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Abstract Introduction Due to variable psoriasis symptoms, disease progression, and individual responses to therapy, patients may start, stop, or switch biologic therapies. Real-world data on the associated disease burden of patients with psoriasis who do and do not switch biologics are incomplete. Methods This study compared disease burden among patients from the CorEvitas Psoriasis Registry (July 2017–December 2021) who switched biologics and those who did not within 4–12 months following initiation. Disease-related patient-reported outcomes (PROs) were recorded, including skin pain, itching, activity impairment, and effects on health-related quality of life (HRQoL). Disease severity was measured by body surface area (BSA) and Psoriasis Area and Severity Index (PASI). Unadjusted and adjusted regression models were used to compare study outcome measures between the two groups. Results This study included 2145 patients, with 159 classified as switchers and 1986 as non-switchers. The most common reason for switching therapy was failure to maintain initial response (51.7%; n = 78). Moderate-to-severe disease (BSA ≥ 3) was found among 83.0% (n = 132) of switchers versus 26.1% (n = 516) of non-switchers. PASI > 5 was reported among 49.7% (n = 79) of switchers versus 8.6% (n = 171) of non-switchers. Differences in skin pain, itching, and effects on HRQoL between switchers and non-switchers were larger in magnitude for bio-experienced patients. Conclusions Patients who switched biologic therapy experienced a greater disease burden of psoriasis across PROs than non-switchers. Patient-centered factors may be important drivers of biologic switching. Our findings suggest the association between switching and disease burden may be stronger among patients with prior biologic therapy experience.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson’s disease-like and DBS-induced gait changes.

Abstract Aims Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Methods and results Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON‐HF, EMPEROR‐Preserved, DELIVER, FINE‐ARTS, and SPIRRIT‐HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial‐eligible and trial‐ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75 years, P

Abstract Thermophily is a trait scattered across the fungal tree of life, with its highest prevalence within three fungal families (Chaetomiaceae, Thermoascaceae, and Trichocomaceae), as well as some members of the phylum Mucoromycota. We examined 37 thermophilic and thermotolerant species and 42 mesophilic species for this study and identified thermophily as the ancestral state of all three prominent families of thermophilic fungi. Thermophilic fungal genomes were found to encode various thermostable enzymes, including carbohydrate-active enzymes such as endoxylanases, which are useful for many industrial applications. At the same time, the overall gene counts, especially in gene families responsible for microbial defense such as secondary metabolism, are reduced in thermophiles compared to mesophiles. We also found a reduction in the core genome size of thermophiles in both the Chaetomiaceae family and the Eurotiomycetes class. The Gene Ontology terms lost in thermophilic fungi include primary metabolism, transporters, UV response, and O-methyltransferases. Comparative genomics analysis also revealed higher GC content in the third base of codons (GC3) and a lower effective number of codons in fungal thermophiles than in both thermotolerant and mesophilic fungi. Furthermore, using the Support Vector Machine classifier, we identified several Pfam domains capable of discriminating between genomes of thermophiles and mesophiles with 94% accuracy. Using AlphaFold2 to predict protein structures of endoxylanases (GH10), we built a similarity network based on the structures. We found that the number of disulfide bonds appears important for protein structure, and the network clusters based on protein structures correlate with the optimal activity temperature. Thus, comparative genomics offers new insights into the biology, adaptation, and evolutionary history of thermophilic fungi while providing a parts list for bioengineering applications.

Abstract Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

Abstract The North Temperate Lakes Long-Term Ecological Research (NTL-LTER) program has been extensively used to improve understanding of how aquatic ecosystems respond to environmental stressors, climate fluctuations, and human activities. Here, we report on the metagenomes of samples collected between 2000 and 2019 from Lake Mendota, a freshwater eutrophic lake within the NTL-LTER site. We utilized the distributed metagenome assembler MetaHipMer to coassemble over 10 terabases (Tbp) of data from 471 individual Illumina-sequenced metagenomes. A total of 95,523,664 contigs were assembled and binned to generate 1,894 non-redundant metagenome-assembled genomes (MAGs) with ≥50% completeness and ≤10% contamination. Phylogenomic analysis revealed that the MAGs were nearly exclusively bacterial, dominated by Pseudomonadota (Proteobacteria, N = 623) and Bacteroidota (N = 321). Nine eukaryotic MAGs were identified by eukCC with six assigned to the phylum Chlorophyta. Additionally, 6,350 high-quality viral sequences were identified by geNomad with the majority classified in the phylum Uroviricota. This expansive coassembled metagenomic dataset provides an unprecedented foundation to advance understanding of microbial communities in freshwater ecosystems and explore temporal ecosystem dynamics.

Abstract Migratory distances and stopover locations are changing for many passerines in response to climate change. Morphological changes have been linked to rising global temperatures in both migrants and residents, but the implications of these changes on fuel loads, and associated flight ranges are little studied. Wing length and body mass changes between 1964 and 2020 were calculated for 15 migrant and partially migrant passerines in Britain. Changes in fuel load and lean body mass were also estimated and used to predict flight ranges. Twelve of the species have undergone morphological changes and eight species, estimated fuel load changes. Nine species were estimated to have reduced flight ranges, indicating that the morphological changes have not compensated fully for the reduction in flight range experienced since 1964. Partial migrants showed greater decreases in flight ranges than did full migrants, which may indicate greater behavioural plasticity in the former. Those species which do not adapt morphologically or behaviourally may be unable to complete long migrations, resulting in restriction to sub-optimal breeding/wintering habitats, or a need for a sooner first stop and more stops en route. This highlights the importance of conserving migratory stopover sites, particularly in the Mediterranean and North Africa that immediately precede major geographical barriers, as-well-as breeding and wintering grounds.

