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Abstract The Duke Criteria have shaped the way infectious endocarditis (IE) is diagnosed in the last 30 years. This study aims to evaluate their current validity and importance in the diagnostic of IE. A retrospective cohort study was conducted on 163 consecutive patients who presented at the University Hospital in Ulm (Germany) with clinical suspicion of IE between 2009 and 2019. With patients’ medical records we differentiated between definitive endocarditis (DIE), possible endocarditis (PIE) and rejected endocarditis (RIE) and assessed the validity of the Duke Criteria in comparison to the final discharge diagnosis. We then tried to identify new potential parameters as an addition to the current valid Duke Criteria. The validity of the Duke Criteria improves with the length of hospitalization (especially cardiac imaging criterion, RIE 33.3%, PIE 31.6% and DIE 41.9%, p = 0.622 at admission and RIE 53.3%, PIE 68.4%, DIE 92.2%, p

Abstract Population-scale genome modification can alter the composition or fate of wild populations. Synthetic gene drives provide one set of tools, but their use is complicated by scientific, regulatory, and social issues associated with transgene persistence and flow. Here we propose an alternative approach. An Allele Sail consists of a genome editor (the Wind) that introduces DNA sequence edits, and is inherited in a Mendelian fashion. Meanwhile, the edits (the Sail) experience an arithmetic, Super-Mendelian increase in frequency. We model this system and identify contexts in which a single, low frequency release of an editor brings edits to a very high frequency. We also identify conditions in which manipulation of sex determination can bring about population suppression. In regulatory frameworks that distinguish between transgenics (GMO) and their edited non-transgenic progeny (non-GMO) Allele Sails may prove useful since the spread and persistence of the GM component can be limited.

Abstract Renal fibrosis (RF) represents the most widespread pathological condition in chronic kidney disease (CKD). Recently, protein prenylation has been implicated in the fibrosis’s progression. The research examined the renoprotective effect of zoledronic acid (ZA) (50 µg/kg/week) in a rat model of carbon tetrachloride (CCl4)-induced RF through targeting protein prenylation. Forty Wistar male rats were split up into the control group, vehicle-treated group, model-RF group, and RF-ZA group. Mean arterial blood pressure (MBP), BUN, serum creatinine, and urine albumin–creatinine ratio (uACR), protein levels of farnesyl pyrophosphate (FPP), tumour necrosis factor-alpha (TNF-α), transforming growth factor-β (TGF-β), and malondialdehyde (MDA), and catalase and gene expression of farnesyl pyrophosphate synthase (FPPS) and nuclear factor-kB (NF-κB) were measured. Immunohistochemical staining for renal interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and caspase-3, as well as histopathological alterations, were assessed. ZA considerably ceased the reduction in MBP, markedly reduced uACR, serum creatinine, BUN, and expression of FPPS, FPP, NF-κB, TGF-β, TNF-α, and MDA, and significantly increased catalase levels compared to the model-RF rats. ZA ameliorated the CCl4-induced histopathological alterations and suppressed the expression of caspase-3, α-SMA, and IL-6. In conclusion, ZA preserved renal function and prevented renal fibrosis in a rat model. These were achieved through targeting protein prenylation mainly by inhibiting FPPS.

Abstract Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.

Abstract Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.

Abstract Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

Abstract Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk – specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males – while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

Abstract Head and neck cancer treatments, such as radiotherapy, chemotherapy, and surgery, have diverse effects on patients, leading to dysphagia as a significant post-treatment issue. This study aims to evaluate the effectiveness of the Arabic version of the EAT-10 screening instrument (A-EAT-10) using Fiber-Optic Endoscopic Evaluation of Swallowing (FEES) as an imperfect gold standard. Additionally, we seek to establish a correlation between A-EAT-10 and PEG tube insertion in head and neck cancer (HNC) patients. Our sample comprised 130 head and neck cancer patients with varying cancer types at King Hussein Cancer Center (KHCC). We followed these patients throughout their distinct treatment plans up to one month after their final treatment session. During follow-up visits, we administered the A-Eat-10 instrument to monitor dysphagia. FEES were conducted at the initial and concluding visits to compare results with A-EAT-10 scores. The results in our tests, assuming independence or dependence, demonstrated excellent agreement. A-EAT-10 exhibited outstanding predictive capabilities with an AUC ranging from 93 to 97%. A-EAT-10 tended to slightly overestimate dysphagia at later treatment stages by approximately 20% compared to FEES, with an RR of 1.2 (95% CI 0.91, 1.56, p-value = 0.21), indicating statistical insignificance. In conclusion, A-EAT-10 is an excellent option for dysphagia evaluation, offering non-invasive, straightforward, and cost-effective advantages compared to FEES. Its utility extends to predicting the need for PEG tube insertion at initial patient visits, making it a valuable tool for informed treatment decisions. Notably, A-EAT-10 demonstrates a diminishing correlation with FEES over time.

