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Abstract Increasing water stress is emerging as a global phenomenon, and is anticipated to have a marked impact on forest function. The role of tree functional strategies is pivotal in regulating forest fitness and their ability to cope with water stress. However, how the functional strategies found at the tree or species level scale up to characterise forest communities and their variation across regions is not yet well-established. By combining eight water-stress-related functional traits with forest inventory data from the USA and Europe, we investigated the community-level trait coordination and the biogeographic patterns of trait associations for woody plants, and analysed the relationships between the trait associations and climate factors. We find that the trait associations at the community level are consistent with those found at the species level. Traits associated with acquisitive-conservative strategies forms one dimension of variation, while leaf turgor loss point, associated with stomatal water regulation strategy, loads along a second dimension. Surprisingly, spatial patterns of community-level trait association are better explained by temperature than by aridity, suggesting a temperature-driven adaptation. These findings provide a basis to build predictions of forest response under water stress, with particular potential to improve simulations of tree mortality and forest biomass accumulation in a changing climate.

Abstract The efficient release of magnetic energy in astrophysical plasmas, such as during solar flares, can in principle be achieved through magnetic diffusion, at a rate determined by the associated electric field. However, attempts at measuring electric fields in the solar atmosphere are scarce, and none exist for sites where the magnetic energy is presumably released. Here, we present observations of an energetic event using the National Science Foundation’s Daniel K. Inouye Solar Telescope, where we detect the polarization signature of electric fields associated with magnetic diffusion. We measure the linear and circular polarization across the hydrogen Hε Balmer line at 397 nm at the site of a brightening event in the solar chromosphere. Our spectro-polarimetric modeling demonstrates that the observed polarization signals can only be explained by the presence of electric fields, providing conclusive evidence of magnetic diffusion, and opening a new window for the quantitative study of this mechanism in space plasmas.

Abstract Background Depression is a leading cause of disability worldwide, and treatments could be more effective. Identifying methods to improve treatment success has the potential to reduce disease burden dramatically. Preparing or “priming” someone to respond more effectively to psychotherapy (e.g., cognitive behavioral therapy [CBT]) by preceding sessions with aerobic exercise, a powerful neurobiological activator, could enhance the success of the subsequently performed therapy. However, the success of this priming approach for increasing engagement of working mechanisms of psychotherapy (e.g., increased working alliance and behavioral activation) has yet to be formally tested. Methods The CBT + trial will be a parallel-arm randomized controlled trial that will recruit 40 adult participants with DSM-5 diagnosed depression (verified with clinical interview) via referrals, mass emails, local flyers, and social media posts. Participants will be randomized to an ActiveCBT or CalmCBT condition. The ActiveCBT group will receive an 8-week CBT intervention primed with 30 min of moderate-intensity aerobic exercise (cycling on a stationary bike at a 13 rating of perceived exertion). The CalmCBT group will receive the same 8-week CBT intervention while resting for 30 min before CBT (i.e., cycling vs no cycling is the only difference). The primary outcome measures will be mean working alliance (assessed with the client version of the Working Alliance Inventory—Short Revised) and mean behavioral activation (self-reported Behavioral Activation for Depression Scale) recorded at each of the 8 therapy sessions. Secondary outcomes include evaluation of state anhedonia and serum brain-derived neurotrophic factor before the active/calm conditions, between the condition and therapy, and after the therapy. Additional exploratory analyses will evaluate group differences in algorithm-generated ratings of therapist-participant interactions via the Lyssn platform. Discussion The novel approach of priming CBT with moderate-intensity aerobic exercise evaluated in a randomized controlled trial (CBT + trial) has the potential to demonstrate the usefulness of exercise as an augmentation strategy that improves working mechanisms of therapy and overall treatment outcomes for adults with depression. Trial registration ClinicalTrials.gov NCT06001346 . Registered on August 21, 2023.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Abstract The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Abstract With the National Institutes of Health’s mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.

Abstract Onsite production of gigawatt-scale wind- and solar-sourced hydrogen (H2) at industrial locations depends on the ability to store and deliver otherwise-curtailed H2 during times of power shortages. Thousands of tonnes of H2 will require storage in regions where subsurface storage is scarce, which may only be possible using liquid organic H2 carriers. We evaluate aboveground system with a focus on providing technical insights into toluene/methylcyclohexane (TOL/MCH) storage systems in locations suitable for gigawatt-scale wind- and solar-powered electrolyzer systems in the United States. Here we show that the levelized cost of storage, at a national median of US dollar $1.84/kg-H2 is spatially heterogeneous, causing minor impact on the cost of H2 supply in the Midwest, and significant impact in Central California and the Southeast. While TOL/MCH may be the cheapest aboveground bulk storage solution evaluated, upfront capital costs, modest energy efficiency, reliance on critical materials and pre-sulfided catalysts, and greenhouse gas emissions from heating are opportunities for further development.