Introduction: Boerhaave syndrome is a rare condition associated with high morbidity and mortality. Prompt intervention greatly improves outcomes, with surgery traditionally being the mainstay of management. Recent advances in therapeutic endoscopy have led to increasing interest in endoluminal vacuum therapy (EVT), a minimally invasive technique, allowing wound debridement and drainage, encouraging granulation tissue formation. EVT has been associated with positive clinical outcomes, including lower mortality rates compared to surgery and stenting for the management of anastomotic leaks, and to a lesser extent, oesophageal perforations. EVT has been adopted into practice across Europe; however, only few cases have been reported from the UK. Case Presentations: We report three cases of Boerhaave syndrome, successfully managed with EVT, using the Eso-SPONGE ® (B.Braun Medical Ltd, Sheffield, UK). EVT involves the placement of a polyurethane sponge into the wound cavity. The cavity is initially assessed, then an overtube is introduced through which the sponge is inserted, and then the overtube is removed. Sponge position is confirmed and adjusted if necessary. The sponge is connected via a trans-nasal drain to continuous negative pressure suction and is changed every 3–5 days. Having been deemed surgically unfit, all 3 patients were referred for EVT. All patients made excellent recovery and were discharged home. Conclusion: EVT is an effective management strategy for surgically unfit Boerhaave syndrome patients. Eso-SPONGE use aided drainage of the septic focus and closure of the defect, leading to complete recovery. Our findings support the existing evidence that EVT is a promising solution for Boerhaave syndrome.

Abstract Background Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. Methods To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. Results In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7—most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or −7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66–3.86]; P

Abstract Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdelta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetricdelta between groups (p = 0.041). The reduced ECdelta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.

Abstract In the AdS/CFT correspondence, the causal structure of the bulk AdS spacetime is tied to entanglement in the dual CFT. This relationship is captured by the connected wedge theorem [1], which states that a bulk scattering process implies the existence of O(1/G N ) entanglement between associated boundary subregions. In this paper, we study the connected wedge theorem in two asymptotically AdS2+1 spacetimes: the conical defect and BTZ black hole geometries. In these settings, we find that bulk scattering processes require not just large entanglement, but also additional restrictions related to candidate RT surfaces which are non-minimal. We argue these extra relationships imply a certain CFT entanglement structure involving internal degrees of freedom. Because bulk scattering relies on sub-AdS scale physics, this supports the idea that sub-AdS scale locality emerges from internal degrees of freedom. While the new restriction that we identify on non-minimal surfaces is stronger than the initial statement of the connected wedge theorem, we find that it is necessary but still not sufficient to imply bulk scattering in mixed states.

Abstract Postnatal kidney growth is substantial and involves expansion in kidney tubules without growth of new nephrons, which are the functional units of the kidney. Proliferation and differentiation pathways underpinning nephron elongation are not well defined. To address this, we performed sequential characterization of mouse kidney transcriptomics at the single cell level. Single nuclear RNA sequencing (snRNA-seq) was performed on kidney tissue from male and female mice at 1, 2, 4 and 12 weeks of age using the 10x Chromium platform. Unbiased clustering was performed on 68,775 nuclei from 16 animals. 31 discrete cellular clusters were seen, which were identified through comparison of their gene expression profiles to canonical markers of kidney cell populations. High levels of proliferation were evident at early time points in some cell types, especially tubular cells, but not in other cell types, for example podocytes. Proliferation was especially evident in Proximal Tubular Cells (PTCs) which are the most abundant cell type in the adult kidney. Uniquely when compared to other kidney cell types, PTCs demonstrated sex-specific expression profiles at late, but not early, time points. Mapping of PTC differentiation pathways using techniques including trajectory and RNA Velocity analyses delineated increasing PTC specialization and sex-specific phenotype specification. Our single-cell transcriptomics data characterise cellular states observed during kidney growth. We have identified PTC differentiation pathways that lead to sex-specific tubular cell phenotypes. Tubular proliferative responses are of central importance in postnatal kidney growth and have also been linked to kidney recovery versus fibrosis following injury. Our unbiased and comprehensive dataset of tubular cell development can be used to identify candidate pathways for therapeutic targeting.

Abstract Natural Killer (NK) cells are pivotal in immune responses to viral infections, malignancies, autoimmune diseases, and transplantation. Assessment of NK cell adhesion, migration, and cytotoxicity is fundamental for in vitro studies. We propose a novel live-cell tracking method that addresses these three major aspects of NK cell function using human NK cells and primary porcine aortic endothelial cells (PAECs) in two-dimensional (2D) static assays and an in-house cylindrical 3D microfluidic system. The results showed a significant increase of NK cytotoxicity against pTNF-activated PAECs, with apoptotic cell death observed in the majority of dead cells, while no difference was observed in the conventional Delfia assay. Computed analysis of NK cell trajectories revealed distinct migratory behaviors, including trajectory length, diameter, average speed, and arrest coefficient. In 3D microfluidic experiments, NK cell attachment to pTNF-activated PAECs substantially increased, accompanied by more dead PAECs compared to control conditions. NK cell trajectories showed versatile migration in various directions and interactions with PAECs. This study uniquely demonstrates NK attachment and killing in a 3D system that mimics blood vessel conditions. Our microscope method offers sensitive single-cell level results, addressing diverse aspects of NK functions. It is adaptable for studying other immune and target cells, providing insights into various biological questions.