Abstract Giant viruses (Nucleocytoviricota) are significant lethality agents of various eukaryotic hosts. Although metagenomics indicates their ubiquitous distribution, available giant virus isolates are restricted to a very small number of protist and algal hosts. Here we report on the first viral isolate that replicates in the amoeboflagellate Naegleria. This genus comprises the notorious human pathogen Naegleria fowleri, the causative agent of the rare but fatal primary amoebic meningoencephalitis. We have elucidated the structure and infection cycle of this giant virus, Catovirus naegleriensis (a.k.a. Naegleriavirus, NiV), and show its unique adaptations to its Naegleria host using fluorescence in situ hybridization, electron microscopy, genomics, and proteomics. Naegleriavirus is only the fourth isolate of the highly diverse subfamily Klosneuvirinae, and like its relatives the NiV genome contains a large number of translation genes, but lacks transfer RNAs (tRNAs). NiV has acquired genes from its Naegleria host, which code for heat shock proteins and apoptosis inhibiting factors, presumably for host interactions. Notably, NiV infection was lethal to all Naegleria species tested, including the human pathogen N. fowleri. This study expands our experimental framework for investigating giant viruses and may help to better understand the basic biology of the human pathogen N. fowleri.

Abstract Directed evolution of computationally designed enzymes has provided new insights into the emergence of sophisticated catalytic sites in proteins. In this regard, we have recently shown that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita-Baylis-Hillman (MBH) reaction with unrivalled efficiency. Here, we show that replacing the catalytic histidine with a non-canonical N δ-methylhistidine (MeHis23) nucleophile leads to a substantially altered evolutionary outcome in which the catalytic Arg124 has been abandoned. Instead, Glu26 has emerged, which mediates a rate-limiting proton transfer step to deliver an enzyme (BHMeHis1.8) that is more than an order of magnitude more active than our earlier MBHase. Interestingly, although MeHis23 to His substitution in BHMeHis1.8 reduces activity by 4-fold, the resulting His containing variant is still a potent MBH biocatalyst. However, analysis of the BHMeHis1.8 evolutionary trajectory reveals that the MeHis nucleophile was crucial in the early stages of engineering to unlock the new mechanistic pathway. This study demonstrates how even subtle perturbations to key catalytic elements of designed enzymes can lead to vastly different evolutionary outcomes, resulting in new mechanistic solutions to complex chemical transformations.

Abstract Stable solid electrolytes are essential to high-safety and high-energy-density lithium batteries, especially for applications with high-voltage cathodes. In such conditions, solid electrolytes may experience severe oxidation, decomposition, and deactivation during charging at high voltages, leading to inadequate cycling performance and even cell failure. Here, we address the high-voltage limitation of halide solid electrolytes by introducing local lattice distortion to confine the distribution of Cl−, which effectively curbs kinetics of their oxidation. The confinement is realized by substituting In with multiple elements in Li3InCl6 to give a high-entropy Li2.75Y0.16Er0.16Yb0.16In0.25Zr0.25Cl6. Meanwhile, the lattice distortion promotes longer Li-Cl bonds, facilitating favorable activation of Li+. Our results show that this high-entropy halide electrolyte boosts the cycle stability of all-solid-state battery by 250% improvement over 500 cycles. In particular, the cell provides a higher discharge capacity of 185 mAh g−1 by increasing the charge cut-off voltage to 4.6 V at a small current rate of 0.2 C, which is more challenging to electrolytes|cathode stability. These findings deepen our understanding of high-entropy materials, advancing their use in energy-related applications.

Abstract Coral reefs are in global decline with coral diseases playing a significant role. This is especially true for Acroporid corals that represent ~25% of all Pacific coral species and generate much of the topographic complexity supporting reef biodiversity. Coral diseases are commonly sediment-associated and could be exacerbated by overharvest of sea cucumber detritivores that clean reef sediments and may suppress microbial pathogens as they feed. Here we show, via field manipulations in both French Polynesia and Palmyra Atoll, that historically overharvested sea cucumbers strongly suppress disease among corals in contact with benthic sediments. Sea cucumber removal increased tissue mortality of Acropora pulchra by ~370% and colony mortality by ~1500%. Additionally, farmerfish that kill Acropora pulchra bases to culture their algal gardens further suppress disease by separating corals from contact with the disease-causing sediment—functioning as mutualists rather than parasites despite killing coral bases. Historic overharvesting of sea cucumbers increases coral disease and threatens the persistence of tropical reefs. Enhancing sea cucumbers may enhance reef resilience by suppressing disease.

Abstract Chewing tobacco use poses serious health risks; yet it has not received as much attention as other tobacco-related products. This study synthesizes existing evidence regarding the health impacts of chewing tobacco while accounting for various sources of uncertainty. We conducted a systematic review and meta-analysis of chewing tobacco and seven health outcomes, drawing on 103 studies published from 1970 to 2023. We use a Burden of Proof meta-analysis to generate conservative risk estimates and find weak-to-moderate evidence that tobacco chewers have an increased risk of stroke, lip and oral cavity cancer, esophageal cancer, nasopharynx cancer, other pharynx cancer, and laryngeal cancer. We additionally find insufficient evidence of an association between chewing tobacco and ischemic heart disease. Our findings highlight a need for policy makers, researchers, and communities at risk to devote greater attention to chewing tobacco by both advancing tobacco control efforts and investing in strengthening the existing evidence base.