Abstract The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90’s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.

Abstract Background Health-related stigma and its internalization among individuals with chronic health conditions contribute to impaired mental and physical health and quality of life. Research on health-related stigma has been siloed, with disease-specific measures that may not capture the experiences of individuals with multiple health conditions and that prevent comparisons across health conditions. The current study aimed to develop and test a transdiagnostic measure of internalized health-related stigma for use among adults with different physical health conditions. Methods An existing measure of internalized mental health stigma was adapted to assess stigma due to chronic physical health conditions following COSMIN procedures, with input from advisory boards of community members living with a range of stigmatized health conditions (obesity, type 1 and type 2 diabetes, skin diseases, HIV, chronic pain, and cancers) and of health professionals who specialized in these conditions. The new Internalized Health-Related Stigma (I-HEARTS) Scale was tested in an online sample of 300 adults with these health conditions, recruited from ResearchMatch. Additional psychosocial measures of mental health and quality of life were administered, and participants provided information about their health conditions and demographic characteristics. Exploratory factor analysis and tests of reliability and validity were conducted to determine the psychometric properties of the I-HEARTS Scale, and k-means clustering and receiver of characteristic curve analysis were used to determine a clinically meaningful cutoff score indicating high levels of internalized stigma. Results Factor analysis results yielded a 25-item scale with a 3-factor solution, with subscales of Perceived and Anticipated Stigma, Stereotype Application and Self-Devaluation, and Stigma Resistance. Psychometric properties for internal consistency, inter-item and item-total correlations, and test-retest reliability were strong. Certain demographics (e.g., younger age) and characteristics related to health conditions (e.g., greater symptom severity) were associated with higher levels of internalized stigma. I-HEARTS Scale scores correlated moderately to strongly with related but distinct psychosocial measures, and a cutoff score of 3.40 or higher on the 1–7 rating scale was determined to indicate clinically meaningful levels of internalized stigma. Conclusions The I-HEARTS Scale is a reliable and valid measure for the assessment of internalized health-related stigma among adults with varied stigmatized chronic health conditions. Study pre-registration https://osf.io/84c5d/?view_only=87238512f6d6475c87f8f64280a8a15f .

Abstract Hyperemia in response to neural activity is essential for brain health. A hyperemic response delivers O2 and nutrients, clears metabolic waste, and concomitantly exposes cerebrovascular endothelial cells to hemodynamic forces. While neurovascular research has primarily centered on the front end of hyperemia—neuronal activity-to-vascular response—the mechanical consequences of hyperemia have gone largely unexplored. Piezo1 is an endothelial mechanosensor that senses hyperemia-associated forces. Using genetic mouse models and pharmacologic approaches to manipulate endothelial Piezo1 function, we evaluated its role in blood flow control and whether it impacts cognition. We provide evidence of a built-in brake system that sculpts hyperemia, and specifically show that Piezo1 activation triggers a mechano-feedback system that promotes blood flow recovery to baseline. Further, genetic Piezo1 modification led to deficits in complementary memory tasks. Collectively, our findings establish a role for endothelial Piezo1 in cerebral blood flow regulation and a role in its behavioral sequelae.

Abstract Finalization of eukaryotic nuclear DNA replication relies on DNA ligase 1 (LIG1) to seal DNA nicks generated during Okazaki Fragment Maturation (OFM). Using a mutational reporter in Saccharomyces cerevisiae, we previously showed that mutation of the high-fidelity magnesium binding site of LIG1Cdc9 strongly increases the rate of single-base insertions. Here we show that this rate is increased across the nuclear genome, that it is synergistically increased by concomitant loss of DNA mismatch repair (MMR), and that the additions occur in highly specific sequence contexts. These discoveries are all consistent with incorporation of an extra base into the nascent lagging DNA strand that can be corrected by MMR following mutagenic ligation by the Cdc9-EEAA variant. There is a strong preference for insertion of either dGTP or dTTP into 3–5 base pair mononucleotide sequences with stringent flanking nucleotide requirements. The results reveal unique LIG1Cdc9-dependent mutational motifs where high fidelity DNA ligation of a subset of OFs is critical for preventing mutagenesis across the genome.

