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Abstract Introduction Psychiatric emergency departments (EDs) in France have been under pressure from several factors, exacerbated by the COVID-19 pandemic. The pandemic led to an increase in psychiatric disorders, particularly anxiety and depression, with younger people and women being most affected. The aim of this study was to provide a comprehensive description of the trends in the number of visits to the largest psychiatric emergency department in France, with a particular focus on the period preceding and following the advent of COVID-19 pandemic. Methods This retrospective study analyzed data from 69,764 visits to the Centre Psychiatrique d’Orientation et d’Accueil (CPOA) in Paris from 2016 to 2023. Patient data, including demographics, reasons for visit, and diagnoses, were collected and analyzed to identify trends over this period. Results The study observed a 28.5% increase in ED visits from 2016 to 2023. The increase was primarily driven by mood and anxiety disorders, which showed increases of 38.6% and 75.4%, respectively. The average age of patients decreased, reflecting a younger population increasingly affected by psychiatric problems. Interestingly, despite the increase in ED visits, hospital admissions decreased by 11.9%, with a notable decrease in involuntary commitment. Discussion The findings highlight a paradox where increased psychiatric ED visits are not accompanied by an increase in hospital admissions. This suggests a shift toward outpatient care due to systemic factors, including reduced hospital bed availability and challenges in accessing timely outpatient services. This study underscores the need to strengthen outpatient mental health services to effectively manage the growing demand. Further research, especially multicenter studies, is recommended to validate these findings and inform policy changes.

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.

Abstract Intestinal epithelial cells are segregated into proliferative crypts and differentiated regions. This organization relies on specific signals, including Wnt3a, which regulates cell proliferation within crypts, and Eph/Ephrin, which dictates cell positioning along the crypt-villus axis. However, studying how the spatial distributions of these signals influences crypt-villus organization is challenging both in vitro and in vivo. Here we show that micropatterns of Wnt3a can govern the size, shape and long-range organization of crypts in vitro. By adjusting the spacing between Wnt3a ligand patterns at the microscale over large surfaces, we override endogenous Wnt3a to precisely control the distribution and long-range order of crypt-like regions in primary epithelial monolayers. Additionally, an agent-based model integrating Wnt3a/BMP feedback and Eph/Ephrin repulsion effectively replicates experimental tissue compartmentalization, crypt size, shape, and organization. This combined experimental and computational approach offers a framework to study how signaling pathways help organize intestinal epithelial tissue.

Abstract Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging unsolved problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign tasks, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 19 new homo-oligomers and structurally recombined them to make 24 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system have identical or nearly identical backbones, and hence are ideal building blocks for generating and functionalizing larger symmetric and pseudosymmetric assemblies.

The grocery retail sector in Indonesia plays an important role in meeting people's basic needs, with grocery merchants in urban and rural areas serving as the main middlemen in the distribution of staples to end consumers. Grocery merchants in Indonesia often face challenges in improving sales efficiency due to the use of conventional methods that are slow, unstructured, and prone to recording errors. These challenges can potentially lead to loss of customers, financial losses, and hinder business growth. This research aims to develop an Android-based cashier application specifically designed for grocery merchants to improve transaction efficiency and stock management. Using a qualitative approach, in-depth interviews were conducted to understand the needs and constraints faced by merchants in the transaction process. The findings were used to design the main features of the application, such as CRUD-based item management (Create, Read, Update, Delete), barcode scanning with a smartphone camera, digital receipt sending via WhatsApp, and payment support via QRIS E-wallet and cash transactions. This application is assumed to be used on Android devices with adequate internet access. The results show that this application is able to reduce recording errors, speed up transactions, and increase customer satisfaction compared to the manual method. The solution is expected to improve productivity, drive business growth, service quality and customer satisfaction as well as the competitiveness of grocers in the digital era. Future recommendations include the development of analytics features to monitor sales performance and support strategic decision-making.

Abstract Practical quantum networks will require multi-qubit quantum nodes. This in turn will increase the complexity of the photonic circuits needed to control each qubit and require strategies to multiplex memories. Integrated photonics operating at visible to near-infrared (VNIR) wavelength range can provide solutions to these needs. In this work, we realize a VNIR thin-film lithium niobate (TFLN) integrated photonics platform with the key components to meet these requirements, including low-loss couplers (20 dB extinction), and high-bandwidth electro-optic modulators (>50 GHz). With these devices, we demonstrate high-efficiency and CW-compatible frequency shifting (>50% efficiency at 15 GHz), as well as simultaneous laser amplitude and frequency control. Finally, we highlight an architecture for multiplexing quantum memories and outline how this platform can enable a 2-order of magnitude improvement in entanglement rates over single memory nodes. Our results demonstrate that TFLN can meet the necessary performance and scalability benchmarks to enable large-scale quantum nodes.

Abstract To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)−155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.

