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Abstract More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.

Objectives: Short child occupational profile (SCOPE) screening tool is used to assess different factors of functional abilities and record the progress levels of individuals in occupational therapy interventions. This study aimed to validate a Persian version of the SCOPE test. Methods: This methodological research was conducted in two stages, including translation and psychometric properties. A total of 182 people aged 3-21 years were recruited using the convenience sampling method for the second stage. Results: The results of the content validity of the questionnaire were in acceptable ranges. The total intra-class correlation coefficient and total Cronbach's α were 0.97 and 0.93, respectively. The results of the discriminant validity between the normal and disabled groups showed significant differences between the normal and disabled groups in all items of the questionnaire. Discussion: The findings demonstrated that the Persian version of the SCOPE questionnaire could be used as a valid and reliable tool.

Background Despite the increasing availability of electronic healthcare record (EHR) data and wide availability of plug-and-play machine learning (ML) Application Programming Interfaces, the adoption of data-driven decision-making within routine hospital workflows thus far, has remained limited. Through the lens of deriving clusters of diagnoses by age, this study investigated the type of ML analysis that can be performed using EHR data and how results could be communicated to lay stakeholders.Methods Observational EHR data from a tertiary paediatric hospital, containing 61 522 unique patients and 3315 unique ICD-10 diagnosis codes was used, after preprocessing. K-means clustering was applied to identify age distributions of patient diagnoses. The final model was selected using quantitative metrics and expert assessment of the clinical validity of the clusters. Additionally, uncertainty over preprocessing decisions was analysed.Findings Four age clusters of diseases were identified, broadly aligning to ages between: 0 and 1; 1 and 5; 5 and 13; 13 and 18. Diagnoses, within the clusters, aligned to existing knowledge regarding the propensity of presentation at different ages, and sequential clusters presented known disease progressions. The results validated similar methodologies within the literature. The impact of uncertainty induced by preprocessing decisions was large at the individual diagnoses but not at a population level. Strategies for mitigating, or communicating, this uncertainty were successfully demonstrated.Conclusion Unsupervised ML applied to EHR data identifies clinically relevant age distributions of diagnoses which can augment existing decision making. However, biases within healthcare datasets dramatically impact results if not appropriately mitigated or communicated.

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

The use of nature-based solutions (NbS) to address the risks posed by hydro-meteorological hazards have not yet become part of the mainstream policy response, and one of the main reasons cited for this, is the lack of evidence that they can effectively reduce disaster risk. This paper addresses this issue, by providing model-based evidence from five European case studies which demonstrate the effectiveness of five different NbS in reducing the magnitude of the hazard and thus risk, in present-day and possible future climates. In OAL-Austria, the hazard is a deep-seated landslide, and the NbS analysed is afforestation. Modelling results show that in today's climate and a landcover scenario of mature forest, a reduction in landslide velocity of 27.6 % could be achieved. In OAL-Germany, the hazard is river flooding and the NbS analysed is managed grazing with removal of woody vegetation. Modelling results show that the NbS could potentially reduce maximum flood water depth in the near-future (2031–2060) and far-future (2070–2099), by 0.036 m and 0.155 m, respectively. In OAL-Greece, the hazard is river flooding, and the NbS is upscaled natural storage reservoirs. Modelling results show that in a possible future climate the upscaled NbS show most potential in reducing the total flooded area by up to 1.26 km2. In OAL-Ireland, the hazard is surface and river flooding, and the NbS is green roofs. Results from a modelled upscaling analysis under two different climate scenarios show that both maximum flood water depth, and total flooded area were able to be reduced. In OAL-UK, the hazard is shallow landslides, and the NbS is high-density planting of two different tree species. Modelling results under two different climate scenarios show that both tree species were able to improve slope stability, and that this increased over time as the NbS matured. The significance of these results is discussed within the context of the performance of the NbS over time, to different magnitude events, impact with stakeholders in engendering wider support for the adoption of the NbS in the OALs, and the uncertainty in the modelling analyses.

Illawarra plum (IP) is a fruit native to Australia and is a source of antioxidants including phenolics and anthocyanins which contribute important functions in food preservation and quality. However, the retention of natural antioxidants is influenced by thermal processing due to their sensitivity to heat. This study measured the impact of three common drying methods to identify the best processing conditions, including cost effectiveness on retaining the quality of IP. The colour (L*, a*, b*), levels of total phenolics, flavonoids, proanthocyanidins, anthocyanins and antioxidant scavenging capacity of the samples were measured on dried IP fruits (freeze dried, convection oven 70, 90, 110 °C or vacuum oven 70, 90 or 110 °C). The freeze dried sample observed the best colour (L* 44.18±0.50, a* 16.72±0.15, b* 1.66±0.04) and highest levels of compounds from the methods observed: TPC 679.19±15.04 mM GAE/g DW, TFC 190.25±4.65 mM CE/g DW, proanthocyanidins 422.46 ± 21.52 mM CE/g DW, DPPH 562.51±40.69 mM TE/g DW, monomeric anthocyanins 402.58±3.97 µg C3G/L DW and 57.97±2.84 % polymeric anthocyanins. For maximum retention of quality, freeze drying is recommended, however, it is costly and for a more economical approach, vacuum drying at 90 °C or convection oven drying at 110 °C are identified as suitable conditions for drying IP to prevent unnecessary loss of phenolic quality, however these methods will cause shrinkage and browning in the fruit. These conditions can be applied for drying IP for direct use as a dried product or for further applications in food

