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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 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.

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?

Abstract Forensic case samples collected in sexual assaults typically contain DNA from multiple sources, which complicates short‐tandem repeat (STR) profiling. These samples are typically sent to a laboratory to separate the DNA from sperm and non‐sperm sources prior to analysis. Here, the automation and miniaturization of these steps using digital microfluidics (DMF) is reported, which may eventually enable processing sexual assault samples outside of the laboratory, at the point of need. When applied to vaginal swab samples collected up to 12 h post‐coitus (PC), the new method identifies single‐source (male) STR profiles. When applied to samples collected 24–72 h PC, the method identifies mixed STR profiles, suggesting room for improvement and/or potential for data deconvolution. In sum, an automated, miniaturized sample pre‐processing method for separating the DNA contained in sexual assault samples is demonstrated. This type of automated processing using DMF, especially when combined with Rapid DNA Analysis, has the potential to be used for processing of sexual assault samples in hospitals, police offices, and other locations outside of the laboratory.

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.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Abstract Today, many social groups face negative stereotypes. Is such negativity a stable feature of society and, if so, what mechanisms maintain stability both within and across group targets? Answering these theoretically and practically important questions requires data on dozens of group stereotypes examined simultaneously over historical and societal scales, which is only possible through recent advances in Natural Language Processing. Across two studies, we use word embeddings from millions of English-language books over 100 years (1900–2000) and extract stereotypes for 58 stigmatized groups. Study 1 examines aggregate, societal-level trends in stereotype negativity by averaging across these groups. Results reveal striking persistence in aggregate negativity (no meaningful slope), suggesting that society maintains a stable level of negative stereotypes. Study 2 introduces and tests a new framework identifying potential mechanisms upholding stereotype negativity over time. We find evidence of two key sources of this aggregate persistence: within-group “reproducibility” (e.g., stereotype negativity can be maintained by using different traits with the same underlying meaning) and across-group “replacement” (e.g., negativity from one group is transferred to other related groups). These findings provide novel historical evidence of mechanisms upholding stigmatization in society and raise new questions regarding the possibility of future stigma change.

Abstract Background Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC. Methods A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants. Discussion Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections. Ethics and dissemination Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences. Trial registration Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Abstract Background Pneumothorax can cause distressing breathlessness, however the effect of the accumulated air in the pleural space and its association with diaphragmatic function and symptoms of breathlessness is not well understood. Bendopnoea is an evolving clinical symptom that has been demonstrated as clinically useful in some heart and lung conditions. Whether bendopnoea is present in patients with pneumothorax, and its potential clinical usefulness has not yet been investigated. The PASE study is a pilot study to explore the incidence and clinical relevance of bendopnoea in patients with pneumothorax and may provide better understanding of pneumothorax related dyspnoea. Methods PASE is a prospective study. Eligible patients are assessed at baseline (pre air drainage/lung reinflation) and in patients whose pneumothorax resolves once the lung has re‐expanded (post conservative management or air drainage procedure). Outcome measures include the incidence of bendopnoea, correlation of the associated symptoms (pain and breathlessness) to the severity of bendopnoea and the size of pneumothorax; and correlation with clinical outcome (i.e., response to air drainage/lung reinflation). The study will recruit 50 participants. Discussion This is the first study to explore bendopnoea in patients with pneumothorax. The presence and significance of bendopnoea in relation to clinical and physiological parameters in patients with pneumothorax requires investigation. The findings of this study may further current understanding of dyspnoea related pneumothorax. Trial Registration Name of the registry: Australia New Zealand Clinical Trial Registry Trial registration number: ACTRN12623001109695p. URL of the trial registry record for this trial: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386631&isReview=true Date of registration: Registered on 24 October 2023. Funding of the trial: This study has not received grant support. The study is sponsored by the Institute for Respiratory Health, a not‐for‐profit organisation. Name and contact information for the trial sponsor: Mr Bi Lam; Finance manager. Level 2, 6 Verdun Street, Nedlands, WA 6009. Role of sponsor: The funder is not involved in the planning of the study, gathering, analysing, and interpreting the data, or in preparing the manuscript. Protocol version: 1.