Abstract BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Abstract Background Missing data in confounding variables present a frequent challenge in generating evidence using real-world data, including electronic health records (EHR). Our objective was to apply a recently published toolkit for characterizing missing data patterns and based on the toolkit results about likely missingness mechanisms, illustrate the decision-making process for analyses in an empirical case example. Methods We utilized the Structural Missing Data Investigations (SMDI) toolkit to characterize missing data patterns in the context of a pharmacoepidemiology study comparing cardiovascular outcomes of initiating sodium-glucose-cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase‐4 inhibitors (DPP‐4i) among older adults. The study used a linked EHR-Medicare claims dataset from Duke Health patients (2015–2017), focusing on partially observed confounders from EHR data (HbA1c lab and body mass index [BMI] values). Our analysis incorporated SMDI's descriptive functions and diagnostic tests to explore missingness patterns and determine missingness mitigation approaches. We used findings from these investigations to inform estimation of adjusted hazard ratios comparing the two classes of medications. Results High levels of missingness were noted for important confounding variables including HbA1c (63.6%) and BMI (16.5%). Diagnostic tests resulted in output that described: 1) the distributions of patient characteristics, exposure, and outcome between patients with or without an observed value of the partially observed covariate, 2) the ability to predict missingness based on observed covariates, and 3) estimate if the missingness of a partially observed covariate is differential with respect to the outcome. There was evidence that missingness could be sufficiently described using observed data, which allowed multiple imputation by chained equations using random forests to address missing confounder data in estimating treatment effects. Multiple imputation resulted in improved alignment of effect estimates with previous studies. Conclusions We were able to demonstrate the practical application of the SMDI toolkit in a real-world setting. Application of the SMDI toolkit and the resulting insights of potential missingness patterns can inform the choice of appropriate analytic methods and increase transparency of research methods in handling missing data. This type of approach can inform analytic decision making and may increase our ability to generate evidence from real-world data.

Abstract Identifying genetic drivers of chronic diseases is necessary for drug discovery. Here, we develop a machine learning-assisted genetic priority score, which we call ML-GPS, that incorporates genetic associations with predicted disease phenotypes to enhance target discovery. First, we construct gradient boosting models to predict 112 chronic disease phecodes in the UK Biobank and analyze associations of predicted and observed phenotypes with common, rare, and ultra-rare variants to model the allelic series. We integrate these associations with existing evidence using gradient boosting with continuous feature encoding to construct ML-GPS, training it to predict drug indications in Open Targets and externally testing it in SIDER. We then generate ML-GPS predictions for 2,362,636 gene-phecode pairs. We find that the use of predicted phenotypes, which identify substantially more genetic associations than observed phenotypes across the allele frequency spectrum, significantly improves the performance of ML-GPS. ML-GPS increases coverage of drug targets, with the top 1% of all scores providing support for 15,077 gene-phecode pairs that previously had no support. ML-GPS can also identify well-known target-disease relationships, promising targets without indicated drugs, and targets for several drugs in clinical trials, including LRRK2 inhibitors for Parkinson’s disease and olpasiran for cardiovascular disease.

Abstract Methyl bromide (CH3Br) is an important ozone-depleting substance whose use is regulated under the Montreal Protocol. Quantifying emissions on the national scale is required to assess compliance with the Montreal Protocol and thereby ensure the timely recovery of the ozone layer. However, the spatial-temporal patterns of China’s national CH3Br emissions remain unclear. Here we estimate the national emissions of CH3Br in China during 2011−2020 using atmospheric observations at 10 sites across China combined with an inversion technique (top-down) and compare those with an updated inventory of identified emission sources (bottom-up). Measured CH3Br mole fractions are enhanced well above the background mole fractions, especially at sites in eastern China. Top-down emission estimates exceed bottom-up estimates by 5.5 ± 1.4 gigagrams per year, with the largest fraction (60%) of observationally derived CH3Br emissions arising from underestimated or unidentified emissions sources. This study shows the potential impacts of the unaccounted emissions on stratospheric ozone depletion, with implications for the Montreal Protocol.

Abstract It has long been recognised that spreading ridges are kept in place by competing subduction forces that drive plate motions. Asymmetric strain rates pull spreading ridges in the direction of the strongest slab pull force, which partially explains why spreading ridges can migrate vast distances. However, the interaction between mantle plumes and spreading ridges plays a relatively unknown role on the evolution of plate boundaries. Using a numerical model of mantle convection, we show that plumes with high buoyancy flux (>3000 kg/s) can capture spreading ridges within a 1000 km radius and anchor them in place. Exceptionally high buoyancy fluxes may fragment the overriding plate into smaller plates to accommodate more efficient plate motion. If the plume buoyancy flux wanes below 1000 kg/s the ridge may be de-anchored, leading to rapid ridge migration rates when combined with asymmetric plate boundary forces. Our results show that plume-ridge de-anchoring may have contributed to the rapid migration of the SE Indian Ridge from 43 million years ago (Ma) due to waning buoyancy flux from the Kerguelen plume, supported by magma flux estimates and radiogenic isotope geochemistry of eruption products. The plume-ridge de-anchoring mechanism we have identified has global implications for the evolution of plate boundaries near mantle plumes.

Abstract Protein kinases are critical components of a myriad biological processes and strongly associated with various diseases. While kinase research has been a point of focus in biomedical research for several decades, a large portion of the kinome is still considered understudied or “dark,” because prior research is targeted towards a subset of kinases with well-established roles in cellular processes. We present an empirical and in-silico hybrid workflow to extend the functional knowledge of understudied kinases. Utilizing multiplex peptide activity arrays and robust in-silico analyses, we extended the functional knowledge of five dark tyrosine kinases (AATK, EPHA6, INSRR, LTK, TNK1) and explored their roles in schizophrenia, Alzheimer’s dementia (AD), and major depressive disorder (MDD). Using this hybrid approach, we identified 195 novel kinase-substrate interactions with variable degrees of affinity and linked extended functional networks for these kinases to biological processes that are impaired in psychiatric and neurological disorders. Biochemical assays and mass spectrometry were used to confirm a putative substrate of EPHA6, an understudied dark tyrosine kinase. We examined the EPHA6 network and knowledgebase in schizophrenia using reporter peptides identified and validated from the multi-plex array with high affinity for phosphorylation by EPHA6. Identification and confirmation of putative substrates for understudied kinases provides a wealth of actionable information for the development of new drug treatments as well as exploration of the pathophysiology of disease states using signaling network approaches.