Abstract Drone-person tracking in uniform appearance crowds poses unique challenges due to the difficulty in distinguishing individuals with similar attire and multi-scale variations. To address this issue and facilitate the development of effective tracking algorithms, we present a novel dataset named D-PTUAC (Drone-Person Tracking in Uniform Appearance Crowd). The dataset comprises 138 sequences comprising over 121 K frames, each manually annotated with bounding boxes and attributes. During dataset creation, we carefully consider 18 challenging attributes encompassing a wide range of viewpoints and scene complexities. These attributes are annotated to facilitate the analysis of performance based on specific attributes. Extensive experiments are conducted using 44 state-of-the-art (SOTA) trackers, and the performance gap between the visual object trackers on existing benchmarks compared to our proposed dataset demonstrate the need for a dedicated end-to-end aerial visual object tracker that accounts the inherent properties of aerial environment.

Abstract The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.

Abstract The performance and dependability of distribution networks may be enhanced by the incorporation of microgrids (MGs). However, it is necessary to enhance low voltage fault-ride-through (LVFRT), which has the capacity to prevent abrupt grid disconnections during LV occurrences under problematic circumstances. In this study, a control strategy for energy storage elements (ESDs) which includes batteries and supercapacitors is proposed to enhance LVFRT under balanced and unbalanced faults. The MG comprises wind farms and/or photovoltaic arrays. Based on the dynamic simulations using MATLAB/SIMULINK, the ESDs can enhance LVFRT capability. A comparison of the conventional crowbar scheme and ESDs is realized, and the latter has a better performance than the former in retaining the DC-link voltage within satisfactory bounds. For the purpose of maintaining the DC-link voltage at a reference level, the battery stores extra power in the DC-bus of three systems. LVFRT is improved by the crowbar circuit, however the resistance consumes the extra power. Super capacitors (SCs) prevent DC voltage fluctuations, reduce active power oscillations, and hasten system stabilization when present. At an advanced stage of this effort, the coot bird optimizer (CBO) is applied to generate the best gains of bi-directional converter PI-controller and the ESDs ratings to have minimum ripples in the DC-bus voltage and to boost the LVFRT capability of the MGs. The viability of the proposed method based on the CBO’s results is indicated with further validations under different operating scenarios.

Abstract Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer’s vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase–soluble guanylate cyclase–cyclic GMP that is necessary for normal cilia motility and left-right patterning.

Abstract The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person’s relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person’s relative ability to clear SARS-CoV-2 infection that persists across sequential infections.

In recent years, the Ningbo Plain has experienced significant surface subsidence due to urbanization and industrialization, combined with the area’s unique geological and hydrological conditions. To study the surface subsidence and its causes in the Ningbo Plain, this study analyzed 166 scenes of Sentinel-1A SAR images between January 2018 and June 2023. The time series interferometric synthetic aperture radar (TS-InSAR) technique was used to acquire surface subsidence information in the area. The causes of subsidence were analyzed. The results show that: (1) the annual deformation rate of the Ningbo Plain ranges from −44 mm/yr to 12 mm/yr between 2018 and 2023. A total of 15 major subsidence zones were identified by using both the subsidence rate map and optical imagery. The most severe subsidence occurred in the northern industrial park of Cixi City, with a maximum subsidence rate of −37 mm/yr. The study reveals that the subsidence issue in the main urban area has been significantly improved compared to the 2017 subsidence data from the Ningbo Bureau of Natural Resources and Planning. However, three new subsidence areas have emerged in the main urban area, located, respectively, in Gaoqiao Town, Lishe Town, and Qiuyi Village, with maximum rates of −29 mm/year, −24 mm/year, and −23 mm/year, respectively. (2) The causes of subsidence were analyzed using various data, including land use data, geological data, groundwater-monitoring data, and transportation network data. It is found that a strong link exists between changes in groundwater levels, compressible layer thickness, and surface subsidence. The groundwater levels changes and the soft soil layer thickness are the main natural factors causing subsidence in the Ningbo Plain. Additionally, the interaction between static loads from large-scale industrial production and urban construction, along with the dynamic loads from transportation networks, contribute significantly to surface subsidence in the Ningbo Plain. The results from this study enhance the understanding of the driving factors of subsidence in the Ningbo Plain, which can provide necessary guidance for the economic development and decision-making in the region, helping to manage and potentially mitigate future subsidence issues.