Abstract Background Amplicon-based mycobiome analysis has the potential to identify all fungal species within a sample and hence could provide a valuable diagnostic assay for use in clinical mycology settings. In the last decade, the mycobiome has been increasingly characterised by targeting the internal transcribed spacer (ITS) regions. Although ITS targets give broad coverage and high sensitivity, they fail to provide accurate quantitation as the copy number of ITS regions in fungal genomes is highly variable even within species. To address these issues, this study aimed to develop a novel NGS fungal diagnostic assay using an alternative amplicon target. Methods Novel universal primers were designed to amplify a highly diverse single copy and uniformly sized DNA target (Tef1) to enable mycobiome analysis on the Illumina iSeq100 which is a low cost, small footprint and simple to use next-generation sequencing platform. To enable automated analysis and rapid results, a streamlined bioinformatics workflow and sequence database were also developed. Sequencing of mock fungal communities was performed to compare the Tef1 assay and established ITS1-based method. The assay was further evaluated using clinical respiratory samples and the feasibility of using internal spike-in quantitative controls was assessed. Results The Tef1 assay successfully identified and quantified Aspergillus, Penicillium, Candida, Cryptococcus, Rhizopus, Fusarium and Lomentospora species from mock communities. The Tef1 assay was also capable of differentiating closely related species such as A. fumigatus and A. fischeri. In addition, it outperformed ITS1 at identifying A. fumigatus and other filamentous pathogens in mixed fungal communities (in the presence or absence of background human DNA). The assay could detect as few as 2 haploid genome equivalents of A. fumigatus from clinical respiratory samples. Lastly, spike-in controls were demonstrated to enable semi-quantitation of A. fumigatus load in clinical respiratory samples using sequencing data. Conclusions This study has developed and tested a novel metabarcoding target and found the assay outperforms ITS1 at identifying clinically relevant filamentous fungi. The assay is a promising diagnostic candidate that could provide affordable NGS analysis to clinical mycology laboratories.

Abstract Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β = 0.579; 95% CI −1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (β = −0.482; 95% CI,−0.813, −0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.

To harness the power of pre-trained image classification models on the extensive ImageNet dataset, early layers of pre-trained backbones have been used to capture relevant information about iris texture in the field of Iris Recognition (IR). This addresses the lack of extensive iris datasets that are required for adjusting millions of parameters in deep networks for IR. However, using intermediate layers as feature extractors introduces problems due to image alterations and aliasing effects due to down-sampling. This paper proposes an IR method that employs low-level convolutional filters from a pre-trained backbone, incorporating low-pass filters to mitigate aliasing effects resulting from both down-sampling and horizontal shifting, caused by minor head rotations during image acquisition. Furthermore, the backbone is enhanced by adapting circular padding to reduce the impact of horizontal discontinuities in the Rubber Sheet representation. The extracted features are then encoded using a novel adaptive threshold method, increasing the variability of binary iris codes, which are matched by using a single Hamming Distance without a bit-shifting process. The proposed model exhibits significantly improved performance on publicly available CASIA and IITD datasets, along with datasets containing examples of substantial pupil dilation. Finally, we tested the robustness of our proposed method against head rotations by using datasets that were modified by horizontal shifting to simulate small head rotations.

Designing Convolutional Neural Networks (CNNs) for a specific task requires not only Deep Learning expertise but also knowledge of the problem. The goal of Neuroevolution is to find CNN architectures automatically through evolution. The search time, however, is a critical problem in Neuroevolution since multiple CNNs must be trained in the evolutionary process. In this work, we propose a Neural Architecture Classifier (NAC) to avoid training architectures that would not have good performance, based on knowledge of previously trained architectures. The NAC evaluates each CNN using the CNN architecture encoding as the input. A genetic algorithm (GA) is used for evolution, and a search space with few restrictions; hence, CNN architectures can have any width, depth or shape as well as the suitable number of skip connections. We applied this methodology to solving pattern recognition problems on six well-known datasets: five subsets of the MNIST-Variations (MNIST-V) dataset and the CIFAR-10 dataset. Experiments demonstrated that integrating the NAC in the GA reduces the search time by up to 44% compared to conventional GAs. Additionally, the architectures found by evolution with our classifier achieved a better performance (4.6% on average) than those found by traditional evolution. Our results improved the state-of-the-art by 5.2% (0.33% error reduction) on the most difficult dataset of the MNIST-V (MRDBI), and an average of 4% (0.24% error reduction) on the MNIST-V datasets. Additionally, our results on CIFAR-10 are close to those of the state-of-the-art but with significantly reduced search time. The application of a classifier can be relevant and useful not only for genetic algorithms, but also for other evolutionary algorithms.

Abstract Schistosomiasis is caused by parasites of the genus Schistosoma, which infect more than 200 million people. Praziquantel (PZQ) has been the main drug for controlling schistosomiasis for over four decades, but despite that it is ineffective against juvenile worms and size and taste issues with its pharmaceutical forms impose challenges for treating school-aged children. It is also important to note that PZQ resistant strains can be generated in laboratory conditions and observed in the field, hence its extensive use in mass drug administration programs raises concerns about resistance, highlighting the need to search for new schistosomicidal drugs. Schistosomes survival relies on the redox enzyme thioredoxin glutathione reductase (TGR), a validated target for the development of new anti-schistosomal drugs. Here we report a high-throughput fragment screening campaign of 768 compounds against S. mansoni TGR (SmTGR) using X-ray crystallography. We observed 49 binding events involving 35 distinct molecular fragments which were found to be distributed across 16 binding sites. Most sites are described for the first time within SmTGR, a noteworthy exception being the “doorstop pocket” near the NADPH binding site. We have compared results from hotspots and pocket druggability analysis of SmTGR with the experimental binding sites found in this work, with our results indicating only limited coincidence between experimental and computational results. Finally, we discuss that binding sites at the doorstop/NADPH binding site and in the SmTGR dimer interface, should be prioritized for developing SmTGR inhibitors as new antischistosomal drugs.

Abstract Phosphorus (P) is the key nutrient thought to limit primary productivity on geological timescales, and hence P bioavailability exerted a major influence on Earth’s surface oxygenation dynamics through the Precambrian, with ensuing implications for biological evolution. Here, we document highly elevated P contents in non-glacial Ediacaran (635–541 Ma) iron formations from Northwestern China, with P dominantly occurring as carbonate fluorapatite formed during early diagenesis. These analyses, in combination with marine sediment P contents and phosphorite abundance data, point to a state change in oceanic P concentrations during the Ediacaran, which we attribute to enhanced recycling from marine sediments under redox-stratified conditions. Subsequent elevated rates of primary productivity and organic carbon production may have sustained the contemporaneous first appearance of complex deep marine habitats, and would have increased the extent and stability of surface water oxygen concentrations, leading to conditions conducive to the subsequent evolution of more complex animals.

