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Background Attractive targeted sugar baits (ATSBs) are promising new interventions that can complement existing vector control tools. However, reproducible and quantitative information on the level of attractiveness of ATSBs under field conditions is needed. Therefore, we customized camera traps for close-up imaging. We integrated them into a rugged ATSB monitoring station for day and nighttime recording of mosquitoes landing on the bait. Methods The camera traps were evaluated in a semifield system and then in the field in rural Tanzania. In semifield experiments, camera traps were set up in large cages (2 m × 5 m × 2 m) to record mosquitoes landing on an attractive sugar bait (ASB), a blank ASB, or 20% sucrose (w/v). Next, 198 mosquitoes (33 males and 33 females of Anopheles arabiensis, An. funestus and Aedes aegypti) were released into each large cage and allowed to seek a sugar meal for 72 h with a camera recording images of the mosquitoes present on the ASB at 1-min intervals. In the field, 16 camera traps were set in 16 households, 7 with ASB attractant, 7 with ASB blank, and 2 with 20% sucrose (w/v). Human landing catch (HLC) was performed on the same nights as the camera trap recordings. Results Under semifield conditions, significantly more mosquitoes visited the ASBs than the blank baits, with An. funestus visiting more frequently than An. arabiensis. There were no significant differences between female and male An. arabiensis visits, but female An. funestus visited more than their conspecific males did. The duration of visits did not vary between the ASB and blank controls or between the mosquito species. Moreover, mosquitoes visited the ASB or sucrose equally, with An. arabiensis visiting the baits more than An. funestus. Compared with male mosquitoes, female mosquitoes visited the baits more often. There was no significant difference in visit duration between the species. In the field study, a mean of 70 An. arabiensis were caught per person per night on HLC, while 1 individual was caught per night on ASBs. There were significantly more visits by mosquitoes to the ASB than to the ASB blanks or sucrose solution, with more An. arabiensis visiting the baits than An. funestus or Culex quinquefasciatus. Significantly more females than males visited the baits of all the species. Again, the duration of visits was similar among An. arabiensis, An. funestus and C. quinquefasciatus. Aedes aegypti very rarely visited ASBs in the semifield experiments, and none were observed on baits in the field. Conclusions Using camera traps to record still images of mosquitoes on ASBs offers reliable, reproducible and quantitative information on their attractiveness in various environmental conditions. Thus, camera traps serve as effective tools for evaluating and improving ATSB technology. Graphical abstract

Abstract Background Wound infections are a common complication of injuries negatively impacting the patient’s recovery, causing tissue damage, delaying wound healing, and possibly leading to the spread of the infection beyond the wound site. The current gold-standard diagnostic methods based on microbiological testing are not optimal for use in austere medical treatment facilities due to the need for large equipment and the turnaround time. Clinical metagenomics (CMg) has the potential to provide an alternative to current diagnostic tests enabling rapid, untargeted identification of the causative pathogen and the provision of additional clinically relevant information using equipment with a reduced logistical and operative burden. Methods This study presents the development and demonstration of a CMg workflow for wound swab samples. This workflow was applied to samples prospectively collected from patients with a suspected wound infection and the results were compared to routine microbiology and real-time quantitative polymerase chain reaction (qPCR). Results Wound swab samples were prepared for nanopore-based DNA sequencing in approximately 4 h and achieved sensitivity and specificity values of 83.82% and 66.64% respectively, when compared to routine microbiology testing and species-specific qPCR. CMg also enabled the provision of additional information including the identification of fungal species, anaerobic bacteria, antimicrobial resistance (AMR) genes and microbial species diversity. Conclusions This study demonstrates that CMg has the potential to provide an alternative diagnostic method for wound infections suitable for use in austere medical treatment facilities. Future optimisation should focus on increased method automation and an improved understanding of the interpretation of CMg outputs, including robust reporting thresholds to confirm the presence of pathogen species and AMR gene identifications.

Abstract Transparent conducting oxides (TCOs) are crucial for high-performance displays, solar cells, and wearable sensors. However, their high process temperatures and brittle nature have hindered their use in flexible electronics. In this paper, we overturn these limitations by harnessing Cabrera-Mott oxidation to fabricate large-area, two-dimensional (2D) transparent electrodes via liquid metal printing. Our robotic, vacuum-free process deposits ultrathin (2–10 nm) indium tin oxide (ITO) with exceptional flexibility, transparency (>95%) and conductivity (>1300 S/cm) by utilizing hypoeutectic In-Sn alloys to print at

Abstract Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities in isoniazid-resistant katG mutants, providing potential pathway targets to combat isoniazid resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used to generate a genome-wide map of cellular vulnerabilities in an isoniazid-resistant katG mutant strain of M. tuberculosis. Here, we show that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in respiration, ribosome biogenesis, and nucleotide and amino acid metabolism. Importantly, these vulnerabilities are more sensitive to inhibition in an isoniazid-resistant katG mutant and translated to clinical isolates. This work highlights how changes in the physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes.

Abstract We present the discovery and characterization of a new multi-planetary system around the Sun-like star K2-360 (EPIC 201595106). K2-360 was first identified in K2 photometry as the host of an ultra-short-period (USP) planet candidate with a period of 0.88 d. We obtained follow-up transit photometry, confirming the star as the host of the signal. High precision radial velocity measurements from HARPS and HARPS-N confirm the transiting USP planet and reveal the existence of an outer (non-transiting) planet with an orbital period of $$\sim$$ ∼ 10 d. We measure a mass of $$7.67 \pm 0.75$$ 7.67 ± 0.75 $$M_{\oplus }$$ M ⊕ and a radius of $$1.57 \pm 0.08$$ 1.57 ± 0.08 $$R_{\oplus }$$ R ⊕ for the transiting planet, yielding a high mean density of $$11 \pm 2$$ 11 ± 2 g $$\hbox {cm}^{-3}$$ cm - 3 , making it the densest well-characterized USP super-Earth discovered to date. We measure a minimum mass of $$15.2 \pm 1.8$$ 15.2 ± 1.8 $$M_{\oplus }$$ M ⊕ for the outer planet, and explore a migration formation pathway via the von Zeipel–Kozai–Lidov (ZKL) mechanism and tidal dissipation.

Abstract Background Secondary autoimmune disease (SAID) in the context of alemtuzumab treatment is one of the main safety concerns that may arise following administration in people with multiple sclerosis (pwMS). Contributing factors underlying this adverse event are not well understood. The purpose of this systematic review was to appraise the literature investigating the role of alemtuzumab in the development of SAID in pwMS following treatment and identify potential biomarkers/ risk factors that may be predictive of onset of this manifestation. Methods Relevant publications were retrieved from PubMed, Embase, and Web of Science using a three-pronged search strategy containing the following keywords: “multiple sclerosis”; “alemtuzumab”; and “autoimmunity”. Studies that fulfilled the specified eligibility criteria and investigated SAID development after alemtuzumab in pwMS were included in the final analysis. Results 19 papers were included in the final review. Approximately, 47.92% of pwMS treated with alemtuzumab experienced SAID. A variety of biomarkers and risk factors were noted in the development of SAID, with a focus on immunological changes, including: increased homeostatic proliferation and T cell cycling, along with consistently elevated baseline serum IL-21 levels and thyroid autoantibodies. There was no significant association between known human leukocyte antigen (HLA) risk alleles, lymphocyte profile or dynamics and SAID development. Conclusions While the mechanism underlying SAID following alemtuzumab is not fully understood, potential biomarkers and risk factors that may assist in elucidating mechanisms underlying this phenomenon have been documented in several independent studies. Following immunodepletion from alemtuzumab, an IL-21 driven increase in homeostatic proliferation and T cell cycling may disrupt tolerance mechanisms leading to an increase in the propensity toward alemtuzumab-induced autoimmunity. Further research is necessary to clarify the physiological changes after alemtuzumab therapy that trigger SAID in pwMS.