Abstract Biochar offers opportunities for improving soil carbon (C) sequestration and reducing CO2 emissions to the atmosphere. It has emerged as a strategy for mitigating climate change and improving the soil carbon cycle (SCC). While previous review studies have primarily investigated the effects of biochar on greenhouse gas (GHG) emissions, a considerable research gap remains regarding its impact on the SCC. The present study aims to bridge this gap by examining the main SCC components: total CO2 flux, total microbial respiration, and C sequestration. We conducted a global meta-analysis which included 75 studies and 250 observations. The results show an average 11% increase in soil total CO2 flux from biochar, but the confidence interval (CI) slightly touches the no-effect line (CI [0%, 23%]). Total microbial respiration remains unchanged after the application (10%, CI [− 2%, 23%]). In contrast, soil C sequestration benefits from biochar by 61% (CI [36%, 90%]). Our analysis identified key predictors affecting SCC components: experimental design, continent, biochar application rate, feedstock type, and pyrolysis temperature. Incubation experiments reveal benefits for all SCC components. The Middle East, Europe, and Asia exhibit potential for enhancing C sequestration with biochar. Higher application rates amplify C sequestration and total microbial respiration. Manure biochar enhances total microbial respiration, while woody biochar influences total CO2 flux. Furthermore, lower pyrolysis temperatures show promise for improving C sequestration and total microbial respiration. In conclusion, while biochar holds promise for C sequestration, its impact on total microbial respiration and total CO2 flux remains inconclusive.

Abstract Background Electroconvulsive therapy (ECT) is an important treatment for several severe psychiatric conditions, yet its precise mechanism of action remains unknown. Increased inhibition in the brain after ECT seizures, mediated by γ-aminobutyric acid (GABA), has been linked to clinical effectiveness. Case series on epileptic patients report a postictal serum concentration increase of the GABAA receptor agonist allopregnanolone. Serum allopregnanolone remains unchanged after a full ECT series, but possible transient effects directly after a single ECT seizure remain unexplored. The primary aim was to measure serum concentrations of allopregnanolone and its substrate progesterone after one ECT seizure. Secondary aims were to examine whether concentrations at baseline, or postictal changes, either correlate with seizure generalization or predict clinical outcome ratings after ECT. Methods A total of 130 participants (18–85 years) were included. Generalization parameters comprised peak ictal heart rate, electroencephalographic (EEG) seizure duration, and prolactin increase. Outcome measures were ratings of clinical global improvement, perceived health status and subjective memory impairment. Non-parametric tests were used for group comparisons and correlations. The prediction analyses were conducted with binary logistic and simple linear regression analyses. Results Allopregnanolone and progesterone remained unchanged and correlated neither with seizure generalization nor with clinical outcome. In men (n = 50), progesterone increased and allopregnanolone change correlated negatively with EEG seizure duration. In a subgroup analysis (n = 62), higher baseline allopregnanolone and progesterone correlated with postictal EEG suppression. Conclusions ECT seizures have different physiologic effects than generalized seizures in epilepsy. Progesterone might have implications for psychiatric illness in men.

Abstract Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²). Genetically-predicted body mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-to-hip ratio (WHR) are significantly (FDR

Abstract MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected

Abstract Background Malaria is one of the world’s most lethal vector-borne diseases, causing significant health burdens in endemic countries. Several studies on the prevalence of malaria among pregnant women in Ghana have been conducted in various parts of the country, yielding evidence pointing to intra- and inter-regional variations. The current study assessed the prevalence, risk factors, and sociodemographic predictors of malaria among pregnant women in the Bono East Region of Ghana. Methods This multicentre hospital-based study employed a mixed-method cross-sectional design. A multistage sampling technique was used to select seven health facilities and recruited 1452 pregnant women who attended ANC at seven selected health facilities. Haematological examination, a structured closed-ended questionnaire, in-depth interviews (IDIs), and focus group discussions (FGDs) were used to obtain relevant data. Quantitative data were analysed with STATA 14 (StataCorp, College Station, USA). Likewise, the four-step thematic analysis was used to analyse qualitative data. A significant level was set at (p

Abstract Background Dry eye disease (DED) is a prevalent condition affecting over 16 million patients in the USA. DED and the symptoms of ocular discomfort are debilitating and a significant burden on patients. If left untreated, DED can progress to cause severe pathology. Treatment is often initiated by patients without consulting a healthcare professional. This study investigated the safety and efficacy of a novel lipid-containing eye drop (BTC), which might better mimic the components of natural tears. Methods This was a multicenter, randomized, double-masked, active control, two arm, parallel group study of eye drops in adult subjects with self-reported DED. Subjects were randomly assigned to BTC or control (commercially available non-lipid eye drops; NLED) arm and were followed for 30 days. Assessments using visual analog scale and patient-reported outcomes (PRO) questionnaires, non-invasive tear break up time, slit-lamp examination, and subject-reported ocular symptoms were conducted at baseline and at days 7 and 30. The primary endpoint was change in overall ocular comfort score from baseline to day 30. Results 158 subjects were randomized, of whom 130 completed the study per protocol (PP). Mean (SD) age was 47.8 (14.14) years. The mean (95% CI) change in overall comfort scores at the 30-day follow-up in the PP population was 21.4 (15.1, 27.7) for the test drop and 10.0 (3.9, 16.1) for the comparator. The mean (95% CI) treatment difference was 11.3 (2.6, 20.1); this met the pre-defined requirements for non-inferiority. There was no significant difference in the proportion of eyes with reported ocular symptoms between the groups. At day 7, the OR (95% CI) was 0.967 (0.528, 1.770) and at day 30 was 1.160 (0.610, 2.203). There were no Grade 3 or higher corneal edema, corneal neovascularization, corneal staining, conjunctival injection, tarsal abnormalities or any other biomicroscopy findings, and no corneal infiltrates observed during the study. Conclusions The investigational lipid eye drop BTC was noninferior to the commercially available non-lipid comparator in all parameters measured and has the potential to provide an effective therapy for subjects with symptoms of dry eye who would benefit from a lipid-based artificial tear. Trial Registration NCT03995355 ( http://www.clinicaltrials.gov ), registered June 24, 2019.