Objectives This study sought to explore whether generalised joint hypermobility (GJH, a common marker of variant connective tissue) was a risk factor for self-reported non-recovery from COVID-19 infection.Design Prospective observational study.Setting COVID Symptom Study Biobank (https://cssbiobank.com/) UKParticipants Participants were surveyed in August 2022. 3064 (81.4%) reported at least one infection with COVID-19. These individuals self-reported on recovery and completed a self-report questionnaire to detect GJH (Hakim and Grahame 5-part questionnaire, 5PQ).Main outcome measures The primary outcome was the presence of self-reported non-recovery from COVID-19 infection at the time of the survey. Additional outcomes included scores on 5PQ and self-reported fatigue level (Chalder Fatigue Scale).Results The presence of GJH was not specifically associated with reported COVID-19 infection risk per se. However, it was significantly associated with non-recovery from COVID-19 (OR 1.43 (95% CI 1.20 to 1.70)). This association remained after sequential models adjusting for age, sex, ethnic group, education level and index of multiple deprivation (OR 1.33 (95% CI 1.10 to 1.61)) and further adjustment for vaccination status and number of vaccinations (OR 1.33 (95% CI 1.10 to 1.60)). Additionally, including in a model adjusting for all covariates, hypermobility significantly predicted higher fatigue levels (B=0.95, SE=0.25, t=3.77, SE, p=0.002). Fatigue levels mediated the link between GJH and non-recovery from COVID-19 (estimate of indirect effect=0.18, 95% bootstrapped CI 0.08 to 0.29).Conclusions Individuals with GJH were approximately 30% more likely not to have recovered fully from COVID-19 infection at the time of the questionnaire, and this predicted the fatigue level. This observation is clinically important through its potential impact for understanding and identifying sub-phenotypes of long COVID for screening and personalised targeted interventions. More generally, greater awareness of GJH and its extra-articular associations is needed for effective patient stratification and implementation of personalised medicine.

Background Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctrough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W.Methods In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review.Results Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0–39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue.Conclusions Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit−risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.

Abstract Controls on Mesoproterozoic ocean redox heterogeneity, and links to nutrient cycling and oxygenation feedbacks, remain poorly resolved. Here, we report ocean redox and phosphorus cycling across two high-resolution sections from the ~1.4 Ga Xiamaling Formation, North China Craton. In the lower section, fluctuations in trade wind intensity regulated the spatial extent of a ferruginous oxygen minimum zone, promoting phosphorus drawdown and persistent oligotrophic conditions. In the upper section, high but variable continental chemical weathering rates led to periodic fluctuations between highly and weakly euxinic conditions, promoting phosphorus recycling and persistent eutrophication. Biogeochemical modeling demonstrates how changes in geographical location relative to global atmospheric circulation cells could have driven these temporal changes in regional ocean biogeochemistry. Our approach suggests that much of the ocean redox heterogeneity apparent in the Mesoproterozoic record can be explained by climate forcing at individual locations, rather than specific events or step-changes in global oceanic redox conditions.

The Illawarra plum (IP) is native to Australia and has been used as a bush food for centuries. With rich phytochemicals and natural pigments, IP has the potential to be an added ingredient to improve the physicochemical properties of food, including yoghurt. This study prepared dried IP powders through vacuum drying (VD) and freeze drying (FD), produced extracts from these dried powders, and fortified them into Greek-style set yoghurt. The changes in colour, pH, titratable acidity (TA), syneresis, total soluble solids (TS), and phytochemicals were measured throughout a chilled storage period of 28 days. The results showed that FD and FD extract could provide a stable, distinct pink colour to yoghurt. IP powders and their extracts improved TS content and, thus, the consistency of yoghurt. Compared to the control, VD, FD, and FD extract of IP did not significantly affect the level of acidity or syneresis after 28 days of chilled storage. Yoghurt fortified with FD and FD extract had the greatest level of phenolics, anthocyanins, and radical scavenging antioxidant activities. This study revealed that IP powders and their extracts can positively improve the physicochemical properties of Greek-style set yoghurt. FD powder is recommended over its extract to fortify this yoghurt, as it can be cost-effectively prepared by freeze drying and then grinding the fresh fruit into powder. Future studies are needed to evaluate other variables in yoghurt preparation, including the concentration of IP and strains of yoghurt culture. Further, the consumer perception of sensory quality and acceptability of yoghurt fortified with FD IP powder should be investigated.

Abstract Background Early language difficulties are associated with poor school readiness and can impact lifelong attainment. The quality of the early home language environment is linked to language outcomes. However, few home-based language interventions have sufficient evidence of effectiveness in improving preschool children’s language abilities. This study reports the first stage in the evaluation of a theory-based programme, Talking Together (developed and delivered by BHT Early Education and Training) given over 6 weeks to families in the home setting. We aimed to test the feasibility and acceptability of delivering Talking Together in the Better Start Bradford community prior to a definitive trial, using a two-armed randomised controlled feasibility study. Methods Families from a single site within the Better Start Bradford reach area were randomly allocated (1:1) to the Talking Together intervention or a wait list control group. Child language and parent-level outcome measures were administered before randomisation (baseline), pre-intervention (pre-test), 2 months post-intervention start (post-test), and 6 months post-intervention start (follow-up). Routine monitoring data from families and practitioners were also collected for eligibility, consent, protocol adherence, and attrition rates. Descriptive statistics on the feasibility and reliability of potential outcome measures were analysed alongside qualitative feedback on trial design acceptability. Pre-defined progression-to-trial criteria using a traffic light system were assessed using routine monitoring data. Results Two-hundred and twenty-two families were assessed for eligibility; of these, 164 were eligible. A total of 102 families consented and were randomised (intervention: 52, waitlist control: 50); 68% of families completed outcome measures at 6-month follow-up. Recruitment (eligibility and consent) reached ‘green’ progression criteria; however, adherence reached ‘amber’ and attrition reached ‘red’ criteria. Child- and parent-level data were successfully measured, and the Oxford-CDI was identified as a suitable primary outcome measure for a definitive trial. Qualitative data not only indicated that the procedures were largely acceptable to practitioners and families but also identified areas for improvement in adherence and attrition rates. Conclusions Referral rates indicate that Talking Together is a much-needed service and was positively received by the community. A full trial is feasible with adaptations to improve adherence and reduce attrition. Trial registration ISRCTN registry ISRCTN13251954. Retrospectively registered 21 February 2019