Abstract A well-documented consequence of global warming is increased psychological distress and climate anxiety, but data gaps limit action. While climate anxiety garners attention, its expression in therapy remains unexplored. Natural language processing (NLP) models can identify climate discussions in therapy, aiding therapists and informing training. This study analyzed 32,542 therapy sessions provided by 849 therapists to 7,916 clients in U.S. behavioral health programs between July 2020 and December 2022, yielding 1,722,273 labeled therapist-client micro-dialogues. Climate- and weather-related topics constituted a mere 0.3% of the sessions. Clients exhibiting higher levels of depressive or anxiety symptoms were less likely to discuss weather and climate compared to those with mild or no symptoms. Findings suggest that although global warming is known to impact mental health, these issues are not yet adequately addressed in psychotherapy. This study suggests a potential gap between the documented mental health concerns associated with climate change and their representation in psychotherapy. NLP models can provide valuable feedback to therapists and assist in identifying key moments and conversational topics to inform training and improve the effectiveness of therapy sessions.

Abstract Transcriptional control is fundamental to cellular function. However, despite knowing that transcription factors can repress or activate specific genes, how these functions are implemented at the molecular level has remained elusive, particularly in the endogenous context of developing animals. Here, we combine optogenetics, single-cell live-imaging, and mathematical modeling to study how a zinc-finger repressor, Knirps, induces switch-like transitions into long-lived quiescent states. Using optogenetics, we demonstrate that repression is rapidly reversible (~1 min) and memoryless. Furthermore, we show that the repressor acts by decreasing the frequency of transcriptional bursts in a manner consistent with an equilibrium binding model. Our results provide a quantitative framework for dissecting the in vivo biochemistry of eukaryotic transcriptional regulation.

Abstract Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T cells. For unbiased assessment of cellular immunopathogenesis, here we perform single-cell (sc) transcriptome, surface proteome, and T cell receptor (TCR) sequencing on unaffected skin, affected skin, and blister fluid from 15 SJS/TEN patients. From 109,888 cells, we identify 15 scRNA-defined subsets. Keratinocytes express markers indicating HLA class I-restricted antigen presentation and appear to trigger the proliferation of and killing by cytotoxic CD8+ tissue-resident T cells that express granulysin, granzyme B, perforin, LAG3, CD27, and LINC01871, and signal through the PKM, MIF, TGFβ, and JAK-STAT pathways. In affected tissue, cytotoxic CD8+ T cells express private expanded and unexpanded TCRαβ that are absent or unexpanded in unaffected skin, and mixed populations of macrophages and fibroblasts express pro-inflammatory markers or those favoring repair. This data identifies putative cytotoxic TCRs and therapeutic targets.

Abstract Inhibitors of the integrated stress response (ISR) have been used to explore the potential beneficial effects of reducing the activation of this pathway in diseases. As the ISR is in essence a protective response, there is, however, a risk that inhibition may compromise the cell’s ability to restore protein homeostasis. Here, we show that the experimental compound ISRIB impairs degradation of proteins by the ubiquitin-proteasome system (UPS) during proteotoxic stress in the cytosolic, but not nuclear, compartment. Accumulation of a UPS reporter substrate that is intercepted by ribosome quality control was comparable to the level observed after blocking the UPS with a proteasome inhibitor. Consistent with impairment of the cytosolic UPS, ISRIB treatment caused an accumulation of polyubiquitylated and detergent insoluble defective ribosome products (DRiPs) in the presence of puromycin. Our data suggest that the persistent protein translation during proteotoxic stress in the absence of a functional ISR increases the pool of DRiPs, thereby hindering the efficient clearance of cytosolic substrates by the UPS.

Abstract Background As precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method. Results The S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics. Conclusions Taken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations.

Abstract The physical characterization of proteins in terms of their sizes, interactions, and assembly states is key to understanding their biological function and dysfunction. However, this has remained a difficult task because proteins are often highly polydisperse and present as multicomponent mixtures. Here, we address this challenge by introducing single-molecule microfluidic diffusional sizing (smMDS). This approach measures the hydrodynamic radius of single proteins and protein assemblies in microchannels using single-molecule fluorescence detection. smMDS allows for ultrasensitive sizing of proteins down to femtomolar concentrations and enables affinity profiling of protein interactions at the single-molecule level. We show that smMDS is effective in resolving the assembly states of protein oligomers and in characterizing the size of protein species within complex mixtures, including fibrillar protein aggregates and nanoscale condensate clusters. Overall, smMDS is a highly sensitive method for the analysis of proteins in solution, with wide-ranging applications in drug discovery, diagnostics, and nanobiotechnology.

Laser interferometry is a well-established and widely used technique for precise displacement measurements. In a non-contact atomic force microscope (NC-AFM), it facilitates the force measurement by recording the periodic displacement of an oscillating microcantilever. To understand signal generation in a NC-AFM-based Michelson-type interferometer, we evaluate the non-linear response of the interferometer to the harmonic displacement of the cantilever in the time domain. As the interferometer signal is limited in amplitude because of the spatial periodicity of the interferometer light field, an increasing cantilever oscillation amplitude creates an output signal with an increasingly complex temporal structure. By the fit of a model to the measured time-domain signal, all parameters governing the interferometric displacement signal can precisely be determined. It is demonstrated, that such an analysis specifically allows for the calibration of the cantilever oscillation amplitude with 2% accuracy.

Abstract Deep-water formation in the eastern Subpolar North Atlantic Ocean (eSPNA) and Nordic Seas is crucial for maintaining the lower limb of the Atlantic Meridional Overturning Circulation (AMOC), of consequence for global climate. However, it is still uncertain which processes determine the deep-water formation and how much Atlantic and Arctic waters respectively contribute to the lower limb. To address this, here we used Lagrangian trajectories to diagnose a global eddy-resolving ocean model that agrees well with recent observations highlighting the eSPNA as a primary source of the AMOC lower limb. Comprised of 72% Atlantic waters and 28% Arctic waters, the density and depth of the AMOC lower limb is critically dependent on Atlantic-Arctic mixing, primarily in the vicinity of Denmark Strait. In contrast, Atlantic waters gaining density through air-sea interaction along the eastern periphery of Nordic Seas and not entering the Arctic Ocean make a negligible contribution to the lower limb.