BackgroundRespiratory tract infections are readily transmitted in care homes. Airborne transmission of pathogens causing respiratory tract illness is largely unmitigated. Portable high-efficiency-particulate-air (HEPA) filtration units capture microbial particles from the air, but it is unclear whether this is sufficient to reduce infections in care home residents. The Air Filtration to prevent symptomatic winter Respiratory Infections (including COVID-19) in care homes (AFRI-c) randomized controlled trial will determine whether using HEPA filtration units reduces respiratory infection episodes in care home residents.MethodsAFRI-c is a cluster randomized controlled trial that will be delivered in residential care homes for older people in England. Ninety-one care homes will be randomised to take part for one winter period. The intervention care homes will receive HEPA filtration units for use in communal areas and private bedrooms. Normal infection control measures will continue in all care homes. Anonymised daily data on symptoms will be collected for up to 30 residents. Ten to 12 of these residents will be invited to consent to a primary care medical notes review and (in intervention homes) to having an air filter switched on in their private room. The primary outcome will be number of symptomatic winter respiratory infection episodes. Secondary outcomes include specific clinical measures of infection, number of falls / near falls, number of laboratory confirmed infections, hospitalisations, staff sickness and cost-effectiveness. A mixed methods process evaluation will assess intervention acceptability and implementation.DiscussionThe results of AFRI-c will provide vital information about whether portable HEPA filtration units reduce symptomatic winter respiratory infections in older care home residents. Findings about effectiveness, fidelity, acceptability and cost-effectiveness will support stakeholders to determine the use of HEPA filtration units as part of infection control policies.

BackgroundThe symptom profiles of acute SARS-CoV-2 infection and long-COVID in children and young people (CYP), risk factors, and associated healthcare needs, are poorly defined. The Schools Infection Survey 1 (SIS-1) was a nationwide study of SARS-CoV-2 infection in primary and secondary schools in England during the 2020/21 school year. The Covid-19 Mapping and Mitigation in Schools (CoMMinS) study was conducted in schools in the Bristol area over a similar period. Both studies conducted testing to identify current and previous SARS-CoV-2 infection, and recorded symptoms and school attendance. These research data have been linked to routine electronic health record (EHR) data.AimsTo better understand the short- and long-term consequences of SARS-CoV-2 infection, and their risk factors, in CYP.MethodsRetrospective cohort and nested case-control analyses will be conducted for SIS-1 and CoMMinS data linked to EHR data for the association between (1) acute symptomatic SARS-CoV-2 infection and risk factors; (2) SARS-CoV-2 infection and long-term effects on health: (a) persistent symptoms; (b) any new diagnosis; (c) a new prescription in primary care; (d) health service attendance; (e) a high rate of school absence.ResultsOur study will improve understanding of long-COVID in CYP by characterising the trajectory of long-COVID in CYP in terms of things like symptoms and diagnoses of conditions. The research will inform which groups of CYP are more likely to get acute- and long-term outcomes of SARS-CoV-2 infection, and patterns of related healthcare-seeking behaviour, relevant for healthcare service planning. Digested information will be produced for affected families, doctors, schools, and the public, as appropriate.ConclusionLinked SIS-1 and CoMMinS data represent a unique and rich resource for understanding the impact of SARS-CoV-2 infection on children's health, benefiting from enhanced SARS-CoV-2 testing and ability to assess a wide range of outcomes.

BackgroundAntibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite good evidence of there being no benefit to the patient, and evidence of over prescribing driving microbial resistance. The high treatment rates are attributed to uncertainty regarding microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as potential antibiotic stewardship tools, with some providing microbiological results in 15 minutes. However, there is little research on their impact on antibiotic use and clinical outcomes in primary care.MethodsThis is a multi-centre, individually randomised controlled trial with mixed-methods investigation of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12 months and over presenting to primary care in the UK with a suspected respiratory tract infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, necessary. Once consented, all participants are asked to provide a combined nose and throat swab sample and randomised to have a rapid microbiological point-of-care-test or no point-of-care-test. For intervention patients, clinicians review the result of the test, before contacting the patient to finalise treatment. Treatment decisions are made as per usual care in control group patients. The primary outcome is whether an antibiotic is prescribed at this point. All swab samples are sent to the central laboratory for further testing. Patients are asked to complete a diary to record the severity and duration of symptoms until resolution or day 28, and questionnaires at 2 months about their beliefs and intention to consult for similar future illnesses. Primary care medical records are also reviewed at 6-months to collect further infection consultations, antibiotic prescribing and hospital admissions. The trial aims to recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute reduction in antibiotic prescribing. Qualitative interviews are being conducted with approximately 20 clinicians and 30 participants to understand any changes in beliefs and behaviour resulting from the point-of-care-test and generate attributes for clinician and patient discrete choice experiments.DiscussionThis trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary care.Trial registrationISRCTN16039192, prospectively registered on 08/11/2022.