A heavily impacted river basin (Caudal River, NW Spain) by Hg and Cu mining activities, abandoned decades ago, was used to evaluate the environmental quality of their river sediments. The obtained results compared with reference values established by the US EPA and the Canadian Council of Ministers of the Environment for river sediments, have shown that the main elements of environmental concern are arsenic (As), mercury (Hg) and, to a lesser extent, copper (Cu), which reach concentrations up to 1080, 80 and 54 mg kg−1, respectively. To understand the role that river sediments play in terms of risk to ecosystem health, a comparison has been made between the total content of metal(oid)s in the sediments and the bioavailable contents of the same elements in pore water, passive DGT (Diffusive Gradients in Thin films) samplers and the sediment extractant using acetic acid. A good correlation between the As and Cu contents in the DGTs and the pore water was found, resulting in a transfer from the pore water to the DGT of at least 47 % of the Cu and more than 75 % of the As when the concentrations were low, with a deployment time of 4 days. When As and Cu concentrations were higher, their transfer was not so high (above 23.6 % for As and 19.3 % for Cu). The transfer of Hg from the pore water to the DGT was practically nil and does not seem to depend on the content of this metal. The fraction extracted with acetic acid, conventionally accepted as bioavailable, was clearly lower than that captured by DGTs for As and Cu (≤5 % and ≤8.5 % of the total amount, respectively), while it was similar for Hg (0.2 %).

Early detection of cancer will improve survival rates. The blood biomarker 5-hydroxymethylcytosine has been shown to discriminate cancer. In a large covariate-controlled study of over two thousand individual blood samples, we created, tested and explored the properties of a 5-hydroxymethylcytosine-based classifier to detect colorectal cancer (CRC). In an independent validation sample set, the classifier discriminated CRC samples from controls with an area under the receiver operating characteristic curve (AUC) of 90% (95% CI [87, 93]). Sensitivity was 55% at 95% specificity. Performance was similar for early stage 1 (AUC 89%; 95% CI [83, 94]) and late stage 4 CRC (AUC 94%; 95% CI [89, 98]). The classifier could detect CRC even when the proportion of tumor DNA in blood was undetectable by other methods. Expanding the classifier to include information about cell-free DNA fragment size and abundance across the genome led to gains in sensitivity (63% at 95% specificity), with similar overall performance (AUC 91%; 95% CI [89, 94]). We confirm that 5-hydroxymethylcytosine can be used to detect CRC, even in early-stage disease. Therefore, the inclusion of 5-hydroxymethylcytosine in multianalyte testing could improve sensitivity for the detection of early-stage cancer.

Abstract Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

Water vapour in the upper troposphere and lower stratosphere (UTLS) is a key radiative agent and a crucial factor in the Earth's climate system. Here, we investigate a common regional moist bias in the Pacific UTLS during Northern Hemisphere summer in state-of-the-art climate models. We demonstrate, through a combination of climate model experiments and satellite observations, that the Pacific moist bias amplifies local long-wave cooling, which ultimately impacts regional circulation systems in the UTLS. Related impacts involve a strengthening of isentropic potential vorticity gradients, strengthened westerlies in the Pacific westerly duct region, and a zonally displaced anticyclonic monsoon circulation. Furthermore, we show that the regional Pacific moist bias can be significantly reduced by applying a Lagrangian, less-diffusive transport scheme and that such a model improvement could be important for improving the simulation of regional circulation systems, in particular in the Asian monsoon and Pacific region.

Antimicrobial resistance (AMR) has emerged as a global health threat, necessitating immediate actions to develop novel antimicrobial strategies and enforce strong stewardship of existing antibiotics to manage the emergence of drug-resistant strains. This issue is particularly concerning when it comes to Gram-negative bacteria, which possess an almost impenetrable outer membrane (OM) that acts as a formidable barrier to existing antimicrobial compounds. This OM is an asymmetric structure, composed of various components that confer stability, fluidity, and integrity to the bacterial cell. The maintenance and restoration of membrane integrity are regulated by envelope stress response systems (ESRs), which monitor its assembly and detect damages caused by external insults. Bacterial communities encounter a wide range of environmental niches to which they must respond and adapt for survival, sustenance, and virulence. ESRs play crucial roles in coordinating the expression of virulence factors, adaptive physiological behaviors, and antibiotic resistance determinants. Given their role in regulating bacterial cell physiology and maintaining membrane homeostasis, ESRs present promising targets for drug development. Considering numerous studies highlighting the involvement of ESRs in virulence, antibiotic resistance, and alternative resistance mechanisms in pathogens, this review aims to present these systems as potential drug targets, thereby encouraging further research in this direction.