Abstract A large-scale biophysical network model for the isolated striatal body is developed to optimise potential intrastriatal deep brain stimulation applied to, e.g. obsessive-compulsive disorder. The model is based on modified Hodgkin–Huxley equations with small-world connectivity, while the spatial information about the positions of the neurons is taken from a detailed human atlas. The model produces neuronal spatiotemporal activity patterns segregating healthy from pathological conditions. Three biomarkers were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the frequency spectrum of the entire network (rhythmicity) and a combination of the above two. By minimising the deviation of the aforementioned biomarkers from the normal state, we compute the optimal deep brain stimulation parameters, regarding position, amplitude and frequency. Our results suggest that in the DBS optimisation process, there is a clear trade-off between frequency synchronisation and overall network activity, which has also been observed during in vivo studies.

Abstract Adenoid cystic carcinoma (AdCC) is a salivary gland neoplasm that infrequently appears in the sinonasal region. The aim of this study was to evaluate the outcome and clinicopathological parameters of sinonasal AdCC. A retrospective analysis was conducted on all cases of AdCC affecting the nasal cavity or paranasal sinuses between 2000 and 2018 at the University Hospital Zurich. Tumor material was examined for morphological features and analyzed for molecular alterations. A total of 14 patients were included. Mean age at presentation was 57.7 years. Sequencing revealed MYB::NFIB gene fusion in 11/12 analyzable cases. Poor prognostic factors were solid variant (p 30%), high-grade transformation, and sphenoid sinus involvement are negative prognostic factors for sinonasal AdCC. A high prevalence of MYB::NFIB gene fusion may help to correctly classify diagnostically challenging (e.g. metatypical) cases.

Abstract The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC.

Abstract Over 125 million years of ant-plant interactions have culminated in one of the most intriguing evolutionary outcomes in life history. The myrmecophyte Duroia hirsuta (Rubiaceae) is known for its mutualistic association with the ant Myrmelachista schumanni and several other species, mainly Azteca, in the north-western Amazon. While both ants provide indirect defences to plants, only M. schumanni nests in plant domatia and has the unique behaviour of clearing the surroundings of its host tree from heterospecific plants, potentially increasing resource availability to its host. Using a 12-year survey, we asked how the continuous presence of either only M. schumanni or only Azteca spp. benefits the growth and defence traits of host trees. We found that the continuous presence of M. schumanni improved relative growth rates and leaf shearing resistance of Duroia better than trees with Azteca. However, leaf herbivory, dry matter content, trichome density, and secondary metabolite production were the same in all trees. Survival depended directly on ant association (> 94% of trees died when ants were absent). This study extends our understanding of the long-term effects of strict ant-plant mutualism on host plant traits in the field and reinforces the use of D. hirsuta–M. schumanni as a model system suitable for eco-co-evolutionary research on plant–animal interactions.

Background: Consensus guidelines regarding the amount and necessity of post-operative imaging in thoracic surgery are lacking. The efficacy of daily chest radiographs (CXR) following video-assisted (VATS) and robotic-assisted (RATS) thoracoscopic surgery in directing management has not been previously studied. We hypothesize that abnormal clinical findings, rather than abnormal imaging findings, better predict post-operative complications in patients undergoing VATS/RATS lobectomies. Methods: A retrospective review of VATS and RATS lobectomy patients were performed at a tertiary referral center from 1/1/2019–12/31/2021. Demographics, hospital course, and imaging were evaluated. Descriptive statistics, Chi-Square test, Fisher's exact, Wilcoxon rank sum, and multivariable logistic regression were performed. Our outcomes were post-operative complications requiring a procedure and extended length of stay (LOS) (>2 days post-operatively). Results: Out of 362 VATS/RATS lobectomy patients, 15 patients had post-operative complications requiring a procedure. Almost all patients who required a procedure had abnormal clinical signs and symptoms (14/15; p

Synchrotron light sources require X-ray optics with extremely demanding accuracy for the surface profile, with less than 100 nrad slope errors and sub-nanometre height errors. Such errors are challenging to achieve for aspheres using traditional polishing methods. However, post-polishing error correction can be performed using techniques such as ion beam figuring (IBF) to improve optics to the desired quality. This work presents a brief overview of the history of IBF, introduces some of the challenges for obtaining such demanding figure errors, and highlights the work done at several in-house IBF facilities at synchrotron light sources worldwide to obtain state-of-the-art optical quality.

Abstract Background SARS-CoV-2 remains rapidly evolving, and many biologically important genomic substitutions/indels have characterised novel SARS-CoV-2 lineages, which have emerged during successive global waves of the pandemic. Worldwide genomic sequencing has been able to monitor these waves, track transmission clusters, and examine viral evolution in real time to help inform healthcare policy. One school of thought is that an apparent greater than average divergence in an emerging lineage from contemporary variants may require persistent infection, for example in an immunocompromised host. Due to the nature of the COVID-19 pandemic and sampling, there were few studies that examined the evolutionary trajectory of SARS-CoV-2 in healthy individuals. Methods We investigated viral evolutionary trends and participant symptomatology within a cluster of 16 SARS-CoV-2 infected, immunocompetent individuals with no co-morbidities in a closed transmission chain. Longitudinal nasopharyngeal swab sampling allowed characterisation of SARS-CoV-2 intra-host variation over time at both the dominant and minor genomic variant levels through Nimagen-Illumina sequencing. Results A change in viral lineage assignment was observed in individual infections; however, there was only one indel and no evidence of recombination over the period of an acute infection. Minor and dominant genomic modifications varied between participants, with some minor genomic modifications increasing in abundance to become the dominant viral sequence during infection. Conclusions Data from this cohort of SARS-CoV-2-infected participants demonstrated that long-term persistent infection in an immunocompromised host was not necessarily a prerequisite for generating a greater than average frequency of amino acid substitutions. Amino acid substitutions at both the dominant and minor genomic sequence level were observed in immunocompetent individuals during infection showing that viral lineage changes can occur generating viral diversity.

Abstract Background Malaria is a life-threatening parasitic disease typically transmitted through the bite of an infected Anopheles mosquito. There is ample evidence showing the potential of malaria infection to affect the counts of lymphocyte subpopulations in the peripheral blood, but the extent of alteration might not be consistent in all geographical locations, due to several local factors. Although Ghana is among the malaria-endemic countries, there is currently no available data on the level of alterations that occur in the counts of lymphocyte subpopulations during P. falciparum malaria infection among adults. Aim The study was to determine the immunophenotypic alterations in the level of peripheral blood lymphocytes and their subsets in adults with uncomplicated P. falciparum malaria infection and apparently healthy participants. Methods The study was a cross-sectional comparative study conducted in two municipalities of the Volta region of Ghana. Blood samples were collected from study participants and taken through serology (P. falciparum/Pan Rapid Diagnostic Kits), microscopy (Thick and thin blood films) and Haematological (Flow cytometric and Full blood count) analysis. Results A total of 414 participants, comprising 214 patients with malaria and 200 apparently healthy individuals (controls) were recruited into this study. Parasite density of the malaria patients ranged from 75/µL to 84,364/µL, with a mean of 3,520/µL. It was also observed that the total lymphocytes slightly decreased in the P. falciparum-infected individuals (Mean ± SD: 2.08 ± 4.93 × 109/L) compared to the control group (Mean ± SD: 2.47 ± 0.80 × 109/L). Again, there was a significant moderate positive correlation between parasite density and haematocrit levels (r = 0.321, p