Abstract Light profoundly impacts many aspects of human physiology and behaviour, including the synchronization of the circadian clock, the production of melatonin, and cognition. These effects of light, termed the non-visual effects of light, have been primarily investigated in laboratory settings, where light intensity, spectrum and timing can be carefully controlled to draw associations with physiological outcomes of interest. Recently, the increasing availability of wearable light loggers has opened the possibility of studying personal light exposure in free-living conditions where people engage in activities of daily living, yielding findings associating aspects of light exposure and health outcomes, supporting the importance of adequate light exposure at appropriate times for human health. However, comprehensive protocols capturing environmental (e.g., geographical location, season, climate, photoperiod) and individual factors (e.g., culture, personal habits, behaviour, commute type, profession) contributing to the measured light exposure are currently lacking. Here, we present a protocol that combines smartphone-based experience sampling (experience sampling implementing Karolinska Sleepiness Scale, KSS ratings) and high-quality light exposure data collection at three body sites (near-corneal plane between the two eyes mounted on spectacle, neck-worn pendant/badge, and wrist-worn watch-like design) to capture daily factors related to individuals’ light exposure. We will implement the protocol in an international multi-centre study to investigate the environmental and socio-cultural factors influencing light exposure patterns in Germany, Ghana, Netherlands, Spain, Sweden, and Turkey (minimum n = 15, target n = 30 per site, minimum n = 90, target n = 180 across all sites). With the resulting dataset, lifestyle and context-specific factors that contribute to healthy light exposure will be identified. This information is essential in designing effective public health interventions.

Abstract APC/C is a multi-subunit complex that functions as a master regulator of cell division. It controls progression through the cell cycle by timely marking mitotic cyclins and other cell cycle regulatory proteins for degradation. The APC/C itself is regulated by the sequential action of its coactivator subunits CDC20 and CDH1, post-translational modifications, and its inhibitory binding partners EMI1 and the mitotic checkpoint complex. In this study, we took advantage of developments in cryo-electron microscopy to determine the structures of human APC/CCDH1:EMI1 and apo-APC/C at 2.9 Å and 3.2 Å resolution, respectively, providing insights into the regulation of APC/C activity. The high-resolution maps allow the unambiguous assignment of an α-helix to the N-terminus of CDH1 (CDH1α1) in the APC/CCDH1:EMI1 ternary complex. We also identify a zinc-binding module in APC2 that confers structural stability to the complex, and we confirm the presence of zinc ions experimentally. Finally, due to the higher resolution and well defined density of these maps, we are able to build, aided by AlphaFold predictions, several intrinsically disordered regions in different APC/C subunits that likely play a role in proper APC/C assembly and regulation of its activity.

(1) Background: Effective wound management aims for expedited healing, improved functional and scar outcomes, and reduced complications including infection. Delayed wound healing remains a prevalent problem in the elderly. Suprathel is a synthetic absorbable skin substitute and an attractive option in partial thickness wounds. The objective of this randomised controlled study was to assess the effect of skin substitute dressings on elderly split-skin graft (STSG) donor sites, evaluating time to heal, pain, itch and scar outcome. (2) Methods: 40 patients over 65 undergoing split-thickness skin grafting for non-melanoma skin cancer excision were randomised to STSG donor site dressings with either Suprathel or Hypafix. Patients were followed up weekly until healed and at 13 weeks post-procedure. (3) Results: There was no significant difference in time to healing, pain, itch, or scar outcome at 13 weeks between the two groups. The mean time to healing was 31.7 days for the skin substitute group and 27.3 days for the adhesive tape control group (p = 0.182). (4) Conclusions: Both dressings are appropriate for STSG donor sites. Hypafix remains a cost-effective dressing of choice for donor sites. Benefits demonstrated in other studies using skin substitutes have not translated into the elderly population. There remains scope in developing dressings that reduce elderly donor site morbidity.

Abstract The projected winter changes of the North Atlantic eddy-driven jet (EDJ) under climate change conditions have been extensively analysed. Previous studies have reported a squeezed and elongated EDJ. However, other changes present large uncertainties, specifically those related to the intensity and latitude. Here, the projections of the EDJ in a multimodel ensemble of CMIP6 are scrutinised by using a multiparametric description of the EDJ. The multimodel mean projects non-stationary responses of the EDJ latitude through the winter, characterised by a poleward shift in early winter and equator migration in late winter. These intraseasonal shifts (rather than a genuine narrowing) explain the previously established squeezing of the EDJ and are linked to the future changes in different drivers: the 200 hPa meridional temperature gradient and Atlantic warming hole in early winter, and the stratospheric vortex in late winter. Model biases also influence EDJ projections, contributing to the poleward shift in early winter.

Abstract Flexible action selection requires cognitive control mechanisms capable of mapping the same inputs to different output actions depending on the context. From a neural state-space perspective, this requires a control representation that separates similar input neural states by context. Additionally, for action selection to be robust and time-invariant, information must be stable in time, enabling efficient readout. Here, using EEG decoding methods, we investigate how the geometry and dynamics of control representations constrain flexible action selection in the human brain. Participants performed a context-dependent action selection task. A forced response procedure probed action selection different states in neural trajectories. The result shows that before successful responses, there is a transient expansion of representational dimensionality that separated conjunctive subspaces. Further, the dynamics stabilizes in the same time window, with entry into this stable, high-dimensional state predictive of individual trial performance. These results establish the neural geometry and dynamics the human brain needs for flexible control over behavior.