Depression is a common stress disability disorder that affects higher mental functions including emotion, cognition, and behavior. It may be mediated by inflammatory cytokines that interfere with neuroendocrine function, and synaptic plasticity. Therefore, reductions in inflammation might contribute to treatment response. The current study aims to evaluate the role of Protein Kinase (PKA)- cAMP response element-binding protein (CREB)- brain derived neurotropic factor (BDNF) signaling pathway in depression and the effects of roflumilast (PDE4 inhibitor) as potential antidepressant on the activity of the PKA-CREB-BDNF signaling pathway, histology, and pro-inflammatory cytokine production. Forty Adult male Wistar rats were divided into 4 groups: Control group, Positive Control group: similar to the controls but received Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment, Depressed group which were exposed to chronic stress for 6 weeks, and Roflumilast-treated group which were exposed to chronic stress for 6 weeks and treated by Roflumilast (3 mg / kg / day) by oral gavage for the last 4 weeks of the experiment. The depressed group showed significant increase in immobility time with significant decrease in swimming and struggling times, significant decrease in hippocampal PKA, CERB, BDNF, Dopamine, Cortisone, and Superoxide dismutase while hippocampal Phosphodiesterase-E4, Interleukin-6, and Malondialdhyde levels were significantly elevated. These findings were significantly reversed upon Roflumilast treatment. Therefore, it could be concluded that depression is a neurodegenerative inflammatory disease and oxidative stress plays a key role in depression. Roflumilast treatment attenuated the depression behavior in rats denoting its neuroprotective, and anti-inflammatory effects.

Abstract In this work, successful nanocomposites composed of different ratios of reduced graphene oxide and copper sulphide (xCuS–rGO) were fabricated to aid in treating water contaminated with organic dyes. XRD, TEM, SEM, XPS, IR, EDX and BET were applied for the characterization of (CuS–rGO). The photocatalytic strength of the prepared nanocomposites was evaluated using artificial sunlight irradiation. The nanocomposites were tested for their ability to degrade both anionic and cationic organic dyes, including amaranth and rhodamine B (RhB). The excellent photocatalytic strength of our composites, relative to pristine CuS and rGO, was interpreted as rGO sheets being very porous. In addition, the charge moved efficiently from rGO to CuS. The combined properties enhanced the efficiency of photodegradation of CuS–rGO composite across the dyes under the illumination of simulated sunlight. The electron transportation from rGO sheets to the CuS conduction band enhances the charge separation and transportation. The role of superoxide radicals in photocatalytic degradation was unveiled and the interactions between the studied dyes and our catalysts were investigated by density functional theory study and scavenging investigation. This work gives new ideas about the preparation and properties of (CuS–rGO) composites and their broad application in solving environmental problems.

Abstract DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.

Abstract CarH is a coenzyme B12-dependent photoreceptor involved in regulating carotenoid biosynthesis. How light-triggered cleavage of the B12 Co-C bond culminates in CarH tetramer dissociation to initiate transcription remains unclear. Here, a series of crystal structures of the CarH B12-binding domain after illumination suggest formation of unforeseen intermediate states prior to tetramer dissociation. Unexpectedly, in the absence of oxygen, Co-C bond cleavage is followed by reorientation of the corrin ring and a switch from a lower to upper histidine-Co ligation, corresponding to a pentacoordinate state. Under aerobic conditions, rapid flash-cooling of crystals prior to deterioration upon illumination confirm a similar B12-ligand switch occurs. Removal of the upper His-ligating residue prevents monomer formation upon illumination. Combined with detailed solution spectroscopy and computational studies, these data demonstrate the CarH photoresponse integrates B12 photo- and redox-chemistry to drive large-scale conformational changes through stepwise Co-ligation changes.

Abstract Reliable estimates of subnational vaccination coverage are critical to track progress towards global immunisation targets and ensure equitable health outcomes for all children. However, conflict can limit the reliability of coverage estimates from traditional household-based surveys due to an inability to sample in unsafe and insecure areas and increased uncertainty in underlying population estimates. In these situations, model-based geostatistical (MBG) approaches offer alternative coverage estimates for administrative units affected by conflict. We estimated first- and third-dose diphtheria-tetanus-pertussis vaccine coverage in Borno state, Nigeria, using a spatiotemporal MBG modelling approach, then compared these to estimates from recent conflict-affected, household-based surveys. We compared sampling cluster locations from recent household-based surveys to geolocated data on conflict locations and modelled spatial coverage estimates, while also investigating the importance of reliable population estimates when assessing coverage in conflict settings. These results demonstrate that geospatially-modelled coverage estimates can be a valuable additional tool to understand coverage in locations where conflict prevents representative sampling.

Abstract Coral reefs are under existential threat from climate change and anthropogenic impacts. Genomic studies have enhanced our knowledge of resilience and responses of some coral species to environmental stress, but reference genomes are lacking for many coral species. The blue coral Heliopora is the only reef-building octocoral genus and exhibits optimal growth at a temperature close to the bleaching threshold of scleractinian corals. Local and high-latitude expansions of Heliopora coerulea were reported in the last decade, but little is known about the molecular mechanisms underlying its thermal resistance. We generated a draft genome of H. coerulea with an assembled size of 429.9 Mb, scaffold N50 of 1.42 Mb and BUSCO completeness of 94.9%. The genome contains 239.1 Mb repetitive sequences, 27,108 protein coding genes, 6,225 lncRNAs, and 79 miRNAs. This reference genome provides a valuable resource for in-depth studies on the adaptive mechanisms of corals under climate change and the evolution of skeleton in cnidarian.

Abstract Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.