Physical restraints are widely used and accepted as protective measures during treatment in intensive care unit (ICU). This review of the literature summarizes the adverse events and outcomes associated with physical restraint use, and the risk factors associated with their use during treatment in the ICU. The PubMed, Scopus, and Google Scholar databases were screened using predefined search terms to identify studies pertaining to adverse events and/or outcomes associated with physical restraint use, and the factors associated with their use in adult patients admitted to the ICU. A total of 24 articles (including 6126 patients) that were published between 2006 and 2022 were identified. The described adverse events associated with physical restraint use included skin injuries, subsequent delirium, neurofunctional impairment, and a higher rate of post-traumatic stress disorder. Subsequent delirium was the most frequent adverse event to be reported. No alternative measures to physical restraints were discussed, and only one study reported a standardized protocol for their use. Although physical restraint use has been reported to be associated with adverse events (including neurofunctional impairment) in the literature, the available evidence is limited. Although causality cannot be confirmed, a definite association appears to exist. Our findings suggest that it is essential to improve awareness regarding their adverse impact and optimize approaches for their detection, management, and prevention using protocols or checklists.

Projects are discussed as social processes that are bounded in both time and space. Elaborating on space is still scarce in studies on project organising. The aim in this paper is to explore space influence on project planning, to extend our understanding of the relationship between space and project organising. Through two illustrative examples, construction project planning practices were followed within and between projects as the actors sought to handle space. Contribution develops current understanding of how projects are embedded in space and its influence on project planning practices, by shedding light on the recursive relationship between space and project organising. Furthermore, to trace planning practice both within a project and between parallel projects visualise how a broader perspective of the embeddedness is necessary. The findings nuance the current understanding of project's embeddedness, by visualising how planning practices can be directed to both changing space or to maintain space by changing practices.

Background: Large language models (LLMs) such as ChatGPT-4 (CG4) are proving to be valuable tools in the medical field, not only in facilitating administrative tasks, but in augmenting medical decision-making. LLMs have previously been tested for diagnostic accuracy with expert-generated questions and standardized test data. Among those studies, CG4 consistently outperformed alternative LLMs, including ChatGPT-3.5 (now no longer publicly available for use) and Google Bard (now known as “Google Gemini”). The next logical step was to begin to explore CG4’s accuracy within a specific clinical domain. Our study evaluated the diagnostic accuracy of CG4 within an inpatient neurology consultation service. Methods: We conducted a review of all patients listed on the daily neurology consultation roster at Arrowhead Regional Medical Center in Colton, CA, for all days surveyed until we reached a total of 51 patients, ensuring a complete and representative sample of the patient population. ChatGPT-4, using HIPAA-compliant methodology, received patient data from the Epic EHR as input and was asked to provide an initial differential diagnoses list, investigations and recommended actions, a final diagnosis, and a treatment plan for each patient. A comprehensiveness scale (an ordinal scale between 0 and 3) was then used to rate match accuracy between consultant and CG4 initial diagnoses and the consultants’ final diagnoses. In this proof-of-concept study, we assumed that the neurology consultants’ final diagnoses were accurate. We employed a non-parametric bootstrap resampling method to create 95 % confidence intervals around mean scores, a Fisher’s Exact test, a Wilcoxon Rank Sum test, and ordinal logistic regression models to compare the performance between consultant and CG4 groups. Findings: Our study found that CG4 demonstrated diagnostic accuracy comparable to that of consultant neurologists. The most frequent comprehensiveness score achieved by both groups was ''3,'' with consultant neurologists achieving this score 43 times and CG4 achieving it 31 times. The mean comprehensiveness scores were 2.75 (95 % CI: 2.49–2.90) for the consultant group and 2.57 (95 % CI: 2.31–2.67) for the CG4 group. The success rate for comprehensive diagnoses (a score of ''2″ or ''3″) was 94.1 % (95 % CI: 84.1%–98.0 %) for consultants and 96.1 % (95 % CI: 86.8%–98.9 %) for CG4, with no statistically significant difference in success rates (p = 1.00). The Wilcoxon Rank Sum Test indicated that the consultant group had a higher likelihood of providing more comprehensive diagnoses (W = 1583, p = 0.02). Ordinal logistic regression models identified significant predictors of diagnostic accuracy, with the consultant diagnosis group showing an odds ratio of 3.68 (CI 95 %: 1.28–10.55) for higher value outcomes. Notably, integrating CG4’s initial diagnoses with those from consultants could achieve comprehensive diagnostics in all cases, indicating a number needed to treat (NNT) of 17 to attain one additional comprehensive diagnosis. Interpretation: Our findings suggest that CG4 can serve as a valuable diagnostic tool within the domain of inpatient neurology, providing comprehensive and accurate initial diagnoses comparable to those of consultant neurologists. The use of CG4 might contribute to better patient outcomes by serving as an aid in diagnosis and treatment recommendations, potentially leading to reduced missed diagnoses and quicker diagnostic processes. Continuous strategies and evaluations to improve LLMs' accuracy remain crucial. Further studies with larger sample sizes and independent third-party evaluations are recommended to confirm these findings and assess the impact of LLMs on patient health.

This TATuP Special topic is intended to contribute to interdisciplinary, problemoriented research on the shift toward bio- and earth-based building materials considering the related socio-technical, economic, political, ecological, and regulatory adaptation and adoption processes. It aims to examine the research and use of sustainable building materials from an integrative perspective, emphasizing the associated visions of the future, implementation opportunities and obstacles, conditions of use and acceptability, as well as the requirements of integration into the planning phases in architecture and construction. Pointed international perspectives referring to the local built heritage are also welcome.

In the introduction, we discuss the need for a material transition in architecture and construction and the challenges it poses. Drawing on innovation research, the multi-level perspective (MLP), and thousands of years of building history, we identify the potential for change, the obstacles that need to be overcome, and the importance of standards, in particular of established industry standards. The introduction also includes a brief description of each article.

Movements are performed by motoneurons transforming synaptic inputs into an activation signal that controls muscle force. The control signal emerges from interactions between ionotropic and neuromodulatory inputs to motoneurons. Critically, these interactions vary across motoneuron pools and differ between muscles. To provide the most comprehensive framework to date of motor unit activity during isometric contractions, we identified the firing activity of extensive samples of motor units in the tibialis anterior (129 ± 44 per participant; n=8) and the vastus lateralis (130 ± 63 per participant; n=8) muscles during isometric contractions of up to 80% of maximal force. From this unique dataset, the rate coding of each motor unit was characterised as the relation between its instantaneous firing rate and the applied force, with the assumption that the linear increase in isometric force reflects a proportional increase in the net synaptic excitatory inputs received by the motoneuron. This relation was characterised with a natural logarithm function that comprised two stages. The initial stage was marked by a steep acceleration of firing rate, which was greater for low- than medium- and high-threshold motor units. The second stage comprised a linear increase in firing rate, which was greater for high- than medium- and low-threshold motor units. Changes in firing rate were largely non-linear during the ramp-up and ramp-down phases of the task, but with significant prolonged firing activity only evident for medium-threshold motor units. Contrary to what is usually assumed, our results demonstrate that the firing rate of each motor unit can follow a large variety of trends with force across the pool. From a neural control perspective, these findings indicate how motor unit pools use gain control to transform inputs with limited bandwidths into an intended muscle force.