Participants in biomonitoring studies who receive personal exposure reports seek information to reduce exposures. Many chemical exposures are driven by systems-level policies rather than individual actions; therefore, change requires engagement in collective action. Participants' perceptions of collective action and use of report-back to support engagement remain unclear. We conducted virtual focus groups during summer 2020 in a diverse group of peripartum people from cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program (N = 18). We assessed baseline exposure and collective action experience, and report-back preferences. Participants were motivated to protect the health of their families and communities despite significant time and cognitive burdens. They requested time-conscious tactics and accessible information to enable action to reduce individual and collective exposures. Participant input informed the design of digital report-back in the cohorts. This study highlights opportunities to shift responsibility from individuals to policymakers to reduce chemical exposures at the systems level.

Muscarinic acetylcholine receptors are prototypical G protein-coupled receptors (GPCRs), members of a large family of 7 transmembrane receptors mediating a wide variety of extracellular signals. We show here, in cultured cells and in a murine model, that the carboxyl terminal fragment of the muscarinic M2 receptor, comprising the transmembrane regions 6 and 7 (M2tail), is expressed by virtue of an internal ribosome entry site localized in the third intracellular loop. Single-cell imaging and import in isolated yeast mitochondria reveals that M2tail, whose expression is up-regulated in cells undergoing integrated stress response, does not follow the normal route to the plasma membrane, but is almost exclusively sorted to the mitochondria inner membrane: here, it controls oxygen consumption, cell proliferation, and the formation of reactive oxygen species (ROS) by reducing oxidative phosphorylation. Crispr/Cas9 editing of the key methionine where cap-independent translation begins in human-induced pluripotent stem cells (hiPSCs), reveals the physiological role of this process in influencing cell proliferation and oxygen consumption at the endogenous level. The expression of the C-terminal domain of a GPCR, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism notably unrelated to its canonical signaling function as a GPCR at the plasma membrane. This work thus highlights a potential novel mechanism that cells may use for controlling their metabolism under variable environmental conditions, notably as a negative regulator of cell respiration.

Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.

BackgroundEndocrine disrupting chemicals have harmful effects on reproductive, perinatal, and obstetric outcomes.ObjectiveTo analyze the evidence on nutritional interventions to reduce the negative effects of endocrine disruptors on reproductive, perinatal, and obstetric outcomes.Search strategyA search of MEDLINE (PubMed), Allied Health Literature (CINAHL), EMBASE, Web of Science, and the Cochrane Database was conducted from inception to May 2021.Selection criteriaExperimental studies on human populations.Data collection and analysisData were collected from eligible studies. Risk of bias assessment was completed using the Cochrane risk of bias tool and the ROBINS-I Tool.ResultsDatabase searches yielded 15 362 articles. Removing 11 181 duplicates, 4181 articles underwent abstract screening, 26 articles were eligible for full manuscript review, and 16 met full inclusion criteria. Several interventions were found to be effective in reducing exposure to endocrine disruptors: avoidance of plastic containers, bottles, and packaging; avoidance of canned food/beverages; consumption of fresh and organic food; avoidance of fast/processed foods; and supplementation with vitamin C, iodine, and folic acid. There were some interventional studies examining therapies to improve clinical outcomes related to endocrine disruptors.ConclusionDietary alterations can reduce exposure to endocrine disruptors, with limited data on interventions to improve endocrine-disruptor-related clinical outcomes. This review provides useful instruction to women, their families, healthcare providers, and regulatory bodies.