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by the absence of complement regulatory proteins on the surface of erythrocytes, leading to intravascular hemolysis and thrombosis. Managing PNH during pregnancy poses significant challenges due to increased risks of morbidity and mortality. This case report describes the detailed obstetric course of a 44‐year‐old woman with PNH and additional hereditary protein C deficiency who had previously experienced multiple thrombotic events and adverse pregnancy outcomes (two early miscarriages and one stillbirth at 25 weeks gestation [WG]), treated with eculizumab (terminal C5 inhibitor) and optimal anticoagulation management. Close monitoring of hemolysis and hemostasis parameters was conducted throughout the gestation period together with increased obstetrical surveillance. The pregnancy progressed without thrombotic complications or breakthrough hemolysis, and the patient delivered a healthy newborn at 36 WG after induction of labor due to restricted fetal growth. To the best of our knowledge, this is the first reported case of a positive pregnancy outcome despite PNH in conjunction with hereditary thrombophilia. This case report highlights the importance of a multidisciplinary approach involving hematologists and obstetricians in the management of pregnant women with PNH. Tailored therapy, close monitoring, and comprehensive care are crucial to minimize risks and optimize outcomes.

Abstract Neurotrophic growth factor (GF) loaded hydrogels have shown promise as a treatment approach for spinal cord injury (SCI). However, SCI presents complex challenges for the direct administration of treatment due to the spinal cord’s intricate anatomy and highly sensitive environment. Many current hydrogel administration approaches overlook this complexity, limiting their translational potential. To address this, we propose a novel intrathecal administration method using an in situ gelling, hyaluronic acid-modified heparin-poloxamer hydrogel loaded with neurotrophin-3 (NT-3) for the direct delivery of NT-3 to the spinal cord. We injected a NT-3 loaded hydrogel into the intrathecal space immediately after contusion SCI in Sprague Dawley (SpD) rats. Our results indicate that injecting the NT-3 loaded hydrogel into the intrathecal space was safe and that the gel was retained alongside the cord for at least one week. Additionally, no adverse effects were observed on rat behaviour. While functional improvement trends were noted, statistical significance was not reached, and immunohistochemistry results showed no significant difference between treatment groups. Overall, our findings suggest the feasibility, safety, and potential of the developed intrathecal administration technique for delivering diverse therapeutic molecules for SCI recovery.

Abstract By 2050, 1 in 4 people worldwide will be living with hearing impairment. We propose a digital Speech Hearing Screener (dSHS) using short nonsense word recognition to measure speech-hearing ability. The importance of hearing screening is increasing due to the anticipated increase in individuals with hearing impairment globally. We compare dSHS outcomes with standardized pure-tone averages (PTA) and speech-recognition thresholds (SRT). Fifty participants (aged 55 or older underwent pure-tone and speech-recognition thresholding. One-way ANOVA was used to compare differences between hearing impaired and hearing not-impaired groups, by the dSHS, with a clinical threshold of moderately impaired hearing at 35 dB and severe hearing impairment at 50 dB. dSHS results significantly correlated with PTAs/SRTs. ANOVA results revealed the dSHS was significantly different (F(1,47) = 38.1, p

Abstract Background Arbuscular mycorrhizas (AM) are the most widespread terrestrial symbiosis and are both a key determinant of plant health and a major contributor to ecosystem processes through their role in biogeochemical cycling. Until recently, it was assumed that the fungi which form AM comprise the subphylum Glomeromycotina (G-AMF), and our understanding of the diversity and ecosystem roles of AM is based almost exclusively on this group. However recent evidence shows that fungi which form the distinctive 'fine root endophyte’ (FRE) AM morphotype are members of the subphylum Mucoromycotina (M-AMF), so that AM symbioses are actually formed by two distinct groups of fungi. Results We investigated the influence of nitrogen (N) addition and wheat variety on the assembly of AM communities under field conditions. Visual assessment of roots showed co-occurrence of G-AMF and M-AMF, providing an opportunity to compare the responses of these two groups. Existing ‘AM’ 18S rRNA primers which co-amplify G-AMF and M-AMF were modified to reduce bias against Mucoromycotina, and compared against a new ‘FRE’ primer set which selectively amplifies Mucoromycotina. Using the AM-primers, no significant effect of either N-addition or wheat variety on G-AMF or M-AMF diversity or community composition was detected. In contrast, using the FRE-primers, N-addition was shown to reduce M-AMF diversity and altered community composition. The ASV which responded to N-addition were closely related, demonstrating a clear phylogenetic signal which was identified only by the new FRE-primers. The most abundant Mucoromycotina sequences we detected belonged to the same Endogonales clades as dominant sequences associated with FRE morphology in Australia, indicating that closely related M-AMF may be globally distributed. Conclusions The results demonstrate the need to consider both G-AMF and M-AMF when investigating AM communities, and highlight the importance of primer choice when investigating AMF community dynamics.