The host restricts Salmonella enterica serovar Typhimurium infection of the gut via inflammasome-dependent sloughing of infected epithelial cells. Here we determined that concurrent caspase 1/11-dependent release of the goblet cell-derived mucin, Muc2, into the intestinal lumen also controls Salmonella burdens in infected mice. The increased release of mucins from goblet cells in the cecum and nearby proximal colon, and the subsequent thickening of the protective mucus barrier layer in the distal colon, were all dependent on the cytokines interleukin (IL)-18 and IL-22, as deficiencies in either cytokine resulted in reduced mucin secretion. Supplementation of IL-18 into IL-22 deficient mice restored mucin secretion, indicating that IL-22 acted upstream of IL-18 secretion during infection. In contrast, IL-18 and IL-22 independent signaling through Nlrp6 underlies only a modest, infection-induced increase in mucin secretion from goblet cells in the distal colon. These findings reveal that inflammasome signaling orchestrates multiple levels of protection centered on the intestinal epithelium, including pyroptosis and expulsion of infected enterocytes, as well as the release of mucins by goblet cells in the cecum and along the length of the colon. Our studies underscore the pivotal, multi-faceted role of inflammasome signaling in promoting host defense at the intestinal mucosal surface.

This paper aims to explore the likelihood of lost items to be recovered by public transport (PT) users with a focus on the moral values of other PT users in the city of Accra. To achieve this goal, a non-experimental research design was employed to identify the factors influencing PT users’ decisions to return lost items. Data were collected using a revealed preference survey (RP), which was distributed both manually and online using Google Form. The survey consisted of a structured questionnaire with close-ended questions. A total of 603 respondents completed the survey, and the reliability of the questionnaire was verified using Cronbach’s Alpha (CA), yielding a score of 0.804. The study’s findings revealed that religious values (Mean = 4.41, SD = 1.97) and empathy (Mean = 4.37, SD = 1.92) were the two most significant factors that influenced respondents’ decisions to return lost items. Regarding the ‘value of an item’, the high standard deviation indicates that respondents’ perceptions of an item’s value varied greatly and may not have affected respondents decision to return lost but found item. Future research in urban transportation should concentrate on experimental research where reflection of respondents’ true decision to return or keep a found item can be ascertained.

ObjectivesTo assess changes in trainees’ knowledge and application of Diversity, Equity, Inclusion, and Justice (DEIJ) concepts after participating in a midwestern academic medical center Leadership Education in Neurodevelopmental and Related Disabilities (LEND) program. LEND is a federally funded year-long program training individuals of various disciplines (e.g., speech pathology, family advocacy, psychology) to better support the health of individuals with disabilities.MethodsTrainees (n = 46) answered questions about their knowledge and application of DEIJ topics before and after program participation in 2021–2022 and 2022–2023. Changes in trainees’ responses were examined using paired-samples t-tests.ResultsThirty-six (78%) participants identified as White, 7 (15%) as Black, 2 (4%) as Asian, and 2 (4%) as more than one race. Three (7%) participants identified as Hispanic/Latino. Over the one-year program, trainees’ perceived knowledge increased [t(45) = 5.84, p

Background Microbial Keratitis (MK) is a leading cause of corneal blindness due to infection and its consequences, with a higher incidence in resource-limited nations. Hospital-based patient records from different parts of Nepal suggest patients often use traditional eye medicine to treat MK. Traditional healers (TH) within the community are often the first point of care for MK management. Little is known of their practice, perceptions, and knowledge around MK management. We aimed to understand the role of traditional healers in the management of MK in south-eastern Nepal. Methods A cross-sectional, mixed method, descriptive study was conducted in the Siraha district of Nepal. A total of 109 traditional healers consented to participate in a survey of knowledge, attitude, and practices. Some participants were also invited to participate in in-depth interviews and focus group discussions. Interviews and focus groups were conducted and recorded in the Maithili language by a native speaking interviewer and transcribed into English. Descriptive analysis was performed for the survey. Data saturation was considered the endpoint for qualitative data collection, and a thematic was analysis applied. Results Traditional healers believe that infection of the eye can be caused by trauma, conjunctivitis, or evil spirits. They were unclear about differentiating MK from other eye conditions. They provided various types of treatment. Some were confident that they could treat severe ulcers that had not responded to medical therapy, while others thought treating larger diameter ulcers would be difficult. Although there were mixed responses in referring patients with MK, the majority of TH were willing to refer. Conclusion In a weak health system, traditional healers may help address barriers to healthcare access and reduce delays to definitive care, upon integration into the formal health system and referral pathway.

We present a detailed mass spectrometric analysis of three 2 + 1 T-cell bispecific monoclonal antibodies (TCB mAbs), where an unexpected +15.9950 Da mass shift in tryptic peptides was observed. This modification was attributed to the occurrence of 5R-hydroxylysine (Hyl) using a hybrid LC–MS/MS molecular characterization and CRISPR/Cas9 gene deletion approach. The modification was found at various sites within TCB mAbs, with a conspicuous hot spot motif mirroring a prior observation where Hyl was mapped to the CH1–VH Fab domain interface of IgGs. In contrast to the preceding report, our structural modeling analysis on TCB mAbs unveiled substantial differences in the orientation and flexibility of motifs in immediate proximity and across the artificial CH1–VL cross Fab interface and upstream elbow segment. Utilizing a hybrid database search, RNAseq, and a CRISPR/Cas9 knockout methodology in Chinese hamster ovary (CHO) production cell lines, procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) were conclusively identified as the catalyzing enzymes accountable for the 5R-Hyl modification in TCB mAbs. To quantitatively inhibit Hyl formation in TCB mAbs, the activity of all three Chinese hamster PLOD isoenzymes needs to be depleted via CRISPR/Cas9 gene knockout. Moreover, our investigation identified cell culture iron availability, process duration, and clonal variability in CHO cells as elements influencing the levels of Hyl formation in TCB mAbs. This research offers a solution for circumventing Hyl formation in therapeutic complex mAb formats, such as TCB mAbs, produced in CHO cell culture processes, thereby addressing potential technical and biological challenges associated with unintended Hyl modification.