Abstract Background 3D cell culture models have recently garnered increasing attention for replicating organ microarchitecture and eliciting in vivo-like responses, holding significant promise across various biological disciplines. Broadly, 3D cell culture encompasses organoids as well as single- and multicellular spheroids. While the latter have found successful applications in tumor research, there is a notable scarcity of standardized intestinal models for infection biology that mimic the microarchitecture of the intestine. Hence, this study aimed to develop structured multicellular intestinal spheroids (SMIS) specifically tailored for studying molecular basis of infection by intestinal pathogens. Results We have successfully engineered human SMIS comprising four relevant cell types, featuring a fibroblast core enveloped by an outer monolayer of enterocytes and goblet cells along with monocytic cells. These SMIS effectively emulate the in vivo architecture of the intestinal mucosal surface and manifest differentiated morphological characteristics, including the presence of microvilli, within a mere two days of culture. Through analysis of various differentiation factors, we have illustrated that these spheroids attain heightened levels of differentiation compared to 2D monolayers. Moreover, SMIS serve as an optimized intestinal infection model, surpassing the capabilities of traditional 2D cultures, and exhibit a regulatory pattern of immunological markers similar to in vivo infections after Campylobacter jejuni infection. Notably, our protocol extends beyond human spheroids, demonstrating adaptability to other species such as mice and pigs. Conclusion Based on the rapid attainment of enhanced differentiation states, coupled with the emergence of functional brush border features, increased cellular complexity, and replication of the intestinal mucosal microarchitecture, which allows for exposure studies via the medium, we are confident that our innovative SMIS model surpasses conventional cell culture methods as a superior model. Moreover, it offers advantages over stem cell-derived organoids due to scalability and standardization capabilities of the protocol. By showcasing differentiated morphological attributes, our model provides an optimal platform for diverse applications. Furthermore, the investigated differences of several immunological factors compared to monotypic monolayers after Campylobacter jejuni infection underline the refinement of our spheroid model, which closely mimics important features of in vivo infections.

Abstract Meaning salience, or awareness of meaning in the present moment, is an emerging concept with potential implications for health and wellness. The purpose of this study was to understand the relationships between meaning salience and eight dimensions of wellness, and to see whether meaning salience moderated the relationship between presence of meaning and wellness. Participants (N = 1711) were recruited to complete a cross-sectional survey through Amazon’s Mechanical Turk. Meaning salience was related to better wellness in seven of the eight wellness domains (healthy eating and activity, financial stress, occupational wellness, sleep, perceived wellness, social wellness, and stress, excluding avoiding unhealthy foods). Meaning salience significantly moderated the relationships between presence of meaning and four of eight wellness dimensions, such that at high levels of meaning salience, both high and low presence of meaning had stronger relationships with wellness. Those with high meaning salience and high presence of meaning scored best on four wellness dimensions; however, those with high meaning salience and low presence of meaning scored the worst on four wellness dimensions. Future research should explore what factors drive the relationship between meaning salience and wellness.

Abstract Background Mobile device-based cognitive screening has the potential to overcome the limitations in diagnostic precision and efficiency that characterize conventional pen and paper cognitive screening. Several mobile device-based cognitive testing platforms have demonstrated usability, but the usability of take-home mobile device-based cognitive screening in typical adult primary care patients requires further investigation. Methods This study set out to test the usability of a prototype mobile device-based cognitive screening test in older adult primary care patients across a range of cognitive performance. Participants completed the St. Louis University Mental Status Examination (SLUMS) and then used a study-supplied mobile device application at home for 5 days. The application presented 7 modules lasting approximately 15 min. Participants completed the System Usability Scale (SUS) after using the application. Results A total of 51 individuals participated, with a median (IQR) age of 81 (74–85) years. Cognitive impairment (SLUMS score

Missing data and class imbalance hinder the accurate prediction of rare events such as dairy mastitis. Resampling and imputation are employed to handle these problems. These methods are often used arbitrarily, despite their profound impact on prediction due to changes caused to the data structure. We hypothesize that their use affects the performance of ML models fitted to automated milking systems (AMSs) data for mastitis prediction. We compare three imputations—simple imputer (SI), multiple imputer (MICE) and linear interpolation (LI)—and three resampling techniques: Synthetic Minority Oversampling Technique (SMOTE), Support Vector Machine SMOTE (SVMSMOTE) and SMOTE with Edited Nearest Neighbors (SMOTEEN). The classifiers were logistic regression (LR), multilayer perceptron (MLP), decision tree (DT) and random forest (RF). We evaluated them with various metrics and compared models with the kappa score. A complete case analysis fitted the RF (0.78) better than other models, for which SI performed best. The DT, RF, and MLP performed better with SVMSMOTE. The RF, DT and MLP had the overall best performance, contributed by imputation or resampling (SMOTE and SVMSMOTE). We recommend carefully selecting resampling and imputation techniques and comparing them with complete cases before deciding on the preprocessing approach used to test AMS data with ML models.