Abstract Background There is a large population of restless legs syndrome (RLS) patients who are refractory to medication. Whereas experts recommend off-label opioids as an effective long-term treatment for refractory RLS, reducing opioid dose could substantially reduce side effects and risks. Tonic motor activation (TOMAC) is a nonpharmacological therapeutic device indicated for refractory RLS. Here, we investigated if TOMAC could enable opioid dose reduction for refractory RLS. Methods This prospective, open-label, single-arm clinical trial [NCT04698343] enrolled 20 adults taking ≤ 60 morphine milligram equivalents (MMEs) per day for refractory RLS. Participants self-administered 30-min TOMAC sessions bilaterally over the peroneal nerve when RLS symptoms presented. During TOMAC treatment, opioid dose was reduced iteratively every 2–3 weeks until Clinician Global Impression of Improvement (CGI-I) score relative to baseline exceeded 5. Primary endpoint was percent of participants who successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Secondary endpoints included mean successful percent opioid dose reduction with CGI-I ≤ 5. Results On average, participants were refractory to 3.2 medications (SD 1.6) and were taking a stable dose of opioids for 5.3 years (SD 3.9). Seventy percent of participants (70%, 14 of 20) successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Mean percent opioid dose reduction with CGI-I ≤ 5 was 29.9% (SD 23.7%, n = 20) from 39.0 to 26.8 MME per day. Mean CGI-I score at the reduced dose was 4.0 (SD 1.4), indicating no change to RLS severity. Conclusions For refractory RLS, TOMAC enabled substantial opioid dose reduction without increased RLS symptoms. These results suggest that TOMAC has the potential to reduce the risk profile associated with opioid therapy for refractory RLS. Trial registration ClinicalTrials.gov trial number NCT04698343 registered on January 6, 2021.

Abstract Introduction Biocrust cyanobacteria have a large potential as biofertilizers for restoring degraded ecosystems because of their ability to improve soil nutrition and stabilisation, and to produce metabolites such as phytohormones to enhance plant growth. However, important aspects regarding the effects of cyanobacteria on native plants, such as metabolite production or concentration of inoculants, remain unknown. Here, we investigated the effects of different concentrations of cyanobacteria, on the germination and seedling growth of keystone plant species used in dryland restoration. We hypothesised that the studied inoculant would improve germination and seedling growth rates, with specific effects associated with the inoculant's concentration and metabolomic profiles. Methods We bioprimed seeds of four native plant species, using a cyanobacterial inoculant with different proportions of Nostoc and Leptolyngbya at two different concentrations. We recorded germination, measured seedling growth, and determined the corrected vigour for each treatment and species. Metabolites produced by the cyanobacterial inoculant were assessed to identify plant growth hormones potentially driving any effects. Results There was a clear positive effect on the total germination of Triodia epactia and Triodia wiseana, but negative impacts for Senna notabilis and Grevillea wickhamii. There were also positive effects on root growth, but only for T. epactia, with negative or neutral impacts on the root and shoot growth of other species tested. We detected phytohormones, salicylic acid and indole‐3‐acetic acid, that were produced by our cyanobacteria inoculant, which are strongly linked to positive effects in early plant growth stages, but also known to inhibit growth when in higher concentrations. Conclusion The positive effects of the biopriming protocol used are not uniform and highlight the need to improve our understanding of the effects provided both from different consortia and the concentrations applied when inoculating. There is a very high value in improving restoration outcomes for native vegetation communities in arid and semi‐arid regions.

Abstract The indirect contribution of multiple sclerosis (MS) relapses to disability worsening outcomes, and vice-versa, remains unclear. Disease modifying therapies (DMTs) are potential modulators of this association. Understanding how these endo-phenotypes interact may provide insights into disease pathogenesis and treatment practice in relapse-onset MS (ROMS). Utilising a unique, prospectively collected clinical data from a longitudinal cohort of 279 first demyelinating event cases followed for up to 15 years post-onset, we examined indirect associations between relapses and treatment and the risk of disability worsening, and vice-versa. Indirect association parameters were estimated using joint models for longitudinal and survival data. Early relapses within 2.5 years of MS onset predicted early disability worsening outcomes (HR = 3.45, C.I 2.29–3.61) per relapse, but did not contribute to long-term disability worsening thereinafter (HR = 0.21, C.I 0.15–0.28). Conversely, disability worsening outcomes significantly contributed to relapse risk each year (HR = 2.96, C.I 2.91–3.02), and persisted over time (HR = 3.34, C.I 2.90–3.86), regardless of DMT treatments. The duration of DMTs significantly reduced the hazards of relapses (1st-line DMTs: HR = 0.68, C.I 0.58–0.79; 3rd-line DMTs: HR = 0.37, C.I 0.32–0.44) and disability worsening events (1st-line DMTs: HR = 0.74, C.I 0.69–0.79; 3rd-line DMTs: HR = 0.90, C.I 0.85–0.95), respectively. Results from time-dynamic survival probabilities further revealed individuals having higher risk of future relapses and disability worsening outcomes, respectively. The study provided evidence that in ROMS, relapses accrued within 2.5 years of MS onset are strong indicators of disability worsening outcomes, but late relapses accrued 2.5 years post onset are not overt risk factors for further disability worsening. In contrast, disability worsening outcomes are strong positive predictors of current and subsequent relapse risk. Long-term DMT use and older age strongly influence the individual outcomes and their associations.