Snowfall/cover and snowmelt are essential determinants of winter soil processes/events that may force the biogeochemical dynamics of soils in temperate regions. Increasing variability of the European hydroclimate is expected to lead to more frequent intermittent warm periods, which cause snowmelt during winter and rapidly mobilize large amounts of dissolved organic matter (DOM). This study, conducted at the Hainich Critical Zone Exploratory in Germany, seeks to address a significant gap in understanding the molecular impacts of snowmelt-induced DOM flows and their ability to alter soil ecosystems rapidly. During two snowmelt events between January and March 2021, we observed that DOM concentration and composition varied more in forest soil seepage than in grassland soil seepage. Forest seepage showed a pronounced DOM flux peak and synchronous increases in the relative abundances of aromatic DOM components, indicating surface-derived transport of plant litter carbon. In the grassland, however, peak DOM fluxes were characterized by a marked increase in nitrogen-containing (N-containing) DOM components, indicating a predominance of microbial carbon. Notably, the unique DOM components specific to each ecosystem increased during peak fluxes in the forest but decreased in the grassland. We suggest that an overall higher molecular richness and the broader functional metabolic potentials in grassland may account for its relatively greater DOM stability compared to the forest during peak snowmelt events.

Himatiichnus mangano igen. et isp. nov., a new trace fossil from the late Ediacaran Huns Member of the Urusis Formation, southern Namibia, comprises intertwining tubes exhibiting dual lineation patterns and reminiscent of both modern and early Cambrian examples of priapulid worm burrows. These similarities support the interpretation of a total-group scalidophoran tracemaker for H. mangano, thus providing direct evidence for the first appearance date of Scalidophora in the late Ediacaran ca 539 Ma. This new material is thus indicative of the presence of total-group scalidophorans below the Cambrian boundary and supports inference of a lengthy Precambrian fuse for the Cambrian explosion.

IntroductionHow to adapt the curriculum of medicine, pharmacy, and biomedical sciences to prepare future health professionals to meet the challenge of maintaining quality care in a period of socio-ecological crisis? Addressing connections between humanity and sustainable environment should include an analysis of the reciprocal influence of various ecosystems, since it is now clear that healthcare systems have an impact on ecosystems and vice versa. Here, we propose that integrating the United Nations Sustainable Development Goals (SDGs) into the curriculum could be a first step in such a transversal education.MethodsMembers of the faculty of medicine at the University of Namur, Belgium, including teaching staff of the department of medicine, pharmacy, biomedical sciences and psychology, were invited to respond anonymously to a questionnaire about their views on the feasibility of integrating the SDGs into their teaching. A subsequent survey on students’ perceptions of such teaching was conducted by student representatives.ResultsSeventy-nine percent of surveyed members of the medical faculty believe that it is possible to integrate SDGs into their lectures. However, 44–86% of them did not know how to integrate each individual goal. 94.4% of students would like SDGs to play a greater role in their education; 64.4% of them would integrate them into existing modules; 23.9% would create an optional module, and 11.9% would create a mandatory module.ConclusionSustainable Development Goals integration into the curriculum of medicine, pharmacy, and biomedical sciences is perceived as challenging in a dense teaching program. To clarify how SDGs can translate into traditional lectures, we provide for each SDG targeted applications for bachelor’s, master’s and continuing education.

Background: Hospital mergers remain common, but their influence on healthcare quality varies. Data on effects of European hospital mergers are ill defined, and academic hospitals in particular. This case study assesses early quality of care changes in two formerly competing Dutch academic hospitals that merged on June 6, 2018. Methods: Statistical process control and interrupted time series analysis were performed. All adult, non-psychiatric patients, admitted between 01-03–2016 and 01-10-2022 were eligible for analysis. Primary outcome measure was all cause in-hospital mortality (or hospice), secondary outcomes were unplanned 30-day readmissions to same hospital, length of stay, and patients’ hospital rating. Data were obtained from electronic health records, and patient experience surveys. Findings: The mean (SD) age of the 573 813 included patients was 54·3 (18·9) years. The minority was female (277 817, 48·4 %), and most admissions were acute (308 597, 53·8 %). No merger related change in mortality was found in the first 20 months post-merger (limited to the pre-Covid-19 era). For this same period, the 30-day readmission incidence changed to a downward slope post-merger, and the length of stay shortened (immediate level-change −3·796 % (95 % CI, −5·776 % to −1·816 %) and trend-change −0·150 % per month (95 % CI, −0·307 % to 0·007 %)). Patients’ hospital ratings seemed to improve post-merger. Interpretation: In this quality improvement study, a full- and gradual post-merger integration strategy for a Dutch academic hospital merger was not associated with changes in in-hospital mortality, and yielded slight improved results for secondary quality of care outcomes.

Decoding the activity of individual neural cells during natural behaviours allows neuroscientists to study how the nervous system generates and controls movements. Contrary to other neural cells, the activity of spinal motor neurons can be determined non-invasively (or minimally invasively) from the decomposition of electromyographic (EMG) signals into motor unit firing activities. For some interfacing and neuro-feedback investigations, EMG decomposition needs to be performed in real time. Here, we introduce an open-source software that performs real-time decoding of motor neurons using a blind-source separation approach for multichannel EMG signal processing. Separation vectors (motor unit filters) are optimised for each motor unit from baseline contractions and then re-applied in real time during test contractions. In this way, the firing activity of multiple motor neurons can be provided through different forms of visual feedback. We provide a complete framework with guidelines and examples of recordings to guide researchers who aim to study movement control at the motor neuron level. We first validated the software with synthetic EMG signals generated during a range of isometric contraction patterns. We then tested the software on data collected using either surface or intramuscular electrode arrays from five lower limb muscles (gastrocnemius lateralis and medialis, vastus lateralis and medialis, and tibialis anterior). We assessed how the muscle or variation of contraction intensity between the baseline contraction and the test contraction impacted the accuracy of the real-time decomposition. This open-source software provides a set of tools for neuroscientists to design experimental paradigms where participants can receive real-time feedback on the output of the spinal cord circuits.

The reality of human-induced climate change is unequivocal and exerts an ever-increasing global impact. Access to the latest scientific information on current climate change and projection of future trends is important for planning adaptation measures and for informing international efforts to reduce emissions of greenhouse gases (GHGs). Identification of hazards and risks may be used to assess vulnerability, determine limits to adaptation, and enhance resilience to climate change. This article highlights how recent research programs are continuing to elucidate current processes and advance projections across major climate systems and identifies remaining knowledge gaps. Key findings include projected future increases in monsoon rainfall, resulting from a changing balance between the rainfall-reducing effect of aerosols and rainfall-increasing GHGs; a strengthening of the storm track in the North Atlantic; an increase in the fraction of precipitation that falls as rain at both poles; an increase in the frequency and severity of El Niño Southern Oscillation (ENSO) events, along with changes in ENSO teleconnections to North America and Europe; and an increase in the frequency of hazardous hot-humid extremes. These changes have the potential to increase risks to both human and natural systems. Nevertheless, these risks may be reduced via urgent, science-led adaptation and resilience measures and by reductions in GHGs.