As the global community continues to recover from the COVID-19 pandemic, the World Health Organization has issued a warning of another viral infection, mpox (monkeypox), that can pose a significant threat to public health. Mpox was once endemic in Africa but has spread globally, prompting the World Health Organization to declare it a public health emergency. In response, healthcare personnel must initiate timely, decisive, and robust action before the infection escalates. Moreover, accurate diagnosis is crucial, given the similarity between mpox and other rash-causing infections. This article provides a comprehensive overview of the symptoms, differentiating it from similar diseases, risk assessment, and treatment strategies. In addition, it aims to educate healthcare personnel with the necessary knowledge to educate others and take preventative measures when handling cases, thereby avoiding the spread of infection.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and severe asthma (SA) are 2 frequently coexisting conditions that are, in most cases, associated with eosinophilic inflammation. The concurrence of both diseases has a negative synergistic impact on disease severity and patients’ health-related quality of life. Thus, a holistic, collaborative management of these patients is a critical unmet need. Mepolizumab, a systemic anti–IL-5 therapy, has been shown to be effective as an add-on treatment in both SA and CRSwNP, with more literature available on asthma outcomes than on CRSwNP. Objectives: The primary objective of the study is to evaluate the real-world effectiveness of mepolizumab in improving the health-related quality of life of comorbid patients at 12 months using the SNOT-22 questionnaire. Secondary objectives include safety and efficacy outcomes of mepolizumab treatment in the 2 populations, which are expected to have variable severity of the respective comorbid conditions. Methods: RESPONSE is a European real-world prospective cohort study designed to assess the effectiveness of mepolizumab in 2 cohorts of adult patients: one with SA as primary diagnosis with (secondary diagnosis) comorbid CRSwNP, and another with CRSwNP as primary diagnosis with (secondary diagnosis) comorbid asthma. Up to 350 patients receiving newly prescribed mepolizumab will be followed up for 12 months as per the investigators’ standard of care. Conclusion: This study will report the effects of anti–IL-5 therapy in both diseases investigated and the respective comorbidity, as well as the consequence of treating milder forms of asthma and CRSwNP with mepolizumab, supporting the emerging evidence on early treatment optimization.

Introduction: Organ preservation (OP) strategies are gaining interest in improving the quality of life in the management of rectal cancer, particularly for tumors located in the distal or middle rectum. The optimal OP protocol is still not standardized and relies on randomized trials. This review summarizes past and ongoing studies on OP protocols for adenocarcinoma of the distal and middle rectum. Method: We searched for articles and abstracts on randomized clinical trials investigating OP approaches for rectal cancer, including data presented at the LUCARRE Congress held in Nice on November 25, 2023, covering ongoing and recently published trials on rectal preservation. Results: Our review’s findings are presented in four tables: the first evaluates key trials with overall survival (OS) as the primary endpoint; the second provides an overview of past Phase III trials; the third reviews Phase II/III trials that specifically focus on local excisions (LE); and finally, the fourth summarizes ongoing trials. Each table is accompanied by detailed comments elucidating the significance and implications of the presented data, alongside a review of current guidelines. Interpretation: We highlight the growing interest in OP strategies for rectal cancer management to enhance patients’ quality of life. Despite the lack of international consensus on the optimal OP protocol, past and ongoing randomized trials provide valuable findings into the evolving management strategies of rectal cancer treatment. The presented data supports the role of randomized phase III trials to provide evidence for a change in clinical practice.

Abstract The journal Earth and Space Science (ESS) was founded in 2014 to offer the scientific community a new platform for the dissemination of key new data, observations, methods, instruments, and models, presented within the context of their application. Thus, the aim of the journal was (and is) to highlight the complexity and importance of experimental design, methodology, data acquisition and processing, intertwined with data interpretation. Such approach is consistent with the mission of most AGU journals, but the distinctive element for ESS is its focus on the concept of the useful impact of publication, progressively replacing that on conventional publication metrics. In this context, the journal has been, since its inception, the preferred home for studies stemming from both global and local geoscience research. This special collection contains 16 papers published in ESS, selected by the Editorial Board to highlight the aims, scope and path of evolution and growth of the journal since it inaugural issue, in 2014.

The excavation of the legionary camp at Brigetio began in 2021. Throughout the last four campaigns, 2,200 square meters of the baths were unearthed, which span a total of well over 6,000 square meters. In 2024 the work continued across four surfaces. The excavations here shed a light on the size of the bath, which extended westward over a much larger area than previous excavations and radar surveys had suggested. In connection with the heating systems of the baths, two praefurnia preserved in excellent condition, along with their two adjoining service rooms, were also unearthed. In the southern section of the baths, three lime slaking pits were discovered, a rare occurrence in military context within the Roman Empire.

Summary: Background: Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility. Methods: We developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer’s Disease Neuroimaging Initiative, the National Alzheimer’s Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models. Findings: Our fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer’s disease biomarkers. Interpretation: These robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia. Funding: US National Institutes of Health.

Previous abdominal surgery (PAS) increases risk of small bowel obstruction (SBO) due to adhesions, and appendectomy (appy) is an independent risk factor for abdominal adhesion-related complications. Peritoneal inflammation, e.g., acute appendicitis (AA), causes formation of reactive ascitic fluid (rA) that activates peritoneum surface mesothelial cells (MCs) to form adhesions. Pathologic adhesions may arise if restoration of MC-regulated fibrinolysis and secretion of glycocalyx (GCX) are disrupted. Proteins affecting these processes may originate from peritoneal rA. This is a prospective observational IRB-approved study at three Level 1 trauma centers where rA is collected prior to surgical intervention for non-perforated AA or adhesiolysis for SBO. Samples from 48 appy and 15 SBO patients were used to treat human MCs and subjected to quantification of 85 inflammatory mediators. Results were compared between patients with surgically naïve abdomens (naïve) and patients with >1 PAS. Select rA caused MCs to form clusters of fibroblastic cells, extracellular matrix fibers (FIB), and secretion of GCX. PAS and naïve patient rA fluids were clustered into "fiber-GCX" (FIB-GCX) groups: highFIB-highGCX, highFIB-lowGCX, noFIB-highGCX, noFIB-lowGCX, and noFIB-noGCX. Between groups, 26 analytes were differentially abundant including innate immune response, wound healing, and mucosal defense proteins. Factors that contributed to the differences between groups were rA-induced highFIB and history of PAS. Overall, PAS patient rA showed a muted immune response compared to rA from naïve patients. Our data suggest that abdominal surgery may negatively impact future immune responses in the abdomen. Further, quantifying immunomodulators in peritoneal rA may lead to the development a personalized approach to post-surgical adhesion treatment and prevention.