Abstract Background Recreational water activities at beaches are popular among Canadians. However, these activities can increase the risk of recreational water illnesses (RWI) among beachgoers. Few studies have been conducted in Canada to determine the risk of these illnesses. This protocol describes the methodology for a study to determine the risk and burden of RWI due to exposure to fecal pollution at beaches in Canada. Methods This study will use a mixed-methods approach, consisting of a prospective cohort study of beachgoers with embedded qualitative research. The cohort study involves recruiting and enrolling participants at public beaches across Canada, ascertaining their water and sand contact exposure status, then following-up after seven days to determine the incidence of acute RWI outcomes. We will test beach water samples each recruitment day for culture-based E. coli, enterococci using rapid molecular methods, and microbial source tracking biomarkers. The study started in 2023 and will continue to 2025 at beaches in British Columbia, Manitoba, Ontario, and Nova Scotia. The target enrollment is 5000 beachgoers. Multilevel logistic regression models will be fitted to examine the relationships between water and sand contact and RWI among beachgoers. We will also examine differences in risks by beachgoer age, gender, and beach location and the influence of fecal indicator bacteria and other water quality parameters on these relationships. Sensitivity analyses will be conducted to examine the impact of various alternative exposure and outcome definitions on these associations. The qualitative research phase will include focus groups with beachgoers and key informant interviews to provide additional contextual insights into the study findings. The study will use an integrated knowledge translation approach. Discussion Initial implementation of the study at two Toronto, Ontario, beaches in 2023 confirmed that recruitment is feasible and that a high completion rate (80%) can be achieved for the follow-up survey. While recall bias could be a concern for the self-reported RWI outcomes, we will examine the impact of this bias in a negative control analysis. Study findings will inform future recreational water quality guidelines, policies, and risk communication strategies in Canada.

Abstract Background Cisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients. Methods This is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed. Results Mortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA. Conclusions Our study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.

Abstract Background We compared ultra-high resolution (UHR), standard resolution (SR), and virtual non-calcium (VNCa) reconstruction for coronary artery stenosis evaluation using photon-counting computed tomography (PC-CT). Methods One vessel phantom (4-mm diameter) containing solid calcified lesions with 25% and 50% stenoses inside a thorax phantom with motion simulation underwent PC-CT using UHR (0.2-mm slice thickness) and SR (0.6-mm slice thickness) at heart rates of 60 beats per minute (bpm), 80 bpm, and 100 bpm. A paired t-test or Wilcoxon test with Bonferroni correction was used. Results For 50% stenosis, differences in percent mean diameter stenosis between UHR and SR at 60 bpm (51.0 vs 60.3), 80 bpm (51.7 vs 59.6), and 100 bpm (53.7 vs 59.0) (p ≤ 0.011), as well as between VNCa and SR at 60 bpm (50.6 vs 60.3), 80 bpm (51.5 vs 59.6), and 100 bpm (53.7 vs 59.0) were significant (p ≤ 0.011), while differences between UHR and VNCa at all heart rates (p ≥ 0.327) were not significant. For 25% stenosis, differences between UHR and SR at 60 bpm (28.0 vs 33.7), 80 bpm (28.4 vs 34.3), and VNCa vs SR at 60 bpm (29.1 vs 33.7) were significant (p ≤ 0.015), while differences for UHR vs SR at 100 bpm (29.9 vs 34.0), as well as for VNCa vs SR at 80 bpm (30.7 vs 34.3) and 100 bpm (33.1 vs 34.0) were not significant (p ≥ 0.028). Conclusion Stenosis quantification accuracy with PC-CT improved using either UHR acquisition or VNCa reconstruction. Relevance statement PC-CT offers to scan with UHR mode and the reconstruction of VNCa images both of them could provide improved coronary stenosis quantification at increased heart rates, allowing a more accurate stenosis grading at low and high heart rates compared to SR. Key Points Evaluation of coronary stenosis with conventional CT is challenging at high heart rates. PC-CT allows for scanning with ECG-gated UHR and SR modes. UHR and VNCa images were compared in a dynamic phantom. UHR improves stenosis quantification up to 100 bpm. VNCa reconstruction improves stenosis evaluation up to 80 bpm. Graphical Abstract

Abstract Background Osteoporosis is increasingly being recognized in children, mostly secondary to systemic underlying conditions or medication. However, no imaging modality currently provides a full evaluation of bone health in children. We compared DXA, a radiographic bone health index (BHI (BoneXpert) and cone-beam CT for the assessment of low bone mass in children with juvenile idiopathic arthritis (JIA). Methods Data used in the present study was drawn from a large multicentre study including 228 children aged 4–16 years, examined between 2015 and 2020. All had a radiograph of the left hand, a DXA scan and a cone-beam CT of the temporomandibular joints within four weeks of each other. For the present study, we included 120 subjects, selected based on DXA BMD and BoneXpert BHI to secure values across the whole range to be tested. Results One hundred and twenty children (60.0% females) were included, mean age 11.6 years (SD 3.1 years). There was a strong correlation between the absolute values of BHI and BMD for both total body less head (TBLH) (r = 0.75, p

Abstract Background Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked. Methods Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi). Results Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (Csf3, Cxcr2, Il16, and Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, and Ptger3), and markers of neurodegeneration (Gfap, Grin2b, and Homer1). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2–50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved. Conclusions Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood–brain barrier breakdown, immune cell penetration–activation, and microglial activation.