Abstract The large-scale wind energy conversion system (WECS) based on a doubly fed induction generator (DFIG) has gained popularity in recent years because of its various economic and technical merits. The fast integration of WECS with existing power grids has caused negative influence on the stability and reliability of power systems. Grid voltage sags produce a high overcurrent in the DFIG rotor circuit. Such these challenges emphasise the necessity of the low voltage ride through (LVRT) capability of a DFIG for ensuring power grid stability during voltage dips. To deal with these issues simultaneously, this paper aims to obtain the optimal values of injected rotor phase voltage for DFIG and wind turbine pitch angles for all operating wind speeds in order to achieve LVRT capability. Bonobo optimizer (BO) is a new optimization algorithm that is applied to crop the optimum values of injected rotor phase voltage for DFIG and wind turbine pitch angles. These optimal values provide the maximum possible DFIG mechanical power to guarantee rotor and stator currents do not exceed the rated values and also deliver the maximum reactive power for supporting grid voltage during faults. The ideal power curve of a 2.4 MW wind turbine has been estimated to get the allowable maximum wind power for all wind speeds. To validate the results accuracy, the BO results are compared to two other optimization algorithms: particle swarm optimizer and driving training optimizer. Adaptive neuro fuzzy inference system is employed as an adaptive controller for the prediction of the values of rotor voltage and wind turbine pitch angle for any stator voltage dip and any wind speed.

Abstract Strategic, sustainable, and ecofriendly alternatives to chemical pesticides are needed to effectively control mosquitoes and reduce the incidence of their vectored diseases. We evaluated several Brassicaceae (mustard family) seed meals as sources of plant derived isothiocyanates produced from the enzymatic hydrolysis of biologically inactive glucosinolates for the control of Aedes aegypti (L., 1762). Five defatted seed meals (Brassica juncea (L) Czern., 1859, Lepidium sativum L., 1753, Sinapis alba L., 1753, Thlaspi arvense L., 1753, and Thlaspi arvense—heat inactivated and three major chemical products of enzymatic degradation (allyl isothiocyanate, benzyl isothiocyanate and 4-hydroxybenzyl isothiocyanate) were assayed to determine toxicity (LC50) to Ae. aegypti larvae. All seed meals except the heat inactivated T. arvense were toxic to mosquito larvae. L. sativum seed meal was the most toxic treatment to larvae (LC50 = 0.04 g/120 mL dH2O) at the 24-h exposure. At the 72-h evaluation, the LC50 values for B. juncea, S. alba and T. arvense seed meals were 0.05, 0.08 and 0.1 g/120 mL dH2O, respectively. Synthetic benzyl isothiocyanate was more toxic to larvae 24-h post treatment (LC50 = 5.29 ppm) compared with allyl isothiocyanate (LC50 = 19.35 ppm) and 4-hydroxybenzyl isothiocyanate (LC50 = 55.41 ppm). These results were consistent with the higher performance of the benzyl isothiocyanate producing L. sativum seed meal. Isothiocyanates produced from seed meals were more effective than the pure chemical compounds, based on calculated LC50 rates. Using seed meal may provide an effective method of delivery for mosquito control. This is the first report evaluating the efficacy of five Brassicaceae seed meals and their major chemical constituent against mosquito larvae and demonstrates how natural compounds from Brassicaceae seed meals can serve as a promising ecofriendly larvicides to control mosquitoes.

PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible.

In recent years, Geoscience Australia has undertaken a successful continental-scale validation program, targeting Landsat and Sentinel analysis-ready data surface reflectance products. The field validation model used for this program was successfully built upon earlier studies, and the measurement uncertainties associated with these protocols have been quantified and published. As a consequence, the Australian earth observation community was well-prepared to respond to the United States Geological Survey (USGS) call for collaborators with the 2021 Landsat 8 (L8) and Landsat 9 (L9) underfly. Despite a number of challenges, seven validation datasets were captured across five sites. As there was only a single 100% overlap transit across Australia, and the country was amidst a strong La Niña climate cycle, it was decided to deploy teams to the two available overpasses with only 15% side lap. The validation sites encompassed rangelands, chenopod shrublands, and a large inland lake. Apart from instrument problems at one site, good weather enabled the capture of high-quality field data allowing for meaningful comparisons between the radiometric performance of L8 and L9, as well as the USGS and Australian Landsat analysis-ready data processing models. Duplicate (cross-calibration) spectral sampling at different sites provides evidence of the field protocol reliability, while the off-nadir view of L9 over the water site has been used to better compare the performance of different water and atmospheric correction processing models.

Abstract Prion diseases are characterized by the cellular prion protein, PrPC, misfolding and aggregating into the infectious prion protein, PrPSc, which leads to neurodegeneration and death. An early sign of disease is inflammation in the brain and the shift of resting glial cells to reactive astrocytes and activated microglia. Few therapeutics target this stage of disease. Mesenchymal stromal cells produce anti-inflammatory molecules when exposed to inflammatory signals and damaged tissue. Here, we show that adipose-derived mesenchymal stromal cells (AdMSCs) migrate toward prion-infected brain homogenate and produce the anti-inflammatory molecules transforming growth factor β (TGFβ) and tumor necrosis factor-stimulated gene 6 (TSG-6). In an in vitro model of prion exposure of both primary mixed glia and BV2 microglial cell line, co-culturing with AdMSCs led to a significant decrease in inflammatory cytokine mRNA and markers of reactive astrocytes and activated microglia. This protection against in vitro prion-associated inflammatory responses is independent of PrPSc replication. These data support a role for AdMSCs as a beneficial therapeutic for decreasing the early onset of glial inflammation and reprogramming glial cells to a protective phenotype.