Abstract Whilst most individuals with SARS-CoV-2 infection have relatively mild disease, managed in the community, it was noted early in the pandemic that individuals with cardiovascular risk factors were more likely to experience severe acute disease, requiring hospitalisation. As the pandemic has progressed, increasing concern has also developed over long symptom duration in many individuals after SARS-CoV-2 infection, including among the majority who are managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. Here, we examine post-illness metabolomic profiles, using nuclear magnetic resonance (Nightingale Health Oyj), and gut-microbiome profiles, using shotgun metagenomic sequencing (Illumina Inc), in 2561 community-dwelling participants with SARS-CoV-2. Illness duration ranged from asymptomatic (n = 307) to Post-COVID Syndrome (n = 180), and included participants with prolonged non-COVID-19 illnesses (n = 287). We also assess a pre-established metabolomic biomarker score, previously associated with hospitalisation for both acute pneumonia and severe acute COVID-19 illness, for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, including biomarkers such as fatty acids and cholesterol, was associated with longer duration of illness, both in individuals with and without SARS-CoV-2 infection. Greater values of a pre-existing metabolomic biomarker score also associated with longer duration of illness, regardless of SARS-CoV-2 infection. We found no association between illness duration and gut microbiome profiles in convalescence. This highlights the potential role of cardiometabolic dysfunction in relation to the experience of long duration symptoms after symptoms of acute infection, both COVID-19 as well as other illnesses.

Light-sheet microscopy has made possible the 3D imaging of both fixed and live biological tissue, with samples as large as the entire mouse brain. However, segmentation and quantification of that data remains a time-consuming manual undertaking. Machine learning methods promise the possibility of automating this process. This study seeks to advance the performance of prior models through optimizing transfer learning. We fine-tuned the existing TrailMap model using expert-labeled data from noradrenergic axonal structures in the mouse brain. By changing the cross-entropy weights and using augmentation, we demonstrate a generally improved adjusted F1-score over using the originally trained TrailMap model within our test datasets.

Background Preschool language skills and language delay predict academic and socioemotional outcomes. Children from deprived environments are at a higher risk of language delay, and both minority ethnic and bilingual children can experience a gap in language skills at school entry. However, research that examines late talking (preschool language delay) in an ethnically diverse, bilingual, deprived environment at age 2 is scarce.Methods Data from Born in Bradford’s Better Start birth cohort were used to identify rates of late talking (≤10th percentile on the Oxford-Communicative Development Inventory: Short) in 2-year-old children within an ethnically diverse, predominantly bilingual, deprived UK region (N=712). The relations between known demographic, maternal, distal and proximal child risk factors, and language skills and language delay were tested using hierarchical linear and logistic regression.Results A total of 24.86% of children were classified as late talkers. Maternal demographic factors (ethnicity, born in UK, education, financial security, employment, household size, age) predicted 3.12% of the variance in children’s expressive vocabulary. Adding maternal language factors (maternal native language, home languages) and perinatal factors (birth weight, gestation) to the model predicted 3.76% of the variance. Adding distal child factors (child sex, child age) predicted 11.06%, and adding proximal child factors (receptive vocabulary, hearing concerns) predicted 49.51%. Significant risk factors for late talking were male sex (OR 2.07, 95% CI 1.38 to 3.09), receptive vocabulary delay (OR 8.40, 95% CI 4.99 to 14.11) and parent-reported hearing concerns (OR 7.85, 95% CI 1.90 to 32.47). Protective factors were increased household size (OR 0.85, 95% CI 0.77 to 0.95) and age (OR 0.82, 95% CI 0.70 to 0.96).Conclusions Almost one in four children living in an ethnically diverse and deprived UK area have early language delay. Demographic factors explained little variance in early vocabulary, whereas proximal child factors held more predictive value. The results indicate further research on early language delay is warranted for vulnerable groups.

Objective:. The objective of the study was to compare the use of ordinal scales and interval scales for capturing surgical competency information for general surgeons performing 3 complex trauma procedures. Background:. Surgical performance assessment is typically captured using nonparametric data (eg, checklists) that do not support inferential analyses. Interval scales support parametric analyses that are essential for determining competency. We compared assessment outcomes for surgeons performing 3 complex trauma procedures using ordinal and interval scales. Methods:. All participants were board-certified or eligible general surgeons. Each participant was assessed by an experienced trauma surgeon while performing 3 trauma procedures on cadavers. All assessors completed a rigorous assessment certification process. We calculated descriptive statistics to examine the differences between interval (parametric) and ordinal (nonparametric) outcomes. Results:. Ordinal scales overestimated competence in up to 100% of the participants and did not identify specific performance gaps. Interval scales provided more granularity and identified specific capability gaps. Conclusions:. Imprecise instrumentation conveys a false sense of competence and deprives surgeons of opportunities to close capability gaps. Measuring discrete procedural components with interval scales provides a more precise measurement of surgical competency.

Purpose: To assess the incidence of adverse cerebrovascular events following shoulder arthroscopy in the beach-chair position when compared with the lateral position. Methods: Records of 5 shoulder surgeons were searched using Current Procedural Technology codes to identify patients who underwent arthroscopic shoulder surgery in both the beach-chair and lateral positions between 2015 and 2020. Using both Current Procedural Technology codes for cerebrovascular accident (CVA) imaging as well as the International Classification of Diseases, Tenth Revision, codes for CVA and late neurologic sequela, patient charts were analyzed in the 30-day postoperative period. The anesthesiology record also was queried for data regarding the blood pressure management intraoperatively, recording mean arterial pressures (MAPs), and vasopressor administration. Patient demographics, comorbidities, and complications were compared between the 2 cohorts using the Student 2-tailed t-test for continuous variables and χ2 analysis for categorical variables. Significance was set at P < .05. Results: There were 711 patients included in the analysis, with 471 in the beach-chair cohort and 240 in the lateral cohort. Baseline demographics were similar between groups, except for age and American Society of Anesthesiologists physical status classification, with the lateral group being significantly younger (P < .001) and lower American Society of Anesthesiologists physical status classification (P = .001) than the beach-chair group. Mean body mass index, history of CVA, transient ischemic attack, hypertension, and peripheral vascular disease were not significantly different. There were no documented CVAs in either cohort. There was no significant difference in the number of postoperative radiologic scans to evaluate for CVA (P = .77) or neurologic sequelae (P = .48) between groups. The beach-chair cohort had fewer instances of MAP