Abstract Background COVID-19 added to healthcare provider (HCP) distress, but patterns of change remain unclear. This study sought to determine if and how emotional distress varied among HCP between March 28, 2021 and December 1, 2023. Methods This longitudinal study was embedded within the 42-month prospective COVID-19 Cohort Study that recruited HCP from four Canadian provinces. Information was collected at enrollment, from annual exposure surveys, and vaccination and illness surveys. The 10-item Kessler Psychological Distress Scale (K10) was completed approximately every six months after March 28, 2021. Linear mixed effects models, specifically random intercept models, were generated to determine the impact of time on emotional distress while accounting for demographic and work-related factors. Results Between 2021 and 2023, the mean K10 score fell by 3.1 points, indicating decreased distress, but scores increased during periods of high levels of mitigation strategies against transmission of SARS-CoV-2, during winter months, and if taking antidepression, anti-anxiety or anti-insomnia medications. K10 scores were significantly lower for HCP who were male, older, had more children in their household, experienced prior COVID-19 illness(es), and for non-physician but regulated HCP versus nurses. A sensitivity analysis that included only those who had submitted at least five K10 surveys consisted of the factors in the full model excluding previous COVID-19 illness, occupation, and season, after adjustment. Models were also created for K10 anxiety and depression subscales. Conclusions K10 scores decreased as the COVID-19 pandemic continued but increased during periods of high mitigation and the winter months. Personal and work-place factors also impacted HCP distress scores. Further research into best practices in distress identification and remediation is warranted to ensure future public health disasters are met with healthcare systems that are able to buffer HCP against short- and long-term mental health issues.

Abstract This paper proposes development of optimized heterogeneous ensemble models for prediction of responses based on given sets of input parameters for wire electrical discharge machining (WEDM) processes, which have found immense applications in many of the present-day manufacturing industries because of their ability to generate complicated 2D and 3D profiles on hard-to-machine engineering materials. These ensembles are developed combining predictions of the three base models, i.e. random forest, support vector machine and ridge regression. These three base models are first framed utilizing the training datasets, providing predictions for all the responses under consideration. Based on these predictions, two optimization problems are formulated for each of the responses, while minimizing root mean squared error and mean absolute error, for subsequent development of two optimized ensembles whose predictions are the weighted sum of the predictions of the base models. The prediction performance of all the five models is ascertained through nine statistical metrics, after which a cumulative quality loss-based multi-response signal-to-noise (MRSN) ratio for each model is computed, for each of the responses, where a higher MRSN ratio indicates greater accuracy in prediction. This study is conducted using two experimental datasets of WEDM process. Overall, the optimized ensemble models having higher MRSN ratios than the base models are indicated to deliver better prediction accuracy.

Abstract With global C-section rates rising, understanding potential consequences is imperative. Previous studies suggested links between birth mode and psychological outcomes. This study evaluates the association of birth mode and neurodevelopment in young children across two prospective cohorts, using repeated psychometric assessments. Data from the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) and PROGRESS (Programming Research in Obesity, Growth, and Environment and Social Stress) cohorts, comprising 7158 and 2202 observations of 1402 children aged 2 to 36 months, and 726 children aged 5 to 27 months, respectively, were analyzed. Exclusion criteria for the cohorts were maternal diseases such as preeclampsia, renal or heart disease, gestational diabetes, and epilepsy. Neurodevelopment was gauged via Bayley’s Scales of Infant Development: 2nd edition for ELEMENT and 3rd edition for PROGRESS. Mixed-effects models longitudinally estimated associations between birth mode and neurodevelopment scores, adjusting for cofounders. In ELEMENT, psychomotor development composite scores were significantly affected by birth mode from ages 2 to 8 months; the largest estimate within this range was at 2 months (β =-1.93; 95% CI: [-3.64, -0.22], reference: vaginal delivery). For PROGRESS, a negative association was found with motor development composite scores over all the studied age range (β=-1.91; 95% CI: [-3.01, -0.81]). The association was stronger between ages 6 to 18 months, with the strongest estimate at 11 months (β=-2.58; 95% CI: [-4.37, -0.74]). A negative impact of C-section on language scores in girls was estimated for the PROGRESS cohort (β=-1.92; 95% CI: [-3.57, -0.27]), most marked in ages 22 to 25 months (largest β at 24.5 months=-3.04; 95% CI: [-5.79, -0.30]). Children born by C-section showed lower motor and language development scores during specific age windows in the first three years of life. Further research is necessary to understand the complexities and implications of these findings.

Abstract Background Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials. Methods In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA). Results In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 – 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 – 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 – 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 – 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 – 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA. Conclusions Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL.

Abstract Background Progression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions. Methods Paired 16S rRNA gene amplicon sequencing and untargeted LC–MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development. Results The BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx. Conclusions The BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection. Video Abstract

Abstract Background The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa. Results Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77–82%; lncRNA 15–17%; pseudogenes 4–5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection. Conclusions Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

Abstract Background Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies. Methods Retrospective analysis of 38 consecutive men with BCR (median [minimum–maximum] prostate-specific antigen 0.52 (0.12–2.50 ng/mL) undergoing [89Zr]Zr-PSMA-617 PET/CT post-negative [68Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum–maximum) [89Zr]Zr-PSMA-617 tracer activity of 123 (84–166) MBq. Results [89Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [89Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients. Limitations: retrospective, single center design; infrequent histopathological and imaging verification. Conclusion This large series provides further evidence that [89Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT.