In layered transition metal oxides as cathode active materials for Na-ion batteries, Na+ diffusion kinetics are impacted by Na+/vacancy ordering. Here, the authors suggest that the P2-type Na2/3Ni1/3Mn2/3O2 with large zigzag ordering exhibits high Na+ mobility and thus superior rate capability.

Prussian blue analogues (PBAs) are appealing materials for aqueous Na- and K- ion batteries but are limited for non-aqueous Li-ion storage. Here, the authors report the synthesis of various lithiated PBAs and discuss critical factors for improving the non-aqueous electrochemical storage of Li ions.

Abstract This study aimed to report mortality, risk factors, and burden of diseases in Spain. The Global Burden of Disease, Injuries, and Risk Factors 2019 estimates the burden due to 369 diseases, injuries, and impairments and 87 risk factors and risk factor combinations. Here, we detail the updated Spain 1990–2019 burden of disease estimates and project certain metrics up to 2030. In 2019, leading causes of death were ischaemic heart disease, stroke, chronic obstructive pulmonary disease, Alzheimer’s disease, and lung cancer. Main causes of disability adjusted life years (DALYs) were ischaemic heart disease, diabetes, lung cancer, low back pain, and stroke. Leading DALYs risk factors included smoking, high body mass index, and high fasting plasma glucose. Spain scored 74/100 among all health-related Sustainable Development Goals (SDGs) indicators, ranking 20 of 195 countries and territories. We forecasted that by 2030, Spain would outpace Japan, the United States, and the European Union. Behavioural risk factors, such as smoking and poor diet, and environmental factors added a significant burden to the Spanish population’s health in 2019. Monitoring these trends, particularly in light of COVID-19, is essential to prioritise interventions that will reduce the future burden of disease to meet population health and SDG commitments.

In this disease mapping study, the authors estimate disability-adjusted life year rates for three of the major causes of mortality for children under five 43 countries in sub-Saharan Africa. They identify significant heterogeneity at the subnational level, highlighting the need for a targeted intervention approach.

In arid and hyper-arid areas, groundwater is a precious and rare resource. The need for water supply has grown over the past few decades as a result of population growth, urbanization, and agricultural endeavors. This research aims to locate groundwater recharge potential zones (GWPZs) using multi-criteria evaluation (MCE) in the Wadi Qena Basin, Eastern Desert of Egypt, which represents one of the most promising valleys on which the government depends for land reclamations and developments. These approaches have been used to integrate and delineate the locations of high groundwater recharge and the potential of the Quaternary aquifer in the Wadi Qena basin. After allocating weight factors to identify features in each case based on infiltration, land use/land cover, slope, geology, topology, soil, drainage density, lineament density, rainfall, flow accumulation, and flow direction, these thematic maps were combined. The results of the GIS modeling led to the division of the area’s groundwater recharge potential into five groups, ranging from very high (in the western part) to very low (in the eastern part of the basin). The zones with the best prospects for groundwater exploration turned out to be the alluvial and flood plains, with their thick strata of sand and gravel. The groundwater recharge potential map was validated using data from the field and earlier investigations. The promising recharging areas show high suitability for soil cultivation. The results overall reveal that RS and GIS methodologies offer insightful instruments for more precise assessment, planning, and monitoring of water resources in arid regions and anywhere with similar setups for groundwater prospecting and management.

Abstract High levels of circulating Lipoprotein (a) [Lp(a)] are an independent risk factor for CVD. One of the major limitations to investigating Lp(a) biology is the need for large volumes of plasma (4–10 mL) for its isolation. We developed an isolation technique requiring only 0.4 mL of plasma yielding an enriched Lp(a) fraction suitable for compositional and functional studies. We collected plasma from patients (n = 9) in EDTA presenting to our Center for Preventive Cardiology for CVD risk management and with circulating Lp(a) > 66 mg/dL. 0.4 mL of plasma was added to 90 µL of potassium bromide (1.33 g/mL) and subjected to our two-step density-gradient ultracentrifugation method. The first step separates VLDL and LDL from the Lp(a) and HDL fractions and the second step further separates VLDL from LDL and Lp(a) from HDL. Lp(a) is then dialyzed for up to 24 h in potassium phosphate buffer. We performed cholesterol gel electrophoresis, immunoblotting and LC-MS/MS proteomics on isolated lipoprotein fractions to confirm fraction enrichment. Functional studies including Lp(a)-dependent induction of macrophage gene expression and cholesterol efflux inhibition were performed on isolated Lp(a) to confirm its preserved bioactivity. Lp(a) yields (264 ± 82.3 µg/mL on average) correlated with Lp(a) plasma concentrations (r2 = 0.75; p