El Protocolo de análisis de diseño de logotipos (LDAP) permite analizar marcas visuales de forma sistemática, con vocación de potenciar su comparación. El análisis formal se estructura en tres fases: selección, análisis y comparación. En esta investigación se elabora el protocolo mediante Teoría Fundamentada y se presenta aplicado a 38 marcas (23 para la identificación de variables y 15 para su aplicación y validación). El LDAP analiza 62 variables en 3 dimensiones: marca global (22), elemento textual (23) y elemento icónico (17). Se presenta el manual para su uso en futuras investigaciones.

Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights ranging from population genetics to applications across the social sciences. Here we present quality-controlled whole exome sequencing data from three UK birth cohorts: the Avon Longitudinal Study of Parents and Children (8,436 children and 3,215 parents), the Millenium Cohort Study (7,667 children and 6,925 parents) and Born in Bradford (8,784 children and 2,875 parents). The overall objective of this coordinated effort is to make the resulting high-quality data widely accessible to the global research community in a timely manner. We describe how the datasets were generated and subjected to quality control at the sample, variant and genotype level. We then present some preliminary analyses to illustrate the quality of the datasets and probe potential sources of bias. We introduce measures of ultra-rare variant burden to the variables available for researchers working on these cohorts, and show that the exome-wide burden of deleterious protein-truncating variants, S het burden, is associated with educational attainment and cognitive test scores. The whole exome sequence data from these birth cohorts (CRAM & VCF files) are available through the European Genome-Phenome Archive, and here we provide guidance for their use.

In early-stage Alzheimer's disease (AD) amyloid-β (Aβ) deposition can induce neuronal hyperactivity, thereby potentially triggering activity-dependent neuronal secretion of phosphorylated tau (p-tau), ensuing tau aggregation and spread. Therefore, cortical excitability is a candidate biomarker for early AD detection. Moreover, lowering neuronal excitability could potentially complement strategies to reduce Aβ and tau buildup. There is, however, a lack of understanding of the relationship between cortical excitability and p-tau increase in vivo. Therefore, in a sample of 658 healthy middle-aged (between the ages of 40 and 65) participants of the Barcelona Brain Health Initiative cohort study, we examined the relation of blood-based tau, phosphorylated at amino acid 181 (p-tau181), reflecting neuronal p-tau secretion; neurofilament light chain (NfL), as a passively released control for p-tau181; and electroencephalography (EEG) markers of cortical excitability. A subsample of 47 participants also completed a controlled brain perturbation approach via transcranial magnetic stimulation (TMS) with concurrent EEG. Results show that both spontaneous (i.e., resting-state) and perturbation-based TMS-EEG markers, are associated with blood p-tau181, particularly in older individuals. The perturbation-based marker was a significantly more sensitive predictor of p-tau181 concentration than the spontaneous resting state EEG-based marker. The relationships observed are not present for the NfL control. These results show that relationships between p-tau181 and cortical excitability are present in healthy middle-aged subjects and that p-tau181 increases may reflect activity-dependent secretion.

ABSTRACT Objective: The frequency of obstructive sleep apnea (OSA) in patients with idiopathic pulmonary fibrosis (IPF) is high. The clinical course of non-IPF interstitial lung disease (ILD) can be similar to that of IPF. We sought to assess the frequency and predictors of OSA in patients with non-IPF fibrotic ILD, as well as the impact of positive airway pressure (PAP) therapy on the quality of life of such patients. Methods: This was a prospective study in which non-IPF fibrotic ILD patients underwent a home sleep apnea test. The patients with and without OSA were compared, and a multivariate logistic regression model was used to identify independent predictors of OSA. At 3 months after initiation of PAP therapy, we evaluated the participating patients for respiratory events, nocturnal hypoxemia, and changes in quality of life. Results: Of a total of 50 patients, 50% were male, and 76% were diagnosed with OSA. The mean age was 67.8 ± 8.3 years. The patients with OSA had significantly lower TLC (p = 0.033) and awake SpO2 (p = 0.023) than did those without OSA. In the multivariate logistic regression model, SpO2 (OR = 0.46; p = 0.016) and TLC (OR = 0.95; p = 0.026) remained significantly associated with OSA risk. A total of 12 patients received PAP therapy. At 3 months after initiation of PAP therapy, 91.7% were well controlled, Epworth Sleepiness Scale scores decreased significantly (p = 0.006), and emotional well-being tended to improve (p = 0.068). PAP therapy corrected nocturnal hypoxemia in all patients. Conclusions: We found a high frequency of OSA in patients with non-IPF fibrotic ILD. A low TLC was an independent predictor of a higher risk of OSA. PAP therapy can correct nocturnal hypoxemia. There should be a low threshold for suspicion of OSA and initiation of PAP therapy in patients with non-IPF fibrotic ILD.