Abstract Purpose To evaluate the long-term clinical outcomes in patients with combined pars plana vitrectomy (PPV) with anterior chamber intraocular lens (ACIOL) to intrascleral haptic fixation (ISHF) using the Agarwal technique with fibrin glue to secure the scleral flap of a posterior chamber intraocular lens. Methods Retrospective, consecutive, single-center, comparative case series. 83 eyes were studied. Patients with

Abstract Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.

Abstract Background The Coronavirus disease-2019 (COVID-19) vaccines were rolled out in many countries; however, sub-optimal COVID-19 vaccine uptake remains a major public health concern globally. This study aimed at assessing the factors that affected the uptake, hesitancy, and resistance of the COVID-19 vaccine among university undergraduate students in Malawi, a least developed country in Africa. Methods A descriptive cross-sectional study design was conducted using an online semi-structured questionnaire. A total of 343 University undergraduate students in Blantyre participated in this study after obtaining ethical clearance. Data was exported from Survey Monkey to Microsoft Excel version-21 for cleaning and was analysed using SPSS version-29. Descriptive statistics, including percentages, were performed to define the sample characteristics. Pearson Chi-square and Fisher’s exact test were performed to identify significant relationships between vaccine uptake and demographics. A 95% confidence interval was set, and a p-value of

Abstract By connecting old and recent notions, different spatial scales, and research domains, we introduce a novel framework on the consequences of brain injury focusing on a key role of slow waves. We argue that the long-standing finding of EEG slow waves after brain injury reflects the intrusion of sleep-like cortical dynamics during wakefulness; we illustrate how these dynamics are generated and how they can lead to functional network disruption and behavioral impairment. Finally, we outline a scenario whereby post-injury slow waves can be modulated to reawaken parts of the brain that have fallen asleep to optimize rehabilitation strategies and promote recovery.

Abstract Background Emergency department (ED) crowding is a major patient safety concern and has a negative impact on healthcare systems and healthcare providers. We hypothesized that it would be feasible to control crowding by employing a multifaceted approach consisting of systematically fast-tracking patients who are mostly not in need of a hospital stay as assessed by an initial nurse and treated by decision competent physicians. Methods Data from 120,901 patients registered in a secondary care ED from the 4tth quarter of 2021 to the 1st quarter of 2024 was drawn from the electronic health record’s data warehouse using the SAP Web Intelligence tool and processed in the Python programming language. Crowding was compared before and after ED transformation from a uniform department into a high flow (α) and a low flow (β) section with patient placement in gurneys/chairs or beds, respectively. Patients putatively not in need of hospitalization were identified by nurse, placed in in the α setting and assessed and treated by decision competent physicians. Incidence of crowding, number of patients admitted per day and readmittances within 72 h following ED admission before and after changes were determined. Values are number of patients, mean ± SEM and mean differences with 95% CIs. Statistical significance was ascertained using Student’s two tailed t-test for unpaired values. Results Before and after ED changes crowding of 130% amounted to 123.8 h and 19.3 h in the latter. This is a difference of -104.6 ± 23.9 h with a 95% CI of -159.9 to -49.3, Δ% -84 (p = 0.002). There was the same amount of patients / day amounting to 135.8 and 133.5 patients / day Δ% = -1.7 patients 95% CI -6.3 to 1.6 (p = 0.21). There was no change in readmittances within 72 h before and after changes amounting to 9.0% versus 9.5%, Δ% = 0.5, 95%, CI -0.007 to 1.0 (p > 0.052). Conclusion It appears feasible to abate crowding with unchanged patient admission and without an increase in readmittances by fast-track assessment and treatment of patients who are not in need of hospitalization.

Abstract The ongoing efforts to optimize rechargeable Li-ion batteries led to the interest in intercalation of nanoscale layered compounds, including bilayer graphene. Its lithium intercalation has been demonstrated recently but the mechanisms underpinning the storage capacity remain poorly understood. Here, using magnetotransport measurements, we report in-operando intercalation dynamics of bilayer graphene. Unexpectedly, we find four distinct intercalation stages that correspond to well-defined Li-ion densities. Transitions between the stages occur rapidly (within 1 sec) over the entire device area. We refer to these stages as ‘in-plane’, with no in-plane analogues in bulk graphite. The fully intercalated bilayers represent a stoichiometric compound C14LiC14 with a Li density of ∼2.7·1014 cm−2, notably lower than fully intercalated graphite. Combining the experimental findings and DFT calculations, we show that the critical step in bilayer intercalation is a transition from AB to AA stacking which occurs at a density of ∼0.9·1014 cm−2. Our findings reveal the mechanism and limits for electrochemical intercalation of bilayer graphene and suggest possible avenues for increasing the Li storage capacity.