Precise organization of growing structures is a fundamental process in developmental biology. In plants, radial growth is mediated by the cambium, a stem cell niche continuously producing wood (xylem) and bast (phloem) in a strictly bidirectional manner. While this process contributes large parts to terrestrial biomass, cambium dynamics eludes direct experimental access due to obstacles in live-cell imaging. Here, we present a cell-based computational model visualizing cambium activity and integrating the function of central cambium regulators. Performing iterative comparisons of plant and model anatomies, we conclude that the receptor-like kinase PXY and its ligand CLE41 are part of a minimal framework sufficient for instructing tissue organization. By integrating tissue-specific cell wall stiffness values, we moreover probe the influence of physical constraints on tissue geometry. Our model highlights the role of intercellular communication within the cambium and shows that a limited number of factors are sufficient to create radial growth by bidirectional tissue production.

Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.

BackgroundResistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence.AimTo undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs.MethodsA systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs.Trial registrationPROSPERO Registration number: CRD42023376769.

[This corrects the article DOI: 10.1371/journal.pone.0265254.].

In cut flowers, xylem occlusion or blockage by bacteria negatively affects water balance and postharvest quality. Many studies have used culture-based methods to examine bacterial populations in vase water and their effects on flower longevity. It is still unclear if and how bacterial communities at the 16S rRNA gene (16S) level change during the vase period and how such change might correlate with postharvest longevity. This study compared the sequences of 16S amplicons from 4 different types of flowers and their vase water over the course of 7 days (Rosa spp., Gerbera jamesonii, and two Lilium varieties). The relative abundance of plant chloroplast and mitochondria 16S decreased significantly over the course 7 days in all 4 flowers as bacterial diversity increased. Richness and evenness of the bacterial communities increased over time, as did the number of rare taxa and phylogenetic diversity. Bacterial communities varied with time, as well as by flower source, types, and sample location (water, stem surface, whole stem). Some taxa, such as Enterobacteriacea and Bradyhizobiaceae decreased significantly over time while others such as Pseudomonas spp. increased. For example, Pseudomonas veronii, implicated in soft rot of calla lily, increased in both whole stem samples and water samples from Gerbera jamesonii. Erwinia spp., which includes plant pathogenic species, also increased in water samples. This work highlights the dynamic and complex nature of bacterial succession in the flower vase ecosystem. More work is needed to understand if and how bacterial community structure can be managed to improve cut flower vase life.

Most non-Māori-speaking New Zealanders are regularly exposed to Māori throughout their lives without seeming to build any extensive Māori lexicon; at best, they know a small number of words which are frequently used and sometimes borrowed into English. Here, we ask how many Māori words non-Māori-speaking New Zealanders know, in two ways: how many can they identify as real Māori words, and how many can they actively define? We show that non-Māori-speaking New Zealanders can readily identify many more Māori words than they can define, and that the number of words they can reliably define is quite small. This result adds crucial support to the idea presented in earlier work that non-Māori-speaking New Zealanders have implicit form-based (proto-lexical) knowledge of many Māori words, but explicit semantic (lexical) knowledge of few. Building on this distinction, we further ask how different levels of word knowledge modulate effects of phonotactic probability on the accessing of that knowledge, across both tasks and participants. We show that participants' implicit word knowledge leads to effects of phonotactic probability-and related effects of neighbourhood density-in a word/non-word discrimination task, but not in a more explicit task that requires the active definition of words. Similarly, we show that the effects of phonotactic probability on word/non-word discrimination are strong among participants who appear to lack explicit word knowledge, as indicated by their weak discrimination performance, but absent among participants who appear to have explicit word knowledge, as indicated by their strong discrimination performance. Together, these results suggest that phonotactic probability plays its strongest roles in the absence of explicit semantic knowledge.

PurposeThere is robust evidence for offering supported self-management interventions for people with severe mental illness (SMI) throughout secondary mental health services, but their availability remains patchy. The aim of this systematic review is to synthesise the evidence on barriers and facilitators to implementing self-management interventions for people with SMI in secondary mental health care settings.MethodsThe review protocol was registered with PROSPERO (CRD42021257078). Five databases were searched to identify relevant studies. We included full-text journal articles with primary qualitative or quantitative data on factors which affect the implementation of self-management interventions for people with SMI in secondary mental health services. The included studies were analysed using narrative synthesis, using the Consolidated Framework for Implementation Research and an established taxonomy of implementation outcomes.ResultsTwenty-three studies from five countries met eligibility criteria. The barriers and facilitators identified in the review were mainly on the organisational level, but included some individual-level influences. Facilitators included high feasibility, high fidelity, a strong team structure, sufficient number of staff, support from colleagues, staff training, supervision, the presence of an implementation champion and adaptability of the intervention. Barriers to implementation include high staff turnover, staff shortage, lack of supervision, lack of support for staff delivering the programme, staff struggling with their increased workload, a lack of senior clinical leadership, and programme content perceived as irrelevant.ConclusionThe findings from this research suggest promising strategies to improve implementation of self-management interventions. For services providing support for people with SMI, organisational culture should be considered, as well as the adaptability of interventions.