Background In sub-Saharan Africa, the origins of asthma and high prevalence of abnormal lung function remain unclear. In high-income countries (HICs), associations between birth measurements and childhood asthma and lung function highlight the importance of antenatal and early life factors in the aetiology of asthma and abnormal lung function in children. We present here the first study in sub-Saharan Africa to relate birth characteristics to both childhood respiratory symptoms and lung function.Methods Children attending schools in two socioeconomically contrasting but geographically close areas of Nairobi, Kenya, were recruited to a cross-sectional study of childhood asthma and lung function. Questionnaires quantified respiratory symptoms and preterm birth; lung function was measured by spirometry; and parents were invited to bring the child’s immunisation booklet containing records of birth weight and serial weights in the first year.Results 2373 children participated, 52% girls, median age (IQR), 10 years (8–13). Spirometry data were available for 1622. Child immunisation booklets were available for 500 and birth weight and infant weight gain data were available for 323 and 494 children, respectively. In multivariable analyses, preterm birth was associated with the childhood symptoms ‘wheeze in the last 12 months’; OR 1.64, (95% CI 1.03 to 2.62), p=0.038; and ‘trouble breathing’ 3.18 (95% CI 2.27 to 4.45), p

ABSTRACTPulmonary infections caused by the mould pathogen Aspergillus fumigatus are a major cause of morbidity and mortality globally. Compromised lung defences arising from immunosuppression, chronic respiratory conditions or more recently, concomitant viral or bacterial pulmonary infections are recognised risks factors for the development of pulmonary aspergillosis. In this review, we will summarise our current knowledge of the mechanistic basis of pulmonary aspergillosis with a focus on emerging at-risk populations.

Abstract Background A. fumigatus has been associated with a wide spectrum of allergic disorders such as ABPA or SAFS. It is poorly understood what allergens in particular are being expressed during fungal invasion and which are responsible for stimulation of immune responses. Study of the dynamics of allergen production by fungi may lead to insights into how allergens are presented to the immune system. Methods Expression of 17 A. fumigatus allergen genes was examined in response to various culture conditions and stimuli as well as in the presence of macrophages in order to mimic conditions encountered in the lung. Results Expression of 14/17 allergen genes was strongly induced by oxidative stress caused by hydrogen peroxide (Asp f 1, -2, -4, -5, -6, -7, -8, -10, -13, -17 and -18, all >10-fold and Asp f 11, -12, and -22, 5-10-fold) and 16/17 allergen genes were repressed in the presence of cAMP. The 4 protease allergen genes (Asp f -5, -10, -13 and -18) were expressed at very low levels compared to the comparator (β-tubulin) under all other conditions examined. Mild heat shock, anoxia, lipid and presence of macrophages did not result in coordinated changes in allergen gene expression. Growth on lipid as sole carbon source contributed to the moderate induction of most of the allergen genes. Heat shock (37°C > 42°C) caused moderate repression in 11/17 genes (Asp f 1, -2, -4, -5, -6, -9, -10, -13, -17, -18 and -23) (2- to 9-fold), which was mostly evident for Asp f 1 and -9 (~9-fold). Anaerobic stress led to moderate induction of 13/17 genes (1.1 to 4-fold) with one, Asp f 8 induced over 10-fold when grown under mineral oil. Complex changes were seen in gene expression during co-culture of A. fumigatus with macrophages. Conclusions Remarkable coordination of allergen gene expression in response to a specific condition (oxidative stress or the presence of cAMP) has been observed, implying that a single biological stimulus may play a role in allergen gene regulation. Interdiction of a putative allergen expression induction signalling pathway might provide a novel therapy for treatment of fungal allergy.

COVID-19 vaccination rates are lower in women of reproductive age (WRA), including pregnant/postpartum women, despite their poorer COVID-19-related outcomes. We evaluated the vaccination experiences of 3568 U.K. WRA, including 1983 women (55.6%) experiencing a pandemic pregnancy, recruited through the ZOE COVID Symptom Study app. Two staggered online questionnaires (Oct–Dec 2021: 3453 responders; Aug–Sept 2022: 2129 responders) assessed reproductive status, COVID-19 status, vaccination, and attitudes for/against vaccination. Descriptive analyses included vaccination type(s), timing relative to age-based eligibility and reproductive status, vaccination delay (first vaccination >28 days from eligibility), and rationale, with content analysis of free-text comments. Most responders (3392/3453, 98.2%) were vaccinated by Dec 2021, motivated by altruism, vaccination supportiveness in general, low risk, and COVID-19 concerns. Few declined vaccination (by Sept/2022: 20/2129, 1.0%), citing risks (pregnancy-specific and longer-term), pre-existing immunity, and personal/philosophical reasons. Few women delayed vaccination, although pregnant/postpartum women (vs. other WRA) received vaccination later (median 3 vs. 0 days after eligibility, p < 0.0001). Despite high uptake, concerns included adverse effects, misinformation (including from healthcare providers), ever-changing government advice, and complex decision making. In summary, most women in this large WRA cohort were promptly vaccinated, including pregnant/post-partum women. Altruism and community benefit superseded personal benefit as reasons for vaccination. Nevertheless, responders experienced angst and received vaccine-related misinformation and discouragement. These findings should inform vaccination strategies in WRA.

Abstract Background Allergy is a common debilitating and occasionally life threatening condition. The fungal kingdom contains a number of species that produce a wide range of well defined protein allergens although the vast majority of fungal species have unknown allergenic potential. The recent genome sequencing of a variety of fungi provides the opportunity to assess the occurrence of allergen orthologues across the fungal kingdom. Here we use comparative genomics to survey the occurrence of allergen orthologues in fungi. Results A database of 82 allergen sequences was compiled and used to search 22 fungal genomes. Additionally we were able to model allergen structure for representative members of several highly homologous allergen orthologue classes. We found that some allergen orthologue classes that had predicted structural congruence to allergens and allergen epitopes were ubiquitous in all fungi. Other allergen orthologues classes were less well conserved and may not possess conserved allergen epitope orthologues in all fungi. A final group of allergen orthologues, including the major allergens Asp f 1 and Alt a 1, appear to be present in only a limited number of species. Conclusion These results imply that most fungi may possess proteins that have potential to be allergens or to cross react with allergens. This, together with the observation that important allergens such as Asp f 1 are limited to genera or species, has significant implications for understating fungal sensitization, and interpreting diagnosis and management of fungal allergy.