Abstract Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65–92%). Median progression free and overall survival were 14.0 (95% CI, 11.3–36.4) and 23.2 months (95% CI, 16.6–36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2–8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Abstract Background In the context of rheumatoid arthritis and its systemic inflammatory implications, there is an increasing interest in investigating the role of prolactin in the clinical and metabolic aspects of the disease. This study aimed to explore the potential links between serum prolactin levels, serum glucose levels, and the clinical manifestations of arthritis. Methods This exploratory, cross-sectional, observational study focused on women diagnosed with rheumatoid arthritis. The research involved assessing prolactin and blood glucose concentrations, alongside specific clinical traits such as disease-related inflammation, morning stiffness, and fatigue intensity. The presence of changes in serum prolactin (PRL) was initially compared among the groups based on disease activity intensity. Using a multinomial regression analysis, the study analyzed the impact of predetermined clinical and metabolic factors on various categories of prolactin concentration. Results Out of the 72 participants included in the study, hyperprolactinemia was detected in 9.1% of the sample. No differences in serum PRL were identified among the evaluated groups based on disease activity. Following multivariate analysis, no statistically significant differences were identified for the outcomes of inflammatory activity and morning stiffness within each PRL category when compared to the reference category for PRL. There was no increased likelihood of encountering blood glucose levels below 100 mg/dl among individuals with higher prolactin concentrations compared to those in the lowest prolactin category (OR 5.43, 95% CI 0.51–58.28). The presence of clinically significant fatigue revealed a higher likelihood of encountering this outcome among patients with intermediate PRL values (prolactin categories 7.76–10.35 with OR 5.18, 95% CI 1.01–26.38 and 10.36–15.29 with OR 6.25, 95% CI 1.2–32.51) when compared to the reference category. Conclusions The study found no discernible correlation between prolactin concentrations and worse scores for inflammatory activity of the disease, nor between prolactin concentrations and serum glucose levels. The findings regarding fatigue should be approached with caution given the exploratory nature of this study.

Abstract Extreme ecosystem modification by humans has caused drastic reductions in populations and ranges of top mammalian predators, while simultaneously allowing synanthropic mesopredator species to expand. These conditions often result in inflated local densities of highly adaptable mesopredators that disrupt trophic dynamics and place unsustainable predation pressure on native prey populations. Colonization of a dominant predator may lead to top-down control of mesopredators and restore trophic balance. Coyotes are a novel colonizer of some coastal barrier islands of eastern North America, offering an opportunity to test how the addition of an apex predator impacts an established guild of mesopredators. To assess their trophic impact, we conducted 75,576 camera trapping hours over an 18-month study period, capturing > 1.5 million images across 108 coastal camera sites. Using two-species occupancy and habitat use models, we found sizeable effects of coyote habitat use on that of red foxes and free-ranging domestic cats, suggesting that coyotes function as apex predators in barrier island ecosystems. In fact, the only factor that determined the spatial pattern of highly ubiquitous red foxes was the sympatric habitat use of the largest carnivore in the food web—coyotes. That ‘novel’ apex predators can become established in coastal food webs illustrates the highly dynamic nature of conservation challenges for habitats and species at the edge of the sea.

Abstract While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8 jck ), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

Dual-energy or spectral computed tomography (CT) information may be obtained by either sending X-ray beams of different energy spectra through the patient or by discriminating the energy of the X-rays that reach the detector. The spectral signal is then used to generate multiple results: conventional, virtual monoenergetic (MonoE), effective atomic number, electron density, and other material specific (e.g., iodine, calcium, or uric acid). This report demonstrates the potential benefits of spectral CT imaging during percutaneous tumor ablation procedures, specifically regarding visualization of inconspicuous tumors, accurate probe placement, and assessment of treatment efficacy.