Summary: Background: Surgical care holds significant importance in healthcare, especially in low and middle-income countries, as at least 50% of the 4.2 million deaths within the initial 30 days following surgery take place in these countries. The Lancet Commission on Global Surgery proposed six indicators to enhance surgical care. In Colombia, studies have been made using secondary data. However, strategies to reduce perioperative mortality have not been implemented. This study aims to describe the fourth indicator, perioperative mortality rate (POMR), with primary data in Colombia. Methods: A multicentre prospective cohort study was conducted across 54 centres (hospitals) in Colombia. Each centre selected a 7-day recruitment period between 05/2022 and 01/2023. Inclusion criteria involved patients over 18 years of age undergoing surgical procedures in operating rooms. Data quality was ensured through a verification guideline and statistical analysis using mixed-effects multilevel modelling with a case mix analysis of mortality by procedure-related, patient-related, and hospital-related conditions. Findings: 3807 patients were included with a median age of 48 (IQR 32–64), 80.3% were classified as ASA I or II, and 27% of the procedures had a low-surgical complexity. Leading procedures were Orthopedics (19.2%) and Gynaecology/Obstetrics (17.7%). According to the Clavien–Dindo scale, postoperative complications were distributed in major complications (11.7%, 10.68–12.76) and any complication (31.6%, 30.09–33.07). POMR stood at 1.9% (1.48–2.37), with elective and emergency surgery mortalities at 0.7% (0.40–1.23) and 3% (2.3–3.89) respectively. Interpretation: The POMR was higher than the ratio reported in previous national studies, even when patients had a low–risk profile and low-complexity procedures. The present research represents significant public health progress with valuable insights for national decision-makers to improve the quality of surgical care. Funding: This work was supported by Universidad del Rosario and Fundación Cardioinfantil-Instituto de Cardiología grant number CTO-057-2021, project-ID IV-FGV017.

Study’s Novelty/Excerpt • This study investigates into the microbial contamination of second-hand clothes, highlighting their potential role in infection transmission. • The research highlights the significant phosphate-solubilizing activity of these native strains, which enhances phosphorus availability to plants through the secretion of organic acids and enzymes. • The findings underscore the need for public health interventions, including the washing and disinfection of second-hand clothing to mitigate the risk of spreading antibiotic-resistant pathogens. Full Abstract Used clothes can potentially be an element in the chain of infection transmission during normal daily activities. Second-hand wear is among such used clothes purchased by many people and used directly without considering any attending health implications. This study, therefore, examined the level of microbial contamination of second-hand clothes and the association between the different categories of the clothes and microbial contaminants. Second-hand clothes such as shirts, trousers, vests, socks, and shoes were bought from three Markets in Girei, Yola North and Yola South. Isolation of organisms was carried out via Standard Plate Count. Isolates were identified using morphology and appropriate biochemical methods. A chi-square test (P ≤ 0.05 significant) was done to analyze some of the data obtained. Antibiotic susceptibility of the bacterial isolates was also determined using the Kirby-Bauer method. The most frequently isolated bacteria were Staphylococcus aureus. Other bacteria isolated were Pseudomonas spp and E. coli. A total of four fungal species were isolated. These are Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Trichophyton rubrum. Trousers had the highest bacterial count (1.10 x103 CFU/mL) and fungal count (8.00 x104 CFU/mL). The data obtained shows no significant association between fungal species and the categories of clothes with (P = 0.15), but there is a significant association between bacterial species isolated and the categories of clothes analyzed (P = 0.02). S. aureus was susceptible to ciprofloxacin (100%) and erythromycin (92.8%), while Pseudomonas sp and E. coli were most susceptible to ciprofloxacin and sparfloxacin (100%). The least susceptibility was observed with amoxicillin and sulfamethoxazole-trimethoprim. It became obvious that these clothes are possible carriers of antibiotic-resistant pathogens for skin and other infections. Washing and disinfecting second-hand wear before use may be important in minimizing the potential health implications associated with the isolated pathogens.

Introduction: Acute hematogenous osteomyelitis may have significant morbidity and mortality if undiagnosed. Because it is uncommon in developed countries and has variable presentations, the patient may undergo several healthcare visits prior to diagnosis. Case Report: We report the case of a 9-year-old male who presented with hip and knee pain with associated fevers and was found to have osteomyelitis and intraosseous abscess in the diaphysis of the right femur. He had multiple emergency department and outpatient visits before the ultimate diagnosis was made. He was treated with irrigation and debridement in addition to intravenous antibiotics. Conclusion: Pediatric acute hematogenous osteomyelitis can have subtle presentations, and this case illustrates some of the difficulties in making the diagnosis. This condition should be considered in the workup of a child with undifferentiated fever, pain, or decrease in mobility.

Abstract Engineered mammalian cells are key for biotechnology by enabling broad applications ranging from in vitro model systems to therapeutic biofactories. Engineered cell lines exist as a population containing sub-lineages of cell clones that exhibit substantial genetic and phenotypic heterogeneity. There is still a limited understanding of the source of this inter-clonal heterogeneity as well as its implications for biotechnological applications. Here, we developed a genomic barcoding strategy for a targeted integration (TI)-based CHO antibody producer cell line development process. This technology provided novel insights about clone diversity during stable cell line selection on pool level, enabled an imaging-independent monoclonality assessment after single cell cloning, and eventually improved hit-picking of antibody producer clones by monitoring of cellular lineages during the cell line development (CLD) process. Specifically, we observed that CHO producer pools generated by TI of two plasmids at a single genomic site displayed a low diversity (

Abstract Background Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3–5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials. Methods We recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed. Results Analyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective. Conclusion 5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the ‘trough’ periods before the next dosing, even with this intensive regimen.

Abstract Background Effective testing for malaria, including the detection of infections at very low densities, is vital for the successful elimination of the disease. Unfortunately, existing methods are either inexpensive but poorly sensitive or sensitive but costly. Recent studies have shown that mid-infrared spectroscopy coupled with machine learning (MIRs-ML) has potential for rapidly detecting malaria infections but requires further evaluation on diverse samples representative of natural infections in endemic areas. The aim of this study was, therefore, to demonstrate a simple AI-powered, reagent-free, and user-friendly approach that uses mid-infrared spectra from dried blood spots to accurately detect malaria infections across varying parasite densities and anaemic conditions. Methods Plasmodium falciparum strains NF54 and FCR3 were cultured and mixed with blood from 70 malaria-free individuals to create various malaria parasitaemia and anaemic conditions. Blood dilutions produced three haematocrit ratios (50%, 25%, 12.5%) and five parasitaemia levels (6%, 0.1%, 0.002%, 0.00003%, 0%). Dried blood spots were prepared on Whatman™ filter papers and scanned using attenuated total reflection-Fourier Transform Infrared (ATR-FTIR) for machine-learning analysis. Three classifiers were trained on an 80%/20% split of 4655 spectra: (I) high contrast (6% parasitaemia vs. negative), (II) low contrast (0.00003% vs. negative) and (III) all concentrations (all positive levels vs. negative). The classifiers were validated with unseen datasets to detect malaria at various parasitaemia levels and anaemic conditions. Additionally, these classifiers were tested on samples from a population survey in malaria-endemic villages of southeastern Tanzania. Results The AI classifiers attained over 90% accuracy in detecting malaria infections as low as one parasite per microlitre of blood, a sensitivity unattainable by conventional RDTs and microscopy. These laboratory-developed classifiers seamlessly transitioned to field applicability, achieving over 80% accuracy in predicting natural P. falciparum infections in blood samples collected during the field survey. Crucially, the performance remained unaffected by various levels of anaemia, a common complication in malaria patients. Conclusion These findings suggest that the AI-driven mid-infrared spectroscopy approach holds promise as a simplified, sensitive and cost-effective method for malaria screening, consistently performing well despite variations in parasite densities and anaemic conditions. The technique simply involves scanning dried blood spots with a desktop mid-infrared scanner and analysing the spectra using pre-trained AI classifiers, making it readily adaptable to field conditions in low-resource settings. In this study, the approach was successfully adapted to field use, effectively predicting natural malaria infections in blood samples from a population-level survey in Tanzania. With additional field trials and validation, this technique could significantly enhance malaria surveillance and contribute to accelerating malaria elimination efforts.