Abstract Background It is challenging to predict long-term outcomes of interventions without understanding how they work. Health economic models of public health interventions often do not incorporate the many determinants of individual and population behaviours that influence long term effectiveness. The aim of this paper is to draw on psychology, sociology, behavioural economics, complexity science and health economics to: (a) develop a toolbox of methods for incorporating the influences on behaviour into public health economic models (PHEM-B); and (b) set out a research agenda for health economic modellers and behavioural/ social scientists to further advance methods to better inform public health policy decisions. Methods A core multidisciplinary group developed a preliminary toolbox from a published review of the literature and tested this conceptually using a case study of a diabetes prevention simulation. The core group was augmented by a much wider group that covered a broader range of multidisciplinary expertise. We used a consensus method to gain agreement of the PHEM-B toolbox. This included a one-day workshop and subsequent reviews of the toolbox. Results The PHEM-B toolbox sets out 12 methods which can be used in different combinations to incorporate influences on behaviours into public health economic models: collaborations between modellers and behavioural scientists, literature reviewing, application of the Behaviour Change Intervention Ontology, systems mapping, agent-based modelling, differential equation modelling, social network analysis, geographical information systems, discrete event simulation, theory-informed statistical and econometric analyses, expert elicitation, and qualitative research/process tracing. For each method, we provide a description with key references, an expert consensus on the circumstances when they could be used, and the resources required. Conclusions This is the first attempt to rigorously and coherently propose methods to incorporate the influences on behaviour into health economic models of public health interventions. It may not always be feasible or necessary to model the influences on behaviour explicitly, but it is essential to develop an understanding of the key influences. Changing behaviour and maintaining that behaviour change could have different influences; thus, there could be benefits in modelling these separately. Future research is needed to develop, collaboratively with behavioural scientists, a suite of more robust health economic models of health-related behaviours, reported transparently, including coding, which would allow model reuse and adaptation.

Abstract Background Mitochondrial genes and nuclear genes cooperate closely to maintain the functions of mitochondria, especially in the oxidative phosphorylation (OXPHOS) pathway. However, mitochondrial genes among arthropod lineages have dramatic evolutionary rate differences. Haplodiploid arthropods often show fast-evolving mitochondrial genes. One hypothesis predicts that the small effective population size of haplodiploid species could enhance the effect of genetic drift leading to higher substitution rates in mitochondrial and nuclear genes. Alternatively, positive selection or compensatory changes in nuclear OXPHOS genes could lead to the fast-evolving mitochondrial genes. However, due to the limited number of arthropod genomes, the rates of evolution for nuclear genes in haplodiploid species, besides hymenopterans, are largely unknown. To test these hypotheses, we used data from 76 arthropod genomes, including 5 independently evolved haplodiploid lineages, to estimate the evolutionary rates and patterns of gene family turnover of mitochondrial and nuclear genes. Results We show that five haplodiploid lineages tested here have fast-evolving mitochondrial genes and fast-evolving nuclear genes related to mitochondrial functions, while nuclear genes not related to mitochondrion showed no significant evolutionary rate differences. Among hymenopterans, bees and ants show faster rates of molecular evolution in mitochondrial genes and mitochondrion-related nuclear genes than sawflies and wasps. With genome data, we also find gene family expansions and contractions in mitochondrion-related genes of bees and ants. Conclusions Our results reject the small population size hypothesis in haplodiploid species. A combination of positive selection and compensatory changes could lead to the observed patterns in haplodiploid species. The elevated evolutionary rates in OXPHOS complex 2 genes of bees and ants suggest a unique evolutionary history of social hymenopterans.

Abstract Background Currently, there is no consensus on the optimal management of women with low prognosis in ART. In this Delphi consensus, a panel of international experts provided real-world clinical perspectives on a series of literature-supported consensus statements regarding the overall relevance of the POSEIDON criteria for women with low prognosis in ART. Methods Using a Delphi-consensus framework, twelve experts plus two Scientific Coordinators discussed and amended statements and supporting references proposed by the Scientific Coordinators (Round 1). Statements were distributed via an online survey to an extended panel of 53 experts, of whom 36 who voted anonymously on their level of agreement or disagreement with each statement using a six-point Likert-type scale (1 = Absolutely agree; 2 = More than agree; 3 = Agree; 4 = Disagree; 5 = More than disagree; 6 = Absolutely disagree) (Round 2). Consensus was reached if > 66% of participants agreed or disagreed. Results The extended panel voted on seventeen statements and subcategorized them according to relevance. All but one statement reached consensus during the first round; the remaining statement reached consensus after rewording. Statements were categorized according to impact, low-prognosis validation, outcomes and patient management. The POSEIDON criteria are timely and clinically sound. The preferred success measure is cumulative live birth and key management strategies include the use of recombinant FSH preparations, supplementation with r-hLH, dose increases and oocyte/embryo accumulation through vitrification. Tools such as the ART Calculator and Follicle-to-Oocyte Index may be considered. Validation data from large, prospective studies in each POSEIDON group are now needed to corroborate existing retrospective data. Conclusions This Delphi consensus provides an overview of expert opinion on the clinical implications of the POSEIDON criteria for women with low prognosis to ovarian stimulation.

Introduction: Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer in adults, presents significant challenges owing to its resistance to conventional therapies. Standard treatment primarily revolves around surgical methods, particularly nephrectomy, which is critical for managing localized diseases. Despite recent advancements, the metastatic potential of ccRCC necessitates ongoing vigilance in postoperative monitoring to manage and detect disease recurrence. Recent shifts in treatment paradigms, especially with the integration of molecular patterns in ccRCC, have enabled the development of targeted therapies. Immune checkpoint and tyrosine kinase inhibitors (TKIs) have become central to managing metastatic ccRCC, offering new hope through improved survival outcomes. Recent studies have corroborated this by demonstrating the benefits of combining these therapies. Case Presentation: This report discusses a case study of a patient with high-grade ccRCC and thyroid metastases initially deemed non-resectable. The combination of immunotherapy and TKIs reduced tumor size, transforming the thyroid metastasis to a resectable state. Conclusion: This case highlights significant advancements in treatment approaches and the critical in the management of ccRCC, underscoring the necessity for continuous adaptation of clinical practices to incorporate new therapeutic developments.