Background Pulmonary and extrapulmonary incidental findings are frequently identified on CT scans performed for lung cancer screening. Uncertainty regarding their clinical significance and how and when such findings should be reported back to clinicians and participants persists. We examined the prevalence of non-malignant incidental findings within a lung cancer screening cohort and investigated the morbidity and relevant risk factors associated with incidental findings. We quantified the primary and secondary care referrals generated by our protocol.Methods The SUMMIT study (NCT03934866) is a prospective observational cohort study to examine the performance of delivering a low-dose CT (LDCT) screening service to a high-risk population. Spirometry, blood pressure, height/weight and respiratory history were assessed as part of a Lung Health Check. Individuals at high risk of lung cancer were offered an LDCT and returned for two further annual visits. This analysis is a prospective evaluation of the standardised reporting and management protocol for incidental findings developed for the study on the baseline LDCT.Results In 11 115 participants included in this analysis, the most common incidental findings were coronary artery calcification (64.2%) and emphysema (33.4%). From our protocolised management approach, the number of participants requiring review for clinically relevant findings in primary care was 1 in 20, and the number potentially requiring review in secondary care was 1 in 25.Conclusions Incidental findings are common in lung cancer screening and can be associated with reported symptoms and comorbidities. A standardised reporting protocol allows systematic assessment and standardises onward management.

Abstract Women of reproductive age are a group of particular concern with regards to vaccine uptake, related to their unique considerations of menstruation, fertility, and pregnancy. To obtain vaccine uptake data specific to this group, we obtained vaccine surveillance data from the Office for National Statistics, linked with COVID-19 vaccination status from the National Immunisation Management Service, England, from 8 Dec 2020 to 15 Feb 2021; data from 13,128,525 such women at population-level, were clustered by age (18–29, 30–39, and 40–49 years), self-defined ethnicity (19 UK government categories), and index of multiple deprivation (IMD, geographically-defined IMD quintiles). Here we show that among women of reproductive age, older age, White ethnicity and being in the least-deprived index of multiple deprivation are each independently associated with higher vaccine uptake, for first and second doses; however, ethnicity exerts the strongest influence (and IMD the weakest). These findings should inform future vaccination public messaging and policy.

Abstract Background Predicting the likely size of future SARS-CoV-2 waves is necessary for public health planning. In England, voluntary “plan B” mitigation measures were introduced in December 2021 including increased home working and face coverings in shops but stopped short of restrictions on social contacts. The impact of voluntary risk mitigation behaviours on future SARS-CoV-2 burden is unknown. Methods We developed a rapid online survey of risk mitigation behaviours ahead of the winter 2021 festive period and deployed in two longitudinal cohort studies in the UK (Avon Longitudinal Study of Parents and Children (ALSPAC) and TwinsUK/COVID Symptom Study (CSS) Biobank) in December 2021. Using an individual-based, probabilistic model of COVID-19 transmission between social contacts with SARS-CoV-2 Omicron variant parameters and realistic vaccine coverage in England, we predicted the potential impact of the SARS-CoV-2 Omicron wave in England in terms of the effective reproduction number and cumulative infections, hospital admissions and deaths. Using survey results, we estimated in real-time the impact of voluntary risk mitigation behaviours on the Omicron wave in England, if implemented for the entire epidemic wave. Results Over 95% of survey respondents (NALSPAC = 2686 and NTwins = 6155) reported some risk mitigation behaviours, with vaccination and using home testing kits reported most frequently. Less than half of those respondents reported that their behaviour was due to “plan B”. We estimate that without risk mitigation behaviours, the Omicron variant is consistent with an effective reproduction number between 2.5 and 3.5. Due to the reduced vaccine effectiveness against infection with the Omicron variant, our modelled estimates suggest that between 55% and 60% of the English population could be infected during the current wave, translating into between 12,000 and 46,000 cumulative deaths, depending on assumptions about severity and vaccine effectiveness. The actual number of deaths was 15,208 (26 November 2021–1 March 2022). We estimate that voluntary risk reduction measures could reduce the effective reproduction number to between 1.8 and 2.2 and reduce the cumulative number of deaths by up to 24%. Conclusions Predicting future infection burden is affected by uncertainty in disease severity and vaccine effectiveness estimates. In addition to biological uncertainty, we show that voluntary measures substantially reduce the projected impact of the SARS-CoV-2 Omicron variant but that voluntary measures alone would be unlikely to completely control transmission.

During the Cambrian Radiation, oxygenation occurred in a series of short pulses. Here, the authors quantify episodic changes in reef size, extent of habitat and in metacommunity ecological complexity associated with these oxygenation pulses by examining archaeocyath sponges.

Abstract The oral microbiota is emerging as an influential factor of host physiology and disease state. Factors influencing oral microbiota composition have not been well characterised. In particular, there is a lack of population-based studies. We undertook a large hypothesis-free study of the saliva microbiota, considering potential influential factors of host health (frailty; diet; periodontal disease), demographics (age; sex; BMI) and sample processing (storage time), in a sample (n = 679) of the TwinsUK cohort of adult twins. Alpha and beta diversity of the saliva microbiota was associated most strongly with frailty (alpha diversity: β = −0.16, Q = 0.003, Observed; β = −0.16, Q = 0.002, Shannon; β = −0.16, Q = 0.003, Simpson; Beta diversity: Q = 0.002, Bray Curtis dissimilarity) and age (alpha diversity: β = 0.15, Q = 0.006, Shannon; β = 0.12, Q = 0.003, Simpson; beta diversity: Q = 0.002, Bray Curtis dissimilarity; Q = 0.032, Weighted UniFrac) in multivariate models including age, frailty, sex, BMI, frailty and diet, and adjustment for multiple testing. Those with a more advanced age were more likely to be dissimilar in the saliva microbiota composition than younger participants (P = 5.125e−06, ANOVA). In subsample analyses, including consideration of periodontal disease (total n = 138, periodontal disease n = 66), the association with frailty remained for alpha diversity (Q = 0.002, Observed ASVs; Q = 0.04 Shannon Index), but not beta diversity, whilst age was not demonstrated to associate with alpha or beta diversity in this subsample, potentially due to insufficient statistical power. Length of time that samples were stored prior to sequencing was associated with beta diversity (Q = 0.002, Bray Curtis dissimilarity). Six bacterial taxa were associated with age after adjustment for frailty and diet. Of the factors studied, frailty and age emerged as the most influential with regards to saliva microbiota composition. Whilst age and frailty are correlates, the associations were independent of each other, giving precedence to both biological and chronological ageing as processes of potential importance when considering saliva microbiota composition.