Abstract Background The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p

Abstract Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is considered a growing health concern. The majority of NTM-PD cases in Europe are caused by slow-growing mycobacteria (SGM). However, distinct radiological features of different SGM remain largely uninvestigated. We applied a previously described radiological score to a patient cohort consisting of individuals with isolation of different SGM. Correlations between clinical data, species and computed tomography (CT) features were examined by logistic and linear regression analyses, as well as over the course of time. Overall, 135 pulmonary CT scans from 84 patients were included. The isolated NTM-species were mainly Mycobacterium avium complex (MAC, n = 49), as well as 35 patients with non-MAC-species. Patients with isolation of M. intracellulare had more extensive CT findings compared to all other SGM species (coefficient 3.53, 95% Cl − 0.37 to 7.52, p = 0.075) while patients meeting the ATS criteria and not undergoing therapy exhibited an increase in CT scores over time. This study provides insights into differential radiological features of slow-growing NTM. While M. intracellulare exhibited a tendency towards higher overall CT scores, the radiological features were similar across different SGM. The applied CT score might be a useful instrument for monitoring patients and could help to guide antimycobacterial therapy.

Abstract Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Abstract Background The clinical description of superior vena cava syndrome has been widely studied; however, there is limited information on bronchoscopic findings in clinical practice. Case presentation A 57-year-old man presented with facial and neck swelling and pedal edema of 6 months duration. Computed tomography showed mediastinal lesions in the right paratracheal stations with thrombosis of the right internal jugular vein and superior vena cava (SVC). Without establishing a diagnosis, he was started on oral steroids elsewhere and his symptoms progressed. He did not receive anticoagulation therapy. Bronchoscopy showed edematous supraglottic and glottic regions with hyperemia of the airway mucosa. Endobronchial Ultrasonography revealed a mediastinal mass of heterogeneous echotexture in the lower right paratracheal region, with mediastinal collateral blood vessels. He underwent EBUS-guided aspiration cytology and intranodal forceps biopsy, which confirmed the diagnosis of non-Hodgkin’s. Conclusion In cases with an unconfirmed diagnosis of lymphoma, it is prudent to refrain from administering glucocorticoids, as these medications can exhibit lympholytic properties and may hinder the diagnostic process. Due to extensive collateral formation in superior vena cava syndrome, utilizing Doppler during endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA) can identify numerous mediastinal collateral vessels, thus minimizing the risk of bleeding.

Abstract Background We quantified SARS-CoV-2 dynamics in different community settings and the direct and indirect effect of the BNT162b2 mRNA vaccine in Monaco for different variants of concern (VOC). Methods Between July 2021 and September 2022, we prospectively investigated 20,443 contacts from 6320 index cases using data from the Monaco COVID-19 Public Health Programme. We calculated secondary attack rates (SARs) in households (n = 13,877), schools (n = 2508) and occupational (n = 6499) settings. We used binomial regression with a complementary log–log link function to measure adjusted hazard ratios (aHR) and vaccine effectiveness (aVE) for index cases to infect contacts and contacts to be infected in households. Results In households, the SAR was 55% (95% CI 54–57) and 50% (48–51) among unvaccinated and vaccinated contacts, respectively. The SAR was 32% (28–36) and 12% (10–13) in workplaces, and 7% (6–9) and 6% (3–10) in schools, among unvaccinated and vaccinated contacts respectively. In household, the aHR was lower in contacts than in index cases (aHR 0.68 [0.55–0.83] and 0.93 [0.74–1.1] for delta; aHR 0.73 [0.66–0.81] and 0.89 [0.80–0.99] for omicron BA.1&2, respectively). Vaccination had no significant effect on either direct or indirect aVE for omicron BA.4&5. The direct aVE in contacts was 32% (17, 45) and 27% (19, 34), and for index cases the indirect aVE was 7% (− 17, 26) and 11% (1, 20) for delta and omicron BA.1&2, respectively. The greatest aVE was in contacts with a previous SARS-CoV-2 infection and a single vaccine dose during the omicron BA.1&2 period (45% [27, 59]), while the lowest were found in contacts with either three vaccine doses (aVE − 24% [− 63, 6]) or one single dose and a previous SARS-CoV-2 infection (aVE − 36% [− 198, 38]) during the omicron BA.4&5 period. Conclusions Protection conferred by the BNT162b2 mRNA vaccine against transmission and infection was low for delta and omicron BA.1&2, regardless of the number of vaccine doses and previous SARS-CoV-2 infection. There was no significant vaccine effect for omicron BA.4&5. Health authorities carrying out vaccination campaigns should bear in mind that the current generation of COVID-19 vaccines may not represent an effective tool in protecting individuals from either transmitting or acquiring SARS-CoV-2 infection.