Purpose: The purpose of the present scoping review is to identify sources of heterogeneity in reporting domains that have the potential to improve surgical decision-making in reverse shoulder arthroplasty associated with glenoid bone grafting. Methods: A scoping review was conducted according to the JBI and PRISMA ScR guidelines. Articles covering glenoid bone grafting at the time of reverse shoulder replacement, published between 2012 and 2022 in MEDLINE, Scopus, Epistemonikos, Web of Science, and Cochrane Database of Systematic Reviews, were searched. Reporting of core outcome measures, as well as prosthesis-related variables, rehabilitation protocols, radiographic evaluation methods, and bone graft incorporation assessments, were collected. Results: For the final analysis, a total of 14 articles were considered. There were 649 operated shoulders with a mean patient age of 72 years, ranging from 48 to 85 years. Analysis of preoperative ranges of motion and patient-reported outcome measures revealed increased heterogeneity in patient selection between studies. Reporting of implant-related parameters was the most inconsistent. Rehabilitation protocols were scarcely reported. Assessment of graft incorporation and radiographic evaluation of choice revealed that there is no consistent method or measurement and the clinical relevance of radiolucent lines at the graft-glenoid bone interface is unclear. Conclusion: Addressing implant-related reporting gaps has the highest potential to improve surgical decision-making and provide orthopedic surgeons with a more comprehensive understanding of published results on glenoid bone grafting at the time of primary reverse shoulder arthroplasty.

Abstract Lifestyle interventions are strategies used to self‐manage medical conditions, such as epilepsy, and often complement traditional pharmacologic and surgical therapies. The need for integrating evidence‐based lifestyle interventions into mainstream medicine for the treatment of epilepsy is evident given that despite the availability of a multitude of treatments with medications and surgical techniques, a significant proportion of patients have refractory seizures, and even those who are seizure‐free report significant adverse effects with current treatments. Although the evidence base for complementary medicine is less robust than it is for traditional forms of medicine, the evidence to date suggests that several forms of complementary medicine including yoga, mindfulness meditation, cognitive behavioral therapy, diet and nutrition, exercise and memory rehabilitation, and music therapy may have important roles as adjuncts in the treatment armamentarium for epilepsy. These topics were discussed by a diverse group of medical providers and scientists at the “Lifestyle Intervention for Epilepsy (LIFE)” symposium hosted by Cleveland Clinic. Plain Language Summary There are many people with epilepsy who continue to have seizures even though they are being treated with medication or brain surgery. Even after seizures stop, some may experience medication side effects. There is research to suggest that certain lifestyle changes, such as yoga, mindfulness, exercise, music therapy, and adjustments to diet, could help people with epilepsy, when used along with routine treatment. Experts discussed the latest research at the “Lifestyle Intervention for Epilepsy (LIFE)” symposium hosted by Cleveland Clinic.

Abstract Introduction Neurological disorders (ND) have a high incidence in sub-Saharan Africa (SSA). In this region, systemic challenges of conventional medicine (CM) and cultural beliefs have contributed to a large utilization of traditional medicine (TM). Yet, data on TM and those who use it in the treatment of ND in SSA are scarce. Here, we systematically analyze its role as a therapy modality for ND in Mali, the socio-demographic characteristics of its users, and propose next steps to optimize the dual usages of TM and CM for patients with ND. Methods We conducted a questionnaire study in two phases. In phase one, patients with ND answered questions on their usage of and attitudes towards TM. In phase two, the TM therapists who provided care to the patients in phase one answered questions regarding their own practices for treating ND. Patients were recruited from the country's two university neurology departments. Results 3,534 of the 4,532 patients seen in the Departments of Neurology in 2019 met the inclusion criteria. Among these 3,534 patients, 2,430 (68.8%) had previously consulted TM for their present ND. Patients over 60 years of age most often used TM (83.1%). By education, illiterate patients utilized TM the most (85.5%) while those with more than a secondary education used TM the least (48.6%). An income greater than the minimum guaranteed salary was associated with decreased use of traditional medicine (OR 0.29, CI 0.25–0.35, p

Abstract Background We report the impact of HIV infection within a household on oral Kaposi’s sarcoma-associated herpesvirus (KSHV) shedding. Methods We enrolled 469 individuals from 90 households. Mouthwash rinse samples collected at three monthly visits were analyzed for KSHV DNA using quantitative polymerase chain reaction (qPCR). Generalized linear mixed effects logistic models were applied to analyze factors associated with KSHV ever shedding, and among shedders, always versus intermittent shedding. Linear mixed effects models were applied to models of KSHV viral loads. Intraclass correlation coefficients (ICCs) were calculated to assess the contribution of household-level factors to variations in shedding probabilities. Hotspot analyses of geospatial feature clusters were calculated using Getis-Ord Gi* statistic and visualized using inverse distance weighted interpolation. Results Analyses included 340 KSHV seropositive individuals, aged 3 + years, with qPCR results from 89 households. Forty households had 1 + persons living with HIV (PLWH), while 49 had none. Among participants, 149(44%) were KSHV ever shedders. Of 140 who shed KSHV at two or more visits, 34(24%) were always shedders. Increasing number of KSHV seropositive household members was significantly associated with ever shedding [Odds ratio(OR) (95% Confidence Interval(95%CI)):1.14(1.03,1.26);p = 0.013]. Among KSHV shedders, a statistically significant age-related trend was identified with 10–19 years being more likely to be always shedders (type III test p = 0.039) and to have higher viral loads (type III test p = 0.027). In addition, higher viral loads were significantly associated with increasing number of household members [coefficient(95%CI):0.06(0.01,0.12);p = 0.042], increasing number of KSHV seropositive members [coefficient(95%CI):0.08(0.01,0.15);p = 0.021], and living in households with 1 + PLWH [coefficient(95%CI):0.51(0.04,0.98);p = 0.033]. Always shedders exhibited higher viral loads than intermittent shedders [coefficient(95%CI):1.62(1.19,2.05);p