Background. Lymphedema affects a significant number of women with breast cancer. Self-Management Programs (SMP) are important in the long-term management of chronic conditions such as lymphedema. Motivation is crucial in the daily performance of the SMP. The study explored the effect of the Remotivation Process on the motivation of women with breast cancer-related lymphedema to incorporate an SMP into their daily routine. Methodology. The study was a within-subjects quasi-experimental design that used the Volitional Questionnaire, frequency count of the SMP, and circumferential measurement as outcome measures. Eleven participants (n = 11) with breast cancer-related lymphedema completed the study that used the Remotivation Process as the intervention for 4 weeks with a follow-up session during the 8th week. Results. The participants progressed to a higher state of motivation on the Volitional Questionnaire at the end of the study. There was an increase in the performance of the exercise component of the SMP in 7 days, and a significant decrease in the circumferential measurement of the affected arm. There was also a positive correlation between VQ and circumferential measurements. Conclusion. The study suggests the usefulness of the Remotivation Process in an occupational therapy intervention to promote self-management. It can possibly facilitate motivation, improvement in the manifestation of lymphedema, and the daily performance of the self-management program for lymphedema.

Abstract There has been a renewed interest in the role of dietary therapies to manage irritable bowel syndrome (IBS), with diet high on the agenda for patients. Currently, interest has focussed on the use of traditional dietary advice (TDA), a gluten-free diet (GFD) and the low FODMAP diet (LFD). A consensus meeting was held to assess the role of these dietary therapies in IBS, in Sheffield, United Kingdom. Evidence for TDA is from case control studies and clinical experience. Randomised controlled trials (RCT) have demonstrated the benefit of soluble fibre in IBS. No studies have assessed TDA in comparison to a habitual or sham diet. There have been a number of RCTs demonstrating the efficacy of a GFD at short-term follow-up, with a lack of long-term outcomes. Whilst gluten may lead to symptom generation in IBS, other components of wheat may also play an important role, with recent interest in the role of fructans, wheat germ agglutinins, as well as alpha amylase trypsin inhibitors. There is good evidence for the use of a LFD at short-term follow-up, with emerging evidence demonstrating its efficacy at long-term follow-up. There is overlap between the LFD and GFD with IBS patients self-initiating gluten or wheat reduction as part of their LFD. Currently, there is a lack of evidence to suggest superiority of one diet over another, although TDA is more acceptable to patients. In view of this evidence, our consensus group recommends that dietary therapies for IBS should be offered by dietitians who first assess dietary triggers and then tailor the intervention according to patient choice. Given the lack of dietetic services, novel approaches such as employing group clinics and online webinars may maximise capacity and accessibility for patients. Further research is also required to assess the comparative efficacy of dietary therapies to other management strategies available to manage IBS.

The fungus Aspergillus fumigatus causes invasive and chronic diseases worldwide. Here, Bowyer et al. use long-read and short-read sequencing to generate complete chromosome assemblies and telomere-to-telomere coverage for two isolates, thus providing high-quality reference genomes as fundamental resources to study this pathogen.

Summary: Background: Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods: Cognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings: 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs, 95% confidence intervals, CI: −0.21, −0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, β = −0.22 SDs, 95% CI: −0.35, −0.09). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs, 95% CI: −0.44, −0.18), and 10 years age difference (60–70 years vs. 50–60 years, β = −0.21 SDs, 95% CI: −0.30, −0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation: Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding: Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency.

Summary: Background: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. Methods: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. Findings: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. Interpretation: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. Funding: LSHTM COVID-19 Response Grant (DONAT15912).

Summary: Background: Self-reported symptom studies rapidly increased understanding of SARS-CoV-2 during the COVID-19 pandemic and enabled monitoring of long-term effects of COVID-19 outside hospital settings. Post-COVID-19 condition presents as heterogeneous profiles, which need characterisation to enable personalised patient care. We aimed to describe post-COVID-19 condition profiles by viral variant and vaccination status. Methods: In this prospective longitudinal cohort study, we analysed data from UK-based adults (aged 18–100 years) who regularly provided health reports via the Covid Symptom Study smartphone app between March 24, 2020, and Dec 8, 2021. We included participants who reported feeling physically normal for at least 30 days before testing positive for SARS-CoV-2 who subsequently developed long COVID (ie, symptoms lasting longer than 28 days from the date of the initial positive test). We separately defined post-COVID-19 condition as symptoms that persisted for at least 84 days after the initial positive test. We did unsupervised clustering analysis of time-series data to identify distinct symptom profiles for vaccinated and unvaccinated people with post-COVID-19 condition after infection with the wild-type, alpha (B.1.1.7), or delta (B.1.617.2 and AY.x) variants of SARS-CoV-2. Clusters were then characterised on the basis of symptom prevalence, duration, demography, and previous comorbidities. We also used an additional testing sample with additional data from the Covid Symptom Study Biobank (collected between October, 2020, and April, 2021) to investigate the effects of the identified symptom clusters of post-COVID-19 condition on the lives of affected people. Findings: We included 9804 people from the COVID Symptom Study with long COVID, 1513 (15%) of whom developed post-COVID-19 condition. Sample sizes were sufficient only for analyses of the unvaccinated wild-type, unvaccinated alpha variant, and vaccinated delta variant groups. We identified distinct profiles of symptoms for post-COVID-19 condition within and across variants: four endotypes were identified for infections due to the wild-type variant (in unvaccinated people), seven for the alpha variant (in unvaccinated people), and five for the delta variant (in vaccinated people). Across all variants, we identified a cardiorespiratory cluster of symptoms, a central neurological cluster, and a multi-organ systemic inflammatory cluster. These three main clusers were confirmed in a testing sample. Gastrointestinal symptoms clustered in no more than two specific phenotypes per viral variant. Interpretation: Our unsupervised analysis identified different profiles of post-COVID-19 condition, characterised by differing symptom combinations, durations, and functional outcomes. Our classification could be useful for understanding the distinct mechanisms of post-COVID-19 condition, as well as for identification of subgroups of individuals who might be at risk of prolonged debilitation. Funding: UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, UK Alzheimer's Society, and ZOE.