We investigate the barrier properties of phosphorus-doped Si-rich silicon carbide (SixCy) thin films deposited by PECVD against Al/Si alloying in the context of poly-Si/SiOx passivating contacts. The stability of the implied open circuit voltage (iVOC) after firing of single-sided, full area screen-printed Al-contacts increases with carbon content of the barrier layer and depends on the crystallization scheme applied to the samples. Crystallized SixCy layers with an atomic C concentration of about 20 at.% deposited on pre-crystallized poly-Si predominantly show no significant decrease in iVOC values for peak firing temperatures up to 725°C.

Parkinson's Disease (PD) is a common and debilitating neurodegenerative disorder affecting millions worldwide. The hallmark pathological feature of PD is the accumulation and aggregation of α-Synuclein (α-Syn), a protein involved in synaptic function and neuronal survival. The formation of α-Syn aggregates, also known as Lewy bodies and Lewy neurites, leads to neuronal dysfunction and death, resulting in PD's characteristic motor and non-motor symptoms. Current treatments for PD are mainly symptomatic and do not address the underlying cause of the disease. Therefore, there is an urgent need for disease-modifying therapies that can prevent, slow, or reverse the progression of PD by targeting α-Syn aggregation. In this review, we summarize the current status of pharmacological interventions that aim to reduce α-Syn levels in PD and other Synucleinopathies by various mechanisms, such as inhibiting α-Syn aggregation, enhancing α-Syn clearance, modulating α-Syn-related enzymes, or blocking α-Syn transmission. We focus on agents that have reached phase 1 or 2 clinical trials and provide an overview of their preclinical and clinical data and their safety and efficacy profiles. While fewer candidates have shown positive results in clinical trials, they are awaiting further evaluation in larger and longer-term studies. None of the placebo-controlled, blind trials, except Prasinezumab, have demonstrated efficacy. These novel disease-modifying therapy approaches can potentially change the landscape of PD treatment and improve the quality of life for PD patients.

PD-1 checkpoint inhibition has revolutionized the care of cancer. A small portion of patients with stage IV cancer achieve durable control. But, early progression is common and dramatic control is achieved for only a minority. We hypothesized that ilixadencel, an allogeneic monocyte-derived dendritic cell product could be injected into tumor to potentiate PD-1 response and thus conducted a phase I study of pembrolizumab plus ilixadencel. Twenty-one patients were accrued. The most common treatment emergent adverse events were fatigue, injection site pain, anemia, weight decreased and hyponatremia, mostly grade 1-2. No dose limiting toxicities were observed and the recommended phase II dose was established at 10 million cells administered twice. Two unconfirmed responses were observed, with no confirmed responses.

Patient interviewing pedagogy in medical education has not evolved to comprehensively capture the biopsychosocial model of healthcare delivery. While gathering a patient’s social history targets important aspects of social context it does not adequately capture and account for the real-time reassessment required to understand evolving factors that influence exposure to drivers of health inequities, social determinants of health, and access to supports that promote health. The authors offer a patient interviewing approach called the Contextual Interview (CI) that specifically targets dynamic and ever-changing social context information. To substantiate the use of the CI in medical education, the authors conducted a qualitative review of the Accreditation Council for Graduate Medical Education Milestones for primary care specialties (Family Medicine, Internal Medicine, and Pediatrics). Milestones were coded to the extent to which they reflected the learner’s need to acknowledge, assess, synthesize and/or apply patient contextual data in real-time patient encounters. Approximately 1 in 5 milestones met the context-related and patient-facing criteria. This milestone review further highlights the need for more intentional training in eliciting meaningful social context data during patient interviewing. The CI as a cross-cutting, practical, time-conscious, and semi-structured patient interviewing approach that deliberately elicits information to improve the clinician’s sense and understanding of a patient’s social context. The authors reviewed future directions in researching adapted versions of the CI for undergraduate and graduate medical education.

Background Growing evidence supports the ergogenic effects of creatine supplementation on muscle power/strength, but its effects on endurance performance remain unclear. We assessed the effects of high-dose short-term creatine supplementation in professional cyclists during a training camp.Methods The study followed a double-blind, randomized parallel design. Twenty-three professional U23 cyclists (19 ± 1 years, maximum oxygen uptake: 73.0 ± 4.6 mL/kg/min) participated in a 6-day training camp. Participants were randomized to consume daily either a recovery drink (containing carbohydrates and protein) with a 20-g creatine supplement (creatine group, n = 11) or just the recovery drink (placebo group, n = 12). Training loads and dietary intake were monitored, and indicators of fatigue/recovery (Hooper index, countermovement jump height), body composition, and performance (10-second sprint, 3-, 6-, and 12-minute time trials, respectively, as well as critical power and W’) were assessed as study outcomes.Results The training camp resulted in a significant (p 0.05).Conclusions High-dose short-term creatine supplementation seems to exert no consistent beneficial effects on recovery, body composition or performance indicators during a strenuous training period in professional cyclists.