Coronary-pulmonary artery fistulas (CPAFs) are rare entities that can cause significant left-to-right shunting and complicate routine coronary artery bypass grafting. There are no best practice guidelines and a scarcity of reports regarding concomitant treatment of CPAF with coronary artery disease. We present a case of bilateral CPAFs in a 60-year-old man with symptomatic coronary artery disease treated successfully with coronary artery bypass, epicardial ligation, and transpulmonary closure of CPAF with patch reconstruction. This case highlights the importance of optimal myocardial protection and complete closure of the fistula to prevent risk of coronary steal.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Freshwater crayfish are amongst the largest macroinvertebrates and play a keystone role in the ecosystems they occupy. Understanding the global distribution of these animals is often hindered due to a paucity of distributional data. Additionally, non-native crayfish introductions are becoming more frequent, which can cause severe environmental and economic impacts. Management decisions related to crayfish and their habitats require accurate, up-to-date distribution data and mapping tools. Such data are currently patchily distributed with limited accessibility and are rarely up-to-date. To address these challenges, we developed a versatile e-portal to host distributional data of freshwater crayfish and their pathogens (using Aphanomyces astaci, the causative agent of the crayfish plague, as the most prominent example). Populated with expert data and operating in near real-time, World of Crayfish™ is a living, publicly available database providing worldwide distributional data sourced by experts in the field. The database offers open access to the data through specialized standard geospatial services (Web Map Service, Web Feature Service) enabling users to view, embed, and download customizable outputs for various applications. The platform is designed to support technical enhancements in the future, with the potential to eventually incorporate various additional features. This tool serves as a step forward towards a modern era of conservation planning and management of freshwater biodiversity.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Reproducible and standardised neurological assessment scales are important in quantifying research outcomes. These scales are often performed by non-neurologists and/or non-clinicians and must be robust, quantifiable, reproducible and comparable to a neurologist's assessment. COVID-CNS is a multi-centre study which utilised the Neurological Impairment Scale (NIS) as a core assessment tool in studying neurological outcomes following COVID-19 infection. We investigated the strengths and weaknesses of the NIS when used by non-neurology clinicians and non-clinicians, and compared performance to a structured neurological examination performed by a neurology clinician. Through our findings, we provide practical advice on how non-clinicians can be readily trained in conducting reproducible and standardised neurological assessments in a multi-centre study, as well as illustrating potential pitfalls of these tools.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Objectives: To determine the associated pathogen during the 2023 conjunctivitis outbreak in Vietnam Methods: RNA-sequencing was used to identify pathogens before and during the outbreak. Results: 24 patients with infectious conjunctivitis between March and October 2023 from Hai Yen Vision Institute in Vietnam were swabbed. Coxsackievirus A24v was the most common pathogen identified. Phylogenetic analysis of these strains demonstrates similarities to the Coxsackievirus identified in the 2022 India outbreak. Human adenovirus D was also circulating. Ocular findings of tearing, purulence, and itching were common in this outbreak. Conclusions: Multiple viruses can co-circulate during conjunctivitis outbreaks. Hemorrhagic conjunctivitis, commonly associated with coxsackievirus conjunctivitis, was not a common clinical sign in this outbreak. Repeat genetic surveillance, with the notable inclusion of RNA virus detection strategies, is important for outbreak detection.

Background: Solid pseudopapillary neoplasm (SPN) of the pancreas in children is a rare tumor with low malignant potential. Some tumors, however, behave aggressively. There is very little literature on managing these variants, especially in children. We share our experience of managing large and recurrent SPN and explore the clinicopathological findings correlating to the risk of recurrence. Methods: This is a retrospective study of children treated for SPN between 2012 and 2022 at a tertiary care center in India. The clinicopathological features and management strategies in these children were evaluated. Results: Sixteen children with SPN were treated during this period (88% of girls). The median age of presentation was 12 years (interquartile range [IQR]: 9–14). All children presented with abdominal pain. Computed tomography gave a definitive diagnosis in 81% of cases. The tumor predominantly involved the head of the pancreas (n = 9, 56%). Eight of nine children classified as high-grade (HG) malignant had a benign course. One child had a recurrence of the tumor 4 years after the initial resection and further recurrence on chemotherapy. She required radiation therapy in addition to reoperation following which she was disease free for 77 months. The overall median follow-up was 46 months (IQR: 18–72 months). Conclusion: Complete resection of the tumor provides a cure in most patients with SPN. Recurrent tumors require a multi-modality approach. Long-term survival is good. There is a need for clear definitions of the components within the WHO criteria for HG malignancy.

Successful problem-based learning (PBL) often requires students to collectively regulate their learning processes as a group and engage in socially shared regulation of learning (SSRL). This paper focuses on how facilitators supported SSRL in the context of middle-school game-based PBL. Using conversation analysis, this study analyzed text-based chat messages of facilitators and students collected during gameplay. The analysis revealed direct modeling strategies such as performing regulative processes, promoting group awareness, and dealing with contingency as well as indirect strategies including prompting questions and acknowledgment of regulation, and the patterns of how facilitation faded to yield responsibilities to students to regulate their own learning. The findings will inform researchers and practitioners to design prompts and develop technological tools such as adaptive scaffolding to support SSRL in PBL or other collaborative inquiry processes.