Abstract Background Palmitoylethanolamide (PEA) has analgesic/anti-inflammatory properties that may be a suitable alternative to over-the-counter (OTC) non-steroidal analgesics/anti-inflammatories. While OTC pain medications can impair strength training adaptations, the mechanism of action of PEA is distinct from these and it may not negatively affect skeletal muscle adaptations to strength training. Methods The primary aim of this study was to investigate the effects of daily PEA supplementation (350 mg Levagen + equivalent to 300 mg PEA) combined with 8-weeks of resistance training on lean body mass with secondary aims addressing strength, power, sleep, and wellbeing compared to placebo (PLA) in young, healthy, active adults. In a randomized, controlled, double-blinded trial, 52 untrained, recreationally active participants aged 18–35 y were allocated to either the PEA or PLA groups. Participants consumed either 2 × 175 mg Levagen + PEA or identically matched maltodextrin capsules during an 8-week period of whole-body resistance training. This trial assessed the pre- to post- changes in total and regional lean body mass, muscular strength (1-RM bench, isometric mid-thigh pull), muscular power [countermovement jump (CMJ), bench throw], pain associated with exercise training, sleep, and wellbeing compared with the PEA or PLA condition. Results 48 Participants were included in the final intention to treat (ITT) analysis and we also conducted per protocol (PP) analysis (n = 42). There were no significant between-group differences for total or regional lean muscle mass post-intervention. There was a significantly higher jump height (CMJ) at week 10 in the PEA group compared to the PLA (Adjusted mean difference [95% CI] p-value; ITT: − 2.94 cm [− 5.15, − 0.74] p = 0.010; PP: − 2.93 cm [− 5.31, − 0.55] p = 0.017). The PLA group had higher 1-RM bench press post-intervention compared with the PEA group (ITT: 2.24 kg [0.12, 4.37] p = 0.039; PP: 2.73 kg [0.40, 5.06] p = 0.023). No significant treatment effects were noted for any of the other outcomes. Conclusion PEA supplementation, when combined with 8 weeks of strength training, did not impair lean mass gains and it resulted in significantly higher dynamic lower-body power when compared with the PLA condition. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR: ACTRN12621001726842p).

Abstract Field-derived metrics are critical for effective control of malaria, particularly in sub-Saharan Africa where the disease kills over half a million people yearly. One key metric is entomological inoculation rate, a direct measure of transmission intensities, computed as a product of human biting rates and prevalence of Plasmodium sporozoites in mosquitoes. Unfortunately, current methods for identifying infectious mosquitoes are laborious, time-consuming, and may require expensive reagents that are not always readily available. Here, we demonstrate the first field-application of mid-infrared spectroscopy and machine learning (MIRS-ML) to swiftly and accurately detect Plasmodium falciparum sporozoites in wild-caught Anopheles funestus, a major Afro-tropical malaria vector, without requiring any laboratory reagents. We collected 7178 female An. funestus from rural Tanzanian households using CDC-light traps, then desiccated and scanned their heads and thoraces using an FT-IR spectrometer. The sporozoite infections were confirmed using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), to establish references for training supervised algorithms. The XGBoost model was used to detect sporozoite-infectious specimen, accurately predicting ELISA and PCR outcomes with 92% and 93% accuracies respectively. These findings suggest that MIRS-ML can rapidly detect P. falciparum in field-collected mosquitoes, with potential for enhancing surveillance in malaria-endemic regions. The technique is both fast, scanning 60–100 mosquitoes per hour, and cost-efficient, requiring no biochemical reactions and therefore no reagents. Given its previously proven capability in monitoring key entomological indicators like mosquito age, human blood index, and identities of vector species, we conclude that MIRS-ML could constitute a low-cost multi-functional toolkit for monitoring malaria risk and evaluating interventions.

Abstract To develop and assess a deep learning (DL) pipeline to learn dynamic MR image reconstruction from publicly available natural videos (Inter4K). Learning was performed for a range of DL architectures (VarNet, 3D UNet, FastDVDNet) and corresponding sampling patterns (Cartesian, radial, spiral) either from true multi-coil cardiac MR data (N = 692) or from synthetic MR data simulated from Inter4K natural videos (N = 588). Real-time undersampled dynamic MR images were reconstructed using DL networks trained with cardiac data and natural videos, and compressed sensing (CS). Differences were assessed in simulations (N = 104 datasets) in terms of MSE, PSNR, and SSIM and prospectively for cardiac cine (short axis, four chambers, N = 20) and speech cine (N = 10) data in terms of subjective image quality ranking, SNR and Edge sharpness. Friedman Chi Square tests with post-hoc Nemenyi analysis were performed to assess statistical significance. In simulated data, DL networks trained with cardiac data outperformed DL networks trained with natural videos, both of which outperformed CS (p

Abstract Background Antimicrobial resistance (AMR) represents a significant threat to global health with Neisseria gonorrhoea emerging as a key pathogen of concern. In Australia, the Australian Gonococcal Surveillance Program (AGSP) plays a critical role in monitoring resistance patterns. However, antibiotic susceptibility test (AST) uptake – a crucial component for effective resistance surveillance – remains to be a limiting factor. The study aims to model the processes involved in generating AST tests for N. gonorrhoea isolates within the Australian healthcare system and assess the potential impact of systematic and policy-level changes. Methods Two models were developed. The first model was a mathematical stochastic health systems model (SHSM) and a Bayesian Belief Network (BBN) to simulate the clinician-patient dynamics influencing AST initiation. Key variables were identified through systematic literature review to inform the construction of both models. Scenario analyses were conducted with the modification of model parameters. Results The SHSM and BBN highlighted clinician education and the use of clinical support tools as effective strategies to improve AST. Scenario analysis further identified adherence to guidelines and changes in patient-level factors, such as persistence of symptoms and high-risk behaviours, as significant determinants. Both models supported the notion of mandated testing to achieve higher AST initiation rates but with considerations necessary regarding practicality, laboratory constraints, and culture failure rate. Conclusion The study fundamentally demonstrates a novel approach to conceptualising the patient-clinician dynamic within AMR testing utilising a model-based approach. It suggests targeted interventions to educational, support tools, and legislative framework as feasible strategies to improve AST initiation rates. However, the research fundamentally highlights substantial research gaps in the underlying understanding of AMR.