Systematic studies on the economic competitiveness of organic farming systems compared to conventional farming systems are particularly lacking in tropical environments. In tropical regions, the evaluation of organic production systems typically concentrates on main cash crops earmarked for export markets. Consequently, crops grown in rotation or in association with these main crops have been largely overlooked, with their contribution to farm profitability is often considered negligible due to perceived challenges in securing premium organic prices. To address this knowledge gap, we conducted an analysis of twelve years of economic data from four long-term farming system comparison trials in tropical regions. Our objective was to delve into the economic competitiveness of both organic and conventional production systems at the system level, considering not only the main cash crops but also the associated and rotational crops. The outcomes of our analysis revealed that in three out of four systems, the gross margins of organic and conventional systems were comparable. In the fourth system, the gross margins of the organic system were 13.13% lower, equivalent to $169.8 per hectare per year compared to the conventional system. Furthermore, the contribution of crops grown in rotation with these main crops remains similar even when premium prices are not obtained. In instances where premium prices for non-cash crops are secured, their profitability can even surpass that of cash crops. Additionally, in the case of agroforestry, companion plantings serve as valuable additions for both dietary and income diversity. These findings suggest that the profitability of an agricultural system is not solely dependent on whether it is organic or conventional but is instead influenced by various system components. The emphasis should shift from a singular focus on main cash crops to a more comprehensive understanding that considers the entire spectrum of crops within a farming system.

Objectives: To separate estimates of mean change in a health outcome into components of aging and disease progression for different severity groups of chronic obstructive pulmonary disease (COPD). Study design and methods: A longitudinal model can be used to estimate mean change in a health outcome over time. Methods to separate this change into portions due to aging and disease progression are discussed, including conditions that allow for accurate estimation. Linear mixed models were used to estimate these changes for forced expiratory volume in 1 s (FEV1) for various COPD severity and smoking groups using a large cohort (COPDGene) followed for over 10 years. Results: Based on an analysis of 4967 subjects, age-related loss in FEV1 was found to be about 1 % per year, consistent with published work. Excess average losses (those beyond natural aging) were significant for all severity groups (except nonsmokers), including those with smoking history but normal lung function. Subjects in higher severity groups tended to have less loss in FEV1, but more relative loss, compared to baseline averages. Losses in FEV1 that included both aging and disease progression ranged from 1 to 3 % over severity groups, with current smokers generally exhibiting greater mean losses in FEV1 than former smokers. Discussion: Effects of disease progression separate from aging can be estimated in observational studies, although care should be taken in order to make sure assumptions involving this separation are reasonable for a given study. This article demonstrates methods to estimate such effects using temporal changes in lung function for subjects in the COPDGene study.

The production gap between current and attainable yields is highest on Africa's smallholder farms, and some studies indicate that they might not benefit from the yield gains offered by conventional farming. Simultaneously, alternative farming systems like organic provide biodiversity and soil fertility advantages, but their ability to produce sufficient food is still under debate. Additionally, comparative data on the productivity of organic versus conventional in tropical regions are scarce or short-term. We investigated the crop productivity of organic and conventional farming systems using 15 years in two long-term systems comparison trials in Kenya. The trials were established in 2007 at two sites in the Central Highlands of Kenya. At each site, conventional and organic systems were compared at high input levels. The trial involved a three-year crop rotation cycle of maize, vegetables, legumes, and potatoes, repeated five times since its establishment. Management practices were kept similar in the first four rotations and revised in the fifth to improve systems representing best practices. Our results showed that while maize and baby corn had relatively low yield gaps (−13 to +12 %) between organic and conventional systems, cabbage, French beans, and potato had high yield gaps (−50 to −30 %). We attributed this to nutrient limitations and higher pest and disease damage. The yield gap could partially be closed by adopting best practices in the organic system, including system diversification and effective soil fertility, nutrient, and integrated pest management.

Abstract Background Limited research has explored the effect of Circle of Willis (CoW) anatomy among blunt cerebrovascular injuries (BCVI) on outcomes. It remains unclear if current BCVI screening and scanning practices are sufficient in identification of concomitant COW anomalies and how they affect outcomes. Methods This retrospective cohort study included adult traumatic BCVIs at 17 level I-IV trauma centers (08/01/2017-07/31/2021). The objectives were to compare screening criteria, scanning practices, and outcomes among those with and without COW anomalies. Results Of 561 BCVIs, 65% were male and the median age was 48 y/o. 17% (n = 93) had a CoW anomaly. Compared to those with normal CoW anatomy, those with CoW anomalies had significantly higher rates of any strokes (10% vs. 4%, p = 0.04), ICHs (38% vs. 21%, p = 0.001), and clinically significant bleed (CSB) before antithrombotic initiation (14% vs. 3%, p

Abstract Incorporating automation into wind turbine blade manufacturing is important for reducing costs to meet current offshore wind energy production goals in the United States. This work proposes a process for automating three operations in wind blade manufacturing: trimming to remove flashing left over after bonding two blade skins together, grinding to produce a desired leading‐edge shape, and sanding to prepare the blade for bonding overlamination or adding paint to the surface. The majority of this work focuses on the toolpath generation. The algorithms were tested on a 5‐m blade section, and the results were analyzed in terms of operation speed and accuracy. Finally, future work is discussed to improve the performance of the system.