Summary: Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.

BackgroundFarmers have higher rates of depression than nonfarmers and higher rates of suicide than the general population. Several barriers to help seeking have been identified in farmers, which may be overcome by offering web-based mental health support. Computerized cognitive behavioral therapy (cCBT) is an effective intervention used to prevent and treat mild to moderate depression but has not been evaluated in the farming community. ObjectiveThis study explored the feasibility of delivering a cCBT course tailored to farmers using a mixed methods approach. MethodsFarmers (aged ≥18 years) with no, minimal, or moderately severe depressive symptoms (Patient Health Questionnaire–9 [PHQ-9] score

Introduction Patients with episodes of supraventricular tachycardia (SVT), a common heart arrhythmia, are often attended by ambulance services. International guidelines advocate treatment with the Valsalva manoeuvre (VM), but this simple physical treatment has a low success rate, with most patients requiring conveyance to hospital. The Valsalva Assist Device (VAD) is a simple device that might help practitioners and patients perform a more effective VM and reduce the need for patients to be taken to hospital.Methods and analysis This stepped wedge cluster randomised controlled trial, conducted within a UK ambulance service, compares the current standard VM with a VAD-delivered VM in stable adult patients presenting to the ambulance service with SVT. The primary outcome is conveyance to hospital; secondary outcomes measures include cardioversion rates, duration of ambulance care and number of subsequent episodes of SVT requiring ambulance service care. We plan to recruit approximately 800 patients, to have 90% power to detect an absolute reduction in conveyance rate of 10% (from 90% to 80%) between the standard VM (control) and VAD-delivered VM (intervention). Such a reduction in conveyance would benefit patients, the ambulance service and receiving emergency departments. It is estimated potential savings would pay for devices for the entire ambulance trust within 7 months.Ethics and dissemination The study has been approved by the Oxford Research Ethics Committee (reference 22/SC/0032). Dissemination will be through peer-reviewed journal publication, presentation at national and international conferences and by the Arrhythmia Alliance, a patient support charity.Trial registration number ISRCTN16145266.

Keywords: Employability, soft skills, work-integrated learning, curriculum development, Australia. The future of work has generated robust debate among governments, industry, academics and social commentators. The intensity of these debates has extended to the accounting profession. Accordingly, and drawing on the experiences and interpretations of accounting professionals, tertiary students, and academics involved in a Work Integrated Learning (WIL) experience, the present research problematises tensions and gaps between employer skill and knowledge expectations and student interpretations of what employers want. The research unpacks how tertiary curriculum development and learning, and teaching practice innovations can meet employer skill and knowledge expectations. Key findings include students interpreting that highly developed technical skills and grades would enhance their post-degree employability. In contrast and problematically, employers were seeking graduates with highly developed soft skills. The research findings have significant implications for graduate employability and can inform contemporary tertiary accounting curriculum development.

New assemblages of skeletal fossils chemically extracted from carbonates of the Cambrian Stage 2–Drumian Stage are reported from the lower reaches of the Lena River as well as from the Khorbusuonka, Malaya Kuonamka, and Bol’shaya Kuonamka rivers in northern part of the Siberian Platform. The fauna studied with scanning electron microscopy includes brachiopods, molluscs, hyoliths, halkieriids, chancelloriids, tommotiids, lobopodians, palaeoscolecidans, bradoriids, echinoderms, anabaritids, hyolithelminths, and sponges showing similarity to previously described fossil assemblages from Siberia, Laurentia, and Gondwana. The material includes emended descriptions of Halkieria proboscidea, Hadimopanella knappologica, Archaeopetasus typicus, and first descriptions of Hadimopanella foveata Kouchinsky sp. nov. and Archaeopetasus pachybasalis Kouchinsky sp. nov. Affinity of Archaeopetasus to chancelloriids is suggested. Finding of an in-place operculum in a planispiral shell of Michniakia minuta enables reinterpretation of this form as a hyolith, not a mollusc. The cambroclavids Cambroclavus sp. and Zhijinites clavus and the earliest echinoderms belonging to the Rhombifera and Ctenocystoidea are reported respectively from the lower Botoman stage and Botoman–Toyonian transitional beds, correlated with Cambrian Stage 4. Carbon isotopes are analysed from sections of the Chuskuna (upper Kessyusa Group), Erkeket, Kuonamka, Olenyok, Yunkyulyabit-Yuryakh, Tyuser and Sekten formations. A major part of the δ13C record is obtained from the Cambrian Stage 4–Drumian Stage strata which remain incompletely characterised by chemostratigraphy. The Lower Anomocarioides limbataeformis Carbon isotope Excursion (LACE) from the Drumian Stage of the Khorbusuonka River is introduced herein. New chemostratigraphic data are used for regional and global correlation and facilitate study of the evolutionary development of animals and faunas through the “Cambrian explosion”.

Current understanding of Long COVID is limited, in part, due to lack of evidence from population-representative studies. Here, the authors analyse data from ten UK population-based studies and electronic health records, and find wide variation in the frequency of Long COVID between studies but some consistent risk factors.

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2–4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

Mammals are imperiled worldwide, primarily from habitat loss or modification, and exhibit downward trends in their populations and distributions. Likewise, large-bodied herbivores have undergone a collapse in numbers and are at the highest extinction risk of all mammals. Bighorn sheep (Ovis canadensis) are among those large-bodied herbivores that possess a slow-paced life history, suffer from debilitating diseases, and have experienced range contractions across their historical distribution since the late 1800s. Translocations and reintroductions of these mountain ungulates are key aspects of restoration and often are used to re-establish populations in historical habitat or to supplement declining herds. Millions of US dollars and much effort by state and federal natural resource agencies, as well as public and private organizations, have been expended to restore bighorn sheep. Despite those efforts, translocated populations of bighorn sheep have not always been successful. We assessed restoration of bighorn sheep to provide insights in the context of conservation of populations of bighorn sheep, because this management tool is a frequently used to re-establish populations. We focused briefly on past efforts to restore bighorn sheep populations and followed with updates on the value of habitat enhancements, genetic issues, the importance of ecotypic or phenotypic adaptations when restoring populations, predation, and disease transmission. We also raised issues and posed questions that have potential to affect future decisions regarding the restoration of bighorn sheep. This information will help conservationists improve the success of conserving these iconic large mammals.