Abstract Water vapor plays an important role in many aspects of the climate system, by affecting radiation, cloud formation, atmospheric chemistry and dynamics. Even the low stratospheric water vapor content provides an important climate feedback, but current climate models show a substantial moist bias in the lowermost stratosphere. Here we report crucial sensitivity of the atmospheric circulation in the stratosphere and troposphere to the abundance of water vapor in the lowermost stratosphere. We show from a mechanistic climate model experiment and inter-model variability that lowermost stratospheric water vapor decreases local temperatures, and thereby causes an upward and poleward shift of subtropical jets, a strengthening of the stratospheric circulation, a poleward shift of the tropospheric eddy-driven jet and regional climate impacts. The mechanistic model experiment in combination with atmospheric observations further shows that the prevailing moist bias in current models is likely caused by the transport scheme, and can be alleviated by employing a less diffusive Lagrangian scheme. The related effects on atmospheric circulation are of similar magnitude as climate change effects. Hence, lowermost stratospheric water vapor exerts a first order effect on atmospheric circulation and improving its representation in models offers promising prospects for future research.

Abstract Objectives To evaluate the Versius surgical system for robot‐assisted prostatectomy in a preclinical cadaveric model using varying system setups and collect surgeon feedback on the performance of the system and instruments, in line with IDEAL‐D recommendations. Materials and methods Procedures were performed in cadaveric specimens by consultant urological surgeons to evaluate system performance in completing the surgical steps required for a prostatectomy. Procedures were conducted using either a 3‐arm or 4‐arm bedside unit (BSU) setup. Optimal port placements and BSU layouts were determined and surgeon feedback collected. Procedure success was defined as the satisfactory completion of all steps of the procedure, according to the operating surgeon. Results All four prostatectomies were successfully completed; two were completed with a 3‐arm BSU setup and two using a 4‐arm BSU setup. Small adjustments were made to the port and BSU positioning, according to surgeon preference, in order to complete the surgical steps. The surgeons noted some instrument difficulties with the Monopolar Curved Scissor tip and the Needle Holders, which were subsequently refined between the first and second sessions of the study, in line with surgeon feedback. Three cystectomies were also successfully completed, demonstrating the capability of the system to perform additional urological procedures. Conclusions This study provides a preclinical assessment of a next‐generation surgical robot for prostatectomies. All procedures were completed successfully, and port and BSU positions were validated, thus supporting the progression of the system to further clinical development according to the IDEAL‐D framework.

Abstract Africa's population is expected to triple by 2050, owing to rapid urbanisation and overall demographic trends. The combined pressures of urbanisation and climate change impact the ecosystem and the services it provides. As a result, additional dangers such as increased flooding, and environmental disruption have risen. Therefore, devising adaptive solutions to mitigate flood risk impacts while also building community resilience is needed. Evidence suggests that Nature‐based Solutions (NbS) can potentially alleviate floods and mitigate climate change impacts while also delivering other societal benefits. Despite rising NbS popularity following its recognition in the last decade, studies on its recognition in Africa remain limited. For this reason, this paper reviewed NbS studies conducted in East Africa (EA) to evaluate opportunities and barriers surrounding NbS adoption in EA. Academic literature published from January 2012 to May 2022 was reviewed using a comprehensive search of the SCOPUS database. Results show 14 papers have been published during the period, with the majority being post‐2020. In addition, the majority of the articles focused on cities and peri‐urban settlements, while public awareness, clear guidelines on performance monitoring, stakeholder inclusion, and diverse demonstration projects were highlighted as potential success factors for the adoption of NbS in EA.