Abstract Background Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. Methods We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. Discussion This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. Systematic review registration PROSPERO CRD42023402365.

Abstract Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects.

Abstract Background We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression. Methods & results Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality. Conclusion Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

Abstract Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins. We then demonstrate the capacity of select lipid tags to mediate increased EV loading and functional delivery of an engineered transcription factor to modulate gene expression in target cells. We envision that this technology could be leveraged to develop new EV-based therapeutics that deliver a wide array of macromolecular cargo.

Abstract Human activities and climate change are transforming fire regimes globally. The interaction between these two drivers is poorly understood, yet critical if we aim at predicting how biomes will respond to novel fire regimes. In the Brazilian Cerrado, altered fire regimes are threatening its unique biodiversity and ecosystem functioning. Here, using geospatial data for the period 1985-2020 and a causal inference framework to design Bayesian statistical models, we demonstrate that a larger human presence in the landscape (≥40% land-use area) reduces the Cerrado’s burned area and hinders its responsiveness to climate; while climatic effects only become apparent in landscapes with little human presence, where hotter and drier conditions increase burned area. Finally, we find spatially heterogeneous burned area trends over time, with increases associated to climate change in landscapes that have remained mostly intact, and decreases caused by anthropic expansion. Both diverging trends have important implications for the conservation of the Cerrado as land-use expansion and climate change continue to unfold.

Abstract Background Inappropriate or overuse of antibiotic prescribing in primary care highlights an opportunity for antimicrobial stewardship (AMS) programs aimed at reducing unnecessary use of antimicrobials through education, policies and practice audits that optimize antibiotic prescribing. Evidence from the early part of the pandemic indicates a high rate of prescribing of antibiotics for patients with COVID-19. It is crucial to surveil antibiotic prescribing by primary care providers from the start of the pandemic and into its endemic stage to understand the effects of the pandemic and better target effective AMS programs. Methods This was a matched pair population-based cohort study that used electronic medical record (EMR) data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). Participants included all patients that visited their primary care provider and met the inclusion criteria for COVID-19, respiratory tract infection (RTI), or non-respiratory or influenza-like-illness (negative). Four outcomes were evaluated (a) receipt of an antibiotic prescription; (b) receipt of a non-antibiotic prescription; (c) a subsequent primary care visit (for any reason); and (d) a subsequent primary care visit with a bacterial infection diagnosis. Conditional logistic regression was used to evaluate the association between COVID-19 and each of the four outcomes. Each model was adjusted for location (rural or urban), material and social deprivation, smoking status, alcohol use, obesity, pregnancy, HIV, cancer and number of chronic conditions. Results The odds of a COVID-19 patient receiving an antibiotic within 30 days of their visit is much lower than for patients visiting for RTI or for a non-respiratory or influenza-like-illnesses (AOR = 0.08, 95% CI[0.07, 0.09] compared to RTI, and AOR = 0.43, 95% CI[0.38, 0.48] compared to negatives). It was found that a patient visit for COVID-19 was much less likely to have a subsequent visit for a bacterial infection at all time points. Conclusions Encouragingly, COVID-19 patients were much less likely to receive an antibiotic prescription than patients with an RTI. However, this highlights an opportunity to leverage the education and attitude change brought about by the public health messaging during the COVID-19 pandemic (that antibiotics cannot treat a viral infection), to reduce the prescribing of antibiotics for other viral RTIs and improve antibiotic stewardship.

Abstract Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.

Abstract This study examined the perspectives of Ghanaian higher education students on the use of ChatGPT. The Students’ ChatGPT Experiences Scale (SCES) was developed and validated to evaluate students’ perspectives of ChatGPT as a learning tool. A total of 277 students from universities and colleges participated in the study. Through exploratory factor analysis, a three-factor structure of students' perspectives (ChatGPT academic benefits, ChatGPT academic concerns, and accessibility and attitude towards ChatGPT) was identified. A confirmatory factor analysis was carried out to confirm the identified factors. The majority of students are aware of and recognize the potential of Gen AI tools like ChatGPT in supporting their learning. However, a significant number of students reported using ChatGPT mainly for non-academic purposes, citing concerns such as academic policy violations, excessive reliance on technology, lack of originality in assignments, and potential security risks. Students mainly use ChatGPT for assignments rather than for class or group projects. Students noted that they have not received any training on how to use ChatGPT safely and effectively. The implications for policy and practice are discussed in terms of how well-informed policy guidelines and strategies on the use of Gen AI tools like ChatGPT can support teaching and improve student learning.

Undergirded by “economic theory of the principal–agent problem”, the study investigated secondary school teachers’ perception of the influence of large-scale testing accountability on teaching and learning. Cross-sectional survey design was used. Simple random sampling was also employed to select 200 teachers for this study. The exploratory factor analysis results showed that although large-scale testing accountability serves as a motivational factor for teachers to be more productive, it puts pressure on teachers and students. Teachers reported teaching to the test (i.e. washback) and spending a lot of instructional time preparing students for the test. Teachers suggested that large-scale testing results should not be seen as the sole basis for teacher effectiveness. Rather, they indicated that large-scale testing results should be used to foster equitable distribution of educational resources and support teachers’ professional development to enhance teaching and learning. Implications for policy and practice are discussed.