Abstract Background Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer’s disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. Methods The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. Results EQW affected FCN2 (Cohen’s d -0.019), PAI-1 (Cohen’s d -0.033), sVCAM-1 (Cohen’s d 0.035) and a cytokine-cytokine cluster (Cohen’s d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. Conclusions EQW treatment was associated with significant change in inflammatory proteins associated with AD. Trial Registration EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Abstract Traditionally, language learners have relied on dictionaries when trying to read or write in a foreign language. However, new LLM-based chatbots may offer an alternative to traditional dictionaries as lexical tools. This study assesses the effectiveness of ChatGPT versus the monolingual Longman Dictionary of Contemporary English (LDOCE, 2024) and the bilingual Diki.pl (Diki.pl, 2024) online dictionaries in supporting English language learners in receptive and productive lexical tasks. With a sample of 166 university students at B2 to C1 proficiency levels and forty uncommon English phrasal verbs, we investigate whether a leading AI-driven chatbot, a high-quality learners’ dictionary, or a popular free bilingual dictionary offers better support in accurately understanding and producing English. The results reveal ChatGPT to be more effective than either dictionary in production, and better than the monolingual dictionary, but not the bilingual dictionary, in reception.

Abstract Adaptive optics ophthalmoscopy has enabled visualization of the in vivo human photoreceptor mosaic in health, disease and its treatment. Despite this, the clinical utility of the imaging technology has been limited by a lack of automated analysis techniques capable of accurately quantifying photoreceptor structure and a lack of an available normative image database. Here, we present a fully automated algorithm for estimating cone spacing and density over a complete adaptive optics montage along with a database of normative images and cone densities. We imaged the cone mosaics surrounding the fovea and along the horizontal and vertical meridians of fifty normal-sighted controls with a custom-built, multimodal adaptive optics scanning light ophthalmoscope. Cone spacing was automatically measured in the frequency domain and spacing measurements were converted to estimates of cone density at all locations across the montage. Consistent with previous reports, cone density measurements were highest near fovea (152,906 ± 53,209 cones/mm2) and decreased exponentially with eccentricity. A 2.5-fold variation was found in cone density estimates at 0.1 mm, this variation decreased to 1.75-fold at 1 mm. We provide all images, mosaic quantifications, and automated software open source. This database will aid investigators in translating adaptive optics ophthalmoscopy to clinical applications.

Abstract Vector control in the Bijagós Archipelago of Guinea-Bissau currently relies on pyrethroid insecticide-treated nets. However, data on insecticide resistance in Guinea-Bissau is limited. This study identified deltamethrin resistance in the Anopheles gambiae sensu lato complex on Bubaque island using WHO tube tests in November 2022. Whole genome sequencing of An. gambiae sensu stricto mosquitoes identified six single nucleotide polymorphisms (SNPs) previously associated with, or putatively associated with, insecticide resistance: T791M, L995F, N1570Y, A1746S and P1874L in the vgsc gene, and L119V in the gste2 gene. Twenty additional non-synonymous SNPs were identified in insecticide-resistance associated genes. Four of these SNPs were present at frequencies over 5% in the population: T154S, I126F and G26S in the vgsc gene and A65S in ace1. Genome wide selection scans using Garud’s H12 statistic identified two selective sweeps: one in chromosome X and one in chromosome 2R. Both selective sweeps overlap with metabolic genes previously associated with insecticide resistance, including cyp9k1 and the cyp6aa/cyp6p gene cluster. This study presents the first phenotypic testing for deltamethrin resistance and the first whole genome sequence data for Anopheles gambiae mosquitoes from the Bijagós, contributing data of significance for vector control policy in this region.

Abstract Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) represents the standard treatment for therapy-refractory, malignant or complicated ulcerative colitis (UC) and can be performed as a 2-stage or 3-stage procedure. This study aimed to compare the short- and long-term outcomes after 2- and 3-stage IPAA in patients with UC in our department. A retrospective analysis of 176 patients with UC who received 2- or 3-stage restorative proctocolectomy with IPAA at our institution from 2001 to 2021 was performed. Outcomes for short-term (morbidity, longer hospital stay, readmission) and long-term (pouch failure and quality of life) parameters were compared between the 2- and 3-stage procedure. Regarding short-term outcomes for all patients, in-hospital morbidity and readmission rates after any surgical stage were observed in 69% and 24%, respectively. Morbidity and readmission did not differ significantly between the 2- and 3-stage procedure in uni- and multivariate analysis. Median length of hospital stay for all stages was 17 days. The 3-stage procedure was identified as an independent factor for longer hospital stay (OR 3.8 (CI 1.3–10.8), p = 0.014). Pouch failure and failure of improved quality of life during long-term follow-up occurred both in 10% of patients, with no significant differences between the 2- and 3-stage procedure in uni- and multivariate analysis. Our data suggest that both the 2- and 3-stage proctocolectomy with IPAA demonstrate favourable and comparable postoperative short- and long-term outcomes, with a high rate of improved quality of life in patients with UC.

Abstract Laser-lubricant interaction has been a critical reliability issue in a thermo-tribological system named heat-assisted magnetic recording, one of the next generation hard disk drive solutions to increasing data storage. The lubricant response under laser irradiation and the subsequent lubricant recovery are crucial to the system’s reliability and longevity, however, they cannot be diagnosed locally and timely so far. Here, we propose a thermal scheme to in-situ characterize the mechanical laser-lubricant interaction. The nanometer-thick lubricant has a thermal barrier effect on the near-field thermal transport in the system, according to which the lubricant thickness can be determined. As demonstrations, this paper reports the first quantitative in-situ measurements of the laser-induced lubricant depletion and the subsequent reflow dynamics. The proposed scheme shows a sub-angstrom resolution (~0.2 Å) and a fast response time within seconds, rendering in-situ real-time lubricant diagnosis feasible in the practical hard disk drive products.