Introduction Many people living with dementia experience sleep disturbance and there are no known effective treatments. Non-pharmacological treatment options should be the first-line sleep management. For family carers, relatives’ sleep disturbance leads to interruption of their sleep, low mood and breakdown of care. Our team developed and delivered DREAMS START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives), a multimodal non-pharmacological intervention, showing it to be feasible and acceptable. The aim of this randomised controlled trial is to establish whether DREAMS START is clinically cost-effective in reducing sleep disturbances in people living with dementia living at home compared with usual care.Methods and analysis We will recruit 370 participant dyads (people living with dementia and family carers) from memory services, community mental health teams and the Join Dementia Research Website in England. Those meeting inclusion criteria will be randomised (1:1) either to DREAMS START or to usual treatment. DREAMS START is a six-session (1 hour/session), manualised intervention delivered every 1–2 weeks by supervised, non-clinically trained graduates. Outcomes will be collected at baseline, 4 months and 8 months with the primary outcome being the Sleep Disorders Inventory score at 8 months. Secondary outcomes for the person with dementia (all proxy) include quality of life, daytime sleepiness, neuropsychiatric symptoms and cost-effectiveness. Secondary outcomes for the family carer include quality of life, sleep disturbance, mood, burden and service use and caring/work activity. Analyses will be intention-to-treat and we will conduct a process evaluation.Ethics and dissemination London—Camden & Kings Cross Ethics Committee (20/LO/0894) approved the study. We will disseminate our findings in high-impact peer-reviewed journals and at national and international conferences. This research has the potential to improve sleep and quality of life for people living with dementia and their carers, in a feasible and scalable intervention.Trial registration number ISRCTN13072268.

Objective: We sought to identify differentially expressed proteins in serum, plasma, and plaque samples of patients with carotid atherosclerotic lesions. Methods: We performed a systematic review of the proteomic profile of serum, plasma, and plaque samples of patients with carotid artery disease. We included full-length peer-reviewed studies of adult humans and reported them using PRISMA guidelines. The quality of the design and content of the articles included in the review was assessed using the Newcastle-Ottawa scale. Results: We included six peer-reviewed articles reporting protein expression in serum, plasma, or plaque samples from patients with carotid atherosclerosis. Three were single-center cross-sectional studies, two were single-center case-control studies, and one was a single-center cohort study. Thirty-six proteins were found to be expressed differentially when comparing samples from healthy subjects and individuals with diseased carotid vessels and between patients with symptomatic and asymptomatic carotid artery atherosclerotic lesions. Some of these were shown to be related to inflammatory or anti-inflammatory pathways in atherogenesis. CD5L and S100A12 were both found to be upregulated in patients with unstable plaque, the former owing to its anti-inflammatory properties and the latter for its pro-oxidant effects in atherosclerosis. ACTB is involved in cellular structure and integrity and was found to be downregulated in patients with ruptured carotid plaques. Conclusions: Atherosclerotic carotid disease places the patient at increased risk of ischemic neurological events. Proteomics may help to understand their pathophysiological processes and can identify differential protein expression in blood samples from healthy subjects and patients with carotid artery plaques. This patient-centered approach will allow for the timely identification of individuals at higher risk of experiencing stroke.

Objectives Glaucoma care demand in UK hospitals has exploded in recent years. This has resulted in a push to community (shared, virtual, etc) care models to reduce the burden on hospital systems and on patients. The study aimed to ascertain patient’s experiences around various aspects of their care delivered in community clinics.Design Observational study.Setting Glaucoma Community Clinic, Cambridge, UK.Participants Ninety-six consecutive patients (M:F 47:49, mean age 70±12 years), recruited from July to September 2022.Outcome measures Patients completed a modified glaucoma patient-reported outcome and experience measure (POEM) regarding their clinic experience and perspective on their diagnosis, treatment and fear of blindness. Patient’s thoughts of feeling safe under the community clinical team were gathered. Patient demographics including age, gender, postcodes and education history were used to find their corresponding Lower-Layer Super Output Areas and socioeconomic status.Results Patients had positive perceptions of their clinic experience. Ninety-six per cent of patients reported that their experience of attending the community clinic was comfortable, and 93% (n=92) felt the experience was the same as expected from the hospital. Feeling safe under the clinician team produced a mean Visual Analogue Scale (VAS) score of 90 (SD 15) and feeling care was organised produced a mean VAS score of 87 (SD 17). Age, gender, disease characteristics and socioeconomic status had no influence on perceived experience. Patients aged