagnostic codes, the period prevalence of rare diseases in Tasmania across all age groups was estimated at 3.5%, with a point prevalence of 1.5% in December 2020. In 2020, 3384 individuals within the Tasmanian rare disease cohort, representing 0.6% of the Tasmanian population, accessed the public hospital system and accounted for 5.6% of all admissions. The mean length of stay for rare disease-related hospital admissions was 5.0 days, compared to 3.3 days for non-rare disease-related admissions. The mean cost per admission for the rare disease cohort was AUD$11,310, compared to AUD$6475 for all admissions statewide. In 2020, using the expanded resource set, the total cost of public hospital admissions in Tasmania was estimated to be AUD$979 million, with rare disease-related hospital admissions accounting for 9.1% of this cost, increasing to 19.0% when the costs for all admissions for the rare disease patients were included. Conclusions Patients with rare diseases had more admissions, longer length of stay, and a higher average cost per admission. Patients with rare diseases have a disproportionate impact on statewide hospital activity and costs in Tasmania.

BackgroundAeromedical transfer of patients with ischemic stroke to access hyperacute stroke treatment is becoming increasingly common. Little is known about how rapid changes of altitude and atmospheric pressure can impact cerebral perfusion and ischemic burden. In patients with ischemic stroke, there is a theoretical possibility that this physiologic response of hypoxia-driven hyperventilation at higher altitude can lead to a relative drop in PaCO2. This would ultimately result in cerebral vasoconstriction, and therefore worsening of the ischemic burden in patients with ischemic stroke. Currently, there are no specific recommendations in stroke guidelines for optimizing altitude of aeromedical transportation to minimize the rate of ischemic burden. In this scoping review, we aim to map the available literature that addressed whether PaCO2 changes with altitude. This would be the steppingstone for more in-depth analyses into the cerebral autoregulatory consequences of high altitude on cerebral ischemia to form future guidelines.Methods and analysisWe will follow scoping review methods recommended by the Joanna Briggs Institute. Electronic databases MEDLINE, Embase, Web of Science, and Cochrane Central Register of Systematic will be systematically searched to identify articles that report on the acute response of PaCO2 on acute change in altitude. Two independent investigators will perform duplicate title and abstract screening and full-text review, followed by duplicate data extraction. We will present quantitative data using descriptive statistics. Key textual information will be synthesized in a tabular format Simple statistics on the frequency of papers, data will be presented via histogram.Ethics and disseminationThis scoping review does not require ethical approval. The results of our scoping review will be published in academic medical journals and presented at medical conferences. The findings will highlight the current availability of literature on PaCO2 changes with altitude.RegistrationThis scoping review protocol has been registered in Open Science Framework (DOI 10.17605/OSF.IO/UVK83).

Deteriorating water quality poses a substantial risk to human health, with billions at risk of waterborne diseases due to contamination. Insufficient water quality data augment risks as conventional monitoring methods lack comprehensive coverage. Technologies like the Internet of Things and machine learning offer real-time water quality monitoring and classification. IoT nodes often provide point data insufficient for monitoring the quality of entire water bodies. Remote sensing, though useful, has limitations such as measuring only optically active parameters and being affected by climate and resolution issues. To address these challenges, an unmanned surface vehicle named `AquaDrone' has been developed. AquaDrone traverses water bodies, collecting data of four key parameters (pH, dissolved oxygen, electrical conductivity, and temperature) along with GPS coordinates. The data is transmitted to a web portal via LoRa communication and Wi-Fi, where visualizations like data tables, trendlines and color-coded heatmaps are generated. A multilayer perceptron classifies water quality into five categories, aiding in real-time classification. A comparative analysis of various oversampling techniques has been conducted in the context of water quality classification. The AquaDrone offers a feasible solution for monitoring quality of small to medium-sized water bodies, crucial for safeguarding public health. HIGHLIGHTS AquaDrone measures four physicochemical parameters of water along with GPS coordinates to monitor water quality in real-time.; A multilayer perceptron classifies water quality into five categories, with oversampling used to enhance model training.; AquaDrone wirelessly transmits data to the web portal, where trendlines, data table and a color-coded heatmap are generated to visualize water quality.; This ensures effective real-time monitoring in small to medium-sized water bodies, protecting both water sources and human health.;

Whatever the nature of the contemporary climate crisis, its status has become an aspect of global politics. Whether the nature of this necessity is natural or political is the question. The idea of natural necessity is driving the political necessity of the acceptance of a range of frameworks concerning governance. The climate is being symbolically represented via powerful institutional agencies carrying out a labor of legitimation. How will this affect the ground of public existence?

Integrating spatial inequality perspectives in strategic decision-making can ensure positive impacts on resource distribution for public welfare and sustainable development. This study aims to apply evidence-based approaches in deploying permanent deacons. The empirical case study has been conducted at the St Helens denary of the Liverpool archdiocese, UK. Assisting with charitable works is one of three served areas by the Roman Catholic Church facilitated by deacons. The deployment of permanent deacons could benefit from being evidence-based so that a deacon can serve to ease the socio-economic (e.g., population density, long-term health conditions, housing system, employment status, education level, social status) inequality in the most deprived area. We used geographic information system (GIS) based algorithms, Getis-Ord Gi* for hot spot analysis to find the clustered area by considering the socio-economic factors. The open/freely available government census dataset was found to help extract socio-economic parameters. Furthermore, a GIS-based multi-criteria assessment technique was conducted by applying map algebra (raster calculator) to identify the deprived area with ranks considering multiple socio-economic conditions, where served areas by the existing deacons were considered to constrain. The served areas were estimated by applying network analysis where OpenStreetMap and location existing deacons were used as input. Our empirical case study identified the central and northern parts of the deanery as the most and least deprived areas, respectively. Finally, Liverpool archdiocese could consider deploying new permanent deacons in St Helens denary based on suggested deprivation ranks. Therefore, the appropriate number of deacons in the deprived areas can quickly and effectively respond to the needy and enhance communities’ resilience and sustainable development by ensuring proportionate resource distribution.